Author Report for: Chen LContact information:Chen LinMolecular and Computational Biology, Departments of Biological Sciences and Chemistry, University of Southern California, Los Angeles, CaliforniaUSAPhone : Fax : Send E-Mail to Chen Lin Wellcome Trust Nicotinic Acetylcholine Receptors 2011 (Cambridge, UK) Wellcome Trust Nicotinic Acetylcholine Receptors 2014 (Cambridge, UK)
Chen Y, Chen L, Xu H, Cao R, Morisseau C, Zhang M, Shi Y, Hammock BD, Wang J and Chen G <2 more author(s)> Chen Y, Chen L, Xu H, Cao R, Morisseau C, Zhang M, Shi Y, Hammock BD, Wang J, Zhuang J, Liu Z, Chen G (- 2) Ref: Journal of Medicinal Chemistry, :, 2023 : PubMed ESTHER: Chen_2023_J.Med.Chem__ PubMedSearch: Chen 2023 J.Med.Chem PubMedID: 36689364 Abstract Soluble epoxide hydrolase (sEH) has been identified as an attractive target for anti-inflammatory drug design in recent years. Picomolar level compound G1 against sEH was obtained by introducing the hydrophilic group homopiperazine and hydrophobic fragment propionyl onto the structure of lead compound A. G1 showed good microsomal stability, a moderate plasma protein binding rate, and good oral bioavailability and was well tolerated in rats. G1 has significant analgesic effects on CFA-induced AIA mice, ameliorated the pancreatic injury in acute pancreatitis induced by l-arginine, reversed pancreatic injury, edema, and neutrophil infiltration, and increased the survival time of C57BL/6 mice in a lipopolysaccharide (LPS)-induced sepsis model. Moreover the expression levels of sEH, COX-2, NOS-2, vascular cell adhesion molecule (VCAM), IL-6, MCP-5, and tumor necrosis factor alpha (TNF-alpha) were measured by Western blot or enzyme-linked immunosorbent assay (ELISA), with varying degrees of decrease. These results suggested that G1 is a drug candidate worthy of further evaluation for the treatment of inflammation-induced diseases such as arthritis, acute pancreatitis, and sepsis. Title: Rational design of a turn-on near-infrared fluorescence probe for the highly sensitive and selective monitoring of carboxylesterase 2 in living systems Chen Z, Yu J, Sun K, Song J, Chen L, Jiang Y, Wang Z Ref: Analyst, :, 2023 : PubMed ESTHER: Chen_2023_Analyst__ PubMedSearch: Chen 2023 Analyst PubMedID: 36661088 Abstract In vivo selective fluorescence imaging of carboxylesterase 2 (CES2) remains a great challenge because existing fluorescence probes can potentially suffer from interference by other hydrolases. In addition, some fluorescent probes that have been separately reported for measuring CES2 activity in vitro are affected by autofluorescence and absorption of the biological matrix due to their limited emission wavelength or short Stokes shift. Herein, based on the substrate preference and catalytic performance of CES2, a novel and NIR fluorescent probe was developed, in which a hemi-cyanine dye ester derivative was used as the basic fluorescent group. In the presence of CES2, the probe was hydrolyzed to expose the fluorophore CZX-OH (lambda(abs) - 675 nm, lambda(em) - 850 nm), which led to a notable red-shift in the fluorescence (-175 nm) spectrum. Confocal imaging of cells and live mice demonstrated that the fluorescent signal of this probe was related to the real activities of CES2 in cancer cells. All these results will powerfully promote the screening of CES2 regulators and the analysis of CES2-related physiological and pathological processes. Title: Effects of Methyl Jasmonate Fumigation on the Growth and Detoxification Ability of Spodoptera litura to Xanthotoxin Chen L, Song J, Wang J, Ye M, Deng Q, Wu X, Ren B Ref: Insects, 14:, 2023 : PubMed ESTHER: Chen_2023_Insects_14_ PubMedSearch: Chen 2023 Insects 14 PubMedID: 36835714 Abstract Methyl jasmonate (MeJA) is a volatile substance derived from jasmonic acid (JA), and it responds to interbiotic and abiotic stresses by participating in interplant communication. Despite its function in interplant communication, the specific role of MeJA in insect defense responses is poorly understood. In this study, we found that carboxylesterase (CarE) activities, glutathione-S-transferase (GSTs) activities, and cytochrome mono-oxygenases (P450s) content increased more after the feeding of diets containing xanthotoxin, while larvae exposed to MeJA fumigation also showed higher enzyme activity in a dose-dependent manner: lower and medium concentrations of MeJA induced higher detoxification enzyme activities than higher concentrations of MeJA. Moreover, MeJA improved the growth of larvae fed on the control diet without toxins and diets with lower concentrations of xanthotoxin (0.05%); however, MeJA could not protect the larvae against higher concentrations of xanthotoxin (0.1%, 0.2%). In summary, we demonstrated that MeJA is effective at inducing S. litura defense response, but the enhanced detoxifying ability could not overcome the strong toxins. Title: TPPU inhibits inflammation-induced excessive autophagy to restore the osteogenic differentiation potential of stem cells and improves alveolar ridge preservation Dang H, Chen W, Chen L, Huo X, Wang F Ref: Sci Rep, 13:1574, 2023 : PubMed ESTHER: Dang_2023_Sci.Rep_13_1574 PubMedSearch: Dang 2023 Sci.Rep 13 1574 PubMedID: 36709403 Inhibitor(s) related to this paper: TPPU Abstract Inflammation-induced autophagy is a double-edged sword. Dysfunction of autophagy impairs the differentiation capacity of mesenchymal stem cells and enhances inflammation-induced bone loss. Tooth extraction with periodontal and/or endodontic lesions exacerbates horizontal and vertical resorption of alveolar bone during the healing period. Alveolar socket preservation (ASP) procedure following tooth extraction has important clinical implications for future prosthodontic treatments. Studies have shown that epoxyeicosatrienoic acids (EETs) have significant anti-inflammatory effects and participate in autophagy. However, whether EETs can minimize alveolar bone resorption and contribute to ASP by regulating autophagy levels under inflammatory conditions remain elusive. Here, we figured out that LPS-induced inflammatory conditions increased the inflammatory cytokine and inhibited osteogenic differentiation of human dental pulp stem cells (hDPSCs), and led to excessive autophagy of hDPSCs. Moreover, we identified that increased EETs levels using TPPU, a soluble epoxide hydrolase inhibitor, reversed these negative outcomes. We further demonstrated the potential of TPPU to promote early healing of extraction sockets and ASP, and speculated that it was related to autophagy. Taken together, these results suggest that targeting inhibition of soluble epoxide hydrolase using TPPU plays a protective role in the differentiation and autophagy of mesenchymal stem cells and provides potential feasibility for applying TPPU for ASP, especially under inflammatory conditions. Title: Degradation of poly(butylene adipate-co-terephthalate) films by Thermobifida fusca FXJ-1 isolated from compost Jia X, Zhao K, Zhao J, Lin C, Zhang H, Chen L, Chen J, Fang Y Ref: J Hazard Mater, 441:129958, 2023 : PubMed ESTHER: Jia_2023_J.Hazard.Mater_441_129958 PubMedSearch: Jia 2023 J.Hazard.Mater 441 129958 PubMedID: 36122523 Abstract In recent years, Poly(butylene adipate-co-terephthalate) (PBAT) films were wildly used due to its biodegradable properties. However, there are few reports of strains that can high efficiently degrade PBAT. Thermobifida fusca FXJ-1, a thermophilic actinomycete, was screened and identified from compost. FXJ-1 can efficiently degrade PBAT at 55C in MSM medium. The degradation rates of the pure PBAT film (PF), PBAT film used for mulching on agricultural fields (PAF), and PBAT-PLA-ST film (PPSF) were 82.871.01%, 87.832.00% and 52.530.54%, respectively, after nine days of incubation in MSM medium. Cracking areas were monitored uniformly distributed on the surfaces of three kinds of PBAT-based films after treatment with FXJ-1 using scanning electron microscopy. The LC-MS results showed that PBAT might be degraded into adipic acid, terephthalic acid, butylene adipate, butylene terephthalate and butylene adipate-co-terephthalate, and these products are involved in the cleavage of ester bonds. We also found that amylase produced by FXJ-1 played an important role in the degradation of PPSF. FXJ-1 also showed an efficient PBAT-based films degradation ability in simulating compost environment, which implied its potential application in PBAT and starch-based film degradation by industrial composting. Title: Screening and identification of lipase inhibitors extracted from Dioscorea nipponica Makino by UV-vis and HPLC coupled to UPLC-Q-TOF-MS/MS Jin P, Chen L, Zhong J, Yuan T, Gan L, Huang J, Wang L, Fan H, Lin C Ref: Int J Biol Macromol, :123427, 2023 : PubMed ESTHER: Jin_2023_Int.J.Biol.Macromol__123427 PubMedSearch: Jin 2023 Int.J.Biol.Macromol 123427 PubMedID: 36706882 Abstract Dioscoreae nipponica Makino (D. nipponica) as the rhizome of dioscoreaceae rich in steroidal saponins, have been reported to have the hypolipidemic effects etc. However, it is still unclear which exact active components are primary responsible for the beneficial effects. This study was conducted to fish out the lipase inhibitors from D. nipponica, and evaluate the inhibitory activity on porcine pancreatic lipase (PPL) through in vitro kinetic assay using p-nitrophenyl palmitate as substrate. Accordingly, the ethanolic extract was subjected to D101 macroporous resin purification for spectrophotometric screening, high performance liquid chromatography (HPLC) separation and structural characterization by ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry. Through orlistat validation, the PPL inhibitory activity and IC(50) value of the extract were respectively 68.34 +/- 1.47 % and 107.05 microg/mL under the optimized inhibition conditions. From 6 steroidal saponins identified, the inhibitory components named the protodioscin, protogracillin, dioscin and gracillin were fished out by grouping separation and HPLC analysis. Furthermore, dioscin and gracillin with the parent structure of diogenin were confirmed as the major inhibitors by virtue of stability tests based on transformation of protodioscin and protogracillin. Finally, the inhibitory mechanism of the major inhibitors toward PPL was further clarified by kinetic analysis and molecular docking analysis. The proposed method not only revealed the PPL inhibitory components in D. nipponica, but also provided an effective approach to hierarchical screening of PPL inhibitors from natural plants. Title: Response Surface Optimization of Extraction Conditions for the Active Components with High Acetylcholinesterase Inhibitory Activity and Identification of Key Metabolites from Acer truncatum Seed Oil Residue Meng R, Ou K, Chen L, Jiao Y, Jiang F, Gu R Ref: Foods, 12:, 2023 : PubMed ESTHER: Meng_2023_Foods_12_ PubMedSearch: Meng 2023 Foods 12 PubMedID: 37174291 Abstract The State Council of China has called for the comprehensive development and utilization of Acer truncatum resources. However, research on one of its by-products, namely seed oil residue (ASR), from seed oil extraction is seriously insufficient, resulting in a waste of these precious resources. We aimed to optimize the conditions of ultrasound-assisted extraction (UAE) using a response surface methodology to obtain high acetylcholinesterase (AChE) inhibitory components from ASR and to tentatively identify the active metabolites in ASR using non-targeted metabolomics. Based on the results of the independent variables test, the interaction effects of three key extracting variables, including methanol concentration, ultrasonic time, and material-to-liquid ratio, were further investigated using the Box-Behnken design (BBD) to obtain prior active components with high AChE inhibitory activity. UPLC-QTOF-MS combined with a multivariate method was used to analyze the metabolites in ASR and investigate the causes of activity differences. Based on the current study, the optimal conditions for UAE were as follows: methanol concentration of 85.06%, ultrasonic time of 39.1 min, and material-to-liquid ratio of 1.06:10 (g/mL). Under these optimal conditions, the obtained extracts show strong inhibitions against AChE with half maximal inhibitory concentration (IC(50)) values ranging from 0.375 to 0.459 microg/mL according to an Ellman's method evaluation. Furthermore, 55 metabolites were identified from the ASR extracted using methanol in different concentrations, and 9 biomarkers were subsequently identified as potential compounds responsible for the observed AChE inhibition. The active extracts have potential to be used for the development of functional foods with positive effects on Alzheimer's disease owing to their high AChE inhibition activity. Altogether, this study provides insights into promoting the comprehensive utilization of A. truncatum resources. Title: Soluble polysaccharides decrease inhibitory activity of banana condensed tannins against porcine pancreatic lipase Pu Y, Chen L, He X, Cao J, Jiang W Ref: Food Chem, 418:136013, 2023 : PubMed ESTHER: Pu_2023_Food.Chem_418_136013 PubMedSearch: Pu 2023 Food.Chem 418 136013 PubMedID: 36989646 Abstract The inhibition of soluble polysaccharides (SPs) (arabic gum, dextran and pectin from citrus) on the binding between banana condensed tannins (BCTs) and pancreatic lipase (PL) was studied from variant aspects. Molecular docking simulations predicted that BCTs strongly bound SPs and PL through non-covalent interactions. The experimental results showed that SPs reduced the inhibition of BCTs on PL, and the IC(50) value increased. However, the addition of SPs did not change the inhibitory type of BCTs on PL, which all were non-competitive inhibition. BCTs quenched PL fluorescence through static quenching mechanism and changed the secondary structure of PL. The addition of SPs alleviated the trending. The effect of SPs on the binding of BCTs-PL was mainly due to the strong non-covalent interaction between SPs and BCTs. This study emphasized that attention should be paid to the counteracting effects of polysaccharides and polyphenols in dietary intake to maximize their respective roles. Title: Polygoni Multiflori Radix Praeparata and Acori Tatarinowii Rhizoma ameliorate scopolamine-induced cognitive impairment by regulating the cholinergic and synaptic associated proteins Xie Y, Liu L, Zheng J, Shi K, Ai W, Zhang X, Wang P, Lan Z, Chen L Ref: J Ethnopharmacol, 311:116400, 2023 : PubMed ESTHER: Xie_2023_J.Ethnopharmacol_311_116400 PubMedSearch: Xie 2023 J.Ethnopharmacol 311 116400 PubMedID: 37003402 Abstract ETHNOPHARMACOLOGICAL RELEVANCE: The combination of Polygoni Multiflori Radix Praeparata (PMRP) and Acori Tatarinowii Rhizoma (ATR) is often used in traditional Chinese medicine to prevent and treat Alzheimer's disease (AD). However, it is not clear whether the effects and mechanisms of the decoction prepared by traditional decocting method (PA) is different from that prepared by modern decocting method (P + A). AIM OF THE STUDY: The present study aimed to investigate the differences in the protective effects of PA and P + A on scopolamine induced cognitive impairment, and to explore its potential mechanism. MATERIALS AND METHODS: To assess the protective effect of PA and P + A on cognitive dysfunction, the mice were orally administrated with PA (1.56, 6.24 g kg(-1)day(-1)) and P + A (1.56, 6.24 g kg(-1)day(-1)) for 26 days before co-treatment with scopolamine (4 mg kg(-1)day(-1), i.p.). The learning and memory abilities of mice were examined by Morris water maze test, and the expressions of proteins related to cholinergic system and synaptic function were detected by the methods of ELISA, real-time PCR and Western blotting. Then, molecular docking technique was used to verify the effect of active compounds in plasma after PA administration on Acetylcholinesterase (AChE) protein. Finally, the Ellman method was used to evaluate the effects of different concentrations of PA, P + A (1 microg/mL-100 mg/mL) and the compounds (1-100 microM) on AChE activity in vitro. RESULTS: On one hand, in the scopolamine-induced cognitive impairment mouse model, both of PA and P + A could improve the cognitive impairment, while the effect of PA on cognitive amelioration was better than that of P + A. Moreover, PA regulated the cholinergic and synaptic functions by enhancing the concentration of acetylcholine (ACh), the mRNA levels of CHT1, Syn, GAP-43 and PSD-95, and the related proteins (CHT1, VACHT, Syn, GAP-43 and PSD-95), and significantly inhibiting the expression of AChE protein. Meanwhile, P + A only up-regulated the mRNA levels of GAP-43 and PSD-95, increased the expressions of CHT1, VACHT, Syn, GAP-43 and PSD-95 proteins, and inhibited the expression of AChE protein. On the other hand, the in vitro study showed that some compounds including emodin-8-o-beta-d-Glucopyranoside, THSG and alpha-Asarone inhibited AChE protein activity with the IC(50) values 3.65 microM, 5.42 microM and 9.43 microM, respectively. CONCLUSIONS: These findings demonstrate that both of PA and P + A can ameliorate the cognitive deficits by enhancing cholinergic and synaptic related proteins, while PA has the stronger improvement effect on the cholinergic function, which may be attributed to the compounds including THSG, emodin, emodin-8-O-beta-D-glucopyranoside and alpha-asarone. The present study indicated that PA has more therapeutic potential in the treatment of neurodegenerative diseases such as AD. The results provide the experimental basis for the clinical use of PA. Title: A New Berberine Preparation Protects Pancreatic Islet Cells from Apoptosis Mediated by Inhibition of Phospholipase A(2)/p38 MAPK Pathway Bi XJ, Lv YQ, Yang XH, Ge Y, Han H, Feng JS, Zhang M, Chen L, Xu MZ, Guan FY Ref: Bulletin of Experimental Biology & Medicine, 173:346, 2022 : PubMed ESTHER: Bi_2022_Bull.Exp.Biol.Med_173_346 PubMedSearch: Bi 2022 Bull.Exp.Biol.Med 173 346 PubMedID: 35852692 Abstract We studied an amorphous solid dispersion of berberine with absorption enhancer sodium caprate (Huang-Gui solid dispersion preparations, HGSD). A therapeutic effect of HGSD was revealed in mice with type 2 diabetes mellitus and palmitate-induced injury to MIN6 beta-cells. HGSD treatment (150 mg/kg) improved glucose metabolism and decreased beta-cell apoptosis in diabetic mice. Furthermore, the effective component of HGSD berberine significantly attenuated the palmitate-induced decrease in MIN6 beta-cells viability and insulin secretion. Moreover, molecular docking analysis and Western blotting showed that berberine decreased cell apoptosis and expression of group VIA phospholipase A(2) (iPLA(2)), p38 mitogen-activated protein kinase (p38 MAPK), and caspase-3. These data suggest that HGSD treatment protected beta-cells via inhibiting the iPLA(2)/p38 MAPK pathway. Title: Design, synthesis, and evaluation of 8-aminoquinoline-melatonin derivatives as effective multifunctional agents for Alzheimer's disease Chen Z, Yu X, Chen L, Xu L, Cai Y, Hou S, Zheng M, Liu F Ref: Ann Transl Med, 10:303, 2022 : PubMed ESTHER: Chen_2022_Ann.Transl.Med_10_303 PubMedSearch: Chen 2022 Ann.Transl.Med 10 303 PubMedID: 35433950 Abstract BACKGROUND: Alzheimer's disease (AD) is thought to be a complex, multifactorial syndrome with many related molecular lesions contributing to its pathogenesis. Thus, multi-target-directed ligands are considered an effective way of treating AD. This study sought to evaluate 8-aminoquinoline-melatonin derivatives as effective multifunctional agents for AD. METHODS: Thioflavin-T fluorescence assays were used to detect the inhibitory potency of 8-aminoquinoline-melatonin hybrids (a1-a5, b1-b5, and c1-c5) on self- and acetylcholinesterase (AChE)-induced amyloid-beta (Abeta) aggregation. The AChE and butyrylcholinesterase (BuChE) inhibitory potency within the compounds was evaluated by Ellman's assays. Methyl thiazolyl tetrazolium (MTT) assays were performed to evaluate the cytotoxicity of the compounds to C17.2 cells. MTT assay was used to detect the cell viability of HT22 cells to evaluate the antioxidant effect of the compounds. Metal chelation property was measured by ultraviolet-visible spectrophotometry. RESULTS: Compounds c3 and c5 had superior inhibitory activity against self-induced Abeta aggregation (with inhibitory rates of 41.4+/-2.1 and 25.5+/-3.2 at 10 microM, respectively) compared to the other compounds. Compounds in the carbamate group (i.e., a4, a5, b4, b5, c4, and c5) showed significant BuChE inhibitory activity and excellent selectivity over AChE. Most of the compounds exhibited low cytotoxicity in the C17.2 cells. Notably, a2, a3, b2, and b3 and series c (c1-c5) exhibited strong protective effects. Additionally, a3 and c1 specifically chelated with copper ions. CONCLUSIONS: Taking all of the promising results together, 8-aminoquinoline-melatonin hybrids can serve as lead molecules in the further development of new multi-functional anti-AD agents. Title: Screening models combining maternal characteristics and multiple markers for the early prediction of preeclampsia in pregnancy: a nested case-control study Chen L, Pi Y, Chang K, Luo S, Peng Z, Chen M, Yu L Ref: J Obstet Gynaecol, :1, 2022 : PubMed ESTHER: Chen_2022_J.Obstet.Gynaecol__1 PubMedSearch: Chen 2022 J.Obstet.Gynaecol 1 PubMedID: 35634766 Abstract To identify maternal laboratory markers to predict the risk of preeclampsia (PE) in different stages of pregnancy, we analysed 67, 25, and 73, pregnancies developing PE at 11-13, 16-20, and 24-28 wks, respectively. Routine laboratory markers were measured in whole blood or serum and binary logistic regression analysis was used to identify predictive models. At 11-13 wks of gestation, patients who went on to develop PE showed significantly higher concentrations of alanine aminotransferase, aspartate aminotransferase, alpha-L-fucosidase, 5'-nucleotidase, glutamyl transpeptidase, cholinesterase, and uric acid; plateletcrit was also higher. At 16-20 wks, inhibin A concentration and plateletcrit were significantly elevated. At 24-28 wks, platelets, plateletcrit, and glucose concentration were significantly elevated. Logistic regression analysis showed that an elevation in 5'-nucleotidase was independently associated with PE at 11-13 wks. The combination of inhibin A, diastolic blood pressure, and body mass index was a significant predictor for PE at 16-20 wks, while the combination of glucose and systolic blood pressure was a significant predictor for PE at 24-28 wks. In conclusion, when combined with maternal characteristics, the measurement of 5'-nucleotidase, inhibin A, and glucose levels, represents a potentially valuable risk assessment for PE.Impact statementWhat is already known on this subject? Preeclampsia (PE) may be viewed as a spectrum of disorders with a severity that is reflected in the levels of specific biomarkers. Consequently, there is a clear need for additional biomarkers that can be used to stratify pregnancies as high or low risk soon after conception.What do the results of this study add? At 11-13 wks of gestation, maternal assays for platelets, plateletcrit, alanine aminotransferase, aspartate aminotransferase, alpha-L-fucosidase, 5'-nucleotidase, glutamyl transpeptidase, cholinesterase, and uric acid, demonstrated significantly higher values in patients with PE when compared with normal controls. Furthermore, assay results for inhibin A and platelets showed increased values at 16-20 wks of gestation. Assays performed at 24-28 wks of gestation revealed elevated levels of platelets, plateletcrit, and glucose. Our analysis indicated that increases in the levels of 5'-nucleotidase, inhibin A, and glucose, are effective and significant biomarkers that could be used in combination with maternal characteristics to screen for PE at 11-13, 16-20, and 24-28 wks of gestation, respectively. These findings provide a new basis for our understanding of the aetiology underlying PE.What are the implications of these findings for clinical practice and/or further research? Further studies that consider the entire population are now needed and should include the investigation of laboratory markers across different stages of pregnancy. Long-term follow up would also be necessary if we are to explore the full role of laboratory markers in the pathophysiology of PE. Title: Nanoporous ZIF-8 Microparticles as Acetylcholinesterase and Alkaline Phosphatase Mimics for the Selective and Sensitive Detection of Ascorbic Acid Oxidase and Copper Ions Chen GY, Yin SJ, Chen L, Zhou X, Yang FQ Ref: Biosensors (Basel), 12:, 2022 : PubMed ESTHER: Chen_2022_Biosensors.(Basel)_12_ PubMedSearch: Chen 2022 Biosensors.(Basel) 12 PubMedID: 36421167 Abstract In this study, the alkaline phosphatase (ALP)-like activity of zeolitic-imidazolate framework-8 (ZIF-8) is reported for the first time. Then, colorimetric sensors for the ascorbic acid oxidase (AAO) and copper ion (Cu(2+)) detection were developed based on the acetylcholinesterase (AChE)- and ALP-like activities of ZIF-8. The ZIF-8 has good mimetic enzyme activity and exhibits high affinity to the substrates. Its AChE- and ALP-like activities also have good reusability and storage stability. Good linear dependences are obtained in the range of 1.3-250.0 microM (AChE-like activity-based) and 4.5-454.5 microM (ALP-like activity based) for Cu(2+) detection. Furthermore, good linear dependence is also obtained based on the ALP-like activity of ZIF-8 for AAO detection in the range of 2.3-454.5 U/L. Their limits of detection (LODs) are calculated to be 0.7 microM, 2.8 microM, and 1.8 U/L, respectively. Finally, the sample spiked recoveries of Cu(2+) in tap water, Cu(2+), and AAO in human serum and rabbit plasma were measured, and the results are in the range of 80.0-119.3%. In short, the preparation of ZIF-8 is simple, environmentally friendly, and harmless, and can realize highly selective detection of AAO and Cu(2+) in an efficient and fast process. Title: Structure-guided discovery of potent and oral soluble epoxide hydrolase inhibitors for the treatment of neuropathic pain Du F, Cao R, Chen L, Sun J, Shi Y, Fu Y, Hammock BD, Zheng Z, Liu Z, Chen G Ref: Acta Pharm Sin B, 12:1377, 2022 : PubMed ESTHER: Du_2022_Acta.Pharm.Sin.B_12_1377 PubMedSearch: Du 2022 Acta.Pharm.Sin.B 12 1377 PubMedID: 35530144 Inhibitor(s) related to this paper: EC5026 Abstract Soluble epoxide hydrolase (sEH) is related to arachidonic acid cascade and is over-expressed in a variety of diseases, making sEH an attractive target for the treatment of pain as well as inflammatory-related diseases. A new series of memantyl urea derivatives as potent sEH inhibitors was obtained using our previous reported compound 4 as lead compound. A preferential modification of piperidinyl to 3-carbamoyl piperidinyl was identified for this series via structure-based rational drug design. Compound A20 exhibited moderate percentage plasma protein binding (88.6%) and better metabolic stability in vitro. After oral administration, the bioavailability of A20 was 28.6%. Acute toxicity test showed that A20 was well tolerated and there was no adverse event encountered at dose of 6.0 g/kg. Inhibitor A20 also displayed robust analgesic effect in vivo and dose-dependently attenuated neuropathic pain in rat model induced by spared nerve injury, which was better than gabapentin and sEH inhibitor (+/-)-EC-5026. In one word, the oral administration of A20 significantly alleviated pain and improved the health status of the rats, demonstrating that A20 was a promising candidate to be further evaluated for the treatment of neuropathic pain. Title: Development and Validation of a Non-invasive Model to Predict Liver Histological Lesions in Chronic Hepatitis B Patients With Persistently Normal Alanine Aminotransferase and Detectable Viremia Hu Q, Wang Q, Xu W, Huang C, Tao S, Qi X, Zhang Y, Li X, Jiang X and Huang Y <3 more author(s)> Hu Q, Wang Q, Xu W, Huang C, Tao S, Qi X, Zhang Y, Li X, Jiang X, Song J, Li Q, Chen L, Huang Y (- 3) Ref: Front Med (Lausanne), 9:944547, 2022 : PubMed ESTHER: Hu_2022_Front.Med.(Lausanne)_9_944547 PubMedSearch: Hu 2022 Front.Med.(Lausanne) 9 944547 PubMedID: 35911415 Abstract BACKGROUND: A critical and controversial issue is whether antiviral therapy should be recommended in chronic hepatitis B virus (HBV) infection patients with persistently normal alanine aminotransferase (PNALT) and detectable HBV DNA. The study aimed to develop a non-invasive model for predicting significant liver histological changes (SLHC), which is the histological indication for antiviral therapy in chronic hepatitis B (CHB) patients with PNALT and detectable HBV DNA. METHODS: 398 chronic HBV infection patients with PNALT and detectable HBV DNA who underwent liver biopsy were divided into the estimation set (n = 256) and validation set (n = 142). A multivariate logistic regression model was developed to predict SLHC in the estimation set, and the diagnostic performance was further validated in the validation set. RESULTS: 132 patients (33.2%) with PNALT and detectable HBV DNA had SLHC. Aspartate aminotransferase (AST), cholinesterase (ChE), and liver stiffness measurement (LSM) were identified as the independent predictors of SLHC. The AUROC of the SLHC index, which combined AST, ChE, and LSM, was 0.824 and 0.816 in the estimation and validation set, respectively, for the prediction of SLHC. Applying the SLHC index >= 0.15, the presence of SLHC could be excluded with high negative predictive value in the estimation set (93.2%) and in the validation set (90.2%). Applying the SLHC index <= 0.55, the presence of SLHC could be considered with high positive predictive value in the estimation set (79.2%) and in the validation set (76.5%). CONCLUSION: The SLHC index provides a high accuracy in predicting liver histological indication for antiviral therapy in CHB patients with PNALT and detectable HBV DNA. Title: Targeting LIPA independent of its lipase activity is a therapeutic strategy in solid tumors via induction of endoplasmic reticulum stress Liu X, Viswanadhapalli S, Kumar S, Lee TK, Moore A, Ma S, Chen L, Hsieh M, Li M and Raj GV <19 more author(s)> Liu X, Viswanadhapalli S, Kumar S, Lee TK, Moore A, Ma S, Chen L, Hsieh M, Li M, Sareddy GR, Parra K, Blatt EB, Reese TC, Zhao Y, Chang A, Yan H, Xu Z, Pratap UP, Liu Z, Roggero CM, Tan Z, Weintraub ST, Peng Y, Tekmal RR, Arteaga CL, Lippincott-Schwartz J, Vadlamudi RK, Ahn JM, Raj GV (- 19) Ref: Nat Cancer, :, 2022 : PubMed ESTHER: Liu_2022_Nat.Cancer__ PubMedSearch: Liu 2022 Nat.Cancer PubMedID: 35654861 Gene_locus related to this paper: human-LIPA Inhibitor(s) related to this paper: ERX-41 Abstract Triple-negative breast cancer (TNBC) has a poor clinical outcome, due to a lack of actionable therapeutic targets. Herein we define lysosomal acid lipase A (LIPA) as a viable molecular target in TNBC and identify a stereospecific small molecule (ERX-41) that binds LIPA. ERX-41 induces endoplasmic reticulum (ER) stress resulting in cell death, and this effect is on target as evidenced by specific LIPA mutations providing resistance. Importantly, we demonstrate that ERX-41 activity is independent of LIPA lipase function but dependent on its ER localization. Mechanistically, ERX-41 binding of LIPA decreases expression of multiple ER-resident proteins involved in protein folding. This targeted vulnerability has a large therapeutic window, with no adverse effects either on normal mammary epithelial cells or in mice. Our study implicates a targeted strategy for solid tumors, including breast, brain, pancreatic and ovarian, whereby small, orally bioavailable molecules targeting LIPA block protein folding, induce ER stress and result in tumor cell death. Title: An artificial self-assembling peptide with carboxylesterase activity and substrate specificity restricted to short-chain acid p-nitrophenyl esters Liu Y, Gan L, Feng P, Huang L, Chen L, Li S, Chen H Ref: Front Chem, 10:996641, 2022 : PubMed ESTHER: Liu_2022_Front.Chem_10_996641 PubMedSearch: Liu 2022 Front.Chem 10 996641 PubMedID: 36199662 Abstract Natural enzymes possess remarkable catalytic activity and high substrate specificity. Many efforts have been dedicated to construct artificial enzymes with high catalytic activity. However, how to mimic the exquisite substrate specificity of a natural enzyme remains challenging because of the complexity of the enzyme structure. Here, we report artificial carboxylesterases that are specific for short chain fatty acids and were constructed via peptide self-assembly. These artificial systems have esterase-like activity rather than lipase-like activity towards p-nitrophenyl esters. The designer peptides self-assembled into nanofibers with strong beta-sheet character. The extending histidine units and the hydrophobic edge of the fibrillar structure collectively form the active center of the artificial esterase. These artificial esterases show substrate specificity for short-chain acids esters. Moreover, 1-isopropoxy-4-nitrobenzene could function as a competitive inhibitor of hydrolysis of p-nitrophenyl acetate for an artificial esterase. Title: Association Lp-PLA2 Gene Polymorphisms with Coronary Heart Disease Ma S, Ding L, Cai M, Chen L, Yan B, Yang J Ref: Dis Markers, 2022:9775699, 2022 : PubMed ESTHER: Ma_2022_Dis.Markers_2022_9775699 PubMedSearch: Ma 2022 Dis.Markers 2022 9775699 PubMedID: 35818585 Gene_locus related to this paper: human-PLA2G7 Abstract OBJECTIVES: The study evaluated the association between lipoprotein-associated phospholipase A2 (Lp-PLA2) gene polymorphisms and coronary heart disease (CHD), in order to explore the molecular genetics of CHD. METHODS: Groups of CHD patients (n = 283) and healthy controls (n = 261) were involved in this study. R92H, V279F, and A379V polymorphisms of LP-PLA2 gene were confirmed using polymerase chain reaction (PCR) and direct DNA sequencing. These polymorphisms and their interaction were also analyzed as potential risk factors of CHD. RESULTS: In this study population, the genotypes of R92H (GG, GA, and AA), V279F (CC, AC, and AA) and A379V (GG, GA, and AA) were studied. There was a significantly difference in frequencies of R92H between CHD patients and controls (P < 0.05). In contrast, no significant difference in frequencies of V279F and A379V existed between CHD patients and controls. Furthermore, R92H and A379V were in strong linkage disequilibrium. CONCLUSIONS: These results suggested that R92H polymorphism might contribute to increased risk of CHD. Title: Tanshinone IIA regulates glycogen synthase kinase-3beta-related signaling pathway and ameliorates memory impairment in APP/PS1 transgenic mice Peng X, Chen L, Wang Z, He Y, Ruganzu JB, Guo H, Zhang X, Ji S, Zheng L, Yang W Ref: European Journal of Pharmacology, :174772, 2022 : PubMed ESTHER: Peng_2022_Eur.J.Pharmacol__174772 PubMedSearch: Peng 2022 Eur.J.Pharmacol 174772 PubMedID: 35090935 Inhibitor(s) related to this paper: Tanshinone-IIA Abstract Our previous findings indicated that tanshinone IIA (tan IIA), a natural component extracted from the root and rhizome of danshen, significantly attenuated beta-amyloid accumulation, neuroinflammation, and endoplasmic reticulum stress, as well as improved learning and memory deficits in APP/PS1 transgenic mouse model of Alzheimer's disease (AD). However, whether tan IIA can ameliorate tau pathology and the underlying mechanism in APP/PS1 mice remains unclear. In the current study, tan IIA (15 mg/kg and 30 mg/kg) or saline was intraperitoneally administered to the 5-month-old APP/PS1 mice once daily for 4 weeks. The open-field test, novel object recognition test, Y-maze test, and Morris water maze test were performed to assess the cognitive function. Nissl staining, immunohistochemistry, TUNEL, and western blotting were conducted to explore tau hyperphosphorylation, neuronal injury, and phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt)/glycogen synthase kinase-3beta (GSK-3beta) signaling pathway. The activity of GSK-3beta, acetylcholinesterase (AChE), choline acetyltransferase (ChAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px), and the level of malondialdehyde (MDA) were measured using commercial kits. Our results revealed that tan IIA treatment significantly ameliorated behavioral deficits and improved spatial learning and memory ability of APP/PS1 mice. Additionally, tan IIA markedly attenuated tau hyperphosphorylation and prevented neuronal loss and apoptosis in the parietal cortex and hippocampus. Simultaneously, tan IIA reversed cholinergic dysfunction and reduced oxidative stress. Furthermore, tan IIA activated the PI3K/Akt signaling pathway and suppressed GSK-3beta. Taken together, the above findings suggested that tan IIA improves cognitive decline and tau pathology may through modulation of PI3K/Akt/GSK-3beta signaling pathway. Title: Biodegradation of diphenyl ether herbicide lactofen by Bacillus sp. YS-1 and characterization of two initial degrading esterases Shang N, Chen L, Cheng M, Tian Y, Huang X Ref: Sci Total Environ, 806:151357, 2022 : PubMed ESTHER: Shang_2022_Sci.Total.Environ_806_151357 PubMedSearch: Shang 2022 Sci.Total.Environ 806 151357 PubMedID: 34742792 Gene_locus related to this paper: bacsp-a0a6b9cu04, 9baci-a0a0d7fsc6 Abstract The extensive use of the diphenyl ether herbicide lactofen in recent years has caused serious environmental problems. Therefore, detoxification and elimination of lactofen from the environment are urgently required. In this study, the lactofen-degrading strain Bacillus sp. YS-1 was isolated, which achieved a 97.6% degradation rate of 50 mg/L lactofen within 15 h. The ester bond of lactofen was hydrolyzed, which generated acifluorfen, and then, the nitro group was reduced to the amino group, which generated aminoacifluorfen. Finally, the amino group was acetylated, which formed acetylated aminoacifluorfen, a novel end product in the degradation of lactofen. The toxicity of acetylated aminoacifluorfen to the root and seedling growth of cucumber and sorghum was significantly decreased compared with that of lactofen. The two esterase genes rhoE and rapE, encoding two esterases responsible for lactofen hydrolysis to acifluorfen, were cloned and expressed. The amino acid sequences encoded by rhoE and rapE were 27.78% and 88.21% identical with known esterases, respectively. The optimum temperatures for RhoE and RapE degradation of lactofen were 35 degreesC and 25 degreesC, respectively, and both esterases displayed maximal activity at pH 8.0. Both RhoE and RapE prioritized the degradation of (S)-(+)-lactofen, (S)-(-)-quizalofop-ethyl, and (S)-(-)-diclofop-methyl. This study provided the resources of bacterial strain and hydrolyzing enzyme for the removal of lactofen from the environment and the bioremediation of herbicide-contaminated soil. Title: Design, synthesis and insecticidal activity and mechanism research of Chasmanthinine derivatives Song Z, Li X, Xu K, Sun G, Yang L, Huang L, Liu J, Yin P, Huang S and Chen L <2 more author(s)> Song Z, Li X, Xu K, Sun G, Yang L, Huang L, Liu J, Yin P, Huang S, Gao F, Zhou X, Chen L (- 2) Ref: Sci Rep, 12:15290, 2022 : PubMed ESTHER: Song_2022_Sci.Rep_12_15290 PubMedSearch: Song 2022 Sci.Rep 12 15290 PubMedID: 36088472 Abstract Unrestricted reproduction and spread of pest had caused great damage to the quality and yield of crops in recent years. Besides the use of traditional chemical pesticides, natural products also make a huge contribution against pests. Chasmanthinine, a diterpenoid alkaloid isolated from Aconitum franchetii var. villosulum, shown extremely antifeedant activity against Spodoptera exigua. Therefore, a series of novel Chasmanthinine derivatives were synthesized and their biological activity was studied in this work. Compound 33 showed the strongest antifeedant activity (EC(50) = 0.10 mg/cm(2)) among all the test compounds. The mechanism research of 33 revealed that its antifeedant effect was related to the inhibition of carboxylesterase (CES), and proved the thiophene acyl group could form a strong binding effect with CES by molecular docking. Moreover, compound 10 exhibited the strongest cytotoxicity (IC(50) = 12.87 microM) against Sf9 cell line and moderate contact toxicity. The mechanism research indicated that compound 10 could induce Sf9 cells apoptosis. In summary, the results lay a foundation for the application of diterpene alkaloids in plant protection. Title: Development of 5-hydroxyl-1-azabenzanthrone derivatives as dual binding site and selective acetylcholinesterase inhibitors Sun X, Wang Y, Lei Z, Yue S, Chen L, Sun J Ref: Eur Journal of Medicinal Chemistry, 234:114210, 2022 : PubMed ESTHER: Sun_2022_Eur.J.Med.Chem_234_114210 PubMedSearch: Sun 2022 Eur.J.Med.Chem 234 114210 PubMedID: 35303485 Abstract A series of novel 5-hydroxyl-1-azabenzanthrone derivatives were designed, synthesized and evaluated as dual binding site acetylcholinesterase inhibitors for the treatment of Alzheimer's disease (AD). The most effective Compound 16 showed selective inhibition of acetylcholinesterase (eeAChE IC(50) = 0.045 microM; eeBuChE IC(50) = 19.68 microM; SI = 437.33). Most of the compounds showed cytoprotective effects on PC12 cells damaged by hydrogen peroxide, which might be related to their antioxidant activity. Further experiments confirmed that 16 exhibited anti-apoptotic effects at low concentrations and reduced the relative level of ROS generation in PC12 cells. The expression level of proteins related to antioxidant stress pathway in PC12 cells was relatively increased after administrated with 16, which may be beneficial to delay the progression of the disease. Moreover, 16 was evaluated to be safe in vivo and in vitro, and showed good overall pharmacokinetic performance and high bioavailability (Foral = 55.5%). Besides, 16 showed comparable performance in ameliorating the scopolamine-induced cognition impairment to donepezil. In addition, in vitro BBB permeability experiments confirmed that 16 had high BBB permeability. Title: Changes and significance of serum monocyte chemoattractant protein-1 and Lp-PLA2 in patients with hypertension and coronary heart disease Tian Y, Fan Y, Chen L, Sun M Ref: J Pak Med Assoc, 72:1114, 2022 : PubMed ESTHER: Tian_2022_J.Pak.Med.Assoc_72_1114 PubMedSearch: Tian 2022 J.Pak.Med.Assoc 72 1114 PubMedID: 35751319 Gene_locus related to this paper: human-PLA2G7 Abstract OBJECTIVE: To explore the combined application value of serum monocyte chemoattractant protein-1 and lipoprotein-associated phospholipase A2 in the diagnosis of hypertension and coronary heart disease. METHODS: The cross-sectional case-control study was conducted at Baoji Hospital of Traditional Chinese medicine, Shaanxi, China, from April 2018 to May 2020, and comprised patients with suspected hypertension and coronary heart disease. Patients with both hypertension and coronary heart disease formed Group A, and those with simple hypertension formed Group B. Healthy individuals formed the control Group C. Receiver operating characteristic curve was used to evaluate the value of serum monocyte chemoattractant protein-1 combined with lipoprotein-associated phospholipase A2 in the diagnosis of hypertension complicated with coronary heart disease. Data was analysed using SPSS 25. RESULTS: Of the 306 subjects, there were 122(40%) in Group A; 68(55.7%) males and 54(44.3%) females with mean age 68.77+/-5.76 years. There were 92(30%) cases in Group B; 51(55.4%) males and 41(44.6%) females with mean age 68.80+/-5.28 years. Group C had 92(30%) cases; 50(54.3%) males and 42(45.7%) females with mean age 67.85+/-5.29 years. Serum monocyte chemoattractant protein-1 and lipoprotein-associated phospholipase A2 levels were higher in Group A than the other two groups (p<0.001), and the levels in patients with carotid plaque total score <2 were lower than those with carotid plaque total score >2 (p<0.001). Area under receiver operating characteristic curve of the combination of the serum markers was 0.883 (95% confidence interval: 0.837-0.929, p<0.001), which was greater than that of two serum markers alone (p<0.05). CONCLUSIONS: Monocyte chemoattractant protein-1 and lipoprotein-associated phospholipase A2 may be involved in pathogenesis of elevated blood pressure and coronary artery disease. Combined detection of the two serum markers can provide a certain basis for the diagnosis and treatment of hypertension and coronary heart disease. Title: Assessment of parental benzo[a]pyrene exposure-induced cross-generational neurotoxicity and changes in offspring sperm DNA methylome in medaka fish Wan T, Au DW, Mo J, Chen L, Cheung KM, Kong RY, Seemann F Ref: Environ Epigenet, 8:dvac013, 2022 : PubMed ESTHER: Wan_2022_Environ.Epigenet_8_dvac013 PubMedSearch: Wan 2022 Environ.Epigenet 8 dvac013 PubMedID: 35769199 Abstract Previous studies have revealed that DNA methylation changes could serve as potential genomic markers for environmental benzo[a]pyrene (BaP) exposure and intergenerational inheritance of various physiological impairments (e.g. obesity and reproductive pathologies). As a typical aromatic hydrocarbon pollutant, direct BaP exposure has been shown to induce neurotoxicity. To unravel the inheritance mechanisms of the BaP-induced bone phenotype in freshwater medaka, we conducted whole-genome bisulfite sequencing of F1 sperm and identified 776 differentially methylated genes (DMGs). Ingenuity pathway analysis revealed that DMGs were significantly enriched in pathways associated with neuronal development and function. Therefore, it was hypothesized that parental BaP exposure (1 microg/l, 21 days) causes offspring neurotoxicity. Furthermore, the possibility for sperm methylation as an indicator for a neurotoxic phenotype was investigated. The F0 adult brains and F1 larvae were analyzed for BaP-induced direct and inherited toxicity. Acetylcholinesterase activity was significantly reduced in the larvae, together with decreased swimming velocity. Molecular analysis revealed that the marker genes associated with neuron development and growth (alpha1-tubulin, mbp, syn2a, shh, and gap43) as well as brain development (dlx2, otx2, and krox-20) were universally downregulated in the F1 larvae (3 days post-hatching). While parental BaP exposure at an environmentally relevant concentration could induce neurotoxicity in the developing larvae, the brain function of the exposed F0 adults was unaffected. This indicates that developmental neurotoxicity in larvae may result from impaired neuronal development and differentiation, causing delayed brain growth. The present study demonstrates that the possible adverse health effects of BaP in the environment are more extensive than currently understood. Thus, the possibility of multigenerational BaP toxicity should be included in environmental risk assessments. Title: Characterization of the synergistic inhibitory effect of cyanidin-3-O-glucoside and catechin on pancreatic lipase Wang Y, Chen L, Liu H, Xie J, Yin W, Xu Z, Ma H, Wu W, Zheng M and Liu J <1 more author(s)> Wang Y, Chen L, Liu H, Xie J, Yin W, Xu Z, Ma H, Wu W, Zheng M, Liu M, Liu J (- 1) Ref: Food Chem, 404:134672, 2022 : PubMed ESTHER: Wang_2022_Food.Chem_404_134672 PubMedSearch: Wang 2022 Food.Chem 404 134672 PubMedID: 36323025 Abstract This study aimed to identify novel pancreatic lipase (PL) inhibitors using affinity ultrafiltration combined with spectroscopy and molecular docking. Cyanidin-3-O-glucoside (C3G; IC(50): 0.268 mg/mL) and catechin (IC(50): 0.280 mg/mL) were shown to be potent PL inhibitors extracted from black rice and adzuki bean coat extracts. Isobologram analysis revealed that the combined use of C3G and catechin at a ratio of 2:3 had a remarkable synergistic effect (IC(50) of the mixture: 0.201 mg/mL). The inhibitory mechanism of C3G-catechin mixture was of mixed type. The C3G-catechin mixture had a great impact on PL secondary structures. Molecular docking analysis further demonstrated that these polyphenols formed hydrophobic interactions and hydrogen bonds with amino acid residues in the binding pocket of PL. Collectively, C3G and catechin were shown to inhibit PL in a synergistic manner and can be potentially used for the development of food supplements for obesity prevention. Title: Effects of ABCG1 knockout on proteomic composition of HDL in mice on a chow diet and a high-fat diet Wu Y, Chen L, Xie Z, Wang C, Zhang J, Yan X Ref: Proteomics, :e2100028, 2022 : PubMed ESTHER: Wu_2022_Proteomics__e2100028 PubMedSearch: Wu 2022 Proteomics e2100028 PubMedID: 35234362 Abstract ATP-binding cassette transporter G1 (ABCG1) is a cellular transmembrane protein that transports oxysterol efflux from cells to high-density lipoprotein (HDL) particles in the plasma. Previous studies have demonstrated that an ABCG1 deficiency exerts an antiatherosclerotic function through the effects of oxysterol accumulation in cells to enhance apoptosis and regulate inflammatory processes. However, whether the deficiency of ABCG1 and the corresponding changes in the efflux of oxysterols could take a series of impacts on the proteomic composition of HDL remains unclear. Here, plasma HDL of ABCG1(-/-) mice and their wild-type controls on a normal chow diet (NCD) or a high-fat diet (HFD) were isolated by ultracentrifugation. The proportion of 7-ketocholesterol and the proteomic composition of samples were comparatively analyzed by LC-MS/MS. In NCD-fed mice, lipid metabolism-related protein (arachidonate 12-lipoxygenase) and antioxidative protein (pantetheinase) exhibited increased accumulation, and inflammatory response protein (alpha-1-antitrypsin) was decreased in accumulation in ABCG1(-/-) mice HDL. In HFD-fed mice, fewer proteins were detected than that of NCD-fed mice. The ABCG1(-/-) mice HDL exhibited increased accumulation of lipid metabolism-related proteins (e.g., carboxylesterase 1C, apolipoprotein (apo)C-4) and decreased accumulation of alpha-1-antitrypsin, as well as significantly reduced proportion of 7-ketocholesterol. Additionally, positive correlations were found between 7-ketocholesterol and some essential proteins on HDL, such as alpha-1-antitrypsin, apoA-4, apoB-100, and serum amyloid A (SAA). These results suggest a detrimental impact of oxysterols on HDL composition, which might affect the antiatherosclerotic properties of HDL. Title: Invasive Plants Have Higher Resistance to Native Generalist Herbivores Than Exotic Noninvasive Congeners Wu S, Chen L, Zhou Y, Xiao F, Liu D, Wang Y Ref: Environ Entomol, :, 2022 : PubMed ESTHER: Wu_2022_Environ.Entomol__ PubMedSearch: Wu 2022 Environ.Entomol PubMedID: 36545824 Abstract Research on the invasive plant Phytolacca americana (L.) mostly focuses on its medicinal value and enrichment of heavy metals. However, little is known regarding its impact on native herbivorous insects. In this study, we explored the effects of P. americana and the exotic noninvasive Phytolacca icosandra (L.) on the Spodoptera litura (Fabricius) (native tobacco cutworm) via bioassay, oviposition preference, detoxifying enzyme activity analysis, and phytochemical determination. We found that the oviposition preference index (OPI) of S. litura feeding on P. icosandra was higher than that of P. americana. The developmental duration of S. litura feeding on P. icosandra was shorter than that of P. americana. Additionally, the Acetylcholinesterase (AchE) and Glutathione-S-transferase (GST) activities of S. litura feeding on P. americana were higher than that of S. litura feeding on artificial diets or P. icosandra. The content of lignin and flavonoids in P. americana was relatively high, whereas starch content was relatively low. These findings suggest invasive plants have higher resistance to herbivores, thereby suffering less damage than exotic noninvasive plants. Title: Microplastics exposure as an emerging threat to ancient lineage: A contaminant of concern for abnormal bending of amphioxus via neurotoxicity Xiang K, He Z, Fu J, Wang G, Li H, Zhang Y, Zhang S, Chen L Ref: J Hazard Mater, 438:129454, 2022 : PubMed ESTHER: Xiang_2022_J.Hazard.Mater_438_129454 PubMedSearch: Xiang 2022 J.Hazard.Mater 438 129454 PubMedID: 35803186 Abstract Growing inputs of microplastics into marine sediment have increased significantly the needs for assessment of their potential risks to the marine benthos. A knowledge gap remains with regard to the effect of microplastics on benthos, such as cephalochordates. By employing amphioxus as a model benthic chordate, here we show that exposure to microplastics for 96 h at doses of 1 mg/L and 100 mg/L results in evident accumulation of the polyethylene microplastics. The accumulated microplastics are as much as 0.027% of body weight upon high-dose exposure, causing an abnormal body-bending phenotype that limits the locomotion capability of amphioxus. Mechanistic insight reveals that microplastics can bring about histological damages in gill, intestine and hepatic cecum; In-depth assay of relevant biomarkers including superoxide dismutase, catalase, glutathione, pyruvic acid and total cholesterol indicates the occurrence of oxidative damage and metabolic disorder; Further, microplastics exposure depresses the activity of acetylcholinesterase while allowing the level of acetylcholine to rise in muscle, suggesting the emergence of neurotoxicity. These consequences eventually contribute to the muscle dysfunction of amphioxus. This study rationalizes the abnormal response of the vulnerable notochord to microplastics, signifying the dilemma suffered by the ancient lineage under the emerging threat. Given the enrichment of microplastics through marine food chains, this study also raises significant concerns on the impact of microplastics to other marine organisms, and eventually human beings. Title: SARM1 deletion in parvalbumin neurons is associated with autism-like behaviors in mice Xiang L, Wu Q, Sun H, Miao X, Lv Z, Liu H, Chen L, Gu Y, Chen J and Huang Z <13 more author(s)> Xiang L, Wu Q, Sun H, Miao X, Lv Z, Liu H, Chen L, Gu Y, Chen J, Zhou S, Jiang H, Du S, Zhou Y, Dong H, Fan Y, Miao S, Lu Q, Chang L, Wang H, Lu Y, Xu X, Wang W, Huang Z (- 13) Ref: Cell Death Dis, 13:638, 2022 : PubMed ESTHER: Xiang_2022_Cell.Death.Dis_13_638 PubMedSearch: Xiang 2022 Cell.Death.Dis 13 638 PubMedID: 35869039 Abstract Autism spectrum disorder (ASD), a group of neurodevelopmental disorder diseases, is characterized by social deficits, communication difficulties, and repetitive behaviors. Sterile alpha and TIR motif-containing 1 protein (SARM1) is known as an autism-associated protein and is enriched in brain tissue. Moreover, SARM1 knockdown mice exhibit autism-like behaviors. However, its specific mechanism in ASD pathogenesis remains unclear. Here we generated parvalbumin-positive interneurons (PVI)-specific conditional SARM1 knockout (SARM1(PV)-CKO) mice. SARM1(PV)-CKO male mice showed autism-like behaviors, such as mild social interaction deficits and repetitive behaviors. Moreover, we found that the expression level of parvalbumin was reduced in SARM1(PV)-CKO male mice, together with upregulated apoptosis-related proteins and more cleaved-caspase-3-positive PVIs, suggesting that knocking out SARM1 may cause a reduction in the number of PVIs due to apoptosis. Furthermore, the expression of c-fos was shown to increase in SARM1(PV)-CKO male mice, in combination with upregulation of excitatory postsynaptic proteins such as PSD-95 or neuroligin-1, indicating enhanced excitatory synaptic input in mutant mice. This notion was further supported by the partial rescue of autism-like behavior deficits by the administration of GABA receptor agonists in SARM1(PV)-CKO male mice. In conclusion, our findings suggest that SARM1 deficiency in PVIs may be involved in the pathogenesis of ASD. Title: A Novel Paper-Based Electrochemical Biosensor Based on N,O-Rich Covalent Organic Frameworks for Carbaryl Detection Xiao Y, Wu N, Wang L, Chen L Ref: Biosensors (Basel), 12:, 2022 : PubMed ESTHER: Xiao_2022_Biosensors.(Basel)_12_ PubMedSearch: Xiao 2022 Biosensors.(Basel) 12 PubMedID: 36291036 Abstract A new N,O-rich covalent organic framework (COF(DHNDA-BTH)) was synthesized by an amine-aldehyde condensation reaction between 2,6-dialdehyde-1,5-dihydroxynaphthalene (DHNDA) and 1,3,5-phenyltriformylhydrazine (BTH) for carbaryl detection. The free NH, OH, and C=O groups of COF(DHNDA-BTH) not only covalently couples with acetylcholinesterase (AChE) into the pores of COF(DHNDA-BTH), but also greatly improves the catalytic activity of AChE in the constrained environment of COF(DHNDA-BTH)'s pore. Under the catalysis of AChE, the acetylthiocholine (ATCl) was decomposed into positively charged thiocholine (TCl), which was captured on the COF(DHNDA-BTH) modified electrode. The positive charges of TCl can attract anionic probe [Fe(CN)(6)](3-/4-) on the COF(DHNDA-BTH)-modified electrode to show a good oxidation peak at 0.25 V (versus a saturated calomel electrode). The carbaryl detection can inhibit the activity of AChE, resulting in the decrease in the oxidation peak. Therefore, a turn-off electrochemical carbaryl biosensor based on a flexible carbon paper electrode loaded with COF(DHNDA-BTH) and AChE was constructed using the oxidation peak of an anionic probe [Fe(CN)(6)](3-/4-) as the detection signal. The detection limit was 0.16 microM (S/N = 3), and the linear range was 0.48~35.0 microM. The sensor has good selectivity, repeatability, and stability, and has a good application prospect in pesticide detection. Title: Structure-guided rational design of the Geobacillus thermoglucosidasius feruloyl esterase GthFAE to improve its thermostability Yang W, Sun L, Dong P, Chen Y, Zhang H, Huang X, Wu L, Chen L, Jing D, Wu Y Ref: Biochemical & Biophysical Research Communications, 600:117, 2022 : PubMed ESTHER: Yang_2022_Biochem.Biophys.Res.Commun_600_117 PubMedSearch: Yang 2022 Biochem.Biophys.Res.Commun 600 117 PubMedID: 35219099 Gene_locus related to this paper: partm-GthFAE Abstract Feruloyl esterases are indispensable biocatalysts catalyzing the cleavage of ester bonds between polysaccharides and their hydroxycinnamoyl cross-links. GthFAE from Geobacillus thermoglucosidasius was identified as a thermophilic alkaline feruloyl esterase with potential applications in paper manufacturing. To improve the enzymatic properties rationally and efficiently, the structure of GthFAE was solved at 1.9 A, revealing a core domain of classical alpha/beta hydrolase fold and an inserted alpha/beta cap domain. In silico analysis based on it helped us to investigate whether the residues at the active center have positive effects on the stability, and how. Several site-directed mutations were conducted, of which substitutions at residues T41 and T150 apparently improved the thermostability. The combination mutant T41N/T150R exhibited an optimal temperature of 65 degreesC, a 6.4 degreesC higher T(m) compared to wild type by 80 degreesC, and a 35-fold longer in half-life (201 min) at 70 degreesC. Molecular dynamics simulations further illustrated that the structure of T41N/T150R was more stable than the wild type and T150R stabilized the cap domain by introducing salt bridges to the region with E154 and D164. This study not only highlighted residues within the active center on their thermostability improving effects, but also contributed to the prospective industrial application of GthFAE. Title: Acute thiamethoxam exposure induces hepatotoxicity and neurotoxicity in juvenile Chinese mitten crab (Eriocheir sinensis) Yang Y, Yu Q, Zhang C, Wang X, He L, Huang Y, Li E, Qin J, Chen L Ref: Ecotoxicology & Environmental Safety, 249:114399, 2022 : PubMed ESTHER: Yang_2022_Ecotoxicol.Environ.Saf_249_114399 PubMedSearch: Yang 2022 Ecotoxicol.Environ.Saf 249 114399 PubMedID: 36508784 Abstract The similar nervous system structure between crustaceans and insects and the high-water solubility of thiamethoxam can lead to the more severe toxicity of thiamethoxam to crustaceans. However, the effects of thiamethoxam on crustaceans are unclear. Therefore, a 96-h acute toxicity test was performed to explore the hepatotoxicity and neurotoxicity effects of thiamethoxam on Chinese mitten crab (Eriocheir sinensis) at concentrations 0 microg/L, 150 microg/L and 300 microg/L. The antioxidant and detoxification systems (including phases I and II) were significantly activated after exposure of juvenile crabs to thiamethoxam for 24sh in 300 microg/L group, whereas the toxic activation effect in 150 microg/L group was delayed. Moreover, a similar pattern was observed for the transcription levels of immune-related genes. Further analysis of inflammatory signaling pathway-related genes showed that thiamethoxam exposure with 300 microg/L for 24sh may induce a pro-inflammatory response through the NF-kappaB pathway. In contrast, the gene expression levels in 150 microg/L group were significantly upregulated compared with 0 microg/L group after 96sh. In addition, although the acute exposure of 150 microg/L thiamethoxam did not seem to induce significant neurotoxicity, the acetylcholinesterase activity was significantly decreased in 300 microg/L group after thiamethoxam exposure for 96sh. Correspondingly, thiamethoxam exposure with 300 microg/L for 24sh resulted in significantly downregulated transcriptional levels of synaptic transmission-related genes (e.g. dopamine-, gamma-aminobutyric acid- and serotonin-related receptors). Therefore, thiamethoxam may be harmful and cause potential toxic threats such as neurotoxicity and metabolic damage to crustaceans. Title: Strigolactone signaling complex formation in yeast: A paradigm for studying hormone-induced receptor interaction with multiple downstream proteins Yu H, Yang L, Long H, Su X, Wang Y, Xing Q, Yao R, Zhang M, Chen L Ref: Methods Enzymol, 674:519, 2022 : PubMed ESTHER: Yu_2022_Methods.Enzymol_674_519 PubMedSearch: Yu 2022 Methods.Enzymol 674 519 PubMedID: 36008019 Abstract Strigolactones (SLs) are bioactive carotenoid derivatives which function as signaling molecules to regulate plant architecture, nutrient absorption and communication with other organisms. The alpha/beta-fold hydrolase, D14, hydrolyzes SLs, and the hydrolysis product activates D14 to bind to downstream signaling partners, including an E3 ubiquitin ligase MAX2 and SMXL6/7/8 proteins. What was not known was whether binding with one downstream partner would alter the affinity of D14 for other binding partners. Here, we developed an efficient yeast four-hybrid (Y4H) detection system and demonstrate that SL induces the interaction of D14 with both SMXL7 and MAX2 in a dose-dependent manner. Moreover, using our newly established yeast four-hybrid system, we found that the SL-induced D14 interaction with SMXL7 was strengthened by MAX2 while SMXL7 weakened the SL-induced D14 interaction with MAX2. Our findings provide novel insights into the regulatory effects of these signaling components and shed light on the molecular mechanism controlling the core SL signaling pathway. Furthermore, the heterologous yeast platform used for investigating SL complex formation has great potential to explore dynamic interactions in other signaling pathways or elucidate the unknown complex formation for biosynthesis of the parent carotenoids of SLs. Title: Two new C18-diterpenoid alkaloids from Aconitum leucostomum Worosch Zhou X, Yang HB, Luo YY, Xu JB, Liu Y, Gao F, Huang S, Chen L Ref: Chem Biodivers, :, 2022 : PubMed ESTHER: Zhou_2022_Chem.Biodivers__ PubMedSearch: Zhou 2022 Chem.Biodivers PubMedID: 36094326 Abstract Two new lappaconitine-type C18-diterpenoid alkaloids, named as leucostosines C (1) and D (2), together with six known compounds (3-8), were isolated from the roots of Aconitum leucostomum Worosch. Their structures were elucidated by various spectroscopic analyses, including IR, HR-ESI-MS, NMR spectra and X-ray experiments. Leucostosine C is the first diterpenoid alkaloid bearing the 7-amino group. The isolated compounds were tested for the acetylcholinesterase (AChE) inhibitory effect and neuroprotective activity, none of them showed significant activities. Title: Detecting the combined toxicity of 18 binary and 24 ternary pesticide combinations to carboxylesterase based on fluorescence probe technology Zhu X, Chen L, Liu T, He S, Zhao X, Tian Y, Fang Y, Cui J Ref: J Environ Sci Health B, :1, 2022 : PubMed ESTHER: Zhu_2022_J.Environ.Sci.Health.B__1 PubMedSearch: Zhu 2022 J.Environ.Sci.Health.B 1 PubMedID: 35287560 Abstract A rapid test method for the determination of pesticide toxicity was established by using carboxylesterase (CES) and fluorescence probe ACE-NH based on the principle of enzyme inhibition, and this method was applied to detect the combined toxicity of 18 binary and 24 ternary pesticide combinations commonly used for fruits and vegetables to CES. The results show that chlorpyrifos + carbendazim, carbofuran + carbendazim, imidacloprid + carbendazim, imidacloprid + dimethomorph, dimethoate + dimethomorph, prochloraz + carbendazim and imidacloprid + acetamiprid + carbendazim had synergistic effects under three concentration gradients, it indicated that most binary combinations containing carbendazim or imidacloprid had synergistic effects. Based on structure-activity relationship between pesticides and CES, pesticides with phosphate ester bonds had great toxicity to CES, or though they have no toxicity to CES alone, they showed a strong synergistic effect when mixed with other pesticides. Pesticides with amide or ester bond had medium toxicity and little synergistic effect. Pesticides with urea, carbamate or nitrite nitrogen group had little or no toxicity, while there was a strong synergistic effect after mixing with other pesticides. The test method and results in this study can provide scientific basis for risk assessment of cumulative exposure to mixed pesticide residues. Title: Cholinesterase is Associated With Prognosis and Response to Chemotherapy in Advanced Gastric Cancer Bi Y, Zhang J, Zeng D, Chen L, Ye W, Yang Q, Ling Y Ref: Pathol Oncol Res, 27:580800, 2021 : PubMed ESTHER: Bi_2021_Pathol.Oncol.Res_27_580800 PubMedSearch: Bi 2021 Pathol.Oncol.Res 27 580800 PubMedID: 34257526 Abstract Background: Cholinesterase (CHE) is a routine serum biomarker in gastric cancer (GC). However, little research has been done on its clinical value in advanced GC. In addition, it is not clear whether it can be used as biomarker for the response and prognosis of advanced GC patients. Methods: Between Jan. 2013 and Dec. 2016, a total of 150 patients with advanced GC treated with first-line chemotherapy were admitted to Changzhou Tumor Hospital Affiliated to Soochow University. We retrospectively identified serum CHE level on the day before chemotherapy and at the end of chemotherapy and abstracted clinicopathologic features and treatment outcomes. Univariate and multivariate survival analyses were performed to assess the relationship between serum CHE levels and progression-free survival (PFS) and overall survival (OS). Results: A total of 150 advanced GC patients were included and divided into serum level <=5,000 IU/L and serum level <5,000 IU/L. CHE level lower than 5,000 IU/L was associated with poorer PFS (HR, 1.60; 95% CI, 1.141-2.243; p = 0.006), poorer OS (HR, 1.76; 95% CI, 1.228-2.515; p = 0.002) and trend of poorer response (HR, 0.56; 95% CI, 0.272-1.129; p = 0.104). In univariate and multivariate logistic regression analysis, only liver metastasis and PS score were significantly associated with objective response (p < 0.05). The medium PFS was 8.0 months in patients with post-treatment CHE increased vs. 3.8 months in patients with CHE decreased after chemotherapy (HR, 1.82; 95% CI 1.28-2.57; p = 0.0002). The medium OS was 13.1 months in patients with increased post-treatment CHE vs. 8.1 months in patients with decreased post-treatment CHE (HR, 1.87; 95% CI 1.29-2.71; p = 0.0002). Conclusion: Advanced GC with CHE levels below 5,000 IU/L was significantly associated with poor PFS and OS. The results suggested that CHE analysis before chemotherapy was a promising prognostic marker for advanced GC. Title: Broad-spectrum pesticide screening by multiple cholinesterases and thiocholine sensors assembled high-throughput optical array system Chen L, Tian X, Li Y, Lu L, Nie Y, Wang Y Ref: J Hazard Mater, 402:123830, 2021 : PubMed ESTHER: Chen_2021_J.Hazard.Mater_402_123830 PubMedSearch: Chen 2021 J.Hazard.Mater 402 123830 PubMedID: 33254811 Abstract Accurate screening of organophosphorus and carbamates pesticides from the complex real sample is crucial for water quality analysis and food safety control. Herein, a simple, low-cost and accurate pesticides screening method based on a high-throughput optical array system assembled by multiple cholinesterases (ChE) and thiocholine (TCh) sensors is described. The detection mechanism is that the inhibition of ChE activity by pesticides reduces the TCh produced by the hydrolysis of butyryl/acetylthiocholine iodide, thus changing the fluorescence intensity of TCh sensor. The diverse response of ChEs to pesticides and different affinity of sensors to TCh ensure the high-throughput and distinguishable signal output, which allow the establishment of high discrete pesticide database with intra-cluster agglomeration and inter-cluster dispersion. By using the database, the screening of unknown real contaminated samples were successfully operated, and the screened pesticide species and concentrations were consistent with high-performance liquid chromatography. This screening strategy demonstrates the feasibility of replacing existing complex mass spectrometry-based screening strategy with simple optical analysis, providing a new idea for the development of simple accurate screening technologies for widespread organic pollutants including pesticides. Title: Synergistic enhancement of the emergency treatment effect of organophosphate poisoning by a supramolecular strategy Chen J, Zhang Y, Chai Y, Meng Z, Chen L, Quan D, Wang Y, Meng Q, Li C Ref: Chem Sci, 12:5202, 2021 : PubMed ESTHER: Chen_2021_Chem.Sci_12_5202 PubMedSearch: Chen 2021 Chem.Sci 12 5202 PubMedID: 34163757 Abstract Poisoning by organophosphorus agents (OPs) is a serious public health issue across the world. These compounds irreversibly inhibit acetylcholinesterase (AChE), resulting in the accumulation of acetylcholine (ACh) and overstimulation of ACh receptors. A supramolecular detoxification system (SDS) has been designed with a view to deliver pyridine-2-aldoxime methochloride (PAM) with a synergistic inhibition effect on the ACh-induced hyperstimulation through host-guest encapsulation. NMR and fluorescence titration served to confirm the complexation between carboxylatopillar[6]arene (CP6A) and PAM as well as ACh with robust affinities. Patch-clamp studies proved that CP6A could exert an inhibition effect on the ACh-induced hyperstimulation of ACh receptors. Support for the feasibility of this strategy came from fluorescence imaging results. In vivo studies revealed that complexation by CP6A serves to increase the AChE reactivation efficiency of PAM. The formation of the PAM/CP6A complex contributed to enhance in a statistically significant way the ability of PAM not only to relieve symptoms of seizures but also to improve the survival ratio in paraoxon-poisoned model rats. These favorable findings are attributed to synergistic effects that PAM reactivates AChE to hydrolyze ACh and excess ACh is encapsulated in the cavity of CP6A to relieve cholinergic crisis symptoms. Title: Near-infrared fluorescent probe for evaluating the acetylcholinesterase effect in the aging process and dietary restriction via fluorescence imaging He N, Yu L, Xu M, Huang Y, Wang X, Chen L, Yue S Ref: J Mater Chem B, :, 2021 : PubMed ESTHER: He_2021_J.Mater.Chem.B__ PubMedSearch: He 2021 J.Mater.Chem.B PubMedID: 33666613 Abstract Dietary restriction (DR), as a natural intervention, not only benefits the neuroendocrine system, but also has an antiaging action. Acetylcholinesterase (AChE) is one of the most important bioactive substances and plays a major part in choline changes in the aging process. Thus, we aim to evaluate the effect of DR on AChE in the brains of aging animals. In this study, we synthesize a NIR fluorescent probe BD-AChE for the real-time and in situ monitoring of AChE level changes in living cells and living mice, notably in brains. In situ visualization with BD-AChE verified a decrease in the AchE level in the brains of mice aging models. Evidently, the prepared probe has the excellent capability of measuring AChE variation in the brains of aging mice with DR via NIR fluorescence bioimaging, indicating that long-term DR can effectively affect AChE levels in the brain. The attenuation of AChE level in the brain of aging mice after DR could be helpful in infering the advantageous impact of DR on age-related neurodegenerative disease, as a better treatment alternative in the future. Title: Identification of Conserved and Divergent Strigolactone Receptors in Sugarcane Reveals a Key Residue Crucial for Plant Branching Control Hu A, Zhao Q, Chen L, Zhao J, Wang Y, Feng K, Wu L, Xie M, Zhou X and Yao R <3 more author(s)> Hu A, Zhao Q, Chen L, Zhao J, Wang Y, Feng K, Wu L, Xie M, Zhou X, Xiao L, Ming Z, Zhang M, Yao R (- 3) Ref: Front Plant Sci, 12:747160, 2021 : PubMed ESTHER: Hu_2021_Front.Plant.Sci_12_747160 PubMedSearch: Hu 2021 Front.Plant.Sci 12 747160 PubMedID: 34858455 Gene_locus related to this paper: 9poal-a0a0d5nt23 Abstract Strigolactones (SLs) are a class of important plant hormones mainly regulating plant architecture such as branching, which is crucial for crop yield. It is valuable to study SL signaling pathway and its physiological function in sugarcane, the most important sugar crop, for further molecular breeding. Here, two putative SL receptors SsD14a/b and the interacting F-box protein SsMAX2 were identified in Saccharum spontaneum. SL induced both SsD14a and SsD14b to interact with SsMAX2 in yeast. SsD14a, but not SsD14b, could bind with AtMAX2 and AtSMXL7/SsSMXL7. Overexpression of SsD14a or SsMAX2 rescued the increased branching phenotypes of Arabidopsis thaliana d14-1 or max2-3 mutants, respectively. Moreover, the crystal structure of N-terminal truncated SsD14a was solved, with an overall structure identical to AtD14 and OsD14 in the open state, consistent with its conserved branching suppression capacity in Arabidopsis. In line with the biochemical observations, SsD14b could not completely complement in d14-1 although these two SsD14 proteins have almost identical primary sequences except for very few residues. Complement with the combination of SsD14b and SsMAX2 still failed to rescue the d14-1 max2-3 double mutant multi-branching phenotype, indicating SsD14b-AtSMXL7 complex formation is required for regulating branching. Mutagenesis analyses revealed that residue R310 at alpha10 helix of SsD14a was crucial for the binding with SsSMXL7/AtSMXL7 but not SsMAX2. The site-equivalent single-residue P304R substitution enabled SsD14b to bind with AtMAX2 and AtSMXL7/SsSMXL7 and to rescue the phenotype of d14-1 max2-3 together with SsMAX2. Moreover, this conserved Arg residue across species including rice and Arabidopsis determined the activity of SL receptors through maintaining their interaction with SMXL repressors. Taken together, our work identified conserved and divergent strigolactone receptors in sugarcane core SL signaling pathway and revealed a key residue crucial for plant branching control. Title: Strigolactone mimic 2-nitrodebranone is highly active in Arabidopsis growth and development Li S, Li Y, Chen L, Zhang C, Wang F, Li H, Wang M, Wang Y, Nan F and Yan J <1 more author(s)> Li S, Li Y, Chen L, Zhang C, Wang F, Li H, Wang M, Wang Y, Nan F, Xie D, Yan J (- 1) Ref: Plant J, :, 2021 : PubMed ESTHER: Li_2021_Plant.J__ PubMedSearch: Li 2021 Plant.J PubMedID: 33860570 Abstract Strigolactones play crucial roles in regulating plant architecture and development, as endogenous hormones, and orchestrating symbiotic interactions with fungi and parasitic plants, as components of root exudates. rac-GR24 is currently the most widely used strigolactone analog and serves as a reference compound in investigating the action of strigolactones. In this study, we evaluated a suite of debranones and found that 2-nitrodebranone (2NOD) exhibited higher biological activity than rac-GR24 in various aspects of plant growth and development in Arabidopsis, including hypocotyl elongation inhibition, root hair promotion and senescence acceleration. The enhanced activity of 2NOD in promoting AtD14-SMXL7 and AtD14-MAX2 interactions indicates that the molecular structure of 2NOD is a better match for the ligand perception site pocket of D14. Moreover, 2NOD showed lower activity than rac-GR24 in promoting Orobanche cumana seed germination, suggesting its higher ability to control plant architecture than parasitic interactions. In combination with the improved stability of 2NOD, these results demonstrate that 2NOD is a strigolactone analog that can specifically mimic the activity of strigolactones and that 2NOD exhibits strong potential as a tool for studying the strigolactone signaling pathway in plants. Title: A new diterpenoid alkaloid from Delphinium gyalanum C. Marquand & Airy Shaw Li X, Ye M, Gao F, Zhou X, Chen L, Huang S Ref: Nat Prod Res, :1, 2021 : PubMed ESTHER: Li_2021_Nat.Prod.Res__1 PubMedSearch: Li 2021 Nat.Prod.Res 1 PubMedID: 34241556 Abstract A new C(19)-diterpenoid alkaloid named gyalanutine A (1) and fourteen known compounds 2-15 were isolated from the plant of Delphinium gyalanum C. Marquand & Airy Shaw. Compound 1 displayed an unusual lycoctonine-type C(19)-diterpenoid alkaloid skeleton with the cleavage of N-C(19) and C(7)-C(17) bonds, and the construction of the N-C(7) bond. Structures were identified by multiple spectroscopic analyses including 1 D, 2 D NMR, IR and HR-ESI-MS. Compounds were tested for acetylcholinesterase inhibitory and anti-inflammatory activity. Title: Electro-Acupuncture Improve the Early Pattern Separation in Alzheimer's Disease Mice via Basal Forebrain-Hippocampus Cholinergic Neural Circuit Li L, Li J, Dai Y, Yang M, Liang S, Wang Z, Liu W, Chen L, Tao J Ref: Front Aging Neurosci, 13:770948, 2021 : PubMed ESTHER: Li_2021_Front.Aging.Neurosci_13_770948 PubMedSearch: Li 2021 Front.Aging.Neurosci 13 770948 PubMedID: 35185516 Abstract OBJECTIVES: To explore the effect of electro-acupuncture (EA) treatment on pattern separation and investigate the neural circuit mechanism involved in five familial mutations (5 x FAD) mice. METHODS: Five familial mutations mice were treated with EA at Baihui (DU20) and Shenting (DU24) acupoints for 30 min each, lasting for 4 weeks. Cognitive-behavioral tests were performed to evaluate the effects of EA treatment on cognitive functions. (1)H-MRS, Nissl staining, immunohistochemistry, and immunofluorescence were performed to examine the cholinergic system alteration. Thioflavin S staining and 6E10 immunofluorescence were performed to detect the amyloid-beta (Abeta). Furthermore, hM4Di designer receptors exclusively activated by designer drugs (DREADDs) virus and long-term clozapine-N-oxide injection were used to inhibit the medial septal and vertical limb of the diagonal band and dentate gyrus (MS/VDB-DG) cholinergic neural circuit. Cognitive-behavioral tests and immunofluorescence were performed to investigate the cholinergic neural circuit mechanism of EA treatment improving cognition in 5 x FAD mice. RESULTS: Electro-acupuncture treatment significantly improved spatial recognition memory and pattern separation impairment, regulated cholinergic system via reduction neuron loss, upregulation of choline/creatine, choline acetyltransferase, vesicular acetylcholine transporter, and downregulation of enzyme acetylcholinesterase in 5 x FAD mice. Abeta deposition was reduced after EA treatment. Subsequently, the monosynaptic hM4Di DREADDs virus tracing and inhibiting strategy showed that EA treatment activates the MS/VDB-DG cholinergic neural circuit to improve the early pattern separation. In addition, EA treatment activates this circuit to upregulating M1 receptors positive cells and promoting hippocampal neurogenesis in the dentate gyrus (DG). CONCLUSION: Electro-acupuncture could improve the early pattern separation impairment by activating the MS/VDB-DG cholinergic neural circuit in 5 x FAD mice, which was related to the regulation of the cholinergic system and the promotion of neurogenesis by EA treatment. Title: Molecular basis for high ligand sensitivity and selectivity of strigolactone receptors in Striga Wang Y, Yao R, Du X, Guo L, Chen L, Xie D, Smith SM Ref: Plant Physiol, 185:1411, 2021 : PubMed ESTHER: Wang_2021_Plant.Physiol_185_1411 PubMedSearch: Wang 2021 Plant.Physiol 185 1411 PubMedID: 33793945 Gene_locus related to this paper: strhe-ShHTL7 Abstract Seeds of the root parasitic plant Striga hermonthica can sense very low concentrations of strigolactones (SLs) exuded from host roots. The S. hermonthica hyposensitive to light (ShHTL) proteins are putative SL receptors, among which ShHTL7 reportedly confers sensitivity to picomolar levels of SL when expressed in Arabidopsis thaliana. However, the molecular mechanism underlying ShHTL7 sensitivity is unknown. Here we determined the ShHTL7 crystal structure and quantified its interactions with various SLs and key interacting proteins. We established that ShHTL7 has an active-site pocket with broad-spectrum response to different SLs and moderate affinity. However, in contrast to other ShHTLs, we observed particularly high affinity of ShHTL7 for F-box protein AtMAX2. Furthermore, ShHTL7 interacted with AtMAX2 and with transcriptional regulator AtSMAX1 in response to nanomolar SL concentration. ShHTL7 mutagenesis analyses identified surface residues that contribute to its high-affinity binding to AtMAX2 and residues in the ligand binding pocket that confer broad-spectrum response to SLs with various structures. Crucially, yeast-three hybrid experiments showed that AtMAX2 confers responsiveness of the ShHTL7-AtSMAX1 interaction to picomolar levels of SL in line with the previously reported physiological sensitivity. These findings highlight the key role of SL-induced MAX2-ShHTL7-SMAX1 complex formation in determining the sensitivity to SL. Moreover, these data suggest a strategy to screen for compounds that could promote suicidal seed germination at physiologically relevant levels. Title: Autistic-like behavior, spontaneous seizures, and increased neuronal excitability in a Scn8a mouse model Wong JC, Grieco SF, Dutt K, Chen L, Thelin JT, Inglis GAS, Parvin S, Garraway SM, Xu X and Escayg A <1 more author(s)> Wong JC, Grieco SF, Dutt K, Chen L, Thelin JT, Inglis GAS, Parvin S, Garraway SM, Xu X, Goldin AL, Escayg A (- 1) Ref: Neuropsychopharmacology, :, 2021 : PubMed ESTHER: Wong_2021_Neuropsychopharmacology__ PubMedSearch: Wong 2021 Neuropsychopharmacology PubMedID: 33658654 Abstract Patients with SCN8A epileptic encephalopathy exhibit a range of clinical features, including multiple seizure types, movement disorders, and behavioral abnormalities, such as developmental delay, mild-to-severe intellectual disability, and autism. Recently, the de novo heterozygous SCN8A R1620L mutation was identified in an individual with autism, intellectual disability, and behavioral seizures without accompanying electrographic seizure activity. To date, the effects of SCN8A mutations that are primarily associated with behavioral abnormalities have not been studied in a mouse model. To better understand the phenotypic and functional consequences of the R1620L mutation, we used CRISPR/Cas9 technology to generate mice expressing the corresponding SCN8A amino acid substitution. Homozygous mutants exhibit tremors and a maximum lifespan of 22 days, while heterozygous mutants (RL/+) exhibit autistic-like behaviors, such as hyperactivity and learning and social deficits, increased seizure susceptibility, and spontaneous seizures. Current clamp analyses revealed a reduced threshold for firing action potentials in heterozygous CA3 pyramidal neurons and reduced firing frequency, suggesting that the R1620L mutation has both gain- and loss-of-function effects. In vivo calcium imaging using miniscopes in freely moving RL/+ mutants showed hyperexcitability of cortical excitatory neurons that is likely to increase seizure susceptibility. Finally, we found that oxcarbazepine and Huperzine A, a sodium channel blocker and reversible acetylcholinesterase inhibitor, respectively, were capable of conferring robust protection against induced seizures in RL/+ mutants. This mouse line will provide the opportunity to better understand the range of clinical phenotypes associated with SCN8A mutations and to develop new therapeutic approaches. Title: Efficiency of donepezil in elderly patients undergoing orthopaedic surgery due to underlying post-operative cognitive dysfunction: study protocol for a multicentre randomised controlled trial Zhu H, Cong L, Chen Y, Chen S, Chen L, Huang Z, Zhou J, Xiao J, Huang Y, Su D Ref: Trials, 22:688, 2021 : PubMed ESTHER: Zhu_2021_Trials_22_688 PubMedSearch: Zhu 2021 Trials 22 688 PubMedID: 34627332 Abstract BACKGROUND: Post-operative cognitive dysfunction (POCD) is an overarching term used to describe cognitive impairment identified in the preoperative or post-operative period. After surgical operations, older patients are particularly vulnerable to memory disturbances and other types of cognitive impairment. However, the pathogenesis of POCD remains unclear with no confirmed preventable or treatable strategy available. Our previous study demonstrated that the concentration of choline acetyl transferase in the cerebral spinal fluid was a predictive factor of POCD and that donepezil, which is an acetylcholinesterase inhibitor used in clinical settings for the treatment of Alzheimer's disease, can prevent learning and memory impairment after anaesthesia/surgery in aged mice. This study aimed to determine the critical role of donepezil in preventing cognitive impairment in elderly patients undergoing orthopaedic surgery. METHODS: A multicentre, double-blind, placebo-controlled, crossover clinical trial will be performed to assess the efficacy of donepezil in elderly patients undergoing orthopaedic surgery. Participants (n = 360) will receive donepezil (5 mg once daily) or placebo from 1 day prior to surgery until 5 days after surgery. Neuropsychological tests will be measured at 1 day before the operation and 1 week, 1 month, 6 months and 1 year after the operation. DISCUSSION: This research project mainly aimed to study the effects of donepezil in elderly patients undergoing orthopaedic surgery due to underlying POCD and to investigate the underlying physiological and neurobiological mechanisms of these effects. The results may provide important implications for the development of effective interfering strategies, specifically regarding cognitive dysfunction therapy using drugs. TRIAL REGISTRATION: ClinicalTrials.gov NCT04423276 . Registered on 14 June 2020. Title: Structural basis for the inhibitor and substrate specificity of the unique Fph serine hydrolases of Staphylococcus aureus Fellner M, Lentz CS, Jamieson SA, Brewster JL, Chen L, Bogyo M, Mace PD Ref: ACS Infect Dis, 6:2771, 2020 : PubMed ESTHER: Fellner_2020_ACS.Infect.Dis_6_2771 PubMedSearch: Fellner 2020 ACS.Infect.Dis 6 2771 PubMedID: 32865965 Gene_locus related to this paper: staau-MW0741, staau-MW2456, staau-SA1143, staau-SA2240, staau-SA2306, staau-SA2367, staau-SA2422, staau-SAV0457, staau-SAV1793, staau-SAV2188 Inhibitor(s) related to this paper: KT129, KT130, JCP678 Abstract Staphylococcus aureus is a prevalent bacterial pathogen in both community and hospital settings, and its treatment is made particularly difficult by resilience within biofilms. Within this niche, serine hydrolase enzymes play a key role in generating and maintaining the biofilm matrix. Activity-based profiling has previously identified a family of serine hydrolases, designated fluorophosphonate-binding hydrolases (Fphs), some of which contribute to the virulence of S. aureus in vivo. These ten Fph proteins have limited annotation, and have few, if any, characterized bacterial or mammalian homologs. This suggests unique hydrolase functions even within bacterial species. Here we report structures of one of the most abundant Fph family members, FphF. Our structures capture FphF alone, covalently bound to a substrate analog, and bound to small molecule inhibitors that occupy the hydrophobic substrate-binding pocket. In line with these findings, we show that FphF has promiscuous esterase activity towards hydrophobic lipid substrates. We present docking studies that characterize interactions of inhibitors and substrates within the active site environment, which can be extended to other Fph family members. Comparison of FphF to other esterases and the wider Fph protein family suggest that FphF forms a new esterase subfamily. Our data suggest that other Fph enzymes, including the virulence factor FphB, are likely to have more restricted substrate profiles than FphF. This work demonstrates a clear molecular rationale for the specificity of fluorophosphonate probes that target FphF and provides a structural template for the design of enhanced probes and inhibitors of the Fph family of serine hydrolases. Title: Improved production of recombinant Rhizomucor miehei lipase by coexpressing protein folding chaperones in Pichia pastoris, which triggered ER stress Huang J, Zhao Q, Chen L, Zhang C, Bu W, Zhang X, Zhang K, Yang Z Ref: Bioengineered, 11:375, 2020 : PubMed ESTHER: Huang_2020_Bioengineered_11_375 PubMedSearch: Huang 2020 Bioengineered 11 375 PubMedID: 32175802 Gene_locus related to this paper: rhimi-lipas Abstract Rhizomucor miehei lipase (RML) is a biocatalyst that widely used in laboratory and industrial. Previously, RML with a 70-amino acid propeptide (pRML) was cloned and expressed in P. pastoris. Recombinant strains with (strain containing 4-copy prml) and without ER stress (strain containing 2-copy prml) were obtained. However, the effective expression of pRML in P. pastoris by coexpressing ER-related elements in pRML-produced strain with or without ER stress has not been reported to date. In this study, an efficient way to produce functional pRML was explored in P. pastoris. The coexpression of protein folding chaperones, including PDI and ERO1, in different strains with or without ER stress, was investigated. PDI overexpression only increased pRML production in 4-copy strain from 705 U/mL to 1430 U/mL because it alleviated the protein folded stress, increased the protein concentration from 0.56 mg/mL to 0.65 mg/mL, and improved enzyme-specific activity from 1238 U/mg to 2186 U/mg. However, PDI coexpression could not improve pRML production in the 2-copy strain because it increased protein folded stress, while ERO1 coexpression in the two strains all had a negative effect on pRML expression. We also investigated the effect of the propeptide on the substrate specificity and the condition for pRML enzyme powder preparation. Results showed that the relative activity exceeded 80% when the substrates C8-C10 were detected at 35 degrees C and pH 6, and C8-C12 at 45 degrees C and pH 8. The optimal enzyme powder preparation pH was 7, and the maximum recovery rate for pRML was 73.19%. Title: Diterpenoid alkaloids from Aconitum anthoroideum that offer protection against MPP(+)-Induced apoptosis of SH-SY5Y cells and acetylcholinesterase inhibitory activity Huang S, Zhang JF, Chen L, Gao F, Zhou XL Ref: Phytochemistry, 178:112459, 2020 : PubMed ESTHER: Huang_2020_Phytochemistry_178_112459 PubMedSearch: Huang 2020 Phytochemistry 178 112459 PubMedID: 32888673 Abstract Nine unprecedented diterpenoid alkaloid, including a diterpenoid alkaloid featuring a diterpenoid moiety, anthoroidine A; one bisditerpenoid alkaloid joined with a carbon-carbon single bond, anthoroidine B; three racemulosine-type C(20)-diterpenoid alkaloids, anthoroidines C-E; one hetidine-type C(20)-diterpenoid alkaloid, anthoroidine F; and three hetisine-type C(20)-diterpenoid alkaloids, anthoroidines G-I, together with ten known diterpenoid alkaloids were isolated from Aconitum anthoroideum DC. Their structures were established via detailed spectroscopic analyses. Most of the isolated compounds along with five known diterpenoid alkaloids obtained in a previous study were screened for neuroprotective activities and acetylcholinesterase inhibitory effects. Nominine showed potent protective activity against MPP(+)-induced apoptosis in SH-SY5Y cells, with a rescue rate of 34.4% (50 muM). Rotundifosine F showed a significant inhibitory activity against AChE (IC(50) = 0.3 muM). The structure-activity relationship of these alkaloids is also briefly discussed. Title: Lipase catalysis of alpha-linolenic acid-rich medium- and long-chain triacylglycerols from perilla oil and medium-chain triacylglycerols with reduced by-products Huang Z, Cao Z, Guo Z, Chen L, Wang Z, Sui X, Jiang L Ref: J Sci Food Agric, 100:4565, 2020 : PubMed ESTHER: Huang_2020_J.Sci.Food.Agric_100_4565 PubMedSearch: Huang 2020 J.Sci.Food.Agric 100 4565 PubMedID: 32419135 Abstract BACKGROUND: Medium- and long- chain triacylglycerols (MLCTs) are functional structural lipids that can provide the human body with essential fatty acids and a faster energy supply. This study aimed to prepare MLCTs rich in alpha-linolenic by enzymatic interesterification of perilla oil and medium-chain triacylglycerols (MCTs), catalyzed by Lipozyme RM IM, Lipozyme TL IM, Lipozyme 435, and Novozyme 435 respectively. RESULTS: The effects of lipase loading, concentration of MCTs, reaction temperature, and reaction time on the yield of MLCTs were investigated. It was found that the reaction achieved more than a 70% yield of MLCTs in triacylglycerols under the conditions of 400 g kg(-1) MCTs and 60 g kg(-1) lipase loading after equilibrium. A novel two-stage deodorization was also applied to purify the interesterification products. The triacylglycerols reach over 97% purity in the products with significant removal (P < 0.05) of the free fatty acids, and the trans fatty acids were strictly controlled at below 1%. There was more than 40% alpha-linolenic in the purified products, with long-chain fatty acids mostly occupying the desired sn-2 position in acylglycerols, which are more active in hydrolysis. CONCLUSION: A series of novel alpha-linolenic acid-rich medium- and long-chain triacylglycerols was prepared. Under appropriate reaction conditions, the yield of MLCTs in triacylglycerols was above 70%. A novel two-stage deodorization can be used to promote the elimination of free fatty acids and limit the generation of trans fatty acids. Title: Rhizomucor miehei lipase-catalysed synthesis of cocoa butter equivalent from palm mid-fraction and stearic acid: Characteristics and feasibility as cocoa butter alternative Huang Z, Guo Z, Xie D, Cao Z, Chen L, Wang H, Jiang L, Shen Q Ref: Food Chem, :128407, 2020 : PubMed ESTHER: Huang_2020_Food.Chem__128407 PubMedSearch: Huang 2020 Food.Chem 128407 PubMedID: 33129620 Abstract In this study, cocoa butter equivalents (CBEs) were prepared through enzymatic interesterification of palm mid-fraction (PMF) with stearic acid (SA). The reaction process parameters were experimented and the performance of the product was analysed. PMF and stearic acid (at a mass ratio of 1:2) were catalysed by 80 g kg(-1) enzyme loading of Lipozyme RM IM fromRhizomucor mieheiat 60 degreeC for 120 min. The yield of the CBE product was more than 92%, and the CBE resembled cocoa butter (CB) in terms of its triacylglycerol composition. The hardness of the CBE product was higher than that of CB at different storage temperatures, but this difference was not obvious at 25 degreeC. The polymorphic structures and SFC curve of the CBE were similar to those of the CB. In addition, the CBE could be mixed with CB in any ratio without an obvious eutectic phenomena. Up to 40% CBE could be added to CB without significantly affecting the thermodynamic properties of CB. Thus, replacing CB with the CBE product is feasible. Title: Rational design and biological evaluation of a new class of thiazolopyridyl tetrahydroacridines as cholinesterase and GSK-3 dual inhibitors for Alzheimer's disease Jiang X, Zhou J, Wang Y, Chen L, Duan Y, Huang J, Liu C, Chen Y, Liu W and Qu W <2 more author(s)> Jiang X, Zhou J, Wang Y, Chen L, Duan Y, Huang J, Liu C, Chen Y, Liu W, Sun H, Feng F, Qu W (- 2) Ref: Eur Journal of Medicinal Chemistry, 207:112751, 2020 : PubMed ESTHER: Jiang_2020_Eur.J.Med.Chem_207_112751 PubMedSearch: Jiang 2020 Eur.J.Med.Chem 207 112751 PubMedID: 32950908 Abstract A key factor in the success of the MTDLs drug discovery approach is the selection of suitable target proteins. Based on the results of our previous research regarding dual-target inhibitors of AChE/GSK-3beta and analysis of target proteins, in the current study, 28 hybrids were designed and synthesized. Docking studies allowed us to rationalize the binding mode of the synthesized compounds in both targets. In vitro enzyme inhibition studies identified compound GT15 as a lead molecule with preferential AChE/GSK-3beta inhibition (hAChE IC(50) = 1.2 +/- 0.1 nM; hGSK-3beta IC(50) = 22.2 +/- 1.4 nM). In addition, GT15 showed high kinase selectivity for GSK-3, except for DYRK1, with inhibition rate of 83.69% and 67.94% against DYRK1alpha and DYRK1beta at a concentration of 20 muM. The compound also exhibited good permeability across the blood-brain-barrier and ability to inhibit the phosphorylation of tau protein. Upon oral administration, GT15 exhibited promising cognitive improvement in the scopolamine-induced cognitive deficit mice in the Morris water maze model. These results suggest that AChE and GSK-3 based multitargeted approach have therapeutic potential for Alzheimer's disease. Title: An optimized acetylcholine sensor for monitoring in vivo cholinergic activity Jing M, Li Y, Zeng J, Huang P, Skirzewski M, Kljakic O, Peng W, Qian T, Tan K and Cheng H <13 more author(s)> Jing M, Li Y, Zeng J, Huang P, Skirzewski M, Kljakic O, Peng W, Qian T, Tan K, Zou J, Trinh S, Wu R, Zhang S, Pan S, Hires SA, Xu M, Li H, Saksida LM, Prado VF, Bussey TJ, Prado MAM, Chen L, Cheng H (- 13) Ref: Nat Methods, 17:1139, 2020 : PubMed ESTHER: Jing_2020_Nat.Methods_17_1139 PubMedSearch: Jing 2020 Nat.Methods 17 1139 PubMedID: 32989318 Abstract The ability to directly measure acetylcholine (ACh) release is an essential step toward understanding its physiological function. Here we optimized the GRAB(ACh) (GPCR-activation-based ACh) sensor to achieve substantially improved sensitivity in ACh detection, as well as reduced downstream coupling to intracellular pathways. The improved version of the ACh sensor retains the subsecond response kinetics, physiologically relevant affinity and precise molecular specificity for ACh of its predecessor. Using this sensor, we revealed compartmental ACh signals in the olfactory center of transgenic flies in response to external stimuli including odor and body shock. Using fiber photometry recording and two-photon imaging, our ACh sensor also enabled sensitive detection of single-trial ACh dynamics in multiple brain regions in mice performing a variety of behaviors. Title: Dietary administration of probiotic Lactobacillus rhamnosus modulates the neurological toxicities of perfluorobutanesulfonate in zebrafish Liu M, Song S, Hu C, Tang L, Lam JCW, Lam PKS, Chen L Ref: Environ Pollut, 265:114832, 2020 : PubMed ESTHER: Liu_2020_Environ.Pollut_265_114832 PubMedSearch: Liu 2020 Environ.Pollut 265 114832 PubMedID: 32454362 Abstract Perfluorobutanesulfonate (PFBS), an aquatic pollutant of emerging concern, is found to disturb the neural signaling along gut-brain axis, whereas probiotic additives have been applied to improve neuroendocrine function of teleosts. Both PFBS and probiotics can commonly target nervous system. However, whether and how probiotic bacteria can modulate the neurotoxicities of PFBS remain not explored. It is thus necessary to elucidate the probiotic modulation of PFBS neurotoxicity, which can provide implications to the application of probiotic bacteria in aquaculture industry. In the present study, adult zebrafish were exposed to 0, 10 and 100 mug/L PFBS with or without dietary administration of probiotic Lactobacillus rhamnosus. Interaction between PFBS and probiotic along gut-brain axis was examined, covering three dominant pathways (i.e., neurotransmission, immune response and hypothalamic-pituitary-adrenal (HPA) axis). The results showed that, compared to the single effects, PFBS and probiotic coexposure significantly altered the acetylcholinesterase activity and neurotransmitter profiles in gut and brain of zebrafish, with mild effects on neuronal integrity. Neurotransmitters closely correlated reciprocally in intestines, which, however, was distinct from the correlation profile in brains. In addition, PFBS and probiotic were combined to impact brain health through absorption of bacterial lipopolysaccharides and production of inflammatory cytokines. Relative to neurotransmission and immune signaling, HPA axis was not involved in the neurotoxicological interaction between PFBS and probiotic. Furthermore, it needs to point out that interactive modes between PFBS and probiotic varied a lot, depending on exposure concentrations, sex and toxic indices. Overall, the present study provided the first evidence that probiotic supplement could dynamically modulate the neurotoxicities of PFBS in teleost. Title: Ajmalicine and its Analogues against AChE and BuChE for the Management of Alzheimer's Disease: An In-silico study Liu S, Dang M, Lei Y, Ahmad SS, Khalid M, Kamal MA, Chen L Ref: Curr Pharm Des, :, 2020 : PubMed ESTHER: Liu_2020_Curr.Pharm.Des__ PubMedSearch: Liu 2020 Curr.Pharm.Des PubMedID: 32264807 Abstract BACKGROUND: Alzheimer's disease (AD) is the most well-known reason for disability in persons aged greater than 65 years worldwide. AD influences the part of the brain that controls cognitive and noncognitive functions. OBJECTIVE: The study focuses on the screening of natural compounds for the inhibition of AChE and BuChE using a computational methodology. METHODS: We performed a docking-based virtual screening utilizing the 3D structure of AChE and BuChE to search for potential inhibitors for AD. In this work, a screened inhibitor Ajmalicine similarity search was carried out against a natural products database (Super Natural II). Lipinski rule of five was carried out and docking studies were performed between ligands and enzyme using 'Autodock4.2'. RESULTS: Two phytochemical compounds SN00288228 and SN00226692 were predicted for the inhibition of AChE and BuChE, respectively. The docking results revealed Ajmalicine, a prominent natural alkaloid, showing promising inhibitory potential against AChE and BuChE with the binding energy of - 9.02 and -8.89 kcal/mole respectively. However, SN00288228- AChE, and SN00226692-BuChE were found to have binding energy -9.88 and -9.54 kcal/mole, respectively. These selected phytochemical compounds showed better interactions in comparison to Ajmalicine with the target molecule. CONCLUSION: The current study verifies that SN00288228 and SN00226692 are more capable inhibitors of human AChE and BuChE as compared to Ajmalicine with reference to DeltaG values. Title: Increased cross-linking micelle retention in the brain of Alzheimer's disease mice by elevated asparagine endopeptidase protease responsive aggregation Ren J, Jiang F, Wang M, Hu H, Zhang B, Chen L, Dai F Ref: Biomater Sci, 8:6533, 2020 : PubMed ESTHER: Ren_2020_Biomater.Sci_8_6533 PubMedSearch: Ren 2020 Biomater.Sci 8 6533 PubMedID: 33111725 Abstract Current forms of medication for Alzheimer's disease (AD) provide a symptomatic benefit limited to those with early onset, but there is no single drug available for later stage patients. Given the recent failures of AD drugs in clinical trials, an intensive treatment strategy based on drug combination that is approved is attractive. At present, the greatest difficulty lies in the low accumulation of drugs in the brain. All hydrophilic drugs are limited by the physical and biochemical barriers within the blood-brain barrier and lipophilic drugs are often transported back into the blood by efflux pumps located in the blood-brain barrier. Here, we select elevated asparagine endopeptidase (AEP) as a target to trigger in situ cross-linking of small sized particles to form large sized drug clusters to block the efflux of the brain. Subsequently, responsive cross-linking micelles (RCMs) loaded with the acetylcholinesterase inhibitor, donepezil (DON), the microtubule therapeutic agent, Paclitaxel (PTX), and the glucose metabolism disorder regulator, insulin (INS) are investigated, with a focus on high levels of drug accumulation in the brain in AD. These smart multi-drug delivery RCMs provide a powerful system for AD treatment and can be adapted for other central nervous system (CNS) disorders. Title: In vitro biolayer interferometry analysis of acetylcholinesterase as a potential target of aryl-organophosphorus flame-retardants Shi Q, Guo W, Shen Q, Han J, Lei L, Chen L, Yang L, Feng C, Zhou B Ref: J Hazard Mater, 409:124999, 2020 : PubMed ESTHER: Shi_2020_J.Hazard.Mater_409_124999 PubMedSearch: Shi 2020 J.Hazard.Mater 409 124999 PubMedID: 33454525 Inhibitor(s) related to this paper: TPHP Abstract Organophosphorus flame retardants (OPFRs) have been implicated as neurotoxicants, but their potential neurotoxicity and mechanisms remain poorly understood. Herein, we investigated the neurotoxicity of selected OPFRs using zebrafish as a model organism. Environmentally relevant concentrations (3-1500 nM) of three classes of OPFRs (aryl-OPFRs, chlorinated-OPFRs, and alkyl-OPFRs) were tested in zebrafish larvae (2-144 h post-fertilisation) alongside the neurotoxic chemical chlorpyrifos (CPF) that inhibits acetylcholinesterase (AChE). Exposure to aryl-OPFRs and CPF inhibited AChE activities, while chlorinated- and alkyl-OPFRs did not inhibit these enzymes. Biolayer interferometry (BLI) was used to probe interactions between OPFRs and AChE. The association and dissociation response curves showed that, like CPF, all three selected aryl-OPFRs, triphenyl phosphate (TPHP), tricresyl phosphate (TCP) and cresyl diphenyl phosphate (CDP), bound directly to AChE. The affinity constant (K(D)) for TPHP, TCP, CDP and CPF was 2.18 x 10(-4), 5.47 x 10(-5), 1.05 x 10(-4) and 1.70 x 10(-5) M, respectively. In addition, molecular docking revealed that TPHP, TCP, CDP and CPF bound to AChE with glide scores of - 7.8, - 8.3, - 8.1 and - 7.3, respectively. Furthermore, the calculated binding affinity between OPFRs and AChE correlated well with the K(D) values measured by BLI. The present study revealed that aryl-OPFRs can act as potent AChE inhibitors, and may therefore present a significant ecological risk to aquatic organisms. Title: Molecular Basis for the Biosynthesis of an Unusual Chain-Fused Polyketide Gregatin A Wang WG, Wang H, Du LQ, Li M, Chen L, Yu J, Cheng GG, Zhan MT, Hu QF and Matsuda Y <2 more author(s)> Wang WG, Wang H, Du LQ, Li M, Chen L, Yu J, Cheng GG, Zhan MT, Hu QF, Zhang L, Yao M, Matsuda Y (- 2) Ref: Journal of the American Chemical Society, 142:8464, 2020 : PubMed ESTHER: Wang_2020_J.Am.Chem.Soc_142_8464 PubMedSearch: Wang 2020 J.Am.Chem.Soc 142 8464 PubMedID: 32275405 Gene_locus related to this paper: pensq-GrgF Abstract Gregatin A (1) is a fungal polyketide featuring an alkylated furanone core, but the biosynthetic mechanism to furnish the intri-guing molecular skeleton has yet to be elucidated. Herein, we have identified the biosynthetic gene cluster of gregatin A (1) in Penicillium sp. sh18, and investigated the mechanism that produces the intriguing structure of 1 by in vivo and in vitro recon-stitution of its biosynthesis. Our study established the biosynthetic route leading to 1, and illuminated that 1 is generated by the fusion of two different polyketide chains, which are, amazingly, synthesized by a single PKS GrgA with the aid of a trans-acting enoylreductase GrgB. Chain fusion, as well as chain hydrolysis, is catalyzed by an alpha/beta hydrolase GrgF, hybridizing the C11 and C4 carbon chains by Claisen condensation. Finally, structural analysis and mutational experiments using GrgF provided insight into how the enzyme facilitates the unusual chain-fusing reaction. In unraveling a new biosynthetic strategy involving a bifunc-tional PKS and a polyketide fusing enzyme, our study expands our knowledge concerning fungal polyketide biosynthesis. Title: Discovery of Pyranoviolin A and Its Biosynthetic Gene Cluster in Aspergillus violaceofuscus Wei X, Chen L, Tang JW, Matsuda Y Ref: Front Microbiol, 11:562063, 2020 : PubMed ESTHER: Wei_2020_Front.Microbiol_11_562063 PubMedSearch: Wei 2020 Front.Microbiol 11 562063 PubMedID: 33117309 Gene_locus related to this paper: aspv1-pyvd Abstract A new polyketide-non-ribosomal peptide hybrid molecule, pyranoviolin A (1), was discovered from the genome-sequenced fungus Aspergillus violaceofuscus CBS 115571 and was characterized to be the first pyranonigrin analog harboring the C-3 methoxy group. Examination of the genome sequence of the fungus identified a putative biosynthetic gene cluster of 1, which was designated as the pyv cluster. The gene deletion experiment of the polyketide synthase (PKS)-non-ribosomal peptide synthetase (NRPS) hybrid gene in the cluster confirmed the involvement of the pyv cluster in the pyranoviolin A biosynthesis. Finally, a plausible biosynthetic route leading to 1 has been proposed based on the bioinformatic analysis. Our study indicates that metabolite analysis of genome-sequenced microorganisms whose metabolites have been largely unexplored facilitates the discovery of new secondary metabolites along with their biosynthetic gene clusters. Title: Colonization of Beauveria bassiana 08F04 in root-zone soil and its biocontrol of cereal cyst nematode (Heterodera filipjevi) Zhang J, Fu B, Lin Q, Riley IT, Ding S, Chen L, Cui J, Yang L, Li H Ref: PLoS ONE, 15:e0232770, 2020 : PubMed ESTHER: Zhang_2020_PLoS.One_15_e0232770 PubMedSearch: Zhang 2020 PLoS.One 15 e0232770 PubMedID: 32369513 Abstract Cereal cyst nematodes cause serious yield losses of wheat in Hunaghuai winter wheat growing region in China. Beauveria bassiana 08F04 isolated from the surface of cysts is a promising biological control agent for cereal cyst nematodes. As the colonization capacity is a crucial criteria to assess biocontrol effectiveness for a microbial agent candidate, we aimed to label B. bassiana 08F04 for efficient monitoring of colonization in the soil. The binary pCAM-gfp plasmid containing sgfp and hph was integrated into B. bassiana 08F04 using the Agrobacterium tumefaciens-mediated transformation. The transformation caused a significant change in mycelial and conidial yields, and in extracellular chitinase activity in some transformants. The cultural filtrates of some transformants also decreased acetylcholinesterase activity and the survival of Heterodera filipjevi second-stage juveniles relative to the wild-type strain. One transformant (G10) had a growth rate and biocontrol efficacy similar to the wild-type strain, so it was used for a pilot study of B. bassiana colonization conducted over 13 weeks. Real-time PCR results and CFU counts revealed that the population of G10 increased quickly over the first 3 weeks, then decreased slowly over the following 4 weeks before stabilizing. In addition, the application of wild-type B. bassiana 08F04 and transformant G10 significantly reduced the number of H. filipjevi females in roots by 64.4% and 60.2%, respectively. The results of this study have practical applications for ecological, biological and functional studies of B. bassiana 08F04 and for bionematicide registration. Title: Preventive Effects of Different Fermentation Times of Shuidouchi on Diphenoxylate-Induced Constipation in Mice Chen L, Zhang J, Suo H, Wang W, Wang H, Zhang Y, Hu Q, Zhao X, Li J Ref: Foods, 8:, 2019 : PubMed ESTHER: Chen_2019_Foods_8_ PubMedSearch: Chen 2019 Foods 8 PubMedID: 30832248 Abstract This study compares the prevention effects of Shuidouchi with different fermentation times on constipation in mice. Shuidouchi is a short-time fermented soybean product. By improving its processing technology, it can incur better biological activity and become a health food. The Shuidouchi-treated mice were evaluated using constipation-related kits, quantitative polymerase chain reaction (qPCR), and Western blot assays. After the mice were fed 72-h-fermented Shuidouchi (72-SDC) for 9 d, the defecation time to excrete the first black stool was lower than that of the control and 24-SDC and 48-SDC groups, but was much higher than that of the normal group. The gastrointestinal (GI) transit of the small intestine of the 72-SDC group was higher than that of the control and the 24-SDC and 48-SDC groups, but lower that of the normal group. Meanwhile, 72-SDC could significantly increase the levels of ghrelin, endothelin-1 (ET-1), vasoactive intestinal peptide (VIP), and acetylcholinesterase (AchE) in the serum of constipated mice compared to the levels in mice in the control group. Moreover, 72-SDC could raise c-Kit, stem cell factor (SCF), glial cell-derived neurotrophic factor (GNDF), neuronal nitric oxide synthase (nNOS), and endothelial nitric oxide synthase (eNOS) messenger RNA (mRNA) and protein expression levels, and reduce transient receptor potential cation channel subfamily V member 1 (TRPV1) and inducible nitric oxide synthase (iNOS) expression levels in small-intestinal tissue compared to the levels in the control group. Meanwhile, 72-SDC also raised ghrelin mRNA expression in gastric tissue and transient receptor potential ankyrin 1 (TRPA1) mRNA expression in colon tissue compared to the control group mice; these effects were stronger than those of 24-SDC and 48-SDC. Shuidouchi has good preventative effects on constipation and performs best when fermented for at least 72 h. Title: Fluorescent Triazole Urea Activity-Based Probes for the Single-Cell Phenotypic Characterization of Staphylococcus aureus Chen L, Keller LJ, Cordasco E, Bogyo M, Lentz CS Ref: Angew Chem Int Ed Engl, 58:5643, 2019 : PubMed ESTHER: Chen_2019_Angew.Chem.Int.Ed.Engl_58_5643 PubMedSearch: Chen 2019 Angew.Chem.Int.Ed.Engl 58 5643 PubMedID: 30768830 Inhibitor(s) related to this paper: KT129, KT130 Abstract Phenotypically distinct cellular (sub)populations are clinically relevant for the virulence and antibiotic resistance of a bacterial pathogen, but functionally different cells are usually indistinguishable from each other. Herein, we introduce fluorescent activity-based probes as chemical tools for the single-cell phenotypic characterization of enzyme activity levels in Staphylococcus aureus. We screened a 1,2,3-triazole urea library to identify selective inhibitors of fluorophosphonate-binding serine hydrolases and lipases in S. aureus and synthesized target-selective activity-based probes. Molecular imaging and activity-based protein profiling studies with these probes revealed a dynamic network within this enzyme family involving compensatory regulation of specific family members and exposed single-cell phenotypic heterogeneity. We propose the labeling of enzymatic activities by chemical probes as a generalizable method for the phenotyping of bacterial cells at the population and single-cell level. Title: Effects of Picrasma quassioides and its active constituents on Alzheimer's disease in vitro and in vivo Guo E, Hu Y, Du T, Zhu H, Chen L, Qu W, Zhang J, Xie N, Liu W and Xu J <1 more author(s)> Guo E, Hu Y, Du T, Zhu H, Chen L, Qu W, Zhang J, Xie N, Liu W, Feng F, Xu J (- 1) Ref: Bioorg Chem, 92:103258, 2019 : PubMed ESTHER: Guo_2019_Bioorg.Chem_92_103258 PubMedSearch: Guo 2019 Bioorg.Chem 92 103258 PubMedID: 31520892 Abstract Alzheimer disease (AD), a prevalent neurodegenerative disorder, is one of the leading causes of dementia. However, there is no effective drug for this disease to date. Picrasma quassioides (D.Don) Benn, a Chinese traditional medicine, was used mainly for the treatment of inflammation, fever, microbial infection and dysentery. In this paper, we reported that the EtOAc extract of Picrasma quassioides stems showed potential neuroprotective activities in l-glutamate-stimulated PC12 and Abeta25-35-stimulated SH-SY5Y cell models, as well as improved memory and cognitive abilities in AD mice induced by amyloid-beta peptide. Moreover, it was revealed that the anti-AD mechanism was related to suppressing neuroinflammatory and reducing Abeta1-42 deposition using ELISA assay kits. To clarify the active components of the EtOAc extract of Picrasma quassioides stems, a systematic phytochemistry study led to isolate and identify six beta-carboline alkaloids (1-6), seven canthin-6-one alkaloids (7-13), and five quassinoids (14-18). Among them, four beta-carbolines (1-3, and 6) and six canthin-6-ones (7-11, and 13) exhibited potential neuroprotective activities in vitro. Based on these date, the structure-activity relationships of alkaloids were discussed. Furthermore, molecular docking experiments showed that compounds 2 and 3 have high affinity for both of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYPKIA) and butyrylcholinesterase (BuChE). Title: Single-particle enumeration-based ultrasensitive enzyme activity quantification with fluorescent polymer nanoparticles Han Y, Ye Z, Wang F, Chen T, Wei L, Chen L, Xiao L Ref: Nanoscale, 11:14793, 2019 : PubMed ESTHER: Han_2019_Nanoscale_11_14793 PubMedSearch: Han 2019 Nanoscale 11 14793 PubMedID: 31353389 Abstract Acetylcholinesterase (AChE) plays a vital role in nerve conduction through rapidly hydrolyzing the neurotransmitter acetylcholine (ACh) and is correlated with Alzheimer's disease. In this work, a label-free single-particle enumeration (SPE) method for the quantitative detection of acetylcholinesterase (AChE) activity is developed. The design is based on the fluorescence resonance energy transfer (FRET) between fluorescent conjugated polymer nanoparticles (FCPNPs) and MnO2 nanosheets. The fluorescence of FCPNPs can be effectively quenched by MnO2 nanosheets via hydrogen bonding interaction. In the presence of acetylcholinesterase (AChE), acetylthiocholine (ATCh) could be hydrolyzed to thiocholine (TCh), which can reduce MnO2 to Mn2+ and trigger the decomposition of MnO2 nanosheets. As a result, the fluorescence of FCPNPs is restored. Taking advantage of the superior brightness and stable fluorescence emission from individual FCPNPs, the accurate quantification of AChE is achieved by statistically counting the fluorescent particles on the glass slide surface. A linear range from 5 to 1600 muU mL-1 is obtained for AChE assay and the limit-of-detection (LOD) is 1.02 muU mL-1, which is far below the spectroscopic measurements in bulk solution. In the human serum sample, satisfactory recovery efficiencies are determined in a range of 91.0%-103.0%. Furthermore, pesticide carbaryl as an inhibitor of AChE activity was detected. The LOD is 1.12 pg mL-1 with linear responses ranging from 5 to 300 pg mL-1, which demonstrates the feasibility of this approach for AChE inhibitor screening. As a consequence, the label-free SPE-based method affords a promising platform for the sensitive detection of target molecules in the future. Title: Long noncoding RNA ABHD11-AS1 promote cells proliferation and invasion of colorectal cancer via regulating the miR-1254-WNT11 pathway He D, Yue Z, Liu L, Fang X, Chen L, Han H Ref: Journal of Cellular Physiology, 234:12070, 2019 : PubMed ESTHER: He_2019_J.Cell.Physiol_234_12070 PubMedSearch: He 2019 J.Cell.Physiol 234 12070 PubMedID: 30537177 Gene_locus related to this paper: human-ABHD11 Abstract The purpose of our study was to investigate the effects of the long noncoding RNA (lncRNA) ABHD11-AS1 on colorectal cancer (CRC) progression and further explore its possible underlying mechanisms. In the study, we found that ABHD11-AS1 was highly expressed in CRC tissues and cell lines. High ABHD11-AS1 expression was correlated with poor overall survival of patients with CRC. ABHD11-AS1 knockdown reduced CRC cell proliferation, in vitro invasion, and in vivo tumor growth. Investigation of the underlying mechanism showed that ABHD11-AS1 could act as a molecular sponge of miR-1254, and WNT11 was a downstream target of miR-1254 in CRC. Moreover, there was a negative association between ABHD11-AS1 expression (or WNT11) and miR-1254 in CRC tissues. The rescue assays showed that WNT11 overexpression partially rescued the effects of ABHD11-AS1 inhibition on CRC progression. Thus, we demonstrated that ABHD11-AS1 promotes CRC progression through the miR-1254-WNT11 pathway, which provides a new insight into the therapeutic strategies for CRC. Title: Different construction strategies affected on the physiology of Pichia pastoris strains highly expressed lipase by transcriptional analysis of key genes Huang J, Wang Q, Bu W, Chen L, Yang Z, Zheng W, Li Y, Li J Ref: Bioengineered, 10:150, 2019 : PubMed ESTHER: Huang_2019_Bioengineered_10_150 PubMedSearch: Huang 2019 Bioengineered 10 150 PubMedID: 31079540 Abstract We demonstrated previously that expression of Rhizomucor miehei lipase (RML) in Pichia pastoris could be significantly increased by addition of gene propeptide, optimized signal peptide codons and manipulation of gene dosage. In this study, effects of various strategies on the protein synthesis and secretion pathways were analyzed. Using nine strains previously constructed, we evaluated cell culture properties, enzymatic activities, and analyzed transcriptional levels of nine genes involved in protein synthesis and secretion pathways by qPCR. We observed that (i) Addition of propeptide decreased lipase folding stress by down-regulated four UPR-related genes. (ii) Signal peptide codons optimization had no effect on host with no change in the nine detected genes. (iii) Folding stress and limited transport capacity produced when rml gene dosage exceed 2. Different limiting factors on lipase expression in strains with different construction strategies were identified. This study provides a theoretical basis for further improving RML by transforming host. Title: Distribution characteristics of sweat gland nerve fibres in normal humans identified by acetylcholinesterase histochemical staining Ling L, Liu Y, Sun Y, Cai Y, Jiang Y, Chen L, He L, Xue J Ref: Clin Neurol Neurosurg, 189:105620, 2019 : PubMed ESTHER: Ling_2019_Clin.Neurol.Neurosurg_189_105620 PubMedSearch: Ling 2019 Clin.Neurol.Neurosurg 189 105620 PubMedID: 31812030 Abstract OBJECTIVE: To quantitatively analyze distribution characteristics of sweat gland nerve fibres (SGNF) in normal Chinese individuals for obtaining a reference for early diagnosis of peripheral neuropathy. PATIENTS AND METHODS: Skin biopsy samples were collected from 192 normal Chinese individuals and divided into six, four and two groups according to anatomic sites, age and gender, respectively. SGNF morphology was observed and SGNF density (SGNFD) was determined. RESULTS: There was a significant difference in SGNFD among different anatomic sites, age and gender. A degressive tendency was observed from proximal to distal anatomic sites. SGNFD was the lowest in subjects in the 21-40-year-old age group, but was the highest in subjects in the >61-year-old age group. Overall, SGNFD fluctuated with age. SGNFD in males was significantly higher than that in females. CONCLUSIONS: Distribution characteristics of SGNF in normal individuals may serve as a reference for early diagnosis of nerve fibre damage. Title: Acute exposure to triphenyl phosphate (TPhP) disturbs ocular development and muscular organization in zebrafish larvae Shi Q, Tsui MMP, Hu C, Lam JCW, Zhou B, Chen L Ref: Ecotoxicology & Environmental Safety, 179:119, 2019 : PubMed ESTHER: Shi_2019_Ecotoxicol.Environ.Saf_179_119 PubMedSearch: Shi 2019 Ecotoxicol.Environ.Saf 179 119 PubMedID: 31035246 Inhibitor(s) related to this paper: TPHP Abstract Triphenyl phosphate (TPhP) is an organophosphate flame retardant that is frequently detected in the environments. TPhP exposure is known to cause developmental toxicity. However, the underlying molecular mechanisms remain underestimated. In the present study, zebrafish embryos were acutely exposed to 0, 4 and 100mug/L TPhP until 144h post-fertilization. Profiles of differentially expressed proteins were constructed using a shotgun proteomic. With the input of differential proteins, principal component analysis suggested different protein expression profiles for 4 and 100mug/L TPhP. Gene ontology and KEGG pathway analyses further found that effects of TPhP at 4mug/L targeted phagosome and lysosome activity, while 100mug/L TPhP mainly affected carbohydrate metabolism, muscular contraction and phagosome. Based on proteomic data, diverse bioassays were employed to ascertain the effects of TPhP on specific proteins and pathways. At gene and protein levels, expressions of critical visual proteins were significantly changed by TPhP exposure, including retinoschisin 1a, opsins and crystallins, implying the impairment of ocular development and function. TPhP exposure at 100mug/L also altered the abundances of diverse muscular proteins and disordered the assembly of muscle fibers. Effects of TPhP on visual development and motor activity may be combined to disturb larval swimming behavior. In summary, current results provided mechanistic clues to the developmental toxicities of TPhP. Future works are inspired to broaden the toxicological knowledge of TPhP based on current proteomic results. Title: Central cholinergic neuronal degeneration promotes the development of postoperative cognitive dysfunction Xu H, Chen L, Zhang X, Jiang X, Tian W, Yu W, Wang X, Tian J, Su D Ref: Lab Invest, 99:1078, 2019 : PubMed ESTHER: Xu_2019_Lab.Invest_99_1078 PubMedSearch: Xu 2019 Lab.Invest 99 1078 PubMedID: 30626892 Abstract Postoperative cognitive dysfunction (POCD) is consistently associated with increased morbidity and mortality. However, its mechanism remains poorly understood. We hypothesized that central cholinergic neuronal degeneration facilitates the development of POCD. The impact of anesthesia/surgery (appendectomy) on learning and memory and the levels of choline acetyltransferase (ChAT), acetylcholinesterase (AChE), vesicular acetylcholine transporter (VAChT), and choline transporter (CHT) in adult and aged mice were measured. Separate cohorts were analyzed after pretreatment with donepezil, an AChE inhibitor, in aged mice or with murine-p75-saporin (mu-p75-sap), a cholinergic-specific immunotoxin, in adult mice. Morris Water Maze was used to measure the learning and memory changes after anesthesia/surgery. Western blot was used to measure the changes in the protein levels of the biomarkers of the central cholinergic system. We found that anesthesia/surgery-induced memory decline and attenuation of central cholinergic biomarkers (ChAT and VAChT) in aged mice but not in adult mice. Donepezil pretreatment reduced central cholinergic impairment in the aged mice and prevented learning and memory declines after anesthesia/surgery. In contrast, when central cholinergic neurons were pre-injured with mu-p75-sap, cognitive dysfunction developed in the adult mice after anesthesia/surgery. These data suggest that central cholinergic neuronal degeneration facilitates the development of POCD. Title: Pharmacological Effects of Verticine: Current Status Yin Z, Zhang J, Guo Q, Chen L, Zhang W, Kang W Ref: Evid Based Complement Alternat Med, 2019:2394605, 2019 : PubMed ESTHER: Yin_2019_Evid.Based.Complement.Alternat.Med_2019_2394605 PubMedSearch: Yin 2019 Evid.Based.Complement.Alternat.Med 2019 2394605 PubMedID: 30956677 Abstract Verticine is the major bioactive constituent of Fritillaria as a kind of Traditional Chinese Medicine. Pharmacological researches have reported various benefits of verticine, including anticancer, anti-inflammatory, protecting against acute lung injury, tracheobronchial relaxation, antitussive, expectorant, sedative, and analgesic activities, in addition to inhibiting proliferation of cultured orbital fibroblast, angiotensin converting enzyme (ACE), and acetylcholinesterase (AChE) and inhibiting hERG potassium channels. The underlying mechanisms of verticine are still under investigation. This review will comprehensively summarize the metabolism, biological activities, and possible mechanism of verticine. Title: Bioaccumulation, behavior changes and physiological disruptions with gender-dependent in lizards (Eremias argus) after exposure to glufosinate-ammonium and l-glufosinate-ammonium Zhang L, Chen L, Meng Z, Zhang W, Xu X, Wang Z, Qin Y, Deng Y, Liu R and Diao J <1 more author(s)> Zhang L, Chen L, Meng Z, Zhang W, Xu X, Wang Z, Qin Y, Deng Y, Liu R, Zhou Z, Diao J (- 1) Ref: Chemosphere, 226:817, 2019 : PubMed ESTHER: Zhang_2019_Chemosphere_226_817 PubMedSearch: Zhang 2019 Chemosphere 226 817 PubMedID: 30965253 Abstract Reptiles, the most diverse taxon of terrestrial vertebrates, might be particularly vulnerable to soil pollution. Reptiles especially lizards have been rarely evaluated in ecotoxicological studies, and there is a very limited report for effects of soil pesticide contaminants on lizards. In this study, male and female lizards (Eremias argus) were exposed to Glufosinate-ammonium (GLA) and l- Glufosinate-ammonium (L-GLA) for 60 days. Slower sprint speed, higher frequency of turning back and reduced brain index were observed in treatment groups. The accumulation of GLA in the brain of lizard was higher than that of L-GLA. Moreover, the activities of neurotoxicity-related enzymes and biomarkers of oxidative stress were also investigated. In summary, the neurotoxic effects of lizards have been observed after exposure to GLA and L-GLA. Based on the result of the Integrated Biomarker Response (IBR), males were more sensitive to contaminants than females. On the other hand, the neurotoxic pathways by GLA and L-GLA triggered were slightly different: GLA mainly acted on glutamine synthetase (GS), acetylcholinesterase (AchE) and Catalase (CAT) and L-GLA aimed at AchE, Na(+)/K(+)-ATPase, Superoxide dismutase (SOD) and Malondialdehyde (MDA). In summary, the accumulation of GLA and L-GLA in lizard's brain induced neurotoxicity by altering the levels of enzymes related to nervous system and antioxidant activity and further resulted in the decrease of brain index and locomotor performance. Title: Biodegradation of mycotoxin fumonisin B1 by a novel bacterial consortium SAAS79 Zhao Z, Zhang Y, Gong A, Liu N, Chen S, Zhao X, Li X, Chen L, Zhou C, Wang J Ref: Applied Microbiology & Biotechnology, 103:7129, 2019 : PubMed ESTHER: Zhao_2019_Appl.Microbiol.Biotechnol_103_7129 PubMedSearch: Zhao 2019 Appl.Microbiol.Biotechnol 103 7129 PubMedID: 31230101 Abstract Fumonisin B1 (FB1) contamination in cereals and cereal products remains an important aspect of food safety because of its wide distribution and the potential health hazard. However, only a few microorganisms have been reported to effectively degrade FB1. In this present study, a bacterial consortium SAAS79 with highly FB1-degrading activity was isolated from the spent mushroom compost. The combination of antibiotic-driven selection and 16S rDNA sequencing identified the Pseudomonas genus as the key FB1-degrading member. The microbial consortium could degrade more than 90% of 10 microg/mL FB1 after incubation for 24 h at pH of 5-7 and temperature of 28-35 degreesC. The enzymes from the intracellular space were proved to be responsible for FB1 degradation, which eliminated about 90% of 10 microg/mL FB1 in 3 h. Besides, liquid chromatography time-of-flight mass spectrometry (LC-TOF/MS) analysis identified two degradation products of FB1, and their toxicity on the monkey kidney cells (MARC-145) was significantly lower (p < 0.05) compared with the parent FB1. Overall, the consortium SAAS79 and its crude enzymes may be a potential choice for the decontamination of FB1 in the feed and food industry. Also, the bacterial consortium provides a new source of genes for the development of enzymatic detoxification agent. Title: Synthesis and biological evaluation of calycanthaceous alkaloid analogs Zheng S, Zhu R, Zhou X, Chen L, Bai H, Zhang J Ref: Bioorganic & Medicinal Chemistry, :115088, 2019 : PubMed ESTHER: Zheng_2019_Bioorg.Med.Chem__115088 PubMedSearch: Zheng 2019 Bioorg.Med.Chem 115088 PubMedID: 31521458 Abstract Starting from 9-methyl-1,2,3,4,9,9a-hexahydro-4aH-pyrido[2,3-b]indol-4a-ol, or indole-3-acetonitrile, 40 new calycanthaceous alkaloid analogs were synthesized in excellent yields. The prepared compounds were evaluated for biological activity against acetylcholinesterase and a broad range of plant pathogen fungi. The results of bioassays indicated that the majority of tested compounds displayed comparable or better in vitro bioactivity than the positive control. Notably, compounds b8 and b9 showed higher activity against Verticillium dahlia than chlorothalonil, with MIC values of 62.5 and 7.81microgmL(-1), respectively. Compound b3 had a higher activity against Bacillus cereus, with a MIC value of 15.63microgmL(-1). Compounds c2 and c11 revealed potent activity against acetylcholinesterase, with MIC values of 0.01 and 0.1ngmL(-1), respectively. Analysis of the molecular docking modes of c2 and c11 with Torpedo californica acetylcholinesterase indicated a medium strong hydrogen bond interaction between the hydroxyl groups of both the ligands and the phenolic hydroxyl of Try121 at a distance of approximately 2.4A. The results obtained in this study will be useful for the further design and structural optimization of calycanthaceous alkaloids as potential agrochemical lead compounds for plant disease control. Title: Enfumafungin synthase represents a novel lineage of fungal triterpene cyclases Kuhnert E, Li Y, Lan N, Yue Q, Chen L, Cox RJ, An Z, Yokoyama K, Bills GF Ref: Environ Microbiol, 20:3325, 2018 : PubMed ESTHER: Kuhnert_2018_Environ.Microbiol_20_3325 PubMedSearch: Kuhnert 2018 Environ.Microbiol 20 3325 PubMedID: 30051576 Gene_locus related to this paper: horcr-efuc, horcr-efuk Abstract Enfumafungin is a glycosylated fernene-type triterpenoid produced by the fungus Hormonema carpetanum. Its potent antifungal activity, mediated by its interaction with beta-1,3-glucan synthase and the fungal cell wall, has led to its development into the semi-synthetic clinical candidate, ibrexafungerp (=SCY-078). We report on the preliminary identification of the enfumafungin biosynthetic gene cluster (BGC) based on genome sequencing, phylogenetic reconstruction, gene disruption, and cDNA sequencing studies. Enfumafungin synthase (efuA) consists of a terpene cyclase domain (TC) fused to a glycosyltransferase (GT) domain and thus represents a novel multifunctional enzyme. Moreover, the TC domain bears a phylogenetic relationship to bacterial squalene-hopene cyclases (SHC) and includes a typical DXDD motif within the active centre suggesting that efuA evolved from SHCs. Phylogenetic reconstruction of the GT domain indicated that this portion of the fusion gene originated from fungal sterol GTs. Eleven genes flanking efuA are putatively involved in the biosynthesis, regulation, transport and self-resistance of enfumafungin and include an acetyltransferase, three P450 monooxygenases, a dehydrogenase, a desaturase and a reductase. A hypothetical scheme for enfumafungin assembly is proposed in which the E-ring is oxidatively cleaved to yield the four-ring system of enfumafungin. EfuA represents the first member of a widespread lineage of fungal SHCs. Title: Palmitoylation signaling: a novel mechanism of mitochondria dynamics and diverse pathologies Tang M, Lu L, Huang Z, Chen L Ref: Acta Biochim Biophys Sin (Shanghai), 50:831, 2018 : PubMed ESTHER: Tang_2018_Acta.Biochim.Biophys.Sin.(Shanghai)_50_831 PubMedSearch: Tang 2018 Acta.Biochim.Biophys.Sin.(Shanghai) 50 831 PubMedID: 29924300 Title: Acetylcholinesterase Inhibitor Donepezil Effects on Plasma beta-Hydroxybutyrate Levels in the Treatment of Alzheimer's Disease Wan L, Lu J, Fu J, Huang J, Yang Q, Xin B, Chen L, Huo Y, Zhong Y, Guo C Ref: Curr Alzheimer Res, 15:917, 2018 : PubMed ESTHER: Wan_2018_Curr.Alzheimer.Res_15_917 PubMedSearch: Wan 2018 Curr.Alzheimer.Res 15 917 PubMedID: 29852870 Abstract BACKGROUND: Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by a multi-factorial etiology that is not completely understood. Donepezil is a first-line acetylcholinesterase inhibitor used for the treatment of AD that has been found, in addition to its potent acetylcholinesterase inhibitory effect, to act through other non-cholinergic mechanisms such as affecting mitochondrial biogenesis through peroxisome proliferator-activated receptor gamma coactivator (PGC1alpha). Mitochondrial biogenesis and PGC-1alpha, at least in part, are associated with hepatic fatty acid oxidation and ketogenesis. Whether donepezil regulates ketogenesis in AD treatment remains unclear. Ketogenesis is important in the progression of AD and is a critical consideration during the therapeutic strategy selection for AD. Thus, our goals were to determine the differences in ketone bodies in patients with AD who were taking donepezil treatment and those who were not, to elucidate the potential effect of AD and donepezil therapy on ketone body metabolic parameters, and to discover the effect of donepezil therapy on ketogenesis in patients with AD. METHODS: Cross-sectional analysis was performed on plasma collected from 145 individuals, namely, elderly adults as healthy controls (n=30), newly diagnosed patients with AD (n=30), patients with AD who responded to donepezil therapy (n=48) and patients with AD who did not respond to donepezil therapy (n=37). Gas chromatography-mass spectrometry was performed to quantify the lipids in the plasma. The level of beta-hydroxybutyrate, a metabolite, was determined by liquid chromatographytandem mass spectrometry, and to gain further insight into the effect of donepezil on ketogenesis, the effects of donepezil were investigated in a mouse model. RESULTS: The level of beta-hydroxybutyrate decreased in AD patients, and donepezil elevated the plasma level of beta-hydroxybutyrate. Donepezil increased the plasma and liver levels of beta-hydroxybutyrate in mice as well as the hepatic expression of PGC-1alpha and the mitochondrial expression of HMG-CoA synthetase 2 (HMGCS2) in response to fasting, causing a subsequent increase in ketogenesis. CONCLUSIONS: Our study revealed that impaired ketogenesis is a metabolic feature of AD. Donepezil had effects on ketogenesis in mice and reversed the decrease in the level of beta-hydroxybutyrate found in patients with AD. Title: IMA Genome-F 9: Draft genome sequence of Annulohypoxylon stygium, Aspergillus mulundensis, Berkeleyomyces basicola (syn. Thielaviopsis basicola), Ceratocystis smalleyi, two Cercospora beticola strains, Coleophoma cylindrospora, Fusarium fracticaudum, Phialophora cf. hyalina, and Morchella septimelata Wingfield BD, Bills GF, Dong Y, Huang W, Nel WJ, Swalarsk-Parry BS, Vaghefi N, Wilken PM, An Z and Zhang X <22 more author(s)> Wingfield BD, Bills GF, Dong Y, Huang W, Nel WJ, Swalarsk-Parry BS, Vaghefi N, Wilken PM, An Z, de Beer ZW, De Vos L, Chen L, Duong TA, Gao Y, Hammerbacher A, Kikkert JR, Li Y, Li H, Li K, Li Q, Liu X, Ma X, Naidoo K, Pethybridge SJ, Sun J, Steenkamp ET, van der Nest MA, van Wyk S, Wingfield MJ, Xiong C, Yue Q, Zhang X (- 22) Ref: IMA Fungus, 9:199, 2018 : PubMed ESTHER: Wingfield_2018_IMA.Fungus_9_199 PubMedSearch: Wingfield 2018 IMA.Fungus 9 199 PubMedID: 30018880 Gene_locus related to this paper: 9helo-a0a370tge3, 9helo-a0a3d8spg6, 9euro-a0a3d8t2t6, 9euro-a0a3d8t644, 9helo-a0a370te58, 9helo-a0a370tt42, 9helo-a0a370u2s4, 9helo-a0a3d8s0y2, 9helo-a0a3d8stp9, 9helo-a0a370u370, 9euro-a0a3d8rk78, 9helo-a0a370tat5, 9helo-a0a3d8qpi0 Abstract Draft genomes of the species Annulohypoxylon stygium, Aspergillus mulundensis, Berkeleyomyces basicola (syn. Thielaviopsis basicola), Ceratocystis smalleyi, two Cercospora beticola strains, Coleophoma cylindrospora, Fusarium fracticaudum, Phialophora cf. hyalina and Morchella septimelata are presented. Both mating types (MAT1-1 and MAT1-2) of Cercospora beticola are included. Two strains of Coleophoma cylindrospora that produce sulfated homotyrosine echinocandin variants, FR209602, FR220897 and FR220899 are presented. The sequencing of Aspergillus mulundensis, Coleophoma cylindrospora and Phialophora cf. hyalina has enabled mapping of the gene clusters encoding the chemical diversity from the echinocandin pathways, providing data that reveals the complexity of secondary metabolism in these different species. Overall these genomes provide a valuable resource for understanding the molecular processes underlying pathogenicity (in some cases), biology and toxin production of these economically important fungi. Title: Synthesis and Evaluation of Novel Ligustrazine Derivatives as Multi-Targeted Inhibitors for the Treatment of Alzheimer's Disease Wu W, Liang X, Xie G, Chen L, Liu W, Luo G, Zhang P, Yu L, Zheng X and Yi W <2 more author(s)> Wu W, Liang X, Xie G, Chen L, Liu W, Luo G, Zhang P, Yu L, Zheng X, Ji H, Zhang C, Yi W (- 2) Ref: Molecules, 23:, 2018 : PubMed ESTHER: Wu_2018_Molecules_23_ PubMedSearch: Wu 2018 Molecules 23 PubMedID: 30301153 Abstract A series of novel ligustrazine derivatives 8a(-)r were designed, synthesized, and evaluated as multi-targeted inhibitors for anti-Alzheimer's disease (AD) drug discovery. The results showed that most of them exhibited a potent ability to inhibit both ChEs, with a high selectivity towards AChE. In particular, compounds 8q and 8r had the greatest inhibitory abilities for AChE, with IC50 values of 1.39 and 0.25 nM, respectively, and the highest selectivity towards AChE (for 8q, IC50 BuChE/IC50 AChE = 2.91 x 10(6); for 8r, IC50 BuChE/IC50 AChE = 1.32 x 10(7)). Of note, 8q and 8r also presented potent inhibitory activities against Abeta aggregation, with IC50 values of 17.36 microM and 49.14 microM, respectively. Further cellular experiments demonstrated that the potent compounds 8q and 8r had no obvious cytotoxicity in either HepG2 cells or SH-SY5Y cells, even at a high concentration of 500 muM. Besides, a combined Lineweaver-Burk plot and molecular docking study revealed that these compounds might act as mixed-type inhibitors to exhibit such effects via selectively targeting both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChEs. Taken together, these results suggested that further development of these compounds should be of great interest. Title: Irreversible strigolactone recognition: a non-canonical mechanism for hormone perception Yao R, Chen L, Xie D Ref: Curr Opin Plant Biol, 45:155, 2018 : PubMed ESTHER: Yao_2018_Curr.Opin.Plant.Biol_45_155 PubMedSearch: Yao 2018 Curr.Opin.Plant.Biol 45 155 PubMedID: 30014890 Gene_locus related to this paper: arath-AtD14 Abstract Unveiling of hormone perception is central to comprehending hormone action. It is generally recognized that an active hormone molecule binds its receptor to initiate hormone signaling, subsequently dissociates from its receptor without being changed, and then initiates the next round of hormone perception. However, recent studies discovered that the alpha/beta hydrolase DWARF14 serves as a non-canonical receptor for the plant hormone strigolactone (SL) to generate the active form of SL which remains covalently bound in an irreversible manner, triggering SL signal transduction. In this short review, we will discuss the recent advances in uncovering this unprecedented non-canonical mechanism for hormone perception. Title: Rice DWARF14 acts as an unconventional hormone receptor for strigolactone Yao R, Wang L, Li Y, Chen L, Li S, Du X, Wang B, Yan J, Li J, Xie D Ref: J Exp Bot, 69:2355, 2018 : PubMed ESTHER: Yao_2018_J.Exp.Bot_69_2355 PubMedSearch: Yao 2018 J.Exp.Bot 69 2355 PubMedID: 29365172 Abstract Strigolactones (SLs) act as an important class of phytohormones to regulate plant shoot branching, and also serve as rhizosphere signals to mediate interactions of host plants with soil microbes and parasitic weeds. SL receptors in dicots, such as DWARF14 in Arabidopsis (AtD14), RMS3 in pea, and ShHTL7 in Striga, serve as unconventional receptors that hydrolyze SLs into a D-ring-derived intermediate CLIM and irreversibly bind CLIM to trigger SL signal transduction. Here, we show that D14 from the monocot rice can complement Arabidopsis d14 mutant and interact with the SL signaling components in Arabidopsis. Our results further reveal that rice D14, similar to SL receptors in dicots, also serves as an unconventional hormone receptor that generates and irreversibly binds the active form of SLs. These findings uncover the conserved functions of D14 proteins in monocots and dicots. Title: Detoxification of diphenyl ether herbicide lactofen by Bacillus sp. Za and enantioselective characteristics of an esterase gene lacE Zhang J, Lu L, Chen F, Chen L, Yin J, Huang X Ref: J Hazard Mater, 341:336, 2018 : PubMed ESTHER: Zhang_2018_J.Hazard.Mater_341_336 PubMedSearch: Zhang 2018 J.Hazard.Mater 341 336 PubMedID: 28802244 Gene_locus related to this paper: bacsu-pnbae Abstract A bacterial strain Za capable of degrading diphenyl ether herbicide lactofen was isolated and identified as Bacillus sp. This strain could degrade 94.8% of 50mgL-1 lactofen after 4days of inoculation in flasks. It was revealed that lactofen was initially hydrolyzed to desethyl lactofen, which was further transformed to acifluorfen, followed by the reduction of the nitro group to yield aminoacifluorfen. The phytotoxicity of the transformed product aminoacifluorfen to maize was decreased significantly compared with the lactofen. A gene lacE, encoding an esterase responsible for lactofen hydrolysis to desethyl lactofen and acifluorfen continuously, was cloned from Bacillus sp. Za. The deduced amino acid belonging to the esterase family VII contained a typical Ser-His-Asp/Glu catalytic triad and the conserved motifs GXSXG. The purified recombinant protein LacE displayed maximal esterase activity at 40 degrees C and pH 7.0. Additionally, LacE had broad substrate specificity and was capable of hydrolyzing p-nitrophenyl esters. The enantioselectivity of LacE during lactofen degradation was further studied, and the results indicated that the (S)-(+)-lactofen was degraded faster than the (R)-(-)-lactofen, which could illustrate the reported phenomenon that (S)-(+)-lactofen was preferentially degraded in soil and sediment. Title: Oxoisoaporphine Alkaloids: Prospective Anti-Alzheimer's Disease, Anticancer, and Antidepressant Agents Zhang J, Chen L, Sun J Ref: ChemMedChem, 13:1262, 2018 : PubMed ESTHER: Zhang_2018_ChemMedChem_13_1262 PubMedSearch: Zhang 2018 ChemMedChem 13 1262 PubMedID: 29696800 Abstract Oxoisoaporphine alkaloids are a family of oxoisoquinoline-derived alkaloids that were first isolated from the rhizome of Menispermum dauricum DC. (Menispermaceae). It has been demonstrated that oxoisoaporphine alkaloids possess various biological properties, such as cholinesterase and beta-amyloid inhibition, acting as a topoisomerase intercalator, monoamine oxidase A inhibition, and are expected to become anti-Alzheimer's disease, anticancer, and antidepressant drugs. This review provides an overview of natural sources, synthetic routes, bioactivities, structure-function relationship, and modification investigations into oxoisoaporphine alkaloids, with the aim of providing references to the structure-activity relationships for the design and development of oxoisoaporphine derivatives with higher efficacy and therapeutic potential. Title: Three-dimensional reconstructed eccrine sweat glands with vascularization and cholinergic and adrenergic innervation Zhang M, Li H, Chen L, Fang S, Xie S, Lin C Ref: J Mol Histol, 49:339, 2018 : PubMed ESTHER: Zhang_2018_J.Mol.Histol_49_339 PubMedSearch: Zhang 2018 J.Mol.Histol 49 339 PubMedID: 29667149 Abstract Functional integrity of the regenerated tissues requires not only structural integrity but also vascularization and innervation. We previously demonstrated that the three-dimensional (3D) reconstructed eccrine sweat glands had similar structures as those of the native ones did, but whether the 3D reconstructed glands possessing vascularization and innervation was still unknown. In the study, Matrigel-embedded eccrine sweat gland cells were implanted under the inguinal skin. Ten weeks post-implantation, the vascularization, and innervation in the 10-week reconstructed eccrine sweat glands and native human eccrine sweat glands were detected by immunofluorescence staining. The results showed that the fluorescent signals of general neuronal marker protein gene product 9.5, adrenergic nerve fiber marker tyrosine hydroxylase, and cholinergic nerve fiber markers acetylcholinesterase and vasoactive intestinal peptide embraced the 3D reconstructed glands in circular patterns, as the signals appeared in native eccrine sweat glands. There were many CD31- and von Willebrand factor-positive vessels growing into the plugs. We demonstrated that the 3D reconstructed eccrine sweat glands were nourished by blood vessels, and we for the first time demonstrated that the engineering sweat glands were innervated by both cholinergic and adrenergic fibers. In conclusion, the 3D reconstructed eccrine sweat glands may have functions as the native ones do. Title: Assessment of tissue-specific accumulation, elimination and toxic effects of dichlorodiphenyltrichloroethanes (DDTs) in carp through aquatic food web Di S, Liu R, Tian Z, Cheng C, Chen L, Zhang W, Zhou Z, Diao J Ref: Sci Rep, 7:2288, 2017 : PubMed ESTHER: Di_2017_Sci.Rep_7_2288 PubMedSearch: Di 2017 Sci.Rep 7 2288 PubMedID: 28536421 Abstract Microcosms containing DDT spiked-sediment, Tubifex tubifex and carp (Cyprinus carpio) were constructed to simulate a freshwater system. The accumulation, elimination and toxic effects of DDT (p,p'-DDT, o,p'-DDT), and its metabolites DDD (p,p'-DDD, o,p'-DDD) and DDE (p,p'-DDE, o,p'-DDE) were studied in T. tubifex and carp. Tissue/organ distributions of DDTs were also investigated in carp. The bioaccumulation and elimination of DDT differed in T. tubifex, carp and its tissues/organs. Unimodal or bimodal distributions were observed, and the concentrations of DDT metabolites (DDD and p,p'-DDE) increased over time. The carp organ with the highest concentrations of DDTs (DDT, DDD and DDE) was the gill. The largest mass distribution of DDTs was also in gill, followed by muscle and gastrointestinal tract. Maximum levels of DDTs in whole carp and carp muscle were 161 and 87 ng/g, respectively; therefore, the levels of DDTs observed in carp in this study were insufficient to constitute a health concern if present in fish for human consumption. Significant changes were observed in some biomarkers, including superoxide dismutase, catalase, glutathione-S-transferase, glutathione, and carboxylesterase, in T. tubifex and carp tissues during DDT exposure. Tissue-specific accumulation of DDTs in carp can be a key indicator of exposure to environmentally relevant concentrations. Title: Colorimetric biosensor for the assay of paraoxon in environmental water samples based on the iodine-starch color reaction Guo L, Li Z, Chen H, Wu Y, Chen L, Song Z, Lin T Ref: Anal Chim Acta, 967:59, 2017 : PubMed ESTHER: Guo_2017_Anal.Chim.Acta_967_59 PubMedSearch: Guo 2017 Anal.Chim.Acta 967 59 PubMedID: 28390486 Abstract In this work, a new colorimetric biosensor for the assay of paraoxon was developed via the conventional iodine-starch color reaction and multi-enzyme cascade catalytic reactions. In the presence of acetylcholine chloride, acetylcholinesterase (AChE) and choline oxidase (ChO) catalyzed the formation of H2O2, which then activated horseradish peroxidase (HRP) to catalyze the oxidation of KI to produce an iodine-starch color reaction. Upon exposure to paraoxon, the catalytic activity of AChE was inhibited and less H2O2 generated, resulting in a decrease in the production of I2 and a drop in the intensity of solution color. This colorimetric biosensor showed high sensitivity for the assay of paraoxon with a limit of detection 4.7 ppb and was applied for the assay of paraoxon in spiked real samples. By employing the conventional iodine-starch color reaction, this biosensor has the potential of on-site assay of OPs residues in environmental samples. Title: Endothelial Nox4-based NADPH oxidase regulates atherosclerosis via soluble epoxide hydrolase Hu P, Wu X, Khandelwal AR, Yu W, Xu Z, Chen L, Yang J, Weisbrod RM, Lee KSS and Tong X <4 more author(s)> Hu P, Wu X, Khandelwal AR, Yu W, Xu Z, Chen L, Yang J, Weisbrod RM, Lee KSS, Seta F, Hammock BD, Cohen RA, Zeng C, Tong X (- 4) Ref: Biochimica & Biophysica Acta, 1863:1382, 2017 : PubMed ESTHER: Hu_2017_Biochim.Biophys.Acta_1863_1382 PubMedSearch: Hu 2017 Biochim.Biophys.Acta 1863 1382 PubMedID: 28185955 Abstract Nox4-based NADPH oxidase is a major reactive oxygen species-generating enzyme in the vasculature, but its role in atherosclerosis remains controversial. OBJECTIVE: Our goal was to investigate the mechanisms of endothelial Nox4 in regulating atherosclerosis. APPROACH AND Title: Design, synthesis and biological evaluation of multifunctional tacrine-curcumin hybrids as new cholinesterase inhibitors with metal ions-chelating and neuroprotective property Liu Z, Fang L, Zhang H, Gou S, Chen L Ref: Bioorganic & Medicinal Chemistry, 25:2387, 2017 : PubMed ESTHER: Liu_2017_Bioorg.Med.Chem_25_2387 PubMedSearch: Liu 2017 Bioorg.Med.Chem 25 2387 PubMedID: 28302511 Abstract Total sixteen tacrine-curcumin hybrid compounds were designed and synthesized for the purpose of searching for multifunctional anti-Alzheimer agents. In vitro studies showed that these hybrid compounds showed good cholinesterase inhibitory activity. Particularly, the potency of K3-2 is even beyond tacrine. Some of the compounds exhibited different selectivity on acetylcholinesterase or butyrylcholinesterase due to the structural difference. Thus, the structure and activity relationship is summarized and further discussed based on molecular modeling studies. The ORAC and MTT assays indicated that the hybrid compounds possessed pronounced antioxidant activity and could effectively protect PC12 cells from the H2O2/Abeta42-induced toxicity. Moreover, the hybrid compounds also showed positive metal ions-chelating ability in vitro, suggesting a potential to halt ion-induced Abeta aggregation. All the obtained results demonstrated that the tacrine-curcumin hybrid compounds, in particular compound K3-2, can be considered as potential therapeutic agents for Alzheimer's disease. Title: Inhibition of the high affinity choline transporter enhances hyperalgesia in a rat model of chronic pancreatitis Luo D, Chen L, Yu B Ref: Biochemical & Biophysical Research Communications, 488:204, 2017 : PubMed ESTHER: Luo_2017_Biochem.Biophys.Res.Commun_488_204 PubMedSearch: Luo 2017 Biochem.Biophys.Res.Commun 488 204 PubMedID: 28483526 Abstract BACKGROUND: The mechanisms underlying chronic and persistent pain associated with chronic pancreatitis (CP) are not completely understood. The cholinergic system is one of the major neural pathways of the pancreas. Meanwhile, this system plays an important role in chronic pain. We hypothesized that the high affinity choline transporter CHT1, which is a main determinant of cholinergic signaling capacity, is involved in regulating pain associated with CP. Title: Deleterious Effect of Butyrylcholinesterase K-Variant in Donepezil Treatment of Mild Cognitive Impairment Sokolow S, Li X, Chen L, Taylor KD, Rotter JI, Rissman RA, Aisen PS, Apostolova LG Ref: J Alzheimers Dis, 56:229, 2017 : PubMed ESTHER: Sokolow_2017_J.Alzheimers.Dis_56_229 PubMedSearch: Sokolow 2017 J.Alzheimers.Dis 56 229 PubMedID: 27911294 Abstract BACKGROUND: Donepezil is an acetylcholinesterase inhibitor frequently prescribed for the treatment of mild cognitive impairment (MCI) though not approved by the Food and Drug Administration for this indication. In Alzheimer's disease, butyrylcholinesterase (BChE) activity increases with disease progression and may replace acetylcholinesterase function. The most frequent polymorphism of BChE is the K-variant, which is associated with lower acetylcholine-hydrolyzing activity. BChE-K polymorphism has been studied in Alzheimer's disease progression and donepezil therapy, and has led to contradictory results. OBJECTIVES: To determine whether BChE-K genotype predicts response to donepezil in MCI. Title: Research Advances and Detection Methodologies for Microbe-Derived Acetylcholinesterase Inhibitors: A Systemic Review Su J, Liu H, Guo K, Chen L, Yang M, Chen Q Ref: Molecules, 22:, 2017 : PubMed ESTHER: Su_2017_Molecules_22_ PubMedSearch: Su 2017 Molecules 22 PubMedID: 28125001 Abstract Acetylcholinesterase inhibitors (AChEIs) are an attractive research subject owing to their potential applications in the treatment of neurodegenerative diseases. Fungi and bacteria are major producers of AChEIs. Their active ingredients of fermentation products include alkaloids, terpenoids, phenylpropanoids, and steroids. A variety of in vitro acetylcholinesterase inhibitor assays have been developed and used to measure the activity of acetylcholinesterases, including modified Ellman's method, thin layer chromatography bioautography, and the combined liquid chromatography-mass spectrometry/modified Ellman's method. In this review, we provide an overview of the different detection methodologies, the microbe-derived AChEIs, and their producing strains. Title: Study of acetylcholinesterase activity and apoptosis in SH-SY5Y cells and mice exposed to ethanol Sun W, Chen L, Zheng W, Wei X, Wu W, Duysen EG, Jiang W Ref: Toxicology, 384:33, 2017 : PubMed ESTHER: Sun_2017_Toxicology_384_33 PubMedSearch: Sun 2017 Toxicology 384 33 PubMedID: 28427893 Abstract Ethanol is one of the most commonly abused psychotropic substances with deleterious effects on the central nervous system. Ethanol exposure during development results in the loss of neurons in brain regions and when exposed to ethanol cultured cells undergo apoptosis. To date no information is available on whether abnormally high AChE activity is characteristic of apoptosis in animals exposed to ethanol. The aims of the present study were to determine whether induction of AChE activity is associated with ethanol-induced apoptosis and to explore the mechanism of enhanced AChE activity induced by ethanol. For this purpose, in vitro and in vivo experiments were performed. AChE activity was quantified by spectrophotometry and apoptosis by flow cytometer in SH-SY5Y cells exposed to ethanol. The results showed that cells treated with 500mM ethanol for 24h had a 9-fold increase in apoptotic cells and a 6-fold increase in AChE activity compared with controls. Mice exposed acutely to 200mul of 20% ethanol daily on days 1-4 had elevated AChE activity in plasma on days 3-7. On day 4, plasma AChE activity was 2.4-fold higher than pretreatment activity. More apoptotic cells were found in the brains of treated mice compared to controls. Cells in brain sections that were positive in the TUNEL assay stained for AChE activity. In conclusion, AChE activity and apoptosis were induced in SH-SY5Y cells and mice treated with ethanol, which may indicate that increased AChE may related to apoptosis induced by ethanol. Unusually high AChE activity may be an effect marker of exposure to ethanol. The relationship between AChE and apoptosis might represent a novel mechanism of ethanol-associated neuronal injury. Title: Chemical Composition and Acetylcholinesterase Inhibitory Activity of Essential Oils from Piper Species Xiang CP, Han JX, Li XC, Li YH, Zhang Y, Chen L, Qu Y, Hao CY, Li HZ and Xu M <2 more author(s)> Xiang CP, Han JX, Li XC, Li YH, Zhang Y, Chen L, Qu Y, Hao CY, Li HZ, Yang CR, Zhao SJ, Xu M (- 2) Ref: Journal of Agricultural and Food Chemistry, 65:3702, 2017 : PubMed ESTHER: Xiang_2017_J.Agric.Food.Chem_65_3702 PubMedSearch: Xiang 2017 J.Agric.Food.Chem 65 3702 PubMedID: 28436658 Abstract The essential oils (EOs) derived from aromatic plants such as Piper species are considered to play a role in alleviating neuronal ailments that are associated with inhibition of acetylcholinesterase (AChE). The chemical compositions of 23 EOs prepared from 16 Piper spp. were analyzed by both gas chromatography with a flame ionization detector (GC-FID) and gas chromatography-mass spectrometry (GC-MS). A total of 76 compounds were identified in the EOs from the leaves and stems of 19 samples, while 30 compounds were detected in the EOs from the fruits of four samples. Sesquiterpenes and phenylpropanoids were found to be rich in these EOs, of which asaricin, caryophyllene, caryophyllene oxide, isospathulenol, (+)-spathulenol, and beta-bisabolene are the major constituents. The EOs from the leaves and stems of Piper austrosinense, P. puberulum, P. flaviflorum, P. betle, and P. hispidimervium showed strong AChE inhibitory activity with IC50 values in the range of 1.51 to 13.9 mg/mL. A thin-layer chromatography (TLC) bioautography assay was employed to identify active compound(s) in the most active EO from P. hispidimervium. The active compound was isolated and identified as asaricin, which gave an IC50 value of 0.44 +/- 0.02 mg/mL against AChE, comparable to galantamine with an IC50 0.15 +/- 0.01 mg/mL. Title: ShHTL7 is a non-canonical receptor for strigolactones in root parasitic weeds Yao R, Wang F, Ming Z, Du X, Chen L, Wang Y, Zhang W, Deng H, Xie D Ref: Cell Res, 27:838, 2017 : PubMed ESTHER: Yao_2017_Cell.Res_27_838 PubMedSearch: Yao 2017 Cell.Res 27 838 PubMedID: 28059066 Gene_locus related to this paper: strhe-ShHTL7 Title: Association between L55M polymorphism in Paraoxonase 1 and cancer risk: a meta-analysis based on 21 studies Chen L, Lu W, Fang L, Xiong H, Wu X, Zhang M, Wu S, Yu D Ref: Onco Targets Ther, 9:1151, 2016 : PubMed ESTHER: Chen_2016_Onco.Targets.Ther_9_1151 PubMedSearch: Chen 2016 Onco.Targets.Ther 9 1151 PubMedID: 27019599 Abstract L55M polymorphism in Paraoxonase 1 (PON1) has been regarded as a risk factor for many cancer types. Nevertheless, the results remain controversial and inconclusive. We therefore performed a meta-analysis of all eligible case-control studies to evaluate the association between L55M polymorphism and cancer risk. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the associations. Finally, a total of 5,627 cases and 6,390 controls, arising from 21 case-control studies, were enrolled in our study. Significant associations between PON1-L55M polymorphism and overall cancer risk were identified in all genetic models. In the stratified analyses by cancer type, PON1-L55M polymorphism was a risk factor for breast cancer in all genetic models, prostate cancer in the heterozygote model (ML vs LL: OR =1.304, 95% CI =1.049-1.620, P heterogeneity=0.067), and ovarian cancer in the recessive model (MM vs ML/LL: OR =1.526, 95% CI =1.110-2.097, P heterogeneity=0.464). Similarly, an increased risk was also identified for the Caucasian population in the heterozygote comparison and homozygote models, and hospital-based controls in all genetic models. To sum up, our study suggests that the PON1-L55M allele increased the risk of cancer. Future well-designed studies with larger sample sizes are warranted to further verify these findings. Title: Engineering of New Pneumocandin Side-Chain Analogues from Glarea lozoyensis by Mutasynthesis and Evaluation of Their Antifungal Activity Chen L, Li Y, Yue Q, Loksztejn A, Yokoyama K, Felix EA, Liu X, Zhang N, An Z, Bills GF Ref: ACS Chemical Biology, 11:2724, 2016 : PubMed ESTHER: Chen_2016_ACS.Chem.Biol_11_2724 PubMedSearch: Chen 2016 ACS.Chem.Biol 11 2724 PubMedID: 27494047 Gene_locus related to this paper: glal2-glon Abstract Pneumocandins are lipohexapeptides of the echinocandin family that inhibit fungal 1,3-beta-glucan synthase. Most of the pathway steps have been identified previously. However, the lipoinitiation reaction has not yet been experimentally verified. Herein, we investigate the lipoinitiation step of pneumocandin biosynthesis in Glarea lozoyensis and demonstrate that the gene product, GLligase, catalyzes this step. Disruption of GLHYD, a gene encoding a putative type II thioesterase and sitting upstream of the pneumocandin acyl side chain synthase gene, GLPKS4, revealed that GLHYD was necessary for optimal function of GLPKS4 and to attain normal levels of pneumocandin production. Double disruption of GLHYD and GLPKS4 did not affect residual function of the GLligase or GLNRPS4. Mutasynthesis experiments with a gene disruption mutant of GLPKS4 afforded us an opportunity to test the substrate specificity of GLligase in the absence of its native polyketide side chain to diversify pneumocandins with substituted side chains. Feeding alternative side chain precursors yielded acrophiarin and four new pneumocandin congeners with straight C14, C15, and C16 side chains. A comprehensive biological evaluation showed that one compound, pneumocandin I (5), has elevated antifungal activity and similar hemolytic activity compared to pneumocandin B(0), the starting molecule for caspofungin. This study demonstrates that the lipoinitiation mechanism in pneumocandin biosynthesis involves interaction among a highly reducing PKS, a putative type II thioesterase, and an acyl AMP-ligase. A comparison of the SAR among pneumocandins with different-length acyl side chains demonstrated the potential for using GLligase for future engineering of new echinocandin analogues. Title: A Three-Dimensional Origami Paper-Based Device for Potentiometric Biosensing Ding J, Li B, Chen L, Qin W Ref: Angew Chem Int Ed Engl, 55:13033, 2016 : PubMed ESTHER: Ding_2016_Angew.Chem.Int.Ed.Engl_55_13033 PubMedSearch: Ding 2016 Angew.Chem.Int.Ed.Engl 55 13033 PubMedID: 27634584 Abstract Current paper-based potentiometric ion-sensing platforms are planar devices used for clinically relevant ions. These devices, however, have not been designed for the potentiometric biosensing of proteins or small molecule analytes. A three-dimensional origami paper-based device, in which a solid-contact ion-selective electrode is integrated with an all-solid-state reference electrode, is described for the first time. The device is made by impregnation of paper with appropriate bioreceptors and reporting reagents on different zones. By folding and unfolding the paper structures, versatile potentiometric bioassays can be performed. A USB-controlled miniaturized electrochemical detector can be used for simple and in situ measurements. Using butyrylcholinesterase as a model enzyme, the device has been successfully applied to the detection of enzyme activities and organophosphate pesticides involved in the enzymatic system as inhibitors. The proposed 3D origami paper device allows the potentiometric biosensing of proteins and small molecules in a simple, portable, and cost-effective way. Title: Ferulic acid-carbazole hybrid compounds: Combination of cholinesterase inhibition, antioxidant and neuroprotection as multifunctional anti-Alzheimer agents Fang L, Chen M, Liu Z, Fang X, Gou S, Chen L Ref: Bioorganic & Medicinal Chemistry, 24:886, 2016 : PubMed ESTHER: Fang_2016_Bioorg.Med.Chem_24_886 PubMedSearch: Fang 2016 Bioorg.Med.Chem 24 886 PubMedID: 26795115 Abstract In order to search for novel multifunctional anti-Alzheimer agents, a series of ferulic acid-carbazole hybrid compounds were designed and synthesized. Ellman's assay revealed that the hybrid compounds showed moderate to potent inhibitory activity against the cholinesterases. Particularly, the AChE inhibition potency of compound 5k (IC50 1.9muM) was even 5-fold higher than that of galantamine. In addition, the target compounds showed pronounced antioxidant ability and neuroprotective property, especially against the ROS-induced toxicity. Notably, the neuroprotective effect of 5k was obviously superior to that of the mixture of ferulic acid and carbazole, indicating the therapeutic effect of the hybrid compound is better than the combination administration of the corresponding mixture. Title: Neuroligin-1 Knockdown Suppresses Seizure Activity by Regulating Neuronal Hyperexcitability Fang M, Wei JL, Tang B, Liu J, Chen L, Tang ZH, Luo J, Chen GJ, Wang XF Ref: Molecular Neurobiology, 53:270, 2016 : PubMed ESTHER: Fang_2016_Mol.Neurobiol_53_270 PubMedSearch: Fang 2016 Mol.Neurobiol 53 270 PubMedID: 25428619 Abstract Abnormally synchronized synaptic transmission in the brain leads to epilepsy. Neuroligin-1 (NL1) is a synaptic cell adhesion molecule localized at excitatory synapses. NL1 modulates synaptic transmission and determines the properties of neuronal networks in the mammalian central nervous system. We showed that the expression of NL1 and its binding partner neurexin-1beta was increased in temporal lobe epileptic foci in patients and lithium-pilocarpine-treated epileptic rats. We investigated electrophysiological and behavioral changes in epileptic rats after lentivirally mediated NL1 knockdown in the hippocampus to determine whether NL1 suppression prevented seizures and, if so, to explore the probable underlying mechanisms. Our behavioral studies revealed that NL1 knockdown in epileptic rats reduced seizure severity and increased seizure latency. Whole-cell patch-clamp recordings of CA1 pyramidal neurons in hippocampal slices from NL1 knockdown epileptic rats revealed a decrease in spontaneous action potential frequency and a decrease in miniature excitatory postsynaptic current (mEPSC) frequency but not amplitude. The amplitude of N-methyl-D-aspartate receptor (NMDAR)-dependent EPSCs was also selectively decreased. Notably, NL1 knockdown reduced total NMDAR1 expression and the surface/total ratio in the hippocampus of epileptic rats. Taken together, these data indicate that NL1 knockdown in epileptic rats may reduce the frequency and severity of seizures and suppress neuronal hyperexcitability via changes in postsynaptic NMDARs. Title: A novel esterase from a marine mud metagenomic library for biocatalytic synthesis of short-chain flavor esters Gao W, Wu K, Chen L, Fan H, Zhao Z, Gao B, Wang H, Wei D Ref: Microb Cell Fact, 15:41, 2016 : PubMed ESTHER: Gao_2016_Microb.Cell.Fact_15_41 PubMedSearch: Gao 2016 Microb.Cell.Fact 15 41 PubMedID: 26892801 Abstract BACKGROUND: Marine mud is an abundant and largely unexplored source of enzymes with unique properties that may be useful for industrial and biotechnological purposes. However, since most microbes cannot be cultured in the laboratory, a cultivation-independent metagenomic approach would be advantageous for the identification of novel enzymes. Therefore, with the objective of screening novel lipolytic enzymes, a metagenomic library was constructed using the total genomic DNA extracted from marine mud. Title: The Pseudomonas aeruginosa Type VI Secretion PGAP1-like Effector Induces Host Autophagy by Activating Endoplasmic Reticulum Stress Jiang F, Wang X, Wang B, Chen L, Zhao Z, Waterfield NR, Yang G, Jin Q Ref: Cell Rep, 16:1502, 2016 : PubMed ESTHER: Jiang_2016_Cell.Rep_16_1502 PubMedSearch: Jiang 2016 Cell.Rep 16 1502 PubMedID: 27477276 Gene_locus related to this paper: pseae-PA1510 Abstract Pseudomonas aeruginosa is an opportunistic pathogen that regularly causes nosocomial infections in hospitalized patients. The type VI secretion system (T6SS) is responsible for the secretion of numerous virulence effector proteins that can both interfere with competing microbes and manipulate host cells.sHere, we report a detailed investigation of a P.saeruginosa H2-T6SS-dependent phospholipase effector, TplE, which acts as a trans-kingdom toxin. Delivery of TplE to the periplasmic space of rival bacteria leads to growth inhibition. Importantly, TplE, also contains a eukaryotic PGAP1-like domain, which targets the host ER apparatus, ultimately leading to disruption of the ER. TplE activity leads to the activation of the unfolded protein response (UPR) through the IRE1alpha-XBP1 pathway, enhancing autophagic flux. These findings indicate that this T6SS-delivered phospholipase effector is active against both prokaryotic and eukaryotic cellular targets, highlighting the T6SS as a versatile weapon in the Pseudomonas arsenal. Title: DWARF14 is a non-canonical hormone receptor for strigolactone Yao R, Ming Z, Yan L, Li S, Wang F, Ma S, Yu C, Yang M, Chen L and Xie D <15 more author(s)> Yao R, Ming Z, Yan L, Li S, Wang F, Ma S, Yu C, Yang M, Chen L, Li Y, Yan C, Miao D, Sun Z, Yan J, Sun Y, Wang L, Chu J, Fan S, He W, Deng H, Nan F, Li J, Rao Z, Lou Z, Xie D (- 15) Ref: Nature, 536:469, 2016 : PubMed ESTHER: Yao_2016_Nature_536_469 PubMedSearch: Yao 2016 Nature 536 469 PubMedID: 27479325 Gene_locus related to this paper: arath-AtD14 Abstract Classical hormone receptors reversibly and non-covalently bind active hormone molecules, which are generated by biosynthetic enzymes, to trigger signal transduction. The alpha/beta hydrolase DWARF14 (D14), which hydrolyses the plant branching hormone strigolactone and interacts with the F-box protein D3/MAX2, is probably involved in strigolactone detection. However, the active form of strigolactone has yet to be identified and it is unclear which protein directly binds the active form of strigolactone, and in which manner, to act as the genuine strigolactone receptor. Here we report the crystal structure of the strigolactone-induced AtD14-D3-ASK1 complex, reveal that Arabidopsis thaliana (At)D14 undergoes an open-to-closed state transition to trigger strigolactone signalling, and demonstrate that strigolactone is hydrolysed into a covalently linked intermediate molecule (CLIM) to initiate a conformational change of AtD14 to facilitate interaction with D3. Notably, analyses of a highly branched Arabidopsis mutant d14-5 show that the AtD14(G158E) mutant maintains enzyme activity to hydrolyse strigolactone, but fails to efficiently interact with D3/MAX2 and loses the ability to act as a receptor that triggers strigolactone signalling in planta. These findings uncover a mechanism underlying the allosteric activation of AtD14 by strigolactone hydrolysis into CLIM, and define AtD14 as a non-canonical hormone receptor with dual functions to generate and sense the active form of strigolactone. Title: Simultaneous bioremediation and biodetection of mercury ion through surface display of carboxylesterase E2 from Pseudomonas aeruginosa PA1 Yin K, Lv M, Wang Q, Wu Y, Liao C, Zhang W, Chen L Ref: Water Res, 103:383, 2016 : PubMed ESTHER: Yin_2016_Water.Res_103_383 PubMedSearch: Yin 2016 Water.Res 103 383 PubMedID: 27486950 Abstract Mercury is a toxic heavy metal and presents significant threats to organisms and natural ecosystems. Recently, the mercury remediation as well as its detection by environmental-friendly biotechnology has received increasing attention. In this study, carboxylesterase E2 from mercury-resistant strain Pseudomonas aeruginosa PA1 has been successfully displayed on the outer membrane of Escherichia coli Top10 bacteria to simultaneously adsorb and detect mercury ion (Hg2+). The transmission electron microscopy analysis shows that Hg2+ can be absorbed by carboxylesterase E2 and accumulated on the outer membrane of surface-displayed E. coli bacteria. The adsorption of Hg2+ followed a physicochemical, equilibrated and saturatable mechanism, which well fits the traditional Langmuir adsorption model. The surface-displayed system can be regenerated through regulating pH values. As its activity can be inhibited by Hg2+, carboxylesterase E2 has been used to detect the concentration of Hg2+ in water samples. The developed surface display system will be of great potential in the simultaneous bioremediation and biodetection of environmental mercury pollution. Title: Novel Tacrine-Benzofuran Hybrids as Potent Multitarget-Directed Ligands for the Treatment of Alzheimer's Disease: Design, Synthesis, Biological Evaluation, and X-ray Crystallography Zha X, Lamba D, Zhang L, Lou Y, Xu C, Kang D, Chen L, Xu Y, De Simone A and Bartolini M <6 more author(s)> Zha X, Lamba D, Zhang L, Lou Y, Xu C, Kang D, Chen L, Xu Y, De Simone A, Samez S, Pesaresi A, Stojan J, Lopez MG, Egea J, Andrisano V, Bartolini M (- 6) Ref: Journal of Medicinal Chemistry, 59:114, 2016 : PubMed ESTHER: Zha_2016_J.Med.Chem_59_114 PubMedSearch: Zha 2016 J.Med.Chem 59 114 PubMedID: 26632651 Gene_locus related to this paper: torca-ACHE Inhibitor(s) related to this paper: Tacrine-Benzofuran Abstract Twenty-six new tacrine-benzofuran hybrids were designed, synthesized, and evaluated in vitro on key molecular targets for Alzheimer's disease. Most hybrids exhibited good inhibitory activities on cholinesterases and beta-amyloid self-aggregation. Selected compounds displayed significant inhibition of human beta-secretase-1 (hBACE-1). Among the 26 hybrids, 2e showed the most interesting profile as a subnanomolar selective inhibitor of human acetylcholinesterase (hAChE) (IC50 = 0.86 nM) and a good inhibitor of both beta-amyloid aggregation (hAChE- and self-induced, 61.3% and 58.4%, respectively) and hBACE-1 activity (IC50 = 1.35 muM). Kinetic studies showed that 2e acted as a slow, tight-binding, mixed-type inhibitor, while X-ray crystallographic studies highlighted the ability of 2e to induce large-scale structural changes in the active-site gorge of Torpedo californica AChE (TcAChE), with significant implications for structure-based drug design. In vivo studies confirmed that 2e significantly ameliorates performances of scopolamine-treated ICR mice. Finally, 2e administration did not exhibit significant hepatotoxicity. Title: Identification and Characterization of Lipase Activity and Immunogenicity of LipL from Mycobacterium tuberculosis Cao J, Dang G, Li H, Li T, Yue Z, Li N, Liu Y, Liu S, Chen L Ref: PLoS ONE, 10:e0138151, 2015 : PubMed ESTHER: Cao_2015_PLoS.One_10_e0138151 PubMedSearch: Cao 2015 PLoS.One 10 e0138151 PubMedID: 26398213 Abstract Lipids and lipid-metabolizing esterases/lipases are highly important for the mycobacterial life cycle and, possibly, for mycobacterial virulence. In this study, we expressed 10 members of the Lip family of Mycobacterium tuberculosis. Among the 10 proteins, LipL displayed a significantly high enzymatic activity for the hydrolysis of long-chain lipids. The optimal temperature for the lipase activity of LipL was demonstrated to be 37 degrees C, and the optimal pH was 8.0. The lipase active center was not the conserved motif G-x-S-x-G, but rather the S-x-x-K and GGG motifs, and the key catalytic amino acid residues were identified as G50, S88, and K91, as demonstrated through site-directed mutagenesis experiments. A three-dimensional modeling structure of LipL was constructed, which showed that the GGG motif was located in the surface of a pocket structure. Furthermore, the subcellular localization of LipL was demonstrated to be on the mycobacterial surface by Western blot analysis. Our results revealed that the LipL protein could induce a strong humoral immune response in humans and activate a CD8+ T cell-mediated response in mice. Overall, our study identified and characterized a novel lipase denoted LipL from M. tuberculosis, and demonstrated that LipL functions as an immunogen that activates both humoral and cell-mediated responses. Title: Bioactivities of phytochemicals in Araiostegia yunnanensis (Christ) Chen L, Xu W, Shao R, Du X Ref: Food Chem, 186:37, 2015 : PubMed ESTHER: Chen_2015_Food.Chem_186_37 PubMedSearch: Chen 2015 Food.Chem 186 37 PubMedID: 25976789 Abstract The profile and bioactivity of phytochemicals in Araiostegia yunnanensis (Christ) Cop were investigated. The total flavonoids content in A. yunnanensis is about 84.90mg/g. By means of HPLC-DAD-ESI-MS, the main flavonoids in A. yunnanensis were tentatively identified as myricetin 3-O-rhamnosylglucoside, eriodictyol 7-O-rutinoside, quercetin 3-O-rutinoside, luteolin-7-O-apiosylglucoside, quercetin 3-O-rhamnosylgalactoside, and luteolin 7-O-glucoside. The extract (0.268mg/ml total flavonoids) from A. yunnanensis showed very strong superoxide anion radical scavenging potential and reducing power, which are higher than those of rutin (0.25mg/ml). The extract (0.268mg/ml total flavonoids) from A. yunnanensis exhibited similar DPPH scavenging activity with rutin (0.25mg/ml). However, rutin (0.25mg/ml) showed a significantly higher ABTS radical scavenging effect than that of the extract (0.268mg/ml total flavonoids) from A. yunnanensis. The methanol extract from A. yunnanensis showed obviously cytotoxic effects on A549 cells and it had no effect against acetylcholinesterase. Title: Disruption of the Arabidopsis Defense Regulator Genes SAG101, EDS1, and PAD4 Confers Enhanced Freezing Tolerance Chen QF, Xu L, Tan WJ, Chen L, Qi H, Xie LJ, Chen MX, Liu BY, Yu LJ and Xiao S <3 more author(s)> Chen QF, Xu L, Tan WJ, Chen L, Qi H, Xie LJ, Chen MX, Liu BY, Yu LJ, Yao N, Zhang JH, Shu W, Xiao S (- 3) Ref: Mol Plant, 8:1536, 2015 : PubMed ESTHER: Chen_2015_Mol.Plant_8_1536 PubMedSearch: Chen 2015 Mol.Plant 8 1536 PubMedID: 26149542 Abstract In Arabidopsis, three lipase-like regulators, SAG101, EDS1, and PAD4, act downstream of resistance protein-associated defense signaling. Although the roles of SAG101, EDS1, and PAD4 in biotic stress have been extensively studied, little is known about their functions in plant responses to abiotic stresses. Here, we show that SAG101, EDS1, and PAD4 are involved in the regulation of freezing tolerance in Arabidopsis. With or without cold acclimation, the sag101, eds1, and pad4 single mutants, as well as their double mutants, exhibited similarly enhanced tolerance to freezing temperatures. Upon cold exposure, the sag101, eds1, and pad4 mutants showed increased transcript levels of C-REPEAT/DRE BINDING FACTORs and their regulons compared with the wild type. Moreover, freezing-induced cell death and accumulation of hydrogen peroxide were ameliorated in sag101, eds1, and pad4 mutants. The sag101, eds1, and pad4 mutants had much lower salicylic acid (SA) and diacylglycerol (DAG) contents than the wild type, and exogenous application of SA and DAG compromised the freezing tolerance of the mutants. Furthermore, SA suppressed the cold-induced expression of DGATs and DGKs in the wild-type leaves. These findings indicate that SAG101, EDS1, and PAD4 are involved in the freezing response in Arabidopsis, at least in part, by modulating the homeostasis of SA and DAG. Title: Engineering of Glarea lozoyensis for exclusive production of the pneumocandin B0 precursor of the antifungal drug caspofungin acetate Chen L, Yue Q, Li Y, Niu X, Xiang M, Wang W, Bills GF, Liu X, An Z Ref: Applied Environmental Microbiology, 81:1550, 2015 : PubMed ESTHER: Chen_2015_Appl.Environ.Microbiol_81_1550 PubMedSearch: Chen 2015 Appl.Environ.Microbiol 81 1550 PubMedID: 25527531 Gene_locus related to this paper: glal2-glon Abstract Pneumocandins produced by the fungus Glarea lozoyensis are acylated cyclic hexapeptides of the echinocandin family. Pneumocandin B0 is the starting molecule for the first semisynthetic echinocandin antifungal drug, caspofungin acetate. In the wild-type strain, pneumocandin B0 is a minor fermentation product, and its industrial production was achieved by a combination of extensive mutation and medium optimization. The pneumocandin biosynthetic gene cluster was previously elucidated by a whole-genome sequencing approach. Knowledge of the biosynthetic cluster suggested an alternative way to produce exclusively pneumocandin B0. Disruption of GLOXY4, encoding a nonheme, alpha-ketoglutarate-dependent oxygenase, confirmed its involvement in l-leucine cyclization to form 4S-methyl-l-proline. The absence of 4S-methyl-l-proline abolishes pneumocandin A0 production, and 3S-hydroxyl-l-proline occupies the hexapeptide core's position 6, resulting in exclusive production of pneumocandin B0. Retrospective analysis of the GLOXY4 gene in a previously isolated pneumocandin B0-exclusive mutant (ATCC 74030) indicated that chemical mutagenesis disrupted the GLOXY4 gene function by introducing two amino acid mutations in GLOXY4. This one-step genetic manipulation can rationally engineer a high-yield production strain. Title: (-)-Meptazinol-melatonin hybrids as novel dual inhibitors of cholinesterases and amyloid-beta aggregation with high antioxidant potency for Alzheimer's therapy Cheng S, Zheng W, Gong P, Zhou Q, Xie Q, Yu L, Zhang P, Chen L, Li J and Chen H <1 more author(s)> Cheng S, Zheng W, Gong P, Zhou Q, Xie Q, Yu L, Zhang P, Chen L, Li J, Chen J, Chen H (- 1) Ref: Bioorganic & Medicinal Chemistry, 23:3110, 2015 : PubMed ESTHER: Cheng_2015_Bioorg.Med.Chem_23_3110 PubMedSearch: Cheng 2015 Bioorg.Med.Chem 23 3110 PubMedID: 26025073 Abstract The multifactorial pathogenesis of Alzheimer's disease (AD) implicates that multi-target-directed ligands (MTDLs) intervention may represent a promising therapy for AD. Amyloid-beta (Abeta) aggregation and oxidative stress, two prominent neuropathological hallmarks in patients, play crucial roles in the neurotoxic cascade of this disease. In the present study, a series of novel (-)-meptazinol-melatonin hybrids were designed, synthesized and biologically characterized as potential MTDLs against AD. Among them, hybrids 7-7c displayed higher dual inhibitory potency toward cholinesterases (ChEs) and better oxygen radical absorbance capacity (ORAC) than the parental drugs. Furthermore, compound 7c could effectively inhibit Abeta self-aggregation, showed favorable safety and the blood-brain barrier (BBB) permeability. Therefore, 7c may serve as a valuable candidate that is worthy of further investigations in the treatment of AD. Title: Expression, Purification and Characterisation of Secreted Esterase Rv2525c from Mycobacterium tuberculosis Dang G, Chen L, Li Z, Deng X, Cui Y, Cao J, Yu S, Pang H, Liu S Ref: Appl Biochem Biotechnol, 176:1, 2015 : PubMed ESTHER: Dang_2015_Appl.Biochem.Biotechnol_176_1 PubMedSearch: Dang 2015 Appl.Biochem.Biotechnol 176 1 PubMedID: 25869294 Abstract Rv2525c from Mycobacterium tuberculosis belongs to the domain of unknown function (DUF) 1906 superfamily, but it also contains the motif G-X-S-X-G, the consensus active site sequence of the ester/lipid family. Biochemical analysis indicated that the mature Rv2525c protein is secreted. The discovery and characterisation of novel enzymes secreted by M. tuberculosis are vital for understanding the pathogenesis of the most important human bacterial pathogen. The proteome of M. tuberculosis contains over 400 potentially secreted proteins, of which the majority remain uncharacterised. In this study, we cloned and expressed the rv2525c gene in Escherichia coli and purified the recombinant protein using a three-step process (affinity chromatography, ion exchange chromatography, gel filtration chromatography), obtaining more than 99% pure protein. Mass spectrometry was performed to confirm that the purified protein was Rv2525c. Circular dichroism spectroscopy results showed that its conformation was stable at pH ranging from 6.0 to 8.0 and at temperatures <= 40 degrees C. Moreover, we tested the esterase activity using p-nitrophenyl esters (C2, C4, C6, C8, C12, C14, C16). This enzyme exhibited broad substrate acceptance, preferentially hydrolysing p-nitrophenyl butyrate (C4) at pH 7.0 and 37 degrees C. The dynamic activity test demonstrated that the optimal conditions were pH 8.0 and 38 degrees C. Site-directed mutagenesis studies revealed that Gly 113, Ser 115 and Gly 117 residues play catalytic roles in Rv2525c. Title: Outbred genome sequencing and CRISPR/Cas9 gene editing in butterflies Li X, Fan D, Zhang W, Liu G, Zhang L, Zhao L, Fang X, Chen L, Dong Y and Wang W <14 more author(s)> Li X, Fan D, Zhang W, Liu G, Zhang L, Zhao L, Fang X, Chen L, Dong Y, Chen Y, Ding Y, Zhao R, Feng M, Zhu Y, Feng Y, Jiang X, Zhu D, Xiang H, Feng X, Li S, Wang J, Zhang G, Kronforst MR, Wang W (- 14) Ref: Nat Commun, 6:8212, 2015 : PubMed ESTHER: Li_2015_Nat.Commun_6_8212 PubMedSearch: Li 2015 Nat.Commun 6 8212 PubMedID: 26354079 Gene_locus related to this paper: papxu-a0a194pj15, papxu-a0a194q254, papma-a0a194rdx2, papxu-a0a194q858, papxu-a0a194pyl3, papxu-a0a194q337, papma-a0a194r1p9, papma-a0a194r6h1, papxu-a0a194q1w8, papma-a0a194ql80, papma-a0a0n1ipl3, papma-a0a194qm14 Abstract Butterflies are exceptionally diverse but their potential as an experimental system has been limited by the difficulty of deciphering heterozygous genomes and a lack of genetic manipulation technology. Here we use a hybrid assembly approach to construct high-quality reference genomes for Papilio xuthus (contig and scaffold N50: 492 kb, 3.4 Mb) and Papilio machaon (contig and scaffold N50: 81 kb, 1.15 Mb), highly heterozygous species that differ in host plant affiliations, and adult and larval colour patterns. Integrating comparative genomics and analyses of gene expression yields multiple insights into butterfly evolution, including potential roles of specific genes in recent diversification. To functionally test gene function, we develop an efficient (up to 92.5%) CRISPR/Cas9 gene editing method that yields obvious phenotypes with three genes, Abdominal-B, ebony and frizzled. Our results provide valuable genomic and technological resources for butterflies and unlock their potential as a genetic model system. Title: Genetic Manipulation of the Pneumocandin Biosynthetic Pathway for Generation of Analogues and Evaluation of Their Antifungal Activity Li Y, Chen L, Yue Q, Liu X, An Z, Bills GF Ref: ACS Chemical Biology, 10:1702, 2015 : PubMed ESTHER: Li_2015_ACS.Chem.Biol_10_1702 PubMedSearch: Li 2015 ACS.Chem.Biol 10 1702 PubMedID: 25879325 Gene_locus related to this paper: glal2-glon Abstract Pneumocandins are lipohexapeptides of the echinocandin family that potently interrupt fungal cell wall biogenesis by noncompetitive inhibition of 1,3-beta-glucan synthase. The pneumocandin biosynthetic gene cluster was previously elucidated by whole genome sequencing. In addition to the core nonribosomal peptide synthetase and polyketide synthase (GLNRPS4 and GLPKS4), the pneumocandin biosynthetic cluster includes two P450-type hemeprotein monooxygenase genes (GLP450-1 and GLP450-2) and four nonheme mononuclear iron oxygenase genes (GLOXY1, GLOXY2, GLOXY3, and GLOXY4), which function to biosynthesize and create the unusual sequence of hydroxylated amino acids of the mature pneumocandin peptide. Insertional inactivation of three of these genes (GLP450-1, GLP450-2, and GLOXY1) generated 13 different pneumocandin analogues that lack one, two, three, or four hydroxyl groups on 4R,5R-dihydroxy-ornithine and 3S,4S-dihydroxy-homotyrosine of the parent hexapeptide. Among them, seven analogues are previously unreported genetically engineered pneumocandins whose structures were established by NMR experiments. These new pneumocandins afforded a unique opportunity for side-by-side exploration of the effects of hydroxylation on pneumocandin antifungal activity. All of these cyclic lipopeptides showed potent antifungal activities, and two new metabolites pneumocandins F (3) and G (4) were more potent in vitro against Candida species and Aspergillus fumigatus than the principal fermentation products, pneumocandins A0 and B0. Title: Conditional neuroligin-2 knockout in adult medial prefrontal cortex links chronic changes in synaptic inhibition to cognitive impairments Liang J, Xu W, Hsu YT, Yee AX, Chen L, Sudhof TC Ref: Mol Psychiatry, 20:850, 2015 : PubMed ESTHER: Liang_2015_Mol.Psychiatry_20_850 PubMedSearch: Liang 2015 Mol.Psychiatry 20 850 PubMedID: 25824299 Abstract Abnormal activity in the medial prefrontal cortex (mPFC) is consistently observed in neuropsychiatric disorders, but the mechanisms involved remain unclear. Chronic aberrant excitation and/or inhibition of mPFC neurons were proposed to cause cognitive impairments. However, direct evidence for this hypothesis is lacking because it is technically challenging to control synaptic properties in a chronic and locally restricted, yet specific, manner. Here, we generated conditional knockout (cKO) mice of neuroligin-2 (Nlgn2), a postsynaptic cell-adhesion molecule of inhibitory synapses linked to neuropsychiatric disorders. cKO of Nlgn2 in adult mPFC rendered Nlgn2 protein undetectable after already 2-3 weeks, but induced major reductions in synaptic inhibition after only 6-7 weeks, and caused parallel impairments in anxiety, fear memory and social interaction behaviors. Moreover, cKO of Nlgn2 severely impaired behavioral stimulation of immediate-early gene expression in the mPFC, suggesting that chronic reduction in synaptic inhibition uncoupled the mPFC from experience-dependent inputs. Our results indicate that Nlgn2 is required for continuous maintenance of inhibitory synapses in the adult mPFC, and that chronic impairment of local inhibition disengages the mPFC from its cognitive functions by partially uncoupling the mPFC from experience-induced inputs. Title: Identification of Pathogenicity-Related Genes in Biofilm-Defective Acidovorax citrulli by Transposon Tn5 Mutagenesis Luo J, Qiu W, Chen L, Anjum SI, Yu M, Shan C, Ilyas M, Li B, Wang Y, Sun G Ref: Int J Mol Sci, 16:28050, 2015 : PubMed ESTHER: Luo_2015_Int.J.Mol.Sci_16_28050 PubMedSearch: Luo 2015 Int.J.Mol.Sci 16 28050 PubMedID: 26602922 Abstract Biofilm formation is important for virulence of a large number of plant pathogenic bacteria. Indeed, some virulence genes have been found to be involved in the formation of biofilm in bacterial fruit blotch pathogen Acidovorax citrulli. However, some virulent strains of A. citrulli were unable to format biofilm, indicating the complexity between biofilm formation and virulence. In this study, virulence-related genes were identified in the biofilm-defective strain A1 of A. citrulli by using Tn5 insertion, pathogenicity test, and high-efficiency thermal asymmetric interlaced PCR (hiTAIL-PCR). Results from this study indicated that 22 out of the obtained 301 mutants significantly decreased the virulence of strain A1 compared to the wild-type. Furthermore, sequence analysis indicated that the obtained 22 mutants were due to the insertion of Tn5 into eight genes, including Aave 4244 (cation diffusion facilitator family transporter), Aave 4286 (hypothetical protein), Aave 4189 (alpha/beta hydrolase fold), Aave 1911 (IMP dehydrogenase/GMP reductase domain), Aave 4383 (bacterial export proteins, family 1), Aave 4256 (Hsp70 protein), Aave 0003 (histidine kinase, DNA gyrase B, and HSP90-like ATPase), and Aave 2428 (pyridoxal-phosphate dependent enzyme). Furthermore, the growth of mutant Aave 2428 was unaffected and even increased by the change in incubation temperature, NaCl concentration and the pH of the LB broth, indicating that this gene may be directly involved in the bacterial virulence. Overall, the determination of the eight pathogenicity-related genes in strain A1 will be helpful to elucidate the pathogenesis of biofilm-defective A. citrulli. Title: Poster: Structural studies of nicotinic acetylcholine receptor alpha1 subunit and Fab35 complex to understand autoimmune disease of myasthenia gravis Noridomi K, Watanabe G, Hansen M, Chen L Ref: Biochemical Pharmacology, 97:627, 2015 : PubMed ESTHER: Noridomi_2015_Biochem.Pharmacol_97(4)_627 PubMedSearch: Noridomi 2015 Biochem.Pharmacol 97(4) 627 Title: Complete Genome Sequence of Elizabethkingia meningoseptica, Isolated from a T-Cell Non-Hodgkin's Lymphoma Patient Sun G, Wang L, Bao C, Li T, Ma L, Chen L Ref: Genome Announc, 3:, 2015 : PubMed ESTHER: Sun_2015_Genome.Announc_3_e00673 PubMedSearch: Sun 2015 Genome.Announc 3 e00673 PubMedID: 26112786 Gene_locus related to this paper: elimr-a0a0a2h0j3 Abstract An Elizabethkingia meningoseptica infection was detected at the end stage of a patient with T-cell non-Hodgkin's lymphoma. The complete genome of this isolated strain, FMS-007, was generated in one contig with a total size of 3,938,967 bp. A preliminary screening indicated that the genome contains drug resistance genes to aminoglycosides and beta-lactams. A clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated proteins (CRISPR/Cas) system with 16 direct repeats and 15 spacers was identified. Title: Comparative safety of the antifouling compound butenolide and 4,5-dichloro-2-n-octyl-4-isothiazolin-3-one (DCOIT) to the marine medaka (Oryzias melastigma) Chen L, Ye R, Xu Y, Gao Z, Au DW, Qian PY Ref: Aquat Toxicol, 149C:116, 2014 : PubMed ESTHER: Chen_2014_Aquat.Toxicol_149C_116 PubMedSearch: Chen 2014 Aquat.Toxicol 149C 116 PubMedID: 24583292 Abstract This study evaluated the potential adverse effects of butenolide, a promising antifouling compound, using the marine medaka (Oryzias melastigma), a model fish for marine ecotoxicology. The active ingredient used in the commercial antifoulant SeaNine 211, 4,5-dichloro-2-n-octyl-4-isothiazolin-3-one (DCOIT) was employed as the positive control. Adult marine medaka (4-month-old) were exposed to various concentrations of butenolide or DCOIT for 28 days and then depurated in clean seawater for 14 days (recovery). A suite of sensitive biomarkers, including hepatic oxidative stress, neuronal signal transmission, endocrine disruption, and reproductive function, was used to measure significant biological effects induced by the chemicals. Compared to DCOIT, chronic exposure to butenolide induced a lower extent of oxidative stress in the liver of male and female medaka. Furthermore, butenolide-exposed fish could recover faster from oxidative stress than fish exposed to DCOIT. Regarding neurotransmission, DCOIT significantly inhibited acetylcholinesterase (AChE) activity in the brain of both male and female medaka, whereas this was not significant for butenolide. In addition, plasma estradiol (E2) level was elevated and testosterone (T) level was decreased in male medaka exposed to DCOIT. This greatly imbalanced sex hormones ratio (E2/T) in exposed males, indicating that DCOIT is a potent endocrine disruptive chemical. In contrast, butenolide induced only moderate effects on sex hormone levels in exposed males, which could be gradually recovered during depuration. Moreover, the endocrine disruptive effect induced by butenolide did not affect normal development of offspring. In contrast, DCOIT-exposed fish exhibited a decrease of egg production and impaired reproductive success. Overall, the above findings demonstrated that chronic exposure to butenolide induced transient, reversible biological effect on marine medaka, while DCOIT could impair reproductive success of fish, as evident by clear alterations of the E2/T ratio. The relatively low toxicity of butenolide on marine biota highlights its promising application in the antifouling industry. The present findings also emphasize gender difference in fish susceptibility to chemical treatment (male>female), which is an important consideration for ecological risk assessment. Title: SK channel blockade reverses cognitive and motor deficits induced by nigrostriatal dopamine lesions in rats Chen L, Deltheil T, Turle-Lorenzo N, Liberge M, Rosier C, Watabe I, Sreng L, Amalric M, Mourre C Ref: Int J Neuropsychopharmacol, 17:1295, 2014 : PubMed ESTHER: Chen_2014_Int.J.Neuropsychopharmacol_17_1295 PubMedSearch: Chen 2014 Int.J.Neuropsychopharmacol 17 1295 PubMedID: 24661728 Abstract Parkinson's disease has traditionally been viewed as a motor disorder caused by the loss of dopamine (DA) neurons. However, emotional and cognitive syndromes can precede the onset of the motor deficits and provide an opportunity for therapeutic intervention. Potassium channels have recently emerged as potential new targets in the treatment of Parkinson's disease. The selective blockade of small conductance calcium-activated K+ channels (SK channels) by apamin is known to increase burst firing in midbrain DA neurons and therefore DA release. We thus investigated the effects of systemic administration of apamin on the motor, cognitive deficits and anxiety present after bilateral nigrostriatal 6-hydroxydopamine (6-OHDA) lesions in rats. Apamin administration (0.1 or 0.3 mg/kg i.p.) counteracted the depression, anxiety-like behaviors evaluated on sucrose consumption and in the elevated plus maze, social recognition and spatial memory deficits produced by partial 6-OHDA lesions. Apamin also reduced asymmetric motor deficits on circling behavior and postural adjustments in the unilateral extensive 6-OHDA model. The partial 6-OHDA lesions (56% striatal DA depletion) produced 20% decrease of iodinated apamin binding sites in the substantia nigra pars compacta in correlation with the loss of tyrosine hydroxylase positive cells, without modifying apamin binding in brain regions receiving DAergic innervation. Striatal extracellular levels of DA, not detectable after 6-OHDA lesions, were enhanced by apamin treatment as measured by in vivo microdialysis. These results indicate that blocking SK channels may reinstate minimal DA activity in the striatum to alleviate the non-motor symptoms induced by partial striatal DA lesions. Title: Molecular dissection of the evolution of carbapenem-resistant multilocus sequence type 258 Klebsiella pneumoniae Deleo FR, Chen L, Porcella SF, Martens CA, Kobayashi SD, Porter AR, Chavda KD, Jacobs MR, Mathema B and Kreiswirth BN <3 more author(s)> Deleo FR, Chen L, Porcella SF, Martens CA, Kobayashi SD, Porter AR, Chavda KD, Jacobs MR, Mathema B, Olsen RJ, Bonomo RA, Musser JM, Kreiswirth BN (- 3) Ref: Proc Natl Acad Sci U S A, 111:4988, 2014 : PubMed ESTHER: Deleo_2014_Proc.Natl.Acad.Sci.U.S.A_111_4988 PubMedSearch: Deleo 2014 Proc.Natl.Acad.Sci.U.S.A 111 4988 PubMedID: 24639510 Gene_locus related to this paper: klep7-a6t9v6, klep7-y1077, klepn-a0a016qwx4, klepn-w8uta0 Abstract Infections caused by drug-resistant bacteria are a major problem worldwide. Carbapenem-resistant Klebsiella pneumoniae, most notably isolates classified as multilocus sequence type (ST) 258, have emerged as an important cause of hospital deaths. ST258 isolates are predominantly multidrug resistant, and therefore infections caused by them are difficult to treat. It is not known why the ST258 lineage is the most prevalent cause of multidrug-resistant K. pneumoniae infections in the United States and other countries. Here we tested the hypothesis that carbapenem-resistant ST258 K. pneumoniae is a single genetic clone that has disseminated worldwide. We sequenced to closure the genomes of two ST258 clinical isolates and used these genomes as references for comparative genome sequencing of 83 additional clinical isolates recovered from patients at diverse geographic locations worldwide. Phylogenetic analysis of the SNPs in the core genome of these isolates revealed that ST258 K. pneumoniae organisms are two distinct genetic clades. This unexpected finding disproves the single-clone hypothesis. Notably, genetic differentiation between the two clades results from an approximately 215-kb region of divergence that includes genes involved in capsule polysaccharide biosynthesis. The region of divergence appears to be a hotspot for DNA recombination events, and we suggest that this region has contributed to the success of ST258 K. pneumoniae. Our findings will accelerate research on novel diagnostic, therapeutic, and vaccine strategies designed to prevent and/or treat infections caused by multidrug resistant K. pneumoniae. Title: Whole-genome sequencing of cultivated and wild peppers provides insights into Capsicum domestication and specialization Qin C, Yu C, Shen Y, Fang X, Chen L, Min J, Cheng J, Zhao S, Xu M and Zhang Z <58 more author(s)> Qin C, Yu C, Shen Y, Fang X, Chen L, Min J, Cheng J, Zhao S, Xu M, Luo Y, Yang Y, Wu Z, Mao L, Wu H, Ling-Hu C, Zhou H, Lin H, Gonzalez-Morales S, Trejo-Saavedra DL, Tian H, Tang X, Zhao M, Huang Z, Zhou A, Yao X, Cui J, Li W, Chen Z, Feng Y, Niu Y, Bi S, Yang X, Cai H, Luo X, Montes-Hernandez S, Leyva-Gonzalez MA, Xiong Z, He X, Bai L, Tan S, Liu D, Liu J, Zhang S, Chen M, Zhang L, Zhang Y, Liao W, Wang M, Lv X, Wen B, Liu H, Luan H, Yang S, Wang X, Xu J, Li X, Li S, Wang J, Palloix A, Bosland PW, Li Y, Krogh A, Rivera-Bustamante RF, Herrera-Estrella L, Yin Y, Yu J, Hu K, Zhang Z (- 58) Ref: Proc Natl Acad Sci U S A, 111:5135, 2014 : PubMed ESTHER: Qin_2014_Proc.Natl.Acad.Sci.U.S.A_111_5135 PubMedSearch: Qin 2014 Proc.Natl.Acad.Sci.U.S.A 111 5135 PubMedID: 24591624 Gene_locus related to this paper: capch-q75qh4, capan-a0a1u8fuf5, capan-a0a1u8gmz3, capan-a0a1u8f879, capan-a0a1u8ftr2, capan-a0a1u8g8s6 Abstract As an economic crop, pepper satisfies people's spicy taste and has medicinal uses worldwide. To gain a better understanding of Capsicum evolution, domestication, and specialization, we present here the genome sequence of the cultivated pepper Zunla-1 (C. annuum L.) and its wild progenitor Chiltepin (C. annuum var. glabriusculum). We estimate that the pepper genome expanded approximately 0.3 Mya (with respect to the genome of other Solanaceae) by a rapid amplification of retrotransposons elements, resulting in a genome comprised of approximately 81% repetitive sequences. Approximately 79% of 3.48-Gb scaffolds containing 34,476 protein-coding genes were anchored to chromosomes by a high-density genetic map. Comparison of cultivated and wild pepper genomes with 20 resequencing accessions revealed molecular footprints of artificial selection, providing us with a list of candidate domestication genes. We also found that dosage compensation effect of tandem duplication genes probably contributed to the pungent diversification in pepper. The Capsicum reference genome provides crucial information for the study of not only the evolution of the pepper genome but also, the Solanaceae family, and it will facilitate the establishment of more effective pepper breeding programs. Title: Whole genome sequence of the Treponema pallidum subsp. endemicum strain Bosnia A: the genome is related to yaws treponemes but contains few loci similar to syphilis treponemes Staudova B, Strouhal M, Zobanikova M, Cejkova D, Fulton LL, Chen L, Giacani L, Centurion-Lara A, Bruisten SM and Smajs D <2 more author(s)> Staudova B, Strouhal M, Zobanikova M, Cejkova D, Fulton LL, Chen L, Giacani L, Centurion-Lara A, Bruisten SM, Sodergren E, Weinstock GM, Smajs D (- 2) Ref: PLoS Negl Trop Dis, 8:e3261, 2014 : PubMed ESTHER: Staudova_2014_PLoS.Negl.Trop.Dis_8_E3261 PubMedSearch: Staudova 2014 PLoS.Negl.Trop.Dis 8 E3261 PubMedID: 25375929 Gene_locus related to this paper: trepa-TP0902 Abstract BACKGROUND: T. pallidum subsp. endemicum (TEN) is the causative agent of bejel (also known as endemic syphilis). Clinical symptoms of syphilis and bejel are overlapping and the epidemiological context is important for correct diagnosis of both diseases. In contrast to syphilis, caused by T. pallidum subsp. pallidum (TPA), TEN infections are usually spread by direct contact or contaminated utensils rather than by sexual contact. Bejel is most often seen in western Africa and in the Middle East. The strain Bosnia A was isolated in 1950 in Bosnia, southern Europe. METHODOLOGY/PRINCIPAL FINDINGS: The complete genome of the Bosnia A strain was amplified and sequenced using the pooled segment genome sequencing (PSGS) method and a combination of three next-generation sequencing techniques (SOLiD, Roche 454, and Illumina). Using this approach, a total combined average genome coverage of 513x was achieved. The size of the Bosnia A genome was found to be 1,137,653 bp, i.e. 1.6-2.8 kbp shorter than any previously published genomes of uncultivable pathogenic treponemes. Conserved gene synteny was found in the Bosnia A genome compared to other sequenced syphilis and yaws treponemes. The TEN Bosnia A genome was distinct but very similar to the genome of yaws-causing T. pallidum subsp. pertenue (TPE) strains. Interestingly, the TEN Bosnia A genome was found to contain several sequences, which so far, have been uniquely identified only in syphilis treponemes. CONCLUSIONS/SIGNIFICANCE: The genome of TEN Bosnia A contains several sequences thought to be unique to TPA strains; these sequences very likely represent remnants of recombination events during the evolution of TEN treponemes. This finding emphasizes a possible role of repeated horizontal gene transfer between treponemal subspecies in shaping the Bosnia A genome. Title: Protective effects of perindopril on d-galactose and aluminum trichloride induced neurotoxicity via the apoptosis of mitochondria-mediated intrinsic pathway in the hippocampus of mice Yang W, Shi L, Chen L, Zhang B, Ma K, Liu Y, Qian Y Ref: Brain Research Bulletin, 109:46, 2014 : PubMed ESTHER: Yang_2014_Brain.Res.Bull_109_46 PubMedSearch: Yang 2014 Brain.Res.Bull 109 46 PubMedID: 25290208 Abstract Perindopril, an angiotensin converting enzyme inhibitor, has been reported to improve learning and memory in a mouse or rat model of Alzheimer's disease (AD) induced by injection of beta-amyloid protein. However, the exact mechanism of perindopril on the cognitive deficits is not fully understood. Our previous data have indicated that perindopril improves learning and memory in a mouse model of AD induced by d-galactose (d-gal) and aluminum trichloride (AlCl3) via inhibition of acetylcholinesterase activity and oxidative stress. Whether perindopril also inhibit apoptosis to prevent cognitive decline remains unknown in mice. Therefore, the present study explored the protective effects of perindopril in the hippocampus of mice further. Perindopril (0.5mg/kg/day) was administered intragastrically for 60 days after the mice were given a d-gal (150mg/kg/day) and AlCl3 (10mg/kg/day) intraperitoneally for 90 days. Then the expression of Bcl-2, Bax, Fas, FasL, caspase-3, caspase-8 and caspase-9 were analyzed by RT-PCR and western blotting in the hippocampus. Perindopril significantly decreased caspase-3 and caspase-9 activities, and elevated Bcl-2/Bax ratio in the hippocampus. However, the expression of Fas, FasL and caspase-8 did not change in the hippocampus whether treatment with d-gal and AlCl3 or perindopril. Taken together, the above findings indicated that perindopril inhibited apoptosis in the hippocampus may be another mechanism by which perindopril improves learning and memory functions in d-gal and AlCl3 treated mice. Title: A novel protein elicitor (SsCut) from Sclerotinia sclerotiorum induces multiple defense responses in plants Zhang H, Wu Q, Cao S, Zhao T, Chen L, Zhuang P, Zhou X, Gao Z Ref: Plant Mol Biol, 86:495, 2014 : PubMed ESTHER: Zhang_2014_Plant.Mol.Biol_86_495 PubMedSearch: Zhang 2014 Plant.Mol.Biol 86 495 PubMedID: 25149470 Abstract In this study, we report the cloning of the SsCut gene encoding cutinase from Sclerotinia sclerotiorum. We isolated a 609-bp cDNA encoding a polypeptide of 202 amino acids with a molecular weight of 20.4 kDa. Heterologous expression of SsCut in Escherichia coli (His-SsCut) caused the formation of lesions in tobacco that closely resembled hypersensitive response lesions. Mutational analysis identified the C-terminal-half peptide and the same amino acids indispensable for both enzyme and elicitor activity. His-SsCut was caused cell death in Arabidopsis, soybean (Glycine max), oilseed rape (Brassica napus), rice (Oryza sativa), maize (Zea mays), and wheat (Triticum aestivum), indicating that both dicot and monocot species are responsive to the elicitor. Furthermore, the elicitation of tobacco was effective in the induction of the activities of hydrogen peroxide, phenylalanine ammonia-lyase, peroxides, and polyphenol oxidase. His-SsCut-treated plants exhibited enhanced resistance as indicated by a significant reduction in the number and size of S. sclerotiorum, Phytophthora sojae, and P. nicotianae lesions on leaves relative to controls. Real-time PCR results indicated that the expression of defense-related genes and genes involved in signal transduction were induced by His-SsCut. Our results demonstrate that SsCut is an elicitor that triggers defense responses in plants and will help to clarify its relationship to downstream signaling pathways that induce defense responses. Title: Genomics-driven discovery of the pneumocandin biosynthetic gene cluster in the fungus Glarea lozoyensis Chen L, Yue Q, Zhang X, Xiang M, Wang C, Li S, Che Y, Ortiz-Lopez FJ, Bills GF and An Z <1 more author(s)> Chen L, Yue Q, Zhang X, Xiang M, Wang C, Li S, Che Y, Ortiz-Lopez FJ, Bills GF, Liu X, An Z (- 1) Ref: BMC Genomics, 14:339, 2013 : PubMed ESTHER: Chen_2013_BMC.Genomics_14_339 PubMedSearch: Chen 2013 BMC.Genomics 14 339 PubMedID: 23688303 Gene_locus related to this paper: glal2-s3cg73, glal2-s3d2r4, glal2-s3dmm6, glal2-s3e306, glal2-s3dl45, glal2-s3d1r9, glal2-s3e4a7, glal2-s3ddr1, glal2-s3ctz6, glal2-s3dy35, glal2-s3dws5, glal2-s3df31, glal2-s3d7q5, glal2-s3cwz5, glal2-s3dcn7, glal2-s3dhj7, glal2-s3dm96, glal2-s3d6q1, glal2-s3cv25, glal2-s3e8v9, glal2-s3crh2, glal2-s3dde8, glal2-s3cxt6, glal2-s3da89, glal2-s3ckn8, glal2-s3d4y3, glal2-s3ddw6, glal2-s3dk02, glal2-s3d048 Abstract BACKGROUND: The antifungal therapy caspofungin is a semi-synthetic derivative of pneumocandin B0, a lipohexapeptide produced by the fungus Glarea lozoyensis, and was the first member of the echinocandin class approved for human therapy. The nonribosomal peptide synthetase (NRPS)-polyketide synthases (PKS) gene cluster responsible for pneumocandin biosynthesis from G. lozoyensis has not been elucidated to date. In this study, we report the elucidation of the pneumocandin biosynthetic gene cluster by whole genome sequencing of the G. lozoyensis wild-type strain ATCC 20868. Title: Beneficial effects of inhibition of soluble epoxide hydrolase on glucose homeostasis and islet damage in a streptozotocin-induced diabetic mouse model Chen L, Fan C, Zhang Y, Bakri M, Dong H, Morisseau C, Maddipati KR, Luo P, Wang CY and Wang MH <1 more author(s)> Chen L, Fan C, Zhang Y, Bakri M, Dong H, Morisseau C, Maddipati KR, Luo P, Wang CY, Hammock BD, Wang MH (- 1) Ref: Prostaglandins Other Lipid Mediat, 104-105:42, 2013 : PubMed ESTHER: Chen_2013_Prostaglandins.Other.Lipid.Mediat_104-105_42 PubMedSearch: Chen 2013 Prostaglandins.Other.Lipid.Mediat 104-105 42 PubMedID: 23247129 Abstract Soluble epoxide hydrolase (sEH) is an enzyme involved in the metabolism of endogenous inflammatory and anti-apoptotic mediators. In the present study, we determined the effects of the inhibition of sEH on glucose homeostasis and islet damage in mice treated with streptozotocin (STZ), a model of chemical-induced diabetes. STZ increased daily water intake and decreased visceral (spleen and pancreas) weight in mice; sEH inhibition in STZ mice decreased water intake, but did not affect visceral weight. Hyperglycemia induced by STZ treatment in mice was attenuated by inhibiting sEH. The beneficial effects of sEH inhibition were accompanied, after 2 and 4 weeks of initial administration, by improving glucose tolerance. In contrast, sEH inhibition did not affect insulin tolerance. Using LC/MS analysis, neither STZ nor STZ plus sEH inhibition affected pancreatic and plasma ratios of epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids (DHETs), an index of EETs levels. Western blot analysis showed that mouse cytochrome P450 (CYP) 2C enzymes are the major epoxygenases in islets. On day 5 after initial STZ treatment, STZ induced islet cell apoptosis, while sEH inhibition in STZ mice significantly reduced islet cell apoptosis. These studies provide pharmacological evidence that inhibiting sEH activity provides significant protection against islet beta-cell damage and improves glucose homeostasis in STZ-induced diabetes. Title: Complex between alpha-bungarotoxin and an alpha7 nicotinic receptor ligand-binding domain chimaera Huang S, Li SX, Bren N, Cheng K, Gomoto R, Chen L, Sine SM Ref: Biochemical Journal, 454:303, 2013 : PubMed ESTHER: Huang_2013_Biochem.J_454_303 PubMedSearch: Huang 2013 Biochem.J 454 303 PubMedID: 23800261 Abstract To identify high-affinity interactions between long-chain alpha-neurotoxins and nicotinic receptors, we determined the crystal structure of the complex between alpha-btx (alpha-bungarotoxin) and a pentameric ligand-binding domain constructed from the human alpha7 AChR (acetylcholine receptor) and AChBP (acetylcholine-binding protein). The complex buries ~2000 A2 (1 A=0.1 nm) of surface area, within which Arg36 and Phe32 from finger II of alpha-btx form a pi-cation stack that aligns edge-to-face with the conserved Tyr184 from loop-C of alpha7, while Asp30 of alpha-btx forms a hydrogen bond with the hydroxy group of Tyr184. These inter-residue interactions diverge from those in a 4.2 A structure of alpha-ctx (alpha-cobratoxin) bound to AChBP, but are similar to those in a 1.94 A structure of alpha-btx bound to the monomeric alpha1 extracellular domain, although compared with the monomer-bound complex, the alpha-btx backbone exhibits a large shift relative to the protein surface. Mutational analyses show that replacing Tyr184 with a threonine residue abolishes high-affinity alpha-btx binding, whereas replacing with a phenylalanine residue maintains high affinity. Comparison of the alpha-btx complex with that coupled to the agonist epibatidine reveals structural rearrangements within the binding pocket and throughout each subunit. The overall findings highlight structural principles by which alpha-neurotoxins interact with nicotinic receptors. Title: Plant-symbiotic fungi as chemical engineers: multi-genome analysis of the clavicipitaceae reveals dynamics of alkaloid loci Schardl CL, Young CA, Hesse U, Amyotte SG, Andreeva K, Calie PJ, Fleetwood DJ, Haws DC, Moore N and Zeng Z <44 more author(s)> Schardl CL, Young CA, Hesse U, Amyotte SG, Andreeva K, Calie PJ, Fleetwood DJ, Haws DC, Moore N, Oeser B, Panaccione DG, Schweri KK, Voisey CR, Farman ML, Jaromczyk JW, Roe BA, O'Sullivan DM, Scott B, Tudzynski P, An Z, Arnaoudova EG, Bullock CT, Charlton ND, Chen L, Cox M, Dinkins RD, Florea S, Glenn AE, Gordon A, Guldener U, Harris DR, Hollin W, Jaromczyk J, Johnson RD, Khan AK, Leistner E, Leuchtmann A, Li C, Liu J, Liu M, Mace W, Machado C, Nagabhyru P, Pan J, Schmid J, Sugawara K, Steiner U, Takach JE, Tanaka E, Webb JS, Wilson EV, Wiseman JL, Yoshida R, Zeng Z (- 44) Ref: PLoS Genet, 9:e1003323, 2013 : PubMed ESTHER: Schardl_2013_PLoS.Genet_9_E1003323 PubMedSearch: Schardl 2013 PLoS.Genet 9 E1003323 PubMedID: 23468653 Gene_locus related to this paper: clap2-m1w2a8, clap2-m1w555, clap2-m1wa31, clap2-m1whd2, clap2-m1weh2, clap2-m1w5y7, clap2-m1wh11, clap2-m1vyn7 Abstract The fungal family Clavicipitaceae includes plant symbionts and parasites that produce several psychoactive and bioprotective alkaloids. The family includes grass symbionts in the epichloae clade (Epichloe and Neotyphodium species), which are extraordinarily diverse both in their host interactions and in their alkaloid profiles. Epichloae produce alkaloids of four distinct classes, all of which deter insects, and some-including the infamous ergot alkaloids-have potent effects on mammals. The exceptional chemotypic diversity of the epichloae may relate to their broad range of host interactions, whereby some are pathogenic and contagious, others are mutualistic and vertically transmitted (seed-borne), and still others vary in pathogenic or mutualistic behavior. We profiled the alkaloids and sequenced the genomes of 10 epichloae, three ergot fungi (Claviceps species), a morning-glory symbiont (Periglandula ipomoeae), and a bamboo pathogen (Aciculosporium take), and compared the gene clusters for four classes of alkaloids. Results indicated a strong tendency for alkaloid loci to have conserved cores that specify the skeleton structures and peripheral genes that determine chemical variations that are known to affect their pharmacological specificities. Generally, gene locations in cluster peripheries positioned them near to transposon-derived, AT-rich repeat blocks, which were probably involved in gene losses, duplications, and neofunctionalizations. The alkaloid loci in the epichloae had unusual structures riddled with large, complex, and dynamic repeat blocks. This feature was not reflective of overall differences in repeat contents in the genomes, nor was it characteristic of most other specialized metabolism loci. The organization and dynamics of alkaloid loci and abundant repeat blocks in the epichloae suggested that these fungi are under selection for alkaloid diversification. We suggest that such selection is related to the variable life histories of the epichloae, their protective roles as symbionts, and their associations with the highly speciose and ecologically diverse cool-season grasses. Title: Molecular cloning of a novel bioH gene from an environmental metagenome encoding a carboxylesterase with exceptional tolerance to organic solvents Shi Y, Pan Y, Li B, He W, She Q, Chen L Ref: BMC Biotechnol, 13:13, 2013 : PubMed ESTHER: Shi_2013_BMC.Biotechnol_13_13 PubMedSearch: Shi 2013 BMC.Biotechnol 13 13 PubMedID: 23413993 Abstract ABSTRACT: BACKGROUND: BioH is one of the key enzymes to produce the precursor pimeloyl-ACP to initiate biotin biosynthesis de novo in bacteria. To date, very few bioH genes have been characterized. In this study, we cloned and identified a novel bioH gene, bioHx, from an environmental metagenome by a functional metagenomic approach. The bioHx gene, encoding an enzyme that is capable of hydrolysis of p-nitrophenyl esters of fatty acids, was expressed in Escherichia coli BL21 using the pET expression system. The biochemical property of the purified BioHx protein was also investigated. Title: Inter-residue coupling contributes to high-affinity subtype-selective binding of alpha-bungarotoxin to nicotinic receptors Sine SM, Huang S, Li SX, daCosta CJ, Chen L Ref: Biochemical Journal, 454:311, 2013 : PubMed ESTHER: Sine_2013_Biochem.J_454_311 PubMedSearch: Sine 2013 Biochem.J 454 311 PubMedID: 23802200 Abstract The crystal structure of a pentameric alpha7 ligand-binding domain chimaera with bound alpha-btx (alpha-bungarotoxin) showed that of the five conserved aromatic residues in alpha7, only Tyr184 in loop C of the ligand-binding site was required for high-affinity binding. To determine whether the contribution of Tyr184 depends on local residues, we generated mutations in an alpha7/5HT3A (5-hydroxytryptamine type 3A) receptor chimaera, individually and in pairs, and measured 125I-labelled alpha-btx binding. The results show that mutations of individual residues near Tyr184 do not affect alpha-btx affinity, but pairwise mutations decrease affinity in an energetically coupled manner. Kinetic measurements show that the affinity decreases arise through increases in the alpha-btx dissociation rate with little change in the association rate. Replacing loop C in alpha7 with loop C from the alpha-btx-insensitive alpha2 or alpha3 subunits abolishes high-affinity alpha-btx binding, but preserves acetylcholine-elicited single channel currents. However, in both the alpha2 and alpha3 construct, mutating either residue that flanks Tyr184 to its alpha7 counterpart restores high-affinity alpha-btx binding. Analogously, in alpha7, mutating both residues that flank Tyr184 to the alpha2 or alpha3 counterparts abolishes high-affinity alpha-btx binding. Thus interaction between Tyr184 and local residues contributes to high-affinity subtype-selective alpha-btx binding. Title: [Risk factors of hepatorenal syndrome in patients with acute on chronic liver failure] Zhang DQ, Chen L, Gan QR, Lin QF, Pan C Ref: Zhonghua Gan Zang Bing Za Zhi, 21:743, 2013 : PubMed ESTHER: Zhang_2013_Zhonghua.Gan.Zang.Bing.Za.Zhi_21_743 PubMedSearch: Zhang 2013 Zhonghua.Gan.Zang.Bing.Za.Zhi 21 743 PubMedID: 24331631 Abstract OBJECTIVE: To identify the risk factors of hepatorenal syndrome in patients with hepatitis B virus (HBV)-related acute-on-chronic liver failure(ACLF). Title: Hopeahainol A attenuates memory deficits by targeting beta-amyloid in APP/PS1 transgenic mice Zhu X, Ye L, Ge H, Chen L, Jiang N, Qian L, Li L, Liu R, Ji S and Xu Y <5 more author(s)> Zhu X, Ye L, Ge H, Chen L, Jiang N, Qian L, Li L, Liu R, Ji S, Zhang S, Jin J, Guan D, Fang W, Tan R, Xu Y (- 5) Ref: Aging Cell, 12:85, 2013 : PubMed ESTHER: Zhu_2013_Aging.Cell_12_85 PubMedSearch: Zhu 2013 Aging.Cell 12 85 PubMedID: 23107435 Inhibitor(s) related to this paper: Hopeahainol-A Abstract Increasing evidence demonstrates that amyloid beta (Abeta) elicits mitochondrial dysfunction and oxidative stress, which contributes to the pathogenesis of Alzheimer's disease (AD). Identification of the molecules targeting Abeta is thus of particular significance in the treatment of AD. Hopeahainol A (HopA), a polyphenol with a novel skeleton obtained from Hopea hainanensis, is potentially acetylcholinesterase-inhibitory and anti-oxidative in H(2) O(2) -treated PC12 cells. In this study, we reported that HopA might bind to Abeta(1-42) directly and inhibit the Abeta(1-42) aggregation using a combination of molecular dynamics simulation, binding assay, transmission electron microscopic analysis and staining technique. We also demonstrated that HopA decreased the interaction between Abeta(1-42) and Abeta-binding alcohol dehydrogenase, which in turn reduced mitochondrial dysfunction and oxidative stress in vivo and in vitro. In addition, HopA was able to rescue the long-term potentiation induction by protecting synaptic function and attenuate memory deficits in APP/PS1 mice. Our data suggest that HopA might be a promising drug for therapeutic intervention in AD. Title: Whole genome sequences of three Treponema pallidum ssp. pertenue strains: yaws and syphilis treponemes differ in less than 0.2% of the genome sequence Cejkova D, Zobanikova M, Chen L, Pospisilova P, Strouhal M, Qin X, Mikalova L, Norris SJ, Muzny DM and Smajs D <4 more author(s)> Cejkova D, Zobanikova M, Chen L, Pospisilova P, Strouhal M, Qin X, Mikalova L, Norris SJ, Muzny DM, Gibbs RA, Fulton LL, Sodergren E, Weinstock GM, Smajs D (- 4) Ref: PLoS Negl Trop Dis, 6:e1471, 2012 : PubMed ESTHER: Cejkova_2012_PLoS.Negl.Trop.Dis_6_E1471 PubMedSearch: Cejkova 2012 PLoS.Negl.Trop.Dis 6 E1471 PubMedID: 22292095 Gene_locus related to this paper: trepa-TP0902 Abstract BACKGROUND: The yaws treponemes, Treponema pallidum ssp. pertenue (TPE) strains, are closely related to syphilis causing strains of Treponema pallidum ssp. pallidum (TPA). Both yaws and syphilis are distinguished on the basis of epidemiological characteristics, clinical symptoms, and several genetic signatures of the corresponding causative agents. METHODOLOGY/PRINCIPAL FINDINGS: To precisely define genetic differences between TPA and TPE, high-quality whole genome sequences of three TPE strains (Samoa D, CDC-2, Gauthier) were determined using next-generation sequencing techniques. TPE genome sequences were compared to four genomes of TPA strains (Nichols, DAL-1, SS14, Chicago). The genome structure was identical in all three TPE strains with similar length ranging between 1,139,330 bp and 1,139,744 bp. No major genome rearrangements were found when compared to the four TPA genomes. The whole genome nucleotide divergence (d(A)) between TPA and TPE subspecies was 4.7 and 4.8 times higher than the observed nucleotide diversity (pi) among TPA and TPE strains, respectively, corresponding to 99.8% identity between TPA and TPE genomes. A set of 97 (9.9%) TPE genes encoded proteins containing two or more amino acid replacements or other major sequence changes. The TPE divergent genes were mostly from the group encoding potential virulence factors and genes encoding proteins with unknown function. CONCLUSIONS/SIGNIFICANCE: Hypothetical genes, with genetic differences, consistently found between TPE and TPA strains are candidates for syphilitic treponemes virulence factors. Seventeen TPE genes were predicted under positive selection, and eleven of them coded either for predicted exported proteins or membrane proteins suggesting their possible association with the cell surface. Sequence changes between TPE and TPA strains and changes specific to individual strains represent suitable targets for subspecies- and strain-specific molecular diagnostics. Title: Prenatal Transfer of Polybrominated Diphenyl Ethers (PBDEs) Results in Developmental Neurotoxicity in Zebrafish Larvae Chen L, Yu K, Huang C, Yu L, Zhu B, Lam PK, Lam JC, Zhou B Ref: Environ Sci Technol, 46:9727, 2012 : PubMed ESTHER: Chen_2012_Environ.Sci.Technol_46_9727 PubMedSearch: Chen 2012 Environ.Sci.Technol 46 9727 PubMedID: 22866812 Abstract Parental exposure to polybrominated diphenyl ethers (PBDEs) in animals has been found to be transferred to the offspring. The environmental health risk and toxicity to the offspring are still unclear. The objective of the present study was to identify environmentally relevant concentrations of PBDEs for parental exposure that would cause developmental neurotoxicity in the offspring. Adult zebrafish were exposed to environmentally relevant concentrations of DE-71 (0.16, 0.8, 4.0 ug/L) via water. The results showed that PBDE exposure did not affect larvae hatching, malformation, or survival. The residue of PBDEs was detected in F1 eggs upon parental exposure. Acetylcholinesterase (AChE) activity was significantly inhibited in F1 larvae. Genes of central nervous system development (e.g., myelin basic protein, synapsin IIa, alpha1-tubulin) were significantly downregulated in larvae. Protein levels of alpha1-tubulin and synapsin IIa were also reduced. Decreased locomotion activity was observed in the larvae. This study provides the first evidence that parental exposure to environmentally relevant concentrations of PBDEs could cause adverse effects on neurodevelopment in zebrafish offspring. Title: Bone marrow-derived mesenchymal stem cells up-regulate acetylcholine receptor delta subunit through NRG/ErbB3-mediated mitogen-activated protein kinase pathway Chen L, Jiang J, Xu J, Gu Y, Xu L Ref: Clin Transl Sci, 5:27, 2012 : PubMed ESTHER: Chen_2012_Clin.Transl.Sci_5_27 PubMedSearch: Chen 2012 Clin.Transl.Sci 5 27 PubMedID: 22376253 Abstract To investigate the effect of bone marrow-derived mesenchymal stem cells (BMSCs) on the expression of acetylcholine receptor delta subunit (AChRd), the murine skeletal muscle cell line Sol8 were grown in DMEM with 20% fetal bovine serum added with (conditional medium group) or without (control group) conditional medium of BMSC cells for 48 hours. RT-PCR and Western blot were performed to access the mRNA and protein levels of AChRd in Sol8 cells, respectively. Western blot was used to detect total and phosphorylated protein levels of Ras, Raf-1, Mek1/2, and Erk1/2, respectively. NRG-1 antibody added in conditional medium of BMSCs, si-ErbB3, and four Ras/Raf/MEK/ERK pathway inhibitors (FTS, Sulindac, U0126, and PD98059) were using to investigate the effect of AChRd levels. Our studies indicated that expression of AChRd was significantly enhanced in the conditional medium group when compared with those in control group and phosphorylation of Ras, Raf, Erk1/2 in Sol8 cells was also increased. Although gene silencing for ErbB3 gene, adding of NRG-1 antibody in conditional medium of BMSCs or treatment of Ras/Raf/MEK/ERK pathway inhibitors can down-regulate expression of AChRd and phosphorylation, which suggesting that the Ras/Raf/MEK/ERK pathway may be involved in BMSCs-induced expression of AChRd. Title: Acute exposure to DE-71: effects on locomotor behavior and developmental neurotoxicity in zebrafish larvae Chen L, Huang C, Hu C, Yu K, Yang L, Zhou B Ref: Environ Toxicol Chem, 31:2338, 2012 : PubMed ESTHER: Chen_2012_Environ.Toxicol.Chem_31_2338 PubMedSearch: Chen 2012 Environ.Toxicol.Chem 31 2338 PubMedID: 22833361 Abstract The aim of the present study was to investigate the acute developmental neurotoxicity of polybrominated diphenyl ethers (PBDEs) in zebrafish larvae. From 2 to 120 h postfertilization zebrafish embryos were exposed to DE-71 (0, 31.0, 68.7, and 227.6 microg/L). The authors studied the locomotor behavior of larvae, involvement of the cholinergic system, and selected gene and protein expressions in the central nervous system. The results showed that low DE-71 concentration caused hyperactivity, whereas higher concentrations decreased activity during the dark period. During the light period, larval activity was significantly reduced in a concentration-dependent manner. In the cholinergic system, acetylcholinesterase activity significantly increased (10.7 and 12.4%) in the 68.7 and 227.6 microg/L exposure groups, respectively, and acetylcholine concentration accordingly decreased (60.5%) in the 227.6 microg/L exposure group. The mRNA expressions of genes encoding myelin basic protein, neuron microtubule protein (alpha1-tubulin), and sonic hedgehog a were significantly downregulated. Western blotting assay demonstrated that the protein concentration of alpha1-tubulin was also decreased. Overall, the present study demonstrated that acute exposure to PBDEs can disrupt the neurobehavior of zebrafish larvae and affect cholinergic neurotransmission and neuron development. Title: Increased genetic vulnerability to smoking at CHRNA5 in early-onset smokers Hartz SM, Short SE, Saccone NL, Culverhouse R, Chen L, Schwantes-An TH, Coon H, Han Y, Stephens SH and Bierut LJ <142 more author(s)> Hartz SM, Short SE, Saccone NL, Culverhouse R, Chen L, Schwantes-An TH, Coon H, Han Y, Stephens SH, Sun J, Chen X, Ducci F, Dueker N, Franceschini N, Frank J, Geller F, Gubjartsson D, Hansel NN, Jiang C, Keskitalo-Vuokko K, Liu Z, Lyytikainen LP, Michel M, Rawal R, Rosenberger A, Scheet P, Shaffer JR, Teumer A, Thompson JR, Vink JM, Vogelzangs N, Wenzlaff AS, Wheeler W, Xiao X, Yang BZ, Aggen SH, Balmforth AJ, Baumeister SE, Beaty T, Bennett S, Bergen AW, Boyd HA, Broms U, Campbell H, Chatterjee N, Chen J, Cheng YC, Cichon S, Couper D, Cucca F, Dick DM, Foroud T, Furberg H, Giegling I, Gu F, Hall AS, Hallfors J, Han S, Hartmann AM, Hayward C, Heikkila K, Hewitt JK, Hottenga JJ, Jensen MK, Jousilahti P, Kaakinen M, Kittner SJ, Konte B, Korhonen T, Landi MT, Laatikainen T, Leppert M, Levy SM, Mathias RA, McNeil DW, Medland SE, Montgomery GW, Muley T, Murray T, Nauck M, North K, Pergadia M, Polasek O, Ramos EM, Ripatti S, Risch A, Ruczinski I, Rudan I, Salomaa V, Schlessinger D, Styrkarsdottir U, Terracciano A, Uda M, Willemsen G, Wu X, Abecasis G, Barnes K, Bickeboller H, Boerwinkle E, Boomsma DI, Caporaso N, Duan J, Edenberg HJ, Francks C, Gejman PV, Gelernter J, Grabe HJ, Hops H, Jarvelin MR, Viikari J, Kahonen M, Kendler KS, Lehtimaki T, Levinson DF, Marazita ML, Marchini J, Melbye M, Mitchell BD, Murray JC, Nothen MM, Penninx BW, Raitakari O, Rietschel M, Rujescu D, Samani NJ, Sanders AR, Schwartz AG, Shete S, Shi J, Spitz M, Stefansson K, Swan GE, Thorgeirsson T, Volzke H, Wei Q, Wichmann HE, Amos CI, Breslau N, Cannon DS, Ehringer M, Grucza R, Hatsukami D, Heath A, Johnson EO, Kaprio J, Madden P, Martin NG, Stevens VL, Stitzel JA, Weiss RB, Kraft P, Bierut LJ (- 142) Ref: Arch Gen Psychiatry, 69:854, 2012 : PubMed ESTHER: Hartz_2012_Arch.Gen.Psychiatry_69_854 PubMedSearch: Hartz 2012 Arch.Gen.Psychiatry 69 854 PubMedID: 22868939 Abstract CONTEXT: Recent studies have shown an association between cigarettes per day (CPD) and a nonsynonymous single-nucleotide polymorphism in CHRNA5, rs16969968. OBJECTIVE: To determine whether the association between rs16969968 and smoking is modified by age at onset of regular smoking. DATA SOURCES: Primary data. STUDY SELECTION: Available genetic studies containing measures of CPD and the genotype of rs16969968 or its proxy. DATA EXTRACTION: Uniform statistical analysis scripts were run locally. Starting with 94,050 ever-smokers from 43 studies, we extracted the heavy smokers (CPD >20) and light smokers (CPD </=10) with age-at-onset information, reducing the sample size to 33,348. Each study was stratified into early-onset smokers (age at onset </=16 years) and late-onset smokers (age at onset >16 years), and a logistic regression of heavy vs light smoking with the rs16969968 genotype was computed for each stratum. Meta-analysis was performed within each age-at-onset stratum. DATA SYNTHESIS: Individuals with 1 risk allele at rs16969968 who were early-onset smokers were significantly more likely to be heavy smokers in adulthood (odds ratio [OR] = 1.45; 95% CI, 1.36-1.55; n = 13,843) than were carriers of the risk allele who were late-onset smokers (OR = 1.27; 95% CI, 1.21-1.33, n = 19,505) (P = .01). CONCLUSION: These results highlight an increased genetic vulnerability to smoking in early-onset smokers. Title: Draft genome of a Brazilian avian-pathogenic Escherichia coli strain and in silico characterization of virulence-related genes Rojas TC, Parizzi LP, Tiba MR, Chen L, Pereira GA, Sangal V, Yang J, Yu J, Dias da Silveira W Ref: Journal of Bacteriology, 194:3023, 2012 : PubMed ESTHER: Rojas_2012_J.Bacteriol_194_3023 PubMedSearch: Rojas 2012 J.Bacteriol 194 3023 PubMedID: 22582380 Gene_locus related to this paper: ecoli-IROD, ecoli-IROE, ecoli-ycfp, ecoli-YFBB, ecoli-ypt1, ecoli-YfhR Abstract Avian-pathogenic Escherichia coli (APEC) strains cause extraintestinal diseases in avian species. Here, we present the draft genome of an APEC strain (SCI-07) from Brazil that was isolated from skin lesions (gelatinous edema) on the head and periorbital tissues of a laying hen with swollen head syndrome. Title: Human Mesenchymal Stem Cell Transfusion Is Safe and Improves Liver Function in Acute-on-Chronic Liver Failure Patients Shi M, Zhang Z, Xu R, Lin H, Fu J, Zou Z, Zhang A, Shi J, Chen L and Wang FS <5 more author(s)> Shi M, Zhang Z, Xu R, Lin H, Fu J, Zou Z, Zhang A, Shi J, Chen L, Lv S, He W, Geng H, Jin L, Liu Z, Wang FS (- 5) Ref: Stem Cells Transl Med, 1:725, 2012 : PubMed ESTHER: Shi_2012_Stem.Cells.Transl.Med_1_725 PubMedSearch: Shi 2012 Stem.Cells.Transl.Med 1 725 PubMedID: 23197664 Abstract Acute-on-chronic liver failure (ACLF) is a severe, life-threatening complication, and new and efficient therapeutic strategies for liver failure are urgently needed. Mesenchymal stem cell (MSC) transfusions have been shown to reverse fulminant hepatic failure in mice and to improve liver function in patients with end-stage liver diseases. We assessed the safety and initial efficacy of umbilical cord-derived MSC (UC-MSC) transfusions for ACLF patients associated with hepatitis B virus (HBV) infection. A total of 43 ACLF patients were enrolled for this open-labeled and controlled study; 24 patients were treated with UC-MSCs, and 19 patients were treated with saline as controls. UC-MSC therapy was given three times at 4-week intervals. The liver function, adverse events, and survival rates were evaluated during the 48-week or 72-week follow-up period. No significant side effects were observed during the trial. The UC-MSC transfusions significantly increased the survival rates in ACLF patients; reduced the model for end-stage liver disease scores; increased serum albumin, cholinesterase, and prothrombin activity; and increased platelet counts. Serum total bilirubin and alanine aminotransferase levels were significantly decreased after the UC-MSC transfusions. UC-MSC transfusions are safe in the clinic and may serve as a novel therapeutic approach for HBV-associated ACLF patients. Title: Draft genome sequence of Alicyclobacillus hesperidum strain URH17-3-68 Wang P, Li L, Chen X, Jiang N, Liu G, Chen L, Xu J, Song H, Chen Z, Ma Y Ref: Journal of Bacteriology, 194:6348, 2012 : PubMed ESTHER: Wang_2012_J.Bacteriol_194_6348 PubMedSearch: Wang 2012 J.Bacteriol 194 6348 PubMedID: 23105079 Gene_locus related to this paper: 9bacl-h2esd6, 9bacl-j9e7t9 Abstract Alicyclobacillus hesperidum is a thermoacidophilic bacterium. We isolated strain URH17-3-68 from hot spring sludge in Tengchong, Yunnan province, China. Its extracellular products include heat- and acid-stable enzymes which are important for industrial applications. Here we report the draft genome of this strain. Title: The oyster genome reveals stress adaptation and complexity of shell formation Zhang G, Fang X, Guo X, Li L, Luo R, Xu F, Yang P, Zhang L, Wang X and Yin Y <66 more author(s)> Zhang G, Fang X, Guo X, Li L, Luo R, Xu F, Yang P, Zhang L, Wang X, Qi H, Xiong Z, Que H, Xie Y, Holland PW, Paps J, Zhu Y, Wu F, Chen Y, Wang J, Peng C, Meng J, Yang L, Liu J, Wen B, Zhang N, Huang Z, Zhu Q, Feng Y, Mount A, Hedgecock D, Xu Z, Liu Y, Domazet-Loso T, Du Y, Sun X, Zhang S, Liu B, Cheng P, Jiang X, Li J, Fan D, Wang W, Fu W, Wang T, Wang B, Zhang J, Peng Z, Li Y, Li N, Chen M, He Y, Tan F, Song X, Zheng Q, Huang R, Yang H, Du X, Chen L, Yang M, Gaffney PM, Wang S, Luo L, She Z, Ming Y, Huang W, Huang B, Zhang Y, Qu T, Ni P, Miao G, Wang Q, Steinberg CE, Wang H, Qian L, Liu X, Yin Y (- 66) Ref: Nature, 490:49, 2012 : PubMed ESTHER: Zhang_2012_Nature_490_49 PubMedSearch: Zhang 2012 Nature 490 49 PubMedID: 22992520 Gene_locus related to this paper: cragi-k1qzk7, cragi-k1rad0, cragi-k1p6v9, cragi-k1pa46, cragi-k1pga2, cragi-k1pp63, cragi-k1pwa8, cragi-k1q0b1.1, cragi-k1q0b1.2, cragi-k1q1h2, cragi-k1q2z6, cragi-k1qaj8, cragi-k1qaw5, cragi-k1qhl5, cragi-k1qly1, cragi-k1qqb1.1, cragi-k1qqb1.2, cragi-k1qs61, cragi-k1qs99, cragi-k1qwl6, cragi-k1r068, cragi-k1r0n3.1, cragi-k1r0n3.2, cragi-k1r0r4, cragi-k1r1i9, cragi-k1r8q9, cragi-k1rgi1, cragi-k1rig4, cragi-k1s0a7.1, cragi-k1s0a7.2, cragi-k1s0a7.3, cragi-k1q6q0, cragi-k1rru1, cragi-k1qfi4, cragi-k1qvm5, cragi-k1qq58, cragi-k1qdc0, cragi-k1r754, cragi-k1pje5, cragi-k1qca6, cragi-k1qdt5, cragi-k1qkz7, cragi-k1rgd2, cragi-k1puh6, cragi-k1raz4, cragi-k1qqj4, cragi-k1rbs1 Abstract The Pacific oyster Crassostrea gigas belongs to one of the most species-rich but genomically poorly explored phyla, the Mollusca. Here we report the sequencing and assembly of the oyster genome using short reads and a fosmid-pooling strategy, along with transcriptomes of development and stress response and the proteome of the shell. The oyster genome is highly polymorphic and rich in repetitive sequences, with some transposable elements still actively shaping variation. Transcriptome studies reveal an extensive set of genes responding to environmental stress. The expansion of genes coding for heat shock protein 70 and inhibitors of apoptosis is probably central to the oyster's adaptation to sessile life in the highly stressful intertidal zone. Our analyses also show that shell formation in molluscs is more complex than currently understood and involves extensive participation of cells and their exosomes. The oyster genome sequence fills a void in our understanding of the Lophotrochozoa. Title: Selective repression of MEF2 activity by PKA-dependent proteolysis of HDAC4 Backs J, Worst BC, Lehmann LH, Patrick DM, Jebessa Z, Kreusser MM, Sun Q, Chen L, Heft C and Olson EN <1 more author(s)> Backs J, Worst BC, Lehmann LH, Patrick DM, Jebessa Z, Kreusser MM, Sun Q, Chen L, Heft C, Katus HA, Olson EN (- 1) Ref: Journal of Cell Biology, 195:403, 2011 : PubMed ESTHER: Backs_2011_J.Cell.Biol_195_403 PubMedSearch: Backs 2011 J.Cell.Biol 195 403 PubMedID: 22042619 Abstract Histone deacetylase 4 (HDAC4) regulates numerous gene expression programs through its signal-dependent repression of myocyte enhancer factor 2 (MEF2) and serum response factor (SRF) transcription factors. In cardiomyocytes, calcium/calmodulin-dependent protein kinase II (CaMKII) signaling promotes hypertrophy and pathological remodeling, at least in part by phosphorylating HDAC4, with consequent stimulation of MEF2 activity. In this paper, we describe a novel mechanism whereby protein kinase A (PKA) overcomes CaMKII-mediated activation of MEF2 by regulated proteolysis of HDAC4. PKA induces the generation of an N-terminal HDAC4 cleavage product (HDAC4-NT). HDAC4-NT selectively inhibits activity of MEF2 but not SRF, thereby antagonizing the prohypertrophic actions of CaMKII signaling without affecting cardiomyocyte survival. Thus, HDAC4 functions as a molecular nexus for the antagonistic actions of the CaMKII and PKA pathways. These findings have implications for understanding the molecular basis of cardioprotection and other cellular processes in which CaMKII and PKA exert opposing effects. Title: The phospholipase A1 activity of lysophospholipase A-I links platelet activation to LPA production during blood coagulation Bolen AL, Naren AP, Yarlagadda S, Beranova-Giorgianni S, Chen L, Norman D, Baker DL, Rowland MM, Best MD and Tigyi G <4 more author(s)> Bolen AL, Naren AP, Yarlagadda S, Beranova-Giorgianni S, Chen L, Norman D, Baker DL, Rowland MM, Best MD, Sano T, Tsukahara T, Liliom K, Igarashi Y, Tigyi G (- 4) Ref: J Lipid Res, 52:958, 2011 : PubMed ESTHER: Bolen_2011_J.Lipid.Res_52_958 PubMedSearch: Bolen 2011 J.Lipid.Res 52 958 PubMedID: 21393252 Abstract Platelet activation initiates an upsurge in polyunsaturated (18:2 and 20:4) lysophosphatidic acid (LPA) production. The biochemical pathway(s) responsible for LPA production during blood clotting are not yet fully understood. Here we describe the purification of a phospholipase A(1) (PLA(1)) from thrombin-activated human platelets using sequential chromatographic steps followed by fluorophosphonate (FP)-biotin affinity labeling and proteomics characterization that identified acyl-protein thioesterase 1 (APT1), also known as lysophospholipase A-I (LYPLA-I; accession code O75608) as a novel PLA(1). Addition of this recombinant PLA(1) significantly increased the production of sn-2-esterified polyunsaturated LPCs and the corresponding LPAs in plasma. We examined the regioisomeric preference of lysophospholipase D/autotaxin (ATX), which is the subsequent step in LPA production. To prevent acyl migration, ether-linked regioisomers of oleyl-sn-glycero-3-phosphocholine (lyso-PAF) were synthesized. ATX preferred the sn-1 to the sn-2 regioisomer of lyso-PAF. We propose the following LPA production pathway in blood: 1) Activated platelets release PLA(1); 2) PLA(1) generates a pool of sn-2 lysophospholipids; 3) These newly generated sn-2 lysophospholipids undergo acyl migration to yield sn-1 lysophospholipids, which are the preferred substrates of ATX; and 4) ATX cleaves the sn-1 lysophospholipids to generate sn-1 LPA species containing predominantly 18:2 and 20:4 fatty acids. Title: Theoretical study of the mechanism of proton transfer in the esterase EstB from Burkholderia gladioli Chen L, Kong X, Liang Z, Ye F, Yu K, Dai W, Wu D, Luo C, Jiang H Ref: J Phys Chem B, 115:13019, 2011 : PubMed ESTHER: Chen_2011_J.Phys.Chem.B_115_13019 PubMedSearch: Chen 2011 J.Phys.Chem.B 115 13019 PubMedID: 21910435 Abstract Esterase EstB from Burkholderia gladioli belongs to a novel class of esterases homologous to penicillin binding proteins, notably DD-peptidase and class C beta-lactamases. It can cleave the side chain acetyl ester group from cephalosporins leaving the beta-lactam ring intact, which is a feature of relevance to industrial biocatalytic applications in the production of semisynthetic cephalosporin derivatives. Due to its important role as a potential biocatalyst in industry, the significance of EstB has been greatly appreciated. However, the molecular basis for those residues involving catalysis of EstB remains elusive. By analyzing the crystal structure of EstB, we identified a conserved water molecule in active-site cavity which might mediate an intramolecular proton transfer (PT) from Lys78 to Asp186 via Tyr133. Then a combined computational approach including molecular dynamics (MD) simulations and quantum mechanics/molecular mechanics (QM/MM) calculations was employed to explore this presumable PT mode in the native enzyme. A 30 ns MD simulation of the enzyme highlights the conserved H-bond network involving Lys78, Tyr133, Asp186, and the conserved water molecule in the active site. In particular, the water molecule did not exchange with bulk solvent, indicating its structural and functional relevance. The energy profile calculated by QM/MM approach displayed a notably low PT barrier (2.2 kcal/mol) and a dramatic energy difference (14.1 kcal/mol) in reactants versus immediate products, which implies that the proposed proton shuttle is concerted and energetically favorable. Our studies offer a reasonable pathway to yield a free base by assisting Lys78 deprotonation, thereby paving the way for future studies on Ser75 activation that is a critical step in catalysis by EstB, as well as biocatalyst development by rational attempts. This PT mode would also afford clues for the forthcoming investigation on acyltransferase LovD that is homologous to EstB. Title: Genome analyses of Icelandic strains of Sulfolobus islandicus, model organisms for genetic and virus-host interaction studies Guo L, Brugger K, Liu C, Shah SA, Zheng H, Zhu Y, Wang S, Lillestol RK, Chen L and Garrett RA <5 more author(s)> Guo L, Brugger K, Liu C, Shah SA, Zheng H, Zhu Y, Wang S, Lillestol RK, Chen L, Frank J, Prangishvili D, Paulin L, She Q, Huang L, Garrett RA (- 5) Ref: Journal of Bacteriology, 193:1672, 2011 : PubMed ESTHER: Guo_2011_J.Bacteriol_193_1672 PubMedSearch: Guo 2011 J.Bacteriol 193 1672 PubMedID: 21278296 Gene_locus related to this paper: sulir-f0nbu1, sulso-APEH1, sulso-APEH3, sulso-dlhh, sulir-f0ndq1 Abstract The genomes of two Sulfolobus islandicus strains obtained from Icelandic solfataras were sequenced and analyzed. Strain REY15A is a host for a versatile genetic toolbox. It exhibits a genome of minimal size, is stable genetically, and is easy to grow and manipulate. Strain HVE10/4 shows a broad host range for exceptional crenarchaeal viruses and conjugative plasmids and was selected for studying their life cycles and host interactions. The genomes of strains REY15A and HVE10/4 are 2.5 and 2.7 Mb, respectively, and each genome carries a variable region of 0.5 to 0.7 Mb where major differences in gene content and gene order occur. These include gene clusters involved in specific metabolic pathways, multiple copies of VapBC antitoxin-toxin gene pairs, and in strain HVE10/4, a 50-kb region rich in glycosyl transferase genes. The variable region also contains most of the insertion sequence (IS) elements and high proportions of the orphan orfB elements and SMN1 miniature inverted-repeat transposable elements (MITEs), as well as the clustered regular interspaced short palindromic repeat (CRISPR)-based immune systems, which are complex and diverse in both strains, consistent with them having been mobilized both intra- and intercellularly. In contrast, the remainder of the genomes are highly conserved in their protein and RNA gene syntenies, closely resembling those of other S. islandicus and Sulfolobus solfataricus strains, and they exhibit only minor remnants of a few genetic elements, mainly conjugative plasmids, which have integrated at a few tRNA genes lacking introns. This provides a possible rationale for the presence of the introns. Title: Evaluation of pharmacokinetic parameters and dipeptidyl peptidase-4 inhibition following single doses of sitagliptin in healthy, young Japanese males Herman GA, Mistry GC, Yi B, Bergman AJ, Wang AQ, Zeng W, Chen L, Snyder K, Ruckle JL and Wagner JA <4 more author(s)> Herman GA, Mistry GC, Yi B, Bergman AJ, Wang AQ, Zeng W, Chen L, Snyder K, Ruckle JL, Larson PJ, Davies MJ, Langdon RB, Gottesdiener KM, Wagner JA (- 4) Ref: British Journal of Clinical Pharmacology, 71:429, 2011 : PubMed ESTHER: Herman_2011_Br.J.Clin.Pharmacol_71_429 PubMedSearch: Herman 2011 Br.J.Clin.Pharmacol 71 429 PubMedID: 21284702 Abstract AIMS: Sitagliptin is a selective inhibitor of dipeptidyl peptidase-4 (DPP-4) used to treat type 2 diabetes. The present aim was to evaluate pharmacokinetic (PK), pharmacodynamic (PD) and safety characteristics of sitagliptin following single doses in healthy, young Japanese males. METHODS: In this alternating two-panel, randomized, controlled double-blind study, six healthy Japanese male subjects (aged 20-46 years) in each panel received single oral doses of 5-400mg sitagliptin and two received placebo. Plasma and urine drug concentrations were measured from 0-48h post dose and plasma DPP-4 inhibition from 0-24h post dose. The results were compared with historical data from young, healthy non-Japanese males. RESULTS: Plasma concentrations of sitagliptin increased approximately in proportion to dose; maximum concentrations occurred 2-6h post-dose. The mean apparent terminal half-life for plasma sitagliptin was 9-14h, with the half-life slightly decreasing as the dose increased. The mean dose fraction excreted unchanged in the urine was 0.73-1.00. Ingestion of a traditional Japanese breakfast prior to dosing had only a minor effect on PK parameters. After correction for dilution and competition effects during assay, doses of sitagliptin >/=50mg resulted in weighted average DPP-4 inhibition from 0-24h post-dose >94% (without correction, >78%). No clinically meaningful differences in PK and DPP-4 inhibition parameters were found between Japanese and non-Japanese subjects. Sitagliptin was generally well tolerated and there were no serious adverse experiences or episodes of hypoglycaemia. CONCLUSIONS: The PK and PD findings from this study are consistent with once daily dosing of sitagliptin in Japanese patients with type 2 diabetes. Title: Genome sequencing reveals insights into physiology and longevity of the naked mole rat Kim EB, Fang X, Fushan AA, Huang Z, Lobanov AV, Han L, Marino SM, Sun X, Turanov AA and Gladyshev VN <26 more author(s)> Kim EB, Fang X, Fushan AA, Huang Z, Lobanov AV, Han L, Marino SM, Sun X, Turanov AA, Yang P, Yim SH, Zhao X, Kasaikina MV, Stoletzki N, Peng C, Polak P, Xiong Z, Kiezun A, Zhu Y, Chen Y, Kryukov GV, Zhang Q, Peshkin L, Yang L, Bronson RT, Buffenstein R, Wang B, Han C, Li Q, Chen L, Zhao W, Sunyaev SR, Park TJ, Zhang G, Wang J, Gladyshev VN (- 26) Ref: Nature, 479:223, 2011 : PubMed ESTHER: Kim_2011_Nature_479_223 PubMedSearch: Kim 2011 Nature 479 223 PubMedID: 21993625 Gene_locus related to this paper: hetga-g5amh8, hetga-g5an68, hetga-g5anw7, hetga-g5as32, hetga-g5atg6, hetga-g5b5b7, hetga-g5b9m6, hetga-g5bdh8, hetga-g5bmv3, hetga-g5bp66, hetga-g5bp67, hetga-g5bp68, hetga-g5bpp3, hetga-g5bsd4, hetga-g5bul0, hetga-g5bw29, hetga-g5bze3, hetga-g5c6q5, hetga-g5bfw4, hetga-g5b832, hetga-g5c6q8, hetga-g5bj87, hetga-a0a0p6jix7, hetga-g5c108, hetga-g5c109, hetga-g5c110, hetga-g5arh0, hetga-g5aua1, hetga-g5are8, hetga-g5ax31, hetga-a0a0p6jud6, hetga-g5b7v3, hetga-a0a0p6jw61, hetga-a0a0p6jdl4, hetga-g5bg83, hetga-g5bcu5, hetga-g5bvp0, hetga-g5b8m7, hetga-g5b709, hetga-g5bt99, hetga-g5b4q4 Abstract The naked mole rat (Heterocephalus glaber) is a strictly subterranean, extraordinarily long-lived eusocial mammal. Although it is the size of a mouse, its maximum lifespan exceeds 30 years, making this animal the longest-living rodent. Naked mole rats show negligible senescence, no age-related increase in mortality, and high fecundity until death. In addition to delayed ageing, they are resistant to both spontaneous cancer and experimentally induced tumorigenesis. Naked mole rats pose a challenge to the theories that link ageing, cancer and redox homeostasis. Although characterized by significant oxidative stress, the naked mole rat proteome does not show age-related susceptibility to oxidative damage or increased ubiquitination. Naked mole rats naturally reside in large colonies with a single breeding female, the 'queen', who suppresses the sexual maturity of her subordinates. They also live in full darkness, at low oxygen and high carbon dioxide concentrations, and are unable to sustain thermogenesis nor feel certain types of pain. Here we report the sequencing and analysis of the naked mole rat genome, which reveals unique genome features and molecular adaptations consistent with cancer resistance, poikilothermy, hairlessness and insensitivity to low oxygen, and altered visual function, circadian rythms and taste sensing. This information provides insights into the naked mole rat's exceptional longevity and ability to live in hostile conditions, in the dark and at low oxygen. The extreme traits of the naked mole rat, together with the reported genome and transcriptome information, offer opportunities for understanding ageing and advancing other areas of biological and biomedical research. Title: Ligand-binding domain of an alpha7-nicotinic receptor chimera and its complex with agonist Li SX, Huang S, Bren N, Noridomi K, Dellisanti CD, Sine SM, Chen L Ref: Nat Neurosci, 14:1253, 2011 : PubMed ESTHER: Li_2011_Nat.Neurosci_14_1253 PubMedSearch: Li 2011 Nat.Neurosci 14 1253 PubMedID: 21909087 Abstract The alpha(7) acetylcholine receptor (AChR) mediates pre- and postsynaptic neurotransmission in the central nervous system and is a potential therapeutic target in neurodegenerative, neuropsychiatric and inflammatory disorders. We determined the crystal structure of the extracellular domain of a receptor chimera constructed from the human alpha(7) AChR and Lymnaea stagnalis acetylcholine binding protein (AChBP), which shares 64% sequence identity and 71% similarity with native alpha(7). We also determined the structure with bound epibatidine, a potent AChR agonist. Comparison of the structures revealed molecular rearrangements and interactions that mediate agonist recognition and early steps in signal transduction in alpha(7) AChRs. The structures further revealed a ring of negative charge within the central vestibule, poised to contribute to cation selectivity. Structure-guided mutational studies disclosed distinctive contributions to agonist recognition and signal transduction in alpha(7) AChRs. The structures provide a realistic template for structure-aided drug design and for defining structure-function relationships of alpha(7) AChRs. Title: Complete genome sequence of Treponema paraluiscuniculi, strain Cuniculi A: the loss of infectivity to humans is associated with genome decay Smajs D, Zobanikova M, Strouhal M, Cejkova D, Dugan-Rocha S, Pospisilova P, Norris SJ, Albert T, Qin X and Weinstock GM <5 more author(s)> Smajs D, Zobanikova M, Strouhal M, Cejkova D, Dugan-Rocha S, Pospisilova P, Norris SJ, Albert T, Qin X, Hallsworth-Pepin K, Buhay C, Muzny DM, Chen L, Gibbs RA, Weinstock GM (- 5) Ref: PLoS ONE, 6:e20415, 2011 : PubMed ESTHER: Smajs_2011_PLoS.ONE_6_E20415 PubMedSearch: Smajs 2011 PLoS.ONE 6 E20415 PubMedID: 21655244 Gene_locus related to this paper: trepa-TP0902 Abstract Treponema paraluiscuniculi is the causative agent of rabbit venereal spirochetosis. It is not infectious to humans, although its genome structure is very closely related to other pathogenic Treponema species including Treponema pallidum subspecies pallidum, the etiological agent of syphilis. In this study, the genome sequence of Treponema paraluiscuniculi, strain Cuniculi A, was determined by a combination of several high-throughput sequencing strategies. Whereas the overall size (1,133,390 bp), arrangement, and gene content of the Cuniculi A genome closely resembled those of the T. pallidum genome, the T. paraluiscuniculi genome contained a markedly higher number of pseudogenes and gene fragments (51). In addition to pseudogenes, 33 divergent genes were also found in the T. paraluiscuniculi genome. A set of 32 (out of 84) affected genes encoded proteins of known or predicted function in the Nichols genome. These proteins included virulence factors, gene regulators and components of DNA repair and recombination. The majority (52 or 61.9%) of the Cuniculi A pseudogenes and divergent genes were of unknown function. Our results indicate that T. paraluiscuniculi has evolved from a T. pallidum-like ancestor and adapted to a specialized host-associated niche (rabbits) during loss of infectivity to humans. The genes that are inactivated or altered in T. paraluiscuniculi are candidates for virulence factors important in the infectivity and pathogenesis of T. pallidum subspecies. Title: Over-expression of human lipoprotein lipase in mouse mammary glands leads to reduction of milk triglyceride and delayed growth of suckling pups Wang Y, Tong J, Li S, Zhang R, Chen L, Zheng M, Wang M, Liu G, Dai Y and Li N <1 more author(s)> Wang Y, Tong J, Li S, Zhang R, Chen L, Zheng M, Wang M, Liu G, Dai Y, Zhao Y, Li N (- 1) Ref: PLoS ONE, 6:e20895, 2011 : PubMed ESTHER: Wang_2011_PLoS.One_6_e20895 PubMedSearch: Wang 2011 PLoS.One 6 e20895 PubMedID: 21698114 Abstract BACKGROUND: The mammary gland is a conserved site of lipoprotein lipase expression across species and lipoprotein lipase attachment to the luminal surface of mammary gland vascular endothelial cells has been implicated in the direction of circulating triglycerides into milk synthesis during lactation. PRINCIPAL FINDINGS: Here we report generation of transgenic mice harboring a human lipoprotein lipase gene driven by a mammary gland-specific promoter. Lipoprotein lipase levels in transgenic milk was raised to 0.16 mg/ml, corresponding to an activity of 8772.95 mU/ml. High lipoprotein lipase activity led to a significant reduction of triglyceride concentration in milk, but other components were largely unchanged. Normal pups fed with transgenic milk showed inferior growth performances compared to those fed with normal milk. CONCLUSION: Our study suggests a possibility to reduce the triglyceride content of cow milk using transgenic technology. Title: Crystal structure of a triacylglycerol lipase from Penicillium expansum at 1.3 A determined by sulfur SAD Bian C, Yuan C, Chen L, Meehan EJ, Jiang L, Huang Z, Lin L, Huang M Ref: Proteins, 78:1601, 2010 : PubMed ESTHER: Bian_2010_Proteins_78_1601 PubMedSearch: Bian 2010 Proteins 78 1601 PubMedID: 20146362 Gene_locus related to this paper: penex-Q9HFW6 Title: A catalog of reference genomes from the human microbiome Nelson KE, Weinstock GM, Highlander SK, Worley KC, Creasy HH, Wortman JR, Rusch DB, Mitreva M, Sodergren E and Zhu D <73 more author(s)> Nelson KE, Weinstock GM, Highlander SK, Worley KC, Creasy HH, Wortman JR, Rusch DB, Mitreva M, Sodergren E, Chinwalla AT, Feldgarden M, Gevers D, Haas BJ, Madupu R, Ward DV, Birren BW, Gibbs RA, Methe B, Petrosino JF, Strausberg RL, Sutton GG, White OR, Wilson RK, Durkin S, Giglio MG, Gujja S, Howarth C, Kodira CD, Kyrpides N, Mehta T, Muzny DM, Pearson M, Pepin K, Pati A, Qin X, Yandava C, Zeng Q, Zhang L, Berlin AM, Chen L, Hepburn TA, Johnson J, McCorrison J, Miller J, Minx P, Nusbaum C, Russ C, Sykes SM, Tomlinson CM, Young S, Warren WC, Badger J, Crabtree J, Markowitz VM, Orvis J, Cree A, Ferriera S, Fulton LL, Fulton RS, Gillis M, Hemphill LD, Joshi V, Kovar C, Torralba M, Wetterstrand KA, Abouellleil A, Wollam AM, Buhay CJ, Ding Y, Dugan S, Fitzgerald MG, Holder M, Hostetler J, Clifton SW, Allen-Vercoe E, Earl AM, Farmer CN, Liolios K, Surette MG, Xu Q, Pohl C, Wilczek-Boney K, Zhu D (- 73) Ref: Science, 328:994, 2010 : PubMed ESTHER: Nelson_2010_Science_328_994 PubMedSearch: Nelson 2010 Science 328 994 PubMedID: 20489017 Gene_locus related to this paper: strp2-q04l35, strpn-AXE1, strpn-pepx Abstract The human microbiome refers to the community of microorganisms, including prokaryotes, viruses, and microbial eukaryotes, that populate the human body. The National Institutes of Health launched an initiative that focuses on describing the diversity of microbial species that are associated with health and disease. The first phase of this initiative includes the sequencing of hundreds of microbial reference genomes, coupled to metagenomic sequencing from multiple body sites. Here we present results from an initial reference genome sequencing of 178 microbial genomes. From 547,968 predicted polypeptides that correspond to the gene complement of these strains, previously unidentified ("novel") polypeptides that had both unmasked sequence length greater than 100 amino acids and no BLASTP match to any nonreference entry in the nonredundant subset were defined. This analysis resulted in a set of 30,867 polypeptides, of which 29,987 (approximately 97%) were unique. In addition, this set of microbial genomes allows for approximately 40% of random sequences from the microbiome of the gastrointestinal tract to be associated with organisms based on the match criteria used. Insights into pan-genome analysis suggest that we are still far from saturating microbial species genetic data sets. In addition, the associated metrics and standards used by our group for quality assurance are presented. Title: The genome of a songbird Warren WC, Clayton DF, Ellegren H, Arnold AP, Hillier LW, Kunstner A, Searle S, White S, Vilella AJ and Wilson RK <72 more author(s)> Warren WC, Clayton DF, Ellegren H, Arnold AP, Hillier LW, Kunstner A, Searle S, White S, Vilella AJ, Fairley S, Heger A, Kong L, Ponting CP, Jarvis ED, Mello CV, Minx P, Lovell P, Velho TA, Ferris M, Balakrishnan CN, Sinha S, Blatti C, London SE, Li Y, Lin YC, George J, Sweedler J, Southey B, Gunaratne P, Watson M, Nam K, Backstrom N, Smeds L, Nabholz B, Itoh Y, Whitney O, Pfenning AR, Howard J, Volker M, Skinner BM, Griffin DK, Ye L, McLaren WM, Flicek P, Quesada V, Velasco G, Lopez-Otin C, Puente XS, Olender T, Lancet D, Smit AF, Hubley R, Konkel MK, Walker JA, Batzer MA, Gu W, Pollock DD, Chen L, Cheng Z, Eichler EE, Stapley J, Slate J, Ekblom R, Birkhead T, Burke T, Burt D, Scharff C, Adam I, Richard H, Sultan M, Soldatov A, Lehrach H, Edwards SV, Yang SP, Li X, Graves T, Fulton L, Nelson J, Chinwalla A, Hou S, Mardis ER, Wilson RK (- 72) Ref: Nature, 464:757, 2010 : PubMed ESTHER: Warren_2010_Nature_464_757 PubMedSearch: Warren 2010 Nature 464 757 PubMedID: 20360741 Gene_locus related to this paper: taegu-b5fyu7, taegu-BCHE, taegu-h0z4h9, taegu-h0z9w8, taegu-h0zat6, taegu-h0ze48, taegu-h0zha8, taegu-h0zkr8, taegu-h0zqp3, taegu-h0zz82, taegu-h0zqs1, taegu-h0yy64, taegu-h0yv40, taegu-h0yyt1, taegu-h0zcc8, taegu-h0z3k5, taegu-h0yw95, taegu-h0zkm7, taegu-h1a198, taegu-h0z6w2, taegu-h0zl93, taegu-h0zt33, taegu-h0yp71, taegu-h0ypu5, taegu-h1a048, taegu-h0ztq1, fical-u3kau2, 9pass-a0a093qu66, taegu-h0z7g0, fical-u3jnn0, taegu-h0zb80, taegu-h0zb89, taegu-h0z994, taegu-h0ztj6 Abstract The zebra finch is an important model organism in several fields with unique relevance to human neuroscience. Like other songbirds, the zebra finch communicates through learned vocalizations, an ability otherwise documented only in humans and a few other animals and lacking in the chicken-the only bird with a sequenced genome until now. Here we present a structural, functional and comparative analysis of the genome sequence of the zebra finch (Taeniopygia guttata), which is a songbird belonging to the large avian order Passeriformes. We find that the overall structures of the genomes are similar in zebra finch and chicken, but they differ in many intrachromosomal rearrangements, lineage-specific gene family expansions, the number of long-terminal-repeat-based retrotransposons, and mechanisms of sex chromosome dosage compensation. We show that song behaviour engages gene regulatory networks in the zebra finch brain, altering the expression of long non-coding RNAs, microRNAs, transcription factors and their targets. We also show evidence for rapid molecular evolution in the songbird lineage of genes that are regulated during song experience. These results indicate an active involvement of the genome in neural processes underlying vocal communication and identify potential genetic substrates for the evolution and regulation of this behaviour. Title: The genome sequence of taurine cattle: a window to ruminant biology and evolution Elsik CG, Tellam RL, Worley KC, Gibbs RA, Muzny DM, Weinstock GM, Adelson DL, Eichler EE, Elnitski L and Zhao FQ <297 more author(s)> Elsik CG, Tellam RL, Worley KC, Gibbs RA, Muzny DM, Weinstock GM, Adelson DL, Eichler EE, Elnitski L, Guigo R, Hamernik DL, Kappes SM, Lewin HA, Lynn DJ, Nicholas FW, Reymond A, Rijnkels M, Skow LC, Zdobnov EM, Schook L, Womack J, Alioto T, Antonarakis SE, Astashyn A, Chapple CE, Chen HC, Chrast J, Camara F, Ermolaeva O, Henrichsen CN, Hlavina W, Kapustin Y, Kiryutin B, Kitts P, Kokocinski F, Landrum M, Maglott D, Pruitt K, Sapojnikov V, Searle SM, Solovyev V, Souvorov A, Ucla C, Wyss C, Anzola JM, Gerlach D, Elhaik E, Graur D, Reese JT, Edgar RC, McEwan JC, Payne GM, Raison JM, Junier T, Kriventseva EV, Eyras E, Plass M, Donthu R, Larkin DM, Reecy J, Yang MQ, Chen L, Cheng Z, Chitko-McKown CG, Liu GE, Matukumalli LK, Song J, Zhu B, Bradley DG, Brinkman FS, Lau LP, Whiteside MD, Walker A, Wheeler TT, Casey T, German JB, Lemay DG, Maqbool NJ, Molenaar AJ, Seo S, Stothard P, Baldwin CL, Baxter R, Brinkmeyer-Langford CL, Brown WC, Childers CP, Connelley T, Ellis SA, Fritz K, Glass EJ, Herzig CT, Iivanainen A, Lahmers KK, Bennett AK, Dickens CM, Gilbert JG, Hagen DE, Salih H, Aerts J, Caetano AR, Dalrymple B, Garcia JF, Gill CA, Hiendleder SG, Memili E, Spurlock D, Williams JL, Alexander L, Brownstein MJ, Guan L, Holt RA, Jones SJ, Marra MA, Moore R, Moore SS, Roberts A, Taniguchi M, Waterman RC, Chacko J, Chandrabose MM, Cree A, Dao MD, Dinh HH, Gabisi RA, Hines S, Hume J, Jhangiani SN, Joshi V, Kovar CL, Lewis LR, Liu YS, Lopez J, Morgan MB, Nguyen NB, Okwuonu GO, Ruiz SJ, Santibanez J, Wright RA, Buhay C, Ding Y, Dugan-Rocha S, Herdandez J, Holder M, Sabo A, Egan A, Goodell J, Wilczek-Boney K, Fowler GR, Hitchens ME, Lozado RJ, Moen C, Steffen D, Warren JT, Zhang J, Chiu R, Schein JE, Durbin KJ, Havlak P, Jiang H, Liu Y, Qin X, Ren Y, Shen Y, Song H, Bell SN, Davis C, Johnson AJ, Lee S, Nazareth LV, Patel BM, Pu LL, Vattathil S, Williams RL, Jr., Curry S, Hamilton C, Sodergren E, Wheeler DA, Barris W, Bennett GL, Eggen A, Green RD, Harhay GP, Hobbs M, Jann O, Keele JW, Kent MP, Lien S, McKay SD, McWilliam S, Ratnakumar A, Schnabel RD, Smith T, Snelling WM, Sonstegard TS, Stone RT, Sugimoto Y, Takasuga A, Taylor JF, Van Tassell CP, Macneil MD, Abatepaulo AR, Abbey CA, Ahola V, Almeida IG, Amadio AF, Anatriello E, Bahadue SM, Biase FH, Boldt CR, Carroll JA, Carvalho WA, Cervelatti EP, Chacko E, Chapin JE, Cheng Y, Choi J, Colley AJ, de Campos TA, De Donato M, Santos IK, de Oliveira CJ, Deobald H, Devinoy E, Donohue KE, Dovc P, Eberlein A, Fitzsimmons CJ, Franzin AM, Garcia GR, Genini S, Gladney CJ, Grant JR, Greaser ML, Green JA, Hadsell DL, Hakimov HA, Halgren R, Harrow JL, Hart EA, Hastings N, Hernandez M, Hu ZL, Ingham A, Iso-Touru T, Jamis C, Jensen K, Kapetis D, Kerr T, Khalil SS, Khatib H, Kolbehdari D, Kumar CG, Kumar D, Leach R, Lee JC, Li C, Logan KM, Malinverni R, Marques E, Martin WF, Martins NF, Maruyama SR, Mazza R, McLean KL, Medrano JF, Moreno BT, More DD, Muntean CT, Nandakumar HP, Nogueira MF, Olsaker I, Pant SD, Panzitta F, Pastor RC, Poli MA, Poslusny N, Rachagani S, Ranganathan S, Razpet A, Riggs PK, Rincon G, Rodriguez-Osorio N, Rodriguez-Zas SL, Romero NE, Rosenwald A, Sando L, Schmutz SM, Shen L, Sherman L, Southey BR, Lutzow YS, Sweedler JV, Tammen I, Telugu BP, Urbanski JM, Utsunomiya YT, Verschoor CP, Waardenberg AJ, Wang Z, Ward R, Weikard R, Welsh TH, Jr., White SN, Wilming LG, Wunderlich KR, Yang J, Zhao FQ (- 297) Ref: Science, 324:522, 2009 : PubMed ESTHER: Elsik_2009_Science_324_522 PubMedSearch: Elsik 2009 Science 324 522 PubMedID: 19390049 Gene_locus related to this paper: bovin-2neur, bovin-a0jnh8, bovin-a5d7b7, bovin-ACHE, bovin-balip, bovin-dpp4, bovin-dpp6, bovin-e1bi31, bovin-e1bn79, bovin-est8, bovin-f1mbd6, bovin-f1mi11, bovin-f1mr65, bovin-f1n1l4, bovin-g3mxp5, bovin-q0vcc8, bovin-q2kj30, bovin-q3t0r6, bovin-thyro Abstract To understand the biology and evolution of ruminants, the cattle genome was sequenced to about sevenfold coverage. The cattle genome contains a minimum of 22,000 genes, with a core set of 14,345 orthologs shared among seven mammalian species of which 1217 are absent or undetected in noneutherian (marsupial or monotreme) genomes. Cattle-specific evolutionary breakpoint regions in chromosomes have a higher density of segmental duplications, enrichment of repetitive elements, and species-specific variations in genes associated with lactation and immune responsiveness. Genes involved in metabolism are generally highly conserved, although five metabolic genes are deleted or extensively diverged from their human orthologs. The cattle genome sequence thus provides a resource for understanding mammalian evolution and accelerating livestock genetic improvement for milk and meat production. Title: The mosaic genome structure of the Wolbachia wRi strain infecting Drosophila simulans Klasson L, Westberg J, Sapountzis P, Naslund K, Lutnaes Y, Darby AC, Veneti Z, Chen L, Braig HR and Andersson SG <2 more author(s)> Klasson L, Westberg J, Sapountzis P, Naslund K, Lutnaes Y, Darby AC, Veneti Z, Chen L, Braig HR, Garrett R, Bourtzis K, Andersson SG (- 2) Ref: Proc Natl Acad Sci U S A, 106:5725, 2009 : PubMed ESTHER: Klasson_2009_Proc.Natl.Acad.Sci.U.S.A_106_5725 PubMedSearch: Klasson 2009 Proc.Natl.Acad.Sci.U.S.A 106 5725 PubMedID: 19307581 Abstract The obligate intracellular bacterium Wolbachia pipientis infects around 20% of all insect species. It is maternally inherited and induces reproductive alterations of insect populations by male killing, feminization, parthenogenesis, or cytoplasmic incompatibility. Here, we present the 1,445,873-bp genome of W. pipientis strain wRi that induces very strong cytoplasmic incompatibility in its natural host Drosophila simulans. A comparison with the previously sequenced genome of W. pipientis strain wMel from Drosophila melanogaster identified 35 breakpoints associated with mobile elements and repeated sequences that are stable in Drosophila lines transinfected with wRi. Additionally, 450 genes with orthologs in wRi and wMel were sequenced from the W. pipientis strain wUni, responsible for the induction of parthenogenesis in the parasitoid wasp Muscidifurax uniraptor. The comparison of these A-group Wolbachia strains uncovered the most highly recombining intracellular bacterial genomes known to date. This was manifested in a 500-fold variation in sequence divergences at synonymous sites, with different genes and gene segments supporting different strain relationships. The substitution-frequency profile resembled that of Neisseria meningitidis, which is characterized by rampant intraspecies recombination, rather than that of Rickettsia, where genes mostly diverge by nucleotide substitutions. The data further revealed diversification of ankyrin repeat genes by short tandem duplications and provided examples of horizontal gene transfer across A- and B-group strains that infect D. simulans. These results suggest that the transmission dynamics of Wolbachia and the opportunity for coinfections have created a freely recombining intracellular bacterial community with mosaic genomes. Title: Complete genome sequence of the extremophilic Bacillus cereus strain Q1 with industrial applications Xiong Z, Jiang Y, Qi D, Lu H, Yang F, Yang J, Chen L, Sun L, Xu X and Jin Q <2 more author(s)> Xiong Z, Jiang Y, Qi D, Lu H, Yang F, Yang J, Chen L, Sun L, Xu X, Xue Y, Zhu Y, Jin Q (- 2) Ref: Journal of Bacteriology, 191:1120, 2009 : PubMed ESTHER: Xiong_2009_J.Bacteriol_191_1120 PubMedSearch: Xiong 2009 J.Bacteriol 191 1120 PubMedID: 19060151 Gene_locus related to this paper: bacah-a0rer5, bacan-BA0954, bacan-BA3703, bacan-BA4338, bacan-BA5009, bacan-DHBF, bacc1-q73br9, bacce-BC0192, bacce-BC0968, bacce-BC1788, bacce-BC2141, bacce-BC2171, bacce-BC4102, bacce-BC4854, bacce-BC4862, bacce-BC5130, bacce-c2mr40, bacce-PHAC, bacce-q72yu1, bacce-q736x9, baccq-b9j170, baccr-pepx, baccz-q636u4, bacti-q3elq7 Abstract Bacillus cereus strain Q1 was isolated from a deep-subsurface oil reservoir in the Daqing oil field in northeastern China. This strain is able to produce biosurfactants and to survive in extreme environments. Here we report the finished and annotated genome sequence of this organism. Title: Complete genome sequence of Haemophilus parasuis SH0165 Yue M, Yang F, Yang J, Bei W, Cai X, Chen L, Dong J, Zhou R, Jin M and Chen H <1 more author(s)> Yue M, Yang F, Yang J, Bei W, Cai X, Chen L, Dong J, Zhou R, Jin M, Jin Q, Chen H (- 1) Ref: Journal of Bacteriology, 191:1359, 2009 : PubMed ESTHER: Yue_2009_J.Bacteriol_191_1359 PubMedSearch: Yue 2009 J.Bacteriol 191 1359 PubMedID: 19074396 Gene_locus related to this paper: haepr-b0qsi5, haepr-b0qve9, haeps-b8f6u1, haeps-b8f692, haeps-b8f714 Abstract Haemophilus parasuis is the causative agent of Glasser's disease, which produces big losses in swine populations worldwide. H. parasuis SH0165, belonging to the dominant serovar 5 in China, is a clinically isolated strain with high-level virulence. Here, we report the first completed genome sequence of this species. Title: Large scale variation in Enterococcus faecalis illustrated by the genome analysis of strain OG1RF Bourgogne A, Garsin DA, Qin X, Singh KV, Sillanpaa J, Yerrapragada S, Ding Y, Dugan-Rocha S, Buhay C and Weinstock GM <18 more author(s)> Bourgogne A, Garsin DA, Qin X, Singh KV, Sillanpaa J, Yerrapragada S, Ding Y, Dugan-Rocha S, Buhay C, Shen H, Chen G, Williams G, Muzny D, Maadani A, Fox KA, Gioia J, Chen L, Shang Y, Arias CA, Nallapareddy SR, Zhao M, Prakash VP, Chowdhury S, Jiang H, Gibbs RA, Murray BE, Highlander SK, Weinstock GM (- 18) Ref: Genome Biol, 9:R110, 2008 : PubMed ESTHER: Bourgogne_2008_Genome.Biol_9_R110 PubMedSearch: Bourgogne 2008 Genome.Biol 9 R110 PubMedID: 18611278 Gene_locus related to this paper: entfa-EF0101, entfa-EF0449, entfa-EF1236, entfa-EF2618, entfa-q5j1l4, entfl-e2z7d4 Abstract BACKGROUND: Enterococcus faecalis has emerged as a major hospital pathogen. To explore its diversity, we sequenced E. faecalis strain OG1RF, which is commonly used for molecular manipulation and virulence studies. RESULTS: The 2,739,625 base pair chromosome of OG1RF was found to contain approximately 232 kilobases unique to this strain compared to V583, the only publicly available sequenced strain. Almost no mobile genetic elements were found in OG1RF. The 64 areas of divergence were classified into three categories. First, OG1RF carries 39 unique regions, including 2 CRISPR loci and a new WxL locus. Second, we found nine replacements where a sequence specific to V583 was substituted by a sequence specific to OG1RF. For example, the iol operon of OG1RF replaces a possible prophage and the vanB transposon in V583. Finally, we found 16 regions that were present in V583 but missing from OG1RF, including the proposed pathogenicity island, several probable prophages, and the cpsCDEFGHIJK capsular polysaccharide operon. OG1RF was more rapidly but less frequently lethal than V583 in the mouse peritonitis model and considerably outcompeted V583 in a murine model of urinary tract infections. CONCLUSION: E. faecalis OG1RF carries a number of unique loci compared to V583, but the almost complete lack of mobile genetic elements demonstrates that this is not a defining feature of the species. Additionally, OG1RF's effects in experimental models suggest that mediators of virulence may be diverse between different E. faecalis strains and that virulence is not dependent on the presence of mobile genetic elements. Title: Genome analysis of the platypus reveals unique signatures of evolution Warren WC, Hillier LW, Marshall Graves JA, Birney E, Ponting CP, Grutzner F, Belov K, Miller W, Clarke L and Wilson RK <94 more author(s)> Warren WC, Hillier LW, Marshall Graves JA, Birney E, Ponting CP, Grutzner F, Belov K, Miller W, Clarke L, Chinwalla AT, Yang SP, Heger A, Locke DP, Miethke P, Waters PD, Veyrunes F, Fulton L, Fulton B, Graves T, Wallis J, Puente XS, Lopez-Otin C, Ordonez GR, Eichler EE, Chen L, Cheng Z, Deakin JE, Alsop A, Thompson K, Kirby P, Papenfuss AT, Wakefield MJ, Olender T, Lancet D, Huttley GA, Smit AF, Pask A, Temple-Smith P, Batzer MA, Walker JA, Konkel MK, Harris RS, Whittington CM, Wong ES, Gemmell NJ, Buschiazzo E, Vargas Jentzsch IM, Merkel A, Schmitz J, Zemann A, Churakov G, Kriegs JO, Brosius J, Murchison EP, Sachidanandam R, Smith C, Hannon GJ, Tsend-Ayush E, McMillan D, Attenborough R, Rens W, Ferguson-Smith M, Lefevre CM, Sharp JA, Nicholas KR, Ray DA, Kube M, Reinhardt R, Pringle TH, Taylor J, Jones RC, Nixon B, Dacheux JL, Niwa H, Sekita Y, Huang X, Stark A, Kheradpour P, Kellis M, Flicek P, Chen Y, Webber C, Hardison R, Nelson J, Hallsworth-Pepin K, Delehaunty K, Markovic C, Minx P, Feng Y, Kremitzki C, Mitreva M, Glasscock J, Wylie T, Wohldmann P, Thiru P, Nhan MN, Pohl CS, Smith SM, Hou S, Nefedov M, de Jong PJ, Renfree MB, Mardis ER, Wilson RK (- 94) Ref: Nature, 453:175, 2008 : PubMed ESTHER: Warren_2008_Nature_453_175 PubMedSearch: Warren 2008 Nature 453 175 PubMedID: 18464734 Gene_locus related to this paper: ornan-f6s0q0, ornan-f6ty74, ornan-f6u2k2, ornan-f6uve1, ornan-f6vpb6, ornan-f6ybp3, ornan-f7bgu8, ornan-f7ct41, ornan-f7cza1, ornan-f7ejp8, ornan-f7exu1, ornan-f7f392, ornan-f7f9y6, ornan-f6ve87, ornan-f7f1d9, ornan-f6z3l1, ornan-f6r3f9, ornan-f6r3g8, ornan-f6vs71, ornan-f7g4v8 Abstract We present a draft genome sequence of the platypus, Ornithorhynchus anatinus. This monotreme exhibits a fascinating combination of reptilian and mammalian characters. For example, platypuses have a coat of fur adapted to an aquatic lifestyle; platypus females lactate, yet lay eggs; and males are equipped with venom similar to that of reptiles. Analysis of the first monotreme genome aligned these features with genetic innovations. We find that reptile and platypus venom proteins have been co-opted independently from the same gene families; milk protein genes are conserved despite platypuses laying eggs; and immune gene family expansions are directly related to platypus biology. Expansions of protein, non-protein-coding RNA and microRNA families, as well as repeat elements, are identified. Sequencing of this genome now provides a valuable resource for deep mammalian comparative analyses, as well as for monotreme biology and conservation. Title: The genome of Hyperthermus butylicus: a sulfur-reducing, peptide fermenting, neutrophilic Crenarchaeote growing up to 108 degrees C Brugger K, Chen L, Stark M, Zibat A, Redder P, Ruepp A, Awayez M, She Q, Garrett RA, Klenk HP Ref: Archaea, 2:127, 2007 : PubMed ESTHER: Brugger_2007_Archaea_2_127 PubMedSearch: Brugger 2007 Archaea 2 127 PubMedID: 17350933 Abstract Hyperthermus butylicus, a hyperthermophilic neutrophile and anaerobe, is a member of the archaeal kingdom Crenarchaeota. Its genome consists of a single circular chromosome of 1,667,163 bp with a 53.7% G+C content. A total of 1672 genes were annotated, of which 1602 are protein-coding, and up to a third are specific to H. butylicus. In contrast to some other crenarchaeal genomes, a high level of GUG and UUG start codons are predicted. Two cdc6 genes are present, but neither could be linked unambiguously to an origin of replication. Many of the predicted metabolic gene products are associated with the fermentation of peptide mixtures including several peptidases with diverse specificities, and there are many encoded transporters. Most of the sulfur-reducing enzymes, hydrogenases and electron-transfer proteins were identified which are associated with energy production by reducing sulfur to H(2)S. Two large clusters of regularly interspaced repeats (CRISPRs) are present, one of which is associated with a crenarchaeal-type cas gene superoperon; none of the spacer sequences yielded good sequence matches with known archaeal chromosomal elements. The genome carries no detectable transposable or integrated elements, no inteins, and introns are exclusive to tRNA genes. This suggests that the genome structure is quite stable, possibly reflecting a constant, and relatively uncompetitive, natural environment. Title: Lead optimization and insecticidal activity of analogues of daphneolone isolated from Stellera chamaejasme L. Chen L, Wang X, Lu T, Hou T Ref: Pest Manag Sci, 63:928, 2007 : PubMed ESTHER: Chen_2007_Pest.Manag.Sci_63_928 PubMedSearch: Chen 2007 Pest.Manag.Sci 63 928 Abstract Starting from the chemical structure of the botanical aphicides 1,5-diphenyl-1-pentanone and 1,5-diphenyl-2-penten-1-one, extracted from Stellera chamaejasme L., the authors designed and synthesized a series of novel compounds following the concept of bioisosterism. Their structures were established on the basis of 1H NMR and GC-MS spectra, and the insecticidal activities of the compounds were evaluated against Aphis gossypii Glover. The results demonstrated that the substitution of a heterocycle for the phenyl ring was favourable. Thus, further modification of compound 2n, containing a furan ring, which showed excellent activity (LC50 = 0.85 g L-1), is of some promise. Title: Effect of a single cyclosporine dose on the single-dose pharmacokinetics of sitagliptin (MK-0431), a dipeptidyl peptidase-4 inhibitor, in healthy male subjects Krishna R, Bergman A, Larson P, Cote J, Lasseter K, Dilzer S, Wang A, Zeng W, Chen L and Herman G <1 more author(s)> Krishna R, Bergman A, Larson P, Cote J, Lasseter K, Dilzer S, Wang A, Zeng W, Chen L, Wagner J, Herman G (- 1) Ref: Journal of Clinical Pharmacology, 47:165, 2007 : PubMed ESTHER: Krishna_2007_J.Clin.Pharmacol_47_165 PubMedSearch: Krishna 2007 J.Clin.Pharmacol 47 165 PubMedID: 17244767 Abstract Sitagliptin (MK-0431) is an orally active, potent, and selective dipeptidyl peptidase-4 inhibitor used for the treatment of patients with type 2 diabetes mellitus. Sitagliptin has been shown to be a substrate for P-glycoprotein in preclinical studies. Cyclosporine was used as a probe P-glycoprotein inhibitor at a high dose to evaluate the potential effect of potent P-glycoprotein inhibition on single-dose sitagliptin pharmacokinetics in healthy male subjects. Eight healthy young men received a single oral 600-mg dose of cyclosporine with a single 100-mg oral sitagliptin dose and a single oral 100-mg sitagliptin dose alone in an open-label, randomized, 2-period, crossover study. Single doses of sitagliptin with or without single doses of cyclosporine were generally well tolerated. The sitagliptin AUC(0-infinity) geometric mean ratio was 1.29 with a 90% confidence interval of (1.24, 1.34). The sitagliptin Cmax geometric mean ratio was 1.68 with a 90% confidence interval of (1.35, 2.08). Cyclosporine coadministration did not appear to affect apparent sitagliptin renal clearance, t(1/2), or C(24 h), suggesting that effects of these high doses of cyclosporine are more likely due to enhanced absorption of sitagliptin, potentially through inhibition of intestinal P-glycoprotein. These results rationalize the use of a single high-dose cyclosporine as a probe inhibitor of P-glycoprotein for compound candidates whose elimination is less dependent on CYP3A4-mediated metabolism. Title: Expression of LPL in endothelial-intact artery results in lipid deposition and vascular cell adhesion molecule-1 upregulation in both LPL and ApoE-deficient mice Wang J, Xian X, Huang W, Chen L, Wu L, Zhu Y, Fan J, Ross C, Hayden MR, Liu G Ref: Arterioscler Thromb Vasc Biol, 27:197, 2007 : PubMed ESTHER: Wang_2007_Arterioscler.Thromb.Vasc.Biol_27_197 PubMedSearch: Wang 2007 Arterioscler.Thromb.Vasc.Biol 27 197 PubMedID: 17038632 Abstract OBJECTIVE: Overexpression of lipoprotein lipase (LPL) in deendothelialized artery led to profound localized lipid deposition. In this study the role of LPL in atherogenesis in endothelial-intact carotid arteries was assessed in genetically hyperlipidemic LPL- and ApoE-deficient mice. METHODS AND RESULTS: Human wild-type LPL (hLPLwt), catalytically inactive LPL (hLPL194), or control alkaline phosphatase (hAP) were expressed in endothelial-intact carotid arteries via adenoviral vectors. Compared with Ad-hAP, lipid deposition in the arterial wall increased 10.0- and 5.1-fold for Ad-hLPLwt and Ad-hLPL194 in LPL-deficient mice, and 10.6- and 6.2-fold in ApoE-deficient mice, respectively. Vascular cell adhesion molecule-1 (VCAM-1) was upregulated in Ad-hLPLwt and Ad-hLPL194 transferred arteries. CONCLUSIONS: Endothelial cell associated LPL, either active or inactive, in the arterial wall is a strong proatherosclerotic factor in both LPL- and ApoE-deficient mice. Title: Structure of the minimized alpha/beta-hydrolase fold protein from Thermus thermophilus HB8 Xie Y, Takemoto C, Kishishita S, Uchikubo-Kamo T, Murayama K, Chen L, Liu ZJ, Wang BC, Manzoku M and Yokoyama S <3 more author(s)> Xie Y, Takemoto C, Kishishita S, Uchikubo-Kamo T, Murayama K, Chen L, Liu ZJ, Wang BC, Manzoku M, Ebihara A, Kuramitsu S, Shirouzu M, Yokoyama S (- 3) Ref: Acta Crystallographica Sect F Struct Biol Cryst Commun, 63:993, 2007 : PubMed ESTHER: Xie_2007_Acta.Crystallogr.Sect.F.Struct.Biol.Cryst.Commun_63_993 PubMedSearch: Xie 2007 Acta.Crystallogr.Sect.F.Struct.Biol.Cryst.Commun 63 993 PubMedID: 18084077 Gene_locus related to this paper: teth8-Q5SI36 Abstract The gene encoding TTHA1544 is a singleton found in the Thermus thermophilus HB8 genome and encodes a 131-amino-acid protein. The crystal structure of TTHA1544 has been determined at 2.0 A resolution by the single-wavelength anomalous dispersion method in order to elucidate its function. There are two molecules in the asymmetric unit. Each molecule consists of four alpha-helices and six beta-strands, with the beta-strands composing a central beta-sheet. A structural homology search revealed that the overall structure of TTHA1544 resembles the alpha/beta-hydrolase fold, although TTHA1544 lacks the catalytic residues of a hydrolase. These results suggest that TTHA1544 represents the minimized alpha/beta-hydrolase fold and that an additional component would be required for its activity. Title: Pharmacokinetic and pharmacodynamic properties of multiple oral doses of sitagliptin, a dipeptidyl peptidase-IV inhibitor: a double-blind, randomized, placebo-controlled study in healthy male volunteers Bergman AJ, Stevens C, Zhou Y, Yi B, Laethem M, De Smet M, Snyder K, Hilliard D, Tanaka W and Herman GA <8 more author(s)> Bergman AJ, Stevens C, Zhou Y, Yi B, Laethem M, De Smet M, Snyder K, Hilliard D, Tanaka W, Zeng W, Tanen M, Wang AQ, Chen L, Winchell G, Davies MJ, Ramael S, Wagner JA, Herman GA (- 8) Ref: Clin Ther, 28:55, 2006 : PubMed ESTHER: Bergman_2006_Clin.Ther_28_55 PubMedSearch: Bergman 2006 Clin.Ther 28 55 PubMedID: 16490580 Abstract BACKGROUND: Dipeptidyl peptidase-IV (DPP-IV) inhibitors represent a new class of oral antihyperglycemic agents. Sitagliptin is an orally active and selective DPP-IV inhibitor currently in Phase III development for the treatment of type 2 diabetes mellitus. OBJECTIVE: The aim of this study was to assess the pharmacokinetic and pharmacodynamic (PK/PD) properties and tolerability of multiple oral once-daily or twice-daily doses of sitagliptin. Title: Pharmacokinetics and pharmacodynamic effects of the oral DPP-4 inhibitor sitagliptin in middle-aged obese subjects Herman GA, Bergman A, Liu F, Stevens C, Wang AQ, Zeng W, Chen L, Snyder K, Hilliard D and Wagner JA <6 more author(s)> Herman GA, Bergman A, Liu F, Stevens C, Wang AQ, Zeng W, Chen L, Snyder K, Hilliard D, Tanen M, Tanaka W, Meehan AG, Lasseter K, Dilzer S, Blum R, Wagner JA (- 6) Ref: Journal of Clinical Pharmacology, 46:876, 2006 : PubMed ESTHER: Herman_2006_J.Clin.Pharmacol_46_876 PubMedSearch: Herman 2006 J.Clin.Pharmacol 46 876 PubMedID: 16855072 Abstract Sitagliptin (MK-0431) is an oral, potent, and selective dipeptidyl peptidase-IV (DPP-4) inhibitor developed for the treatment of type 2 diabetes. This multicenter, randomized, double-blind, placebo-controlled study examined the pharmacokinetic and pharmacodynamic effects of sitagliptin in obese subjects. Middle-aged (45-63 years), nondiabetic, obese (body mass index: 30-40 kg/m2) men and women were randomized to sitagliptin 200 mg bid (n = 24) or placebo (n = 8) for 28 days. Steady-state plasma concentrations of sitagliptin were achieved within 2 days of starting treatment, and >90% of the dose was excreted unchanged in urine. Sitagliptin treatment led to approximately 90% inhibition of plasma DPP-4 activity, increased active glucagon-like peptide-1 (GLP-1) levels by 2.7-fold (P < .001), and decreased post-oral glucose tolerance test glucose excursion by 35% (P < .050) compared to placebo. In nondiabetic obese subjects, treatment with sitagliptin 200 mg bid was generally well tolerated without associated hypoglycemia and led to maximal inhibition of plasma DPP-4 activity, increased active GLP-1, and reduced glycemic excursion. Title: Complete genome sequence of Shigella flexneri 5b and comparison with Shigella flexneri 2a Nie H, Yang F, Zhang X, Yang J, Chen L, Wang J, Xiong Z, Peng J, Sun L and Jin Q <6 more author(s)> Nie H, Yang F, Zhang X, Yang J, Chen L, Wang J, Xiong Z, Peng J, Sun L, Dong J, Xue Y, Xu X, Chen S, Yao Z, Shen Y, Jin Q (- 6) Ref: BMC Genomics, 7:173, 2006 : PubMed ESTHER: Nie_2006_BMC.Genomics_7_173 PubMedSearch: Nie 2006 BMC.Genomics 7 173 PubMedID: 16822325 Gene_locus related to this paper: shifl-AES, shifl-BIOH, shifl-entf, shifl-FES, shifl-PTRB, shifl-S2753, shifl-SF1808, shifl-SF3046, shifl-yafa, shifl-YBFF, shifl-YCDJ, shifl-ycfp, shifl-YCJY, shifl-YFBB, shifl-YHET, shifl-YIEL, shifl-YJFP, shifl-YPFH, shiss-yeiG, shiss-yqia Abstract BACKGROUND: Shigella bacteria cause dysentery, which remains a significant threat to public health. Shigella flexneri is the most common species in both developing and developed countries. Five Shigella genomes have been sequenced, revealing dynamic and diverse features. To investigate the intra-species diversity of S. flexneri genomes further, we have sequenced the complete genome of S. flexneri 5b strain 8401 (abbreviated Sf8401) and compared it with S. flexneri 2a (Sf301). Title: Chronic oral nicotine normalizes dopaminergic function and synaptic plasticity in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned primates Quik M, Chen L, Parameswaran N, Xie X, Langston JW, McCallum SE Ref: Journal of Neuroscience, 26:4681, 2006 : PubMed ESTHER: Quik_2006_J.Neurosci_26_4681 PubMedSearch: Quik 2006 J.Neurosci 26 4681 PubMedID: 16641249 Abstract Our recent studies show that chronic oral nicotine partially protects against striatal damage in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated nonhuman primates. To identify the cellular changes associated with this protective action, we investigated the effects of nicotine treatment on stimulus-evoked dopamine release, dopamine turnover, and synaptic plasticity in striatum from lesioned and unlesioned animals. Monkeys were chronically (6 months) treated with nicotine in the drinking water and subsequently lesioned with the dopaminergic neurotoxin MPTP (6 months) while nicotine was continued. Nigrostriatal damage increased nicotinic acetylcholine receptor (nAChR)-mediated fractional dopamine release from residual terminals, primarily through changes in alpha3*/alpha6* nAChRs. In contrast, fractional receptor-evoked dopamine release was similar to control in unlesioned and lesioned animals with chronic oral nicotine. Long-term nicotine administration also attenuated the enhanced K(+)-evoked fractional dopamine release from synaptosomes of MPTP-lesioned animals, suggesting that nicotine treatment had a generalized effect on dopaminergic function. This premise was further supported by experiments showing that nicotine dosing decreased the elevated dopamine turnover that occurs after nigrostriatal damage. We next investigated changes in synaptic plasticity with lesioning and nicotine treatment. Nicotine treatment alone enhanced synaptic plasticity by lowering the threshold for long-term depression (LTD) in the corticostriatal pathway. MPTP lesioning led to a loss of LTD, a measure of short-term synaptic plasticity. In contrast, LTD was preserved in nicotine-treated lesioned animals. Thus, the present data show that the disruptions in striatal dopaminergic function after nigrostriatal damage were attenuated with chronic nicotine administration. These cellular alterations may underlie the ability of nicotine to maintain/restore normal function with nigrostriatal damage. Title: Localized vessel expression of lipoprotein lipase in rabbits leads to rapid lipid deposition in the balloon-injured arterial wall Wu X, Wang J, Fan J, Chen M, Chen L, Huang W, Liu G Ref: Atherosclerosis, 187:65, 2006 : PubMed ESTHER: Wu_2006_Atherosclerosis_187_65 PubMedSearch: Wu 2006 Atherosclerosis 187 65 PubMedID: 16191430 Abstract Recent studies on mice demonstrated that lipoprotein lipase (LPL) located in the arterial wall might play a pro-atherogenic role. There are major differences between humans and mice in lipoprotein metabolism and in susceptibility to atherosclerosis. We have therefore used rabbits fed normal chow diet as a model to assess such localized effects by adenovirus-mediated gene transfer of human catalytically active wild type LPL (hLPLwt) and an inactive mutant (hLPL194) to balloon-injured carotid arteries. By morphometric analysis on cryosections stained with Oil Red O (ORO) we found 7- and 4-fold increases, respectively, of lipid deposition in the arterial walls 7 days after infection with adenovirus expressing hLPLwt or hLPL194, when compared with a virus expressing human alkaline phosphatase (hAP) as control. Macrophages were detected in the arteries expressing both forms of LPL, but apoB was only found in arteries expressing hLPLwt. Expression of the LPL gene products was transient and was gone after 2 weeks, but the accumulated lipid deposits remained between the neointimal and the media layers even after 8 weeks. Our data demonstrate that expression of LPL in the arterial wall (with or without lipase activity) leads to lipid accumulation in balloon-injured rabbit arteries, and could result in enhanced formation of atherosclerotic lesions. Title: The genome of Sulfolobus acidocaldarius, a model organism of the Crenarchaeota Chen L, Brugger K, Skovgaard M, Redder P, She Q, Torarinsson E, Greve B, Awayez M, Zibat A and Garrett RA <1 more author(s)> Chen L, Brugger K, Skovgaard M, Redder P, She Q, Torarinsson E, Greve B, Awayez M, Zibat A, Klenk HP, Garrett RA (- 1) Ref: Journal of Bacteriology, 187:4992, 2005 : PubMed ESTHER: Chen_2005_J.Bacteriol_187_4992 PubMedSearch: Chen 2005 J.Bacteriol 187 4992 PubMedID: 15995215 Gene_locus related to this paper: sulac-q4j6y4, sulac-q4j7u5, sulac-q4j9r2, sulac-q4j9s2, sulac-q4j9v9, sulac-q4j857, sulac-q4j892, sulac-q4jcd5 Abstract Sulfolobus acidocaldarius is an aerobic thermoacidophilic crenarchaeon which grows optimally at 80 degrees C and pH 2 in terrestrial solfataric springs. Here, we describe the genome sequence of strain DSM639, which has been used for many seminal studies on archaeal and crenarchaeal biology. The circular genome carries 2,225,959 bp (37% G+C) with 2,292 predicted protein-encoding genes. Many of the smaller genes were identified for the first time on the basis of comparison of three Sulfolobus genome sequences. Of the protein-coding genes, 305 are exclusive to S. acidocaldarius and 866 are specific to the Sulfolobus genus. Moreover, 82 genes for untranslated RNAs were identified and annotated. Owing to the probable absence of active autonomous and nonautonomous mobile elements, the genome stability and organization of S. acidocaldarius differ radically from those of Sulfolobus solfataricus and Sulfolobus tokodaii. The S. acidocaldarius genome contains an integrated, and probably encaptured, pARN-type conjugative plasmid which may facilitate intercellular chromosomal gene exchange in S. acidocaldarius. Moreover, it contains genes for a characteristic restriction modification system, a UV damage excision repair system, thermopsin, and an aromatic ring dioxygenase, all of which are absent from genomes of other Sulfolobus species. However, it lacks genes for some of their sugar transporters, consistent with it growing on a more limited range of carbon sources. These results, together with the many newly identified protein-coding genes for Sulfolobus, are incorporated into a public Sulfolobus database which can be accessed at http://dac.molbio.ku.dk/dbs/Sulfolobus. Title: [Associations of genetic polymorphisms in the EPHX1 gene and the GSTT1 gene with low birth weight in neonates] Liang HY, Chen DF, Zhang T, Yang F, Wang LL, Chen L, Wu BY Ref: Beijing Da Xue Xue Bao, 37:85, 2005 : PubMed ESTHER: Liang_2005_Beijing.Da.Xue.Xue.Bao_37_85 PubMedSearch: Liang 2005 Beijing.Da.Xue.Xue.Bao 37 85 PubMedID: 15719050 Abstract OBJECTIVE: To investigate whether genetic polymorphisms in the microsomal epoxide hydrolase gene (EPHX1) and the glutathione S-transferase theta1 gene (GSTT1) are associated with low birth weight in neonates. Title: Postsynaptic assembly induced by neurexin-neuroligin interaction and neurotransmitter Nam CI, Chen L Ref: Proc Natl Acad Sci U S A, 102:6137, 2005 : PubMed ESTHER: Nam_2005_Proc.Natl.Acad.Sci.U.S.A_102_6137 PubMedSearch: Nam 2005 Proc.Natl.Acad.Sci.U.S.A 102 6137 PubMedID: 15837930 Gene_locus related to this paper: human-NLGN1 Abstract Presynaptic and postsynaptic differentiation occurs at axodendritic contacts between CNS neurons. Synaptic adhesion mediated by synaptic cell adhesion molecule (SynCAM) and beta-neurexins/neuroligins triggers presynaptic differentiation. The signals that trigger postsynaptic differentiation are, however, unknown. Here we report that beta-neurexin expressed in nonneuronal cells induced postsynaptic density (PSD)-95 clustering in contacting dendrites of hippocampal neurons. The effect is specific to beta-neurexin and was not observed with other synaptic cell adhesion molecules such as N-cadherin or SynCAM. NMDA receptors, but not alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate receptors (AMPARs), were recruited to this beta-neurexin-induced PSD-95 scaffold. Remarkably, AMPARs were inserted into this scaffold upon glutamate application or expression of a constitutively active form of calmodulin kinase II in neurons. Expression of a dominant-negative neuroligin-1 in cultured neurons markedly reduced the sizes and densities of PSD-95 puncta and AMPAR clusters. In addition, excitatory, but not inhibitory, synaptic functions were impaired in these neurons, confirming that PSD-95/neuroligin-1 interaction is involved in postsynaptic assembly at glutamatergic synapses. These results demonstrate that postsynaptic assembly of the glutamatergic synapse may be initiated by presynaptic beta-neurexin and that glutamate release also is required for maturation of synapses. Title: Polymorphisms for microsomal epoxide hydrolase and genetic susceptibility to COPD Park JY, Chen L, Wadhwa N, Tockman MS Ref: Int J Mol Med, 15:443, 2005 : PubMed ESTHER: Park_2005_Int.J.Mol.Med_15_443 PubMedSearch: Park 2005 Int.J.Mol.Med 15 443 PubMedID: 15702235 Abstract Although smoking is the major causal factor in the development of chronic obstructive pulmonary disease (COPD), only 10-20% of chronic heavy cigarette smokers develop symptomatic COPD, which suggests the presence of genetic susceptibility. The human microsomal epoxide hydrolase (EH) is a metabolizing enzyme which involves the process of numerous reactive epoxide intermediates and contains polymorphic alleles which are associated with altered EH activity and may be linked to increased risk for COPD. To determine whether the EH polymorphisms contributed to increased risk for COPD, prevalence of the EH codons 113 and 139 polymorphisms were compared between COPD patients and controls by a PCR-RFLP analysis using genomic DNA isolated from 131 COPD patients and 262 individually matched controls by age (+/-5 years) among Caucasians with 2:1 ratio. Significantly increased risk for COPD was observed for subjects with the EH(113His/His) genotypes (OR=2.4, 95% CI=1.1-5.1). These results were consistent with the fact that a significant trend towards increased risk was observed with predicted less protective EH codon 113 genotypes (p=0.03, trend test). A similar association was not observed for EH codon 139 polymorphism. As expected, a significant correlation between smoking dose and severity of COPD was observed (p<0.001). These results suggest that EH codon 113 polymorphism may modify risk for COPD. Title: Genome dynamics and diversity of Shigella species, the etiologic agents of bacillary dysentery Yang F, Yang J, Zhang X, Chen L, Jiang Y, Yan Y, Tang X, Wang J, Xiong Z and Jin Q <17 more author(s)> Yang F, Yang J, Zhang X, Chen L, Jiang Y, Yan Y, Tang X, Wang J, Xiong Z, Dong J, Xue Y, Zhu Y, Xu X, Sun L, Chen S, Nie H, Peng J, Xu J, Wang Y, Yuan Z, Wen Y, Yao Z, Shen Y, Qiang B, Hou Y, Yu J, Jin Q (- 17) Ref: Nucleic Acids Research, 33:6445, 2005 : PubMed ESTHER: Yang_2005_Nucleic.Acids.Res_33_6445 PubMedSearch: Yang 2005 Nucleic.Acids.Res 33 6445 PubMedID: 16275786 Gene_locus related to this paper: ecoli-yeiG, shidy-IROD, shidy-q67dv1, shifl-AES, shifl-BIOH, shifl-entf, shifl-FES, shifl-PLDB, shifl-PTRB, shifl-S2753, shifl-SF1334, shifl-SF1808, shifl-SF3046, shifl-SF3908, shifl-yafa, shifl-YBFF, shifl-YCDJ, shifl-ycfp, shifl-YCJY, shifl-YFBB, shifl-YHET, shifl-YJFP, shifl-YPFH, shiss-yaim, shiss-yeiG, shiss-yqia Abstract The Shigella bacteria cause bacillary dysentery, which remains a significant threat to public health. The genus status and species classification appear no longer valid, as compelling evidence indicates that Shigella, as well as enteroinvasive Escherichia coli, are derived from multiple origins of E.coli and form a single pathovar. Nevertheless, Shigella dysenteriae serotype 1 causes deadly epidemics but Shigella boydii is restricted to the Indian subcontinent, while Shigella flexneri and Shigella sonnei are prevalent in developing and developed countries respectively. To begin to explain these distinctive epidemiological and pathological features at the genome level, we have carried out comparative genomics on four representative strains. Each of the Shigella genomes includes a virulence plasmid that encodes conserved primary virulence determinants. The Shigella chromosomes share most of their genes with that of E.coli K12 strain MG1655, but each has over 200 pseudogenes, 300 approximately 700 copies of insertion sequence (IS) elements, and numerous deletions, insertions, translocations and inversions. There is extensive diversity of putative virulence genes, mostly acquired via bacteriophage-mediated lateral gene transfer. Hence, via convergent evolution involving gain and loss of functions, through bacteriophage-mediated gene acquisition, IS-mediated DNA rearrangements and formation of pseudogenes, the Shigella spp. became highly specific human pathogens with variable epidemiological and pathological features. Title: Excessive expression of acetylcholinesterase impairs glutamatergic synaptogenesis in hippocampal neurons Dong H, Xiang YY, Farchi N, Ju W, Wu Y, Chen L, Wang Y, Hochner B, Yang B and Lu WY <1 more author(s)> Dong H, Xiang YY, Farchi N, Ju W, Wu Y, Chen L, Wang Y, Hochner B, Yang B, Soreq H, Lu WY (- 1) Ref: Journal of Neuroscience, 24:8950, 2004 : PubMed ESTHER: Dong_2004_J.Neurosci_24_8950 PubMedSearch: Dong 2004 J.Neurosci 24 8950 PubMedID: 15483114 Abstract Acetylcholinesterase (AChE) exerts noncatalytic activities on neural cell differentiation, adhesion, and neuritogenesis independently of its catalytic function. The noncatalytic functions of AChE have been attributed to its peripheral anionic site (PAS)-mediated protein-protein interactions. Structurally, AChE is highly homologous to the extracellular domain of neuroligin, a postsynaptic transmembrane molecule that interacts with presynaptic beta-neurexins, thus facilitating synaptic formation and maturation. Potential effects of AChE expression on synaptic transmission, however, remain unknown. Using electrophysiology, immunocytochemistry, and molecular biological approaches, this study investigated the role of AChE in the regulation of synaptic formation and functions. We found that AChE was highly expressed in cultured embryonic hippocampal neurons at early culture days, particularly in dendritic compartments including the growth cone. Subsequently, the expression level of AChE declined, whereas synaptic activity and synaptic proteins progressively increased. Chronic blockade of the PAS of AChE with specific inhibitors selectively impaired glutamatergic functions and excitatory synaptic structures independently of cholinergic activation, while inducing AChE overexpression. Moreover, the PAS blockade-induced glutamatergic impairments were associated with a depressed expression of beta-neurexins and an accumulation of other synaptic proteins, including neuroligins, and were mostly preventable by antisense suppression of AChE expression. Our findings demonstrate that interference with the nonenzymatic features of AChE alters AChE expression, which impairs excitatory synaptic structure and functions. Title: Trehalose favors a cutinase compact intermediate off-folding pathway Melo EP, Chen L, Cabral JM, Fojan P, Petersen SB, Otzen DE Ref: Biochemistry, 42:7611, 2003 : PubMed ESTHER: Melo_2003_Biochemistry_42_7611 PubMedSearch: Melo 2003 Biochemistry 42 7611 PubMedID: 12809518 Abstract The folding of cutinase, an enzyme displaying lipolytic activity, has been studied in the presence of trehalose. Equilibrium unfolding data show that trehalose increases the free energy change between folded and unfolded states. Unfolding kinetics reveal the presence of an intermediate which is ca. 60% folded in terms of solvent exposure. Trehalose stabilizes this intermediate relative to the folded state. In contrast, the intermediate revealed by folding kinetics is more compact than the transition state, as shown by the positive slope observed at low denaturant concentration in the chevron plot, as well as the decrease in the observable rate constant for folding with the increase in trehalose concentration. This intermediate displays more than 50% of area buried from the solvent (relative to the native state) compared to around 40% for the transition state for folding and therefore appears to be off the folding pathway. Trehalose stabilizes and guanidine hydrochloride destabilizes this compact intermediate. Both unfolding and folding kinetics show that compact conformational states are stabilized by trehalose, in agreement with current models on the effect of compatible solutes. This effect occurs even for compact states that decelerate the folding as in the case of the intermediate revealed by folding kinetics. Title: Sequence and analysis of rice chromosome 4 Feng Q, Zhang Y, Hao P, Wang S, Fu G, Huang Y, Li Y, Zhu J, Liu Y and Han B <61 more author(s)> Feng Q, Zhang Y, Hao P, Wang S, Fu G, Huang Y, Li Y, Zhu J, Liu Y, Hu X, Jia P, Zhao Q, Ying K, Yu S, Tang Y, Weng Q, Zhang L, Lu Y, Mu J, Zhang LS, Yu Z, Fan D, Liu X, Lu T, Li C, Wu Y, Sun T, Lei H, Li T, Hu H, Guan J, Wu M, Zhang R, Zhou B, Chen Z, Chen L, Jin Z, Wang R, Yin H, Cai Z, Ren S, Lv G, Gu W, Zhu G, Tu Y, Jia J, Chen J, Kang H, Chen X, Shao C, Sun Y, Hu Q, Zhang X, Zhang W, Wang L, Ding C, Sheng H, Gu J, Chen S, Ni L, Zhu F, Chen W, Lan L, Lai Y, Cheng Z, Gu M, Jiang J, Li J, Hong G, Xue Y, Han B (- 61) Ref: Nature, 420:316, 2002 : PubMed ESTHER: Feng_2002_Nature_420_316 PubMedSearch: Feng 2002 Nature 420 316 PubMedID: 12447439 Gene_locus related to this paper: orysa-Q7XTC5, orysa-Q7F959, orysa-q7f9i3, orysa-q7x7y5, orysa-q7xkj9, orysa-q7xr62, orysa-q7xr63, orysa-q7xr64, orysa-q7xsg1, orysa-q7xsq2, orysa-Q7XTM8, orysa-q7xts6, orysa-q7xue7, orysa-q7xv53, orysa-Q7XVB5, orysa-Q7XVG5, orysj-q0jaf0, orysj-q7f8x1 Abstract Rice is the principal food for over half of the population of the world. With its genome size of 430 megabase pairs (Mb), the cultivated rice species Oryza sativa is a model plant for genome research. Here we report the sequence analysis of chromosome 4 of O. sativa, one of the first two rice chromosomes to be sequenced completely. The finished sequence spans 34.6 Mb and represents 97.3% of the chromosome. In addition, we report the longest known sequence for a plant centromere, a completely sequenced contig of 1.16 Mb corresponding to the centromeric region of chromosome 4. We predict 4,658 protein coding genes and 70 transfer RNA genes. A total of 1,681 predicted genes match available unique rice expressed sequence tags. Transposable elements have a pronounced bias towards the euchromatic regions, indicating a close correlation of their distributions to genes along the chromosome. Comparative genome analysis between cultivated rice subspecies shows that there is an overall syntenic relationship between the chromosomes and divergence at the level of single-nucleotide polymorphisms and insertions and deletions. By contrast, there is little conservation in gene order between rice and Arabidopsis. Title: A comparison of whole-genome shotgun-derived mouse chromosome 16 and the human genome Mural RJ, Adams MD, Myers EW, Smith HO, Miklos GL, Wides R, Halpern A, Li PW, Sutton GG and Stephenson LD <169 more author(s)> Mural RJ, Adams MD, Myers EW, Smith HO, Miklos GL, Wides R, Halpern A, Li PW, Sutton GG, Nadeau J, Salzberg SL, Holt RA, Kodira CD, Lu F, Chen L, Deng Z, Evangelista CC, Gan W, Heiman TJ, Li J, Li Z, Merkulov GV, Milshina NV, Naik AK, Qi R, Shue BC, Wang A, Wang J, Wang X, Yan X, Ye J, Yooseph S, Zhao Q, Zheng L, Zhu SC, Biddick K, Bolanos R, Delcher AL, Dew IM, Fasulo D, Flanigan MJ, Huson DH, Kravitz SA, Miller JR, Mobarry CM, Reinert K, Remington KA, Zhang Q, Zheng XH, Nusskern DR, Lai Z, Lei Y, Zhong W, Yao A, Guan P, Ji RR, Gu Z, Wang ZY, Zhong F, Xiao C, Chiang CC, Yandell M, Wortman JR, Amanatides PG, Hladun SL, Pratts EC, Johnson JE, Dodson KL, Woodford KJ, Evans CA, Gropman B, Rusch DB, Venter E, Wang M, Smith TJ, Houck JT, Tompkins DE, Haynes C, Jacob D, Chin SH, Allen DR, Dahlke CE, Sanders R, Li K, Liu X, Levitsky AA, Majoros WH, Chen Q, Xia AC, Lopez JR, Donnelly MT, Newman MH, Glodek A, Kraft CL, Nodell M, Ali F, An HJ, Baldwin-Pitts D, Beeson KY, Cai S, Carnes M, Carver A, Caulk PM, Center A, Chen YH, Cheng ML, Coyne MD, Crowder M, Danaher S, Davenport LB, Desilets R, Dietz SM, Doup L, Dullaghan P, Ferriera S, Fosler CR, Gire HC, Gluecksmann A, Gocayne JD, Gray J, Hart B, Haynes J, Hoover J, Howland T, Ibegwam C, Jalali M, Johns D, Kline L, Ma DS, MacCawley S, Magoon A, Mann F, May D, McIntosh TC, Mehta S, Moy L, Moy MC, Murphy BJ, Murphy SD, Nelson KA, Nuri Z, Parker KA, Prudhomme AC, Puri VN, Qureshi H, Raley JC, Reardon MS, Regier MA, Rogers YH, Romblad DL, Schutz J, Scott JL, Scott R, Sitter CD, Smallwood M, Sprague AC, Stewart E, Strong RV, Suh E, Sylvester K, Thomas R, Tint NN, Tsonis C, Wang G, Williams MS, Williams SM, Windsor SM, Wolfe K, Wu MM, Zaveri J, Chaturvedi K, Gabrielian AE, Ke Z, Sun J, Subramanian G, Venter JC, Pfannkoch CM, Barnstead M, Stephenson LD (- 169) Ref: Science, 296:1661, 2002 : PubMed ESTHER: Mural_2002_Science_296_1661 PubMedSearch: Mural 2002 Science 296 1661 PubMedID: 12040188 Gene_locus related to this paper: mouse-ABH15, mouse-Ces3b, mouse-Ces4a, mouse-dpp4, mouse-FAP, mouse-Lipg, mouse-Q8C1A9, mouse-rbbp9, mouse-SERHL, mouse-SPG21, mouse-w4vsp6 Abstract The high degree of similarity between the mouse and human genomes is demonstrated through analysis of the sequence of mouse chromosome 16 (Mmu 16), which was obtained as part of a whole-genome shotgun assembly of the mouse genome. The mouse genome is about 10% smaller than the human genome, owing to a lower repetitive DNA content. Comparison of the structure and protein-coding potential of Mmu 16 with that of the homologous segments of the human genome identifies regions of conserved synteny with human chromosomes (Hsa) 3, 8, 12, 16, 21, and 22. Gene content and order are highly conserved between Mmu 16 and the syntenic blocks of the human genome. Of the 731 predicted genes on Mmu 16, 509 align with orthologs on the corresponding portions of the human genome, 44 are likely paralogous to these genes, and 164 genes have homologs elsewhere in the human genome; there are 14 genes for which we could find no human counterpart. Title: Agrobacterium type IV secretion is a two-step process in which export substrates associate with the virulence protein VirJ in the periplasm Pantoja M, Chen L, Chen Y, Nester EW Ref: Molecular Microbiology, 45:1325, 2002 : PubMed ESTHER: Pantoja_2002_Mol.Microbiol_45_1325 PubMedSearch: Pantoja 2002 Mol.Microbiol 45 1325 PubMedID: 12207700 Abstract Type IV secretion systems are virulence determinants in many bacteria and share extensive homology with many conjugal transfer systems. Although type IV systems and their homologues have been studied widely, the mechanism by which substrates are secreted remains unclear. In Agrobacterium, we show that type IV secretion substrates that lack signal peptides form a soluble complex in the periplasm with the virulence protein VirJ. Additionally, these proteins co-precipitate with constituents of the type IV transporter: the VirB pilus and the VirD4 protein. Our findings suggest that the substrate proteins localized to the periplasm may associate with the pilus in a manner that is mediated by VirJ, and suggest a two-step process for type IV secretion in Agrobacterium. Our analyses of protein-protein interactions in a variety of mutant backgrounds indicate that substrates are probably secreted independently of one another. Title: Thermal stability of organophosphorus pesticide triazophos and its relevance in the assessment of risk to the consumer of triazophos residues in food Holden AJ, Chen L, Shaw IC Ref: Journal of Agricultural and Food Chemistry, 49:103, 2001 : PubMed ESTHER: Holden_2001_J.Agric.Food.Chem_49_103 PubMedSearch: Holden 2001 J.Agric.Food.Chem 49 103 PubMedID: 11170565 Inhibitor(s) related to this paper: Triazophos Abstract The degradation of triazophos in aqueous solutions was monitored at 205 and 254 nm after separation using high-performance liquid chromatography. An ODS column was used with a mobile phase of 60% acetonitrile and 0.04% phosphoric acid at a flow rate of 1.4 cm(3) min(-)(1). When dissolved in distilled water, approximately 30% of the original triazophos was detected. The effect of heating time and temperature on a 0.5 mg dm(-3) standard was investigated. Over a 150 min period at 100 degrees C the peak area detected for the standard decreased by 58.67 +/- 6.19 and 65.03 +/- 4.61% when measured at 254 and 205 nm, respectively. The precision of the absorbance detected at 205 and 254 nm was 3.54 +/- 2.8 and 3.86 +/- 3.9%, respectively. There was a significant difference (P = 0.10) between the precision of the results obtained at each wavelength. The t(calcd) value was -2.236 and the t(crit) value was 1.94. The most sensitive wavelength was 205 nm. A 54% difference in the gradients of the calibration graphs obtained at each wavelength was observed. The results suggest that approximately 72% of triazophos is degraded during a 20 min cooking period at 100 degrees C, due to ambient and elevated temperature hydrolysis. Therefore, the dose to the consumer of triazophos residues in cooked food is likely to be approximately 72% lower than in the raw food, with a concomitant reduction in toxicological risk. Title: Amperometric microbial biosensor for direct determination of organophosphate pesticides using recombinant microorganism with surface expressed organophosphorus hydrolase Mulchandani P, Chen W, Mulchandani A, Wang J, Chen L Ref: Biosensors & Bioelectronics, 16:433, 2001 : PubMed ESTHER: Mulchandani_2001_Biosens.Bioelectron_16_433 PubMedSearch: Mulchandani 2001 Biosens.Bioelectron 16 433 PubMedID: 11544037 Abstract An amperometric microbial biosensor for the direct measurement of organophosphate nerve agents is described. The sensor is based on a carbon paste electrode containing genetically engineered cells expressing organophosphorus hydrolase (OPH) on the cell surface. OPH catalyzes the hydrolysis of organophosphorus pesticides with p-nitrophenyl substituent such as paraoxon, parathion and methyl parathion to p-nitrophenol. The later is detected anodically at the carbon transducer with the oxidation current being proportional to the nerve-agent concentration. The sensor sensitivity was optimized with respect to the buffer pH and loading of cells immobilized using paraoxon as substrate. The best sensitivity was obtained using a sensor constructed with 10 mg of wet cell weight per 100 mg of carbon paste and operating in pH 8.5 buffer. Using these conditions, the biosensor was used to measure as low as 0.2 microM paraoxon and 1 microM methyl parathion with very good sensitivity, excellent selectivity and reproducibility. The microbial biosensor had excellent storage stability, retaining 100% of its original activity when stored at 4 degrees C for up to 45 days. Title: The sequence of the human genome Venter JC, Adams MD, Myers EW, Li PW, Mural RJ, Sutton GG, Smith HO, Yandell M, Evans CA and Zhu X <264 more author(s)> Venter JC, Adams MD, Myers EW, Li PW, Mural RJ, Sutton GG, Smith HO, Yandell M, Evans CA, Holt RA, Gocayne JD, Amanatides P, Ballew RM, Huson DH, Wortman JR, Zhang Q, Kodira CD, Zheng XH, Chen L, Skupski M, Subramanian G, Thomas PD, Zhang J, Gabor Miklos GL, Nelson C, Broder S, Clark AG, Nadeau J, McKusick VA, Zinder N, Levine AJ, Roberts RJ, Simon M, Slayman C, Hunkapiller M, Bolanos R, Delcher A, Dew I, Fasulo D, Flanigan M, Florea L, Halpern A, Hannenhalli S, Kravitz S, Levy S, Mobarry C, Reinert K, Remington K, Abu-Threideh J, Beasley E, Biddick K, Bonazzi V, Brandon R, Cargill M, Chandramouliswaran I, Charlab R, Chaturvedi K, Deng Z, Di Francesco V, Dunn P, Eilbeck K, Evangelista C, Gabrielian AE, Gan W, Ge W, Gong F, Gu Z, Guan P, Heiman TJ, Higgins ME, Ji RR, Ke Z, Ketchum KA, Lai Z, Lei Y, Li Z, Li J, Liang Y, Lin X, Lu F, Merkulov GV, Milshina N, Moore HM, Naik AK, Narayan VA, Neelam B, Nusskern D, Rusch DB, Salzberg S, Shao W, Shue B, Sun J, Wang Z, Wang A, Wang X, Wang J, Wei M, Wides R, Xiao C, Yan C, Yao A, Ye J, Zhan M, Zhang W, Zhang H, Zhao Q, Zheng L, Zhong F, Zhong W, Zhu S, Zhao S, Gilbert D, Baumhueter S, Spier G, Carter C, Cravchik A, Woodage T, Ali F, An H, Awe A, Baldwin D, Baden H, Barnstead M, Barrow I, Beeson K, Busam D, Carver A, Center A, Cheng ML, Curry L, Danaher S, Davenport L, Desilets R, Dietz S, Dodson K, Doup L, Ferriera S, Garg N, Gluecksmann A, Hart B, Haynes J, Haynes C, Heiner C, Hladun S, Hostin D, Houck J, Howland T, Ibegwam C, Johnson J, Kalush F, Kline L, Koduru S, Love A, Mann F, May D, McCawley S, McIntosh T, McMullen I, Moy M, Moy L, Murphy B, Nelson K, Pfannkoch C, Pratts E, Puri V, Qureshi H, Reardon M, Rodriguez R, Rogers YH, Romblad D, Ruhfel B, Scott R, Sitter C, Smallwood M, Stewart E, Strong R, Suh E, Thomas R, Tint NN, Tse S, Vech C, Wang G, Wetter J, Williams S, Williams M, Windsor S, Winn-Deen E, Wolfe K, Zaveri J, Zaveri K, Abril JF, Guigo R, Campbell MJ, Sjolander KV, Karlak B, Kejariwal A, Mi H, Lazareva B, Hatton T, Narechania A, Diemer K, Muruganujan A, Guo N, Sato S, Bafna V, Istrail S, Lippert R, Schwartz R, Walenz B, Yooseph S, Allen D, Basu A, Baxendale J, Blick L, Caminha M, Carnes-Stine J, Caulk P, Chiang YH, Coyne M, Dahlke C, Mays A, Dombroski M, Donnelly M, Ely D, Esparham S, Fosler C, Gire H, Glanowski S, Glasser K, Glodek A, Gorokhov M, Graham K, Gropman B, Harris M, Heil J, Henderson S, Hoover J, Jennings D, Jordan C, Jordan J, Kasha J, Kagan L, Kraft C, Levitsky A, Lewis M, Liu X, Lopez J, Ma D, Majoros W, McDaniel J, Murphy S, Newman M, Nguyen T, Nguyen N, Nodell M, Pan S, Peck J, Peterson M, Rowe W, Sanders R, Scott J, Simpson M, Smith T, Sprague A, Stockwell T, Turner R, Venter E, Wang M, Wen M, Wu D, Wu M, Xia A, Zandieh A, Zhu X (- 264) Ref: Science, 291:1304, 2001 : PubMed ESTHER: Venter_2001_Science_291_1304 PubMedSearch: Venter 2001 Science 291 1304 PubMedID: 11181995 Gene_locus related to this paper: human-AADAC, human-ABHD1, human-ABHD10, human-ABHD11, human-ACHE, human-BCHE, human-LDAH, human-ABHD18, human-CMBL, human-ABHD17A, human-KANSL3, human-LIPA, human-LYPLAL1, human-NDRG2, human-NLGN3, human-NLGN4X, human-NLGN4Y, human-PAFAH2, human-PREPL, human-RBBP9, human-SPG21 Abstract A 2.91-billion base pair (bp) consensus sequence of the euchromatic portion of the human genome was generated by the whole-genome shotgun sequencing method. The 14.8-billion bp DNA sequence was generated over 9 months from 27,271,853 high-quality sequence reads (5.11-fold coverage of the genome) from both ends of plasmid clones made from the DNA of five individuals. Two assembly strategies-a whole-genome assembly and a regional chromosome assembly-were used, each combining sequence data from Celera and the publicly funded genome effort. The public data were shredded into 550-bp segments to create a 2.9-fold coverage of those genome regions that had been sequenced, without including biases inherent in the cloning and assembly procedure used by the publicly funded group. This brought the effective coverage in the assemblies to eightfold, reducing the number and size of gaps in the final assembly over what would be obtained with 5.11-fold coverage. The two assembly strategies yielded very similar results that largely agree with independent mapping data. The assemblies effectively cover the euchromatic regions of the human chromosomes. More than 90% of the genome is in scaffold assemblies of 100,000 bp or more, and 25% of the genome is in scaffolds of 10 million bp or larger. Analysis of the genome sequence revealed 26,588 protein-encoding transcripts for which there was strong corroborating evidence and an additional approximately 12,000 computationally derived genes with mouse matches or other weak supporting evidence. Although gene-dense clusters are obvious, almost half the genes are dispersed in low G+C sequence separated by large tracts of apparently noncoding sequence. Only 1.1% of the genome is spanned by exons, whereas 24% is in introns, with 75% of the genome being intergenic DNA. Duplications of segmental blocks, ranging in size up to chromosomal lengths, are abundant throughout the genome and reveal a complex evolutionary history. Comparative genomic analysis indicates vertebrate expansions of genes associated with neuronal function, with tissue-specific developmental regulation, and with the hemostasis and immune systems. DNA sequence comparisons between the consensus sequence and publicly funded genome data provided locations of 2.1 million single-nucleotide polymorphisms (SNPs). A random pair of human haploid genomes differed at a rate of 1 bp per 1250 on average, but there was marked heterogeneity in the level of polymorphism across the genome. Less than 1% of all SNPs resulted in variation in proteins, but the task of determining which SNPs have functional consequences remains an open challenge. Title: The genome of the natural genetic engineer Agrobacterium tumefaciens C58 Wood DW, Setubal JC, Kaul R, Monks DE, Kitajima JP, Okura VK, Zhou Y, Chen L, Wood GE and Nester EW <41 more author(s)> Wood DW, Setubal JC, Kaul R, Monks DE, Kitajima JP, Okura VK, Zhou Y, Chen L, Wood GE, Almeida NF, Jr., Woo L, Chen Y, Paulsen IT, Eisen JA, Karp PD, Bovee D, Sr., Chapman P, Clendenning J, Deatherage G, Gillet W, Grant C, Kutyavin T, Levy R, Li MJ, McClelland E, Palmieri A, Raymond C, Rouse G, Saenphimmachak C, Wu Z, Romero P, Gordon D, Zhang S, Yoo H, Tao Y, Biddle P, Jung M, Krespan W, Perry M, Gordon-Kamm B, Liao L, Kim S, Hendrick C, Zhao ZY, Dolan M, Chumley F, Tingey SV, Tomb JF, Gordon MP, Olson MV, Nester EW (- 41) Ref: Science, 294:2317, 2001 : PubMed ESTHER: Wood_2001_Science_294_2317 PubMedSearch: Wood 2001 Science 294 2317 PubMedID: 11743193 Gene_locus related to this paper: agrt5-a9cf94, agrt5-a9cfa9, agrt5-a9cfs8, agrt5-a9cfu7, agrt5-a9cie7, agrt5-a9cj11, agrt5-a9cjp2, agrt5-a9cki2, agrt5-a9ckr2, agrt5-a9ckt2, agrt5-a9cle4, agrt5-a9clq8, agrt5-a9clq9, agrt5-q7cx24, agrt5-q7d1j0, agrt5-q7d1j3, agrt5-q7d3m5, agrt5-y5261, agrtu-ACVB, agrtu-ATTS, agrtu-ATU0253, agrtu-ATU0403, agrtu-ATU0841, agrtu-ATU1045, agrtu-ATU1102, agrtu-ATU1572, agrtu-ATU1617, agrtu-ATU1826, agrtu-ATU1842, agrtu-ATU2061, agrtu-ATU2126, agrtu-ATU2171, agrtu-ATU2409, agrtu-ATU2452, agrtu-ATU2481, agrtu-ATU2497, agrtu-ATU2576, agrtu-ATU3428, agrtu-ATU3651, agrtu-ATU3652, agrtu-ATU4238, agrtu-ATU5190, agrtu-ATU5193, agrtu-ATU5275, agrtu-ATU5296, agrtu-ATU5348, agrtu-ATU5389, agrtu-ATU5446, agrtu-ATU5495, agrtu-CPO, agrtu-DHAA, agrtu-DLHH, agrtu-EPHA, agrtu-GRST, agrtu-PCA, agrtu-PCAD, agrtu-PHBC, agrtu-PTRB, agrt5-a9cji8 Abstract The 5.67-megabase genome of the plant pathogen Agrobacterium tumefaciens C58 consists of a circular chromosome, a linear chromosome, and two plasmids. Extensive orthology and nucleotide colinearity between the genomes of A. tumefaciens and the plant symbiont Sinorhizobium meliloti suggest a recent evolutionary divergence. Their similarities include metabolic, transport, and regulatory systems that promote survival in the highly competitive rhizosphere; differences are apparent in their genome structure and virulence gene complement. Availability of the A. tumefaciens sequence will facilitate investigations into the molecular basis of pathogenesis and the evolutionary divergence of pathogenic and symbiotic lifestyles. Title: [A comparative study on the sensitivity and specificity of cholinesterase and glutathione s-transferase in Gammarus pulex L.] Yin D, Jin H, Yu H, Chen L Ref: Ying Yong Sheng Tai Xue Bao, 12:615, 2001 : PubMed ESTHER: Yin_2001_Ying.Yong.Sheng.Tai.Xue.Bao_12_615 PubMedSearch: Yin 2001 Ying.Yong.Sheng.Tai.Xue.Bao 12 615 PubMedID: 11758396 Abstract Studies on the influences of lindane, pirimiphos, methyl, permethrin, zinc and dodecyl linear alkybenzene sulfonate LAS, on the activity and toxicity of cholinesterase ChE and glutathione s-transferase GST in Gammarus pulex L showed that only pirimiphos methyl caused a change in ChE activity in Gammarus with a significant reduction in enzyme activity after 24 h and 48 h exposure. Both lindane and permethrin caused a change in GST activity in Gammarus with a significant increase in enzyme activity after 48 h exposure. Lindane alos caused a significant increase in GST activity after 24 h exposure. Biomarkers ChE and GST were demonstrated a high degree of specificity and sensitivity in comparison to the lethality assay but GST activity was less specific than ChE activity. Title: Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms Chen L, Chetkovich DM, Petralia RS, Sweeney NT, Kawasaki Y, Wenthold RJ, Bredt DS, Nicoll RA Ref: Nature, 408:936, 2000 : PubMed ESTHER: Chen_2000_Nature_408_936 PubMedSearch: Chen 2000 Nature 408 936 PubMedID: 11140673 Abstract Stargazer, an ataxic and epileptic mutant mouse, lacks functional AMPA (alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate) receptors on cerebellar granule cells. Stargazin, the mutated protein, interacts with both AMPA receptor subunits and synaptic PDZ proteins, such as PSD-95. The interaction of stargazin with AMPA receptor subunits is essential for delivering functional receptors to the surface membrane of granule cells, whereas its binding with PSD-95 and related PDZ proteins through a carboxy-terminal PDZ-binding domain is required for targeting the AMPA receptor to synapses. Expression of a mutant stargazin lacking the PDZ-binding domain in hippocampal pyramidal cells disrupts synaptic AMPA receptors, indicating that stargazin-like mechanisms for targeting AMPA receptors may be widespread in the central nervous system. Title: A whole-genome assembly of Drosophila Myers EW, Sutton GG, Delcher AL, Dew IM, Fasulo DP, Flanigan MJ, Kravitz SA, Mobarry CM, Reinert KH and Venter JC <19 more author(s)> Myers EW, Sutton GG, Delcher AL, Dew IM, Fasulo DP, Flanigan MJ, Kravitz SA, Mobarry CM, Reinert KH, Remington KA, Anson EL, Bolanos RA, Chou HH, Jordan CM, Halpern AL, Lonardi S, Beasley EM, Brandon RC, Chen L, Dunn PJ, Lai Z, Liang Y, Nusskern DR, Zhan M, Zhang Q, Zheng X, Rubin GM, Adams MD, Venter JC (- 19) Ref: Science, 287:2196, 2000 : PubMed ESTHER: Myers_2000_Science_287_2196 PubMedSearch: Myers 2000 Science 287 2196 PubMedID: 10731133 Abstract We report on the quality of a whole-genome assembly of Drosophila melanogaster and the nature of the computer algorithms that accomplished it. Three independent external data sources essentially agree with and support the assembly's sequence and ordering of contigs across the euchromatic portion of the genome. In addition, there are isolated contigs that we believe represent nonrepetitive pockets within the heterochromatin of the centromeres. Comparison with a previously sequenced 2.9- megabase region indicates that sequencing accuracy within nonrepetitive segments is greater than 99. 99% without manual curation. As such, this initial reconstruction of the Drosophila sequence should be of substantial value to the scientific community. Title: Somatomotor neuron-specific expression of the human cholinergic gene locus in transgenic mice Schutz B, Chen L, Schafer MK, Weihe E, Eiden LE Ref: Neuroscience, 96:707, 2000 : PubMed ESTHER: Schutz_2000_Neurosci_96_707 PubMedSearch: Schutz 2000 Neurosci 96 707 PubMedID: 10727789 Abstract We examined the expression pattern of the vesicular acetylcholine transporter in the mouse nervous system, using rodent-specific riboprobes and antibodies, prior to comparing it with the distribution of vesicular acetylcholine transporter expressed from a human transgene in the mouse, using riboprobes and antibodies specific for human. Endogenous vesicular acetylcholine transporter expression was high in spinal and brainstem somatomotor neurons, vagal visceromotor neurons, and postganglionic parasympathetic neurons, moderate in basal forebrain and brainstem projection neurons and striatal interneurons, and low in intestinal intrinsic neurons. Vesicular acetylcholine transporter expression in intrinsic cortical neurons was restricted to the entorhinal cortex. The sequence of the mouse cholinergic gene locus to 5.1kb upstream of the start of transcription of the vesicular acetylcholine transporter gene was determined and compared with the corresponding region of the human gene. Cis-regulatory domains implicated previously in human or rat cholinergic gene regulation are highly conserved in mouse, indicating their probable relevance to the regulation of the mammalian cholinergic gene locus in vivo. Mouse lines were established containing a human transgene that included the vesicular acetylcholine transporter gene and sequences spanning 5kb upstream and 1.8kb downstream of the vesicular acetylcholine transporter open reading frame. In this transgene, the intact human vesicular acetylcholine transporter was able to act as its own reporter. This allowed elements within the vesicular acetylcholine transporter open reading frame itself, shown previously to affect transcription in vitro, to be assessed in vivo with antibodies and riboprobes that reliably distinguished between human and mouse vesicular acetylcholine transporters and their messenger RNAs. Expression of the human vesicular acetylcholine transporter was restricted to mouse cholinergic somatomotor neurons in the spinal cord and brainstem, but absent from other central and peripheral cholinergic neurons. The mouse appears to be an appropriate model for the study of the genetic regulation of the cholinergic gene locus, and the physiology and neurochemistry of the mammalian cholinergic nervous system, although differences exist in the distribution of cortical cholinergic neurons between the mouse and other mammals. The somatomotor neuron-specific expression pattern of the transgenic human vesicular acetylcholine transporter suggests a mosaic model for cholinergic gene locus regulation in separate subdivisions of the mammalian cholinergic nervous system. Title: From the cholinergic gene locus to the cholinergic neuron Weihe E, Schafer MK, Schutz B, Anlauf M, Depboylu C, Brett C, Chen L, Eiden LE Ref: Journal de Physiologie (Paris), 92:385, 1998 : PubMed ESTHER: Weihe_1998_J.Physiol.Paris_92_385 PubMedSearch: Weihe 1998 J.Physiol.Paris 92 385 PubMedID: 9789842 Abstract The cholinergic gene locus (CGL) was first identified in 1994 as the site (human chromosome 10q11.2) at which choline acetyltransferase and a functional vesicular acetylcholine transporter are co-localized. Here, we present recent neuroanatomical, developmental, and evolutionary insights into the chemical coding of cholinergic neurotransmission that have been gleaned from the study of the CGL, and its protein products VAChT and ChAT, which comprise a synthesis-sequestration pathway that functionally defines the cholinergic phenotype. Title: Upstream sequencing and functional characterization of the human cholinergic gene locus Hahm SH, Chen L, Patel C, Erickson J, Bonner TI, Weihe E, Schafer MK, Eiden LE Ref: Journal of Molecular Neuroscience, 9:223, 1997 : PubMed ESTHER: Hahm_1997_J.Mol.Neurosci_9_223 PubMedSearch: Hahm 1997 J.Mol.Neurosci 9 223 PubMedID: 9481623 Abstract The 5' flanking region of the human VAChT gene was sequenced to approx 5350 bases upstream of the initiating methionine codon of the VAChT open reading frame (orf). The 5' flanks of the human and rat cholinergic gene loci were compared to identify regions of local sequence conservation, and therefore of potential regulatory importance. Several discrete domains of high homology, including a cluster of far-upstream cis-active consensus motifs, a neuronally restrictive silencer element consensus sequence, and additional conserved sequences within the putative nerve growth factor response domain of the locus, were identified. The probable start of transcription of the VAChT gene was deduced from mapping of sequences of rat and human VAChT cDNAs onto the 5' flanking regions of the human and rat cholinergic gene loci. The actual utilization of a putative 5' VAChT exon in rat central nervous system (CNS) tissue was assessed by in situ hybridization histochemistry. RNA transcripts containing both VAChT and ChAT protein-coding sequences were abundant in spinal cord motoneurons, sympathetic preganglionic cells, basal forebrain, striatum, and cranial motor nuclei. R-exon-containing transcripts could be detected only at low levels in these cell groups, implying that most transcription of VAChT proceeds from a promoter downstream of the R-exon. To assess the structural requirements for expression of the VAChT gene without bias regarding the actual start of transcription, a 5' fragment of the human gene corresponding to approximately 3 kb of sequence extending upstream from within the presumed 5' untranslated region of VAChT itself was fused to a luciferase-encoding reporter and transfected into VAChT-expressing and nonexpressing human and rat cell lines. This portion of the VAChT gene provided strong promoter expression in both cholinergic and noncholinergic cell lines. Deletion of the putative neuronally restrictive silencer element (NRSE) resulted in enhanced transcription in all cell lines. Lack of differential expression of VAChT transcription in VAChT-expressing vs non-VAChT-expressing cell lines suggested that additional enhancer elements controlling cell-specific expression of the VAChT gene exist further upstream in the cholinergic locus 5' flank. Conservation of potential cis-active elements within a 1.4 kb sequence immediately upstream of the NRSE in both rat and human cholinergic gene loci suggests that this domain is required for cholinergic-specific regulation of VAChT and ChAT gene transcription. Title: HindIII DNA polymorphism in the lipoprotein lipase gene and plasma lipid phenotypes and carotid artery atherosclerosis Chen L, Patsch W, Boerwinkle E Ref: Hum Genet, 98:551, 1996 : PubMed ESTHER: Chen_1996_Hum.Genet_98_551 PubMedSearch: Chen 1996 Hum.Genet 98 551 PubMedID: 8882874 Abstract Lipoprotein lipase (LPL) is the rate limiting enzyme in the hydrolysis of core triglyceride in chylomicron and very low density lipoprotein (VLDL) thus affecting a broad spectrum of plasma lipid levels. In this paper, we investigated the association of a HindIII polymorphism in the LPL gene with plasma lipid levels and carotid artery wall thickness measured by B-mode ultrasonography. A total of 238 Caucasian subjects were selected from the Atherosclerosis Risk In Community (ARIC) study (male = 1.31, female = 107) based on their fasting triglyceride and LDL-cholesterol levels: normolipidemic (n = 48), hypertriglyceridemic (n = 44), hypercholesterolemic (n = 36), and hypertriglyceridemic-hypercholesterolemic (n = 110) groups. We observed a marginally significant association between lipid phenotypes and HindIII genotypes (P = 0.04) in males, with the hypertriglyceridemic and hypercholesterolemic groups having a higher frequency (0.65) of the H+H+ genotype than the other two groups (pooled: 0.55). In males, there was also a significant association between HindIII genotypes and carotid artery wall thickness after considering the effects of age, body mass index, cigarette smoking, lipid phenotype and diabetes status (P = 0.013), with the H+H+ genotype having a higher average value of carotid artery wall thickness (0.84 +/- 0.15 mm) than the other two genotype groups (0.76 +/- 0.14 mm in H+H(+)-genotype class, 0.75 +/- 0.13 mm in H-H- genotype class). In females, no significant associations among LPL HindIII genotype, lipid phenotype and carotid artery wall thickness were observed. These results suggest that the LPL HindIII polymorphism influences LPL-catalyzed, triglyceride-rich lipoprotein metabolism and carotid artery atherosclerosis in a gender-specific manner. Title: The effect of indirect injury to peripheral nerves on wound healing after firearm wounds Lai X, Liu Y, Chen L Ref: Journal of Trauma, 40:S56, 1996 : PubMed ESTHER: Lai_1996_J.Trauma_40_S56 PubMedSearch: Lai 1996 J.Trauma 40 S56 PubMedID: 8606423 Abstract This paper reports the pathologic and functional changes of the sciatic nerve indirectly injured by firearms and its effect on wound healing. Twelve dogs were used. Their hind legs were shot with 1.03-gram steel spheres, avoiding direct injury to the sciatic nerve. The experimental animals were divided into two groups according to the impact velocity, that is, a 1,500 m/sec high velocity projectile (HVP) group and a 400 m/sec, low velocity projectile (LVP) group as a control. After wounding, the same procedure was followed in all dogs. At intervals, the tissues of the wound track were excised to determine the level of cyclic nucleotides (cAMP, cGMP), secondary messengers of neurotransmitters, the activity of acetylcholinesterase (AChE), and the content of hydroxyproline, which indicates the degree of wound healing. The sciatic nerve next to the wound track was excised for light and electron microscopic study. The neurofilament in the sciatic nerve was examined by immunohistochemistry with monoclonal neurofilament-200 antibody. The results showed that the indirect injuries to the sciatic nerves of the HVP group were more severe than in those in the LVP group and included naked axons, stripped myelin sheaths, widened nodes of Ranvier, and decrease in the numbers of neurofilaments. At 6 hours, cAMP content in the HVP group was significantly lower than that in the LVP group. It began to rise and approached to the level of LVP group at 10 days. The cGMP content, activity of AChE, and hydroxyproline content of the HVP group were significantly lower than those of the LVP group. The results suggested that the indirect injury to sciatic nerves, especially to the cytoskeleton, after HVP wounds may induce the disturbance of an axoplasmic flow and influence the metabolism of trophic factors such as cAMP, cGMP, and AChE. All changes could contribute to the delay in wound healing. | |||||||
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