Author Report for: Zhang WNo contact information in database for Zhang W
Saito T, Awad JM, Zhang W Ref: Molecules, 28:, 2023 : PubMed ESTHER: Saito_2023_Molecules_28_ PubMedSearch: Saito 2023 Molecules 28 PubMedID: 36771167 Abstract (-)-Magellanine, (+)-magellaninone, and (+)-paniculatine are three natural products isolated from the Lycopodium family that share a unique 6-5-5-6-fused tetracyclic diquinane core skeleton. Several members of this family have potent s anti-inflammatory and acetylcholinesterase-inhibitory properties and are under development for the treatment of Alzheimer's and other neurodegenerative diseases. Several research groups have undertaken the formal and total syntheses of this class of natural products. This review highlights over 20 reported total syntheses of these three alkaloids and the development of synthetic methods for the assembly of their core skeletons. Title: Strigolactone and gibberellin signalling coordinately regulates metabolic adaptations to changes in nitrogen availability in rice Sun H, Guo X, Zhu X, Gu P, Zhang W, Tao W, Wang D, Wu Y, Zhao Q and Zhang Y <2 more author(s)> Sun H, Guo X, Zhu X, Gu P, Zhang W, Tao W, Wang D, Wu Y, Zhao Q, Xu G, Fu X, Zhang Y (- 2) Ref: Mol Plant, :, 2023 : PubMed ESTHER: Sun_2023_Mol.Plant__ PubMedSearch: Sun 2023 Mol.Plant PubMedID: 36683328 Abstract Modern semi-dwarf rice varieties of the 'Green Revolution' require a high nitrogen (N) fertilizer supply to obtain a high yield. A better understanding of the interplay between N metabolic and developmental processes is required for improved N use efficiency (NUE) and agricultural sustainability. Here, we show that strigolactones (SLs) modulate root metabolic and developmental adaptations to low N availability, which ensure efficient uptake and translocation of available N. The key repressor DWARF 53 (D53) of the SL signalling interacts with the transcription factor GROWTH-REGULATING FACTOR 4 (GRF4) and prevents GRF4 from binding to its target gene promoters. N limitation induces the accumulation of SLs, which in turn promotes SL-mediated degradation of D53, leading to the release of GRF4 and thus promoting the genes expression associated with N metabolism. N limitation also induces degradation of the rice DELLA protein SLENDER RICE 1 (SLR1) in the D14- and D53-dependent manners, and that is effective for the release of GRF4 from the competitive inhibition caused by SLR1. Our findings reveal a previously unknown mechanism underlying SL and gibberellin crosstalk in response to N availability, which advances our understanding of plant growth-metabolic coordination that can be useful to improve NUE in high-yield crops. Title: Soluble Epoxide Hydrolase Contributes to Cell Senescence and ER Stress in Aging Mice Colon Wang Q, Zhang R, Liu M, Ma L, Zhang W, Wang W, Wagner KM, Wang Y, Singh N and Hammock BD <3 more author(s)> Wang Q, Zhang R, Liu M, Ma L, Zhang W, Wang W, Wagner KM, Wang Y, Singh N, Yang J, He Q, Morisseau C, Hammock BD (- 3) Ref: Int J Mol Sci, 24:, 2023 : PubMed ESTHER: Wang_2023_Int.J.Mol.Sci_24_ PubMedSearch: Wang 2023 Int.J.Mol.Sci 24 PubMedID: 36902155 36901999 Abstract Aging, which is characterized by enhanced cell senescence and functional decline of tissues, is a major risk factor for many chronic diseases. Accumulating evidence shows that age-related dysfunction in the colon leads to disorders in multiple organs and systemic inflammation. However, the detailed pathological mechanisms and endogenous regulators underlying colon aging are still largely unknown. Here, we report that the expression and activity of the soluble epoxide hydrolase (sEH) enzyme are increased in the colon of aged mice. Importantly, genetic knockout of sEH attenuated the age-related upregulation of senescent markers p21, p16, Tp53, and beta-galactosidase in the colon. Moreover, sEH deficiency alleviated aging-associated endoplasmic reticulum (ER) stress in the colon by reducing both the upstream regulators Perk and Ire1 as well as the downstream pro-apoptotic effectors Chop and Gadd34. Furthermore, treatment with sEH-derived linoleic acid metabolites, dihydroxy-octadecenoic acids (DiHOMEs), decreased cell viability and increased ER stress in human colon CCD-18Co cells in vitro. Together, these results support that the sEH is a key regulator of the aging colon, which highlights its potential application as a therapeutic target for reducing or treating age-related diseases in the colon. Title: TPB-DMTP@S-CDs/MnO(2) Fluorescence Composite on a Dual-Emission-Capture Sensor Module for Fingerprint Recognition of Organophosphorus Pesticides Yuan L, Tian X, Fan Y, Sun Z, Zheng K, Zou X, Zhang W Ref: Analytical Chemistry, :, 2023 : PubMed ESTHER: Yuan_2023_Anal.Chem__ PubMedSearch: Yuan 2023 Anal.Chem PubMedID: 36689633 Abstract Residues of organophosphorus pesticides (OPs) raise considerable concern, while identifying OPs from unknown sources is still a challenge to onsite fluorescence techniques. Herein, a dual-emission-capture sensor module, based on a TPB-DMTP@S-CDs/MnO(2) fluorescence composite, is developed for OP fingerprint recognition. TPB-DMTP@S-CDs/MnO(2), synthesized by a hydrothermal method and self-assembly, is spectrographically validated as a dual-wavelength fluorescence source. OP-sensitive catalysis (acetylcholinesterase on acetylthiocholine chloride) is designed to regulate fluorescence by decomposing quenchable MnO(2). A flexibly fabricated sensor module supports the optimal dual-wavelength fluorescence excitations and captures and converts fluorescence emissions into equivalent photocurrents for feasible access. The most prominent finding is that dual-fluorescence emissions alternatively respond to levels, species, and multi-pH pretreatments of OPs due to varied MnO(2) sizes and distributions. Therefore, OP fingerprint recognition is conducted by refining the multidimensional information from fluorescence-triggered photocurrents and preset hydrolyzation using principal component analysis and the rule of maximum covariance. The recommended method provides a wide dynamic range (1 x 10(-6) - 12 microg mL(-1)), a good limit of detection (7.9 x 10(-7) microg mL(-1)), 15-day stability, and good selectivity to guarantee fingerprint recognition. For laboratory and natural samples, this method credibly identifies a single kind of OPs from multiple species at trace levels (10(-5) microg mL(-1)) and performs well in two-component and multicomponent analyses. Title: Efficient decolorization of melanoidin in raw molasses wastewater by thermophilic esterase in actual extreme conditions Zhang Z, Hu W, Xie Q, Shi Y, Zhao Y, Deng Y, He J, Wu X, Zhang Y and Wang W <3 more author(s)> Zhang Z, Hu W, Xie Q, Shi Y, Zhao Y, Deng Y, He J, Wu X, Zhang Y, Zhang W, Liu P, Yang H, Wang W (- 3) Ref: Bioresour Technol, 382:129191, 2023 : PubMed ESTHER: Zhang_2023_Bioresour.Technol_382_129191 PubMedSearch: Zhang 2023 Bioresour.Technol 382 129191 PubMedID: 37196742 Abstract This work was developed to explore the versatility of thermophilic esterase for decolorizing raw molasses wastewater at high temperature and acidic pH. Combining covalent crosslinking method with deep eutectic solvent, a thermophilic esterase from Pyrobaculum calidifontis was immobilized on chitosan/macroporous resin composite carrier. The application of this immobilized thermophilic esterase eliminated 92.35% of colorants in raw molasses wastewater, achieving maximal decolorization efficiency across all the enzymes tested. Strikingly, this immobilized thermophilic esterase was capable of engaging in continuous activity for a 5-day period while removing 76.23% of pigments from samples. It effectively and continuously eliminated BOD(5) and COD, effectively and directly facilitating raw molasses wastewater decolorization under extreme conditions more readily than control group. In addition, this thermophilic esterase was believed to achieve decolorization through an addition reaction that disrupted conjugated system of melanoidins. Together, these results highlight an efficient and practical means of achieving enzyme-based molasses wastewater decolorization. Title: Smartphone-based colorimetric sensor array using gold nanoparticles for rapid distinguishment of multiple pesticides in real samples Zhao T, Liang X, Guo X, Yang X, Guo J, Zhou X, Huang X, Zhang W, Wang Y and Zhou H <2 more author(s)> Zhao T, Liang X, Guo X, Yang X, Guo J, Zhou X, Huang X, Zhang W, Wang Y, Liu Z, Jiang Z, Zhou H (- 2) Ref: Food Chem, 404:134768, 2023 : PubMed ESTHER: Zhao_2023_Food.Chem_404_134768 PubMedSearch: Zhao 2023 Food.Chem 404 134768 PubMedID: 36444090 Abstract A simple, sensitive method for pesticide distinguishment based on a colorimetric sensor array using diverse gold nanoparticles (AuNPs) at room temperature is presented in this study. Acetylcholinesterase (AChE) hydrolysis ability was influenced by different pesticides and produced different concentrations of thiocholine by hydrolyzing acetylthiocholine iodide (ATCh). Thiocholine could be easily linked to the AuNPs through an Aus-sS covalent bond, and AuNPs underwent aggregation, resulting in a visible color change due to alteration of surface plasmon resonance properties. Based on these results, we successfully distinguished eight pesticides (glyphosate, thiram, imidacloprid, tribenuron methyl, nicosulfuron, thifensulfuron methyl, dichlorprop, and fenoprop) utilizing five different AuNPs by colorimetric assay. The limit of detection (LOD) of this visual method for all pesticides was less than 1.5x 10(-7) M, which was more sensitive than the U.S. Environmental Protection Agency regulations specify (1.18s-s3.91x10(-6) M). This method was further improved by combining a portable smartphone device with a color picking application using (color name AR) and RGB (red, green, blue) values. The method was successfully applied to pesticide residue distinguishment in real samples by linear discriminant analysis (LDA). Title: Carboxylesterase 2 induces mitochondrial dysfunction via disrupting lipid homeostasis in oral squamous cell carcinoma Chen X, Liu Q, Chen Y, Wang L, Yang R, Zhang W, Pan X, Zhang S, Chen C and Ren X <3 more author(s)> Chen X, Liu Q, Chen Y, Wang L, Yang R, Zhang W, Pan X, Zhang S, Chen C, Wu T, Xia J, Cheng B, Ren X (- 3) Ref: Mol Metab, :101600, 2022 : PubMed ESTHER: Chen_2022_Mol.Metab__101600 PubMedSearch: Chen 2022 Mol.Metab 101600 PubMedID: 36113774 Abstract OBJECTIVE: Oral squamous cell carcinoma (OSCC) is characterized by high recurrence and metastasis and places a heavy burden on societies worldwide. Cancer cells thrive in a changing microenvironment by reprogramming lipidomic metabolic processes to provide nutrients and energy, activate oncogenic signaling pathways, and manage redox homeostasis to avoid lipotoxicity. The mechanism by which OSCC cells maintain lipid homeostasis during malignant progression is unclear. METHODS: The altered expression of fatty acid (FA) metabolism genes in OSCC, compared with that in normal tissues, and in OSCC patients with or without recurrence or metastasis were determined using public data from the TCGA and GEO databases. Immunohistochemistry was performed to examine the carboxylesterase 2 (CES2) protein level in our own cohort. CCK-8 and Transwell assays and an in vivo xenograft model were used to evaluate the biological functions of CES2. Mass spectrometry and RNA sequencing were performed to determine the lipidome and transcriptome alterations induced by CES2. Mitochondrial mass, mtDNA content, mitochondrial membrane potential, ROS levels, and oxygen consumption and apoptosis rates were evaluated to determine the effects of CES2 on mitochondrial function in OSCC. RESULTS: CES2 was downregulated in OSCC patients, especially those with recurrence or metastasis. CES2(high) OSCC patients showed better overall survival than CES2(low) OSCC patients. Restoring CES2 expression reduced OSCC cell viability and suppressed their migration and invasion in vitro, and it inhibited OSCC tumor growth in vivo. CES2 reprogrammed lipid metabolism in OSCC cells by hydrolyzing neutral lipid diacylglycerols (DGs) to release free fatty acids and reduce the membrane structure lipid phospholipids (PLs) synthesis. Free FAs were converted to acyl-carnitines (CARs) and transferred to mitochondria for oxidation, which induced reactive oxygen species (ROS) accumulation, mitochondrial damage, and apoptosis activation. Furthermore, the reduction in signaling lipids, e.g., DGs, PLs and substrates, suppressed PI3K/AKT/MYC signaling pathways. Restoring MYC rescued the diminished cell viability, suppressed migratory and invasive abilities, damaged mitochondria and reduced apoptosis rate induced by CES2. CONCLUSIONS: We demonstrated that CES2 downregulation plays an important role in OSCC by maintaining lipid homeostasis and reducing lipotoxicity during tumor progression and may provide a potential therapeutic target for OSCC. Title: Flavin-enabled reductive and oxidative epoxide ring opening reactions De BC, Zhang W, Yang C, Mandi A, Huang C, Zhang L, Liu W, Ruszczycky MW, Zhu Y and Zhang C <4 more author(s)> De BC, Zhang W, Yang C, Mandi A, Huang C, Zhang L, Liu W, Ruszczycky MW, Zhu Y, Ma M, Bashiri G, Kurtan T, Liu Hw, Zhang C (- 4) Ref: Nat Commun, 13:4896, 2022 : PubMed ESTHER: De BC#Zhang_2022_Nat.Commun_13_4896 PubMedSearch: De BC#Zhang 2022 Nat.Commun 13 4896 PubMedID: 35986005 Abstract Epoxide ring opening reactions are common and important in both biological processes and synthetic applications and can be catalyzed in a non-redox manner by epoxide hydrolases or reductively by oxidoreductases. Here we report that fluostatins (FSTs), a family of atypical angucyclines with a benzofluorene core, can undergo nonenzyme-catalyzed epoxide ring opening reactions in the presence of flavin adenine dinucleotide (FAD) and nicotinamide adenine dinucleotide (NADH). The 2,3-epoxide ring in FST C is shown to open reductively via a putative enol intermediate, or oxidatively via a peroxylated intermediate with molecular oxygen as the oxidant. These reactions lead to multiple products with different redox states that possess a single hydroxyl group at C-2, a 2,3-vicinal diol, a contracted five-membered A-ring, or an expanded seven-membered A-ring. Similar reactions also take place in both natural products and other organic compounds harboring an epoxide adjacent to a carbonyl group that is conjugated to an aromatic moiety. Our findings extend the repertoire of known flavin chemistry that may provide new and useful tools for organic synthesis. Title: Individualized regimen of low-dose rituximab monotherapy for new-onset AChR-positive generalized myasthenia gravis Du Y, Li C, Hao YF, Zhao C, Yan Q, Yao D, Li L, Zhang W Ref: Journal of Neurology, :, 2022 : PubMed ESTHER: Du_2022_J.Neurol__ PubMedSearch: Du 2022 J.Neurol PubMedID: 35243555 Abstract BACKGROUND: Generalized AChR-MG is an archetype of B cell-mediated autoimmune disorders, and use of biologic agent rituximab (RTX) for B cell depletion is generally limited to immunosuppressive therapy-refractory cases. However, benefit of RTX monotherapy and individualized regimen with optimal dosage in early stage of new-onset generalized AChR-MG still remains to be elucidated. In this retrospective study, we explore the efficacy and safety of personalized regimen of 100 mg low-dose rituximab monotherapy in treating new-onset generalized AChR-MG. METHODS: Thirteen new-onset generalized AChR-MG patients were enrolled for the study, initiating RTX treatment from November 2017 to August 2020. The individualized low-dose RTX monotherapy protocol consisted of 100 mg induction treatment weekly with no more than three circles, followed by reinfusion (100 mg once) sequentially according to whether achieving primary endpoint and peripheral CD19 + B-cell repopulation <= 1% of total lymphocytes at each visit (every 3 months). Outcome measures included MGFA-PIS Minimal Manifestation (MM) or better status (primary endpoint), changes in QMG, MMT, MG-ADL and MGQOL-15 scores (secondary endpoint), as well as cholinesterase inhibitors dosage. RESULTS: All 13 patients achieved the primary endpoint in parallel with significant improvement of QMG, MMT, MG-ADL MGQOL-15 scores, and reduction of cholinesterase inhibitors dose. A total of 52 visits were performed during follow-up, and only 10 assessments presenting peripheral CD19 + B-cell repopulation (<= 1%) without "MM or better status" were followed by RTX reinfusions (100 mg once) for clinical remission. The total dosage of RTX was only 346.15 +/- 96.74 mg (including 269.23 +/- 63.04 mg for induction and 76.92 +/- 59.91 mg for reinfusion), which seemed to be much lower than those dosages used in new-onset generalized AChR-MG as described previously. Moreover, compared with patients without thymoma, thymectomy markedly delayed initiation of RTX for patients with thymoma (log-rank test, p = 0.0002), but the delaying treatments showed no influence on the time for achieving primary outcome (log-rank test, p = 0.2517). CONCLUSION: Our study firstly showed that individualized regimen of low-dose RTX monotherapy is effective and safe for early treatment of new-onset generalized AChR-MG, and practicable for directing RTX reinfusion and withdrawal. Moreover, the monotherapy protocol was also indicated to be extensively applicable in both new-onset AChR-MG with thymoma (thymectomy) and without thymoma. Title: Interrelationship between 2019-nCov receptor DPP4 and diabetes mellitus targets based on protein interaction network Gao Q, Zhang W, Li T, Yang G, Zhu W, Chen N, Jin H Ref: Sci Rep, 12:188, 2022 : PubMed ESTHER: Gao_2022_Sci.Rep_12_188 PubMedSearch: Gao 2022 Sci.Rep 12 188 PubMedID: 34996987 Abstract Patients with diabetes are more likely to be infected with Coronavirus disease 2019 (COVID-19), and the risk of death is significantly higher than ordinary patients. Dipeptidyl peptidase-4 (DPP4) is one of the functional receptor of human coronavirus. Exploring the relationship between diabetes mellitus targets and DPP4 is particularly important for the management of patients with diabetes and COVID-19. We intend to study the protein interaction through the protein interaction network in order to find a new clue for the management of patients with diabetes with COVID-19. Diabetes mellitus targets were obtained from GeneCards database. Targets with a relevance score exceeding 20 were included, and DPP4 protein was added manually. The initial protein interaction network was obtained through String. The targets directly related to DPP4 were selected as the final analysis targets. Importing them into String again to obtain the protein interaction network. Module identification, gene ontology (GO) analysis and Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis were carried out respectively. The impact of DPP4 on the whole network was analyzed by scoring the module where it located. 43 DPP4-related proteins were finally selected from the diabetes mellitus targets and three functional modules were found by the cluster analysis. Module 1 was involved in insulin secretion and glucagon signaling pathway, module 2 and module 3 were involved in signaling receptor binding. The scoring results showed that LEP and apoB in module 1 were the highest, and the scores of INS, IL6 and ALB of cross module associated proteins of module 1 were the highest. DPP4 is widely associated with key proteins in diabetes mellitus. COVID-19 may affect DPP4 in patients with diabetes mellitus, leading to high mortality of diabetes mellitus combined with COVID-19. DPP4 inhibitors and IL-6 antagonists can be considered to reduce the effect of COVID-19 infection on patients with diabetes. Title: Enantioselective acute toxicity, oxidative stress effects, neurotoxicity, and thyroid disruption of uniconazole in zebrafish (Danio rerio) Guo D, He R, Luo L, Zhang W, Fan J Ref: Environ Sci Pollut Res Int, :, 2022 : PubMed ESTHER: Guo_2022_Environ.Sci.Pollut.Res.Int__ PubMedSearch: Guo 2022 Environ.Sci.Pollut.Res.Int PubMedID: 35119633 Abstract Uniconazole is a widely used plant growth retardant in the agricultural field. However, toxicological effects of uniconazole in aquatic ecosystem at chiral level are still unclear. Herein, acute toxicity, oxidative stress effects, neurotoxicity, and thyroid disruption of uniconazole enantiomers were investigated through using zebrafish as a model. (R)-Uniconazole possessed 1.16-fold greater acute toxicity to zebrafish than (S)-enantiomer. Then, integrated biomarker response values of oxidative stress parameters in zebrafish exposed to (R)-uniconazole were about 1.27~1.53 times greater than those treated by (S)-uniconazole, revealing that (R)-uniconazole could result in more significant adverse effects than (S)-uniconazole. Subsequently, the results of acetylcholinesterase activity of experimental fish demonstrated a state of inhibition-activation-inhibition after 14-day exposure to uniconazole, and a significant enantioselective neurotoxicity of uniconazole was observed in zebrafish after exposure for 4 and 7 days (p < 0.05). Moreover, thyroxine and triiodothyronine contents in (R)-uniconazole-exposed zebrafish were 0.89-fold (p=0.007) and 0.80-fold (p=0.007) than those in (S)-enantiomer-treated group, respectively. Furthermore, molecular docking results between uniconazole enantiomers and thyroid hormone receptors revealed that (R)-uniconazole was more tightly bound than (S)-uniconazole to the receptors. Briefly, our findings provide favorable information for ecological risk assessments of chiral agrochemicals in the environment and health of aquatic organisms. Title: Enantioselective neurotoxicity and oxidative stress effects of paclobutrazol in zebrafish (Danio rerio) Guo D, Luo L, Kong Y, Kuang Z, Wen S, Zhao M, Zhang W, Fan J Ref: Pestic Biochem Physiol, 185:105136, 2022 : PubMed ESTHER: Guo_2022_Pestic.Biochem.Physiol_185_105136 PubMedSearch: Guo 2022 Pestic.Biochem.Physiol 185 105136 PubMedID: 35772839 Abstract Paclobutrazol is a widely used chiral plant growth regulator and its enantioselective toxicity in aquatic organisms is less explored till now. Herein, the enantioselective neurotoxicity of paclobutrazol mediated by oxidative stress in zebrafish were investigated. The oxidative stress parameters and neurotoxic biomarkers changed significantly in each exposure group, and paclobutrazol showed enantioselective toxicity in zebrafish. Firstly, (2R, 3R)-paclobutrazol exhibited a stronger oxidative stress in zebrafish than (2S, 3S)-enantiomer (P < 0.05). Then, activities of acetylcholinesterase, calcineurin, and total nitric oxide synthase in (2R, 3R)-paclobutrazol treatments were 0.61-0.89, 1.24-1.53, and 1.21-1.35-fold stronger (P < 0.05) than those in (2S, 3S)-enantiomer treatments, respectively. Next, the content variations of four neurotransmitters in zebrafish exposed to (2R, 3R)-paclobutrazol were significantly larger than those in (2S, 3S)-enantiomer treatments (P < 0.05). Moreover, (2R, 3R)-paclobutrazol had stronger binding with the receptors than (2S, 3S)-enantiomer through molecular docking. The integrated biomarker response values further demonstrated that (2R, 3R)-paclobutrazol showed stronger toxicity to zebrafish than (2S, 3S)-enantiomer. Furthermore, the neurotoxicity of paclobutrazol can be interpreted as the mediating effect of oxidative stress in zebrafish through correlation analysis, and an adverse outcome pathway for the nervous system in zebrafish induced by paclobutrazol was proposed. This work will greatly extend our understanding on the enantioselective toxic effects of paclobutrazol in aquatic organisms. Title: Polylactic acid microplastics induce higher biotoxicity of decabromodiphenyl ethane on earthworms (Eisenia fetida) compared to polyethylene and polypropylene microplastics Han Y, Fu M, Wu J, Zhou S, Qiao Z, Peng C, Zhang W, Liu F, Ye C, Yang J Ref: Sci Total Environ, :160909, 2022 : PubMed ESTHER: Han_2022_Sci.Total.Environ__160909 PubMedSearch: Han 2022 Sci.Total.Environ 160909 PubMedID: 36526185 Abstract Decabromodiphenyl ethane (DBDPE) and microplastics (MPs), such as fossil-based polymers polyethylene (PE), polypropylene (PP), and bio-based plastics polylactic acid (PLA) are abundant in e-waste dismantling areas. However, the information on the effects of DBDPE combined with MPs (DBDPE-MPs) on earthworms is still limited. In this study, we explored the impacts of DBDPE-MPs on neurotoxic biomarkers, tissue damage, and transcriptomics of Eisenia fetida by simulating different exposure patterns of 10 mg kg(-1) DBDPE and 10 mg kg(-1) DBDPE-MPs (PLA, PP, and PE). Results showed that the activities of acetylcholinesterase, Na(+)/K(+)-ATPase, Ca(2+)/Mg(2+)-ATPase, carboxylate enzyme, and the contents of calcium and glutamate were significantly stimulated. DBDPE-MP co-exposure caused more severe damage to the epidermis, muscles, and tissues. Transcriptomic analysis revealed that differentially expressed genes (DEGs) of DBDPE-MPs were mainly related to inflammation, the immune system, digestive system, endocrine system, and metabolism. DBDPE and PP-MPs had similar influences on immunity and metabolism. However, DBDPE-PLA and DBDPE-PE further affected the endocrine system and signaling pathways. Specific DEGs showed that detoxification systems in the case of MPs were significantly upregulated. The study indicated that MPs exacerbated DBDPE toxicity in the nervous system, epidermis, and gene regulation of E. fetida, helping to assess the ecological risks of e-wastes and microplastics in soil. Title: Biological activities and gene expression of detoxifying enzymes in Tribolium castaneum induced by Moutan cortex essential oil Li X, Xu Y, Liu J, Yu X, Zhang W, You C Ref: J Toxicol Environ Health A, :1, 2022 : PubMed ESTHER: Li_2022_J.Toxicol.Environ.Health.A__1 PubMedSearch: Li 2022 J.Toxicol.Environ.Health.A 1 PubMedID: 35435144 Abstract Tribolium castaneum is one of the most harmful storage pests in the world. The aim of this study was to determine the chemical composition, repellent, and contact activities of Moutan cortex essential oil against this insect pest. In addition, the effects of Moutan cortex were examined on the expressions of three major detoxifying enzyme genes in T. castaneum. Four components were identified in this essential oil by gas chromatography-mass spectrometry (GC-MS), which was predominantly paeonol (99.13%). Paeonol exerted significant repellent activity against T. castaneum, which was more potent than the positive control N.N-diethyl-meta-toluamide (DEET). The most significant contact toxicity was observed at 24 h after exposure to paeonol. Further, quantitative real-time PCR (qRT-PCR) was used to assess expression changes in three detoxification enzyme genes in T. castaneum, including carboxylesterase (CarE), glutathione S-transferase (Gst) and cytochrome P4506BQ8 (Cyp6bq8). Among these, Gst was most highly up-regulated after treatment with paeonol with the highest expression level of 4.9-fold (Rps18 as internal reference gene) greater than control at 24 h following treatment. Data indicated that Gst might play a critical role in metabolic detoxification of toxic xenobiotics. Taken together, our findings might lay a foundation for development of paeonol as a potential natural repellent or pesticide to control storage pests. Title: The physiological, biochemical and transcriptional responses to sulfamethoxazole in the Asian clam, Corbicula fluminea (O. F. Muller, 1774) Liu S, Zhao H, Zheng M, Wang H, Jing C, Zhang W, Hu F Ref: Comparative Biochemistry & Physiology C Toxicol Pharmacol, 260:109406, 2022 : PubMed ESTHER: Liu_2022_Comp.Biochem.Physiol.C.Toxicol.Pharmacol_260_109406 PubMedSearch: Liu 2022 Comp.Biochem.Physiol.C.Toxicol.Pharmacol 260 109406 PubMedID: 35793736 Abstract Sulfamethoxazole (SMX), a broad-spectrum antibiotic, has been widely used in the treatment and prevention of infection caused by bacteria in recent years. The present study was aimed to evaluate the response mechanisms to SMX stress in gills and digestive gland of Corbicula fluminea (O. F. Mller, 1774). To this end, clams were exposed to environmentally relevant concentrations of SMX (0, 1, 10 and 100 microg/L) for 7 and 28 days, and siphon behavior, tissue-specific enzymatic and transcriptional changes were assayed. Our results showed that exposure to SMX significantly suppressed filtration rate and acetylcholinesterase (AChE) activity, activated antioxidant defense system and elevated transcription of several genes related to cell apoptosis in gills and digestive gland of clams. In general, SMX at environmentally relevant concentrations exhibited a negative impact on siphon behavior and induced neurotoxicology, oxidative stress and cell apoptosis in C. fluminea. The current study will help broaden our understanding of the ecotoxicity of SMX on freshwater bivalves. Title: Isorhapontigenin prevents beta-amyloid-associated cognitive impairments through activation of the PI3K/AKT/GSK-3beta pathway Ma Q, Li C, He Y, Liu P, Gong F, Zhang W Ref: Acta Neurobiol Exp (Wars), 82:389, 2022 : PubMed ESTHER: Ma_2022_Acta.Neurobiol.Exp.(Wars)_82_389 PubMedSearch: Ma 2022 Acta.Neurobiol.Exp.(Wars) 82 389 PubMedID: 36214721 Abstract Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disease that is the most common cause of dementia in the elderly. Abeta1-42 is significantly associated with memory deficits and it can increase the level of acetylcholine, promote the activity of acetylcholinesterase (AChE), and cause cognitive dysfunction. Isorhapontigenin (ISO) is a stilbene derivative that has antioxidant, anti-tumor, and anti-inflammatory effects. However, it is still unclear whether ISO can affect beta-amyloid-associated cognitive impairments. In this study, we found that ISO improved cognitive dysfunction induced by Abeta1-42 in rats. It inhibited the Abeta-induced activation of M1 microglia and reduced the release of inflammatory cytokines. It alleviated amyloid beta-induced oxidative stress and led to an overall improvement in AD symptoms. Cellularly, we found that ISO alleviated Abeta-induced inflammation and oxidative stress by activating the PI3K/AKT/GSK-3beta pathway and ultimately improved cognitive dysfunction in AD rats. Title: Branched poly(ethylenimine) carbon dots-MnO(2) nanosheets based fluorescent sensory system for sensing of malachite green in fish samples Mu X, Liu X, Ye X, Zhang W, Li L, Ma P, Song D Ref: Food Chem, 394:133517, 2022 : PubMed ESTHER: Mu_2022_Food.Chem_394_133517 PubMedSearch: Mu 2022 Food.Chem 394 133517 PubMedID: 35749877 Abstract Malachite green (MG) is an organic dye compound that is frequently used as a fungicide and antiseptic in aquaculture. However, human or animal exposure to MG causes carcinogenic, teratogenic and mutagenic effects. Herein, a novel fluorescent assay was designed for the detection of MG using manganese dioxide nanosheets (MnO(2) NS) as an energy acceptor to quench the fluorescence of branched poly(ethylenimine) carbon dots (BPEI-CDs) via Forster resonance energy transfer. When butyrylcholinesterase is introduced to form thiocholine in the presence of S-butyrylthiocholine iodide, MnO(2) NS can be recovered by thiocholine to Mn(2+), resulting in restoration of the fluorescence of BPEI-CDs. Exploiting these changes in fluorescence intensity in the above system, a fluorescence probe was successfully developed for the quantitative detection of MG. Besides, this assay was applied to fish samples, verifying the high potential for practical application of the proposed sensor for the monitoring of MG in aquatic products. Title: Oxidative stress and detoxification mechanisms of earthworms (Eisenia fetida) after exposure to flupyradifurone in a soil-earthworm system Qiao Z, Li P, Tan J, Peng C, Zhang F, Zhang W, Jiang X Ref: J Environ Manage, 322:115989, 2022 : PubMed ESTHER: Qiao_2022_J.Environ.Manage_322_115989 PubMedSearch: Qiao 2022 J.Environ.Manage 322 115989 PubMedID: 36055090 Abstract Flupyradifurone (FLU) has great application potential in agricultural production as a new generation of neonicotinoid insecticide after imidacloprid. Nevertheless, the toxic effects of FLU on non-target soil organisms remain unclear, resulting in considerable environmental risks. We evaluated the acute and subchronic toxicities of FLU to earthworms. The results of acute toxicity show that the median lethal concentration (LC(50)) values (14 d) of FLU were 186.9773 mg kg(-1) for adult earthworms and 157.6502 mg kg(-1) for juveniles, respectively. The subchronic toxicity of FLU that focused on the activities of antioxidant and detoxication enzymes showed the superoxide dismutase (SOD), catalase (CAT), and glutathione-S transferase (GST) activities in earthworms increased while the peroxidase (POD) and acetylcholinesterase (AChE) activities decreased after exposure to FLU. Oxidative damage analyses revealed that the reactive oxygen species (ROS) level and malonaldehyde (MDA) content in earthworms were increased by FLU, resulting in DNA damage. Transcriptomics and RT-qPCR confirmed that FLU influenced the expression of genes related to antioxidant response and detoxification of earthworms. Ultimately detoxification metabolism, environmental information processing, cell processes, and immune system pathways are significantly enriched to respond jointly to FLU. Our study fills the gaps in the toxicity of FLU to earthworms, providing a basis for its risk assessment of soil ecosystems and non-target biological toxicity. Title: An esterase-activatable prodrug formulated liposome strategy: potentiating the anticancer therapeutic efficacy and drug safety Shi L, Wu X, Li T, Wu Y, Song L, Zhang W, Yin L, Han W, Yang Y Ref: Nanoscale Adv, 4:952, 2022 : PubMed ESTHER: Shi_2022_Nanoscale.Adv_4_952 PubMedSearch: Shi 2022 Nanoscale.Adv 4 952 PubMedID: 36131817 Abstract Liposomal nanomedicine represents a common and versatile carrier for the delivery of both lipophilic and hydrophilic drugs. However, the direct formulation of many chemotherapeutics into a liposomal system remains an enormous challenge. Using the topoisomerase I inhibitor 7-ethyl-10-hydroxycamptothecin (SN38) as a model drug, we combined lipophilic prodrug construction with subsequent integration into an exogenous liposomal scaffold to assemble a prodrug-formulated liposome for systemic administration. Reconstructing SN38 with lipid cholesterol via the esterase-activatable bond endows the resulting prodrug with elevated miscibility with liposomal compositions and esterase-responsive drug release in cancerous cells. The systemic administration of the prodrug-based nanoassemblies (Chol-SN38@LP) exhibited preferential accumulation of therapeutic payloads in tumor lesions. Compared to the SN38 clinical counterpart irinotecan, our prodrug-based nanoassemblies with adaptive features showed elevated therapeutic efficacy (-1.5 times increase of tumor inhibition) in a preclinical A549 lung carcinoma cell-derived mouse model and improved drug tolerability (i.e., alleviated bloody diarrhea and liver damage) in multiple mice models. These results may be ascribed to extended systemic circulation and preferential tumor accumulation of our nanodrugs. Hence, our findings demonstrate that rational engineering of therapeutic nanomedicine is a promising approach for effective and safe delivery of antitumor chemotherapeutics, especially to rescue drug candidates that have failed in clinical trials owing to poor PK properties or severe toxicity in patients. Title: IrO(2) clusters loaded on dendritic mesoporous silica nanospheres with superior peroxidase-like activity for sensitive detection of acetylcholinesterase and its inhibitors Xiao W, Cai S, Wu T, Fu Z, Liu X, Wang C, Zhang W, Yang R Ref: J Colloid Interface Sci, 635:481, 2022 : PubMed ESTHER: Xiao_2022_J.Colloid.Interface.Sci_635_481 PubMedSearch: Xiao 2022 J.Colloid.Interface.Sci 635 481 PubMedID: 36599245 Abstract Nanomaterials-based enzyme mimics (nanozymes), by simulating enzyme catalysis, have shown potential in numerous biocatalytic applications, but nanozymes face significant challenges of catalytic activity and reusability that may restrict their practical uses. Herein, we report facile fabrication of surface-clean IrO(2) clusters supported on dendritic mesoporous silica nanospheres (DMSNs), which exhibit superior peroxidase-like activity, high thermal/long-term stability, and good recyclability. The IrO(2) clusters (1.4s+/-s0.2snm in size) are obtained by the laser ablation without any ligands and possess negative surface charge, which are efficiently loaded on the amino-functionalized DMSNs by electrostatic adsorption. Owing to morphological and structural advantages, the resulted DMSN/IrO(2) heterostructure displays outstanding peroxidase-like catalytic performance. Compared with horseradish peroxidase, it shows comparable affinities but higher reaction rate (2.95sxs10(-7)sM.s(-1)) towards H(2)O(2), resulting from rapid electron transfer during the catalysis. This value is also larger than those of mesoporous silicas supported metal or metal oxides nanoparticles/clusters in the previous studies. Benefitting from excellent peroxidase-catalysis of the DMSN/IrO(2), the colorimetric assays are further successfully established for the detection of acetylcholine esterase and its inhibitor, showing high sensitivity and selectivity. The work provides novel design of supported nanozymes for biosensing. Title: Combined effects of chlorpyrifos and cyfluthrin on neurobehavior and neurotransmitter levels in larval zebrafish Zhang W, Fan R, Luo S, Liu Y, Jin Y, Li Y, Xiong M, Chen Y, Jia L, Yuan X Ref: J Appl Toxicol, :, 2022 : PubMed ESTHER: Zhang_2022_J.Appl.Toxicol__ PubMedSearch: Zhang 2022 J.Appl.Toxicol PubMedID: 35470462 Abstract Chlorpyrifos and cyfluthrin are insecticides commonly used in agriculture. The mixed residues of chlorpyrifos and cyfluthrin in the aquatic environment may have combined effects on non-target species. Therefore, studying the combined toxic effects and mechanisms of pesticide mixtures is of great significance to environmental risk assessment. To evaluate the risk of combined exposure, we examined the effects of both compounds, separately and together, on motor activity, acetylcholinesterase (AChE) activity, and neurotransmitter levels in larval zebrafish. Chlorpyrifos exposure significantly reduced functional motor capacity (swim distance and velocity) and enhanced meandering, while cyfluthrin exposure alone had no significant effects on swim parameters. However, combined exposure significantly reduced total swimming distance and mean velocity, and increased meandering. Both compounds alone and the combination significantly reduced AChE activity, and the combined effect was antagonistic. Combined exposure also significantly altered the concentrations of serotonin, serotonin precursors, and dopamine precursors, as well as concentrations of the amino acid neurotransmitters glycine, alanine, and aspartic acid. Combined exposure to chlorpyrifos and cyfluthrin exhibited distinct joint action modes in terms of neurobehavior, AChE activity, and neurotransmitter levels, thereby providing an experimental basis for assessing the combined exposure to chlorpyrifos and cyfluthrin's environmental risk. Title: Hemoperfusion in combination with hemofiltration for acute severe organophosphorus pesticide poisoning: A systematic review and meta-analysis Zhang M, Zhang W, Zhao S, Tian X, Fu G, Wang B Ref: J Res Med Sci, 27:33, 2022 : PubMed ESTHER: Zhang_2022_J.Res.Med.Sci_27_33 PubMedSearch: Zhang 2022 J.Res.Med.Sci 27 33 PubMedID: 35548179 Abstract BACKGROUND: Acute severe organophosphorus pesticide poisoning (ASOPP) is one of the major diseases that endanger human life and health. However, the effects of conventional therapy including gastric lavages, mechanical ventilation, muscarinic antagonist drugs, and cholinesterase reactivators were uncertain. This meta-analysis aims to investigate the safety and efficacy of hemoperfusion combined with hemofiltration besides routine therapy for ASOPP. MATERIALS AND METHODS: A comprehensive search for candidate publications was performed through PubMed, Medline, Cochrane Library, WanFang, Chinese Biomedical Literature, and China National Knowledge Infrastructure from database inception to May 12, 2020. The retrieved studies were screened by the predefined inclusion and exclusion criteria. The data of important end points were extracted. The risk ratio (RR) and weighted mean difference (WMD) were pooled for categorical variables and continuous variables, respectively. Meta-analyses and publication bias were conducted by using STATA software version 15.1. RESULTS: A total of 11 randomized controlled trials with 811 patients were included. Compared to conventional therapy group, patients in the hemoperfusion plus hemofiltration group were significantly superior with regard to mortality (RR 0.38, 95% confidence interval [CI] [0.25, 0.57], P < 0.001), total atropine dosing (WMD -147.34 mg, 95% CI [-199.49, -95.18], P < 0.001), duration of mechanical ventilation (WMD -2.34 days, 95% CI [-3.77, -0.92], P < 0.001), cholinesterase recovery time (WMD -2.49 days, 95% CI [-3.14, -1.83], P < 0.001), and length of stay (WMD -4.52 days, 95% CI [-5.31, -3.73], P < 0.001). CONCLUSION: Combined hemoperfusion and hemofiltration was a very safe and effective treatment protocol for ASOPP, not only resulting in significantly decreased mortality but also resulting in reduced total atropine dosing, duration of mechanical ventilation, cholinesterase recovery time, and length of stay. Title: Prolonged sevoflurane exposure causes abnormal synapse development and dysregulates beta-neurexin and neuroligins in the hippocampus in neonatal rats Zhang W, Chen Y, Qin J, Lu J, Fan Y, Shi Z, Song X, Li C, Zhao T Ref: J Affect Disord, :, 2022 : PubMed ESTHER: Zhang_2022_J.Affect.Disord__ PubMedSearch: Zhang 2022 J.Affect.Disord PubMedID: 35691415 Abstract BACKGROUND: The underlying molecular mechanisms of the excitatory/inhibitory (E/I) imbalance induced by sevoflurane exposure to neonates remain poorly understood. This study aimed to investigate the long-term effects of prolonged sevoflurane exposure to neonatal rats during the peak period of synaptogenesis on the changes of trans-synaptic neurexin-neuroligin interactions, synaptic ultrastructure in the hippocampus and cognition. METHODS: A total of 30 rat pups at postnatal day (P) 7 was randomly divided into two groups: the control group (exposed to 30 % oxygen balanced with nitrogen) and the sevoflurane group (exposed to 2.5 % sevoflurane plus 30 % oxygen balanced with nitrogen) for 6 h. Neurocognitive behaviors were assessed with the Open field test at P23-25 and the Morris water maze test at P26-30. The expression of beta-neurexin (beta-NRX), N-methyl-d-aspartate receptor 2 subunit (NR2A and NR2B), neuroligin-1 (NLG-1), neuroligin-2 (NLG-2), postsynaptic density protein-95 (PSD-95), alpha1-subunit of the gamma-aminobutyric acid A receptor (GABAAalpha1) and gephyrin in the hippocampus at P30 were measured by Western blot. The ultrastructure of synapses was examined under electron microscope. RESULTS: Prolonged sevoflurane exposure at P7 resulted in cognitive deficiency in adolescence, as well as the downregulation of beta-NRX, NR2A, NR2B, NLG-1, and PSD-95, and the upregulation of GABAAalpha1, NLG-2, and gephyrin in the hippocampal CA3 region. Sevoflurane anesthesia also increased the number of symmetric synapses in the hippocampus. CONCLUSIONS: Prolonged sevoflurane exposure during the brain development leads to cognitive deficiency and disproportion of excitatory/inhibitory synapses which may be caused by dysregulated expression of synaptic adhesion molecules of beta-NRX and neuroligins. Title: Biodegradation of Free Gossypol by Helicoverpa armigera Carboxylesterase Expressed in Pichia pastoris Zhang L, Yang X, Huang R, Nie C, Niu J, Chen C, Zhang W Ref: Toxins (Basel), 14:816, 2022 : PubMed ESTHER: Zhang_2022_Toxins.(Basel)_14_816 PubMedSearch: Zhang 2022 Toxins.(Basel) 14 816 PubMedID: 36548713 Abstract Gossypol is a polyphenolic toxic secondary metabolite derived from cotton. Free gossypol in cotton meal is remarkably harmful to animals. Furthermore, microbial degradation of gossypol produces metabolites that reduce feed quality. We adopted an enzymatic method to degrade free gossypol safely and effectively. We cloned the gene cce001a encoding carboxylesterase (CarE) into pPICZalphaA and transformed it into Pichia pastoris GS115. The target protein was successfully obtained, and CarE CCE001a could effectively degrade free gossypol with a degradation rate of 89%. When esterase was added, the exposed toxic groups of gossypol reacted with different amino acids and amines to form bound gossypol, generating substances with (M + H) m/z ratios of 560.15, 600.25, and 713.46. The molecular formula was C(27)H(28)O(13), C(34)H(36)N(2)O(6), and C(47)H(59)N(3)O(3). The observed instability of the hydroxyl groups caused the substitution and shedding of the group, forming a substance with m/z of 488.26 and molecular formula C(31)H(36)O(5). These properties render the CarE CCE001a a valid candidate for the detoxification of cotton meal. Furthermore, the findings help elucidate the degradation process of gossypol in vitro. Title: FAM135B sustains the reservoir of Tip60-ATM assembly to promote DNA damage response Zhang K, Wu Q, Liu W, Wang Y, Zhao L, Chen J, Liu H, Liu S, Li J and Zhan Q <1 more author(s)> Zhang K, Wu Q, Liu W, Wang Y, Zhao L, Chen J, Liu H, Liu S, Li J, Zhang W, Zhan Q (- 1) Ref: Clin Transl Med, 12:e945, 2022 : PubMed ESTHER: Zhang_2022_Clin.Transl.Med_12_e945 PubMedSearch: Zhang 2022 Clin.Transl.Med 12 e945 PubMedID: 35979619 Gene_locus related to this paper: human-FAM135B Abstract BACKGROUND: Recently, the mechanism by which cells adapt to intrinsic and extrinsic stresses has received considerable attention. Tat-interactive protein 60-kDa/ataxia-telangiectasia-mutated (TIP60/ATM) axis-mediated DNA damage response (DDR) is vital for maintaining genomic integrity. METHODS: Protein levels were detected by western blot, protein colocalisation was examined by immunofluorescence (IF) and protein interactions were measured by co-immunoprecipitation, proximity ligation assay and GST pull-down assays. Flow cytometry, comet assay and IF assays were used to explore the biological functions of sequence similarity 135 family member B (FAM135B) in DDR. Xenograft tumour, FAM135B transgenic mouse models and immunohistochemistry were utilised to confirm in vitro observations. RESULTS: We identified a novel DDR regulator FAM135B which could protect cancer cells from genotoxic stress in vitro and in vivo. The overexpression of FAM135B promoted the removal of gammaH2AX and 53BP1 foci, whereas the elimination of FAM135B attenuated these effects. Consistently, our findings revealed that FAM135B could promote homologous recombination and non-homologous end-joining repairs. Further study demonstrated that FAM135B physically bound to the chromodomain of TIP60 and improved its histone acetyltransferase activity. Moreover, FAM135B enhanced the interactions between TIP60 and ATM under resting conditions. Intriguingly, the protein levels of FAM135B dramatically decreased following DNA damage stress but gradually increased during the DNA repair period. Thus, we proposed a potential DDR mechanism where FAM135B sustains a reservoir of pre-existing TIP60-ATM assemblies under resting conditions. Once cancer cells suffer DNA damage, FAM135B is released from TIP60, and the functioning pre-assembled TIP60-ATM complex participates in DDR. CONCLUSIONS: We characterised FAM135B as a novel DDR regulator and further elucidated the role of the TIP60-ATM axis in response to DNA damage, which suggests that targeting FAM135B in combination with radiation therapy or chemotherapy could be a potentially effective approach for cancer treatment. Title: ATGL activity regulates GLUT1-mediated glucose uptake and lactate production via TXNIP stability in adipocytes Beg M, Zhang W, McCourt AC, Enerback S Ref: Journal of Biological Chemistry, :100332, 2021 : PubMed ESTHER: Beg_2021_J.Biol.Chem__100332 PubMedSearch: Beg 2021 J.Biol.Chem 100332 PubMedID: 33508319 Abstract Traditionally, lipolysis has been regarded as an enzymatic activity that liberates fatty acids as metabolic fuel. However, recent work has shown that novel substrates, including a variety of lipid compounds such as fatty acids and their derivatives, release "lipolysis products" that act as signaling molecules and transcriptional modulators. While these studies have expanded the role of lipolysis, the mechanisms underpinning lipolysis signaling are not fully defined. Here, we uncover a new mechanism regulating glucose uptake whereby activation of lipolysis, in response to elevated cAMP, leads to the stimulation of Thioredoxin Interacting Protein (TXNIP) degradation. This, in turn, selectively induces GLUT1 surface localization and glucose uptake in 3T3-L1 adipocytes, and increases lactate production. Interestingly, cAMP-induced glucose uptake via degradation of TXNIP is largely dependent upon adipose triglyceride lipase (ATGL), and not hormone-sensitive lipase (HSL) or monoacylglycerol lipase (MGL). Pharmacological inhibition or knockdown of ATGL alone prevents cAMP-dependent TXNIP degradation and thus significantly decreases glucose uptake and lactate secretion. Conversely, overexpression of ATGL amplifies the cAMP response, yielding increased glucose uptake and lactate production. Similarly, knockdown of TXNIP elicits enhanced basal glucose uptake and lactate secretion and increased cAMP further amplifies this phenotype. Overexpression of TXNIP reduces basal and cAMP-stimulated glucose uptake and lactate secretion. As a proof of concept, we replicated these findings in human primary adipocytes and observed TXNIP degradation and increased glucose uptake and lactate secretion upon elevated cAMP signaling. Taken together, our results suggest a crosstalk between ATGL-mediated lipolysis and glucose uptake. Title: Binding Peptide-Guided Immobilization of Lipases with Significantly Improved Catalytic Performance Using Escherichia coli BL21(DE3) Biofilms as a Platform Dong H, Zhang W, Xuan Q, Zhou Y, Zhou S, Huang J, Wang P Ref: ACS Appl Mater Interfaces, :, 2021 : PubMed ESTHER: Dong_2021_ACS.Appl.Mater.Interfaces__ PubMedSearch: Dong 2021 ACS.Appl.Mater.Interfaces PubMedID: 33499600 Abstract Developing novel immobilization methods to maximize the catalytic performance of enzymes has been a permanent pursuit of scientific researchers. Engineered Escherichia coli biofilms have attracted great concern as surface display platforms for enzyme immobilization. However, current biological conjugation methods, such as the SpyTag/SpyCatcher tagging pair, that immobilize enzymes onto E. coli biofilms seriously hamper enzymatic performance. Through phage display screening of lipase-binding peptides (LBPs) and co-expression of CsgB (nucleation protein of curli nanofibers) and LBP2-modified CsgA (CsgALBP2, major structural subunit of curli nanofibers) proteins, we developed E. coli BL21::deltaCsgA-CsgB-CsgALBP2 (LBP2-functionalized) biofilms as surface display platforms to maximize the catalytic performance of lipase (Lip181). After immobilization onto LBP2-functionalized biofilm materials, Lip181 showed increased thermostability, pH, and storage stability. Surprisingly, the relative activity of immobilized Lip181 increased from 8.43 to 11.33 U/mg through this immobilization strategy. Furthermore, the highest loading of lipase on LBP2-functionalized biofilm materials reached up to 27.90 mg/g of wet biofilm materials, equivalent to 210.49 mg/g of dry biofilm materials, revealing their potential as a surface with high enzyme loading capacity. Additionally, immobilized Lip181 was used to hydrolyze phthalic acid esters, and the hydrolysis rate against dibutyl phthalate was up to 100%. Thus, LBP2-mediated immobilization of lipases was demonstrated to be far more advantageous than the traditional SpyTag/SpyCatcher strategy in maximizing enzymatic performance, thereby providing a better alternative for enzyme immobilization onto E. coli biofilms. Title: A GRN Autocrine-Dependent FAM135B/AKT/mTOR Feedforward Loop Promotes Esophageal Squamous Cell Carcinoma Progression Dong D, Zhang W, Xiao W, Wu Q, Cao Y, Gao X, Huang L, Wang Y, Chen J and Zhan Q <1 more author(s)> Dong D, Zhang W, Xiao W, Wu Q, Cao Y, Gao X, Huang L, Wang Y, Chen J, Wang W, Zhan Q (- 1) Ref: Cancer Research, 81:910, 2021 : PubMed ESTHER: Dong_2021_Cancer.Res_81_910 PubMedSearch: Dong 2021 Cancer.Res 81 910 PubMedID: 33323378 Gene_locus related to this paper: human-FAM135B Abstract Esophageal squamous cell carcinoma (ESCC) is one of the most common and deadly diseases. In our previous comprehensive genomics study, we found that family with sequence similarity 135 member B (FAM135B) was a novel cancer-related gene, yet its biological functions and molecular mechanisms remain unclear. In this study, we demonstrate that the protein levels of FAM135B are significantly higher in ESCC tissues than in precancerous tissues, and high expression of FAM135B correlates with poorer clinical prognosis. Ectopic expression of FAM135B promoted ESCC cell proliferation in vitro and in vivo, likely through its direct interaction with growth factor GRN, thus forming a feedforward loop with AKT/mTOR signaling. Patients with ESCC with overexpression of both FAM135B and GRN had worse prognosis; multivariate Cox model analysis indicated that high expression of both FAM135B and GRN was an independent prognostic factor for patients with ESCC. FAM135B transgenic mice bore heavier tumor burden than wild-type mice and survived a relatively shorter lifespan after 4-nitroquinoline 1-oxide treatment. In addition, serum level of GRN in transgenic mice was higher than in wild-type mice, suggesting that serum GRN levels might provide diagnostic discrimination for patients with ESCC. These findings suggest that the interaction between FAM135B and GRN plays critical roles in the regulation of ESCC progression and both FAM135B and GRN might be potential therapeutic targets and prognostic factors in ESCC. SIGNIFICANCE: These findings investigate the mechanisms of FAM135B in promoting ESCC progression and suggest new potential prognostic biomarkers and therapeutic targets in patients with ESCC. Title: Clinical and preclinical evidence for roles of soluble epoxide hydrolase in osteoarthritis knee pain Gowler PRW, Turnbull J, Shahtaheri M, Gohir S, Kelly T, McReynolds C, Jun Y, Jha RR, Fernandes GS and Chapman V <6 more author(s)> Gowler PRW, Turnbull J, Shahtaheri M, Gohir S, Kelly T, McReynolds C, Jun Y, Jha RR, Fernandes GS, Zhang W, Doherty M, Walsh DA, Bruce HD, Valdes AM, Barrett DA, Chapman V (- 6) Ref: Arthritis Rheumatol, :, 2021 : PubMed ESTHER: Gowler_2021_Arthritis.Rheumatol__ PubMedSearch: Gowler 2021 Arthritis.Rheumatol PubMedID: 34672113 Abstract OBJECTIVE: Chronic pain due to osteoarthritis (OA) is a major clinical problem, existing analgesics often have limited beneficial effects and/or adverse effects, necessitating the development of novel therapies. Epoxyeicosatrienoic acids (EETs) are endogenous anti-inflammatory mediators, rapidly metabolized by soluble epoxide hydrolase (sEH) to dihydroxyeicosatrienoic acids (DHETs). We hypothesized that sEH driven metabolism of the EETs to DHETs plays a critical role in chronic joint pain associated with OA and provides a new target for treatment. METHODS: Potential associations between chronic knee pain in people and single nucleotide polymorphisms (SNPs) in the gene encoding sEH and circulating levels of the EETs and DHETs were investigated. A surgically-induced murine model of OA was used to determine the effects of both acute and chronic selective inhibition of sEH by N-[1-(1-oxopropy)-4-piperidinyl]-N(') -(trifluoromethoxy)phenyl]urea (TPPU) on weight-bearing asymmetry, hind-paw withdrawal thresholds, joint histology, and circulating concentrations of the EETs and DHETs. RESULTS: In people with chronic knee pain, 3 pain measures were associated with SNPs of the sEH gene, EPHX2, and in two separate cohorts circulating levels of EETs and DHETs were also associated with 3 pain measures. In the murine OA model, systemic administration of TPPU both acutely and chronically reversed established pain behaviours and decreased circulating levels of 8,9-DHET and 14,15-DHET. The levels of the EETs were unchanged by TPPU administration. CONCLUSION: Our novel findings support a role of sEH in OA pain and suggest that inhibition of sEH and protection of endogenous EETs from catabolism represents a potential new therapeutic target for OA pain. Title: Characteristics of a recombinant Fusarium verticillioides cutinase and its effects on enzymatic hydrolysis of rice straw Gu S, Liu C, Zhang W, Qu M, Li Y, Zang Y, Xiong X, Pan K, Zhao X Ref: Int J Biol Macromol, 171:382, 2021 : PubMed ESTHER: Gu_2021_Int.J.Biol.Macromol_171_382 PubMedSearch: Gu 2021 Int.J.Biol.Macromol 171 382 PubMedID: 33434547 Gene_locus related to this paper: gibm7-w7lbp5 Abstract The current study heterologously expressed a cutinase from Fusarium verticillioides by Pichia pastoris and investigated its properties and effects on the hydrolysis of rice straw. The optimal pH and temperature for F. verticillioides cutinase were 8.0 and 50 degreesC, respectively. F. verticillioides cutinase had poor thermal stability and could be inhibited by some metal ions, inhibitors, and detergents (5 mM), including Ni(2+), Zn(2+), Cu(2+), Ca(2+), Mn(2+), sodium dodecyl sulfate, EDTA, and Tween-20. F. verticillioides cutinase could tolerate 15% methanol and dimethyl sulfoxide but was significantly repressed by 15% ethanol and acetone with 48% and 63% residual activity, respectively. F. verticillioides cutinase could degrade the cuticle of rice straw with palmitic acid and stearic acid as the main products. However, the dissolving sugars released from the rice straw treated with F. verticillioides cutinase were significantly reduced by 29.2 microg/mL compared with the control (107.9 microg/mL). Similarly, the reducing sugars produced from the cellulase hydrolysis of rice straw pretreated with F. verticillioides cutinase were reduced by 63.5 microg/mL relative to the control (253.6 microg/mL). Scanning electron microscopy results showed that numerous tuberculate or warty protrusions were present nearly everywhere on the surface of rice straw treated with F. verticillioides cutinase, and some protrusions even covered and blocked the stomata of the rice straw surface. Current limited data indicate that F. verticillioides cutinase might not be an appropriate choice for improving the utilization of agricultural straws. Title: NOTUM promotes thermogenic capacity and protects against diet-induced obesity in male mice Guo F, Seldin M, Peterfy M, Charugundla S, Zhou Z, Lee SD, Mouton A, Rajbhandari P, Zhang W and Shih DM <3 more author(s)> Guo F, Seldin M, Peterfy M, Charugundla S, Zhou Z, Lee SD, Mouton A, Rajbhandari P, Zhang W, Pellegrini M, Tontonoz P, Lusis AJ, Shih DM (- 3) Ref: Sci Rep, 11:16409, 2021 : PubMed ESTHER: Guo_2021_Sci.Rep_11_16409 PubMedSearch: Guo 2021 Sci.Rep 11 16409 PubMedID: 34385484 Abstract We recently showed that NOTUM, a liver-secreted Wnt inhibitor, can acutely promote browning of white adipose. We now report studies of chronic overexpression of NOTUM in liver indicating that it protects against diet-induced obesity and improves glucose homeostasis in mice. Adeno-associated virus (AAV) vectors were used to overexpress GFP or mouse Notum in the livers of male C57BL/6J mice and the mice were fed an obesifying diet. After 14 weeks of high fat, high sucrose diet feeding, the AAV-Notum mice exhibited decreased obesity and improved glucose tolerance compared to the AAV-GFP mice. Gene expression and immunoblotting analysis of the inguinal fat and brown fat revealed increased expression of beige/brown adipocyte markers in the AAV-Notum group, suggesting enhanced thermogenic capacity by NOTUM. A beta3 adrenergic receptor agonist-stimulated lipolysis test suggested increased lipolysis capacity by NOTUM. The levels of collagen and C-C motif chemokine ligand 2 (CCL2) in the epididymal white adipose tissue of the AAV-Notum mice were significantly reduced, suggesting decreased fibrosis and inflammation, respectively. RNA sequencing analysis of inguinal white adipose of 4-week chow diet-fed mice revealed a highly significant enrichment of extracellular matrix (ECM) functional cluster among the down-regulated genes in the AAV-Notum group, suggesting a potential mechanism contributing to improved glucose homeostasis. Our in vitro studies demonstrated that recombinant human NOTUM protein blocked the inhibitory effects of WNT3A on brown adipocyte differentiation. Furthermore, NOTUM attenuated WNT3A's effects on upregulation of TGF-beta signaling and its downstream targets. Overall, our data suggest that NOTUM modulates adipose tissue function by promoting thermogenic capacity and inhibiting fibrosis through inhibition of Wnt signaling. Title: Isoleucine increases muscle mass through promoting myogenesis and intramyocellular fat deposition Liu S, Sun Y, Zhao R, Wang Y, Zhang W, Pang W Ref: Food Funct, 12:144, 2021 : PubMed ESTHER: Liu_2021_Food.Funct_12_144 PubMedSearch: Liu 2021 Food.Funct 12 144 PubMedID: 33289736 Abstract Isoleucine (Ile), as a branched-chain amino acid (BCAA), has a vital role in regulating body weight and muscle protein synthesis. However, the regulatory effect of Ile on muscle mass under high-fat diet (HFD) conditions and intramyocellular lipid deposition remains largely unclear. In this study, a feeding experiment with HFD with or without 25 g L-1 Ile was performed using 32 wild male C57BL/6J mice randomly divided into two groups. The results showed that Ile significantly increased both muscle and fat mass, as well as causing insulin resistance and meanwhile upregulating the levels of key adipogenic and myogenic proteins. More importantly, Ile damaged the mitochondrial function by vacuolation, swelling and cristae fracture in the gastrocnemius (GAS) and tibialis anterior (TA) with downregulation of mitochondrial function-related genes. Furthermore, Ile promoted myogenesis and more lipid droplet accumulation in myotubes. Compared with the control, the protein levels of myosin heavy chain (MyHC), myoblast determination protein 1 (MyoD), myogenin (MyoG), peroxisome proliferator-activated receptor gamma (PPARg) and fatty acid synthase (FAS) were upregulated in the Ile group, whereas the protein levels of adipose triglyceride lipase (ATGL) and lipoprotein lipase (LPL) were downregulated. Collectively, Ile increased muscle mass through myogenesis and intramyocellular lipid deposition. Our findings provide a new perspective for not only improving the lean juiciness of farm animals by increasing intramyocellular lipid accumulation, but also modulating myopathies under obesity. Title: Protein engineering of stable IsPETase for PET plastic degradation by Premuse Meng X, Yang L, Liu H, Li Q, Xu G, Zhang Y, Guan F, Zhang W, Wu N, Tian J Ref: Int J Biol Macromol, 180:667, 2021 : PubMed ESTHER: Meng_2021_Int.J.Biol.Macromol_180_667 PubMedSearch: Meng 2021 Int.J.Biol.Macromol 180 667 PubMedID: 33753197 Gene_locus related to this paper: idesa-peth Abstract Poly(ethylene terephthalate) (PET) is used widely by human beings, but is very difficult to degrade. Up to now, the PET degradation effect of PETase from Ideonella sakaiensis 201-F6 (IsPETase) variants with low stability and activity was not ideal. In this study, a mutation design tool, Premuse, was developed to integrate the sequence alignment and quantitative selection of the preferred mutations based on natural sequence evolution. Ten single point mutants were selected from 1486 homologous sequences using Premuse, and then two mutations (W159H and F229Y) with improved stability were screened from them. The derived double point mutant, W159H/F229Y, exhibited a strikingly enhanced enzymatic performance. Its T(m) and catalytic efficiency values (k(cat)/K(m)) respectively increased by 10.4 degreesC and 2.0-fold using p-NPP as the substrate compared with wild type. The degradation activity for amorphous PET was increased by almost 40-fold in comparison with wild type at 40 degreesC in 24 h. Additionally, the variant could catalyze biodegradation of PET bottle preform at a mean rate of 23.4 mg(PET)/h/mg(enzyme). This study allowed us to design the mutation more efficiently, and provides a tool for achieving biodegradation of PET pollution under mild natural environments. Title: Plasma cholinesterase activity is influenced by interactive effect between omethoate exposure and CYP2E1 polymorphisms Wang T, Zhang H, Li L, Zhang W, Wang Q, Wang W Ref: J Environ Sci Health B, :1, 2021 : PubMed ESTHER: Wang_2021_J.Environ.Sci.Health.B__1 PubMedSearch: Wang 2021 J.Environ.Sci.Health.B 1 PubMedID: 33872129 Abstract The aim of this study was to explore the association between metabolizing enzyme gene polymorphisms and the decrease in cholinesterase activity induced by omethoate exposure. A total of 180 workers exposed to omethoate over an extended period were recruited along with 115 healthy controls. Cholinesterase activity in whole blood, erythrocyte, and plasma was detected using acetylthiocholine and the dithio-bis-(nitrobenzoic acid) method. Six polymorphic loci of GSTT1(+/-), GSTM1(+/-), GSTP1 rs1695, CYP2E1 rs6413432, CYP2E1 rs3813867, and PON2 rs12026 were detected by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). The gene-environment interactions were analyzed using the generalized linear model method. The cholinesterase activity of erythrocyte and plasma in the exposure group was significantly lower than that in the control group (P < 0.001) in general. The plasma cholinesterase activity in the TT + AT genotype in CYP2E1 rs6413432 was lower than that in the AA genotype in the exposure group (P = 0.016). Interaction between the AA genotype in CYP2E1 rs6413432 and omethoate exposure had a significant effect on plasma cholinesterase activity (P = 0.079). The decrease in plasma cholinesterase activity was associated with interaction between the AA genotypes in rs6413432 and omethoate exposure. Title: Absolute protein assay for the simultaneous quantification of two epoxide hydrolases in rats by mass spectrometry-based targeted proteomics Wu T, Xi X, Chen Y, Jiang C, Zhang Q, Dai G, Bai Y, Zhang W, Ni T and Xu M <2 more author(s)> Wu T, Xi X, Chen Y, Jiang C, Zhang Q, Dai G, Bai Y, Zhang W, Ni T, Zou J, Ju W, Xu M (- 2) Ref: J Sep Sci, :, 2021 : PubMed ESTHER: Wu_2021_J.Sep.Sci__ PubMedSearch: Wu 2021 J.Sep.Sci PubMedID: 34008891 Abstract Epoxide hydrolases catalyze the hydrolysis of both exogenous and endogenous epoxides to the corresponding vicinal diols by adding water. Microsomal and soluble epoxide hydrolase are two main mammalian enzymes that have been intensely characterized. The purpose of this investigation was to develop and validate a proteomics assay allowing the simultaneous quantification of microsomal and soluble epoxide hydrolase in rats. Protein quantification was realized through targeted proteomics, using liquid chromatography with tandem mass spectrometry for the determination of trypsin-specific surrogate peptides after digestion. Stable isotope-labeled peptides were used as the internal standards. The chromatography of the surrogate peptides was performed on an Agilent SB C(18) column (100 mm x 4.6 mm, 1.8 microm) with gradient elution. Acetonitrile containing 0.1% formic acid and 0.1% formic acid aqueous solution were used as mobile phases. A multiple reaction monitoring method in a positive ionization mode was used for the simultaneous detection of the peptides. The method was validated concerning the specificity, linearity, within-day and between-day accuracy and precision, matrix effect, stability, and digestion efficiency. The developed assay was successfully used to quantify the protein levels of microsomal and soluble epoxide hydrolase in rat liver, kidney, and heart S9 samples. This article is protected by copyright. All rights reserved. Title: Construction and analysis of the protein-protein interaction network for the detoxification enzymes of the silkworm, Bombyx mori Xin S, Zhang W Ref: Archives of Insect Biochemistry & Physiology, :e21850, 2021 : PubMed ESTHER: Xin_2021_Arch.Insect.Biochem.Physiol__e21850 PubMedSearch: Xin 2021 Arch.Insect.Biochem.Physiol e21850 PubMedID: 34750851 Abstract Detoxification enzymes are necessary for insects to metabolize toxic substances and maintain physiological activities. Cytochromes P450 (CYPs), glutathione S-transferases (GSTs), and carboxylesterase (CarEs) are the main detoxification enzymes in insects. In addition, UDP-glucosyltransferase and ATP-binding cassette transporter also participate in the process of material metabolism. This study collected proteins related to detoxification in the silkworm, Bombyx mori (Lepidoptera: Bombycidae). And we performed Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis on these proteins to understand their biological function. We constructed the protein-protein interaction network for the silkworm's detoxification enzymes and analyzed the network's topological properties. We found that BGIBMGA014046-TA, BGIBMGA003221-TA, BGIBMGA011092-TA, BGIBMGA000074-TA, and LOC732976 are the essential proteins in the network. These proteins are primarily involved in the process of ribosome biogenesis and may be related to protein synthesis. We integrated GO, KEGG, and network analysis and found that ribosome-associated protein and GSTs played a vital role in the detoxification process. Title: Structural basis for substrate specificity of the peroxisomal acyl-CoA hydrolase MpaH' involved in mycophenolic acid biosynthesis You C, Li F, Zhang X, Ma L, Zhang YZ, Zhang W, Li S Ref: Febs J, :, 2021 : PubMed ESTHER: You_2021_FEBS.J__ PubMedSearch: You 2021 FEBS.J PubMedID: 33843134 Inhibitor(s) related to this paper: Mycophenolic-acid Abstract Mycophenolic acid (MPA) is a fungal natural product and first-line immunosuppressive drug for organ transplantations and autoimmune diseases. In the compartmentalized biosynthesis of MPA, the acyl-coenzyme A (CoA) hydrolase MpaH' located in peroxisomes catalyzes the highly specific hydrolysis of MPA-CoA to produce the final product MPA. The strict substrate specificity of MpaH' not only averts undesired hydrolysis of various cellular acyl-CoAs, but also prevents MPA-CoA from further peroxisomal beta-oxidation catabolism. To elucidate the structural basis for this important property, in this study, we solve the crystal structures of the substrate-free form of MpaH' and the MpaH'(S139A) mutant in complex with the product MPA. The MpaH' structure reveals a canonical alpha/beta-hydrolase fold with an unusually large cap domain and a rare location of the acidic residue D163 of catalytic triad after strand beta6. MpaH' also forms an atypical dimer with the unique C-terminal helices alpha13 and alpha14 arming the cap domain of the other protomer and indirectly participating in the substrate binding. With these characteristics, we propose that MpaH' and its homologues form a new subfamily of alpha/beta hydrolase fold protein. The crystal structure of MpaH'(S139A) /MPA complex and the modelled structure of MpaH'/MPA-CoA, together with the structure-guided mutagenesis analysis and isothermal titration calorimetry (ITC) measurements provide important mechanistic insights into the high substrate specificity of MpaH'. Title: Effects of exogenous GR24 on biogas upgrading and nutrient removal by co-culturing microalgae with fungi under mixed LED light wavelengths Zhang W, Zhao C, Liu J, Sun S, Zhao Y, Wei J Ref: Chemosphere, 281:130791, 2021 : PubMed ESTHER: Zhang_2021_Chemosphere_281_130791 PubMedSearch: Zhang 2021 Chemosphere 281 130791 PubMedID: 34020195 Abstract To realize the synchronous purification of raw biogas and biogas slurry, the algal-fungal symbiont pellets were cultivated by supplementing strigolactone (GR24) under different mixed LED light wavelengths. The optimal light intensity was proved to be red and blue in the ratio of 5:5. The symbionts treated with 10(-9) M GR24 had the highest growth rate and mean daily productivity. The extracellular carbonic anhydrase activity and the content of chlorophyll were also affected by GR24 concentrations and mixed light wavelengths. With the induction of 10(-9) M GR24, the maximum removal efficiency of chemical oxygen demand, total nitrogen, and total phosphorus reached 76.35 +/- 6.87%, 78.77 +/- 7.13% and 79.49 +/- 7.43%, respectively. Besides, the CO(2) removal efficiency reached 59.32 +/- 5.19% when the concentration of GR24 was 10(-7) M. This work will be beneficial for large-scale biogas slurry purification and biogas upgrading using co-cultivation of microalgae and fungi. Title: Network Pharmacology-Based Study of the Underlying Mechanisms of Huangqi Sijunzi Decoction for Alzheimer's Disease Zhang W, Lv M, Shi Y, Mu Y, Yao Z, Yang Z Ref: Evid Based Complement Alternat Med, 2021:6480381, 2021 : PubMed ESTHER: Zhang_2021_Evid.Based.Complement.Alternat.Med_2021_6480381 PubMedSearch: Zhang 2021 Evid.Based.Complement.Alternat.Med 2021 6480381 PubMedID: 34650613 Abstract BACKGROUND: Huangqi Sijunzi decoction (HQSJZD) is a commonly used conventional Chinese herbal medicine prescription for invigorating Qi, tonifying Yang, and removing dampness. Modern pharmacology and clinical applications of HQSJZD have shown that it has a certain curative effect on Alzheimer's disease (AD). METHODS: The active components and targets of HQSJZD were searched in the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). The genes corresponding to the targets were retrieved using UniProt and GeneCard database. The herb-compound-target network and protein-protein interaction (PPI) network were constructed by Cytoscape. The core targets of HQSJZD were analysed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). The main active compounds of HQSJZD were docked with acetylcholinesterase (AChE). In vitro experiments were conducted to detect the inhibitory and neuroprotective effects of AChE. RESULTS: Compound-target network mainly contained 132 compounds and 255 corresponding targets. The main compounds contained quercetin, kaempferol, formononetin, isorhamnetin, hederagenin, and calycosin. Key targets contained AChE, PTGS2, PPARG, IL-1B, GSK3B, etc. There were 1708 GO items in GO enrichment analysis and 310 signalling pathways in KEGG, mainly including the cAMP signalling pathway, the vascular endothelial growth factor (VEGF) signalling pathway, serotonergic synapses, the calcium signalling pathway, type II diabetes mellitus, arginine and proline metabolism, and the longevity regulating pathway. Molecular docking showed that hederagenin and formononetin were the top 2 compounds of HQSJZD, which had a high affinity with AChE. And formononetin has a good neuroprotective effect, which can improve the oxidative damage of nerve cells. CONCLUSION: HQSJZD was found to have the potential to treat AD by targeting multiple AD-related targets. Formononetin and hederagenin in HQSJZD may regulate multiple signalling pathways through AChE, which might play a therapeutic role in AD. Title: EZH2-mediated lncRNA ABHD11-AS1 promoter regulates the progression of ovarian cancer by targeting miR-133a-3p Zhang W, Huang X, Shi J Ref: Anticancer Drugs, 32:269, 2021 : PubMed ESTHER: Zhang_2021_Anticancer.Drugs_32_269 PubMedSearch: Zhang 2021 Anticancer.Drugs 32 269 PubMedID: 33491971 Gene_locus related to this paper: human-ABHD11 Abstract Long-chain noncoding RNAs (lncRNAs) are involved in a wide range of biological and pathological processes in ovarian cancer. The purpose of this study was to investigate the effects of EZH2-mediated ABHD11-AS1 promoter on the pathogenesis of ovarian cancer. The expression levels of EZH2, ABHD11-AS1 and miR-133a-3p were examined in ovarian cancer tissues using reverse transcription-quantitative PCR. Cell proliferation was evaluated using cell counting kit 8 assay, and cell invasion/migration was determined using a Transwell assay. Cell apoptosis was evaluated using flow cytometry. Dual luciferase assay was performed to confirm the interaction between ABHD11-AS1 and miR-133a-3p. The binding site of H3K27me3 on ABHD11-AS1 promoter was confirmed by ChIP. The expression of ABHD11-AS1 was significantly upregulated in ovarian cancer samples, and its levels were closely associated with lymph node metastasis, tumor stage and 3-year survival rate. Furthermore, interference of ABHD11-AS1 suppressed the proliferation, migration and invasion of ovarian cancer cells, while cell apoptosis was promoted. Additionally, miR-133a-3p could be a novel target of ABHD11-AS1, and EZH2-mediated H3K27me3 protein might bind to ABHD11-AS1 promoter directly. Moreover, rescue experiments indicated that the effects caused by ABHD11-AS1 knockdown on the malignant characteristics of ovarian cancer cells were notably enhanced by miR-133a-3p mimics, whereas the influences on cell growth and metastasis induced by overexpressed ABHD11-AS1 were abrogated by the restoration of miR-133a-3p expression. In summary, EZH2-mediated enrichment of H3K27me3 on ABHD11-AS1 promoter could regulate the progression of ovarian cancer via miR-133a-3p. Therefore, EZH2/ABHD11-AS1/miR-133a-3p axis might be a putative candidate for targeted treatment of ovarian cancer. Title: Congenital myasthenic syndrome in China: genetic and myopathological characterization Zhao Y, Li Y, Bian Y, Yao S, Liu P, Yu M, Zhang W, Wang Z, Yuan Y Ref: Ann Clin Transl Neurol, :, 2021 : PubMed ESTHER: Zhao_2021_Ann.Clin.Transl.Neurol__ PubMedSearch: Zhao 2021 Ann.Clin.Transl.Neurol PubMedID: 33756069 Abstract OBJECTIVE: We aimed to summarize the clinical, genetic, and myopathological features of a cohort of Chinese patients with congenital myasthenic syndrome, and follow up on therapeutic outcomes. METHODS: The clinical spectrum, mutational frequency of genes, and pathological diagnostic clues of various subtypes of patients with congenital myasthenic syndrome were summarized. Therapeutic effects were followed up. RESULTS: Thirty-five patients from 29 families were recruited. Ten genes were identified: GFPT1 (27.6%), AGRN (17.2%), CHRNE (17.2%), COLQ (13.8%), GMPPB (6.9%), CHAT, CHRNA1, DOK7, COG7, and SLC25A1 (3.4% each, respectively). Sole limb-girdle weakness was found in patients with AGRN (1/8) and GFPT1 (7/8) mutations, whereas distal weakness was all observed in patients with AGRN (6/8) mutations. Tubular aggregates were only found in patients with GFPT1 mutations (5/6). The patients with GMPPB mutations (2/2) had decreased alpha-dystroglycan. Acetylcholinesterase inhibitor therapy resulted in no response or worsened symptoms in patients with COLQ mutations, a diverse response in patients with AGRN mutations, and a good response in patients with other subtypes. Albuterol therapy was effective or harmless in most subtypes. Therapy effects became attenuated with long-term use in patients with COLQ or AGRN mutations. INTERPRETATION: The genetic distribution of congenital myasthenic syndrome in China is distinct from that of other ethnic origins. The appearance of distal weakness, selective limb-girdle myasthenic syndrome, tubular aggregates, and decreased alpha-dystroglycan were indicative of the specific subtypes. Based on the follow-up findings, we suggest cautious evaluation of the long-term efficacy of therapeutic agents in congenital myasthenic syndrome. Title: Biofilm polysaccharide display platform: A natural, renewable, and biocompatible material for improved lipase performance Dong H, Zhang W, Wang Y, Liu D, Wang P Ref: Journal of Agricultural and Food Chemistry, :, 2020 : PubMed ESTHER: Dong_2020_J.Agric.Food.Chem__ PubMedSearch: Dong 2020 J.Agric.Food.Chem PubMedID: 31927950 Abstract Most of microorganisms can form biofilms, which makes biofilms become an abundant bioresource to be exploited. Due to the application limitations of current immobilization methods onto biofilms, we developed an immobilization method called the Biofilm Polysaccharides Display (BPD) strategy while maintaining the native biofilm structure and catalytic microenvironment of C. acetobutylicum B3. Lipase Lip181 showed significant improvements in stability after chemical immobilization. For example, immobilized Lip181 retained 74.23% of its original activity after incubation for 14 days while free Lip181 was totally deactivated. In addition, immobilized Lip181 maintained high residual activity (pH 5.0pH 11.0), which showed improved resistance to pH changes. Notably, this method did not decrease but slightly increased the relative activity of Lip181 from 6.39 to 6.78 U/mg. Immobilized Lip181 was used to prepare cinnamyl acetate, and it showed a maximum yield of 85.09%. Overall, this biofilm immobilization method may promote the development of biocatalysis and biofilm materials. Title: Collaborative Biosynthesis of a Class of Bioactive Azaphilones by Two Separate Gene Clusters Containing Four PKS/NRPSs with Transcriptional Crosstalk in Fungi Huang X, Zhang W, Tang S, Wei S, Lu X Ref: Angew Chem Int Ed Engl, 59:4349, 2020 : PubMed ESTHER: Huang_2020_Angew.Chem.Int.Ed.Engl_59_4349 PubMedSearch: Huang 2020 Angew.Chem.Int.Ed.Engl 59 4349 PubMedID: 31908094 Gene_locus related to this paper: asptn-5moas, asptn-azpb5 Abstract Azaphilones are a family of fungal polyketide metabolites with diverse chemical structures and biological activities with a highly oxygenated pyranoquinone bicyclic core. Here, a class of azaphilones possessing a 6/6/6/6 tetracyclic ring system was identified in Aspergillus terreus, and exhibited potential anticancer activities. The gene deletions and biochemical investigations demonstrated that these azaphilones were collaboratively synthesized by two separate clusters containing four core-enzymes, two nonreducing PKSs, one highly reducing PKS, and one NRPS-like. More interestingly, we found that the biosynthesis is coordinately regulated by a crosstalk mechanism between these two gene clusters based on three transcriptional factors. This is a meaningful mechanism of fungal secondary metabolism, which allows fungi to synthesize more complex compounds and gain new physiological functions. The results provide a new insight into fungal natural product biosynthesis. Title: Single and combined effects of carbamazepine and copper on nervous and antioxidant systems of zebrafish (Danio rerio) Jia D, Li X, Du S, Xu N, Zhang W, Yang R, Zhang Y, He Y Ref: Environ Toxicol, :, 2020 : PubMed ESTHER: Jia_2020_Environ.Toxicol__ PubMedSearch: Jia 2020 Environ.Toxicol PubMedID: 32485069 Abstract Various pollutants co-exist in the aquatic environment such as carbamazepine (CBZ) and copper (Cu), which can cause complex effects on inhabiting organisms. The toxic impacts of the single substance have been studied extensively. However, the studies about their combined adverse impacts are not enough. In the present study, zebrafish were exposed to environmental relevant concentrations of CBZ (1, 10, and 100 mug/L), Cu (0.5, 5, and 10 mug/L) and the mixtures (1 mug/L CBZ + 0.5 mug/L Cu, 10 mug/L CBZ + 5 mug/L Cu, 100 mug/L CBZ + 10 mug/L Cu) for 45 days, the effects on nervous and antioxidant systems of zebrafish were investigated. The results demonstrated that, in comparison with single exposure group, the combined presence of CBZ and Cu exacerbated the effect of antioxidant system (the ability of inhibition of hydroxyl radicals (IHR), superoxide dismutase (SOD), catalase (CAT) and glutathione S-transferase (GST)) but not nervous system (Acetylcholinesterase [AChE]). The qPCR results supported the changes of corresponding enzymes activities. Hepatic histopathological analysis verified the results of biomarkers. Our work illustrated that the toxicity of mixed pollutants is very complicated, which cannot simply be inferred from the toxicity of single pollutant, and calls for more co-exposure experiments to better understanding of the co-effects of pollutants on aquatic organisms. Title: Organophosphate Diesters (Di-OPEs) Play a Critical Role in Understanding Global Organophosphate Esters (OPEs) in Fishmeal Li X, Zhao N, Fu J, Liu Y, Zhang W, Dong S, Wang P, Su X Ref: Environ Sci Technol, 54:12130, 2020 : PubMed ESTHER: Li_2020_Environ.Sci.Technol_54_12130 PubMedSearch: Li 2020 Environ.Sci.Technol 54 12130 PubMedID: 32936633 Abstract Organophosphate triesters (tri-OPEs) have recently been widely identified in aquatic ecosystems, but information on their organophosphate diester (di-OPE) metabolites is sparsely available. Herein, uniform fishmeal products were collected across the globe (the U.S., China, Europe, South America, and Southeast Asia). Sixteen representative tri-OPEs and eight di-OPEs were investigated to reveal whether industrial production, metabolism, environmental persistence, or physicochemical properties are the key factors influencing their environmental burden and distribution. Tri-OPEs and di-OPEs were 100% detected in fishmeal, with bis(2-chloroethyl) hydrogen phosphate (BCEP) and bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) at discernible levels in marine fauna for the first time. Average concentration of di-OPEs (49.6 +/- 27.5 ng/g dw) was of the same order of magnitude as that of tri-OPEs (59.3 +/- 92.2 ng/g dw). Geographical-specific distributions of tris(2-chloroethyl) phosphate (TCEP), tris(2-chloroisopropyl) phosphate (TCIPP), triphenyl phosphate (TPhP), tris(2-butoxyethyl) phosphate (TBOEP), and 2-ethylhexyl diphenyl phosphate (EHDPP) were statistically significant (p < 0.05). Mean concentration ratios ranged from 0.087 for the BCEP-TCEP pair to 507 for the dimethyl phosphate (DMP)-trimethyl phosphate (TMP) pair. Only the TPhP-diphenyl phosphate (DPhP) pair presented a strong positive linear correlation (r = 0.731; p < 0.01), and DPhP was proved a degradation origin. Commercial sources had a significant overall impact on distribution patterns of the DMP-TMP and the dibutyl phosphate (DnBP) - tri-n-butyl phosphate (TnBP) pairs, whereas biotic transformation and abiotic stability profoundly influenced the bis(2-ethylhexyl) phosphate (BEHP)-tris(2-ethylhexyl) phosphate (TEHP), the bis(1-chloro-2-propyl) phosphate (BCIPP)-TCIPP, and the BCEP-TCEP pairs. Di-OPEs are critical to understand environmental behavior of tri-OPEs in marine fauna. Title: Degradation of Acephate and Its Intermediate Methamidophos: Mechanisms and Biochemical Pathways Lin Z, Pang S, Zhang W, Mishra S, Bhatt P, Chen S Ref: Front Microbiol, 11:2045, 2020 : PubMed ESTHER: Lin_2020_Front.Microbiol_11_2045 PubMedSearch: Lin 2020 Front.Microbiol 11 2045 PubMedID: 33013750 Abstract Acephate is an organophosphate pesticide that has been widely used to control insect pests in agricultural fields for decades. However, its use has been partially restricted in many countries due to its toxic intermediate product methamidophos. Long term exposure to acephate and methamidophos in non-target organisms results in severe poisonous effects, which has raised public concern and demand for the removal of these pollutants from the environment. In this paper, the toxicological effects of acephate and/or methamidophos on aquatic and land animals, including humans are reviewed, as these effects promote the necessity of removing acephate from the environment. Physicochemical degradation mechanisms of acephate and/or methamidophos are explored and explained, such as photo-Fenton, ultraviolet/titanium dioxide (UV/TiO(2)) photocatalysis, and ultrasonic ozonation. Compared with physicochemical methods, the microbial degradation of acephate and methamidophos is emerging as an eco-friendly method that can be used for large-scale treatment. In recent years, microorganisms capable of degrading methamidophos or acephate have been isolated, including Hyphomicrobium sp., Penicillium oxalicum, Luteibacter jiangsuensis, Pseudomonas aeruginosa, and Bacillus subtilis. Enzymes related to acephate and/or methamidophos biodegradation include phosphotriesterase, paraoxonase 1, and carboxylesterase. Furthermore, several genes encoding organophosphorus degrading enzymes have been identified, such as opd, mpd, and ophc2. However, few reviews have focused on the biochemical pathways and molecular mechanisms of acephate and methamidophos. In this review, the mechanisms and degradation pathways of acephate and methamidophos are summarized in order to provide a new way of thinking for the study of the degradation of acephate and methamidophos. Title: Analysis of a Chinese Pedigree With Familial Chylomicronemia Syndrome Reveals Two Novel LPL Mutations by Whole-Exome Sequencing Liu Y, Lan Z, Zhao F, Zhang S, Zhang W Ref: Front Genet, 11:741, 2020 : PubMed ESTHER: Liu_2020_Front.Genet_11_741 PubMedSearch: Liu 2020 Front.Genet 11 741 PubMedID: 32765589 Abstract Familial chylomicronemia syndrome (FCS) is a rare monogenic autosomal recessive disease caused by loss-of-function mutations in genes involved in chylomicron breakdown through hydrolysis of triglycerides into free fatty acids. Patients are often diagnosed in early childhood with extremely high triglyceride levels and symptoms including abdominal pain, eruptive cutaneous xanthomata, hepatosplenomegaly, and significant cognitive, psychological, and social impairment. The most serious medical condition suffered by FCS patients is recurrent acute pancreatitis. Lipoprotein lipase (LPL) gene mutation accounts for majority of the known pathogenic mutations. Early diagnosis and strict low-fat diet are critical for successful management of the triglyceride concentration to lower the risk of pancreatitis. The true prevalence of FCS in China is unknown and here we report a Chinese female preterm neonate presented with an extremely high triglyceride level of 22.11 mmol/L on day 13 after birth. Clinical and laboratory workup including whole-exome sequencing revealed two novel compound heterozygous LPL mutations (c.406G > C and c.829G > C) that are co-segregated with her non-consanguineous parents, consistent with autosomal recessive inheritance. A diagnosis of FCS based on clinical, biochemical, and genetic ground was made to guide her management. Title: Alterations in the Blood Parameters and Fecal Microbiota and Metabolites during Pregnant and Lactating Stages in Bama Mini Pigs as a Model Ma C, Gao Q, Zhang W, Azad MAK, Kong X Ref: Mediators Inflamm, 2020:8829072, 2020 : PubMed ESTHER: Ma_2020_Mediators.Inflamm_2020_8829072 PubMedSearch: Ma 2020 Mediators.Inflamm 2020 8829072 PubMedID: 33162832 Abstract This study was conducted to analyze plasma reproductive hormone and biochemical parameter changes, as well as fecal microbiota composition and metabolites in sows, at different pregnancy and lactation stages, using Bama mini pig as an experimental animal model. We found that plasma prolactin (PRL), progesterone, follicle-stimulating hormone (FSH), and estrogen levels decreased from day 45 to day 105 of pregnancy. Plasma total protein and albumin levels were lower in pregnant sows, while glucose, urea nitrogen, total cholesterol, and high-density lipoprotein-cholesterol, as well as fecal acetate, butyrate, valerate, total short-chain fatty acids, skatole, and tyramine levels, were higher in lactating sows. Interestingly, the lactating sows showed lower alpha-diversity and Spirochaetes and Verrucomicrobia relative abundances, while pregnant sows showed a higher Proteobacteria relative abundance. Notably, the Akkermansia relative abundance was highest on day 7 of lactation. Spearman analysis showed a positive correlation between plasma triglyceride and cholinesterase levels and Akkermansia and Streptococcus relative abundances. Moreover, Oscillospira and Desulfovibrio relative abundances were also positively correlated with plasma FSH, LH, and E(2) levels, as well as PRL and LH with Bacteroides. Collectively, plasma reproductive hormones, biochemical parameters, and fecal microbiota composition and metabolite levels could alter along with pregnancy and lactation, which might contribute to the growth and development demands of fetuses and newborns. Title: Carbofuran toxicity and its microbial degradation in contaminated environments Mishra S, Zhang W, Lin Z, Pang S, Huang Y, Bhatt P, Chen S Ref: Chemosphere, 259:127419, 2020 : PubMed ESTHER: Mishra_2020_Chemosphere_259_127419 PubMedSearch: Mishra 2020 Chemosphere 259 127419 PubMedID: 32593003 Abstract Carbofuran is one of the most toxic broad-spectrum and systemic N-methyl carbamate pesticide, which is extensively applied as insecticide, nematicide and acaricide for agricultural, domestic and industrial purposes. It is extremely lethal to mammals, birds, fish and wildlife due to its anticholinesterase activity, which inhibits acetyl-cholinesterase and butyrylcholinesterse activity. In humans, carbofuran is associated with endocrine disrupting activity, reproductive disorders, cytotoxic and genotoxic abnormalities. Therefore, cleanup of carbofuran-contaminated environments is of utmost concern and urgently needs an adequate, advanced and effective remedial technology. Microbial technology (bacterial, fugal and algal species) is a very potent, pragmatic and ecofriendly approach for the removal of carbofuran. Microbial enzymes and their catabolic genes exhibit an exceptional potential for bioremediation strategies. To understand the specific mechanism of carbofuran degradation and involvement of carbofuran hydrolase enzymes and genes, highly efficient genomic approaches are required to provide reliable information and unfold metabolic pathways. This review briefly discusses the carbofuran toxicity and its toxicological impact into the environment, in-depth understanding of carbofuran degradation mechanism with microbial strains, metabolic pathways, molecular mechanisms and genetic basis involved in degradation. Title: Discovery and Characterization of a PKS-NRPS Hybrid in Aspergillus terreus by Genome Mining Tang S, Zhang W, Li Z, Li H, Geng C, Huang X, Lu X Ref: Journal of Natural Products, 83:473, 2020 : PubMed ESTHER: Tang_2020_J.Nat.Prod_83_473 PubMedSearch: Tang 2020 J.Nat.Prod 83 473 PubMedID: 32077283 Gene_locus related to this paper: asptn-pytb, aspte-pyti Abstract Fungal polyketide synthase-nonribosomal peptide synthetase (PKS-NRPS) hybrids have been characterized to produce polyketide-amino acid compounds with striking structural features and biological activities. In this study, a PKS-NRPS hybrid enzyme was found in Aspergillus terreus by genome mining. By activating the cluster-specific transcriptional regulator, this cryptic PKS-NRPS gene cluster was successfully activated and ten products (1-10) were identified as pyranterreones. Using functional genetics, bioinformatics, and isotope-labeling feeding analysis, the biosynthetic pathway was revealed. This is the second PKS-NRPS hybrid identified in A. terreus. Title: A Comparison of the Resolution of Selective (+/-)-Glycidyl Butyrate by Using Free and Nano-SiO(2) Immobilized Porcine Pancreatic Lipase Zhang Q, Qian J, Guo H, Zhang W, Kuang C Ref: J Nanosci Nanotechnol, 20:6168, 2020 : PubMed ESTHER: Zhang_2020_J.Nanosci.Nanotechnol_20_6168 PubMedSearch: Zhang 2020 J.Nanosci.Nanotechnol 20 6168 PubMedID: 32384967 Abstract To explore the hydrolyzed properties of nano-SiO(2) immobilized porcine pancreatic lipase, the selective hydrolysis of immobilized lipase for glycidyl butyrate was compared with the free enzyme. The hydrolysis selectivity of the immobilized biocatalyst was evaluated and compared with the free enzyme using the enantiomeric excess (ee) of resolving racemic glycidyl butyrate as the indicator. The enantiomeric excess of the immobilized biocatalyst could be increased by 4.5%-10.0% which compared with the free enzyme under every single technological condition. The ee was improved from 84.7% for free enzyme to 91.6% for the immobilized enzyme with 61.2% conversion. Compared with free enzyme, the conversion rate of the immobilized enzyme was increased slightly, but the % enantiomeric excess of the immobilized enzyme was increased greatly. Title: Mutation of an atypical oxirane oxyanion hole improves regioselectivity of the alpha/beta-fold epoxide hydrolase Alp1U Zhang L, De BC, Zhang W, Mandi A, Fang Z, Yang C, Zhu Y, Kurtan T, Zhang C Ref: Journal of Biological Chemistry, 295:16987, 2020 : PubMed ESTHER: Zhang_2020_J.Biol.Chem_295_16987 PubMedSearch: Zhang 2020 J.Biol.Chem 295 16987 PubMedID: 33004437 Gene_locus related to this paper: stram-q1rqu8 Abstract Epoxide hydrolases (EHs) have been characterized and engineered as biocatalysts that convert epoxides to valuable chiral vicinal diol precursors of drugs and bioactive compounds. Nonetheless, the regioselectivity control of the epoxide ring opening by EHs remains challenging. Alp1U is an alpha/beta-fold EH that exhibits poor regioselectivity in the epoxide hydrolysis of fluostatin C (1), and produces a pair of stereoisomers. Herein, we established the absolute configuration of the two stereoisomeric products and determined the crystal structure of Alp1U. A W186/W187/Y247 oxirane oxygen hole was identified in Alp1U that replaced the canonical Tyr/Tyr pair in alpha/beta-EHs. Mutation of residues in the atypical oxirane oxygen hole of Alp1U improved the regioselectivity for epoxide hydrolysis on 1. The single site Y247F mutation led to highly regioselective (98%) attack at C-3 of 1, while the double mutation W187F/Y247F resulted in regioselective (94%) nucleophilic attack at C-2. Furthermore, single crystal X-ray structures of the two regioselective Alp1U variants in complex with 1 were determined. These findings allowed insights into the reaction details of Alp1U, and provided a new approach for engineering regioselective epoxide hydrolases. Title: Genome assembly of wild tea tree DASZ reveals pedigree and selection history of tea varieties Zhang W, Zhang Y, Qiu H, Guo Y, Wan H, Zhang X, Scossa F, Alseekh S, Zhang Q and Wen W <11 more author(s)> Zhang W, Zhang Y, Qiu H, Guo Y, Wan H, Zhang X, Scossa F, Alseekh S, Zhang Q, Wang P, Xu L, Schmidt MH, Jia X, Li D, Zhu A, Guo F, Chen W, Ni D, Usadel B, Fernie AR, Wen W (- 11) Ref: Nat Commun, 11:3719, 2020 : PubMed ESTHER: Zhang_2020_Nat.Commun_11_3719 PubMedSearch: Zhang 2020 Nat.Commun 11 3719 PubMedID: 32709943 Gene_locus related to this paper: camsi-a0a7j7g2i2 Abstract Wild teas are valuable genetic resources for studying domestication and breeding. Here we report the assembly of a high-quality chromosome-scale reference genome for an ancient tea tree. The further RNA sequencing of 217 diverse tea accessions clarifies the pedigree of tea cultivars and reveals key contributors in the breeding of Chinese tea. Candidate genes associated with flavonoid biosynthesis are identified by genome-wide association study. Specifically, diverse allelic function of CsANR, CsF3'5'H and CsMYB5 is verified by transient overexpression and enzymatic assays, providing comprehensive insights into the biosynthesis of catechins, the most important bioactive compounds in tea plants. The inconspicuous differentiation between ancient trees and cultivars at both genetic and metabolic levels implies that tea may not have undergone long-term artificial directional selection in terms of flavor-related metabolites. These genomic resources provide evolutionary insight into tea plants and lay the foundation for better understanding the biosynthesis of beneficial natural compounds. Title: Discovery of Aryl Formyl Piperidine Derivatives as Potent, Reversible, and Selective Monoacylglycerol Lipase Inhibitors Zhi Z, Zhang W, Yao J, Shang Y, Hao Q, Liu Z, Ren Y, Li J, Zhang G, Wang J Ref: Journal of Medicinal Chemistry, :, 2020 : PubMed ESTHER: Zhi_2020_J.Med.Chem__ PubMedSearch: Zhi 2020 J.Med.Chem PubMedID: 32429662 Abstract Most of the current MAGL inhibitors function by an irreversible mechanism of action, causing a series of side effects. Herein, starting from irreversible inhibitors, 25 compounds were synthesized and evaluated in vitro for MAGL inhibition, among which, compound 36 showed the most potent inhibitory activity (IC50 = 15 nM).Crucially, docking studies demonstrated that the m-chlorine-substituted aniline fragment occupied a hydrophobic sub-pocket enclosed by side chains of Val191, Tyr194, Val270, and Lys273, which creatively identify a new key anchoring point for the development of new MAGL inhibitors. Furthermore, in vivo evaluation innovatively revealed that this reversible inhibitor 36 significantly displayed the depressive-like behaviors induced by reserpine. To the best of our knowledge, this is the first time that reversible inhibitors of MAGL were developed to support MAGL as a potential therapeutic target for depression. Title: A transcriptomics-based analysis of the toxicity mechanisms of gabapentin to zebrafish embryos at realistic environmental concentrations He Y, Li X, Jia D, Zhang W, Zhang T, Yu Y, Xu Y, Zhang Y Ref: Environ Pollut, 251:746, 2019 : PubMed ESTHER: He_2019_Environ.Pollut_251_746 PubMedSearch: He 2019 Environ.Pollut 251 746 PubMedID: 31121539 Abstract Gabapentin (GPT) has become an emerging contaminant in aquatic environments due to its wide application in medical treatment all over the world. In this study, embryos of zebrafish were exposed to gabapentin at realistically environmental concentrations, 0.1mug/L and 10mug/L, so as to evaluate the ecotoxicity of this emergent contaminant. The transcriptomics profiling of deep sequencing was employed to illustrate the mechanisms. The zebrafish (Danio rerio) embryo were exposed to GPT from 12 hpf to 96 hpf resulting in 136 and 750 genes differentially expressed, respectively. The results of gene ontology (GO) analysis and the Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis illustrated that a large amount of differentially expressed genes (DEGs) were involved in the antioxidant system, the immune system and the nervous system. RT-qPCR was applied to validate the results of RNA-seq, which provided direct evidence that the selected genes involved in those systems mentioned above were all down-regulated. Acetylcholinesterase (AChE), lysozyme (LZM) and the content of C-reactive protein (CRP) were decreased at the end of exposure, which is consistent with the transcriptomics results. The overall results of this study demonstrate that GPT simultaneously affects various vital functionalities of zebrafish at early developmental stage, even at environmentally relevant concentrations. Title: [Distribution characteristics and correlation analysis of antibody detection value in myasthenia gravis] Liu YL, Zheng YM, Luo JJ, Zhang W, Gao F, Yuan Y, Hao HJ Ref: Zhonghua Yi Xue Za Zhi, 99:3221, 2019 : PubMed ESTHER: Liu_2019_Zhonghua.Yi.Xue.Za.Zhi_99_3221 PubMedSearch: Liu 2019 Zhonghua.Yi.Xue.Za.Zhi 99 3221 PubMedID: 31694116 Abstract Objective: To determine the factors affecting distribution and magnitude of antibody detection value in myasthenia gravis (MG). Methods: A total of 406 MG patients diagnosed at Department of Neurology, Peking University First Hospital from May 2015 to November 2017 were included.All of them exhibited muscle fatigue with decreased response in repetitive nerve stimulation test. There were 200 males and 206 females whose ages ranged from 2 to 85 years old. According to clinical classification of MG recommended by Myasthenia Gravis Foundation of America (MGFA), patients assigned to class I to class V included 200,140, 46, 15 and 5 cases, respectively. There were 33 cases of thymic hyperplasia and 63 cases of thymoma confirmed by radiological or pathological findings. Quantile plots and quantile regression model were used to determine the effects of age, gender and MGFA classification, thymus disease on acetylcholine receptors (AChR)antibody, acetylcholinesterase (AChE) antibody, Titin antibody, ryanodine receptor (RyR) antibody and muscle-specific tyrosine kinase (MuSK) antibody detection values detected by enzyme-linked immunosorbent assay (ELISA). Results: MGFA classification had effects on distribution of AChR antibody level. There was a positive correlation between age and AChR antibody level(P<0.05). Negative correlation was found between age and AChE, Titin and RyR antibody level (P<0.05). No significant correlation was shown between any factors and MuSK antibody level(P>/=0.05). MGFA classification had a positive correlation with AChR antibody level (P<0.05) and no correlation with other antibody levels (P>0.05). Gender and thymus disease had no correlation with any tested antibody levels (P>0.05). Conclusion: MGFA classification has significant effects on distribution of AChR antibody level. Age and MGFA classification have positive correlation with AChR antibody level. Title: Plasma levels of soluble ST2, but not IL-33, correlate with the severity of alcoholic liver disease Sun Z, Chang B, Huang A, Hao S, Gao M, Sun Y, Shi M, Jin L, Zhang W and Zou Z <6 more author(s)> Sun Z, Chang B, Huang A, Hao S, Gao M, Sun Y, Shi M, Jin L, Zhang W, Zhao J, Teng G, Han L, Tian H, Liang Q, Zhang JY, Zou Z (- 6) Ref: J Cell Mol Med, 23:887, 2019 : PubMed ESTHER: Sun_2019_J.Cell.Mol.Med_23_887 PubMedSearch: Sun 2019 J.Cell.Mol.Med 23 887 PubMedID: 30478965 Abstract Alcoholic liver disease (ALD) is a complication that is a burden on global health and economy. Interleukin-33 (IL-33) is a newly identified member of the IL-1 cytokine family and is released as an "alarmin" during inflammation. Soluble suppression of tumourigenicity 2 (sST2), an IL-33 decoy receptor, has been reported as a new biomarker for the severity of systemic and highly inflammatory diseases. Here, we found the levels of plasma sST2, increased with the disease severity from mild to severe ALD. Importantly, the plasma sST2 levels in ALD patients not only correlated with scores for prognostic models (Maddrey's discriminant function, model for end-stage liver disease and Child-Pugh scores) and indexes for liver function (total bilirubin, international normalized ratio, albumin, and cholinesterase) but also correlated with neutrophil-associated factors as well as some proinflammatory cytokines. In vitro, lipopolysaccharide-activated monocytes down-regulated transmembrane ST2 receptor but up-regulated sST2 mRNA and protein expression and produced higher levels of tumour necrosis factor-alpha (TNF-alpha). By contrast, monocytes pretreated with recombinant sST2 showed decreased TNF-alpha production. In addition, although plasma IL-33 levels were comparable between healthy controls and ALD patients, we found the IL-33 expression in liver tissues from ALD patients was down-regulated at both RNA and protein levels. Immunohistochemical staining further showed that the decreased of IL-33-positive cells were mainly located in liver lobule area. These results suggested that sST2, but not IL-33, is closely related to the severity of ALD. Consequently, sST2 could be used as a potential biomarker for predicting the prognosis of ALD. Title: CA10 and CA11 negatively regulate neuronal activity-dependent growth of gliomas Tao B, Ling Y, Zhang Y, Li S, Zhou P, Wang X, Li B, Jun Z, Zhang W and Wang L <2 more author(s)> Tao B, Ling Y, Zhang Y, Li S, Zhou P, Wang X, Li B, Jun Z, Zhang W, Xu C, Shi J, Wang L (- 2) Ref: Mol Oncol, 13:1018, 2019 : PubMed ESTHER: Tao_2019_Mol.Oncol_13_1018 PubMedSearch: Tao 2019 Mol.Oncol 13 1018 PubMedID: 30636076 Abstract Recent studies have revealed that neurons can promote glioma growth through activity-dependent secretion of neurotrophins, especially neuroligin-3. It has therefore been suggested that blocking neuron-derived neurotrophins may serve as a therapeutic intervention for gliomas. Carbonic anhydrase-related proteins 11 and 10 (CA11 and CA10) are secreted synaptic proteins which function as neurexin ligands, and the gene-encoding CA11 is part of a gene signature associated with radiotherapy and prognosis in gliomas. We therefore hypothesized that CA11/CA10 might participate in the neuronal activity-dependent regulation of glioma growth. In this study, we report that CA11 secreted by depolarized cultured neurons within conditioned medium (CM) inhibited the growth of glioma cell lines. CM from depolarized neurons inhibited CA11 expression in glioma cell lines via the Akt signaling pathway. Consistently, CA11 expression was also reduced in clinical glioma samples and negatively associated with high histological grade. Low CA11 expression of gliomas was associated with short survival in four independent datasets [repository of brain neoplasia data (REMBRANDT), The Cancer Genome Atlas (TCGA) lower grade glioma (LGG), GSE4271, and GSE42669]. CA11 knockdown promoted cell growth, clone formation, and migration; inhibited apoptosis; and increased tumor size in xenografted nude mice. Similarly, CA10 and CA10 secreted by depolarized cultured neurons also inhibited the growth of glioma cell lines. Low CA10 expression was associated with short survival in REMBRANDT, TCGA LGG, and GEO GSE4271 datasets. Our results suggest that CA11 and CA10 negatively regulate neuronal activity-dependent glioma growth and inhibit glioma aggression. Thus, CA11/CA10 may represent a potential therapeutic target for the treatment of gliomas. Title: Observation of Acetylcholinesterase in Stress-Induced Depression Phenotypes by Two-Photon Fluorescence Imaging in the Mouse Brain Wang X, Li P, Ding Q, Wu C, Zhang W, Tang B Ref: Journal of the American Chemical Society, 141:2061, 2019 : PubMed ESTHER: Wang_2019_J.Am.Chem.Soc_141_2061 PubMedSearch: Wang 2019 J.Am.Chem.Soc 141 2061 PubMedID: 30638380 Abstract Oxidative stress in depression is a prime cause of neurotransmitter metabolism dysfunction in the brain. Acetylcholinesterase (AChE), a key hydrolase in the cholinergic system, directly determines the degradation of neurotransmitters. However, due to the complexity of the brain and lack of appropriate in situ imaging tools, the mechanism underlying the changes in AChE activity in depression remains unclear. Hence, we generated a two-photon fluorescence probe (MCYN) for real-time visualization of AChE with excellent sensitivity and selectivity. AChE can specifically recognize and cleave the carbamic acid ester bond in MCYN, and MCYN emits bright fluorescence at 560 nm by two-photon excitation at 800 nm. By utilizing MCYN to monitor AChE, we discovered a significant increase in AChE activity in the brains of mice with depression phenotypes. Notably, with the assistance of a two-photon fluorescence imaging probe of the superoxide anion radical (O2(*-)), in vivo visualization for the first time revealed the positive correlation between AChE and O2(*-) levels associated with depressive behaviors. This finding suggests that oxidative stress may induce AChE overactivation, leading to depression-related behaviors. This work provides a new and rewarding perspective to elucidate the role of oxidative stress regulating AChE in the pathology of depression. 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: Compartmentalized biosynthesis of mycophenolic acid Zhang W, Du L, Qu Z, Zhang X, Li F, Li Z, Qi F, Wang X, Jiang Y and Li S <6 more author(s)> Zhang W, Du L, Qu Z, Zhang X, Li F, Li Z, Qi F, Wang X, Jiang Y, Men P, Sun J, Cao S, Geng C, Wan X, Liu C, Li S (- 6) Ref: Proc Natl Acad Sci U S A, 116:13305, 2019 : PubMed ESTHER: Zhang_2019_Proc.Natl.Acad.Sci.U.S.A_116_13305 PubMedSearch: Zhang 2019 Proc.Natl.Acad.Sci.U.S.A 116 13305 PubMedID: 31209052 Gene_locus related to this paper: penbr-mpaH, penbr-mpac Abstract Mycophenolic acid (MPA) from filamentous fungi is the first natural product antibiotic to be isolated and crystallized, and a first-line immunosuppressive drug for organ transplantations and autoimmune diseases. However, some key biosynthetic mechanisms of such an old and important molecule have remained unclear. Here, we elucidate the MPA biosynthetic pathway that features both compartmentalized enzymatic steps and unique cooperation between biosynthetic and beta-oxidation catabolism machineries based on targeted gene inactivation, feeding experiments in heterologous expression hosts, enzyme functional characterization and kinetic analysis, and microscopic observation of protein subcellular localization. Besides identification of the oxygenase MpaB' as the long-sought key enzyme responsible for the oxidative cleavage of the farnesyl side chain, we reveal the intriguing pattern of compartmentalization for the MPA biosynthetic enzymes, including the cytosolic polyketide synthase MpaC' and O-methyltransferase MpaG', the Golgi apparatus-associated prenyltransferase MpaA', the endoplasmic reticulum-bound oxygenase MpaB' and P450-hydrolase fusion enzyme MpaDE', and the peroxisomal acyl-coenzyme A (CoA) hydrolase MpaH'. The whole pathway is elegantly comediated by these compartmentalized enzymes, together with the peroxisomal beta-oxidation machinery. Beyond characterizing the remaining outstanding steps of the MPA biosynthetic steps, our study highlights the importance of considering subcellular contexts and the broader cellular metabolism in natural product biosynthesis. Title: Identification of Novel Coumestan Derivatives as Polyketide Synthase 13 Inhibitors against Mycobacterium tuberculosis. Part II Zhang W, Lun S, Liu LL, Xiao S, Duan G, Gunosewoyo H, Yang F, Tang J, Bishai WR, Yu LF Ref: Journal of Medicinal Chemistry, 62:3575, 2019 : PubMed ESTHER: Zhang_2019_J.Med.Chem_62_3575 PubMedSearch: Zhang 2019 J.Med.Chem 62 3575 PubMedID: 30875203 Gene_locus related to this paper: myctu-PKS13 Abstract Our group recently reported the identification of novel coumestan derivatives as Mycobacterium tuberculosis ( Mtb) Pks13-thioesterase (TE) domain inhibitors, with mutations observed (D1644G and N1640K) in the generated coumestan-resistant Mtb colonies. Herein, we report a further structure-activity relationships exploration exploiting the available Pks13-TE X-ray co-crystal structure that resulted in the discovery of extremely potent coumestan analogues 48 and 50. These molecules possess excellent anti-tuberculosis activity against both the drug-susceptible (MIC = 0.0039 microg/mL) and drug-resistant Mtb strains (MIC = 0.0078 microg/mL). Moreover, the excellent in vitro activity is translated to the in vivo mouse serum inhibitory titration assay, with administration of coumestan 48 at 100 mg/kg showing an 8-fold higher activity than that of isoniazid or TAM16 given at 10 or 100 mg/kg, respectively. Preliminary ADME-Tox data for the coumestans were promising and, coupled with the practicality of synthesis, warrant further in vivo efficacy assessments of the coumestan derivatives. Title: Novel Method of Preparation and Activity Research on Arctigenin from Fructus Arctii Cai E, Han J, Yang L, Zhang W, Zhao Y, Chen Q, Guo M, He X Ref: Pharmacogn Mag, 14:87, 2018 : PubMed ESTHER: Cai_2018_Pharmacogn.Mag_14_87 PubMedSearch: Cai 2018 Pharmacogn.Mag 14 87 PubMedID: 29576707 Abstract Background: Arctigenin has many pharmacological activities with clinical significance and is derived from Arctium lappa L. However, the present extraction method is inefficient and does not have meaningful industrial production. Objective: A new method to directly prepare arctigenin was established by combining enzyme-assisted extraction and central composite design. Arctigenin's further pharmacological activity was also surveyed in vitro. Materials and Methods: beta-D-Glucosidase, a food-grade enzyme, was added directly to the fruits of A. lappa L. to hydrolyze the arctiin to arctigenin, and the obtained samples were subsequently subjected to ethanol (30%, v/v) extraction. The pharmacological activity of the extraction and arctigenin was determined by inhibiting acetylcholinesterase (AChE) and scavenging nitrite. Results: The factors investigated include the enzyme concentration (0.5%-2.5%), ultrasound time (10 min(-3) 0 min), and extraction temperature (30 degrees C-50 degrees C). From the analysis of the results by Design-Expert (V8.0.6), the optimal extraction conditions were obtained: enzyme concentration (1.4%), ultrasound time (25 min), and extraction temperature (45 degrees C). The highest yield of arctigenin, obtained under the optimal conditions was 6.39%, representing an increase of 28.15% compared to the reference extraction without enzyme processing. The IC50 values of the extraction and arctigenin, respectively, for inhibiting AChE were 0.572 mg/ml and 0.462 mg/ml, and those for nitrite-scavenging were 34.571 mg/ml and 17.49 mg/ml. Conclusions: The results demonstrate that using an enzyme directly in the production is an effective means for extracting arctigenin from Fructus arctii. The extraction has the activities of inhibiting AChE and scavenging nitrite, probably because there has arctigenin in it. It is implied that the extraction and arctigenin could contribute to human health in clinical applications. SUMMARY: The new method of adding enzyme directly to the preparation of arctigenin was carried out instead of preparing arctigenin by two-step methodThree factors affecting the efficiency of preparation were analyzed and discussed include the enzyme concentration, ultrasound time, and extraction temperature by central composite designThis new method of preparing arctigenin improved the yield significantly than other methodsArctigenin has remarkable pharmacological activities of inhibiting acetylcholinesterase and scavenging nitrite. Abbreviations used: AChE: Acetylcholinesterase, CCD: Central composite design, TCM: Traditional Chinese medicines, AD. Title: Targeting dipeptidyl peptidase 8 genes inhibits proliferation, migration and invasion by inhibition of cyclin D1 and MMP2MMP9 signal pathway in cervical cancer Chen Y, Liu F, Wu K, Wu W, Wu H, Zhang W Ref: J Gene Med, 20:e3056, 2018 : PubMed ESTHER: Chen_2018_J.Gene.Med_20_e3056 PubMedSearch: Chen 2018 J.Gene.Med 20 e3056 PubMedID: 30225951 Abstract BACKGROUND: DPP8 is a member of the dipeptidyl peptidase IV family, which belongs to the S9b protease subfamily. It regulates cell proliferation, apoptosis, migration and invasion during cancer progression. METHODS: To investigate the role of DPP8 in cervical cancer, we examined DPP8 levels in cervical cancer tissues and cells. The localization of DPP8 was determined by immunofluorescence staining. Subsequently, SiHa and HeLa cells were treated with small interfering RNA (siRNA)-DPP8. We used cell cycle analysis, an 5-ethyl-2'-deoxyuridine assay proliferation assay and a cellular apoptosis assay to determine the effect of DPP8 on the proliferation and apoptosis of cervical cancer cells. We used a Transwell assay to assess the number of transfection cancer cells migrating through the matrix. A real-time polymerase chain reaction and western blot analysis were used to analyze the expression of related proteins and to determine the phenotype caused by the depletion or overexpression of DPP8 in cervical cancer cells. RESULTS: We observed that DPP8 was highly expressed in cervical cancer tissues and cells. DPP8 expression was observed in the cytosol and in the perinuclear area, as well as in the nuclei of cervical cancer cells. Notably, when cells were treated with siRNA-DPP8, the expression of BAX increased, and the expression of cyclin D1, Bcl-2, MMP2 and MMP9 was downregulated. In cervical cancer cell lines, silencing the expression of DPP8 not only suppressed the proliferation, migration and invasion of the cervical cancer cells, but also promoted cervical cancer cell apoptosis. CONCLUSIONS: The data obtained in the present study reveal that DPP8 promotes the progression of cervical cancer. Title: CXCL5, the upregulated chemokine in patients with uterine cervix cancer, in vivo and in vitro contributes to oncogenic potential of Hela uterine cervix cancer cells Feng X, Zhang D, Li X, Ma S, Zhang C, Wang J, Li Y, Liang L, Zhang P and Wang W <7 more author(s)> Feng X, Zhang D, Li X, Ma S, Zhang C, Wang J, Li Y, Liang L, Zhang P, Qu Y, Zhang Z, Yang Z, Xiang Y, Zhang W, Wang S, Shao W, Wang W (- 7) Ref: Biomed Pharmacother, 107:1496, 2018 : PubMed ESTHER: Feng_2018_Biomed.Pharmacother_107_1496 PubMedSearch: Feng 2018 Biomed.Pharmacother 107 1496 PubMedID: 30257367 Abstract CXCL5 is showed a surprisingly elevated profile and implicated in tumorigenesis in several tumors. However, the expression and function of CXCL5 in uterine cervix cancer (UCC) remain largely unknown. The current study aimed to elucidate the expression pattern of CXCL5 in human UCC tissues and Hela cervix cancer cell, as well as its functions in Hela cells. Our data showed that CXCL5 and its receptor CXCR2 were expressed by Hela uterine cervix cancer cells. CXCL5 was upregulated in UCC tissues, and its overexpression was positively correlated with age, but did not correlate with clinical stages and tumor infiltration. Exogenous administration of CXCL5 and CXCL5 overexpression contributed to proliferation and migration activities of Hela cells in vitro, consistent with this, CXCL5 overexpression also promoted growth of Hela cells in a nude mouse xenograft model. At the gene level, CXCL5 overexpression regulated the expression of tumor-related genes including ERK, p-ERK, AKT, p-AKT, DIABOL, NUMB, NDRG3 and CXCR2. Taken together, CXCL5 may contribute to a dominant role in UCC progression and sever as a potential molecular therapeutic target for UCC. Title: Enhancement of brain-targeting delivery of danshensu in rat through conjugation with pyrazine moiety to form danshensu-pyrazine ester Hui A, Yin H, Zhang Z, Zhou A, Chen J, Yang L, Wu Z, Zhang W Ref: Drug Deliv Transl Res, 8:787, 2018 : PubMed ESTHER: Hui_2018_Drug.Deliv.Transl.Res_8_787 PubMedSearch: Hui 2018 Drug.Deliv.Transl.Res 8 787 PubMedID: 29524164 Abstract Tetramethylpyrazine was introduced to the structure of danshensu (DSS) as P-glycoprotein (P-gp)-inhibiting carrier, designing some novel brain-targeting DSS-pyrazine derivatives via prodrug delivery strategy. Following the virtual screening, three DSS-pyrazine esters (DT1, DT2, DT3) were selected because of their better prediction parameters related to brain-targeting. Among them, DT3 was thought to be a promising candidate due to its appropriate bioreversible property in vitro release assay. Further investigation with regard to DT3's brain-targeting effects in vivo was also reported in this study. High-performance liquid chromatography-diode array detection (HPLC-DAD) method was established for the quantitative determination of DT3 and DSS in rat plasma, brain homogenate after intravenous injection. In vivo metabolism of DT3 indicated that it was first converted into DT1, DT2, then the generation of DSS, which could be the result of carboxylesterase activity in rat blood and brain tissue. Moreover, the brain pharmacokinetics of DT3 was significantly altered with 2.16 times increase in half-life compared with that of DSS, and its drug targeting index (DTI) was up to 16.95. Above these data demonstrated that DT3 had better tendency of brain-targeting delivery, which would be positive for the treatment of brain-related disorders. Title: A protective role of autophagy in TDCIPP-induced developmental neurotoxicity in zebrafish larvae Li R, Zhang L, Shi Q, Guo Y, Zhang W, Zhou B Ref: Aquat Toxicol, 199:46, 2018 : PubMed ESTHER: Li_2018_Aquat.Toxicol_199_46 PubMedSearch: Li 2018 Aquat.Toxicol 199 46 PubMedID: 29605586 Abstract Tris (1, 3-dichloro-2-propyl) phosphate (TDCIPP), an extensively used organophosphorus flame retardant, is frequently detected in various environmental media and biota, and has been demonstrated as neurotoxic. Autophagy has been proposed as a protective mechanism against toxicant-induced neurotoxicity. The purpose of the present study was to investigate the effect of TDCIPP exposure on autophagy, and its role in TDCIPP-induced developmental neurotoxicity. Zebrafish embryos (2-120h post-fertilization [hpf]) were exposed to TDCIPP (0, 5, 50 and 500mug/l) and a model neurotoxic chemical, chlorpyrifos (CPF, 100mug/l). The developmental endpoints, locomotive behavior, cholinesterase activities, gene and protein expression related to neurodevelopment and autophagy were measured in the larvae. Our results demonstrate that exposure to TDCIPP (500mug/l) and CPF causes developmental toxicity, including reduced hatching and survival rates and increased malformation rate (e.g., spinal curvature), as well as altered locomotor behavior. The expression of selected neurodevelopmental gene and protein markers (e.g., mbp, syn2a, and alpha1-tubulin) was significantly down-regulated in CPF and TDCIPP exposed zebrafish larvae. Treatment with CPF significantly inhibits AChE and BChE, while TDCIPP (0-500mug/l) exerts no effects on these enzymes. Furthermore, the conversion of microtubule-associated protein I (LC3 I) to LC3 II was significantly increased in TDCIPP exposed zebrafish larvae. In addition, exposure to TDCIPP also activates transcription of several critical genes in autophagy (e.g. Becn1, atg3, atg5, map1lc3b and sqstm1). To further investigate the role of autophagy in TDCIPP induced developmental neurotoxicity, an autophagy inducer (rapamycin, Rapa, 1nM) and inhibitor (chloroquine, CQ, 1muM) were used. The results demonstrate that the hatching rate, survival rate, and the expression of mbp and small a, Cyrillic1-tubulin proteins were all significantly increased in larvae treated with TDCIPP (500mug/l) and Rapa compared to TDCIPP alone. In contrast, co-treatment with the autophagy inhibitor CQ results in exacerbated neurodevelopmental toxicity. Taken together, our results confirm that exposure to TDCIPP induces autophagy, which plays a protective role in TDCIPP-induced developmental neurotoxicity in zebrafish embryos and larvae. Title: Discovery of Novel Bat Coronaviruses in South China That Use the Same Receptor as Middle East Respiratory Syndrome Coronavirus Luo CM, Wang N, Yang XL, Liu HZ, Zhang W, Li B, Hu B, Peng C, Geng QB and Shi ZL <2 more author(s)> Luo CM, Wang N, Yang XL, Liu HZ, Zhang W, Li B, Hu B, Peng C, Geng QB, Zhu GJ, Li F, Shi ZL (- 2) Ref: J Virol, 92:, 2018 : PubMed ESTHER: Luo_2018_J.Virol_92_ PubMedSearch: Luo 2018 J.Virol 92 PubMedID: 29669833 Abstract Middle East respiratory syndrome coronavirus (MERS-CoV) has represented a human health threat since 2012. Although several MERS-related CoVs that belong to the same species as MERS-CoV have been identified from bats, they do not use the MERS-CoV receptor, dipeptidyl peptidase 4 (DPP4). Here, we screened 1,059 bat samples from at least 30 bat species collected in different regions in south China and identified 89 strains of lineage C betacoronaviruses, including Tylonycteris pachypus coronavirus HKU4, Pipistrellus pipistrelluscoronavirus HKU5, and MERS-related CoVs. We sequenced the full-length genomes of two positive samples collected from the great evening bat, Ia io, from Guangdong Province. The two genomes were highly similar and exhibited genomic structures identical to those of other lineage C betacoronaviruses. While they exhibited genome-wide nucleotide identities of only 75.3 to 81.2% with other MERS-related CoVs, their gene-coding regions were highly similar to their counterparts, except in the case of the spike proteins. Further protein-protein interaction assays demonstrated that the spike proteins of these MERS-related CoVs bind to the receptor DPP4. Recombination analysis suggested that the newly discovered MERS-related CoVs have acquired their spike genes from a DPP4-recognizing bat coronavirus HKU4. Our study provides further evidence that bats represent the evolutionary origins of MERS-CoV.IMPORTANCE Previous studies suggested that MERS-CoV originated in bats. However, its evolutionary path from bats to humans remains unclear. In this study, we discovered 89 novel lineage C betacoronaviruses in eight bat species. We provide evidence of a MERS-related CoV derived from the great evening bat that uses the same host receptor as human MERS-CoV. This virus also provides evidence for a natural recombination event between the bat MERS-related CoV and another bat coronavirus, HKU4. Our study expands the host ranges of MERS-related CoV and represents an important step toward establishing bats as the natural reservoir of MERS-CoV. These findings may lead to improved epidemiological surveillance of MERS-CoV and the prevention and control of the spread of MERS-CoV to humans. Title: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity Turcot V, Lu Y, Highland HM, Schurmann C, Justice AE, Fine RS, Bradfield JP, Esko T, Giri A and Loos RJF <390 more author(s)> Turcot V, Lu Y, Highland HM, Schurmann C, Justice AE, Fine RS, Bradfield JP, Esko T, Giri A, Graff M, Guo X, Hendricks AE, Karaderi T, Lempradl A, Locke AE, Mahajan A, Marouli E, Sivapalaratnam S, Young KL, Alfred T, Feitosa MF, Masca NGD, Manning AK, Medina-Gomez C, Mudgal P, Ng MCY, Reiner AP, Vedantam S, Willems SM, Winkler TW, Abecasis G, Aben KK, Alam DS, Alharthi SE, Allison M, Amouyel P, Asselbergs FW, Auer PL, Balkau B, Bang LE, Barroso I, Bastarache L, Benn M, Bergmann S, Bielak LF, Bluher M, Boehnke M, Boeing H, Boerwinkle E, Boger CA, Bork-Jensen J, Bots ML, Bottinger EP, Bowden DW, Brandslund I, Breen G, Brilliant MH, Broer L, Brumat M, Burt AA, Butterworth AS, Campbell PT, Cappellani S, Carey DJ, Catamo E, Caulfield MJ, Chambers JC, Chasman DI, Chen YI, Chowdhury R, Christensen C, Chu AY, Cocca M, Collins FS, Cook JP, Corley J, Corominas Galbany J, Cox AJ, Crosslin DS, Cuellar-Partida G, D'Eustacchio A, Danesh J, Davies G, Bakker PIW, Groot MCH, Mutsert R, Deary IJ, Dedoussis G, Demerath EW, Heijer M, Hollander AI, Ruijter HM, Dennis JG, Denny JC, Angelantonio E, Drenos F, Du M, Dube MP, Dunning AM, Easton DF, Edwards TL, Ellinghaus D, Ellinor PT, Elliott P, Evangelou E, Farmaki AE, Farooqi IS, Faul JD, Fauser S, Feng S, Ferrannini E, Ferrieres J, Florez JC, Ford I, Fornage M, Franco OH, Franke A, Franks PW, Friedrich N, Frikke-Schmidt R, Galesloot TE, Gan W, Gandin I, Gasparini P, Gibson J, Giedraitis V, Gjesing AP, Gordon-Larsen P, Gorski M, Grabe HJ, Grant SFA, Grarup N, Griffiths HL, Grove ML, Gudnason V, Gustafsson S, Haessler J, Hakonarson H, Hammerschlag AR, Hansen T, Harris KM, Harris TB, Hattersley AT, Have CT, Hayward C, He L, Heard-Costa NL, Heath AC, Heid IM, Helgeland O, Hernesniemi J, Hewitt AW, Holmen OL, Hovingh GK, Howson JMM, Hu Y, Huang PL, Huffman JE, Ikram MA, Ingelsson E, Jackson AU, Jansson JH, Jarvik GP, Jensen GB, Jia Y, Johansson S, Jorgensen ME, Jorgensen T, Jukema JW, Kahali B, Kahn RS, Kahonen M, Kamstrup PR, Kanoni S, Kaprio J, Karaleftheri M, Kardia SLR, Karpe F, Kathiresan S, Kee F, Kiemeney LA, Kim E, Kitajima H, Komulainen P, Kooner JS, Kooperberg C, Korhonen T, Kovacs P, Kuivaniemi H, Kutalik Z, Kuulasmaa K, Kuusisto J, Laakso M, Lakka TA, Lamparter D, Lange EM, Lange LA, Langenberg C, Larson EB, Lee NR, Lehtimaki T, Lewis CE, Li H, Li J, Li-Gao R, Lin H, Lin KH, Lin LA, Lin X, Lind L, Lindstrom J, Linneberg A, Liu CT, Liu DJ, Liu Y, Lo KS, Lophatananon A, Lotery AJ, Loukola A, Luan J, Lubitz SA, Lyytikainen LP, Mannisto S, Marenne G, Mazul AL, McCarthy MI, McKean-Cowdin R, Medland SE, Meidtner K, Milani L, Mistry V, Mitchell P, Mohlke KL, Moilanen L, Moitry M, Montgomery GW, Mook-Kanamori DO, Moore C, Mori TA, Morris AD, Morris AP, Muller-Nurasyid M, Munroe PB, Nalls MA, Narisu N, Nelson CP, Neville M, Nielsen SF, Nikus K, Njolstad PR, Nordestgaard BG, Nyholt DR, O'Connel JR, O'Donoghue ML, Olde Loohuis LM, Ophoff RA, Owen KR, Packard CJ, Padmanabhan S, Palmer CNA, Palmer ND, Pasterkamp G, Patel AP, Pattie A, Pedersen O, Peissig PL, Peloso GM, Pennell CE, Perola M, Perry JA, Perry JRB, Pers TH, Person TN, Peters A, Petersen ERB, Peyser PA, Pirie A, Polasek O, Polderman TJ, Puolijoki H, Raitakari OT, Rasheed A, Rauramaa R, Reilly DF, Renstrom F, Rheinberger M, Ridker PM, Rioux JD, Rivas MA, Roberts DJ, Robertson NR, Robino A, Rolandsson O, Rudan I, Ruth KS, Saleheen D, Salomaa V, Samani NJ, Sapkota Y, Sattar N, Schoen RE, Schreiner PJ, Schulze MB, Scott RA, Segura-Lepe MP, Shah SH, Sheu WH, Sim X, Slater AJ, Small KS, Smith AV, Southam L, Spector TD, Speliotes EK, Starr JM, Stefansson K, Steinthorsdottir V, Stirrups KE, Strauch K, Stringham HM, Stumvoll M, Sun L, Surendran P, Swift AJ, Tada H, Tansey KE, Tardif JC, Taylor KD, Teumer A, Thompson DJ, Thorleifsson G, Thorsteinsdottir U, Thuesen BH, Tonjes A, Tromp G, Trompet S, Tsafantakis E, Tuomilehto J, Tybjaerg-Hansen A, Tyrer JP, Uher R, Uitterlinden AG, Uusitupa M, Laan SW, Duijn CM, Leeuwen N, van Setten J, Vanhala M, Varbo A, Varga TV, Varma R, Velez Edwards DR, Vermeulen SH, Veronesi G, Vestergaard H, Vitart V, Vogt TF, Volker U, Vuckovic D, Wagenknecht LE, Walker M, Wallentin L, Wang F, Wang CA, Wang S, Wang Y, Ware EB, Wareham NJ, Warren HR, Waterworth DM, Wessel J, White HD, Willer CJ, Wilson JG, Witte DR, Wood AR, Wu Y, Yaghootkar H, Yao J, Yao P, Yerges-Armstrong LM, Young R, Zeggini E, Zhan X, Zhang W, Zhao JH, Zhao W, Zhou W, Zondervan KT, Rotter JI, Pospisilik JA, Rivadeneira F, Borecki IB, Deloukas P, Frayling TM, Lettre G, North KE, Lindgren CM, Hirschhorn JN, Loos RJF (- 390) Ref: Nat Genet, 50:26, 2018 : PubMed ESTHER: Turcot_2018_Nat.Genet_50_26 PubMedSearch: Turcot 2018 Nat.Genet 50 26 PubMedID: 29273807 Abstract Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity. Title: Correlation Between Liver Stiffness Measured by Shear Wave Elastography and Child-Pugh Classification Wang J, Wang Q, Yu G, She Q, Zhang W, Zhang J Ref: Journal of Ultrasound in Medicine, 37:2191, 2018 : PubMed ESTHER: Wang_2018_J.Ultrasound.Med_37_2191 PubMedSearch: Wang 2018 J.Ultrasound.Med 37 2191 PubMedID: 29476558 Abstract OBJECTIVES: To explore the association between liver stiffness and the Child-Pugh classification of liver function by shear wave elastography (SWE). METHODS: A total of 116 patients with liver cirrhosis were divided into 3 groups according to the Child-Pugh classification prospectively. Conventional ultrasound imaging and SWE were performed for all patients. The associations of liver stiffness measured by SWE with ultrasound measurements, serum biochemical indicators, and the Child-Pugh classification were analyzed. Receiver operating characteristic curves were analyzed and compared to determine the ability of liver stiffness to diagnose cirrhosis. RESULTS: Liver stiffness measured by SWE increased with an increasing Child-Pugh classification, internal diameter of the hepatic portal and splenic veins, spleen thickness, spleen length, total bilirubin level, and prothrombin time, which were positively correlated with the Child-Pugh classification (all P < .05). The albumin level and liver stiffness showed higher areas under the curve in comparison with other parameters for evaluating the Child-Pugh classification. Albumin and cholinesterase levels were negatively correlated with the Child-Pugh classification (P < .05). All of these indicators were significantly different between each pair of groups (all P < .05), except for the internal diameter of the hepatic portal vein, prothrombin time, and total bilirubin, and cholinesterase levels between groups B and C (P > 0.05) and the thickness and length of spleen and internal diameter of the splenic vein between groups A and B (P > 0.05). There were no differences among the groups for alanine aminotransferase, aspartate aminotransferase, and globulin levels. CONCLUSIONS: Liver stiffness measured by SWE was correlated with the Child-Pugh classification, and it may be able to help evaluate liver function in patients with cirrhosis. Title: Recovery of respiratory function and autonomic diaphragm movement following unilateral recurrent laryngeal nerve to phrenic nerve anastomosis in rabbits Wen J, Han Y, Guo S, Yang M, Li L, Sun G, Wang J, Hu F, Liang J and Tan J <3 more author(s)> Wen J, Han Y, Guo S, Yang M, Li L, Sun G, Wang J, Hu F, Liang J, Wei L, Zhou Q, Zhang W, Tan J (- 3) Ref: Journal of Neurosurgery Spine, :1, 2018 : PubMed ESTHER: Wen_2018_J.Neurosurg.Spine__1 PubMedSearch: Wen 2018 J.Neurosurg.Spine 1 PubMedID: 29979142 Abstract OBJECTIVE Respiratory dysfunction is the leading cause of mortality following upper cervical spinal cord injury (SCI). The authors' previous study suggested that vagus nerve (VN) and phrenic nerve (PN) anastomosis could partially improve respiratory function in rabbits that had been subjected to PN transection. As a branch of the VN and a motor fiber-dominated nerve, the recurrent laryngeal nerve (RLN) seems a better choice to anastomose with the PN for respiratory function restoration after upper cervical SCI. This study was designed to determine whether RLN-PN anastomosis could restore the respiratory function after upper cervical SCI in rabbits. METHODS Twelve male New Zealand rabbits were randomly divided into 3 groups: 1) sham group (no injury), 2) transection group (right RLN and PN were transected), and 3) bridge group (transected right RLN and PN were immediately anastomosed). Spontaneous discharges of the RLN and PN were compared using a bio-signal collection system. RLN and PN cross sections were stained for acetylcholinesterase (AChE), and the numbers of motor fibers were compared. Three months after the initial surgical procedures, the movement of the diaphragm was assessed using a digital subtraction angiography (DSA) system, and discharges from the right diaphragm muscle were recorded. Toluidine blue staining, electron microscopy, and staining for AChE were used to assess whether motor fibers from the RLN regenerated into the PN, and sections of diaphragm were examined after AChE staining to assess the motor endplates. RESULTS Both the RLN and PN exhibited highly rhythmic discharges, synchronized with respiration, and most fibers in the RLN and PN were found to be motor fibers. Numerous myelinated fibers were observed in anastomosed PN using toluidine blue staining and electron microscopy. Staining for AChE showed that those regenerated fibers had typical characteristics of motor fibers, and motor endplates with typical morphological characteristics were observed in the diaphragm. Reestablished rhythmic contraction of the hemidiaphragm was directly observed using the DSA system, and rhythmic spontaneous discharge was recorded from the reinnervated hemidiaphragm using the bio-signal collection system. CONCLUSIONS Motor fibers from the RLN could regenerate into the PN after end-to-end anastomosis and reinnervate the denervated hemidiaphragm in rabbits. Those regenerated motor fibers restored rhythmic and autonomic movement of the paralyzed diaphragm. These results suggest that the RLN is an optimal donor nerve to anastomose with the PN in order to reestablish the autonomic movement of paralyzed diaphragms after high-level SCI. Title: Repeated Autologous Bone Marrow Transfusion through Portal Vein for Treating Decompensated Liver Cirrhosis after Splenectomy Zhang W, Teng M, Liu B, Liu Q, Liu X, Si Y, Li L Ref: Gastroenterol Res Pract, 2018:4136082, 2018 : PubMed ESTHER: Zhang_2018_Gastroenterol.Res.Pract_2018_4136082 PubMedSearch: Zhang 2018 Gastroenterol.Res.Pract 2018 4136082 PubMedID: 30510572 Abstract Objective: This study is aimed at examining the impact of repeated intraportal autologous bone marrow transfusion (ABMT) in patients with decompensated liver cirrhosis after splenectomy. Methods: A total of 25 patients with decompensated liver cirrhosis undergoing splenectomy were divided into ABMT and control groups. The portal vein was cannulated intraoperatively using Celsite Implantofix through the right gastroomental vein. Both groups were given a routine medical treatment. Then, 18 mL of autologous bone marrow was transfused through the port in the patients of the ABMT group 1 week, 1 month, and 3 months after laminectomy, while nothing was given to the control group. All patients were monitored for adverse events. Liver function tests, including serum albumin (ALB), alanine aminotransferase (ALT), total bilirubin (TB), prothrombin activity (PTA), cholinesterase (CHE), alpha-fetoprotein (AFP), and liver stiffness measurement (LSM), were conducted before surgery and 1, 3, and 6 months after surgery. Results: Significant improvements in ALB, ALT, and CHE levels and decreased LSM were observed in the ABMT group compared with those in the control group (P < 0.05). TB and PTA improved in both groups but with no significant differences between the groups. No significant changes were observed in AFP in the control group, but it decreased in the ABMT group. No major adverse effects were noted during the follow-up period in the patients of either group. Conclusions: Repeated intraportal ABMT was clinically safe, and liver function of patients significantly improved. Therefore, this therapy has the potential to treat patients with decompensated liver cirrhosis after splenectomy. This trial was registered with the identification number of ChiCTR-ONC-17012592. Title: Identification of Novel Coumestan Derivatives as Polyketide Synthase 13 Inhibitors against Mycobacterium tuberculosis Zhang W, Lun S, Wang SH, Jiang XW, Yang F, Tang J, Manson AL, Earl AM, Gunosewoyo H and Yu LF <1 more author(s)> Zhang W, Lun S, Wang SH, Jiang XW, Yang F, Tang J, Manson AL, Earl AM, Gunosewoyo H, Bishai WR, Yu LF (- 1) Ref: Journal of Medicinal Chemistry, 61:791, 2018 : PubMed ESTHER: Zhang_2018_J.Med.Chem_61_791 PubMedSearch: Zhang 2018 J.Med.Chem 61 791 PubMedID: 29328655 Gene_locus related to this paper: myctu-PKS13 Abstract Inhibition of the mycolic acid pathway has proven a viable strategy in antitubercular drug discovery. The AccA3/AccD4/FadD32/Pks13 complex of Mycobacterium tuberculosis constitutes an essential biosynthetic mechanism for mycolic acids. Small molecules targeting the thioesterase domain of Pks13 have been reported, including a benzofuran-based compound whose X-ray cocrystal structure has been very recently solved. Its initial inactivity in a serum inhibition titration (SIT) assay led us to further probe other structurally related benzofurans with the aim to improve their potency and bioavailability. Herein, we report our preliminary structure-activity relationship studies around this scaffold, highlighting a natural product-inspired cyclization strategy to form coumestans that are shown to be active in SIT. Whole genome deep sequencing of the coumestan-resistant mutants confirmed a single nucleotide polymorphism in the pks13 gene responsible for the resistance phenotype, demonstrating the druggability of this target for the development of new antitubercular agents. 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: The Inhibitory Effect of alpha/beta-Hydrolase Domain-Containing 6 (ABHD6) on the Surface Targeting of GluA2- and GluA3-Containing AMPA Receptors Wei M, Jia M, Zhang J, Yu L, Zhao Y, Chen Y, Ma Y, Zhang W, Shi YS, Zhang C Ref: Front Mol Neurosci, 10:55, 2017 : PubMed ESTHER: Wei_2017_Front.Mol.Neurosci_10_55 PubMedSearch: Wei 2017 Front.Mol.Neurosci 10 55 PubMedID: 28303090 Abstract The alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPARs) are major excitatory receptors that mediate fast neurotransmission in the mammalian brain. The surface expression of functional AMPARs is crucial for synaptic transmission and plasticity. AMPAR auxiliary subunits control the biosynthesis, membrane trafficking, and synaptic targeting of AMPARs. Our previous report showed that alpha/beta-hydrolase domain-containing 6 (ABHD6), an auxiliary subunit for AMPARs, suppresses the membrane delivery and function of GluA1-containing receptors in both heterologous cells and neurons. However, it remained unclear whether ABHD6 affects the membrane trafficking of glutamate receptor subunits, GluA2 and GluA3. Here, we examine the effects of ABHD6 overexpression in HEK293T cells expressing GluA1, GluA2, GluA3, and stargazin, either alone or in combination. The results show that ABHD6 suppresses the glutamate-induced currents and the membrane expression of AMPARs when expressing GluA2 or GluA3 in the HEK293T cells. We generated a series of GluA2 and GluA3 C-terminal deletion constructs and confirm that the C-terminus of GluAs is required for ABHD6's inhibitory effects on glutamate-induced currents and surface expression of GluAs. Meanwhile, our pull-down experiments reveal that ABHD6 binds to GluA1-3, and deletion of the C-terminal domain of GluAs abolishes this binding. These findings demonstrate that ABHD6 inhibits the AMPAR-mediated currents and its surface expression, independent of the type of AMPAR subunits, and this inhibitor's effects are mediated through the binding with the GluAs C-terminal regions. Title: Effect of carboxylesterase 1 S75N on clopidogrel therapy among acute coronary syndrome patients Xiao FY, Luo JQ, Liu M, Chen BL, Cao S, Liu ZQ, Zhou HH, Zhou G, Zhang W Ref: Sci Rep, 7:7244, 2017 : PubMed ESTHER: Xiao_2017_Sci.Rep_7_7244 PubMedSearch: Xiao 2017 Sci.Rep 7 7244 PubMedID: 28775293 Gene_locus related to this paper: human-CES1 Abstract Carboxylesterase 1 (CES1) hydrolyzes the prodrug clopidogrel to an inactive carboxylic acid metabolite. The effects of CES1 S75N (rs2307240,C>T) on clopidogrel response among 851 acute coronary syndrome patients who came from the north, central and south of China were studied. The occurrence ratios of each endpoint in the CC group were significantly higher than in the CT + TT group for cerebrovascular events (14% vs 4.8%, p < 0.001, OR = 0.31), acute myocardial infarction (15.1% vs 6.1%, p < 0.001, OR = 0.37) and unstable angina (62.8% vs 37.7%, p < 0.001, OR = 0.36). The results showed that there was a significant association between CES1 S75N (rs2307240) and the outcome of clopidogrel therapy. Moreover, the frequency of the T allele of rs2307240 in acute coronary syndrome patients (MAF = 0.22) was more than four times higher than that in the general public (MAF = 0.05). Title: Pharmacophore-based design and discovery of (-)-meptazinol carbamates as dual modulators of cholinesterase and amyloidogenesis Xie Q, Zheng Z, Shao B, Fu W, Xia Z, Li W, Sun J, Zheng W, Zhang W and Qiu Z <4 more author(s)> Xie Q, Zheng Z, Shao B, Fu W, Xia Z, Li W, Sun J, Zheng W, Zhang W, Sheng W, Zhang Q, Chen H, Wang H, Qiu Z (- 4) Ref: J Enzyme Inhib Med Chem, 32:659, 2017 : PubMed ESTHER: Xie_2017_J.Enzyme.Inhib.Med.Chem_32_659 PubMedSearch: Xie 2017 J.Enzyme.Inhib.Med.Chem 32 659 PubMedID: 28274151 Abstract Multifunctional carbamate-type acetylcholinesterase (AChE) inhibitors with anti-amyloidogenic properties like phenserine are potential therapeutic agents for Alzheimer's disease (AD). We reported here the design of new carbamates using pharmacophore model strategy to modulate both cholinesterase and amyloidogenesis. A five-feature pharmacophore model was generated based on 25 carbamate-type training set compounds. (-)-Meptazinol carbamates that superimposed well upon the model were designed and synthesized, which exhibited nanomolar AChE inhibitory potency and good anti-amyloidogenic properties in in vitro test. The phenylcarbamate 43 was highly potent (IC50 31.6 nM) and slightly selective for AChE, and showed low acute toxicity. In enzyme kinetics assay, 43 exhibited uncompetitive inhibition and reacted by pseudo-irreversible mechanism. 43 also showed amyloid-beta (Abeta) lowering effects (51.9% decrease of Abeta42) superior to phenserine (31% decrease of total Abeta) in SH-SY5Y-APP695 cells at 50 microM. The dual actions of 43 on cholinergic and amyloidogenic pathways indicated potential uses as symptomatic and disease-modifying agents. 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: Neuroprotective Activities of Marine Natural Products from Marine Sponges Alghazwi M, Kan YQ, Zhang W, Gai WP, Yan XX Ref: Curr Med Chem, 23:360, 2016 : PubMed ESTHER: Alghazwi_2016_Curr.Med.Chem_23_360 PubMedSearch: Alghazwi 2016 Curr.Med.Chem 23 360 PubMedID: 26630920 Abstract This review covers the compounds isolated from marine sponges with neuroprotective activities during the period between 1999 and 2014 based on their chemical structures, collections sites, sponge taxonomy and neuroprotective effects. These compounds were isolated from marine sponges collected from 18 countries, most of them in Indonesia, followed by Japan. A total of 90 compounds were reported to exhibit a range of neuroprotective efficacy. These compounds were shown to inhibit beta-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1), modulate the synthesis or activity of some neurotransmitters such as acetylcholinesterase and glutamate, enhancement of serotonin, reducing oxidative stress, inhibition of kinases and proteases, and enhancement of neurite growth. None of them have yet progressed into any marine pharmaceutical development pipeline, therefore sustained researches will be required to enhance the potential of utilizing these compounds in the future for prevention and therapeutic treatment of neurodegenerative diseases. Title: High expression of NDRG3 associates with positive lymph node metastasis and unfavourable overall survival in laryngeal squamous cell carcinoma Ma J, Liu S, Zhang W, Zhang F, Wang S, Wu L, Yan R, Wang C, Zha Z, Sun J Ref: Pathology, 48:691, 2016 : PubMed ESTHER: Ma_2016_Pathology_48_691 PubMedSearch: Ma 2016 Pathology 48 691 PubMedID: 27780595 Abstract N-myc downstream-regulated gene 3 (NDRG3), which belongs to the NDRG family, is believed to play important roles in human cancer. In this present study, one-step quantitative reverse transcription-polymerase chain reaction (qPCR) and western blotting tests with 10 fresh-frozen laryngeal squamous cell carcinoma (LSCC) samples and immunohistochemistry (IHC) analysis in 109 LSCC cases were performed to investigate the relationship between NDRG3 expression and the clinicopathological characteristics of LSCC. Results demonstrated that NDRG3 mRNA and protein expression levels were statistically higher in LSCC tissues than that in non-cancerous tissues (all p<0.05). IHC data showed that the NDRG3 protein expression was remarkably correlated with lymph node metastasis (p=0.043). Univariate and multivariate survival analysis implied that high NDRG3 expression (p=0.004), lymph node metastasis (p=0.044) and TNM stage (p=0.020) were independently associated with the unfavourable overall survival of patients with LSCC. The above findings suggested that NDRG3 may be identified as a novel biomarker predicting the prognosis of LSCC. Title: NPY(+)-, but not PV(+)-GABAergic neurons mediated long-range inhibition from infra- to prelimbic cortex Saffari R, Teng Z, Zhang M, Kravchenko M, Hohoff C, Ambree O, Zhang W Ref: Transl Psychiatry, 6:e736, 2016 : PubMed ESTHER: Saffari_2016_Transl.Psychiatry_6_e736 PubMedSearch: Saffari 2016 Transl.Psychiatry 6 e736 PubMedID: 26882036 Abstract Anxiety disorders are thought to reflect deficits in the regulation of fear memories. While the amygdala has long been considered a site of storage of fear memories, newer findings suggest that the prefrontal cortex (PFC) is essential in the regulation of amygdala-dependent memories and fear expression. Here, activation of the prelimbic cortex (PrL) enhances the expression of fear, while an elevated activity in the infralimbic cortex (IL) enhances fear extinction. Despite the presence of these facts, we still know very little about the synaptic interconnectivity within the PFC. The aim of the present study was to investigate the inhibitory circuits between prelimbic and IL using morphological and electrophysiological methods. Our immunohistochemical analysis revealed that the distribution of PV(+)- and NPY(+)-GABAergic neurons was strikingly different within the PFC. In addition, we provided the first experimental evidence that the pyramidal neurons in the PrL received a direct inhibitory input mediated by bipolar NPY(+)-GABAergic projection neurons in the IL. Deletion of the anxiety-related neuroligin 2 gene caused a decrease of this direct synaptic inhibition that originated from the IL. Thus, our data suggested that activation of the IL might not only directly activate the corresponding downstream anxiolytic pathway, but also suppress the PrL-related anxiogenic pathway and thus could differentially bias the regulation of fear expression and extinction. 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: Insights into Adaptations to a Near-Obligate Nematode Endoparasitic Lifestyle from the Finished Genome of Drechmeria coniospora Zhang L, Zhou Z, Guo Q, Fokkens L, Miskei M, Pocsi I, Zhang W, Chen M, Wang L and Lin M <12 more author(s)> Zhang L, Zhou Z, Guo Q, Fokkens L, Miskei M, Pocsi I, Zhang W, Chen M, Wang L, Sun Y, Donzelli BG, Gibson DM, Nelson DR, Luo JG, Rep M, Liu H, Yang S, Wang J, Krasnoff SB, Xu Y, Molnar I, Lin M (- 12) Ref: Sci Rep, 6:23122, 2016 : PubMed ESTHER: Zhang_2016_Sci.Rep_6_23122 PubMedSearch: Zhang 2016 Sci.Rep 6 23122 PubMedID: 26975455 Gene_locus related to this paper: 9hypo-a0a151ga75, 9hypo-a0a151gbh5, 9hypo-a0a151gd50, 9hypo-a0a151ggb9, 9hypo-a0a151gjd5, 9hypo-a0a151gtv2, 9hypo-a0a151gxh2, 9hypo-a0a151gaw8, 9hypo-a0a151gia2 Abstract Nematophagous fungi employ three distinct predatory strategies: nematode trapping, parasitism of females and eggs, and endoparasitism. While endoparasites play key roles in controlling nematode populations in nature, their application for integrated pest management is hindered by the limited understanding of their biology. We present a comparative analysis of a high quality finished genome assembly of Drechmeria coniospora, a model endoparasitic nematophagous fungus, integrated with a transcriptomic study. Adaptation of D. coniospora to its almost completely obligate endoparasitic lifestyle led to the simplification of many orthologous gene families involved in the saprophytic trophic mode, while maintaining orthologs of most known fungal pathogen-host interaction proteins, stress response circuits and putative effectors of the small secreted protein type. The need to adhere to and penetrate the host cuticle led to a selective radiation of surface proteins and hydrolytic enzymes. Although the endoparasite has a simplified secondary metabolome, it produces a novel peptaibiotic family that shows antibacterial, antifungal and nematicidal activities. Our analyses emphasize the basic malleability of the D. coniospora genome: loss of genes advantageous for the saprophytic lifestyle; modulation of elements that its cohort species utilize for entomopathogenesis; and expansion of protein families necessary for the nematode endoparasitic lifestyle. Title: Discovery of a Novel Series of Imidazo[1,2-a]pyrimidine Derivatives as Potent and Orally Bioavailable Lipoprotein-Associated Phospholipase A2 Inhibitors Chen X, Xu W, Wang K, Mo M, Zhang W, Du L, Yuan X, Xu Y, Wang Y, Shen J Ref: Journal of Medicinal Chemistry, 58:8529, 2015 : PubMed ESTHER: Chen_2015_J.Med.Chem_58_8529 PubMedSearch: Chen 2015 J.Med.Chem 58 8529 PubMedID: 26479945 Gene_locus related to this paper: human-PLA2G7 Abstract Inhibition of lipoprotein-associated phospholipase A2 (Lp-PLA2) has been suggested to be a promising therapeutic strategy for several inflammation-associated diseases, including atherosclerosis, Alzheimer's disease, and diabetic macular edema. Herein, we report the discovery of a novel series of Lp-PLA2 inhibitors constructed on an imidazo[1,2-a]pyrimidine scaffold through a conformational restriction strategy. Structure-activity relationship (SAR) analysis resulted in the identification of several compounds with high potency in vitro and good metabolic stability in liver S9 fractions. Compounds 7c and 14b selected for further exploration in vivo demonstrated excellent pharmacokinetic profiles and exhibited significant inhibitory efficacy in SD rats upon oral dosing. Title: Immobilization of Aspergillus terreus lipase in self-assembled hollow nanospheres for enantioselective hydrolysis of ketoprofen vinyl ester Hu C, Wang N, Zhang W, Zhang S, Meng Y, Yu X Ref: J Biotechnol, 194:12, 2015 : PubMed ESTHER: Hu_2015_J.Biotechnol_194_12 PubMedSearch: Hu 2015 J.Biotechnol 194 12 PubMedID: 25483320 Abstract The aim of this study was to improve the ability of Aspergillus terreus lipase to separate the racemic ketoprofen vinyl ester into individual enantiomers using hollow self-assembly alginate-graft-poly(ethylene glycol)/alpha-cyclodextrins (Alg-g-PEG/alpha-CD) spheres as enzyme immobilization carriers. The morphology and size of the Alg-g-PEG/alpha-CD particles were investigated by transmission electron microscopy (TEM) and were found to be nanoscale. To facilitate recycling, calcium alginate (CA) beads were developed to encapsulate Alg-g-PEG/alpha-CD particles, thereby producing Alg-g-PEG/alpha-CD/CA composite beads. The influence of buffer pH and enzyme concentration during immobilization was studied along with the biocatalyst's kinetic parameters. When the immobilized enzyme was under optimal conditions in the resolution reaction, maximal conversion (approximately 45.9%) and enantioselectivity (approximately 128.8) were obtained. The immobilized A. terreus lipase maintained excellent performance even after 20 reuses and retained nearly 100% of its original activity after 24 weeks of storage at 4 degrees C. 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: Peroxisomal translocation of soluble epoxide hydrolase protects against ischemic stroke injury Nelson JW, Zhang W, Alkayed NJ, Koerner IP Ref: Journal of Cerebral Blood Flow & Metabolism, 35:1416, 2015 : PubMed ESTHER: Nelson_2015_J.Cereb.Blood.Flow.Metab_35_1416 PubMedSearch: Nelson 2015 J.Cereb.Blood.Flow.Metab 35 1416 PubMedID: 26126869 Abstract Soluble epoxide hydrolase (sEH) contributes to cardiovascular disease, including stroke, although the exact mechanism remains unclear. While primarily a cytosolic enzyme, sEH can translocate into peroxisomes. The relevance of this for stroke injury is not understood. We tested the hypothesis that sEH-mediated injury is tied to the cytoplasmic localization. We found that a human sEH variant possessing increased affinity to peroxisomes reduced stroke injury in sEH-null mice, whereas infarcts were significantly larger when peroxisomal translocation of sEH was disrupted. We conclude that sEH contributes to stroke injury only when localized in the cytoplasm, while peroxisomal sEH may be protective. Title: Expanding the biotechnology potential of lactobacilli through comparative genomics of 213 strains and associated genera Sun Z, Harris HM, McCann A, Guo C, Argimon S, Zhang W, Yang X, Jeffery IB, Cooney JC and O'Toole PW <21 more author(s)> Sun Z, Harris HM, McCann A, Guo C, Argimon S, Zhang W, Yang X, Jeffery IB, Cooney JC, Kagawa TF, Liu W, Song Y, Salvetti E, Wrobel A, Rasinkangas P, Parkhill J, Rea MC, O'Sullivan O, Ritari J, Douillard FP, Paul Ross R, Yang R, Briner AE, Felis GE, de Vos WM, Barrangou R, Klaenhammer TR, Caufield PW, Cui Y, Zhang H, O'Toole PW (- 21) Ref: Nat Commun, 6:8322, 2015 : PubMed ESTHER: Sun_2015_Nat.Commun_6_8322 PubMedSearch: Sun 2015 Nat.Commun 6 8322 PubMedID: 26415554 Gene_locus related to this paper: 9laco-a0a0r1hz65, 9laco-a0a0r1j1t4, 9laco-a0a0r1j3p0, 9laco-a0a0r1k3i0, 9laco-a0a0r1k563, 9laco-a0a0r1kgb3, 9laco-a0a0r1kji2, 9laco-a0a0r1kwq5, 9laco-a0a0r1l700, 9laco-a0a0r1p6l8, 9laco-a0a0r1q939, 9laco-a0a0r1qv39, 9laco-a0a0r1wj75, laccl-a0a0r2bne3, 9laco-a0a0r2dnk9, 9laco-a0a0r2ds70, 9laco-a0a0r2k127, 9laco-a0a0r2lee7, 9laco-a0a0r2lqt2, 9laco-a0a0r2m354, 9laco-a0a0r2n9f2, 9laco-a0a0r2nrk2, lacze-a0a0r1ekw6, 9laco-a0a0r1ju11, 9laco-a0a0r1k516, 9laco-a0a0r1leq9, 9laco-a0a0r1lul8, 9laco-a0a0r1lzg4, 9laco-a0a0r1mhp8, 9laco-a0a0r1mjt1, 9laco-a0a0r1nv21, 9laco-a0a0r1q1p6, 9laco-a0a0r1qm41, 9laco-a0a0r1qs58, 9laco-a0a0r1rgu0, 9laco-a0a0r1tg12, 9laco-a0a0r1u777, 9laco-a0a0r1ufv3, 9laco-a0a0r1ul77, 9laco-a0a0r1vad0, 9laco-a0a0r1w3f4, 9laco-a0a0r1w9r8, 9laco-a0a0r1wpq2, 9laco-a0a0r1x2g3, 9laco-a0a0r2abe6, 9laco-a0a0r2b6w1, 9laco-a0a0r2b8g1, 9laco-a0a0r2ch10, 9laco-a0a0r2cld6, 9laco-a0a0r2cv38, 9laco-a0a0r2d3x3, 9laco-a0a0r2dct2, 9laco-a0a0r2flt3, 9laco-a0a0r2frk5, 9laco-a0a0r2guq4, 9firm-a0a0r2h5m0, weivi-a0a0r2h8r4, 9lact-a0a0r2hnx4, 9lact-a0a0r2jkt6, 9lact-a0a0r2jmz1, 9laco-a0a0r2jwg5, 9laco-a0a0r2jxu0, 9laco-a0a0r2jxw0, lacam-a0a0r2kgt3, 9laco-a0a0r2kx86, 9laco-a0a0r2mxi6, 9laco-a0a0r1vln2, 9laco-a0a0r2ca25, 9laco-a0a0r1zjs2, weipa-c5rbw8 Abstract Lactobacilli are a diverse group of species that occupy diverse nutrient-rich niches associated with humans, animals, plants and food. They are used widely in biotechnology and food preservation, and are being explored as therapeutics. Exploiting lactobacilli has been complicated by metabolic diversity, unclear species identity and uncertain relationships between them and other commercially important lactic acid bacteria. The capacity for biotransformations catalysed by lactobacilli is an untapped biotechnology resource. Here we report the genome sequences of 213 Lactobacillus strains and associated genera, and their encoded genetic catalogue for modifying carbohydrates and proteins. In addition, we describe broad and diverse presence of novel CRISPR-Cas immune systems in lactobacilli that may be exploited for genome editing. We rationalize the phylogenomic distribution of host interaction factors and bacteriocins that affect their natural and industrial environments, and mechanisms to withstand stress during technological processes. We present a robust phylogenomic framework of existing species and for classifying new species. Title: Whole-genome optical mapping and finished genome sequence of Sphingobacterium deserti sp. nov., a new species isolated from the Western Desert of China Teng C, Zhou Z, Molnar I, Li X, Tang R, Chen M, Wang L, Su S, Zhang W, Lin M Ref: PLoS ONE, 10:e0122254, 2015 : PubMed ESTHER: Teng_2015_PLoS.ONE_10_E0122254 PubMedSearch: Teng 2015 PLoS.ONE 10 E0122254 PubMedID: 25830331 Gene_locus related to this paper: 9sphi-a0a0b8t8i3, 9sphi-a0a0b8t3y0 Abstract A novel Gram-negative bacterium, designated ZWT, was isolated from a soil sample of the Western Desert of China, and its phenotypic properties and phylogenetic position were investigated using a polyphasic approach. Growth occurred on TGY medium at 5-42 degreesC with an optimum of 30 degreesC, and at pH 7.0-11.0 with an optimum of pH 9.0. The predominant cellular fatty acids were summed feature 3 (C16:1omega7c/C16:1omega6c or C16:1omega6c/C16:1omega7c) (39.22%), iso-C15:0 (27.91%), iso-C17:0 3OH (15.21%), C16:0 (4.98%), iso-C15:0 3OH (3.03%), C16:0 3OH (5.39%) and C14:0 (1.74%). The major polar lipid of strain ZWT is phosphatidylethanolamine. The only menaquinone observed was MK-7. The GC content of the DNA of strain ZWT is 44.9 mol%. rDNA phylogeny, genome relatedness and chemotaxonomic characteristics all indicate that strain ZWT represents a novel species of the genus Sphingobacterium. We propose the name S. deserti sp. nov., with ZWT (= KCTC 32092T = ACCC 05744T) as the type strain. Whole genome optical mapping and next-generation sequencing was used to derive a finished genome sequence for strain ZWT, consisting of a circular chromosome of 4,615,818 bp in size. The genome of strain ZWT features 3,391 protein-encoding and 48 tRNA-encoding genes. Comparison of the predicted proteome of ZWT with those of other sphingobacteria identified 925 species-unique proteins that may contribute to the adaptation of ZWT to its native, extremely arid and inhospitable environment. As the first finished genome sequence for any Sphingobacterium, our work will serve as a useful reference for subsequent sequencing and mapping efforts for additional strains and species within this genus. Title: Functional characterization of MpaG', the O-methyltransferase involved in the biosynthesis of mycophenolic acid Zhang W, Cao S, Qiu L, Qi F, Li Z, Yang Y, Huang S, Bai F, Liu C and Li S <1 more author(s)> Zhang W, Cao S, Qiu L, Qi F, Li Z, Yang Y, Huang S, Bai F, Liu C, Wan X, Li S (- 1) Ref: Chembiochem, 16:565, 2015 : PubMed ESTHER: Zhang_2015_ChemBioChem_16_565 PubMedSearch: Zhang 2015 ChemBioChem 16 565 PubMedID: 25630520 Gene_locus related to this paper: penbr-mpaH, penbr-mpac Abstract Mycophenolic acid (MPA, 1) is a clinically important immunosuppressant. In this report, a gene cluster mpa' responsible for the biosynthesis of 1 was identified from Penicillium brevicompactum NRRL 864. The S-adenosyl-L-methionine-dependent (SAM-dependent) O-methyltransferase encoded by the mpaG' gene was functionally and kinetically characterized in vitro. MpaG' catalyzes the methylation of demethylmycophenolic acid (DMMPA, 6) to form 1. It also showed significant substrate flexibility by methylating two structural derivatives of 6 prepared by organic synthesis. Title: Novel link between prostaglandin E2 (PGE2) and cholinergic signaling in lung cancer: The role of c-Jun in PGE2-induced alpha7 nicotinic acetylcholine receptor expression and tumor cell proliferation Zhong X, Fan Y, Ritzenthaler JD, Zhang W, Wang K, Zhou Q, Roman J Ref: Thorac Cancer, 6:488, 2015 : PubMed ESTHER: Zhong_2015_Thorac.Cancer_6_488 PubMedSearch: Zhong 2015 Thorac.Cancer 6 488 PubMedID: 26273406 Abstract BACKGROUND: Cyclooxygenase-2-derived prostaglandin E2 (PGE2) stimulates tumor cell growth and progression. alpha7 nicotinic acetylcholine receptor (nAChR) is a major mediator of cholinergic signaling in tumor cells. In the present study, we investigated the mechanisms by which PGE2 increases non-small cell lung cancer (NSCLC) proliferation via alpha7 nAChR induction. Title: Genome Sequence of the epsilon-Poly-l-Lysine-Producing Strain Streptomyces albulus NK660, Isolated from Soil in Gutian, Fujian Province, China Gu Y, Yang C, Wang X, Geng W, Sun Y, Feng J, Wang Y, Quan Y, Che Y and Wang S <6 more author(s)> Gu Y, Yang C, Wang X, Geng W, Sun Y, Feng J, Wang Y, Quan Y, Che Y, Zhang C, Gong T, Zhang W, Gao W, Zuo Z, Song C, Wang S (- 6) Ref: Genome Announc, 2:e00532, 2014 : PubMed ESTHER: Gu_2014_Genome.Announc_2_e00532 PubMedSearch: Gu 2014 Genome.Announc 2 e00532 PubMedID: 24926050 Gene_locus related to this paper: stra9-a0a059w351 Abstract We determined the complete genome sequence of a soil bacterium, Streptomyces albulus NK660. It can produce epsilon-poly-l-lysine, which has antimicrobial activity against a spectrum of microorganisms. The genome of S. albulus NK660 contains a 9,360,281-bp linear chromosome and a 12,120-bp linear plasmid. Title: Comparative genomic analysis provides insights into the evolution and niche adaptation of marine Magnetospira sp. QH-2 strain Ji B, Zhang SD, Arnoux P, Rouy Z, Alberto F, Philippe N, Murat D, Zhang WJ, Rioux JB and Wu LF <17 more author(s)> Ji B, Zhang SD, Arnoux P, Rouy Z, Alberto F, Philippe N, Murat D, Zhang WJ, Rioux JB, Ginet N, Sabaty M, Mangenot S, Pradel N, Tian J, Yang J, Zhang L, Zhang W, Pan H, Henrissat B, Coutinho PM, Li Y, Xiao T, Medigue C, Barbe V, Pignol D, Talla E, Wu LF (- 17) Ref: Environ Microbiol, 16:525, 2014 : PubMed ESTHER: Ji_2014_Environ.Microbiol_16_525 PubMedSearch: Ji 2014 Environ.Microbiol 16 525 PubMedID: 23841906 Gene_locus related to this paper: 9prot-w6k5m7, 9prot-w6khf2, 9prot-w6kbu9 Abstract Magnetotactic bacteria (MTB) are capable of synthesizing intracellular organelles, the magnetosomes, that are membrane-bounded magnetite or greigite crystals arranged in chains. Although MTB are widely spread in various ecosystems, few axenic cultures are available, and only freshwater Magnetospirillum spp. have been genetically analysed. Here, we present the complete genome sequence of a marine magnetotactic spirillum, Magnetospira sp. QH-2. The high number of repeats and transposable elements account for the differences in QH-2 genome structure compared with other relatives. Gene cluster synteny and gene correlation analyses indicate that the insertion of the magnetosome island in the QH-2 genome occurred after divergence between freshwater and marine magnetospirilla. The presence of a sodium-quinone reductase, sodium transporters and other functional genes are evidence of the adaptive evolution of Magnetospira sp. QH-2 to the marine ecosystem. Genes well conserved among freshwater magnetospirilla for nitrogen fixation and assimilatory nitrate respiration are absent from the QH-2 genome. Unlike freshwater Magnetospirillum spp., marine Magnetospira sp. QH-2 neither has TonB and TonB-dependent receptors nor does it grow on trace amounts of iron. Taken together, our results show a distinct, adaptive evolution of Magnetospira sp. QH-2 to marine sediments in comparison with its closely related freshwater counterparts. Title: Association between esophageal cancer risk and EPHX1 polymorphisms: a meta-analysis Li QT, Kang W, Wang M, Yang J, Zuo Y, Zhang W, Su DK Ref: World J Gastroenterol, 20:5124, 2014 : PubMed ESTHER: Li_2014_World.J.Gastroenterol_20_5124 PubMedSearch: Li 2014 World.J.Gastroenterol 20 5124 PubMedID: 24803829 Abstract AIM: To summarize the relationship between p.Tyr113His and p.His139Arg polymorphisms in microsomal epoxide hydrolase (EPHX1) and risk for esophageal cancer (EC). Title: Complete Genome Sequence of Magnetospirillum gryphiswaldense MSR-1 Wang X, Wang Q, Zhang W, Wang Y, Li L, Wen T, Zhang T, Zhang Y, Xu J and Li J <9 more author(s)> Wang X, Wang Q, Zhang W, Wang Y, Li L, Wen T, Zhang T, Zhang Y, Xu J, Hu J, Li S, Liu L, Liu J, Jiang W, Tian J, Li Y, Schuler D, Wang L, Li J (- 9) Ref: Genome Announc, 2:, 2014 : PubMed ESTHER: Wang_2014_Genome.Announc_2_e00171 PubMedSearch: Wang 2014 Genome.Announc 2 e00171 PubMedID: 24625872 Gene_locus related to this paper: maggm-v6ezc0 Abstract We report the complete genomic sequence of Magnetospirillum gryphiswaldense MSR-1 (DSM 6361), a type strain of the genus Magnetospirillum belonging to the Alphaproteobacteria. Compared to the reported draft sequence, extensive rearrangements and differences were found, indicating high genomic flexibility and "domestication" by accelerated evolution of the strain upon repeated passaging. Title: Comparative genomic analysis shows that Streptococcus suis meningitis isolate SC070731 contains a unique 105K genomic island Wu Z, Wang W, Tang M, Shao J, Dai C, Zhang W, Fan H, Yao H, Zong J and Lu C <2 more author(s)> Wu Z, Wang W, Tang M, Shao J, Dai C, Zhang W, Fan H, Yao H, Zong J, Chen D, Wang J, Lu C (- 2) Ref: Gene, 535:156, 2014 : PubMed ESTHER: Wu_2014_Gene_535_156 PubMedSearch: Wu 2014 Gene 535 156 PubMedID: 24316490 Gene_locus related to this paper: strej-e8uk64 Abstract Streptococcus suis (SS) is an important swine pathogen worldwide that occasionally causes serious infections in humans. SS infection may result in meningitis in pigs and humans. The pathogenic mechanisms of SS are poorly understood. Here, we provide the complete genome sequence of S. suis serotype 2 (SS2) strain SC070731 isolated from a pig with meningitis. The chromosome is 2,138,568bp in length. There are 1933 predicted protein coding sequences and 96.7% (57/59) of the known virulence-associated genes are present in the genome. Strain SC070731 showed similar virulence with SS2 virulent strains HA9801 and ZY05719, but was more virulent than SS2 virulent strain P1/7 in the zebrafish infection model. Comparative genomic analysis revealed a unique 105K genomic island in strain SC070731 that is absent in seven other sequenced SS2 strains. Further analysis of the 105K genomic island indicated that it contained a complete nisin locus similar to the nisin U locus in S. uberis strain 42, a prophage similar to S. oralis phage PH10 and several antibiotic resistance genes. Several proteins in the 105K genomic island, including nisin and RelBE toxin-antitoxin system, contribute to the bacterial fitness and virulence in other pathogenic bacteria. Further investigation of newly identified gene products, including four putative new virulence-associated surface proteins, will improve our understanding of SS pathogenesis. Title: The Down-Regulation of Neuroligin-2 and the Correlative Clinical Significance of Serum GABA Over-Expression in Hirschsprung's Disease Yang H, Niu J, Wang J, Zhang F, Zhang Q, Zhang W, Li A Ref: Neurochem Res, 39:1451, 2014 : PubMed ESTHER: Yang_2014_Neurochem.Res_39_1451 PubMedSearch: Yang 2014 Neurochem.Res 39 1451 PubMedID: 24842555 Abstract The goal of this study was to investigate the expression level of neuroligin-2 in different colon tissue segments of children with Hirschsprung's disease (HSCR) and the correlative clinical significance of serum Gamma-Aminobutyric Acid (serum GABA) in HSCR. Neuroligin-2 was assessed by Immunohistochemistry staining method on routine paraffin section from different colon tissue segments of HSCR (ganglionic colonic segment, transitional colonic segment and aganglionic colonic segment). Western-blot analysis and real-time fluorescence quantitative PCR(qRT-PCR) were applied to compare and evaluate the expression levels of neuroligin-2 from three segments of HSCR, and we used Enzyme-linked Immunosorbent Assay (ELISA) method to detect and compare the serum GABA between HSCR and non-HSCR. Immunohistochemistry staining demonstrated that intensive neuroligin-2 staining was detected in the ganglion cells in the ganglionic colonic and transitional colonic segments from the HSCR children; however, neuroligin-2 staining was down-regulated significantly in the aganglionic colonic segments. The expression levels of neuroligin-2 mRNA and protein in the aganglionic colonic segment were decreased compared to the ganglionic colonic segment and transitional colonic segment (P < 0.05). And the level of serum GABA was significantly higher in HSCR than that in non-HSCR. The expression of neuroligin-2 varies from different segments of HSCR. The down-regulation of neuroligin-2 in aganglionic colonic segments may be correlated with the excessive intestine contraction and further result in HSCR. The over-expression of serum GABA may be considered as a new diagnostic method of HSCR. Title: Lipase immobilized catalytically active membrane for synthesis of lauryl stearate in a pervaporation membrane reactor Zhang W, Qing W, Ren Z, Li W, Chen J Ref: Bioresour Technol, 172C:16, 2014 : PubMed ESTHER: Zhang_2014_Bioresour.Technol_172C_16 PubMedSearch: Zhang 2014 Bioresour.Technol 172C 16 PubMedID: 25218626 Abstract A composite catalytically active membrane immobilized with Candida rugosa lipase has been prepared by immersion phase inversion technique for enzymatic synthesis of lauryl stearate in a pervaporation membrane reactor. SEM images showed that a "sandwich-like" membrane structure with a porous lipase-PVA catalytic layer uniformly coated on a polyvinyl alcohol (PVA)/polyethersulfone (PES) bilayer was obtained. Optimum conditions for lipase immobilization in the catalytic layer were determined. The membrane was proved to exhibit superior thermal stability, pH stability and reusability than free lipase under similar conditions. In the case of pervaporation coupled synthesis of lauryl stearate, benefited from in-situ water removal by the membrane, a conversion enhancement of approximately 40% was achieved in comparison to the equilibrium conversion obtained in batch reactors. In addition to conversion enhancement, it was also found that excess water removal by the catalytically active membrane appears to improve activity of the lipase immobilized. Title: DWARF3 participates in an SCF complex and associates with DWARF14 to suppress rice shoot branching Zhao J, Wang T, Wang M, Liu Y, Yuan S, Gao Y, Yin L, Sun W, Peng L and Li X <2 more author(s)> Zhao J, Wang T, Wang M, Liu Y, Yuan S, Gao Y, Yin L, Sun W, Peng L, Zhang W, Wan J, Li X (- 2) Ref: Plant Cell Physiol, 55:1096, 2014 : PubMed ESTHER: Zhao_2014_Plant.Cell.Physiol_55_1096 PubMedSearch: Zhao 2014 Plant.Cell.Physiol 55 1096 PubMedID: 24616269 Abstract Strigolactones (SLs) are a novel class of plant hormones that inhibit shoot branching. Currently, two proteins in rice are thought to play crucial roles in SL signal transduction. DWARF14 (D14), an alpha/beta hydrolase, is responsible for SL perception, while DWARF3 (D3), an F-box protein with leucine-rich repeats, is essential for SL signal transduction. However, how these two proteins transmit SL signals to downstream factors remains unclear. Here, we characterized a high-tillering dwarf rice mutant, gsor300097, which is insensitive to GR24, a synthetic analog of SL. Mapping and sequencing analysis showed that gsor300097 is a novel allelic mutant of D3, in which a nonsense mutation truncates the protein from 720 to 527 amino acids. The D3 gene was strongly expressed in root, leaf, shoot base and panicle. Nuclear-localized F-box protein D3 played a role in the SCF complex by interacting with OSK1, OSK5 or OSK20 and OsCullin1. In addition, D3 associated with D14 in a GR24-dependent manner in vivo. Taken together, our findings suggested that D3 assembled into an SCF(D3) complex and associated with D14 to suppress rice shoot branching. Title: Soluble epoxide hydrolase gene deletion improves blood flow and reduces infarct size after cerebral ischemia in reproductively senescent female mice Zuloaga KL, Zhang W, Roese NE, Alkayed NJ Ref: Front Pharmacol, 5:290, 2014 : PubMed ESTHER: Zuloaga_2014_Front.Pharmacol_5_290 PubMedSearch: Zuloaga 2014 Front.Pharmacol 5 290 PubMedID: 25642188 Abstract Soluble epoxide hydrolase (sEH), a key enzyme in the metabolism of vasodilatory epoxyeicosatrienoic acids (EETs), is sexually dimorphic, suppressed by estrogen, and contributes to underlying sex differences in cerebral blood flow and injury after cerebral ischemia. We tested the hypothesis that sEH inhibition or gene deletion in reproductively senescent (RS) female mice would increase cerebral perfusion and decrease infarct size following stroke. RS (15-18 month old) and young (3-4 month old) female sEH knockout (sEHKO) mice and wild type (WT) mice were subjected to 45 min middle cerebral artery occlusion (MCAO) with laser Doppler perfusion monitoring. WT mice were treated with vehicle or a sEH inhibitor t-AUCB at the time of reperfusion and every 24 h thereafter for 3 days. Differences in regional cerebral blood flow were measured in vivo using optical microangiography (OMAG). Infarct size was measured 3 days after reperfusion. Infarct size and cerebral perfusion 24 h after MCAO were not altered by age. Both sEH gene deletion and sEH inhibition increased cortical perfusion 24 h after MCAO. Neither sEH gene deletion nor sEH inhibition reduced infarct size in young mice. However, sEH gene deletion, but not sEH inhibition of the hydrolase domain of the enzyme, decreased infarct size in RS mice. Results of these studies show that sEH gene deletion and sEH inhibition enhance cortical perfusion following MCAO and sEH gene deletion reduces damage after ischemia in RS female mice; however this neuroprotection in absent is young mice. Title: The role of MuSK in synapse formation and neuromuscular disease Burden SJ, Yumoto N, Zhang W Ref: Cold Spring Harb Perspect Biol, 5:a009167, 2013 : PubMed ESTHER: Burden_2013_Cold.Spring.Harb.Perspect.Biol_5_a009167 PubMedSearch: Burden 2013 Cold.Spring.Harb.Perspect.Biol 5 a009167 PubMedID: 23637281 Abstract Muscle-specific kinase (MuSK) is essential for each step in neuromuscular synapse formation. Before innervation, MuSK initiates postsynaptic differentiation, priming the muscle for synapse formation. Approaching motor axons recognize the primed, or prepatterned, region of muscle, causing motor axons to stop growing and differentiate into specialized nerve terminals. MuSK controls presynaptic differentiation by causing the clustering of Lrp4, which functions as a direct retrograde signal for presynaptic differentiation. Developing synapses are stabilized by neuronal Agrin, which is released by motor nerve terminals and binds to Lrp4, a member of the low-density lipoprotein receptor family, stimulating further association between Lrp4 and MuSK and increasing MuSK kinase activity. In addition, MuSK phosphorylation is stimulated by an inside-out ligand, docking protein-7 (Dok-7), which is recruited to tyrosine-phosphorylated MuSK and increases MuSK kinase activity. Mutations in MuSK and in genes that function in the MuSK signaling pathway, including Dok-7, cause congenital myasthenia, and autoantibodies to MuSK, Lrp4, and acetylcholine receptors are responsible for myasthenia gravis. Title: Whole-genome sequencing of Oryza brachyantha reveals mechanisms underlying Oryza genome evolution Chen J, Huang Q, Gao D, Wang J, Lang Y, Liu T, Li B, Bai Z, Luis Goicoechea J and Chen M <30 more author(s)> Chen J, Huang Q, Gao D, Wang J, Lang Y, Liu T, Li B, Bai Z, Luis Goicoechea J, Liang C, Chen C, Zhang W, Sun S, Liao Y, Zhang X, Yang L, Song C, Wang M, Shi J, Liu G, Liu J, Zhou H, Zhou W, Yu Q, An N, Chen Y, Cai Q, Wang B, Liu B, Min J, Huang Y, Wu H, Li Z, Zhang Y, Yin Y, Song W, Jiang J, Jackson SA, Wing RA, Chen M (- 30) Ref: Nat Commun, 4:1595, 2013 : PubMed ESTHER: Chen_2013_Nat.Commun_4_1595 PubMedSearch: Chen 2013 Nat.Commun 4 1595 PubMedID: 23481403 Gene_locus related to this paper: orysa-Q6ZDG3, orysa-q6h415, orysj-q6yse8, orysa-q33aq0, orybr-j3l7k2, orybr-j3m138, orybr-j3l6m8, orybr-j3m3b3, orybr-j3l8d1, orybr-j3kza5, orybr-j3mnb5, orybr-j3n4p4, orybr-j3lg73, orybr-j3l342, orybr-j3msi2, orybr-j3nb83, orybr-j3mpc5 Abstract The wild species of the genus Oryza contain a largely untapped reservoir of agronomically important genes for rice improvement. Here we report the 261-Mb de novo assembled genome sequence of Oryza brachyantha. Low activity of long-terminal repeat retrotransposons and massive internal deletions of ancient long-terminal repeat elements lead to the compact genome of Oryza brachyantha. We model 32,038 protein-coding genes in the Oryza brachyantha genome, of which only 70% are located in collinear positions in comparison with the rice genome. Analysing breakpoints of non-collinear genes suggests that double-strand break repair through non-homologous end joining has an important role in gene movement and erosion of collinearity in the Oryza genomes. Transition of euchromatin to heterochromatin in the rice genome is accompanied by segmental and tandem duplications, further expanded by transposable element insertions. The high-quality reference genome sequence of Oryza brachyantha provides an important resource for functional and evolutionary studies in the genus Oryza. Title: Genome Sequence of Streptomyces violaceusniger Strain SPC6, a Halotolerant Streptomycete That Exhibits Rapid Growth and Development Chen X, Zhang B, Zhang W, Wu X, Zhang M, Chen T, Liu G, Dyson P Ref: Genome Announc, 1:, 2013 : PubMed ESTHER: Chen_2013_Genome.Announc_1_e00494 PubMedSearch: Chen 2013 Genome.Announc 1 e00494 PubMedID: 23868127 Gene_locus related to this paper: 9actn-a0a1d3dv58 Abstract Streptomyces violaceusniger strain SPC6 is a halotolerant streptomycete isolated from the Linze desert in China. The strain has a very high growth rate and a short life cycle for a streptomycete. For surface-grown cultures, the period from spore germination to formation of colonies with mature spore chains is only 2 days at 37 degrees C. Additionally, the strain is remarkably resistant to osmotic, heat, and UV stress compared with other streptomycetes. Analysis of the draft genome sequence indicates that the strain has the smallest reported genome (6.4 Mb) of any streptomycete. The availability of this genome sequence allows us to investigate the genetic basis of adaptation for growth in an extremely arid environment. Title: Genome-wide association study identifies multiple susceptibility loci for pulmonary fibrosis Fingerlin TE, Murphy E, Zhang W, Peljto AL, Brown KK, Steele MP, Loyd JE, Cosgrove GP, Lynch D and Schwartz DA <40 more author(s)> Fingerlin TE, Murphy E, Zhang W, Peljto AL, Brown KK, Steele MP, Loyd JE, Cosgrove GP, Lynch D, Groshong S, Collard HR, Wolters PJ, Bradford WZ, Kossen K, Seiwert SD, du Bois RM, Garcia CK, Devine MS, Gudmundsson G, Isaksson HJ, Kaminski N, Zhang Y, Gibson KF, Lancaster LH, Cogan JD, Mason WR, Maher TM, Molyneaux PL, Wells AU, Moffatt MF, Selman M, Pardo A, Kim DS, Crapo JD, Make BJ, Regan EA, Walek DS, Daniel JJ, Kamatani Y, Zelenika D, Smith K, McKean D, Pedersen BS, Talbert J, Kidd RN, Markin CR, Beckman KB, Lathrop M, Schwarz MI, Schwartz DA (- 40) Ref: Nat Genet, 45:613, 2013 : PubMed ESTHER: Fingerlin_2013_Nat.Genet_45_613 PubMedSearch: Fingerlin 2013 Nat.Genet 45 613 PubMedID: 23583980 Abstract We performed a genome-wide association study of non-Hispanic, white individuals with fibrotic idiopathic interstitial pneumonias (IIPs; n = 1,616) and controls (n = 4,683), with follow-up replication analyses in 876 cases and 1,890 controls. We confirmed association with TERT at 5p15, MUC5B at 11p15 and the 3q26 region near TERC, and we identified seven newly associated loci (Pmeta = 2.4 x 10(-8) to 1.1 x 10(-19)), including FAM13A (4q22), DSP (6p24), OBFC1 (10q24), ATP11A (13q34), DPP9 (19p13) and chromosomal regions 7q22 and 15q14-15. Our results suggest that genes involved in host defense, cell-cell adhesion and DNA repair contribute to risk of fibrotic IIPs. Title: Magnetic FeO@TiO nanoparticles-based test strip immunosensing device for rapid detection of phosphorylated butyrylcholinesterase Ge X, Zhang W, Lin Y, Du D Ref: Biosensors & Bioelectronics, 50C:486, 2013 : PubMed ESTHER: Ge_2013_Biosens.Bioelectron_50C_486 PubMedSearch: Ge 2013 Biosens.Bioelectron 50C 486 PubMedID: 23911770 Abstract An integrated magnetic nanoparticles-based test strip immunosensing device was developed for rapid and sensitive quantification of phosphorylated butyrylcholinesterase (BChE), the biomarker of exposure to organophosphorous pesticides (OP), in human plasma. In order to overcome the difficulty in scarce availability of OP-specific antibody, here magnetic Fe3O4@TiO2 nanoparticles were used and adsorbed on the test strip through a small magnet inserted in the device to capture target OP-BChE through selective binding between TiO2 and OP moiety. Further recognition was completed by horseradish peroxidase (HRP) and anti-BChE antibody (Ab) co-immobilized gold nanoparticles (GNPs). Their strong affinities among Fe3O4@TiO2, OP-BChE and HRP/Ab-GNPs were characterized by quartz crystal microbalance (QCM), surface plasmon resonance (SPR) and square wave voltammetry (SWV) measurements. After cutting off from test strip, the resulted immunocomplex (HRP/Ab-GNPs/OP-BChE/Fe3O4@TiO2) was measured by SWV using a screen printed electrode under the test zone. Greatly enhanced sensitivity was achieved by introduction of GNPs to link enzyme and antibody at high ratio, which amplifies electrocatalytic signal significantly. Moreover, the use of test strip for fast immunoreactions reduces analytical time remarkably. Under the optimized conditions, the developed device shows a broader linear response over the concentration of OP-BChE from 0.05nM to 10nM within 15min, with a detection limit of 0.01nM. Coupling with a portable electrochemical detector, the integrated device with advanced nanotechnology displays great promise for sensitive, rapid and on-site evaluation of OP poisoning. Title: Complete Genome Sequence of the Industrial Strain Gluconobacter oxydans H24 Ge X, Zhao Y, Hou W, Zhang W, Chen W, Wang J, Zhao N, Lin J, Wang W and Xiong X <4 more author(s)> Ge X, Zhao Y, Hou W, Zhang W, Chen W, Wang J, Zhao N, Lin J, Wang W, Chen M, Wang Q, Jiao Y, Yuan Z, Xiong X (- 4) Ref: Genome Announc, 1:, 2013 : PubMed ESTHER: Ge_2013_Genome.Announc_1_E00003 PubMedSearch: Ge 2013 Genome.Announc 1 E00003 PubMedID: 23472221 Gene_locus related to this paper: gluth-t1e0l0, gluoy-k7si88, gluoy-k7smm7 Abstract Gluconobacter oxydans is characterized by its ability to incompletely oxidize carbohydrates and alcohols. The high yields of its oxidation products and complete secretion into the medium make it important for industrial use. We report the finished genome sequence of Gluconobacter oxydans H24, an industrial strain with high l-sorbose productivity. Title: Visible-light-activated photoelectrochemical biosensor for the study of acetylcholinesterase inhibition induced by endogenous neurotoxins Huang Q, Chen H, Xu L, Lu D, Tang L, Jin L, Xu Z, Zhang W Ref: Biosensors & Bioelectronics, 45C:292, 2013 : PubMed ESTHER: Huang_2013_Biosens.Bioelectron_45C_292 PubMedSearch: Huang 2013 Biosens.Bioelectron 45C 292 PubMedID: 23500378 Abstract In this report, a novel visible-light-activated photoelectrochemical biosensor was fabricated to study the inhibition of acetylcholinesterase (AChE) activity induced by two endogenous neurotoxins, 1(R)-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline [(R)-Sal] and 1(R),2(N)-dimethyl-6,7-dihydroxy-1,2,3,4-tetra-hydroisoquinoline [(R)-NMSal], which have drawn much attention in the study of the pathogenesis of neurodegenerative diseases such as Parkinson's disease. The photoelectrode was prepared by three steps, as follows. At first, nitrogen and fluorine co-doped TiO2 nanotubes (TNs) were obtained by anodic oxidation of a Ti sheet. Secondly, silver nanoparticles (AgNPs) were deposited onto the TNs through a microwave-assisted heating polyol (MAHP) process. At last, AChE was immobilized on the obtained photoelectrode and the biosensor was marked as AChE/Ag/NFTNs. Due to the nitrogen and fluorine co-doping, the photoelectrochemical biosensors can produce high photocurrent under visible light irradiation. Moreover, the presence of AgNPs greatly increased the photocurrent response of the biosensor. AChE/Ag/NFTNs hybrid system was used to study AChE inhibition induced by (R)-Sal and (R)-NMSal. The result proved that both (R)-Sal and (R)-NMSal exhibited mixed and reversible inhibition against AChE. This strategy is of great significance for the development of novel photoelectrochemical biosensors in the future. Title: Role of soluble epoxide hydrolase in exacerbation of stroke by streptozotocin-induced type 1 diabetes mellitus Jouihan SA, Zuloaga KL, Zhang W, Shangraw RE, Krasnow SM, Marks DL, Alkayed NJ Ref: Journal of Cerebral Blood Flow & Metabolism, 33:1650, 2013 : PubMed ESTHER: Jouihan_2013_J.Cereb.Blood.Flow.Metab_33_1650 PubMedSearch: Jouihan 2013 J.Cereb.Blood.Flow.Metab 33 1650 PubMedID: 23899929 Abstract Hyperglycemia worsens stroke, yet rigorous glycemic control does not improve neurologic outcome. An alternative is to target downstream molecular mediator(s) triggered by hyperglycemia but independent of prevailing glycemia. Soluble epoxide hydrolase (sEH) is a potential mediator of injury via its metabolism of neuroprotective epoxyeicosatrienoic acids (EETs). We tested whether hyperglycemia exacerbates cerebral injury by upregulating sEH and decreasing brain EET levels. Type 1 diabetes mellitus was modeled by streptozotocin (STZ; 50 mg/kg per day intraperitoneally, 5 days) in male mice. At 4 weeks, STZ-treated and control mice underwent 45-minute middle cerebral artery occlusion (MCAO) with or without sEH blockade by trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB; 1 mg/kg intraperitoneally daily for 6 days before MCAO). The STZ-treated mice had increased sEH mRNA expression in cerebral vessels and decreased EET concentrations in brain. There was no difference in cortical perfusion between groups. The STZ-treated mice sustained larger brain infarct than controls. Pretreatment with t-AUCB eliminated the difference in infarct size and EETs concentration between STZ-treated mice and controls, without altering glycemia. We conclude that type 1 diabetes mellitus upregulates sEH mRNA and decreases concentrations of neuroprotective EETs within the brain, leading to worse stroke outcome. The data indicate that sEH antagonism may be beneficial in the setting of hyperglycemic stroke. Title: Surface Display of Recombinant Drosophila melanogaster Acetylcholinesterase for Detection of Organic Phosphorus and Carbamate Pesticides Li J, Qian B, Yin J, Wu S, Zhuan F, Xu S, Salazar JK, Zhang W, Wang H Ref: PLoS ONE, 8:e72986, 2013 : PubMed ESTHER: Li_2013_PLoS.One_8_e72986 PubMedSearch: Li 2013 PLoS.One 8 e72986 PubMedID: 24039837 Abstract Acetylcholinesterase (AChE) is commonly used for the detection of organophosphate (OP) and carbamate (CB) insecticides. However, the cost of this commercially available enzyme is high, making high-throughput insecticide detection improbable. In this study we constructed a new AChE yeast expression system in Saccharomyces cerevisiae for the expression of a highly reactive recombinant AChE originating from Drosophila melanogaster (DmAChE). Specifically, the coding sequence of DmAChE was fused with the 3'-terminal half of an alpha-agglutinin anchor region, along with an antigen tag for the detection of the recombinant protein. The target sequence was cloned into the yeast expression vector pYes-DEST52, and the signal peptide sequence was replaced with a glucoamylase secretion region for induced expression. The resultant engineered vector was transformed into S. cerevisiae. DmAChE was expressed and displayed on the cell surface after galactose induction. Our results showed that the recombinant protein displayed activity comparable to the commercial enzyme. We also detected different types of OP and CB insecticides through enzyme inhibition assays, with the expressed DmAChE showing high sensitivity. These results show the construction of a new yeast expression system for DmAChE, which can subsequently be used for detecting OP and CB insecticides with reduced economic costs. Title: Molecular basis of binding between novel human coronavirus MERS-CoV and its receptor CD26 Lu G, Hu Y, Wang Q, Qi J, Gao F, Li Y, Zhang Y, Zhang W, Yuan Y and Gao GF <4 more author(s)> Lu G, Hu Y, Wang Q, Qi J, Gao F, Li Y, Zhang Y, Zhang W, Yuan Y, Bao J, Zhang B, Shi Y, Yan J, Gao GF (- 4) Ref: Nature, 500:227, 2013 : PubMed ESTHER: Lu_2013_Nature_500_227 PubMedSearch: Lu 2013 Nature 500 227 PubMedID: 23831647 Gene_locus related to this paper: human-DPP4 Abstract The newly emergent Middle East respiratory syndrome coronavirus (MERS-CoV) can cause severe pulmonary disease in humans, representing the second example of a highly pathogenic coronavirus, the first being SARS-CoV. CD26 (also known as dipeptidyl peptidase 4, DPP4) was recently identified as the cellular receptor for MERS-CoV. The engagement of the MERS-CoV spike protein with CD26 mediates viral attachment to host cells and virus-cell fusion, thereby initiating infection. Here we delineate the molecular basis of this specific interaction by presenting the first crystal structures of both the free receptor binding domain (RBD) of the MERS-CoV spike protein and its complex with CD26. Furthermore, binding between the RBD and CD26 is measured using real-time surface plasmon resonance with a dissociation constant of 16.7 nM. The viral RBD is composed of a core subdomain homologous to that of the SARS-CoV spike protein, and a unique strand-dominated external receptor binding motif that recognizes blades IV and V of the CD26 beta-propeller. The atomic details at the interface between the two binding entities reveal a surprising protein-protein contact mediated mainly by hydrophilic residues. Sequence alignment indicates, among betacoronaviruses, a possible structural conservation for the region homologous to the MERS-CoV RBD core, but a high variation in the external receptor binding motif region for virus-specific pathogenesis such as receptor recognition. Title: Characterization of the biosynthetic genes for 10,11-dehydrocurvularin, a heat shock response-modulating anticancer fungal polyketide from Aspergillus terreus Xu Y, Espinosa-Artiles P, Schubert V, Xu YM, Zhang W, Lin M, Gunatilaka AA, Sussmuth R, Molnar I Ref: Applied Environmental Microbiology, 79:2038, 2013 : PubMed ESTHER: Xu_2013_Appl.Environ.Microbiol_79_2038 PubMedSearch: Xu 2013 Appl.Environ.Microbiol 79 2038 PubMedID: 23335766 Gene_locus related to this paper: aspte-curs2 Abstract 10,11-Dehydrocurvularin is a prevalent fungal phytotoxin with heat shock response and immune-modulatory activities. It features a dihydroxyphenylacetic acid lactone polyketide framework with structural similarities to resorcylic acid lactones like radicicol or zearalenone. A genomic locus was identified from the dehydrocurvularin producer strain Aspergillus terreus AH-02-30-F7 to reveal genes encoding a pair of iterative polyketide synthases (A. terreus CURS1 [AtCURS1] and AtCURS2) that are predicted to collaborate in the biosynthesis of 10,11-dehydrocurvularin. Additional genes in this locus encode putative proteins that may be involved in the export of the compound from the cell and in the transcriptional regulation of the cluster. 10,11-Dehydrocurvularin biosynthesis was reconstituted in Saccharomyces cerevisiae by heterologous expression of the polyketide synthases. Bioinformatic analysis of the highly reducing polyketide synthase AtCURS1 and the nonreducing polyketide synthase AtCURS2 highlights crucial biosynthetic programming differences compared to similar synthases involved in resorcylic acid lactone biosynthesis. These differences lead to the synthesis of a predicted tetraketide starter unit that forms part of the 12-membered lactone ring of dehydrocurvularin, as opposed to the penta- or hexaketide starters in the 14-membered rings of resorcylic acid lactones. Tetraketide N-acetylcysteamine thioester analogues of the starter unit were shown to support the biosynthesis of dehydrocurvularin and its analogues, with yeast expressing AtCURS2 alone. Differential programming of the product template domain of the nonreducing polyketide synthase AtCURS2 results in an aldol condensation with a different regiospecificity than that of resorcylic acid lactones, yielding the dihydroxyphenylacetic acid scaffold characterized by an S-type cyclization pattern atypical for fungal polyketides. Title: Whole-Genome Sequence of Microcystis aeruginosa TAIHU98, a Nontoxic Bloom-Forming Strain Isolated from Taihu Lake, China Yang C, Zhang W, Ren M, Song L, Li T, Zhao J Ref: Genome Announc, 1:, 2013 : PubMed ESTHER: Yang_2013_Genome.Announc_1_e00333 PubMedSearch: Yang 2013 Genome.Announc 1 e00333 PubMedID: 23766403 Abstract Microcystis aeruginosa is a dominant bloom-forming cyanobacterium in many freshwater lakes. This report describes the first whole-genome sequence of the nontoxic strain of M. aeruginosa TAIHU98, which was isolated from Taihu Lake in eastern China. Title: Iron(II)-dependent dioxygenase and N-formylamide deformylase catalyze the reactions from 5-hydroxy-2-pyridone to maleamate Yao Y, Tang H, Ren H, Yu H, Wang L, Zhang W, Behrman EJ, Xu P Ref: Sci Rep, 3:3235, 2013 : PubMed ESTHER: Yao_2013_Sci.Rep_3_3235 PubMedSearch: Yao 2013 Sci.Rep 3 3235 PubMedID: 24241081 Abstract 5-Hydroxy-2-pyridone (2,5-DHP) is a central metabolic intermediate in catabolism of many pyridine derivatives, and has been suggested as a potential carcinogen. 2,5-DHP is frequently transformed to N-formylmaleamic acid (NFM) by a 2,5-DHP dioxygenase. Three hypotheses were formerly discussed for conversion of 2,5-DHP to maleamate. Based on enzymatic reactions of dioxygenase (Hpo) and N-formylamide deformylase (Nfo), we demonstrated that the dioxygenase does not catalyze the hydrolysis of NFM but rather that this activity is brought about by a separate deformylase. We report that the deformylase acts both on NFM and its trans-isomer, N-formylfumaramic acid (NFF), but the catalytic efficiency of Nfo for NFM is about 1,400 times greater than that for NFF. In addition, we uncover catalytic and structural characteristics of the new family that the Hpo belongs to, and support a potential 2-His-1-carboxylate motif (HX52HXD) by three-dimensional modeling and site-directed mutagenesis. This study provides a better understanding of 2,5-DHP catabolism. Title: Expression of neurexin and neuroligin in the enteric nervous system and their down-regulated expression levels in Hirschsprung disease Zhang Q, Wang J, Li A, Liu H, Zhang W, Cui X, Wang K Ref: Mol Biol Rep, 40:2969, 2013 : PubMed ESTHER: Zhang_2013_Mol.Biol.Rep_40_2969 PubMedSearch: Zhang 2013 Mol.Biol.Rep 40 2969 PubMedID: 23264101 Abstract To investigate the expression levels of neurexins and neuroligins in the enteric nervous system (ENS) in Hirschsprung Disease (HSCR). Longitudinal muscles with adherent mesenteric plexus were obtained by dissection of the fresh gut wall of mice, guinea pigs, and humans. Double labeling of neurexin I and Hu (a neuron marker), neuroligin 1 and Hu, neurexin I and synaptophysin (a presynaptic marker), and neuroligin 1 and PSD95 (a postsynaptic marker) was performed by immunofluorescence staining. Images were merged to determine the relative localizations of the proteins. Expression levels of neurexin and neuroligin in different segments of the ENS in HSCR were investigated by immunohistochemistry. Neurexin and neuroligin were detected in the mesenteric plexus of mice, guinea pigs, and humans with HSCR. Neurexin was located in the presynapse, whereas neuroligin was located in the postsynapse. Expression levels of neurexin and neuroligin were significant in the ganglionic colonic segment of HSCR, moderate in the transitional segment, and negative in the aganglionic colonic segment. The expressions of neurexin and neuroligin in the transitional segments were significantly down-regulated compared with the levels in the normal segments (P < 0.05). Expression levels of neurexin and neuroligin in ENS are significantly down-regulated in HSCR, which may be involved in the pathogenesis of HSCR. Title: Role of endothelial soluble epoxide hydrolase in cerebrovascular function and ischemic injury [correction in medline 24204512] Zhang W, Davis CM, Edin ML, Lee CR, Zeldin DC, Alkayed NJ Ref: PLoS ONE, 8:e61244, 2013 : PubMed ESTHER: Zhang_2013_PLoS.One_8_e61244 PubMedSearch: Zhang 2013 PLoS.One 8 e61244 PubMedID: 23585883 Abstract Soluble Epoxide Hydrolase (sEH) is a key enzyme in the metabolism and termination of action of epoxyeicosatrienoic acids, derivatives of arachidonic acid, which are protective against ischemic stroke. Mice lacking sEH globally are protected from injury following stroke; however, little is known about the role of endothelial sEH in brain ischemia. We generated transgenic mice with endothelial-specific expression of human sEH (Tie2-hsEH), and assessed the effect of transgenic overexpression of endothelial sEH on endothelium-dependent vascular reactivity and ischemic injury following middle cerebral artery occlusion (MCAO). Compared to wild-type, male Tie2-hsEH mice exhibited impaired vasodilation in response to stimulation with 1 microM acetylcholine as assessed by laser-Doppler perfusion monitoring in an in-vivo cranial window preparation. No difference in infarct size was observed between wild-type and Tie2-hsEH male mice. In females, however, Tie2-hsEH mice sustained larger infarcts in striatum, but not cortex, compared to wild-type mice. Sex difference in ischemic injury was maintained in the cortex of Tie2-hsEH mice. In the striatum, expression of Tie2-hsEH resulted in a sex difference, with larger infarct in females than males. These findings demonstrate that transgenic expression of sEH in endothelium results in impaired endothelium-dependent vasodilation in the cerebral circulation, and that females are more susceptible to enhanced ischemic damage as a result of increased endothelial sEH than males, especially in end-arteriolar striatal region. Title: Nanoparticle-based immunochromatographic test strip with fluorescent detector for quantification of phosphorylated acetylcholinesterase: an exposure biomarker of organophosphorus agents Zhang W, Ge X, Tang Y, Du D, Liu D, Lin Y Ref: Analyst, 138:5431, 2013 : PubMed ESTHER: Zhang_2013_Analyst_138_5431 PubMedSearch: Zhang 2013 Analyst 138 5431 PubMedID: 23885349 Abstract A nanoparticle-based fluorescence immunochromatographic test strip (FITS) coupled with a hand-held detector for highly selective and sensitive detection of phosphorylated acetylcholinesterase (AChE), an exposure biomarker of organophosphate (OP) pesticides and nerve agents, is reported. In this approach, OP-AChE adducts were selectively captured by quantum dot-tagged anti-AChE antibodies (Qdot-anti-AChE) and zirconia nanoparticles (ZrO2 NPs). The sandwich-like immunoreactions were performed among the Qdot-anti-AChE, OP-AChE and ZrO2 NPs to form a Qdot-anti-AChE-OP-AChE-ZrO2 complex, which was detected by recording the fluorescence intensity of Qdots captured during the test line. Paraoxon was used as the model OP pesticide. Under optimal conditions, this portable FITS immunosensor demonstrates a highly linear absorption response over the range of 0.01 nM to 10 nM OP-AChE, with a detection limit of 4 pM, coupled with good reproducibility. Moreover, the FITS immunosensor has been validated with OP-AChE spiked human plasma samples. This is the first report on the development of ZrO2 NP-based FITS for the detection of the OP-AChE adduct. The FITS immunosensor provides a sensitive and low-cost sensing platform for on-site screening/evaluating OP pesticides and nerve agents poisoning. Title: Soluble Epoxide Hydrolase Deficiency Inhibits Dextran Sulfate Sodium-induced Colitis and Carcinogenesis in Mice Zhang W, Li H, Dong H, Liao J, Hammock BD, Yang GY Ref: Anticancer Research, 33:5261, 2013 : PubMed ESTHER: Zhang_2013_Anticancer.Res_33_5261 PubMedSearch: Zhang 2013 Anticancer.Res 33 5261 PubMedID: 24324059 Abstract Soluble epoxide hydrolase (sEH) hydrolyses/inactivates anti-inflammatory epoxyeicosatrienoic acids (EETs) to their corresponding diols, and targeting sEH leads to strong anti-inflammatory effects. In the present study, using a tissue microarray and immunohistochemical approach, a significant increase of sEH expression was identified in ulcerative colitis (UC)-associated dysplasia and adenocarcinoma. The effects of deficiency in the sEH gene were determined on dextran sulfate sodium (DSS) colitis-induced carcinogenesis. The effects of EETs on lipopolysaccharide (LPS)-activated macrophages were analyzed in vitro. With extensive histopathological and immunohistochemical analyses, compared to wild-type mice, sEH(-/-) mice exhibited a significant decrease in tumor incidence (13/20 vs. 6/19, p<0.05) and a markedly reduced average tumor size (59.62+/-20.91 mm(3) vs. 22.42+/-11.22 mm(3)), and a significant number of pre-cancerous dysplasia (3+/-1.18 vs. 2+/-0.83, p<0.01). The inflammatory activity, as measured by the extent/proportion of erosion/ulceration/dense lymphoplasmacytosis (called active colitis index) in the colon, was significantly lower in sEH(-/-) mice (44.7%+/-24.9% vs. 20.2%+/-16.2%, p<0.01). The quantitative polymerase chain reaction (qPCR) assays demonstrated significantly low levels of cytokines/chemokines including monocyte chemoattractant protein (MCP-1), inducible nitric oxide synthase (iNOS), vasopressin-activated calcium-mobilizing (VCAM-1), interleukin-1 beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha). In vitro, LPS-activated macrophages treated with 14,15-EET showed a significant reduction of LPS-triggered IL-1beta and TNF-alpha expression. Eicosanoic acid metabolic profiling revealed a significant increase of the ratios of EETs/ dihydroeicosatrienoic acids (DHETs) and epoxyoctadecennoic acid/dihydroxyoctadecenoic acid (EpOMEs/DiHOMEs). These results indicate that sEH plays an important role in the development of colitis and in inducing carcinogenesis. Title: Dechlorination of chloral hydrate is influenced by the biofilm adhesin protein LapA in Pseudomonas putida LF54 Zhang W, Huhe, Pan Y, Toyofuku M, Nomura N, Nakajima T, Uchiyama H Ref: Applied Environmental Microbiology, 79:4166, 2013 : PubMed ESTHER: Zhang_2013_Appl.Environ.Microbiol_79_4166 PubMedSearch: Zhang 2013 Appl.Environ.Microbiol 79 4166 PubMedID: 23603683 Gene_locus related to this paper: psepu-PIP, psepu-PP1500, psepu-PP4249, psepu-q9wwz4, psepu-u2t3m5 Abstract LapA is the largest surface adhesion protein of Pseudomonas putida that initiates biofilm formation. Here, by using transposon insertion mutagenesis and a conditional lapA mutant, we demonstrate for the first time that LapA influences chloral hydrate (CH) dechlorination in P. putida LF54. Title: The genome of the hydatid tapeworm Echinococcus granulosus Zheng H, Zhang W, Zhang L, Zhang Z, Li J, Lu G, Zhu Y, Wang Y, Huang Y and Wang S <21 more author(s)> Zheng H, Zhang W, Zhang L, Zhang Z, Li J, Lu G, Zhu Y, Wang Y, Huang Y, Liu J, Kang H, Chen J, Wang L, Chen A, Yu S, Gao Z, Jin L, Gu W, Wang Z, Zhao L, Shi B, Wen H, Lin R, Jones MK, Brejova B, Vinar T, Zhao G, McManus DP, Chen Z, Zhou Y, Wang S (- 21) Ref: Nat Genet, 45:1168, 2013 : PubMed ESTHER: Zheng_2013_Nat.Genet_45_1168 PubMedSearch: Zheng 2013 Nat.Genet 45 1168 PubMedID: 24013640 Gene_locus related to this paper: echgr-k4epc5, echmu-u6hbw4, echgr-w6ugl0, echgr-w6u7y4, echgr-w6vaq5, echgr-a0a068wxj3, echgr-a0a068wgw1, echgr-a0a068wl60 Abstract Cystic echinococcosis (hydatid disease), caused by the tapeworm E. granulosus, is responsible for considerable human morbidity and mortality. This cosmopolitan disease is difficult to diagnose, treat and control. We present a draft genomic sequence for the worm comprising 151.6 Mb encoding 11,325 genes. Comparisons with the genome sequences from other taxa show that E. granulosus has acquired a spectrum of genes, including the EgAgB family, whose products are secreted by the parasite to interact and redirect host immune responses. We also find that genes in bile salt pathways may control the bidirectional development of E. granulosus, and sequence differences in the calcium channel subunit EgCavbeta1 may be associated with praziquantel sensitivity. Our study offers insights into host interaction, nutrient acquisition, strobilization, reproduction, immune evasion and maturation in the parasite and provides a platform to facilitate the development of new, effective treatments and interventions for echinococcosis control. Title: The biochemical anatomy of cortical inhibitory synapses Heller EA, Zhang W, Selimi F, Earnheart JC, Slimak MA, Santos-Torres J, Ibanez-Tallon I, Aoki C, Chait BT, Heintz N Ref: PLoS ONE, 7:e39572, 2012 : PubMed ESTHER: Heller_2012_PLoS.One_7_e39572 PubMedSearch: Heller 2012 PLoS.One 7 e39572 PubMedID: 22768092 Abstract Classical electron microscopic studies of the mammalian brain revealed two major classes of synapses, distinguished by the presence of a large postsynaptic density (PSD) exclusively at type 1, excitatory synapses. Biochemical studies of the PSD have established the paradigm of the synapse as a complex signal-processing machine that controls synaptic plasticity. We report here the results of a proteomic analysis of type 2, inhibitory synaptic complexes isolated by affinity purification from the cerebral cortex. We show that these synaptic complexes contain a variety of neurotransmitter receptors, neural cell-scaffolding and adhesion molecules, but that they are entirely lacking in cell signaling proteins. This fundamental distinction between the functions of type 1 and type 2 synapses in the nervous system has far reaching implications for models of synaptic plasticity, rapid adaptations in neural circuits, and homeostatic mechanisms controlling the balance of excitation and inhibition in the mature brain. Title: Neurexin and neuroligin mediate retrograde synaptic inhibition in C. elegans Hu Z, Hom S, Kudze T, Tong XJ, Choi S, Aramuni G, Zhang W, Kaplan JM Ref: Science, 337:980, 2012 : PubMed ESTHER: Hu_2012_Science_337_980 PubMedSearch: Hu 2012 Science 337 980 PubMedID: 22859820 Abstract The synaptic adhesion molecules neurexin and neuroligin alter the development and function of synapses and are linked to autism in humans. Here, we found that Caenorhabditis elegans neurexin (NRX-1) and neuroligin (NLG-1) mediated a retrograde synaptic signal that inhibited neurotransmitter release at neuromuscular junctions. Retrograde signaling was induced in mutants lacking a muscle microRNA (miR-1) and was blocked in mutants lacking NLG-1 or NRX-1. Release was rapid and abbreviated when the retrograde signal was on, whereas release was slow and prolonged when retrograde signaling was blocked. The retrograde signal adjusted release kinetics by inhibiting exocytosis of synaptic vesicles (SVs) that are distal to the site of calcium entry. Inhibition of release was mediated by increased presynaptic levels of tomosyn, an inhibitor of SV fusion. Title: Genome sequences of wild and domestic bactrian camels Jirimutu, Wang Z, Ding G, Chen G, Sun Y, Sun Z, Zhang H, Wang L, Hasi S and Meng H <57 more author(s)> Jirimutu, Wang Z, Ding G, Chen G, Sun Y, Sun Z, Zhang H, Wang L, Hasi S, Zhang Y, Li J, Shi Y, Xu Z, He C, Yu S, Li S, Zhang W, Batmunkh M, Ts B, Narenbatu, Unierhu, Bat-Ireedui S, Gao H, Baysgalan B, Li Q, Jia Z, Turigenbayila, Subudenggerile, Narenmanduhu, Wang J, Pan L, Chen Y, Ganerdene Y, Dabxilt, Erdemt, Altansha, Altansukh, Liu T, Cao M, Aruuntsever, Bayart, Hosblig, He F, Zha-ti A, Zheng G, Qiu F, Zhao L, Zhao W, Liu B, Li C, Tang X, Guo C, Liu W, Ming L, Temuulen, Cui A, Li Y, Gao J, Wurentaodi, Niu S, Sun T, Zhai Z, Zhang M, Chen C, Baldan T, Bayaer T, Meng H (- 57) Ref: Nat Commun, 3:1202, 2012 : PubMed ESTHER: Jirimutu_2012_Nat.Commun_3_1202 PubMedSearch: Jirimutu 2012 Nat.Commun 3 1202 PubMedID: 23149746 Gene_locus related to this paper: 9ceta-s9yik4, 9ceta-s9yb99, 9ceta-s9x0n3, 9ceta-s9xqa3, 9ceta-s9xi02, camfr-s9wiw9, camfr-s9x3r3, camfr-s9xce1, camfr-s9xcr2, camfr-s9yuz0, camfr-s9xlc8, camfr-s9w5f6, camfr-s9xmm4 Abstract Bactrian camels serve as an important means of transportation in the cold desert regions of China and Mongolia. Here we present a 2.01 Gb draft genome sequence from both a wild and a domestic bactrian camel. We estimate the camel genome to be 2.38 Gb, containing 20,821 protein-coding genes. Our phylogenomics analysis reveals that camels shared common ancestors with other even-toed ungulates about 55-60 million years ago. Rapidly evolving genes in the camel lineage are significantly enriched in metabolic pathways, and these changes may underlie the insulin resistance typically observed in these animals. We estimate the genome-wide heterozygosity rates in both wild and domestic camels to be 1.0 x 10(-3). However, genomic regions with significantly lower heterozygosity are found in the domestic camel, and olfactory receptors are enriched in these regions. Our comparative genomics analyses may also shed light on the genetic basis of the camel's remarkable salt tolerance and unusual immune system. Title: alpha-Synuclein oligomers oppose long-term potentiation and impair memory through a calcineurin-dependent mechanism: relevance to human synucleopathic diseases Martin ZS, Neugebauer V, Dineley KT, Kayed R, Zhang W, Reese LC, Taglialatela G Ref: Journal of Neurochemistry, 120:440, 2012 : PubMed ESTHER: Martin_2012_J.Neurochem_120_440 PubMedSearch: Martin 2012 J.Neurochem 120 440 PubMedID: 22060133 Abstract Intracellular deposition of fibrillar aggregates of alpha-synuclein (alphaSyn) characterizes neurodegenerative diseases such as Parkinson's disease (PD) and dementia with Lewy bodies. However, recent evidence indicates that small alphaSyn oligomeric aggregates that precede fibril formation may be the most neurotoxic species and can be found extracellularly. This new evidence has changed the view of pathological alphaSyn aggregation from a self-contained cellular phenomenon to an extracellular event and prompted investigation of the putative effects of extracellular alphaSyn oligomers. In this study, we report that extracellular application of alphaSyn oligomers detrimentally impacts neuronal welfare and memory function. We found that oligomeric alphaSyn increased intracellular Ca(2+) levels, induced calcineurin (CaN) activity, decreased cAMP response element-binding protein (CREB) transcriptional activity and resulted in calcineurin-dependent death of human neuroblastoma cells. Similarly, CaN induction and CREB inhibition were observed when alphaSyn oligomers were applied to organotypic brain slices, which opposed hippocampal long-term potentiation. Furthermore, alphaSyn oligomers induced CaN, inhibited CREB and evoked memory impairments in mice that received acute intracerebroventricular injections. Notably, all these events were reversed by pharmacological inhibition of CaN. Moreover, we found decreased active CaN and reduced levels of phosphorylated CREB in autopsy brain tissue from patients affected by dementia with Lewy bodies, which is characterized by deposition of alphaSyn aggregates and progressive cognitive decline. These results indicate that exogenously applied alphaSyn oligomers impact neuronal function and produce memory deficits through mechanisms that involve CaN activation. Title: Three-dimensional ordered macroporous (3DOM) composite for electrochemical study on acetylcholinesterase inhibition induced by endogenous neurotoxin Teng Y, Fu Y, Xu L, Lin B, Wang Z, Xu Z, Jin L, Zhang W Ref: J Phys Chem B, 116:11180, 2012 : PubMed ESTHER: Teng_2012_J.Phys.Chem.B_116_11180 PubMedSearch: Teng 2012 J.Phys.Chem.B 116 11180 PubMedID: 22946763 Abstract In this paper, an electrochemical acetylcholinesterase (AChE) inhibition assay based on three-dimensional ordered macroporous (3DOM) composite was conducted. The 3DOM composite was first fabricated on the glassy carbon electrode by electropolymerization of aniline in the presence of ionic liquid (IL) on a sacrificial silica nanospheres template. After the silica nanospheres were etched, an IL-doped polyaniline (IL-PANI) film with 3DOM morphology was formed. Then, gold nanoparticles (AuNPs) were decorated on the IL-PANI film by electrodeposition. The immobilized AChE on the 3DOM composite displayed favorable affinity to substrate acetylthiocholine chloride (ATCh), and the 3DOM composite showed excellent electrocatalytic effect on thiocholine, the hydrolysis product of ATCh. The presence of IL and AuNPs could improve the sensitivity by accelerating the electron transfer. The designed AChE biosensor was successfully applied to evaluate the AChE inhibition induced by endogenous neurotoxin 1(R),2N-dimethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline [(R)-NMSal]. The results demonstrate that (R)-NMSal exerts a considerable effect on AChE activity, and the inhibition is reversible. The developed method offers a new approach for AChE inhibition assay, which is of great benefit in understanding the mechanism behind neurotoxin-induced neurodegenerative disorders. Title: Genome sequence and transcriptome analysis of the radioresistant bacterium Deinococcus gobiensis: insights into the extreme environmental adaptations Yuan M, Chen M, Zhang W, Lu W, Wang J, Yang M, Zhao P, Tang R, Li X and Lin M <8 more author(s)> Yuan M, Chen M, Zhang W, Lu W, Wang J, Yang M, Zhao P, Tang R, Li X, Hao Y, Zhou Z, Zhan Y, Yu H, Teng C, Yan Y, Ping S, Wang Y, Lin M (- 8) Ref: PLoS ONE, 7:e34458, 2012 : PubMed ESTHER: Yuan_2012_PLoS.ONE_7_E34458 PubMedSearch: Yuan 2012 PLoS.ONE 7 E34458 PubMedID: 22470573 Gene_locus related to this paper: deigi-h8gtt4, deigi-h8h0j9 Abstract The desert is an excellent model for studying evolution under extreme environments. We present here the complete genome and ultraviolet (UV) radiation-induced transcriptome of Deinococcus gobiensis I-0, which was isolated from the cold Gobi desert and shows higher tolerance to gamma radiation and UV light than all other known microorganisms. Nearly half of the genes in the genome encode proteins of unknown function, suggesting that the extreme resistance phenotype may be attributed to unknown genes and pathways. D. gobiensis also contains a surprisingly large number of horizontally acquired genes and predicted mobile elements of different classes, which is indicative of adaptation to extreme environments through genomic plasticity. High-resolution RNA-Seq transcriptome analyses indicated that 30 regulatory proteins, including several well-known regulators and uncharacterized protein kinases, and 13 noncoding RNAs were induced immediately after UV irradiation. Particularly interesting is the UV irradiation induction of the phrB and recB genes involved in photoreactivation and recombinational repair, respectively. These proteins likely include key players in the immediate global transcriptional response to UV irradiation. Our results help to explain the exceptional ability of D. gobiensis to withstand environmental extremes of the Gobi desert, and highlight the metabolic features of this organism that have biotechnological potential. Title: Soluble epoxide hydrolase gene deficiency or inhibition attenuates chronic active inflammatory bowel disease in IL-10(-/-) mice Zhang W, Yang AL, Liao J, Li H, Dong H, Chung YT, Bai H, Matkowskyj KA, Hammock BD, Yang GY Ref: Digestive Diseases & Sciences, 57:2580, 2012 : PubMed ESTHER: Zhang_2012_Dig.Dis.Sci_57_2580 PubMedSearch: Zhang 2012 Dig.Dis.Sci 57 2580 PubMedID: 22588244 Abstract BACKGROUND: Soluble epoxide hydrolase (sEH) metabolizes anti-inflammatory epoxyeicosatrienoic acids (EETs) into their much less active dihydroxy derivatives dihydroxyeicosatrienoic acids. Thus, targeting sEH would be important for inflammation. AIMS: To determine whether knockout or inhibition of sEH would attenuate the development of inflammatory bowel disease (IBD) in a mouse model of IBD in IL-10(-/-) mice. Title: Lysophosphatidylcholine is generated by spontaneous deacylation of oxidized phospholipids Choi J, Zhang W, Gu X, Chen X, Hong L, Laird JM, Salomon RG Ref: Chemical Research in Toxicology, 24:111, 2011 : PubMed ESTHER: Choi_2011_Chem.Res.Toxicol_24_111 PubMedSearch: Choi 2011 Chem.Res.Toxicol 24 111 PubMedID: 20973507 Abstract Elevated levels of lysophosphatidylcholine (lysoPC), present in oxidatively damaged low-density lipoprotein (oxLDL), are implicated in cardiovascular complications. LysoPC is generated by free radical-catalyzed oxidation of polyunsaturated PCs to oxidatively truncated phosphophatidylcholines (oxPCs). It is known that oxPCs are especially susceptible to hydrolysis by platelet-activating factor acetylhydrolase, a phospholipase (PL) A(2) that exists in plasma largely in association with LDL. Drugs that aim to prevent the generation of lysoPC by inhibiting this PLA(2)-catalyzed hydrolysis are in advanced clinical trials. We now report that spontaneous deacylation oxPCs, such as 1-palmityl-2-(4-hydroxy-7-oxo-5-heptenoyl)-sn-glycero-3-phosphocholine, occurs readily under physiological conditions of temperature and pH (t(1/2) = 30 min at 37 degreesC and pH 7.4). We also show that this reaction proceeds through an intramolecular transesterification mechanism. Because antiphospholipase drugs cannot block this nonenzymatic pathway to lysoPC, additional therapeutic measures may be needed to avoid the pathological consequences of the newly discovered biomolecular chemistry of oxPCs. Title: Oxidative desorption of thiocholine assembled on core-shell Fe3O4/AuNPs magnetic nanocomposites for highly sensitive determination of acetylcholinesterase activity: an exposure biomarker of organophosphates Du D, Tao Y, Zhang W, Liu D, Li H Ref: Biosensors & Bioelectronics, 26:4231, 2011 : PubMed ESTHER: Du_2011_Biosens.Bioelectron_26_4231 PubMedSearch: Du 2011 Biosens.Bioelectron 26 4231 PubMedID: 21514816 Abstract Acetylcholinesterase (AChE) activity is a well established biomarker for biomonitoring of exposures to organophosphates (OPs) pesticides and chemical nerve agents. In this work, we described a novel electrochemical oxidative desorption-process of thiocholine, the product of enzymatic reaction, for rapid and highly sensitive determination of AChE activity in human serum. This principle is based on self-assembling of produced thiocholine onto core-shell Fe(3)O(4)/Au nanoparticles (Fe(3)O(4)/AuNPs) magnetic nanocomposites and its oxidation at electrode surface. Fe(3)O(4) magnetic core is not only used for magnetic separation from sample solutions, but also carrying more AuNPs due to its large surface-to-volume ratio. The core-shell Fe(3)O(4)/AuNPs nanocomposites were characterized by UV-Vis spectroscopy, field-emission scanning electron microscopy (FE-SEM) and electrochemical measurements. A linear relationship was obtained between the AChE activity and its concentration from 0.05 to 5.0 mU mL(-1) with a detection limit of 0.02 mU mL(-1). The method showed good results for characterization of AChE spiked human serum and detection of OP exposures from 0.05 to 20 nM, with detection limit of 0.02 nM. This new oxidative desorption assay thus provides a sensitive and quantitative tool for biomonitoring of the exposure to OP pesticides and nerve agents. Title: Complete genome sequence of Bacillus amyloliquefaciens LL3, which exhibits glutamic acid-independent production of poly-gamma-glutamic acid Geng W, Cao M, Song C, Xie H, Liu L, Yang C, Feng J, Zhang W, Jin Y and Wang S <1 more author(s)> Geng W, Cao M, Song C, Xie H, Liu L, Yang C, Feng J, Zhang W, Jin Y, Du Y, Wang S (- 1) Ref: Journal of Bacteriology, 193:3393, 2011 : PubMed ESTHER: Geng_2011_J.Bacteriol_193_3393 PubMedSearch: Geng 2011 J.Bacteriol 193 3393 PubMedID: 21551302 Gene_locus related to this paper: baca2-a7z811 Abstract Bacillus amyloliquefaciens is one of most prevalent Gram-positive aerobic spore-forming bacteria with the ability to synthesize polysaccharides and polypeptides. Here, we report the complete genome sequence of B. amyloliquefaciens LL3, which was isolated from fermented food and presents the glutamic acid-independent production of poly-gamma-glutamic acid. Title: Comparative genomic and transcriptomic analysis revealed genetic characteristics related to solvent formation and xylose utilization in Clostridium acetobutylicum EA 2018 Hu S, Zheng H, Gu Y, Zhao J, Zhang W, Yang Y, Wang S, Zhao G, Yang S, Jiang W Ref: BMC Genomics, 12:93, 2011 : PubMed ESTHER: Hu_2011_BMC.Genomics_12_93 PubMedSearch: Hu 2011 BMC.Genomics 12 93 PubMedID: 21284892 Gene_locus related to this paper: cloab-CAC2917, cloab-q97db4, cloac-CAC0719, cloac-CAC1022, cloac-CAC1962, cloac-CAC2246, cloac-CAC3407, cloac-CAP0071, cloac-pnbae Abstract BACKGROUND: Clostridium acetobutylicum, a gram-positive and spore-forming anaerobe, is a major strain for the fermentative production of acetone, butanol and ethanol. But a previously isolated hyper-butanol producing strain C. acetobutylicum EA 2018 does not produce spores and has greater capability of solvent production, especially for butanol, than the type strain C. acetobutylicum ATCC 824. Title: Prospective genomic characterization of the German enterohemorrhagic Escherichia coli O104:H4 outbreak by rapid next generation sequencing technology Mellmann A, Harmsen D, Cummings CA, Zentz EB, Leopold SR, Rico A, Prior K, Szczepanowski R, Ji Y and Karch H <10 more author(s)> Mellmann A, Harmsen D, Cummings CA, Zentz EB, Leopold SR, Rico A, Prior K, Szczepanowski R, Ji Y, Zhang W, McLaughlin SF, Henkhaus JK, Leopold B, Bielaszewska M, Prager R, Brzoska PM, Moore RL, Guenther S, Rothberg JM, Karch H (- 10) Ref: PLoS ONE, 6:e22751, 2011 : PubMed ESTHER: Mellmann_2011_PLoS.ONE_6_E22751 PubMedSearch: Mellmann 2011 PLoS.ONE 6 E22751 PubMedID: 21799941 Gene_locus related to this paper: ecoli-ycfp, ecoli-YFBB, ecoli-yqia, ecoli-YfhR Abstract An ongoing outbreak of exceptionally virulent Shiga toxin (Stx)-producing Escherichia coli O104:H4 centered in Germany, has caused over 830 cases of hemolytic uremic syndrome (HUS) and 46 deaths since May 2011. Serotype O104:H4, which has not been detected in animals, has rarely been associated with HUS in the past. To prospectively elucidate the unique characteristics of this strain in the early stages of this outbreak, we applied whole genome sequencing on the Life Technologies Ion Torrent PGM sequencer and Optical Mapping to characterize one outbreak isolate (LB226692) and a historic O104:H4 HUS isolate from 2001 (01-09591). Reference guided draft assemblies of both strains were completed with the newly introduced PGM within 62 hours. The HUS-associated strains both carried genes typically found in two types of pathogenic E. coli, enteroaggregative E. coli (EAEC) and enterohemorrhagic E. coli (EHEC). Phylogenetic analyses of 1,144 core E. coli genes indicate that the HUS-causing O104:H4 strains and the previously published sequence of the EAEC strain 55989 show a close relationship but are only distantly related to common EHEC serotypes. Though closely related, the outbreak strain differs from the 2001 strain in plasmid content and fimbrial genes. We propose a model in which EAEC 55989 and EHEC O104:H4 strains evolved from a common EHEC O104:H4 progenitor, and suggest that by stepwise gain and loss of chromosomal and plasmid-encoded virulence factors, a highly pathogenic hybrid of EAEC and EHEC emerged as the current outbreak clone. In conclusion, rapid next-generation technologies facilitated prospective whole genome characterization in the early stages of an outbreak. Title: Increased fat mass and insulin resistance in mice lacking pancreatic lipase-related protein 1 Ren J, Chen Z, Zhang W, Li L, Sun R, Deng C, Fei Z, Sheng Z, Wang L and Fei J <2 more author(s)> Ren J, Chen Z, Zhang W, Li L, Sun R, Deng C, Fei Z, Sheng Z, Wang L, Sun X, Wang Z, Fei J (- 2) Ref: J Nutr Biochem, 22:691, 2011 : PubMed ESTHER: Ren_2011_J.Nutr.Biochem_22_691 PubMedSearch: Ren 2011 J.Nutr.Biochem 22 691 PubMedID: 21115337 Gene_locus related to this paper: human-PNLIPRP1, mouse-1plrp Abstract Pancreatic triglyceride lipase (PTL) and its cofactor, colipase, are required for efficient dietary triglyceride digestion. In addition to PTL, pancreatic acinar cells synthesize two pancreatic lipase-related proteins (PLRP1 and PLRP2), which have a high degree of sequence and structural homology with PTL. The lipase activity of PLRP2 has been confirmed, whereas no known triglyceride lipase activity has been detected with PLRP1 up to now. To explore the biological functions of PLRP1 in vivo, we generated Plrp1 knockout (KO) mice in our laboratory. Here we show that the Plrp1 KO mice displayed mature-onset obesity with increased fat mass, impaired glucose clearance and the resultant insulin resistance. When fed on high-fat (HF) diet, the Plrp1 KO mice exhibited an increased weight gain, fat mass and severe insulin resistance compared with wild-type mice. Pancreatic juice extracted from Plrp1 KO mice had greater ability to hydrolyze triglyceride than that from the wild-type littermates. We propose that PLRP1 may function as a metabolic inhibitor in vivo of PLT-colipase-mediated dietary triglyceride digestion and provides potential anti-obesity targets for developing new drugs. Title: Complete genome sequence of the nitrogen-fixing and rhizosphere-associated bacterium Pseudomonas stutzeri strain DSM4166 Yu H, Yuan M, Lu W, Yang J, Dai S, Li Q, Yang Z, Dong J, Sun L and Lin M <8 more author(s)> Yu H, Yuan M, Lu W, Yang J, Dai S, Li Q, Yang Z, Dong J, Sun L, Deng Z, Zhang W, Chen M, Ping S, Han Y, Zhan Y, Yan Y, Jin Q, Lin M (- 8) Ref: Journal of Bacteriology, 193:3422, 2011 : PubMed ESTHER: Yu_2011_J.Bacteriol_193_3422 PubMedSearch: Yu 2011 J.Bacteriol 193 3422 PubMedID: 21515765 Gene_locus related to this paper: pseu5-a4vfn0, pseu5-a4vj02, pseu5-a4vrl9, pseut-f8h720, pseu5-a4vkl7, pseu5-a4vgd4, pseu5-a4vr33 Abstract We present here the analysis of the whole-genome sequence of Pseudomonas stutzeri strain DSM4166, a diazotrophic isolate from the rhizosphere of a Sorghum nutans cultivar. To our knowledge, this is the second genome to be sequenced for P. stutzeri. The availability and analysis of the genome provide insight into the evolution of the nitrogen fixation property and identification of rhizosphere competence traits required in interactions with host plants. Title: Genome sequence of Acinetobacter calcoaceticus PHEA-2, isolated from industry wastewater Zhan Y, Yan Y, Zhang W, Yu H, Chen M, Lu W, Ping S, Peng Z, Yuan M and Lin M <2 more author(s)> Zhan Y, Yan Y, Zhang W, Yu H, Chen M, Lu W, Ping S, Peng Z, Yuan M, Zhou Z, Elmerich C, Lin M (- 2) Ref: Journal of Bacteriology, 193:2672, 2011 : PubMed ESTHER: Zhan_2011_J.Bacteriol_193_2672 PubMedSearch: Zhan 2011 J.Bacteriol 193 2672 PubMedID: 21441526 Gene_locus related to this paper: aciad-q6fc40, aciba-d0c992, aciba-q76hj1, acibt-a3m5r6, acibt-a3m5t3, acibt-a3m5x2, acica-d0ryi9, acica-d0ryx6, acicp-f0kgu1, acicp-f0kh68, acicp-f0khy0, acicp-f0kj61, aciba-w3svn7, aciba-a0a009wzt4 Abstract Genome analysis of Acinetobacter calcoaceticus PHEA-2 was undertaken because of the importance of this bacterium for bioremediation of phenol-polluted water and because of the close phylogenetic relationship of this species with the human pathogen Acinetobacter baumannii. To our knowledge, this is the first strain of A. calcoaceticus whose genome has been sequenced. Title: Agrin binds to the N-terminal region of Lrp4 protein and stimulates association between Lrp4 and the first immunoglobulin-like domain in muscle-specific kinase (MuSK) Zhang W, Coldefy AS, Hubbard SR, Burden SJ Ref: Journal of Biological Chemistry, 286:40624, 2011 : PubMed ESTHER: Zhang_2011_J.Biol.Chem_286_40624 PubMedSearch: Zhang 2011 J.Biol.Chem 286 40624 PubMedID: 21969364 Abstract Neuromuscular synapse formation depends upon coordinated interactions between motor neurons and muscle fibers, leading to the formation of a highly specialized postsynaptic membrane and a highly differentiated nerve terminal. Synapse formation begins as motor axons approach muscles that are prepatterned in the prospective synaptic region in a manner that depends upon Lrp4, a member of the LDL receptor family, and muscle-specific kinase (MuSK), a receptor tyrosine kinase. Motor axons supply Agrin, which binds Lrp4 and stimulates further MuSK phosphorylation, stabilizing nascent synapses. How Agrin binds Lrp4 and stimulates MuSK kinase activity is poorly understood. Here, we demonstrate that Agrin binds to the N-terminal region of Lrp4, including a subset of the LDLa repeats and the first of four beta-propeller domains, which promotes association between Lrp4 and MuSK and stimulates MuSK kinase activity. In addition, we show that Agrin stimulates the formation of a functional complex between Lrp4 and MuSK on the surface of myotubes in the absence of the transmembrane and intracellular domains of Lrp4. Further, we demonstrate that the first Ig-like domain in MuSK, which shares homology with the NGF-binding region in Tropomyosin Receptor Kinase (TrKA), is required for MuSK to bind Lrp4. These findings suggest that Lrp4 is a cis-acting ligand for MuSK, whereas Agrin functions as an allosteric and paracrine regulator to promote association between Lrp4 and MuSK. Title: Crystal structure of FAS thioesterase domain with polyunsaturated fatty acyl adduct and inhibition by dihomo-gamma-linolenic acid Zhang W, Chakravarty B, Zheng F, Gu Z, Wu H, Mao J, Wakil SJ, Quiocho FA Ref: Proc Natl Acad Sci U S A, 108:15757, 2011 : PubMed ESTHER: Zhang_2011_Proc.Natl.Acad.Sci.U.S.A_108_15757 PubMedSearch: Zhang 2011 Proc.Natl.Acad.Sci.U.S.A 108 15757 PubMedID: 21908709 Gene_locus related to this paper: human-FASN Inhibitor(s) related to this paper: Dihomo-gamma-linolenic-acid, Methyl-gamma-linolenyl-fluorophosphonate Abstract Human fatty acid synthase (hFAS) is a homodimeric multidomain enzyme that catalyzes a series of reactions leading to the de novo biosynthesis of long-chain fatty acids, mainly palmitate. The carboxy-terminal thioesterase (TE) domain determines the length of the fatty acyl chain and its ultimate release by hydrolysis. Because of the upregulation of hFAS in a variety of cancers, it is a target for antiproliferative agent development. Dietary long-chain polyunsaturated fatty acids (PUFAs) have been known to confer beneficial effects on many diseases and health conditions, including cancers, inflammations, diabetes, and heart diseases, but the precise molecular mechanisms involved have not been elucidated. We report the 1.48 A crystal structure of the hFAS TE domain covalently modified and inactivated by methyl gamma-linolenylfluorophosphonate. Whereas the structure confirmed the phosphorylation by the phosphonate head group of the active site serine, it also unexpectedly revealed the binding of the 18-carbon polyunsaturated gamma-linolenyl tail in a long groove-tunnel site, which itself is formed mainly by the emergence of an alpha helix (the "helix flap"). We then found inhibition of the TE domain activity by the PUFA dihomo-gamma-linolenic acid; gamma- and alpha-linolenic acids, two popular dietary PUFAs, were less effective. Dihomo-gamma-linolenic acid also inhibited fatty acid biosynthesis in 3T3-L1 preadipocytes and selective human breast cancer cell lines, including SKBR3 and MDAMB231. In addition to revealing a novel mechanism for the molecular recognition of a polyunsaturated fatty acyl chain, our results offer a new framework for developing potent FAS inhibitors as therapeutics against cancers and other diseases. Title: Novel water-soluble red-emitting poly(p-phenylenevinylene) derivative: synthesis, characterization, and fluorescent acetylcholinesterase assays Zhang W, Zhu L, Qin J, Yang C Ref: J Phys Chem B, 115:12059, 2011 : PubMed ESTHER: Zhang_2011_J.Phys.Chem.B_115_12059 PubMedSearch: Zhang 2011 J.Phys.Chem.B 115 12059 PubMedID: 21916483 Abstract A new cyano-substituted poly(p-phenylenevinylene) (PPV) derivative, MEOPS-CNPPV, is synthesized through Knoevenagel condensation of anionic diacetonitrile and neutral dialdehyde and characterized by (1)H NMR, IR, elemental analysis, and gel-permeation chromatography (GPC). To our knowledge, the polymer is the first water-soluble red-emitting PPV derivative. The absorption and emission wavelength of this water-soluble conjugated polymer (CP) depend on the solvent. In buffer solution, the fluorescence of MEOPS-CNPPV is quenched by cationic dinitrobenzene derivatives. Further research indicates that dinitrobenzene derivative with a more flexible structure exhibits a larger K(sv). Making use of the charge reversal of dinitrobenzene-modified substrate, a "turn-on" method is developed for AChE activity assay with the new polymer as a fluorophore. This convenient and direct fluorometric assay thus provides a platform for novel red-emitting sensory systems. Title: A novel cold-adapted lipase from Acinetobacter sp. XMZ-26: gene cloning and characterisation Zheng X, Chu X, Zhang W, Wu N, Fan Y Ref: Applied Microbiology & Biotechnology, 90:971, 2011 : PubMed ESTHER: Zheng_2011_Appl.Microbiol.Biotechnol_90_971 PubMedSearch: Zheng 2011 Appl.Microbiol.Biotechnol 90 971 PubMedID: 21336927 Abstract Acinetobacter sp. XMZ-26 (ACCC 05422) was isolated from soil samples obtained from glaciers in Xinjiang Province, China. The partial nucleotide sequence of a lipase gene was obtained by touchdown PCR using degenerate primers designed based on the conserved domains of cold-adapted lipases. Subsequently, a complete gene sequence encoding a 317 amino acid polypeptide was identified. Our novel lipase gene, lipA, was overexpressed in Escherichia coli. The recombinant protein (LipA) was purified by Ni-affinity chromatography, and then deeply characterised. The LipA resulted to hydrolyse pNP esters of fatty acids with acyl chain length from C2 to C16, and the preferred substrate was pNP octanoate showing a k(cat) = 560.52 +/- 28.32 s(-1), K(m) = 0.075 +/6 0.008 mM, and a k(cat)/K(m) = 7,377.29 +/- 118.88 s(-1) mM(-1). Maximal LipA activity was observed at a temperature of 15 C and pH 10.0 using pNP decanoate as substrate. That LipA peaked at such a low temperature and remained most activity between 5 C and 35 C indicated that it was a cold-adapted enzyme. Remarkably, this lipase retained much of its activity in the presence of commercial detergents and organic solvents, including Ninol, Triton X-100, methanol, PEG-600, and DMSO. This cold-adapted lipase may find applications in the detergent industry and organic synthesis. Title: Amyloid-beta oligomers impair fear conditioned memory in a calcineurin-dependent fashion in mice Dineley KT, Kayed R, Neugebauer V, Fu Y, Zhang W, Reese LC, Taglialatela G Ref: Journal of Neuroscience Research, 88:2923, 2010 : PubMed ESTHER: Dineley_2010_J.Neurosci.Res_88_2923 PubMedSearch: Dineley 2010 J.Neurosci.Res 88 2923 PubMedID: 20544830 Abstract Soluble oligomeric aggregates of the amyloid-beta (A beta) peptide are believed to be the most neurotoxic A beta species affecting the brain in Alzheimer disease (AD), a terminal neurodegenerative disorder involving severe cognitive decline underscored by initial synaptic dysfunction and later extensive neuronal death in the CNS. Recent evidence indicates that A beta oligomers are recruited at the synapse, oppose expression of long-term potentiation (LTP), perturb intracellular calcium balance, disrupt dendritic spines, and induce memory deficits. However, the molecular mechanisms behind these outcomes are only partially understood; achieving such insight is necessary for the comprehension of A beta-mediated neuronal dysfunction. We have investigated the role of the phosphatase calcineurin (CaN) in these pathological processes of AD. CaN is especially abundant in the CNS, where it is involved in synaptic activity, LTP, and memory function. Here, we describe how oligomeric A beta treatment causes memory deficits and depresses LTP expression in a CaN-dependent fashion. Mice given a single intracerebroventricular injection of A beta oligomers exhibited increased CaN activity and decreased pCREB, a transcription factor involved in proper synaptic function, accompanied by decreased memory in a fear conditioning task. These effects were reversed by treatment with the CaN inhibitor FK506. We further found that expression of hippocampal LTP in acutely cultured rodent brain slices was opposed by A beta oligomers and that this effect was also reversed by FK506. Collectively, these results indicate that CaN activation may play a central role in mediating synaptic and memory disruption induced by acute oligomeric A beta treatment in mice. Title: Covalent coupling of organophosphorus hydrolase loaded quantum dots to carbon nanotube/Au nanocomposite for enhanced detection of methyl parathion Du D, Chen W, Zhang W, Liu D, Li H, Lin Y Ref: Biosensors & Bioelectronics, 25:1370, 2010 : PubMed ESTHER: Du_2010_Biosens.Bioelectron_25_1370 PubMedSearch: Du 2010 Biosens.Bioelectron 25 1370 PubMedID: 19926466 Abstract An amperometric biosensor for highly selective and sensitive determination of methyl parathion (MP) was developed based on dual-signal amplification: (1) a large amount of introduced enzyme on the electrode surface and (2) synergistic effects of nanoparticles towards enzymatic catalysis. The fabrication process includes (1) electrochemical deposition of gold nanoparticles by a multi-potential step technique at multiwalled carbon nanotube (MWCNT) film pre-cast on a glassy carbon electrode and (2) immobilization of methyl parathion degrading enzyme (MPDE) onto a modified electrode through CdTe quantum dots (CdTe QDs) covalent attachment. The introduced MWCNT and gold nanoparticles significantly increased the surface area and exhibited synergistic effects towards enzymatic catalysis. CdTe QDs are further used as carriers to load a large amount of enzyme. As a result of these two important enhancement factors, the proposed biosensor exhibited extremely sensitive, perfectly selective, and rapid response to methyl parathion in the absence of a mediator. The detection limit was 1.0 ng/mL. Moreover, since MPDE hydrolyzes pesticides containing the P-S bond, it showed high selectivity for detecting MP and many interfering compounds, such as carbamate pesticides. Other organophosphorous pesticides and oxygen-containing inorganic ions (SO(4)(2-), NO(3)(-)) did not interfere with the determination. The proposed MPDE biosensor presents good reproducibility and stability, and the MPDE is not poisoned by organophosphate pesticides. Unlike cholinesterase-based biosensor, the MPDE biosensor can be potentially reused and is suitable for continuous monitoring. Title: Complete genome sequence of Lactobacillus casei Zhang, a new probiotic strain isolated from traditional homemade koumiss in Inner Mongolia, China Zhang W, Yu D, Sun Z, Wu R, Chen X, Chen W, Meng H, Hu S, Zhang H Ref: Journal of Bacteriology, 192:5268, 2010 : PubMed ESTHER: Zhang_2010_J.Bacteriol_192_5268 PubMedSearch: Zhang 2010 J.Bacteriol 192 5268 PubMedID: 20675486 Gene_locus related to this paper: lacc3-q03b36, lacc3-q035l1, laccb-b3wcx2, lacrh-pepr, lacca-b5qt93, lacca-k0n1x0, lacpa-s2ter8, lacpa-s2rz88 Abstract Lactobacillus casei Zhang is a new probiotic bacterium isolated from koumiss collected in Inner Mongolia, China. Here, we report the main genome features of L. casei Zhang and the identification of several predicted proteins implicated in interactions with the host. Title: Facile synthesis of three bidesmosidic oleanolic acid saponins with strong inhibitory activity on pancreatic lipase Guo T, Liu Q, Wang P, Zhang L, Zhang W, Li Y Ref: Carbohydr Res, 344:1167, 2009 : PubMed ESTHER: Guo_2009_Carbohydr.Res_344_1167 PubMedSearch: Guo 2009 Carbohydr.Res 344 1167 PubMedID: 19463989 Inhibitor(s) related to this paper: Oleanolic-acid Abstract The first synthesis of scabiosaponins E (1), F (2), and G (3), three new oleanolic acid saponins with strong inhibitory activity on pancreatic lipase isolated from the Chinese traditional medicinal herb Scabiosa tschiliensis, was efficiently achieved in an one-pot strategy under the combined use of glycosyl trichloroacetimidates and p-toluene 1-thioglycosides (STol) as donors. Title: Porcine Liver Carboxylesterase Requires Polyisoprenylation for High Affinity Binding to Cysteinyl Substrates Lamango NS, Duverna R, Zhang W, Ablordeppey SY Ref: Open Enzym Inhib J, 2:12, 2009 : PubMed ESTHER: Lamango_2009_Open.Enzym.Inhib.J_2_12 PubMedSearch: Lamango 2009 Open.Enzym.Inhib.J 2 12 PubMedID: 20664805 Gene_locus related to this paper: pig-EST1 Abstract The polyisoprenylation pathway enzymes have been the focus of numerous studies to better understand the roles of polyisoprenylated proteins in eukaryotic cells and to identify novel targets against diseases such as cancer. The final step of the pathway is a reversible reaction catalyzed by isoprenyl carboxylmethyl transferase (icmt) whose products are then hydrolyzed by polyisoprenylated methylated protein methyl esterase (PMPMEase). Unlike the other pathway enzymes, the esterase has received little attention. We recently purified PMPMEase from porcine liver using an S-polyisoprenylated cysteine methyl ester substrate-dependent screening assay. However, no data is available showing its relative interaction with structurally diverse substrates. As such, its role as the putative endogenous PMPMEase has not been demonstrated. A series of substrates with S-alkyl substituents ranging from 2 to 20 carbons, including the two moieties found in polyisoprenylated proteins, were synthesized. Enzyme kinetics analysis revealed a 33-fold increase in affinity (K(M) values) from ethyl- (C-2, 505+/-63 microM), prenyl- (C-5, 294+/-25 microM), trans-geranyl- (C-10, 87+/-12 microM), trans, trans-farnesyl- (C-15, 29+/-2.2 microM) to all trans-geranylgeranyl- (C-20-, 15+/-2.7 microM) based analogs. Comparative molecular field analysis of the data yielded a cross-validated q(2) of 0.863+/-0.365 and a final R(2) of 0.995. Since the substrates with the S-trans, trans-farnesyl and S-all trans-geranylgeranyl moieties that occur in proteins show the highest affinity towards PMPMEase and are not hydrolyzed by the cholinesterases, the results suggest that polyisoprenylated proteins are the endogenous substrates of this esterase. The results suggest design strategies for high affinity and selective inhibitors of PMPMEase. Title: Preparation and application of monoclonal antibody against hNDRG2 Liu X, Hu X, Zhang J, Wang L, Zhang W, Li F, Zhang Y, Yao L Ref: Appl Biochem Biotechnol, 152:306, 2009 : PubMed ESTHER: Liu_2009_Appl.Biochem.Biotechnol_152_306 PubMedSearch: Liu 2009 Appl.Biochem.Biotechnol 152 306 PubMedID: 18758694 Abstract The full-length hNdrg2 cDNA-coded 357 amino acids was cloned and expressed in Escherichia coli strain DH5alpha as a 6x His-tagged protein. The purified 6x His-fusion protein was used to immunize mice for preparing monoclonal antibodies (mAb) against N-myc downstream-regulated gene 2 (Ndrg2). A hybridoma secreting a monoclonal antibody against Ndrg2 was obtained and named FMU-Ndrg2.3. Western blot analysis confirmed that this mAb is specific only to Ndrg2 but not to Ndrg1, Ndrg3, and Ndrg4-B. Some tissue distribution features of Ndrg2 proteins, such as thyroid, kidney, testis, prostate, and pancreas islets, were present by immunohistochemistry. Title: Neuroligin 2 drives postsynaptic assembly at perisomatic inhibitory synapses through gephyrin and collybistin Poulopoulos A, Aramuni G, Meyer G, Soykan T, Hoon M, Papadopoulos T, Zhang M, Paarmann I, Fuchs C and Varoqueaux F <7 more author(s)> Poulopoulos A, Aramuni G, Meyer G, Soykan T, Hoon M, Papadopoulos T, Zhang M, Paarmann I, Fuchs C, Harvey K, Jedlicka P, Schwarzacher SW, Betz H, Harvey RJ, Brose N, Zhang W, Varoqueaux F (- 7) Ref: Neuron, 63:628, 2009 : PubMed ESTHER: Poulopoulos_2009_Neuron_63_628 PubMedSearch: Poulopoulos 2009 Neuron 63 628 PubMedID: 19755106 Abstract In the mammalian CNS, each neuron typically receives thousands of synaptic inputs from diverse classes of neurons. Synaptic transmission to the postsynaptic neuron relies on localized and transmitter-specific differentiation of the plasma membrane with postsynaptic receptor, scaffolding, and adhesion proteins accumulating in precise apposition to presynaptic sites of transmitter release. We identified protein interactions of the synaptic adhesion molecule neuroligin 2 that drive postsynaptic differentiation at inhibitory synapses. Neuroligin 2 binds the scaffolding protein gephyrin through a conserved cytoplasmic motif and functions as a specific activator of collybistin, thus guiding membrane tethering of the inhibitory postsynaptic scaffold. Complexes of neuroligin 2, gephyrin and collybistin are sufficient for cell-autonomous clustering of inhibitory neurotransmitter receptors. Deletion of neuroligin 2 in mice perturbs GABAergic and glycinergic synaptic transmission and leads to a loss of postsynaptic specializations specifically at perisomatic inhibitory synapses. Title: Effects of spinosad on Helicoverpa armigera (Lepidoptera: Noctuidae) from China: tolerance status, synergism and enzymatic responses Wang D, Qiu X, Ren X, Zhang W, Wang K Ref: Pest Manag Sci, 65:1040, 2009 : PubMed ESTHER: Wang_2009_Pest.Manag.Sci_65_1040 PubMedSearch: Wang 2009 Pest.Manag.Sci 65 1040 PubMedID: 19533589 Inhibitor(s) related to this paper: Diethyl-maleate Abstract BACKGROUND: Spinosad is increasingly used in pest management programmes, and resistance to it has been detected in recent years. However, there is no report on the susceptibilities of field populations of Helicoverpa armigera (Hbner) from China. Furthermore, the impact of spinosad on metabolic enzymes in this pest remains unknown. RESULTS: Four populations of H. armigera from different locations in China displayed less than 6.5-fold difference in LC(50) to spinosad, the highest being in the Xinjiang population, followed by Xiajin, Taian and Hubei populations, while there was no significant difference at LC(99) level among the four populations. The toxicity of spinosad could be synergised by piperonyl butoxide (PBO) and triphenylphosphate (TPP), but not by diethyl maleate (DEM). Spinosad exposure for 48 h significantly increased the activities of p-nitroanisole O-demethylase (ODM), while no significant changes in glutathione-S-transferase (GST) and carboxyl esterase (CarE) were observed. CONCLUSION: Field populations of H. armigera from China displayed marginally different susceptibilities to spinosad and had a relatively low LC(50). Cytochrome P450 monooxygenase might be involved in the metabolism of, and hence resistance to, spinosad in this pest in China. Title: Efficient lipase-selective synthesis of dilauryl mannoses by simultaneous reaction-extraction system Zhang W, Wang Y, Hayat K, Zhang X, Shabbar A, Feng B, Jia C Ref: Biotechnol Lett, 31:423, 2009 : PubMed ESTHER: Zhang_2009_Biotechnol.Lett_31_423 PubMedSearch: Zhang 2009 Biotechnol.Lett 31 423 PubMedID: 19039526 Abstract An efficient method for enzymatic-selective synthesis of dilauryl mannoses was developed using lipase-catalyzed condensation of D: -mannose and lauric acid in a simultaneous reaction-extraction system. The highest equilibrium conversion of diesters of 51% (1,6-diester: 14%; 3,6-diester: 18%; 4,6-diester: 19%) and the total conversion of mono and dilauryl mannoses of 76% were achieved at the n-hexane/acetonitrile ratio of 1:1, the molar ratio of lauric acid to mannose of 4:1, 60 g/l molecular sieves and 5 g/l lipase at 50 degrees C for 72 h in 15 ml SRE system. The new system will be important for the synthesis of dilauryl mannoses. Title: A new microdialysis-electrochemical device for in vivo simultaneous determination of acetylcholine and choline in rat brain treated with N-methyl-(R)-salsolinol Zhu W, An Y, Zheng J, Tang L, Zhang W, Jin L, Jiang L Ref: Biosensors & Bioelectronics, 24:3594, 2009 : PubMed ESTHER: Zhu_2009_Biosens.Bioelectron_24_3594 PubMedSearch: Zhu 2009 Biosens.Bioelectron 24 3594 PubMedID: 19523811 Abstract Acetylcholine (ACh) and choline (Ch) play a critical role in cholinergic neurotransmission and the abnormalities in their concentrations are related to several neural diseases. Therefore, the in vivo determination of ACh and Ch is important to the research on neurodegenerative disorders. In this work, electrochemical biosensors based on poly(m-(1,3)-phenylenediamine) (pmPD) and polytyramine (PTy) modified enzyme electrodes were fabricated. The electropolymerized pmPD polymer was used to exclude interfering substances and the PTy layer facilitated the immobilization of acetylcholinesterase (AChE) and choline oxidase (ChOx). Then, ACh/Ch sensor and Ch sensor were coupled with microdialysis to produce a novel device, which provides a sensitive and selective method for simultaneous determination of ACh and Ch. This method has detection limits of 63.0+/-3.4 nM for ACh and 25.0+/-1.2 nM for Ch. The integrated device was successfully applied to assessing the impact of endogenous neurotoxin N-methyl-(R)-salsolinol [1(R),2-dimethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, (R)-NMSal] on ACh and Ch concentration, which is of great benefit to understand the pathogenesis of Parkinson's disease. Title: Study on acetylcholinesterase inhibition induced by endogenous neurotoxin with an enzyme-semiconductor photoelectrochemical system Zhu W, An YR, Luo XM, Wang F, Zheng JH, Tang LL, Wang QJ, Zhang ZH, Zhang W, Jin LT Ref: Chem Commun (Camb), :2682, 2009 : PubMed ESTHER: Zhu_2009_Chem.Commun.(Camb)__2682 PubMedSearch: Zhu 2009 Chem.Commun.(Camb) 2682 PubMedID: 19532920 Abstract The integration of Au-doped TiO(2) nanotubes with biomolecule acetylcholinesterase (AChE) yields a novel AChE-Au-TiO(2) hybrid system, which provides a new rapid and valid photoelectrochemical approach to the determination of AChE inhibition induced by endogenous neurotoxin. Title: Expression of NDRG2 in clear cell renal cell carcinoma Ma J, Jin H, Wang H, Yuan J, Bao T, Jiang X, Zhang W, Zhao H, Yao L Ref: Biol Pharm Bull, 31:1316, 2008 : PubMed ESTHER: Ma_2008_Biol.Pharm.Bull_31_1316 PubMedSearch: Ma 2008 Biol.Pharm.Bull 31 1316 PubMedID: 18591767 Abstract Clear cell renal cell carcinoma (CCRCC) is the most common pathological type of renal cell carcinoma and the main cause of renal carcinoma mortality. NDRG2, a new member of the N-Myc downstream-regulated gene (NDRG) family, is a focus for study at present. Up to now, its expression and function in carcinoma remain unclear. The aim of this study was to investigate its expression in CCRCC tissues and several renal carcinoma cell lines. The expression of NDRG2 was evaluated in renal cell carcinoma cell lines, tumor and adjacent non-tumor tissues from same clear cell renal cell carcinoma patients, by using immunohistochemistry, immunofluorescence, RT-PCR and Western blot. By immunohistochemistry and immunofluorescence we found that NDRG2 was predominantly located in the cytoplasm and membrane of renal carcinoma cancer cells, and the positive rate of NDRG2 in renal carcinoma specimens was 30.3% (40/132), which is significantly lower than 91.67% (121/132) in normal renal tissues (p<0.01). The average staining score in normal renal tissues was significantly higher than renal carcinoma (6.12+/-1.84 versus 2.65+/-1.23, p<0.01). Moreover, NDRG2 mRNA and protein were down-regulated in 6 fresh CCRCC tissues compared with their adjacent noncancerous tissues and normal tissues. Its expression was also lower in the human CCRCC-derived cell lines A-498 and 786-O than in the human proximal tubular cell lines HK-2 and HKC. These results indicated that NDRG2 might play an important role in the carcinogenesis and development of CCRCC and may function as a tumor suppressor in CCRCC. Title: Selective induction of calcineurin activity and signaling by oligomeric amyloid beta Reese LC, Zhang W, Dineley KT, Kayed R, Taglialatela G Ref: Aging Cell, 7:824, 2008 : PubMed ESTHER: Reese_2008_Aging.Cell_7_824 PubMedSearch: Reese 2008 Aging.Cell 7 824 PubMedID: 18782350 Abstract Alzheimer's disease (AD) is a terminal age-associated dementia characterized by early synaptic dysfunction and late neurodegeneration. Although the presence of plaques of fibrillar aggregates of the amyloid beta peptide (Abeta) is a signature of AD, evidence suggests that the preplaque small oligomeric Abeta promotes both synaptic dysfunction and neuronal death. We found that young Tg2576 transgenic mice, which accumulate Abeta and develop cognitive impairments prior to plaque deposition, have high central nervous system (CNS) activity of calcineurin (CaN), a phosphatase involved in negative regulation of memory function via inactivation of the transcription factor cAMP responsive element binding proteins (CREB), and display CaN-dependent memory deficits. These results thus suggested the involvement of prefibrillary forms of Abeta. To investigate this issue, we compared the effect of monomeric, oligomeric, and fibrillar Abeta on CaN activity, CaN-dependent pCREB and phosphorylated Bcl-2 Associated death Protein (pBAD) levels, and cell death in SY5Y cells and in rat brain slices, and determined the role of CaN on CREB phosphorylation in the CNS of Tg2576 mice. Our results show that oligomeric Abeta specifically induces CaN activity and promotes CaN-dependent CREB and Bcl-2 Asociated death Protein (BAD) dephosphorylation and cell death. Furthermore, Tg2576 mice display Abeta oligomers and reduced pCREB in the CNS, which is normalized by CaN inhibition. These findings suggest a role for CaN in mediating effects of oligomeric Abeta on neural cells. Because elevated CaN levels have been reported in the CNS of cognitively impaired aged rodents, our results further suggest that abnormal CaN hyperactivity may be a common event exacerbating the cognitive and neurodegenerative impact of oligomeric Abeta in the aging CNS. Title: Bis-(-)-nor-meptazinols as novel nanomolar cholinesterase inhibitors with high inhibitory potency on amyloid-beta aggregation Xie Q, Wang H, Xia Z, Lu M, Zhang W, Wang X, Fu W, Tang Y, Sheng W and Chen H <4 more author(s)> Xie Q, Wang H, Xia Z, Lu M, Zhang W, Wang X, Fu W, Tang Y, Sheng W, Li W, Zhou W, Zhu X, Qiu Z, Chen H (- 4) Ref: Journal of Medicinal Chemistry, 51:2027, 2008 : PubMed ESTHER: Xie_2008_J.Med.Chem_51_2027 PubMedSearch: Xie 2008 J.Med.Chem 51 2027 PubMedID: 18333606 Inhibitor(s) related to this paper: bis9-(-)-nor-meptazinol Abstract Bis-(-)-nor-meptazinols (bis-(-)-nor-MEPs) 5 were designed and synthesized by connecting two (-)-nor-MEP monomers with alkylene linkers of different lengths via the secondary amino groups. Their acetylcholinesterase (AChE) inhibitory activities were more greatly influenced by the length of the alkylene chain than butyrylcholinesterase (BChE) inhibition. The most potent nonamethylene-tethered dimer 5h exhibited low-nanomolar IC 50 values for both ChEs, having a 10 000-fold and 1500-fold increase in inhibition of AChE and BChE compared with (-)-MEP. Molecular docking elucidated that 5h simultaneously bound to the catalytic and peripheral sites in AChE via hydrophobic interactions with Trp86 and Trp286. In comparison, it folded in the large aliphatic cavity of BChE because of the absence of peripheral site and the enlargement of the active site. Furthermore, 5h and 5i markedly prevented the AChE-induced Abeta aggregation with IC 50 values of 16.6 and 5.8 microM, similar to that of propidium (IC 50 = 12.8 microM), which suggests promising disease-modifying agents for the treatment of AD patients. Title: Soluble epoxide hydrolase gene deletion is protective against experimental cerebral ischemia Zhang W, Otsuka T, Sugo N, Ardeshiri A, Alhadid YK, Iliff JJ, DeBarber AE, Koop DR, Alkayed NJ Ref: Stroke, 39:2073, 2008 : PubMed ESTHER: Zhang_2008_Stroke_39_2073 PubMedSearch: Zhang 2008 Stroke 39 2073 PubMedID: 18369166 Abstract BACKGROUND AND PURPOSE: Cytochrome P450 epoxygenase metabolizes arachidonic acid to epoxyeicosatrienoic acids (EETs). EETs are produced in the brain and perform important biological functions, including vasodilation and neuroprotection. However, EETs are rapidly metabolized via soluble epoxide hydrolase (sEH) to dihydroxyeicosatrienoic acids (DHETs). We tested the hypothesis that sEH gene deletion is protective against focal cerebral ischemia through enhanced collateral blood flow. METHODS: sEH knockout (sEHKO) mice with and without EETs antagonist 14, 15 epoxyeicosa-5(Z)-enoic acid (EEZE) were subjected to 2-hour middle cerebral artery occlusion (MCAO), and infarct size was measured at 24 hours of reperfusion and compared to wild-type (WT) mice. Local CBF rates were measured at the end of MCAO using iodoantipyrine (IAP) autoradiography, sEH protein was analyzed by Western blot and immunohistochemistry, and hydrolase activity and levels of EETs/DHETs were measured in brain and plasma using LC-MS/MS and ELISA, respectively. RESULTS: sEH immunoreactivity was detected in WT, but not sEHKO mouse brain, and was localized to vascular and nonvascular cells. 14,15-DHET was abundantly present in WT, but virtually absent in sEHKO mouse plasma. However, hydrolase activity and free 14,15-EET in brain tissue were not different between WT and sEHKO mice. Infarct size was significantly smaller, whereas regional cerebral blood flow rates were significantly higher in sEHKO compared to WT mice. Infarct size reduction was recapitulated by 14,15-EET infusion. However, 14,15-EEZE did not alter infarct size in sEHKO mice. CONCLUSIONS: sEH gene deletion is protective against ischemic stroke by a vascular mechanism linked to reduced hydration of circulating EETs. Title: Human differentiation-related gene NDRG1 is a Myc downstream-regulated gene that is repressed by Myc on the core promoter region Zhang J, Chen S, Zhang W, Liu X, Shi H, Che H, Wang W, Li F, Yao L Ref: Gene, 417:5, 2008 : PubMed ESTHER: Zhang_2008_Gene_417_5 PubMedSearch: Zhang 2008 Gene 417 5 PubMedID: 18455888 Abstract N-Myc downstream-regulated gene 1 (ndrg1) is up-regulated in N-Myc knockout mouse embryos. The human NDRG family consists of 4 highly homologous members and human Ndrg1 exhibits approximately 94% homology with mouse ndrg1. However, the regulatory mechanism of NDRG1 via Myc repression is as yet unknown. We previously identified human NDRG2 and demonstrated that this gene is transcriptionally down-regulated by Myc via Miz-1-dependent interaction with the core promoter region of NDRG2. Here, we provide evidence that human NDRG1 is regulated by Myc in a manner similar to NDRG2. We found that Ndrg1 expression levels were enhanced as Myc expression declined in differentiated cells, but were down-regulated following Myc induction. The data revealed that both N-Myc and c-Myc can repress human NDRG1 at the transcriptional level. We further determined that the core promoter region of human NDRG1 is required for Myc repression, and verified the interaction of Myc with the core promoter region. However, the presence of the protein synthesis inhibitor cycloheximide could reverse the repression of Myc, indicating the indirect repression of human NDRG1 by Myc. Moreover, we found that c-Myc-mediated repression can be inhibited by TSA, an HDACs inhibitor, which suggests the involvement of HDACs in the repression process. Taken together, our results demonstrate that, in common with NDRG2, human NDRG1 can be indirectly transcriptionally down-regulated by Myc via interaction with the NDRG1 core promoter. Title: Effect of (R)-salsolinol and N-methyl-(R)-salsolinol on the balance impairment between dopamine and acetylcholine in rat brain: involvement in pathogenesis of Parkinson disease Zhu W, Wang D, Zheng J, An Y, Wang Q, Zhang W, Jin L, Gao H, Lin L Ref: Clinical Chemistry, 54:705, 2008 : PubMed ESTHER: Zhu_2008_Clin.Chem_54_705 PubMedSearch: Zhu 2008 Clin.Chem 54 705 PubMedID: 18238832 Abstract BACKGROUND: Parkinson disease (PD), a progressive neurodegenerative disease, affects at least 1% of population above the age of 65. Although the specific etiology of PD remains unclear, recently the endogenous neurotoxins such as (R)-salsolinol [(R)-Sal] and N-methyl-(R)-salsolinol [(R)-NMSal] have been thought to play a major role in PD. Much interest is focused on the degeneration of dopamine neurons induced by these neurotoxins. However, little literature is available on the impact of endogenous neurotoxins on the balance between dopamine (DA) and acetylcholine (ACh). METHODS: After injection of (R)-Sal or (R)-NMSal into the rat brain striatum, the concentrations of DA and its metabolites were detected by HPLC with electrochemical detection. We assessed the influence of neurotoxins on acetylcholinesterase (AChE) activity and developed a microdialysis-electrochemical device to measure ACh concentrations with enzyme-modified electrodes. RESULTS: (R)-Sal and (R)-NMSal led to concentration-dependent decreases in the activity of AChE. ACh concentrations in striatum treated with (R)-Sal or (R)-NMSal were increased to 131.7% and 239.8% of control, respectively. As to the dopaminergic system, (R)-NMSal caused a significant decrease in DA concentrations and (R)-Sal reduced the concentrations of DA metabolites in the striatum. CONCLUSIONS: (R)-Sal and (R)-NMSal exerted a considerable effect on the balance between DA and ACh by impairing the cholinergic system as well as the dopaminergic system. It is likely that the disruption of balance between DA and ACh plays a critical role in the pathogenesis of neurotoxin-induced PD. Title: Deletion of CASK in mice is lethal and impairs synaptic function Atasoy D, Schoch S, Ho A, Nadasy KA, Liu X, Zhang W, Mukherjee K, Nosyreva ED, Fernandez-Chacon R and Sudhof TC <2 more author(s)> Atasoy D, Schoch S, Ho A, Nadasy KA, Liu X, Zhang W, Mukherjee K, Nosyreva ED, Fernandez-Chacon R, Missler M, Kavalali ET, Sudhof TC (- 2) Ref: Proc Natl Acad Sci U S A, 104:2525, 2007 : PubMed ESTHER: Atasoy_2007_Proc.Natl.Acad.Sci.U.S.A_104_2525 PubMedSearch: Atasoy 2007 Proc.Natl.Acad.Sci.U.S.A 104 2525 PubMedID: 17287346 Abstract CASK is an evolutionarily conserved multidomain protein composed of an N-terminal Ca2+/calmodulin-kinase domain, central PDZ and SH3 domains, and a C-terminal guanylate kinase domain. Many potential activities for CASK have been suggested, including functions in scaffolding the synapse, in organizing ion channels, and in regulating neuronal gene transcription. To better define the physiological importance of CASK, we have now analyzed CASK "knockdown" mice in which CASK expression was suppressed by approximately 70%, and CASK knockout (KO) mice, in which CASK expression was abolished. CASK knockdown mice are viable but smaller than WT mice, whereas CASK KO mice die at first day after birth. CASK KO mice exhibit no major developmental abnormalities apart from a partially penetrant cleft palate syndrome. In CASK-deficient neurons, the levels of the CASK-interacting proteins Mints, Veli/Mals, and neurexins are decreased, whereas the level of neuroligin 1 (which binds to neurexins that in turn bind to CASK) is increased. Neurons lacking CASK display overall normal electrical properties and form ultrastructurally normal synapses. However, glutamatergic spontaneous synaptic release events are increased, and GABAergic synaptic release events are decreased in CASK-deficient neurons. In contrast to spontaneous neurotransmitter release, evoked release exhibited no major changes. Our data suggest that CASK, the only member of the membrane-associated guanylate kinase protein family that contains a Ca2+/calmodulin-dependent kinase domain, is required for mouse survival and performs a selectively essential function without being in itself required for core activities of neurons, such as membrane excitability, Ca2+-triggered presynaptic release, or postsynaptic receptor functions. Title: Enzymatic synthesis of aromatic polyketides using PKS4 from Gibberella fujikuroi Ma SM, Zhan J, Watanabe K, Xie X, Zhang W, Wang CC, Tang Y Ref: Journal of the American Chemical Society, 129:10642, 2007 : PubMed ESTHER: Ma_2007_J.Am.Chem.Soc_129_10642 PubMedSearch: Ma 2007 J.Am.Chem.Soc 129 10642 PubMedID: 17696354 Gene_locus related to this paper: gibf5-bik1 Abstract Iterative fungal polyketide synthases (PKSs) use a unique set of biochemical rules in the synthesis of complex polyketides. These rules dictate polyketide starter unit selection, chain length control, and post-PKS processing. We have demonstrated the E. coli expression and reconstitution of an iterative, unreduced fungal PKS. The Gibberella fujikuroi PKS4 was expressed at high levels, purified to homogeneity and functionally characterized. In the presence of malonyl-CoA, PKS4 was able to synthesize the nonaketide 3,8,10,11-tetrahydroxy-1-methyl-12H-benzo[b]xanthen-12-one (2) as the predominant product. PKS4 selectively used octanoyl-CoA as the starter unit and synthesized two novel benzopyrone-containing polyketides. Our work sets the stage for a comprehensive characterization of the intact PKS and its domains, and offers significant opportunity towards the enzymatic synthesis of additional compounds. Title: Soluble epoxide hydrolase: a novel therapeutic target in stroke Zhang W, Koerner IP, Noppens R, Grafe M, Tsai HJ, Morisseau C, Luria A, Hammock BD, Falck JR, Alkayed NJ Ref: Journal of Cerebral Blood Flow & Metabolism, 27:1931, 2007 : PubMed ESTHER: Zhang_2007_J.Cereb.Blood.Flow.Metab_27_1931 PubMedSearch: Zhang 2007 J.Cereb.Blood.Flow.Metab 27 1931 PubMedID: 17440491 Gene_locus related to this paper: human-EPHX2 Inhibitor(s) related to this paper: nbAUDA Abstract The P450 eicosanoids epoxyeicosatrienoic acids (EETs) are produced in brain and perform important biological functions, including protection from ischemic injury. The beneficial effect of EETs, however, is limited by their metabolism via soluble epoxide hydrolase (sEH). We tested the hypothesis that sEH inhibition is protective against ischemic brain damage in vivo by a mechanism linked to enhanced cerebral blood flow (CBF). We determined expression and distribution of sEH immunoreactivity (IR) in brain, and examined the effect of sEH inhibitor 12-(3-adamantan-1-yl-ureido)-dodecanoic acid butyl ester (AUDA-BE) on CBF and infarct size after experimental stroke in mice. Mice were administered a single intraperitoneal injection of AUDA-BE (10 mg/kg) or vehicle at 30 mins before 2-h middle cerebral artery occlusion (MCAO) or at reperfusion, in the presence and absence of P450 epoxygenase inhibitor N-methylsulfonyl-6-(2-propargyloxyphenyl) hexanamide (MS-PPOH). Immunoreactivity for sEH was detected in vascular and non-vascular brain compartments, with predominant expression in neuronal cell bodies and processes. 12-(3-Adamantan-1-yl-ureido)-dodecanoic acid butyl ester was detected in plasma and brain for up to 24 h after intraperitoneal injection, which was associated with inhibition of sEH activity in brain tissue. Finally, AUDA-BE significantly reduced infarct size at 24 h after MCAO, which was prevented by MS-PPOH. However, regional CBF rates measured by iodoantipyrine (IAP) autoradiography at end ischemia revealed no differences between AUDA-BE- and vehicle-treated mice. The findings suggest that sEH inhibition is protective against ischemic injury by non-vascular mechanisms, and that sEH may serve as a therapeutic target in stroke. Title: Transcriptional activation of the carboxylesterase 2 gene by the p53 pathway Choi W, Cogdell D, Feng Y, Hamilton SR, Zhang W Ref: Cancer Biol Ther, 5:1450, 2006 : PubMed ESTHER: Choi_2006_Cancer.Biol.Ther_5_1450 PubMedSearch: Choi 2006 Cancer.Biol.Ther 5 1450 PubMedID: 16963839 Abstract The p53 tumor suppressor is an important regulator of cellular response to chemotherapeutic agents by virtue of the protein's ability, upon activation by phosphorylation, to transcriptionally activate a number of genes involved in cell proliferation, apoptosis, and metabolism. Transcriptome analysis following introduction of a constitutively active form of p53 (p53T18D/S20D) into colon carcinoma cell lines identified transcriptional activation of the carboxylesterase 2 (CES-2) gene, which is involved in drug metabolism. We examined whether p53 activated by the DNA-damaging drug 5-fluorouracil (5-FU) also induces CES-2 expression. Our experiments showed that 5-FU induced CES-2 expression in two colon carcinoma cell lines that express wild-type p53 (HCT116 p53(+/+) and RKO) but not in five lines that are p53-null (HCT116 p53(-/- )) or express mutated p53 (HT29, KM12C, KM12SM, and KM12L4A). Sequence analysis revealed a putative p53-binding element in the first intron of CES-2 that differed from consensus by one nucleotide. A reporter gene assay showed that the luciferase construct with the p53-binding element responded to 5-FU treatment, whereas the reporter construct without the binding element did not. Chromatin immunoprecipitation assay confirmed that p53 bound the CES-2 fragment containing the p53-binding element after 5-FU treatment, whereas p21 binding to p53 was present with or without chemotherapy. Knockdown of expression of CES-2 and p53 by small interference RNA in RKO and HCT116 p53(+/+) cells attenuated the anti-proliferation effects of CPT11. These results taken together show that activated p53 directly regulates CES-2 expression via a p53-binding site, representing a novel mechanism through which the p53 pathway modulates drug metabolism. In addition, the degree of homology in the p53-binding element may determine the strength of p53 regulation. Title: Neuroligins determine synapse maturation and function Varoqueaux F, Aramuni G, Rawson RL, Mohrmann R, Missler M, Gottmann K, Zhang W, Sudhof TC, Brose N Ref: Neuron, 51:741, 2006 : PubMed ESTHER: Varoqueaux_2006_Neuron_51_741 PubMedSearch: Varoqueaux 2006 Neuron 51 741 PubMedID: 16982420 Abstract Synaptogenesis, the generation and maturation of functional synapses between nerve cells, is an essential step in the development of neuronal networks in the brain. It is thought to be triggered by members of the neuroligin family of postsynaptic cell adhesion proteins, which may form transsynaptic contacts with presynaptic alpha- and beta-neurexins and have been implicated in the etiology of autism. We show that deletion mutant mice lacking neuroligin expression die shortly after birth due to respiratory failure. This respiratory failure is a consequence of reduced GABAergic/glycinergic and glutamatergic synaptic transmission and network activity in brainstem centers that control respiration. However, the density of synaptic contacts is not altered in neuroligin-deficient brains and cultured neurons. Our data show that neuroligins are required for proper synapse maturation and brain function, but not for the initial formation of synaptic contacts. Title: The repression of human differentiation-related gene NDRG2 expression by Myc via Miz-1-dependent interaction with the NDRG2 core promoter Zhang J, Li F, Liu X, Shen L, Liu J, Su J, Zhang W, Deng Y, Wang L and Yao L <5 more author(s)> Zhang J, Li F, Liu X, Shen L, Liu J, Su J, Zhang W, Deng Y, Wang L, Liu N, Han W, Ji S, Yang A, Han H, Yao L (- 5) Ref: Journal of Biological Chemistry, 281:39159, 2006 : PubMed ESTHER: Zhang_2006_J.Biol.Chem_281_39159 PubMedSearch: Zhang 2006 J.Biol.Chem 281 39159 PubMedID: 17050536 Abstract The N-myc downstream-regulated gene 1 (ndrg1) is highly expressed in N-myc knock-out mice through an unknown regulatory mechanism. As one member of the human NDRG gene family, NDRG2 encodes a protein highly homologous to Ndrg1. However, it is uncertain whether the expression of human NDRG2 is regulated by Myc because mouse ndrg2 and -3 are not affected by Myc. In this study, we provide the novel evidence that the expression of human NDRG2 is down-regulated by Myc via transcriptional repression. A high level of NDRG2 was observed as Myc expression was reduced in differentiated cells, whereas a low level of NDRG2 was shown following increased Myc expression upon serum stimulation. The ectopic expression of c-Myc dramatically reduces the cellular Ndrg2 protein and mRNA level. We further identified the core promoter region of NDRG2 that is required for Myc repression on NDRG2 transcription, and we verified the interaction of Myc with the core promoter region both in vitro and in vivo. Moreover, the c-Myc-mediated repression of NDRG2 requires association with Miz-1, and possibly the recruitment of other epigenetic factors, such as histone deacetylases, to the promoter. The regulatory function of Myc on NDRG2 gene expression implicated the role of the Ndrg2 in regulating cell differentiation. Title: [Protective effect of Danzhi-xiaoyao San on rat brain energy or material metabolism (correction of matebolism) dealt with D-galactose] Cai DY, Chen JX, Zhang W, Wang X, Sun LP, Zhang JJ, Huang QF Ref: Space Med Med Eng (Beijing), 18:32, 2005 : PubMed ESTHER: Cai_2005_Space.Med.Med.Eng.(Beijing)_18_32 PubMedSearch: Cai 2005 Space.Med.Med.Eng.(Beijing) 18 32 PubMedID: 15852547 Abstract OBJECTIVE: To research the mechanism of Danzhi-xiaoyao San (DZXYS) for treating Alzheimer's disease model of rats dealt with D-galactose. METHOD: An Alzheimer's disease-like model of rats has been set up with sc. D-galactose 150.0 mg kg-1 D-1 x 49 d. Comparing with Acricept in 0.54 mg kg-1 D-1 dosage as a positive control drug, DZXYS in 12.636 g kg-1 D-1 x 49 d dosage has orally been administrated orally to treat the injury in the Alzheimer's disease-like model of rats. The energy charge in the cerebral tissues had been detested with waters liquid chromatography; the protein content and DNA content in the cerebral tissues had been detested with ultraviolet assay, the relative content of aldose reductase-mRNA is detested with RT-PCR. The difference was analyzed between the control rats without D-galactose, the model rats dealt with D-galactose, the model rats treated with Aricept and the model rats treated with DZXYS, it is significant as P<0.05. RESULT: 1) DZXYS can not affect the energy charge in their cerebral tissues. 2) DZXYS can increase the protein content from 0.3139 +/- 0.019468 to 0.3213 +/- 0.015528 (ni=10, P>0.05) in their cerebral tissues. 3) DZXYS can increase the total DNA content from 1.093 +/- 0.267 to 1.488 +/- 0.341 (ni=10, P<0.01) in their cerebral tissues. 4) DZXYS can increase the content of AR-mRNA in their cerebral tissue from 0.732 +/- 0.159 to 1.418 +/- 0.277 (ni=5, P<0.01). CONCLUSION: It suggests that DZXYS could be effective in human Alzheimer's disease for its stabling gene expression, maintaining protein characteristics, recovering signal transduction in the Alzheimer's disease-like model rats dealt with D-galactose. Title: Molecular cloning and functional analysis of two polyhydroxyalkanoate synthases from two strains of Aeromonas hydrophila spp Lu X, Zhang W, Jian J, Wu Q, Chen GQ Ref: FEMS Microbiology Letters, 243:149, 2005 : PubMed ESTHER: Lu_2005_FEMS.Microbiol.Lett_243_149 PubMedSearch: Lu 2005 FEMS.Microbiol.Lett 243 149 PubMedID: 15668013 Gene_locus related to this paper: aerhy-PHAC Abstract Polyhydroxyalkanoate (PHA) synthase genes (phaC) were cloned from two Aeromonas hydrophila strains named WQ and 4AK5, respectively. Both strains are able to produce PHBHHx copolyesters consisting of 3-hydroxybutyrate (3HB) and 3-hydroxyhexanoate (3HHx). Sequence analysis showed that there was only 2 bp difference between these two PHA synthase genes, corresponding to two-amino acid difference at positions of 437 and 458 of the two synthases. PHA productivity and its monomer content produced by A. hydrophila WQ and A. hydrophila 4AK5 were quite different. A. hydrophila WQ accumulated 33% PHBHHx of its cell dry weight (CDW) with 5 mol% 3HHx in the copolyester when cultured in lauric acid for 48 h. Yet A. hydrophila 4AK5 was able to produce 43% PHBHHx of the CDW with 14 mol% 3HHx under the same condition. Hetero-expression of PHA synthase genes of A. hydrophila WQ and A. hydrophila 4AK5, respectively, in Escherichia coli XL1-Blue led to PHBHHx accumulation of 24% and 39% of the CDW and the 3HHx content in PHBHHx were 6 and 15 mol%, respectively. This indicated that the function of these two PHA synthases were different due to these two different residues at positions of 437 and 458. Site specific mutation was carried out to change these two amino acid residues. Results showed that the changes on either of the two amino acids negatively affected the PHA productivity. Title: Ion-pair reverse-phase high performance liquid chromatography method for determination of Huperzine-A in beagle dog serum Ye J, Zeng S, Zhang W, Chen G Ref: Journal of Chromatography B Analyt Technol Biomed Life Sciences, 817:187, 2005 : PubMed ESTHER: Ye_2005_J.Chromatogr.B.Analyt.Technol.Biomed.Life.Sci_817_187 PubMedSearch: Ye 2005 J.Chromatogr.B.Analyt.Technol.Biomed.Life.Sci 817 187 PubMedID: 15686984 Abstract Huperzine-A (Hup-A), a biologically potent, reversible acetylcholinesterase inhibitor for the treatment of Alzheimer disease (AD) in China, has very low blood concentration. In order to study the pharmacokinetics of newly developed Hup-A transdermal patches in animal, a rapid and sensitive ion-pair reverse-phase high performance liquid chromatography (RP-HPLC) method for the determination of Hup-A in beagle dog serum using mebendazole as internal standard has been developed and validated. The analyte and internal standard were extracted from serum using chloroform-isopropanol (95:5, v/v), analyzed on a C (18) column (5 microm, 150 mm x 4.6 mm i.d.) with a mobile phase consisting of methanol-water-glacial acetic acid (50:48.5:1.5, v/v/v), using sodium dodecylsulfonate as an ion-pair reagent, and detected with UV detector at 313 nm. The chromatographic run time was within 15 min. The assay was linear over the concentration range of 1-12 ng/ml and intra- and inter-day precision over this range was not more than 12.8%. The limit of quantification in serum was 1 ng/ml. The method was successfully applied to characterize the Hup-A concentration-time profiles and study the single and multiple doses phamacokinetics of Hup-A transdermal patches in beagle dogs. The pharmacokinetic study results showed that Hup-A patches has the characteristic of sustained or controlled drug release in vivo. Title: Generation and analysis of muscarinic acetylcholine receptor knockout mice. Duttaroy A, Yamada M, Gomeza J, Zhang W, Miyakawa T, Makita R, Bymaster FP, Felder CC, Deng CX, Wess J Ref: Cholinergic Mechanisms, CRC Press, :63, 2004 : PubMed ESTHER: Duttaroy_2004_Cholinergic.Mechanisms.CRC.Press__63 PubMedSearch: Duttaroy 2004 Cholinergic.Mechanisms.CRC.Press 63 Title: Galantamine blocks cloned Kv2.1, but not Kv1.5 potassium channels Zhang HX, Zhang W, Jin HW, Wang XL Ref: Brain Research Mol Brain Res, 131:136, 2004 : PubMed ESTHER: Zhang_2004_Brain.Res.Mol.Brain.Res_131_136 PubMedSearch: Zhang 2004 Brain.Res.Mol.Brain.Res 131 136 PubMedID: 15530663 Abstract Galantamine is a cholinesterase inhibitor (AChEI) currently used in treatment of Alzheimer's disease (AD). In the present study, the effects of galantamine on currents of cloned Kv2.1 and Kv1.5 potassium channels were investigated by using patch-clamp whole cell recording techniques. Kv2.1 and Kv1.5 were stably expressed in HEK293 cells. Galantamine blocked Kv2.1 current in a concentration-dependent manner. When depolarizing from -50 to +40 mV, the IC50 of galantamine for inhibition of Kv2.1 was 5.6 microM. Galantamine 10 microM shifted the activation curve of Kv2.1 to negative potential by 4.0 mV. At the same concentration, galantamine shifted the inactivation curve to negative potential by 25.2 mV. While Kv1.5 was not sensitive to galantamine, Kv1.5 current was not changed by galantamine at concentration of 10 microM. Our data suggest that galantamine potently blocks Kv2.1, but not Kv1.5 channels. Title: Muscarinic receptor subtypes mediating central and peripheral antinociception studied with muscarinic receptor knockout mice: a review Wess J, Duttaroy A, Gomeza J, Zhang W, Yamada M, Felder CC, Bernardini N, Reeh PW Ref: Life Sciences, 72:2047, 2003 : PubMed ESTHER: Wess_2003_Life.Sci_72_2047 PubMedSearch: Wess 2003 Life.Sci 72 2047 PubMedID: 12628455 Abstract To gain new insight into the physiological and pathophysiological roles of the muscarinic cholinergic system, we generated mutant mouse strains deficient in each of the five muscarinic acetylcholine receptor subtypes (M(1)-M(5)). In this chapter, we review a set of recent studies dealing with the identification of the muscarinic receptor subtypes mediating muscarinic agonist-dependent analgesic effects by central and peripheral mechanisms. Most of these studies were carried out with mutant mouse strains lacking M(2) or/and M(4) muscarinic receptors. It is well known that administration of centrally active muscarinic agonists induces pronounced analgesic effects. To identify the muscarinic receptors mediating this activity, wild-type and muscarinic receptor mutant mice were injected with the non-subtype-selective muscarinic agonist, oxotremorine (s.c., i.t., and i.c.v.), and analgesic effects were assessed in the tail-flick and hot-plate tests. These studies showed that M(2) receptors play a key role in mediating the analgesic effects of oxotremorine, both at the spinal and supraspinal level. However, studies with M(2)/M(4) receptor double KO mice indicated that M(4) receptors also contribute to this activity. Recent evidence suggests that activation of muscarinic receptors located in the skin can reduce the sensitivity of peripheral nociceptors. Electrophysiological and neurochemical studies with skin preparations from muscarinic receptor mutant mice indicated that muscarine-induced peripheral antinociception is mediated by M(2) receptors. Since acetylcholine is synthesized and released by different cell types of the skin, it is possible that non-neuronally released acetylcholine plays a role in modulating peripheral nociception. Our results highlight the usefulness of muscarinic receptor mutant mice to shed light on the functional roles of acetylcholine released from both neuronal and non-neuronal cells. Title: Novel insights into M5 muscarinic acetylcholine receptor function by the use of gene targeting technology Yamada M, Basile AS, Fedorova I, Zhang W, Duttaroy A, Cui Y, Lamping KG, Faraci FM, Deng CX, Wess J Ref: Life Sciences, 74:345, 2003 : PubMed ESTHER: Yamada_2003_Life.Sci_74_345 PubMedSearch: Yamada 2003 Life.Sci 74 345 PubMedID: 14607263 Abstract Until recently, little was known about the possible physiological functions of the M(5) muscarinic acetylcholine receptor subtype, the last member of the muscarinic receptor family (M(1)-M(5)) to be cloned. To learn more about the potential physiological roles of this receptor subtype, we generated and analyzed M(5) receptor-deficient mice (M5 -/- mice). Strikingly, acetylcholine, a potent dilator of most vascular beds, virtually lost the ability to dilate cerebral arteries and arterioles in M5 -/- mice, suggesting that endothelial M(5) receptors mediate this activity in wild-type mice. This effect was specific for cerebral blood vessels, since acetylcholine-mediated dilation of extra-cerebral arteries remained fully intact in M5 -/- mice. In addition, in vitro neurotransmitter release experiments indicated that M(5) receptors located on dopaminergic nerve terminals play a role in facilitating muscarinic agonist-induced dopamine release in the striatum, consistent with the observation that the dopaminergic neurons innervating the striatum almost exclusively express the M(5) receptor subtype. We also found that the rewarding effects of morphine, the prototypical opiate analgesic, were substantially reduced in M5 -/- mice, as measured in the conditioned place preference paradigm. Furthermore, both the somatic and affective components of naloxone-induced morphine withdrawal symptoms were significantly attenuated in M5 -/- mice. It is likely that these behavioral deficits are caused by the lack of mesolimbic M(5) receptors, activation of which is known to stimulate dopamine release in the nucleus accumbens. These results convincingly demonstrate that the M(5) muscarinic receptor is involved in modulating several important pharmacological and behavioral functions. These findings may lead to novel therapeutic strategies for the treatment of drug addiction and certain cerebrovascular disorders. 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: Androgen-induced expression of endoplasmic reticulum (ER) stress response genes in prostate cancer cells Segawa T, Nau ME, Xu LL, Chilukuri RN, Makarem M, Zhang W, Petrovics G, Sesterhenn IA, McLeod DG and Srivastava S <2 more author(s)> Segawa T, Nau ME, Xu LL, Chilukuri RN, Makarem M, Zhang W, Petrovics G, Sesterhenn IA, McLeod DG, Moul JW, Vahey M, Srivastava S (- 2) Ref: Oncogene, 21:8749, 2002 : PubMed ESTHER: Segawa_2002_Oncogene_21_8749 PubMedSearch: Segawa 2002 Oncogene 21 8749 PubMedID: 12483528 Abstract Evaluations of androgen regulated gene (ARG) repertoire provide new insights into the androgen receptor (AR) mediated signaling at the transcriptional level. Definition of ARGs having critical functions in the biology of normal and malignant prostate should aid in identifying new bio-markers and therapeutic targets for prostate cancer (CaP). Using Affymetrix HuGene FL oligonucleotide arrays, temporal expression profiles of ARGs in widely used hormone responsive LNCaP cells, were analysed by hierarchical clustering methods and functional classification. ARGs in response to different androgen concentrations showed temporal co-regulation of genes involved in specific biochemical pathways. This study focuses on our new observations of the coordinated androgen induction of genes (NDRG1, PDIR, HERPUD1, ORP150) involved in the endoplasmic reticulum (ER) stress response pathway. Expression analysis of the two selected ER stress responsive genes, NDRG1 and HERPUD1 in primary CaPs revealed a significantly reduced tumor associated expression. Intriguing linkage of the androgen signaling to ER stress responsive genes, a protective response to protein unfolding or protein damage resulting from cellular stress signals, suggests that androgens may induce such stress signals in CaP cells. Decreased CaP associated expression of two ER stress responsive genes also suggests that possible abrogation of this pathway in prostate tumorigenesis. Title: Human carboxylesterase 2 is commonly expressed in tumor tissue and is correlated with activation of irinotecan Xu G, Zhang W, Ma MK, McLeod HL Ref: Clin Cancer Research, 8:2605, 2002 : PubMed ESTHER: Xu_2002_Clin.Cancer.Res_8_2605 PubMedSearch: Xu 2002 Clin.Cancer.Res 8 2605 PubMedID: 12171891 Abstract The prodrug irinotecan is an active agent for the treatment of advanced colorectal cancer and a number of other solid tumors. Irinotecan is converted in vivo to SN-38 (7-ethyl-10-hydroxy-camptothecin), the active metabolite that causes cell death, by human liver carboxylesterases. Previous studies suggest that human carboxylesterase 2 (CES2) is the key activating isoform. Although conversion of irinotecan to SN-38 by liver carboxylesterase is an inefficient process, clinical data indicate that irinotecan has significant antitumor activity. This scenario raises the possibility that local conversion of irinotecan to SN-38 by CES2 in tumor tissues might occur. The expression profile of CES2 protein in human tumor tissues was evaluated in a tissue array of 18 different types of human cancer and in a panel of normal human liver samples by immunohistochemistry and Western blot, respectively. Cytosolic CES2 expression was observed in 101 of 154 tumors (66%) and 55 of 60 normal tissues (92%). Among the 18 types of tumors analyzed, 2 types (gallbladder tumor and lymphoma) did not express CES2, 5 types expressed weak CES2, and 11 types expressed moderate to intense CES2. In functional studies, CES2 protein was highly variable among liver samples, with a 15-fold range in cytosol and a 3-fold range in microsome fractions. Liver microsomal CES2 protein expression was significantly correlated with irinotecan activation to SN-38 (R(s) = 0.70; P = 0.007). This study confirms that CES2 is a key enzyme for irinotecan activation. Tumor CES2 expression may contribute to variable response to irinotecan chemotherapy for solid tumors. Title: Crystal structure of OxyB, a cytochrome P450 implicated in an oxidative phenol coupling reaction during vancomycin biosynthesis Zerbe K, Pylypenko O, Vitali F, Zhang W, Rouset S, Heck M, Vrijbloed JW, Bischoff D, Bister B and Schlichting I <4 more author(s)> Zerbe K, Pylypenko O, Vitali F, Zhang W, Rouset S, Heck M, Vrijbloed JW, Bischoff D, Bister B, Sussmuth RD, Pelzer S, Wohlleben W, Robinson JA, Schlichting I (- 4) Ref: Journal of Biological Chemistry, 277:47476, 2002 : PubMed ESTHER: Zerbe_2002_J.Biol.Chem_277_47476 PubMedSearch: Zerbe 2002 J.Biol.Chem 277 47476 PubMedID: 12207020 Gene_locus related to this paper: amyor-Q8RN07 Abstract Gene-inactivation studies point to the involvement of OxyB in catalyzing the first oxidative phenol coupling reaction during glycopeptide antibiotic biosynthesis. The oxyB gene has been cloned and sequenced from the vancomycin producer Amycolatopsis orientalis, and the hemoprotein has been produced in Escherichia coli, crystallized, and its structure determined to 1.7-A resolution. OxyB gave UV-visible spectra characteristic of a P450-like hemoprotein in the low spin ferric state. After reduction to the ferrous state by dithionite or by spinach ferredoxin and ferredoxin reductase, the CO-ligated form gave a 450-nm peak in a UV-difference spectrum. Addition of putative heptapeptide substrates to resting OxyB produced type I changes to the UV spectrum, but no turnover was observed in the presence of ferredoxin and ferredoxin reductase, showing that either the peptides or the reduction system, or both, are insufficient to support a full catalytic cycle. OxyB exhibits the typical P450-fold, with helix L containing the signature sequence FGHGXHXCLG and Cys(347) being the proximal axial thiolate ligand of the heme iron. The structural similarity of OxyB is highest to P450nor, P450terp, CYP119, and P450eryF. In OxyB, the F and G helices are rotated out of the active site compared with P450nor, resulting in a much more open active site, consistent with the larger size of the presumed heptapeptide substrate. Title: Characterization of central inhibitory muscarinic autoreceptors by the use of muscarinic acetylcholine receptor knock-out mice Zhang W, Basile AS, Gomeza J, Volpicelli LA, Levey AI, Wess J Ref: Journal of Neuroscience, 22:1709, 2002 : PubMed ESTHER: Zhang_2002_J.Neurosci_22_1709 PubMedSearch: Zhang 2002 J.Neurosci 22 1709 PubMedID: 11880500 Abstract Forebrain muscarinic acetylcholine (ACh) receptors (mAChRs; M1-M5) are predicted to play important roles in many fundamental central functions, including higher cognitive processes and modulation of extrapyramidal motor activity. Synaptic ACh levels are known to be regulated by the activity of presynaptic muscarinic autoreceptors mediating inhibition of ACh release. Primarily because of the use of ligands with limited receptor subtype selectivity, classical pharmacological studies have led to conflicting results regarding the identity of the mAChR subtypes mediating this activity in different areas of the brain. To investigate the molecular identity of hippocampal, cortical, and striatal inhibitory muscarinic autoreceptors in a more direct manner, we used genetically altered mice lacking functional M2 and/or M4 mAChRs [knock-out (KO) mice]. After labeling of cellular ACh pools with [3H]choline, potassium-stimulated [3H]ACh release was measured in superfused brain slices, either in the absence or the presence of muscarinic drugs. The nonsubtype-selective muscarinic agonist, oxotremorine (0.1-10 microm), inhibited potassium-stimulated [3H]ACh release in hippocampal, cortical, and striatal slices prepared from wild-type mice by up to 80%. This activity was totally abolished in tissues prepared from M2-M4 receptor double KO mice. Strikingly, release studies with brain slices from M2 and M4 receptor single KO mice indicated that autoinhibition of ACh release is mediated primarily by the M2 receptor in hippocampus and cerebral cortex, but predominantly by the M4 receptor in the striatum. These results, together with additional receptor localization studies, support the novel concept that autoinhibition of ACh release involves different mAChRs in different regions of the brain. Title: Multiple muscarinic acetylcholine receptor subtypes modulate striatal dopamine release, as studied with M1-M5 muscarinic receptor knock-out mice Zhang W, Yamada M, Gomeza J, Basile AS, Wess J Ref: Journal of Neuroscience, 22:6347, 2002 : PubMed ESTHER: Zhang_2002_J.Neurosci_22_6347 PubMedSearch: Zhang 2002 J.Neurosci 22 6347 PubMedID: 12151512 Abstract A proper balance between striatal muscarinic cholinergic and dopaminergic neurotransmission is required for coordinated locomotor control. Activation of striatal muscarinic acetylcholine receptors (mAChRs) is known to modulate striatal dopamine release. To identify the mAChR subtype(s) involved in this activity, we used genetically altered mice that lacked functional M1-M5 mAChRs [knock-out (KO) mice]. In superfused striatal slices from wild-type mice, the non-subtype-selective muscarinic agonist oxotremorine led to concentration-dependent increases in potassium-stimulated [3H]dopamine release (by up to 60%). The lack of M1 or M2 receptors had no significant effect on the magnitude of these responses. Strikingly, oxotremorine-mediated potentiation of stimulated striatal [3H]dopamine release was abolished in M4 receptor KO mice, significantly increased in M3 receptor-deficient mice, and significantly reduced (but not abolished) in M5 receptor KO mice. Additional release studies performed in the presence of tetrodotoxin suggested that the dopamine release-stimulating M4 receptors are probably located on neuronal cell bodies, but that the release-facilitating M5 and the release-inhibiting M3 receptors are likely to be located on nerve terminals. Studies with the GABA(A) receptor blocker bicuculline methochloride suggested that M3 and M4 receptors mediate their dopamine release-modulatory effects via facilitation or inhibition, respectively, of striatal GABA release. These results provide unambiguous evidence that multiple mAChR subtypes are involved in the regulation of striatal dopamine release. These findings should contribute to a better understanding of the important functional roles that the muscarinic cholinergic system plays in striatal function. 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: Poster: Muscarinic receptor characterization and neurochemical effects of the antipsychotic-like muscarinic agonist PTAC Bymaster FP, Shannon HE, DeLapp NW, Calligaro DO, Perry KW, Zhang W, Rasmussen K, Ward JS, Fink-Jensen A and Sauerberg P <5 more author(s)> Bymaster FP, Shannon HE, DeLapp NW, Calligaro DO, Perry KW, Zhang W, Rasmussen K, Ward JS, Fink-Jensen A, Olesen PH, Rasmussen T, Sheardown M, Swedberg MD, Jeppesen L, Sauerberg P (- 5) Ref: Life Sciences, 64:579, 1999 : PubMed Title: A selective role of calcineurin aalpha in synaptic depotentiation in hippocampus Zhuo M, Zhang W, Son H, Mansuy I, Sobel RA, Seidman J, Kandel ER Ref: Proc Natl Acad Sci U S A, 96:4650, 1999 : PubMed ESTHER: Zhuo_1999_Proc.Natl.Acad.Sci.U.S.A_96_4650 PubMedSearch: Zhuo 1999 Proc.Natl.Acad.Sci.U.S.A 96 4650 PubMedID: 10200317 Abstract Pharmacological studies have suggested that long-term potentiation (LTP) and long-term depression (LTD) and depotentiation, three forms of synaptic plasticity in the hippocampus, require the activity of the phosphatase calcineurin. At least two different isoforms of calcineurin are found in the central nervous system. To investigate whether all of these forms of synaptic plasticity require the same isoforms of calcineurin, we have examined LTD, depotentiation, and LTP in mice lacking the predominant calcineurin isoform in the central nervous system, Aalpha-/- mice. Depotentiation was abolished completely whereas neither LTD nor LTP were affected. These studies provide genetic evidence that the Aalpha isoform of calcineurin is important for the reversal of LTP in the hippocampus and indicate that depotentiation and LTD operate through somewhat different molecular mechanisms. Title: Xanomeline compared to other muscarinic agents on stimulation of phosphoinositide hydrolysis in vivo and other cholinomimetic effects Bymaster FP, Carter PA, Peters SC, Zhang W, Ward JS, Mitch CH, Calligaro DO, Whitesitt CA, DeLapp NC and Sauerberg P <5 more author(s)> Bymaster FP, Carter PA, Peters SC, Zhang W, Ward JS, Mitch CH, Calligaro DO, Whitesitt CA, DeLapp NC, Shannon HE, Rimvall K, Jeppesen L, Sheardown MJ, Fink-Jensen A, Sauerberg P (- 5) Ref: Brain Research, 795:179, 1998 : PubMed ESTHER: Bymaster_1998_Brain.Res_795_179 PubMedSearch: Bymaster 1998 Brain.Res 795 179 PubMedID: 9622623 Abstract Activation of muscarinic m1 receptors which are coupled to the phosphoinositide (PI) second messenger transduction system is the initial objective of cholinergic replacement therapy in Alzheimer's disease. Thus, we evaluated the ability of the selective muscarinic receptor agonist (SMRA) xanomeline to stimulate in vivo phosphoinositide (PI) hydrolysis and compared it to a number of direct acting muscarinic agonists, two cholinesterase inhibitors and a putative m1 agonist/muscarinic m2 antagonist. Using a radiometric technique, it was determined that administration of xanomeline robustly stimulated in vivo PI hydrolysis and the effect was blocked by muscarinic antagonists, demonstrating mediation by muscarinic receptors. The non-selective muscarinic agonists pilocarpine, oxotremorine, RS-86, S-aceclidine, but not the less active isomer R-aceclidine, also effectively stimulated PI hydrolysis in mice. Amongst the putative m1 agonists, thiopilocarpine, hexylthio-TZTP as well as xanomeline effectively stimulated PI hydrolysis, but milameline, WAL 2014, SKB 202026 and PD 142505 did not significantly alter PI hydrolysis. Furthermore, WAL 2014 and SKB 202026 inhibited agonist-induced PI stimulation, suggesting that they act as antagonists at PI-coupled receptors in vivo. The cholinesterase inhibitors, tacrine and physostigmine, and the mixed muscarinic m1 agonist/m2 antagonist LU25-109 did not activate in vivo PI hydrolysis. Xanomeline, hexylthio-TZTP and thiopilocarpine were relatively free of cholinergic side effects, whereas milameline, WAL 2014 and SKB 202026 produced non-selective effects. Therefore, these data demonstrate that xanomeline selectively activates in vivo PI hydrolysis, consistent with activation of biochemical processes involved in memory and cognition and xanomeline's beneficial clinical effects on cognition in Alzheimers patients. Title: Pharmacologic inhibition of transglutaminase-induced cross-linking of Alzheimer's amyloid beta-peptide Zhang W, Johnson BR, Bjornsson TD Ref: Life Sciences, 60:2323, 1997 : PubMed ESTHER: Zhang_1997_Life.Sci_60_2323 PubMedSearch: Zhang 1997 Life.Sci 60 2323 PubMedID: 9194688 Abstract The brain of Alzheimer's disease (AD) patients contains deposits of amyloid beta-peptide (A beta). Recent studies have shown that A beta is a substrate for tissue transglutaminase (TGase), which induces the formation of cross-linked dimers and polymers, and that tacrine, indomethacin and deferoxamine, which have widely different chemical structures, attenuate the progression of symptoms of AD. This report evaluated the potential of a total of ten different pharmacological agents to inhibit TGase-induced cross-linking of A beta, including known TGase inhibitors (dansylcadaverine, spermine), non-steroidal anti-inflammatory drugs (indomethacin, meclofenamic acid, diflunisal, salicylic acid), monoamine oxidase inhibitors (tranylcypromine, phenelzine), an acetylcholinesterase inhibitor (tacrine), and an iron chelating agent (deferoxamine). All but one (salicylic acid) of these ten agents had an inhibitory effect on TGase-induced A beta cross-linking. These results suggest that inhibition of TGase-induced cross-linking of A beta is a potential pharmacologic target for the treatment of AD. A method is also presented for the determination of percent inhibition of TGase-induced A beta cross-linking based on the separated monomer, dimer and polymer bands on SDS-PAGE gels. Title: Nitroxidergic innervation of guinea pig cerebral arteries Barroso CP, Edvinsson L, Zhang W, Cunha e Sa M, Springall DR, Polak JM, Gulbenkian S Ref: Journal of the Autonomic Nervous System, 58:108, 1996 : PubMed ESTHER: Barroso_1996_J.Autonom.Nerv.Syst_58_108 PubMedSearch: Barroso 1996 J.Autonom.Nerv.Syst 58 108 PubMedID: 8740667 Abstract The presence and distribution of nitric oxide synthase (NOS)-immunoreactive nerve fibers associated with the guinea pig major cerebral arteries was studied by means of immunohistochemical, histochemical and ultrastructural techniques. Anterior arteries of the circle of Willis received a rich supply of perivascular nerve fibers containing NOS immunoreactivity while posteriorly localized arteries presented a moderate to sparse innervation. A double immunofluorescence staining technique revealed that NOS was localized in nerve fibers distinct from those displaying substance P or tyrosine hydroxylase. Combined immunofluorescence and histochemical staining of the same preparation indicated that NOS immunoreactivity was localized in putative cholinergic nerve fibers (identified by their acetylcholinesterase content) and that NADPH-diaphorase activity (a marker for NOS-containing neurons) was found in nerves which also possessed VIP immunoreactivity. The ultrastructural study revealed that NOS immunoreactivity was present in numerous nerve varicosities at the adventitial-medial border. These results suggest that NO and VIP co-exist in putative parasympathetic nerve fibers supplying the guinea pig cerebral arteries and may be release together in response to nervous stimulation. | |||||||
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