Molecular BioSystems最新文献

{"title":"Systems-level organization of non-alcoholic fatty liver disease progression network†","authors":"K. Shubham, L. Vinay and P. K. Vinod","doi":"10.1039/C7MB00013H","DOIUrl":"https://doi.org/10.1039/C7MB00013H","url":null,"abstract":"<p >Non-Alcoholic Fatty Liver Disease (NAFLD) is a complex spectrum of diseases ranging from simple steatosis to Non-Alcoholic Steatohepatitis (NASH) with fibrosis, which can progress to cirrhosis and hepatocellular carcinoma. The pathogenesis of NAFLD is complex, involving crosstalk between multiple organs, cell-types, and environmental and genetic factors. Dysfunction of the adipose tissue plays a central role in NAFLD progression. Here, we analysed transcriptomics data obtained from the Visceral Adipose Tissue (VAT) of NAFLD patients to understand how the VAT metabolism is altered at the genome scale and co-regulated with other cellular processes during the progression from obesity to NASH with fibrosis. For this purpose, we performed Weighted Gene Co-expression Network Analysis (WGCNA), a method that organizes the disease transcriptome into functional modules of cellular processes and pathways. Our analysis revealed the coordination of metabolic and inflammatory modules (termed “immunometabolism”) in the VAT of NAFLD patients. We found that genes of arachidonic acid, sphingolipid and glycosphingolipid metabolism were upregulated and co-expressed with genes of proinflammatory signalling pathways and hypoxia in NASH/NASH with fibrosis. We hypothesize that these metabolic alterations might play a role in sustaining VAT inflammation. Furthermore, immunometabolism related genes were also co-expressed with genes involved in Extracellular Matrix (ECM) degradation. Our analysis indicates that upregulation of both ECM degrading enzymes and their inhibitors (incoherent feedforward loop) potentially leads to the ECM deposition in the VAT of NASH with fibrosis patients.</p>","PeriodicalId":90,"journal":{"name":"Molecular BioSystems","volume":" 9","pages":" 1898-1911"},"PeriodicalIF":3.743,"publicationDate":"2017-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1039/C7MB00013H","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"3762224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional aqueous droplet networks","authors":"Michael J. Booth, Vanessa Restrepo Schild, Florence G. Downs and Hagan Bayley","doi":"10.1039/C7MB00192D","DOIUrl":"https://doi.org/10.1039/C7MB00192D","url":null,"abstract":"<p >Droplet interface bilayers (DIBs), comprising individual lipid bilayers between pairs of aqueous droplets in an oil, are proving to be a useful tool for studying membrane proteins. Recently, attention has turned to the elaboration of networks of aqueous droplets, connected through functionalized interface bilayers, with collective properties unachievable in droplet pairs. Small 2D collections of droplets have been formed into soft biodevices, which can act as electronic components, light-sensors and batteries. A substantial breakthrough has been the development of a droplet printer, which can create patterned 3D droplet networks of hundreds to thousands of connected droplets. The 3D networks can change shape, or carry electrical signals through defined pathways, or express proteins in response to patterned illumination. We envisage using functional 3D droplet networks as autonomous synthetic tissues or coupling them with cells to repair or enhance the properties of living tissues.</p>","PeriodicalId":90,"journal":{"name":"Molecular BioSystems","volume":" 9","pages":" 1658-1691"},"PeriodicalIF":3.743,"publicationDate":"2017-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1039/C7MB00192D","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"3771708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"pLoc-mPlant: predict subcellular localization of multi-location plant proteins by incorporating the optimal GO information into general PseAAC†","authors":"Xiang Cheng, Xuan Xiao and Kuo-Chen Chou","doi":"10.1039/C7MB00267J","DOIUrl":"https://doi.org/10.1039/C7MB00267J","url":null,"abstract":"<p >One of the fundamental goals in cellular biochemistry is to identify the functions of proteins in the context of compartments that organize them in the cellular environment. To realize this, it is indispensable to develop an automated method for fast and accurate identification of the subcellular locations of uncharacterized proteins. The current study is focused on plant protein subcellular location prediction based on the sequence information alone. Although considerable efforts have been made in this regard, the problem is far from being solved yet. Most of the existing methods can be used to deal with single-location proteins only. Actually, proteins with multi-locations may have some special biological functions. This kind of multiplex protein is particularly important for both basic research and drug design. Using the multi-label theory, we present a new predictor called “pLoc-mPlant” by extracting the optimal GO (Gene Ontology) information into the Chou's general PseAAC (Pseudo Amino Acid Composition). Rigorous cross-validation on the same stringent benchmark dataset indicated that the proposed pLoc-mPlant predictor is remarkably superior to iLoc-Plant, the state-of-the-art method for predicting plant protein subcellular localization. To maximize the convenience of most experimental scientists, a user-friendly web-server for the new predictor has been established at http://www.jci-bioinfo.cn/pLoc-mPlant/, by which users can easily get their desired results without the need to go through the complicated mathematics involved.</p>","PeriodicalId":90,"journal":{"name":"Molecular BioSystems","volume":" 9","pages":" 1722-1727"},"PeriodicalIF":3.743,"publicationDate":"2017-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1039/C7MB00267J","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"3771713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expediting dynamics approach to understand the influence of 14-3-3ζ causing metastatic cancer through the interaction of YAP1 and β-TRCP","authors":"Kamalesh D., Sriroopreddy Ramireddy, Raguraman P. and Sudandiradoss C.","doi":"10.1039/C7MB00271H","DOIUrl":"https://doi.org/10.1039/C7MB00271H","url":null,"abstract":"<p >The 14-3-3ζ protein acts as a molecular switch in regulating the TGF-β pathway, which alters from a tumor suppressor in the early stage of breast cancer to a promoter of metastasis in the late stage. This change is due to the binding of 14-3-3ζ with YAP1 and β-TRCP in premalignant and cancer cells, respectively. Owing to this inappropriate role of 14-3-3ζ when involved in cancer and metastasis, we predicted that Gln15, Glu17, Tyr211, and Gln219 are hotspot residues of 14-3-3ζ during its interaction with YAP1 protein. Similarly, we identified Gln15, Tyr211, Leu216, and Leu220 as hotspot residues of 14-3-3ζ during its interaction with β-TRCP protein. Targeting these residues of 14-3-3ζ can prevent cancer and metastasis caused by malfunctioning of the TGF-β pathway. In this work, we also predicted that YAP1 is an intrinsically disordered protein (IDP), and such proteins bind with other proteins <em>via</em> either an induced fit or a conformational selection mechanism. Intuitively, we found that 14-3-3ζ has high affinity towards phosphorylated YAP1 at Ser127 rather than unphosphorylated YAP1, which is in close agreement with previously reported experimental works. Thus, we performed an analysis by molecular dynamics simulations to reveal the conformational changes in YAP1 after phosphorylation at the atomistic level. Our work clearly illustrates the effect of phosphorylation on YAP1 in terms of conformational changes and the regulation of its function.</p>","PeriodicalId":90,"journal":{"name":"Molecular BioSystems","volume":" 10","pages":" 1981-1992"},"PeriodicalIF":3.743,"publicationDate":"2017-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1039/C7MB00271H","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"3762232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An efficient method to transcription factor binding sites imputation via simultaneous completion of multiple matrices with positional consistency†","authors":"Wei-Li Guo and De-Shuang Huang","doi":"10.1039/C7MB00155J","DOIUrl":"https://doi.org/10.1039/C7MB00155J","url":null,"abstract":"<p >Transcription factors (TFs) are DNA-binding proteins that have a central role in regulating gene expression. Identification of DNA-binding sites of TFs is a key task in understanding transcriptional regulation, cellular processes and disease. Chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) enables genome-wide identification of <em>in vivo</em> TF binding sites. However, it is still difficult to map every TF in every cell line owing to cost and biological material availability, which poses an enormous obstacle for integrated analysis of gene regulation. To address this problem, we propose a novel computational approach, TFBSImpute, for predicting additional TF binding profiles by leveraging information from available ChIP-seq TF binding data. TFBSImpute fuses the dataset to a 3-mode tensor and imputes missing TF binding signals <em>via</em> simultaneous completion of multiple TF binding matrices with positional consistency. We show that signals predicted by our method achieve overall similarity with experimental data and that TFBSImpute significantly outperforms baseline approaches, by assessing the performance of imputation methods against observed ChIP-seq TF binding profiles. Besides, motif analysis shows that TFBSImpute preforms better in capturing binding motifs enriched in observed data compared with baselines, indicating that the higher performance of TFBSImpute is not simply due to averaging related samples. We anticipate that our approach will constitute a useful complement to experimental mapping of TF binding, which is beneficial for further study of regulation mechanisms and disease.</p>","PeriodicalId":90,"journal":{"name":"Molecular BioSystems","volume":" 9","pages":" 1827-1837"},"PeriodicalIF":3.743,"publicationDate":"2017-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1039/C7MB00155J","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"3867419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insights into the RNA binding mechanism of human L1-ORF1p: a molecular dynamics study†","authors":"Muthukumaran Rajagopalan, Sangeetha Balasubramanian and Amutha Ramaswamy","doi":"10.1039/C7MB00358G","DOIUrl":"https://doi.org/10.1039/C7MB00358G","url":null,"abstract":"<p >The recognition and binding of nucleic acids by ORF1p, an L1 retrotransposon protein, have not yet been clearly understood due to the lack of structural knowledge. The present study attempts to identify the probable single-stranded RNA binding pathway of trimeric ORF1p using computational methods like ligand mapping methodology combined with molecular dynamics simulations. Using the ligand mapping methodology, the possible RNA interacting sites on the surface of the trimeric ORF1p were identified. The crystal structure of the ORF1p timer and an RNA molecule of 29 nucleotide bases in length were used to generate the structure of the ORF1p complex based on information on predicted binding sites as well as the functional states of the CTD. The various complexes of ORF1p–RNA were generated using polyU, polyA and L1RNA sequences and were simulated for a period of 75 ns. The observed stable interaction pattern was used to propose the possible binding pathway. Based on the binding free energy for complex formation, both polyU and L1RNA complexes were identified as stable complexes, while the complex formed with polyA was the least stable one. Furthermore, the importance of the residues in the CC domain (Lys137 and Arg141), the RRM loop (Arg206, Arg210 and Arg211) and the CTD (Arg 261 and Arg262) of all three chains in stabilizing the wrapped RNA has been highlighted in this study. The presence of several electrostatic interactions including H-bond interactions increases the affinity towards RNA and hence plays a vital role in retaining the wrapped position of RNA around ORF1p. Altogether, this study presents one of the possible RNA binding pathways of ORF1p and clearly highlights the functional state of ORF1p visited during RNA binding.</p>","PeriodicalId":90,"journal":{"name":"Molecular BioSystems","volume":" 9","pages":" 1728-1743"},"PeriodicalIF":3.743,"publicationDate":"2017-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1039/C7MB00358G","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"3771714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DBA-induced caspase-3-dependent apoptosis occurs through mitochondrial translocation of cyt-c in the rat hippocampus","authors":"Wenbo Jiang, Yingying Chen, Bai Li and Shuying Gao","doi":"10.1039/C7MB00246G","DOIUrl":"https://doi.org/10.1039/C7MB00246G","url":null,"abstract":"<p >Dibromoacetic acid (DBA), a by-product of disinfection, develops in drinking water during chlorination or ozonation processes. Water intake is the main source of DBA exposure in humans, which is potentially neurotoxic. The present study investigated the neurotoxic effects of DBA by assessing the behavioral and biochemical characteristics of Sprague Dawley rats intragastrically treated with DBA at concentrations of 20, 50 and 125 mg kg<small>^?1</small> body weight for 28 consecutive days. The results indicated that animal weight gain and food consumption were not significantly affected by DBA. However, shuttle box tests showed increases in mistake frequency and reaction latency between the control and high-dose group. We found significant changes in hippocampal neurons by histomorphological observation. Additionally, biochemical analysis indicated enhanced production of reactive oxygen species (ROS) resulting in disruption of cellular antioxidant defense systems including decreased mitochondrial superoxide dismutase (SOD) activity and release of cytochrome <em>c</em> (cyt-<em>c</em>) from mitochondria into the cytosol, which can induce neuronal apoptosis. Furthermore, the increase of cyt-<em>c</em> in the cytosol enhanced caspase-3 and caspase-9 activity, which was confirmed by poly ADP-ribose polymerase-1 (PARP-1) cleavage to its signature fragment of 85 kDa and decreased levels of protein kinase C-δ (PKC-δ) in the hippocampus. Meanwhile, DBA treatment caused differential modulation of apoptosis-associated proteins and mRNAs for phosphorylated apoptosis signal regulating kinase 1 (p-ASK-1), phosphorylated c-jun N-terminal kinase (p-JNK), cyt-<em>c</em>, Bax, Bcl-2, caspase-9 and cleaved caspase-3 accompanied by DNA damage. Taken together, these data indicate that DBA may induce neurotoxicity <em>via</em> caspase-3-dependent apoptosis involving mitochondrial translocation of cyt-<em>c</em> in the rat hippocampus.</p>","PeriodicalId":90,"journal":{"name":"Molecular BioSystems","volume":" 9","pages":" 1863-1873"},"PeriodicalIF":3.743,"publicationDate":"2017-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1039/C7MB00246G","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"3762221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of cultured myotubes and fasting plasma metabolite profiles with mitochondrial dysfunction in type 2 diabetes subjects","authors":"Mohamad Hafizi Abu Bakar and Mohamad Roji Sarmidi","doi":"10.1039/C7MB00333A","DOIUrl":"https://doi.org/10.1039/C7MB00333A","url":null,"abstract":"<p >Accumulating evidence implicates mitochondrial dysfunction-induced insulin resistance in skeletal muscle as the root cause for the greatest hallmarks of type 2 diabetes (T2D). However, the identification of specific metabolite-based markers linked to mitochondrial dysfunction in T2D has not been adequately addressed. Therefore, we sought to identify the markers-based metabolomics for mitochondrial dysfunction associated with T2D. First, a cellular disease model was established using human myotubes treated with antimycin A, an oxidative phosphorylation inhibitor. Non-targeted metabolomic profiling of intracellular-defined metabolites on the cultured myotubes with mitochondrial dysfunction was then determined. Further, a targeted MS-based metabolic profiling of fasting blood plasma from normal (<em>n</em> = 32) and T2D (<em>n</em> = 37) subjects in a cross-sectional study was verified. Multinomial logical regression analyses for defining the top 5% of the metabolites within a 95% group were employed to determine the differentiating metabolites. The myotubes with mitochondrial dysfunction exhibited insulin resistance, oxidative stress and inflammation with impaired insulin signalling activities. Four metabolic pathways were found to be strongly associated with mitochondrial dysfunction in the cultured myotubes. Metabolites derived from these pathways were validated in an independent pilot investigation of the fasting blood plasma of healthy and diseased subjects. Targeted metabolic analysis of the fasting blood plasma with specific baseline adjustment revealed 245 significant features based on orthogonal partial least square discriminant analysis (PLS-DA) with a <em>p</em>-value &lt; 0.05. Among these features, 20 significant metabolites comprised primarily of branched chain and aromatic amino acids, glutamine, aminobutyric acid, hydroxyisobutyric acid, pyroglutamic acid, acylcarnitine species (acetylcarnitine, propionylcarnitine, dodecenoylcarnitine, tetradecenoylcarnitine hexadecadienoylcarnitine and oleylcarnitine), free fatty acids (palmitate, arachidonate, stearate and linoleate) and sphingomyelin (d18:2/16:0) were identified as predictive markers for mitochondrial dysfunction in T2D subjects. The current study illustrates how cellular metabolites provide potential signatures associated with the biochemical changes in the dysregulated body metabolism of diseased subjects. Our finding yields additional insights into the identification of robust biomarkers for T2D associated with mitochondrial dysfunction in cultured myotubes.</p>","PeriodicalId":90,"journal":{"name":"Molecular BioSystems","volume":" 9","pages":" 1838-1853"},"PeriodicalIF":3.743,"publicationDate":"2017-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1039/C7MB00333A","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"3867421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Understanding the role of tyrosine in glycogenin†","authors":"Ander Camiruaga, Imanol Usabiaga, Aran Insausti, Emilio J. Cocinero, Iker León and José A. Fernández","doi":"10.1039/C7MB00293A","DOIUrl":"https://doi.org/10.1039/C7MB00293A","url":null,"abstract":"<p >We explored the molecular basis of tyrosine as the docking amino acid for the first glucose molecule during the synthesis of glycogen. The IR spectra show that the aromatic ring acts as bait to keep the position where the next glucose unit has to bind clear, by luring non-desirable molecules towards the aromatic ring. Only, α-/β-glucose shows particular affinity for the O3H and O4H moieties.</p>","PeriodicalId":90,"journal":{"name":"Molecular BioSystems","volume":" 9","pages":" 1709-1712"},"PeriodicalIF":3.743,"publicationDate":"2017-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1039/C7MB00293A","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"3771711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The antiproliferative activity of di-2-pyridylketone dithiocarbamate is partly attributed to catalase inhibition: detailing the interaction by spectroscopic methods†","authors":"Cuiping Li, Youxun Liu, Yun Fu, Tengfei Huang, Lixia Kang and Changzheng Li","doi":"10.1039/C7MB00032D","DOIUrl":"https://doi.org/10.1039/C7MB00032D","url":null,"abstract":"<p >The bioactivity of drugs is attributed to their interaction with biological molecules, embodied in either their direct or indirect influence on enzyme activity and conformation. Di-2-pyridylketone hydrazine dithiocarbamate (DpdtC) exhibits significant antitumor activity in our preliminary study. We speculated that its activity may partly stem from enzyme inhibition due to strong metal chelating ability. To this end, we assessed its effect on catalase from erythrocytes and found evidence of inhibition, which was further confirmed by ROS determination <em>in vivo</em>. Thus, detailing the interaction between the agent and catalase <em>via</em> spectroscopic methods and molecular docking was required to obtain information on both the dynamics and thermodynamic parameters. The Lineweaver–Burk plot implied an uncompetitive pattern between DpdtC and catalase from beef liver, and IC<small>₅₀</small> = ～7 μM. The thermodynamic parameters from fluorescence quenching measurements indicated that DpdtC could bind to catalase with moderate affinity (<em>K</em><small>_a</small> = approximately 10<small>⁴</small> M<small>^?1</small>). CD spectra revealed that DpdtC could significantly disrupt the secondary structure of catalase. Docking studies indicated that DpdtC bound to a flexible region of catalase, involving hydrogen bonds and salt bond; this was consistent with thermodynamic results from spectral investigations. Our data clearly showed that catalase inhibition of DpdtC was not due to direct chelation of iron from heme (killing), but through an allosteric effect. Thus, it can be concluded that the antiproliferative activity of DpdtC is partially attributed to its catalase inhibition.</p>","PeriodicalId":90,"journal":{"name":"Molecular BioSystems","volume":" 9","pages":" 1817-1826"},"PeriodicalIF":3.743,"publicationDate":"2017-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1039/C7MB00032D","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"3867418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}