bluuebunny/crossref_metadata_2025_split huggingface dataset:
Coarse-grained versus atomistic simulations: realistic interaction free energies for real proteins
Authors: May Ali , Pool René , van Dijk Erik , Bijlard Jochem , Abeln Sanne , Heringa Jaap , Feenstra K. Anton 
Published: November 2013

AbstractMotivation: To assess whether two proteins will interact under physiological conditions, information on the interaction free energy is needed. Statistical learning techniques and docking methods for predicting protein–protein interactions cannot quantitatively estimate binding free energies. Full atomistic molecular simulation methods do have this potential, but are completely unfeasible for large-scale applications in terms of computational cost required. Here we investigate whether applying coarse-grained (CG) molecular dynamics simulations is a viable alternative for complexes of known structure.Results: We calculate the free energy barrier with respect to the bound state based on molecular dynamics simulations using both a full atomistic and a CG force field for the TCR–pMHC complex and the MP1–p14 scaffolding complex. We find that the free energy barriers from the CG simulations are of similar accuracy as those from the full atomistic ones, while achieving a speedup of &gt;500-fold. We also observe that extensive sampling is extremely important to obtain accurate free energy barriers, which is only within reach for the CG models. Finally, we show that the CG model preserves biological relevance of the interactions: (i) we observe a strong correlation between evolutionary likelihood of mutations and the impact on the free energy barrier with respect to the bound state; and (ii) we confirm the dominant role of the interface core in these interactions. Therefore, our results suggest that CG molecular simulations can realistically be used for the accurate prediction of protein–protein interaction strength.Availability and implementation: The python analysis framework and data files are available for download at http://www.ibi.vu.nl/downloads/bioinformatics-2013-btt675.tgz.Contact: k.a.feenstra@vu.nlSupplementary information: Supplementary data are available at Bioinformatics online.
DiSWOP: a novel measure for cell-level protein network analysis in localized proteomics image data
Authors: Kovacheva Violeta N. , Khan Adnan M. , Khan Michael , Epstein David B. A. , Rajpoot Nasir M. 
Published: November 2013

Abstract
Motivation: New bioimaging techniques have recently been proposed to visualize the colocation or interaction of several proteins within individual cells, displaying the heterogeneity of neighbouring cells within the same tissue specimen. Such techniques could hold the key to understanding complex biological systems such as the protein interactions involved in cancer. However, there is a need for new algorithmic approaches that analyze the large amounts of multi-tag bioimage data from cancerous and normal tissue specimens to begin to infer protein networks and unravel the cellular heterogeneity at a molecular level.
Results: The proposed approach analyzes cell phenotypes in normal and cancerous colon tissue imaged using the robotically controlled Toponome Imaging System microscope. It involves segmenting the 4',6-diamidino-2-phenylindole-labelled image into cells and determining the cell phenotypes according to their protein–protein dependence profile. These were analyzed using two new measures, Difference in Sums of Weighted cO-dependence/Anti-co-dependence profiles (DiSWOP and DiSWAP) for overall co-expression and anti-co-expression, respectively. These novel quantities were extracted using 11 Toponome Imaging System image stacks from either cancerous or normal human colorectal specimens. This approach enables one to easily identify protein pairs that have significantly higher/lower co-expression levels in cancerous tissue samples when compared with normal colon tissue.
Availability and implementation: http://www2.warwick.ac.uk/fac/sci/dcs/research/combi/research/bic/diswop.
Contact: v.n.kovacheva@warwick.ac.uk or Nasir.Rajpoot@ieee.org
Supplementary Information: Supplementary data are available at Bioinformatics online.
Protein-driven inference of miRNA–disease associations
Authors: Mørk Søren , Pletscher-Frankild Sune , Palleja Caro Albert , Gorodkin Jan , Jensen Lars Juhl 
Published: November 2013

Abstract
Motivation: MicroRNAs (miRNAs) are a highly abundant class of non-coding RNA genes involved in cellular regulation and thus also diseases. Despite miRNAs being important disease factors, miRNA–disease associations remain low in number and of variable reliability. Furthermore, existing databases and prediction methods do not explicitly facilitate forming hypotheses about the possible molecular causes of the association, thereby making the path to experimental follow-up longer.
Results: Here we present miRPD in which miRNA–Protein–Disease associations are explicitly inferred. Besides linking miRNAs to diseases, it directly suggests the underlying proteins involved, which can be used to form hypotheses that can be experimentally tested. The inference of miRNAs and diseases is made by coupling known and predicted miRNA–protein associations with protein–disease associations text mined from the literature. We present scoring schemes that allow us to rank miRNA–disease associations inferred from both curated and predicted miRNA targets by reliability and thereby to create high- and medium-confidence sets of associations. Analyzing these, we find statistically significant enrichment for proteins involved in pathways related to cancer and type I diabetes mellitus, suggesting either a literature bias or a genuine biological trend. We show by example how the associations can be used to extract proteins for disease hypothesis.
Availability and implementation: All datasets, software and a searchable Web site are available at http://mirpd.jensenlab.org.
Contact: lars.juhl.jensen@cpr.ku.dk or gorodkin@rth.dk
MemBuilder: a web-based graphical interface to build heterogeneously mixed membrane bilayers for the GROMACS biomolecular simulation program
Authors: Ghahremanpour Mohammad Mehdi , Arab Seyed Shahriar , Aghazadeh Saman Biook , Zhang Jin , van der Spoel David 
Published: November 2013

Abstract
Motivation: Molecular dynamics (MD) simulations have had a profound impact on studies of membrane proteins during past two decades, but the accuracy of MD simulations of membranes is limited by the quality of membrane models and the applied force fields. Membrane models used in MD simulations mostly contain one kind of lipid molecule. This is far from reality, for biological membranes always contain more than one kind of lipid molecule. Moreover, the lipid composition and their distribution are functionally important. As a result, there is a necessity to prepare more realistic lipid membranes containing different types of lipids at physiological concentrations.
Results: To automate and simplify the building process of heterogeneous lipid bilayers as well as providing molecular topologies for included lipids based on both united and all-atom force fields, we provided MemBuilder as a web-based graphical user interface.
Availability and implementation: MemBuilder is a free web server available from www.membuilder.org.
Contact: sh.arab@modares.ac.ir
In silico site of metabolism prediction for human UGT-catalyzed reactions
Authors: Peng Jianlong , Lu Jing , Shen Qiancheng , Zheng Mingyue , Luo Xiaomin , Zhu Weiliang , Jiang Hualiang , Chen Kaixian 
Published: November 2013

Abstract
Motivation: The human uridine diphosphate-glucuronosyltransferase enzyme family catalyzes the glucuronidation of the glycosyl group of a nucleotide sugar to an acceptor compound (substrate), which is the most common conjugation pathway that serves to protect the organism from the potential toxicity of xenobiotics. Moreover, it could affect the pharmacological profile of a drug. Therefore, it is important to identify the metabolically labile sites for glucuronidation.
Results: In the present study, we developed four in silico models to predict sites of glucuronidation, for four major sites of metabolism functional groups, i.e. aliphatic hydroxyl, aromatic hydroxyl, carboxylic acid or amino nitrogen, respectively. According to the mechanism of glucuronidation, a series of ‘local’ and ‘global’ molecular descriptors characterizing the atomic reactivity, bonding strength and physical–chemical properties were calculated and selected with a genetic algorithm-based feature selection approach. The constructed support vector machine classification models show good prediction performance, with the balanced accuracy ranging from 0.88 to 0.96 on test set. For further validation, our models can successfully identify 84% of experimentally observed sites of metabolisms for an external test set containing 54 molecules.
Availability and implementation: The software somugt based on our models is available at www.dddc.ac.cn/adme/jlpeng/somugt_win32.zip.
Contact: xmluo@simm.ac.cn or myzheng@mail.shcnc.ac.cn
Supplementary information: Supplementary data are available at Bioinformatics online.
The impact of freeze-out on collapsing molecular clouds
Authors: Hocuk S. , Cazaux S. , Spaans M. 
Published: November 2013

Abstract
Atoms and molecules, and in particular CO, are important coolants during the evolution of interstellar star-forming gas clouds. The presence of dust grains, which allow many chemical reactions to occur on their surfaces, strongly impacts the chemical composition of a cloud. At low temperatures, dust grains can lock up species from the gas phase which freeze out and form ices. In this sense, dust can deplete important coolants. Our aim is to understand the effects of freeze-out on the thermal balance and the evolution of a gravitationally bound molecular cloud. For this purpose, we perform 3D hydrodynamical simulations with the adaptive mesh code flash. We simulate a gravitationally unstable cloud under two different conditions, with and without grain surface chemistry. We let the cloud evolve until one free-fall time is reached and track the thermal evolution and the abundances of species during this time. We see that at a number density of 104 cm−3 most of the CO molecules are frozen on dust grains in the run with grain surface chemistry, thereby depriving the most important coolant. As a consequence, we find that the temperature of the gas rises up to ∼25 K. The temperature drops once again due to gas–grain collisional cooling when the density reaches a few × 104 cm−3. We conclude that grain surface chemistry not only affects the chemical abundances in the gas phase, but also leaves a distinct imprint in the thermal evolution that impacts the fragmentation of a star-forming cloud. As a final step, we present the equation of state of a collapsing molecular cloud that has grain surface chemistry included.
Phylogeny of Cas9 determines functional exchangeability of dual-RNA and Cas9 among orthologous type II CRISPR-Cas systems
Authors: Fonfara Ines , Le Rhun Anaïs , Chylinski Krzysztof , Makarova Kira S. , Lécrivain Anne-Laure , Bzdrenga Janek , Koonin Eugene V. , Charpentier Emmanuelle 
Published: November 2013

Abstract
The CRISPR-Cas-derived RNA-guided Cas9 endonuclease is the key element of an emerging promising technology for genome engineering in a broad range of cells and organisms. The DNA-targeting mechanism of the type II CRISPR-Cas system involves maturation of tracrRNA:crRNA duplex (dual-RNA), which directs Cas9 to cleave invading DNA in a sequence-specific manner, dependent on the presence of a Protospacer Adjacent Motif (PAM) on the target. We show that evolution of dual-RNA and Cas9 in bacteria produced remarkable sequence diversity. We selected eight representatives of phylogenetically defined type II CRISPR-Cas groups to analyze possible coevolution of Cas9 and dual-RNA. We demonstrate that these two components are interchangeable only between closely related type II systems when the PAM sequence is adjusted to the investigated Cas9 protein. Comparison of the taxonomy of bacterial species that harbor type II CRISPR-Cas systems with the Cas9 phylogeny corroborates horizontal transfer of the CRISPR-Cas loci. The reported collection of dual-RNA:Cas9 with associated PAMs expands the possibilities for multiplex genome editing and could provide means to improve the specificity of the RNA-programmable Cas9 tool.
Nucleotide selection by the Y-family DNA polymerase Dpo4 involves template translocation and misalignment
Authors: Brenlla Alfonso , Markiewicz Radoslaw P. , Rueda David , Romano Louis J. 
Published: November 2013

AbstractY-family DNA polymerases play a crucial role in translesion DNA synthesis. Here, we have characterized the binding kinetics and conformational dynamics of the Y-family polymerase Sulfolobus solfataricus P2 DNA polymerase IV (Dpo4) using single-molecule fluorescence. We find that in the absence of dNTPs, the binary complex shuttles between two different conformations within ∼1 s. These data are consistent with prior crystal structures in which the nucleotide binding site is either occupied by the terminal base pair (preinsertion conformation) or empty following Dpo4 translocation by 1 base pair (insertion conformation). Most interestingly, on dNTP binding, only the insertion conformation is observed and the correct dNTP stabilizes this complex compared with the binary complex, whereas incorrect dNTPs destabilize it. However, if the n+1 template base is complementary to the incoming dNTP, a structure consistent with a misaligned template conformation is observed, in which the template base at the n position loops out. This structure provides evidence for a Dpo4 mutagenesis pathway involving a transient misalignment mechanism.
DNA transposition by protein transduction of the piggyBac transposase from lentiviral Gag precursors
Authors: Cai Yujia , Bak Rasmus O. , Krogh Louise Bechmann , Staunstrup Nicklas H. , Moldt Brian , Corydon Thomas J. , Schrøder Lisbeth Dahl , Mikkelsen Jacob Giehm 
Published: November 2013

Abstract
DNA transposon-based vectors have emerged as gene vehicles with a wide biomedical and therapeutic potential. So far, genomic insertion of such vectors has relied on the co-delivery of genetic material encoding the gene-inserting transposase protein, raising concerns related to persistent expression, insertional mutagenesis and cytotoxicity. This report describes potent DNA transposition achieved by direct delivery of transposase protein. By adapting integrase-deficient lentiviral particles (LPs) as carriers of the hyperactive piggyBac transposase protein (hyPBase), we demonstrate rates of DNA transposition that are comparable with the efficiency of a conventional plasmid-based strategy. Embedded in the Gag polypeptide, hyPBase is robustly incorporated into LPs and liberated from the viral proteins by the viral protease during particle maturation. We demonstrate lentiviral co-delivery of the transposase protein and vector RNA carrying the transposon sequence, allowing robust DNA transposition in a variety of cell types. Importantly, this novel delivery method facilitates a balanced cellular uptake of hyPBase, as shown by confocal microscopy, and allows high-efficiency production of clones harboring a single transposon insertion. Our findings establish engineered LPs as a new tool for transposase delivery. We believe that protein transduction methods will increase applicability and safety of DNA transposon-based vector technologies.
MICROTUBULE-ASSOCIATED PROTEIN65 Is Essential for Maintenance of Phragmoplast Bipolarity and Formation of the Cell Plate inPhyscomitrella patens
Authors: Kosetsu Ken , de Keijzer Jeroen , Janson Marcel E. , Goshima Gohta 
Published: November 2013

AbstractThe phragmoplast, a plant-specific apparatus that mediates cytokinesis, mainly consists of microtubules (MTs) arranged in a bipolar fashion, such that their plus ends interdigitate at the equator. Membrane vesicles are thought to move along the MTs toward the equator and fuse to form the cell plate. Although several genes required for phragmoplast MT organization have been identified, the mechanisms that maintain the bipolarity of phragmoplasts remain poorly understood. Here, we show that engaging phragmoplast MTs in a bipolar fashion in protonemal cells of the moss Physcomitrella patens requires the conserved MT cross-linking protein MICROTUBULE-ASSOCIATED PROTEIN65 (MAP65). Simultaneous knockdown of the three MAP65s expressed in those cells severely compromised MT interdigitation at the phragmoplast equator after anaphase onset, resulting in the collapse of the phragmoplast in telophase. Cytokinetic vesicles initially localized to the anaphase midzone as normal but failed to further accumulate in the next several minutes, although the bipolarity of the MT array was preserved. Our data indicate that the presence of bipolar MT arrays is insufficient for vesicle accumulation at the equator and further suggest that MAP65-mediated MT interdigitation is a prerequisite for maintenance of bipolarity of the phragmoplast and accumulation and/or fusion of cell plate–destined vesicles at the equatorial plane.
Fatalism and short‐termism as cultural barriers to cardiac rehabilitation among underprivileged men
Authors: Savage Mathieu , Dumas Alex , Stuart Stephen A 
Published: November 2013

AbstractCardiovascular diseases are a leading cause of death and disability in Canada, and individuals of low socioeconomic status appear particularly vulnerable to such disorders. Although many health‐related institutions have promoted cardiovascular health and have created cardiac rehabilitation programmes, they have not attained their desired outcomes, especially amongst socioeconomically deprived men. Drawing on Pierre Bourdieu's sociocultural theory, this qualitative study aims to understand the social mechanisms underpinning the lifestyles and health practices of men who had suffered a cardiovascular incident requiring hospitalisation. In all, 20 interviews were conducted with francophone men aged 40 to 65 years living in the province of Québec, Canada. The analysis strongly suggests that the respondents' living conditions and disease were significant obstacles to their adoption of a healthy lifestyle. Their despair and pessimism, apparently originating in the harshness of their financial realities, physical limitations and social networks, led them to believe that they could do little to control their lives, thereby limiting the fulfillment of any long‐term ambitions. Therefore, the adoption of a habitus characterised by fatalistic and short‐term perceptions of health influenced their lifestyle choices, leading them to maintain lives that were in stark contrast with the recommendations made by health promotion experts.
A novel inhibitor of the insulin/IGF signaling pathway protects from age‐onset, neurodegeneration‐linked proteotoxicity
Authors: El‐Ami Tayir , Moll Lorna , Carvalhal Marques Filipa , Volovik Yuli , Reuveni Hadas , Cohen Ehud 
Published: November 2013

SummaryAging manipulation is an emerging strategy aimed to postpone the manifestation of late‐onset neurodegenerative disorders such as Alzheimer's (AD) and Huntington's diseases (HD) and to slow their progression once emerged. Reducing the activity of the insulin/IGF signaling cascade (IIS), a prominent aging‐regulating pathway, protects worms from proteotoxicity of various aggregative proteins, including the AD‐associated peptide, Aβ‐ and the HD‐linked peptide, polyQ40. Similarly, IGF1 signaling reduction protects mice from AD‐like disease. These discoveries suggest that IIS inhibitors can serve as new drugs for the treatment of neurodegenerative maladies including AD and HD. Here, we report that NT219, a novel IIS inhibitor, mediates a long‐lasting, highly efficient inhibition of this signaling cascade by a dual mechanism; it reduces the autophosphorylation of the IGF1 receptor and directs the insulin receptor substrates 1 and 2 (IRS 1/2) for degradation. NT219 treatment promotes stress resistance and protects nematodes from AD‐ and HD‐associated proteotoxicity without affecting lifespan. Our discoveries strengthen the theme that IIS inhibition has a therapeutic potential as a cure for neurodegenerative maladies and point at NT219 as a promising compound for the treatment of these disorders through a selective manipulation of aging.
Should brief interventions in primary care address alcohol problems more strongly?
Authors: McCambridge Jim , Rollnick Stephen 
Published: November 2013

AbstractBackgroundBrief interventions have well‐established small effects on alcohol consumption among hazardous and harmful drinkers in primary care, and national large‐scale programmes are being implemented in many countries for public health reasons.MethodsThis paper examines data from reviews and draws upon older brief intervention studies and recent developments in the literature on motivational interviewing to consider the capacity of brief interventions to benefit those with problems, including those with severe problems.ResultsEffects on alcohol problems have been shown much less consistently, and evidence cannot be claimed to be strong for any outcomes other than reduced consumption. Combinations of advice and motivational interviewing are a promising target for evaluation in trials, and more detailed studies of the conduct of brief interventions are needed.ConclusionsWe propose that brief interventions in primary care may be more effective if they offer appropriate content in a person‐centred manner, addressing patient concerns more directly.
Systematic review with meta‐analysis: clinical manifestations and management of autoimmune hepatitis in the elderly
Authors: Chen J. , Eslick G. D. , Weltman M. 
Published: November 2013

SummaryBackgroundAutoimmune hepatitis is an uncommon chronic progressive inflammatory disease of the liver, characterised by hypergammaglobulianemia, circulating autoantibodies, and interface hepatitis histologically. It is traditionally thought to be a disease of young women. However, recent epidemiological and retrospective studies suggest that it might be a disease predominantly of older women. Studies of AIH in elderly patients have been fairly limited.AimTo investigate the differences in the clinical presentations and the management of AIH in the elderly and the younger patients.MethodsWe conducted a search on MEDLINE (from 1946), PubMed (1946) and EMBASE (1949) through to November 2013 using the terms ‘autoimmune hepatitis in the elderly’, and the combinations of ‘Autoimmune hepatitis’ AND the following terms: ‘elderly’, ‘aging’, ‘older patients’, and ‘older’. The reference lists of relevant articles were also searched for appropriate studies.ResultsA total of 1063 patients were identified with AIH in 10 retrospective studies. The definition of ‘elderly’ ranged from 60 to 65 years; 264 elderly and 592 younger patients were included for analysis. Elderly, 24.8%, were more likely to present asymptomatically, cirrhotic at presentation and HLA‐DR4‐positive. They are less likely to be HLA‐DR3‐positive and to relapse after treatment withdrawal after complete remission.ConclusionsAIH is an important differential in elderly patients with cirrhosis or abnormal LFTs. Elderly are more likely to be cirrhotic and asymptomatic at presentation. Glucocorticoids use should be readily considered in the elderly patients as the current evidence suggests that they respond well to the therapy, with less relapse after treatment withdrawal.