bluuebunny/crossref_metadata_2025_split huggingface dataset:
A nonsense mutation in Myelin Protein Zero causes congenital hypomyelination neuropathy through altered P0 membrane targeting and gain of abnormal function
Authors: Fratta Pietro , Ornaghi Francesca , Dati Gabriele , Zambroni Desirée , Saveri Paola , Belin Sophie , D’Adamo Patrizia , Shy Michael , Quattrini Angelo , Laura Feltri M. , Wrabetz Lawrence 
Published: June 2018

AbstractProtein Zero (P0) is the major structural protein in peripheral myelin and mutations in the Myelin Protein Zero (Mpz) gene produce wide ranging hereditary neuropathy phenotypes. To gain insight in the mechanisms underlying a particularly severe form, congenital hypomyelination (CH), we targeted mouse Mpz to encode P0Q215X, a nonsense mutation associated with the disease, that we show escapes nonsense mediated decay and is expressed in CH patient nerves. The knock-in mice express low levels of the resulting truncated protein, producing a milder phenotype when compared to patients, allowing to dissect the subtle pathogenic mechanisms occurring in otherwise very compromised peripheral myelin. We find that P0Q215X does not elicit an unfolded protein response, which is a key mechanism for other pathogenic MPZ mutations, but is instead aberrantly trafficked to non-myelin plasma membranes and induces defects in radial sorting of axons by Schwann cells (SC). We show that the loss of the C-terminal YAML motif is responsible for P0 mislocalisation, as its addition is able to restore correct P0Q215X trafficking in vitro. Lastly, we show that P0Q215X acts through dose-dependent gain of abnormal function, as wildtype P0 is unable to rescue the hypomyelination phenotype. Collectively, these data indicate that alterations at the premyelinating stage, linked to altered targeting of P0, may be responsible for CH, and that different types of gain of abnormal function produce the diverse neuropathy phenotypes associated with MPZ, supporting future allele-specific therapeutic silencing strategies.
Citizen science data enhance spatio-temporal extent and resolution of animal population studies
Authors: Sun Catherine C. , Fuller Angela K. , Hurst Jeremy E. 
Published: June 2018

AbstractInformed management and conservation decisions for animal populations often require data at sufficient geographic, temporal, and demographic resolutions for precise and unbiased estimates of parameters including population size and demographic rates. Recently developed integrated population models estimate such parameters by unifying population presence-absence and demographic data, and we demonstrate how citizen science offers a cost-efficient mechanism to collect such data. We describe the early results of iSeeMammals, a citizen science project that collects opportunistic data on the black bear population in New York State by enlisting volunteers to collect data through observations, hikes, and trail cameras. In 10 months, iSeeMammals increased the spatio-temporal extent of data collection by approximately fourfold and reduced cost by 83% compared to systematic sampling. In combination with other datasets in integrated population model frameworks, large, spatiotemporally extensive datasets from citizen science projects like iSeeMammals can help improve inferences about population-level structure and dynamics.
Simulation of P2X-mediated calcium signaling in microglia
Authors: Chun Ben , Stewart Bradley D. , Vaughan Darin , Bachstetter Adam D. , Kekenes-Huskey Peter M. 
Published: June 2018

AbstractMicroglia function is orchestrated through highly-coupled signaling pathways that depend on calcium (Ca2+). In response to extracellular adenosine triphosphate (ATP), transient increases in intracellular Ca2+driven through the activation of purinergic receptors, P2X and P2Y, are sufficient to promote cytokine synthesis and potentially their release. While steps comprising the pathways bridging purinergic receptor activation with transcriptional responses have been probed in great detail, a quantitative model for how these steps collectively control cytokine production has not been established. Here we developed a minimal computational model that quantitatively links extracellular stimulation of two prominent ionotropic puriner-gic receptors, P2X4and P2X7, with the graded production of a gene product, namely the tumor necrosis factorα(TNFα) cytokine. In addition to Ca2+handling mechanisms common to eukaryotic cells, our model includes microglia-specific processes including ATP-dependent P2X4and P2X7activation, activation of NFAT transcription factors, and TNFαproduction. Parameters for this model were optimized to reproduce published data for these processes, where available. With this model, we determined the propensity for TNFαproduction in microglia, subject to a wide range of ATP exposure amplitudes, frequencies and durations that the cells could encounterin vivo.Furthermore, we have investigated the extent to which modulation of the signal transduction pathways influence TNFαproduction. Our key findings are that TNFαproduction via P2X4is maximized at low ATP when subject to high frequency ATP stimulation, whereas P2X7contributes most significantly at millimolar ATPranges. Given that Ca2+homeostasis in microglia is profoundly important to its function, this computational model provides a quantitative framework to explore hypotheses pertaining to microglial physiology.
Spatial Organization of Rho GTPase signaling by RhoGEF/RhoGAP proteins
Authors: Müller Paul M. , Rademacher Juliane , Bagshaw Richard D. , Alp Keziban M. , Giudice Girolamo , Heinrich Louise E. , Barth Carolin , Eccles Rebecca L. , Sanchez-Castro Marta , Brandenburg Lennart , Mbamalu Geraldine , Tucholska Monika , Spatt Lisa , Wortmann Celina , Czajkowski Maciej T. , Welke Robert-William , Zhang Sunqu , Nguyen Vivian , Rrustemi Trendelina , Trnka Philipp , Freitag Kiara , Larsen Brett , Popp Oliver , Mertins Philipp , Bakal Chris , Gingras Anne-Claude , Pertz Olivier , Roth Frederick P. , Colwill Karen , Pawson Tony , Petsalaki Evangelia , Rocks Oliver 
Published: June 2018

AbstractRho GTPases control cell morphogenesis and thus fundamental processes in all eukaryotes. They are regulated by 145 RhoGEF and RhoGAP multi-domain proteins in humans. How the Rho signaling system is organized to generate localized responses in cells and prevent their spreading is not understood. Here, we systematically characterized the substrate specificities, localization and interactome of the RhoGEFs/RhoGAPs and revealed their critical role in contextualizing and spatially delimiting Rho signaling. They localize to multiple compartments providing positional information, are extensively interconnected to jointly coordinate their signaling networks and are widely autoinhibited to remain sensitive to local activation. RhoGAPs exhibit lower substrate specificity than RhoGEFs and may contribute to preserving Rho activity gradients. Our approach led us to uncover a multi-RhoGEF complex downstream of G-protein-coupled receptors controlling a Cdc42/RhoA crosstalk. The spatial organization of Rho signaling thus differs from other small GTPases and expands the repertoire of mechanisms governing localized signaling activity.
Mutational likeliness and entropy help to identify driver mutations and their functional role in cancer
Authors: Mattiuz Giorgio , Giorgio Salvatore Di , Tofani Lorenzo , Frandi Antonio , Donati Francesco , Brilli Matteo , Conticello Silvestro G 
Published: June 2018

AbstractAlterations in cancer genomes originate from mutational processes taking place throughout oncogenesis and cancer progression. We show that likeliness and entropy are two properties of somatic mutations crucial in cancer evolution, as cancer-driver mutations stand out, with respect to both of these properties, as being distinct from the bulk of passenger mutations. Our analysis can identify novel cancer driver genes and differentiate between gain and loss of function mutations.
Deep SNP: An End-to-end Deep Neural Network with Attention-based Localization for Break-point Detection in SNP Array Genomic data
Authors: Eghbal-zadeh Hamid , Fischer Lukas , Popitsch Niko , Kromp Florian , Taschner-Mandl Sabine , Koutini Khaled , Gerber Teresa , Bozsaky Eva , Ambros Peter F. , Ambros Inge M. , Widmer Gerhard , Moser Bernhard A. 
Published: June 2018

AbstractDiagnosis and risk stratification of cancer and many other diseases require the detection of genomic breakpoints as a prerequisite of calling copy number alterations (CNA). This, however, is still challenging and requires time-consuming manual curation. As deep-learning methods outperformed classical state-of-the-art algorithms in various domains and have also been successfully applied to life science problems including medicine and biology, we here propose Deep SNP, a novel Deep Neural Network to learn from genomic data. Specifically, we used a manually curated dataset from 12 genomic single nucleotide polymorphism array (SNPa) profiles as truth-set and aimed at predicting the presence or absence of genomic breakpoints, an indicator of structural chromosomal variations, in windows of 40,000 probes. We compare our results with well-known neural network models as well as Rawcopy though this tool is designed to predict breakpoints and in addition genomic segments with high sensitivity. We show, that Deep SNP is capable of successfully predicting the presence or absence of a breakpoint in large genomic windows and outperforms state-of-the-art neural network models. Qualitative examples suggest that integration of a localization unit may enable breakpoint detection and prediction of genomic segments, even if the breakpoint coordinates were not provided for network training. These results warrant further evaluation of DeepSNP for breakpoint localization and subsequent calling of genomic segments.
The washing machine as a reservoir for transmission of ESBL-producingKlebsiella oxytocain newborns
Authors: Schmithausen R.M. , Exner M. , Rösing C. , Savin M. , Hack S. , Bloomfield S.F. , Kaase M. , Gebel J. , Engelhart S. , Exner D. 
Published: June 2018

AbstractDuring the period from April 2012 to May 2013, 13 newborns and one child in a paediatric hospital ward in Germany were found to be colonised with a distinct clinical clone of an (extended spectrum β-lactamase) (ESBL)-producingKlebsiella oxytoca. This clone was specific to this hospital and had not been previously isolated in Germany.A source-tracking analysis was carried out to identify the source and transmission pathways of the ESBL-producingK. oxytocaclone. A systematic environmental survey of the ward and an audit of the procedures for cleaning and disinfecting surfaces, instruments, incubators, and washing machines was performed. Microbiological samples were obtained from environmental surfaces. Risk factors were analysed for epidemiological linkage.Isolates of an ESBL-producingK. oxytocawere found in the detergent drawer and on the rubber door seal of a washing machine and in two sinks. These strains were typed by pulsed-field-gel-electrophoresis (PFGE) and compared with the isolates from the newborns and their clothing and found to be identical. The retrospective analysis demonstrated that only newborns who had worn clothes that had been washed in the washing machine were colonised with the identical clone. After the washing machine was taken out of use, no further cases were detected over the following 4-year period.We conclude that washing machines are potential reservoirs and vectors for transmission ofEnterobacteriaceae, and likely other bacteria.ImportanceWashing machines should be further investigated as possible sites for horizontal gene transfer (ESBL-/carbapenemase-genes) and cross-contamination of clinically important Gram-negative strains. Particularly in the healthcare sector, the knowledge of possible (re-) contamination of laundry (patients clothes, staff uniforms) with multidrug-resistant Gram-negative bacteria could help to prevent and control nosocomial infections. To date, the potential of the washing machine as a source and vector of antibiotic-resistant gram-negative bacteria causing an outbreak in a clinical setting has not been investigated. This report shows that sampling of washing machines should be included in environmental audits associated with outbreak control management, and conditions for the laundering of baby 64 clothing should be reviewed.
Analysis and Correction of Inappropriate Image Duplication: The Molecular and Cellular Biology Experience
Authors: Bik Elisabeth M. , Fang Ferric C. , Kullas Amy L. , Davis Roger J. , Casadevall Arturo 
Published: June 2018

AbstractThe present study analyzed 960 papers published in Molecular and Cellular Biology (MCB) from 2009-2016 and found 59 (6.1%) to contain inappropriately duplicated images. The 59 instances of inappropriate image duplication led to 42 corrections, 5 retractions and 12 instances in which no action was taken. Our experience suggests that the majority of inappropriate image duplications result from errors during figure preparation that can be remedied by correction. Nevertheless, ~10% of papers with inappropriate image duplications in MCB were retracted. If this proportion is representative, then as many as 35,000 papers in the literature are candidates for retraction due to image duplication. The resolution of inappropriate image duplication concerns after publication required an average of 6 h of journal staff time per published paper. MCB instituted a pilot program to screen images of accepted papers prior to publication that identified 12 manuscripts (14.5% out of 83) with image concerns in two months. The screening and correction of papers before publication required an average of 30 min of staff time per problematic paper. Image screening can identify papers with problematic images prior to publication, reduces post-publication problems and requires significantly less staff time than the correction of problems after publication.
Modeling of DNA replication in rapidly growing bacteria with one and two replication origins
Authors: Retkute Renata , Hawkins Michelle , Rudolph Christian J. , Nieduszynski Conrad A. 
Published: June 2018

AbstractIn rapidly growing bacteria initiation of DNA replication occurs at intervals shorter than the time required for completing genome duplication, leading to overlapping rounds of replication. We propose a mathematical model of DNA replication defined by the periodicity of replication initiation. Our model predicts that a steeper gradient of the replication profile is to be expected in origin proximal regions due to the overlapping rounds of synthesis. By comparing our model with experimental data from a strain with an additional replication origin, we predict defined alterations to replication parameters: (i) a reduced fork velocity when there were twice as many forks as normal; (ii) a slower fork speed if forks move in a direction opposite to normal, in line with head-on replication-transcription collisions being a major obstacle for fork progression; (iii) slower cell doubling for a double origin strain compared to wild-type cells; and (iv) potentially an earlier initiation of replication at the ectopic origin than at the natural origin, which, however, does not a˙ect the overall time required to complete synthesis.
Modification and de novo design of non-ribosomal peptide synthetases (NRPS) using specific assembly points within condensation domains
Authors: Bozhüyük Kenan A. J. , Linck Annabell , Tietze Andreas , Wesche Frank , Nowak Sarah , Fleischhacker Florian , Bode Helge B. 
Published: June 2018

AbstractMany important natural products are produced by non-ribosomal peptide synthetases (NRPSs) 1.These giant enzyme machines activate amino acids in an assembly line fashion in which a set of catalytically active domains is responsible for the section, activation, covalent binding and connection of a specific amino acid to the growing peptide chain 1,2. Since NRPS are not restricted to the incorporation of the 20 proteinogenic amino acids, their efficient manipulation would give access to a diverse range of peptides available biotechnologically. Here we describe a new fusion point inside condensation (C) domains of NRPSs that enables the efficient production of peptides, even containing non-natural amino acids, in yields higher than 280 mg/L. The technology called eXchange Unit 2.0 (XU2.0) also allows the generation of targeted peptide libraries and therefore might be suitable for the future identification of bioactive peptide derivatives for pharmaceutical and other applications.
The Ly6/uPAR protein Bouncer is necessary and sufficient for species-specific fertilization
Authors: Herberg Sarah , Gert Krista R. , Schleiffer Alexander , Pauli Andrea 
Published: June 2018

AbstractFertilization is fundamental for sexual reproduction, yet its molecular mechanisms are poorly understood. Here, we identify an oocyte-expressed Ly6/uPAR protein, which we call Bouncer, as a crucial fertilization factor in zebrafish. We show that membrane-bound Bouncer mediates sperm-egg binding and is thus essential for sperm entry into the egg. Remarkably, Bouncer is not only required for sperm-egg interaction, but also sufficient to allow cross-species fertilization between zebrafish and medaka, two fish species that diverged over 150 million years ago. Our study thus identifies Bouncer as a key determinant of species-specific fertilization in fish. Bouncer’s closest homolog in tetrapods, SPACA4, is restricted to the male gonad in internally fertilizing vertebrates, suggesting that our findings in fish have relevance to human biology.
Drosophila small ovaryencodes a zinc-finger repressor required for ovarian differentiation
Authors: Benner Leif , Castro Elias A. , Whitworth Cale , Venken Koen J.T. , Yang Haiwang , Oliver Brian , Cook Kevin R. , Lerit Dorothy A. 
Published: June 2018

AbstractRepression is essential for coordinated cell type-specific gene regulation and controlling the expression of transposons. In theDrosophilaovary, stem cell regeneration and differentiation requires controlled gene expression, with derepression leading to tissue degeneration and ovarian tumors. Likewise, the ovary is acutely sensitive to deleterious consequences of transposon derepression. Thesmall ovary(sov) locus was identified in a female sterile screen, and mutants show dramatic ovarian morphogenesis defects. We mapped the locus to the uncharacterized geneCG14438, which encodes a zinc-finger protein that colocalizes with the essential Heterochromatin Protein 1 (HP1a). We demonstrate that Sov functions to repress inappropriate cell signaling, silence transposons, and suppress position-effect variegation in the eye, suggesting a central role in heterochromatin stabilization.
TP53mutations promote immunogenic activity in breast cancer
Authors: Liu Zhixian , Jiang Zehang , Gao Yingsheng , Wang Lirui , Chen Cai , Wang Xiaosheng 
Published: June 2018

AbstractBackgroundAlthough immunotherapy has recently achieved clinical successes in a variety of cancers, thus far there is no any immunotherapeutic strategy for breast cancer (BC). Thus, it is important to discover biomarkers for identifying the BC patients responsive to immunotherapy.TP53mutations were often associated with worse clinical outcome in BC, of which the triple-negative BC (TNBC) has a highTP53mutation rate (approximately 80%). TNBC is high-risk due to its high invasiveness, and lack of targeted therapy. To explore a potentially promising therapeutic option for theTP53-mutated BC subtype, we studied the associations betweenTP53mutations and immunogenic activity in BC.MethodsWe compared enrichment levels of 26 immune gene-sets that indicated activities of diverse immune cells, functions, and pathways betweenTP53-mutated andTP53-wildtype BCs based on two large-scale BC multi-omics data. Moreover, we explored the molecular cues that were associated with the differences in immunogenic activity betweenTP53-mutated andTP53-wildtype BCs. Furthermore, we performed experimental validation of the findings from bioinformatics analysis.ResultsWe found that almost all analyzed immune gene-sets had significantly higher enrichment levels inTP53-mutated BCs compared toTP53-wildtype BCs. Moreover, our experiments confirmed that mutant p53 could increase BC immunogenicity. Furthermore, our computational and experimental results showed thatTP53mutations could promote BC immunogenicityviaregulation of the p53-mediated pathways including cell cycle, apoptosis, Wnt, Jak-STAT, NOD-like receptor, and glycolysis. Interestingly, we found that elevated immune activities were likely to be associated with better survival prognosis inTP53-mutated BCs, but not necessarily inTP53-wildtype BCs.ConclusionsTP53mutations promote immunogenic activity in breast cancer. This finding demonstrates a different effect of p53 dysfunction on tumor immunogenicity from that of previous studies, suggesting that theTP53mutation status could be a useful biomarker for stratifying BC patients responsive to immunotherapy.
ATR repression at telomeres by POT1a and POT1b: RPA exclusion and interference by CST
Authors: Kratz Katja , Lange Titia de 
Published: June 2018

ABSTRACTTelomeres carry a constitutive 3’ overhang that can bind RPA and activate ATR signaling. POT1a, a single-stranded (ss) DNA binding protein in mouse shelterin, has been proposed to repress ATR signaling by preventing RPA binding. Repression of ATR at telomeres requires the TPP1/TIN2 mediated tethering of POT1a to the the rest of the shelterin complex situated on the ds telomeric DNA. The simplest version of the tethered exclusion model for ATR repression suggests that the only critical features of POT1a are its connection to shelterin and its binding to ss telomeric DNA binding. In agreement with the model, we show that a shelterin-tethered RPA70 mutant, lacking the ATR recruitment domain, is effective in repressing ATR signaling at telomeres. However, arguing against the simple tethered exclusion model, the nearly identical POT1b subunit of shelterin is much less proficient in ATR repression than POT1a. We now show that POT1b has the intrinsic ability to fully repress ATR but is prevented from doing so when bound to the CST/Polα/primase complex. The data establish that shelterin represses ATR with a tethered ssDNA-binding domain that excludes RPA from the 3’ overhang and suggest that ATR repression does not require the interaction of POT1 with the 3’ end or G4 DNA.
Slow Normal Modes of Proteins are Accurately Reproduced across Different Platforms
Authors: Na Hyuntae , ben-Avraham Daniel , Tirion Monique M. 
Published: June 2018

AbstractThe Protein Data Bank (PDB) [1] contains the atomic structures of over 105biomolecules with better than 2.8Å resolution. The listing of the identities and coordinates of the atoms comprising each macromolecule permits an analysis of the slow-time vibrational response of these large systems to minor perturbations. 3D video animations of individual modes of oscillation demonstrate how regions interdigitate to create cohesive collective motions, providing a comprehensive framework for and familiarity with the overall 3D architecture. Furthermore, the isolation and representation of the softest, slowest deformation coordinates provide opportunities for the development of mechanical models of enzyme function. The eigenvector decomposition, therefore, must be accurate, reliable as well as rapid to be generally reported upon. We obtain the eigenmodes of a 1.2Å 34kDa PDB entry using either exclusively heavy atoms or partly or fully reduced atomic sets; Cartesian or internal coordinates; interatomic force fields derived either from a full Cartesian potential, a reduced atomic potential or a Gaussian distance-dependent potential; and independently developed software. These varied technologies are similar in that each maintains proper stereochemistry either by use of dihedral degrees of freedom which freezes bond lengths and bond angles, or by use of a full atomic potential that includes realistic bond length and angle restraints. We find that the shapes of the slowest eigenvectors are nearly identical, not merely similar.