bluuebunny/crossref_metadata_2025_split huggingface dataset:
SurA is a “Groove-y” Chaperone That Expands Unfolded Outer Membrane Proteins
Authors: Marx Dagan C. , Plummer Ashlee M. , Faustino Anneliese M. , Devlin Taylor , Roskopf Michaela A. , Leblanc Mathis J. , Lessen Henry J. , Amann Barbara T. , Fleming Patrick J. , Krueger Susan , Fried Stephen D. , Fleming Karen G. 
Published: December 2019

AbstractThe periplasmic chaperone network ensures the biogenesis of bacterial outer membrane proteins (OMPs) and has recently been identified as a promising target for antibiotics. SurA is the most important member of this network both due to its genetic interaction with the β-barrel assembly machinery complex as well as its ability to prevent unfolded OMP (uOMP) aggregation. Using only binding energy, the mechanism by which SurA carries out these two functions is not well understood. Here we use a combination of photo-crosslinking, mass spectrometry, solution scattering, and molecular modeling techniques to elucidate the key structural features that define how SurA solubilizes uOMPs. Our experimental data support a model in which SurA binds uOMPs in a groove formed between the core and P1 domains. This binding event results in a drastic expansion of the rest of the uOMP, which has many biological implications. Using these experimental data as restraints, we adopted an integrative modeling approach to create a sparse ensemble of models of a SurA•uOMP complex. We validated key structural features of the SurA•uOMP ensemble using independent scattering and chemical crosslinking data. Our data suggest that SurA utilizes three distinct binding modes to interact with uOMPs and that more than one SurA can bind a uOMP at a time. This work demonstrates that SurA operates in a distinct fashion compared to other chaperones in the OMP biogenesis network.Significance StatementOuter membrane proteins play critical roles in bacterial physiology and increasingly are exploited as antibiotic targets. SurA is the most important chaperone in the OMP biogenesis network and is thought to initiate their folding through an interaction with the BAM complex. We observe an unprecedented expansion of unfolded outer membrane proteins when bound to SurA. This expansion suggests a potential mechanism by which SurA can deliver uOMPs to the BAM complex. In addition, this study highlights the use of an integrative/hybrid structural biology approach and emerging methods to map highly heterogeneous structural ensembles such as that of an unfolded protein bound to a chaperone.
Design of Experiments for Fine-Mapping Quantitative Trait Loci in Livestock Populations
Authors: Wittenburg Dörte , Bonk Sarah , Doschoris Michael , Reyer Henry 
Published: December 2019

AbstractSingle nucleotide polymorphisms (SNPs) which capture a significant impact on a trait can be identified with genome-wide association studies. High linkage disequilibrium (LD) among SNPs makes it difficult to identify causative variants correctly. Thus, often target regions instead of single SNPs are reported. Sample size has not only a crucial impact on the precision of parameter estimates, it also ensures that a desired level of statistical power can be reached. We study the design of experiments for fine-mapping of signals of a quantitative trait locus in such a target region.A multi-locus model allows to identify causative variants simultaneously, to state their positions more precisely and to account for existing dependencies. Based on the commonly applied SNP-BLUP approach, we determine the z-score statistic for locally testing non-zero SNP effects and investigate its distribution under the alternative hypothesis. This quantity employs the theoretical instead of observed dependence between SNPs; it can be set up as a function of paternal and maternal LD for any given population structure.We simulated multiple paternal half-sib families and considered a target region of 1 Mbp. A bimodal distribution of estimated sample size was observed, particularly if more than two causative variants were assumed. The median of estimates constituted the final proposal of optimal sample size; it was consistently less than sample size estimated from single-SNP investigations which was used as a baseline approach. The second mode pointed to inflated sample sizes and could be explained by blocks of varying linkage phases leading to negative correlations between SNPs. Optimal sample size increased almost linearly with number of signals to be identified but depended much stronger on the assumption on heritability. For instance, three times as many samples were required if heritability was 0.1 compared to 0.3. These results enable the resource-saving design of future experiments for fine-mapping of candidate variants in structured and unstructured populations.
Zika and dengue viruses infecting wild-caught mosquitoes in an environmental protection area in Brazil
Authors: Barrio-Nuevo Karolina Morales , Medeiros-Sousa Antônio Ralph , Ceretti-Junior Walter , Fernandes Aristides , Rocco Iray Maria , Cunha Mariana Sequetin , Luchs Adriana , Mucci Luis Filipe , de Souza Renato Pereira , Marrelli Mauro Toledo 
Published: December 2019

AbstractSpecies of the genusFlavivirusare widespread in Brazil and are a major public health concern. The city of São Paulo is in a highly urbanized area with some green spaces which are used for recreation and where potential vertebrate hosts and mosquito vectors of these arboviruses can be found, a scenario that can contribute to the transmission of flaviviruses to humans. This study therefore sought to investigate natural flavivirus infection in mosquitoes collected in the Capivari-Monos Environmental Protection Area (EPA) in the south of the city. Monthly mosquito collections were carried out from March 2016 to April 2017 with CO2-baited CDC light traps. Specimens were identified morphologically and grouped in pools. A total of 260 pools of non-engorged females were inoculated into the C6/36 cell lineage after analysis by indirect immunofluorescence assay (IFA). IFA-positive specimens were tested by qRT-PCR with genus-specific primers targeting a region of ~260 nucleotides in the flavivirus NS5 gene, and the PCR products were sequenced to confirm and identify the flavivirus species.Anopheles(Kerteszia)cruziiandWyeomyia(Prosopolepis)confusawere the most frequent species collected. Zika virus (ZIKV) nucleotide sequences were detected in three mosquito species,An. cruzii,Limatus durhamiandWy. confusa, and dengue virus 2 (DENV-2) sequences inCulex. spp. andCulex. (Mel.)vaxus. To our knowledge, this is the first report of natural isolation of DENV-2 and ZIKV in sylvatic species of mosquitoes in the Capivari-Monos EPA. Our findings suggest that DENV-2 is present inCulexmosquitoes, and ZIKV inAnopheles,WyeomyiaandLimatus. The flavivirus species identified here are of medical importance; surveillance is therefore recommended in this EPA, where vertebrates and mosquitoes can act as flavivirus hosts and vectors.
A non-linear system patterns Rab5 GTPase on the membrane
Authors: Cezanne A , Lauer J , Solomatina A , Sbalzarini IF , Zerial M 
Published: December 2019

AbstractProteins can self-organize into spatial patterns via non-linear dynamic interactions on cellular membranes. Modelling and simulations have shown that small GTPases can generate patterns by coupling guanine nucleotide exchange factors (GEF) to effector binding, generating a positive feedback of GTPase activation and membrane recruitment. Here, we reconstituted the patterning of the small GTPase Rab5 and its GEF/effector complex Rabex5/Rabaptin5 on supported lipid bilayers as a model system for membrane patterning. We show that there is a “handover” of Rab5 from Rabex5 to Rabaptin5 upon nucleotide exchange. A minimal system consisting of Rab5, RabGDI and a complex of full length Rabex5/Rabaptin5 was necessary to pattern Rab5 into membrane domains. Surprisingly, a lipid membrane composition mimicking that of the early endosome was required for Rab5 patterning. The prevalence of GEF/effector coupling in nature suggests a possible universal system for small GTPase patterning involving both protein and lipid interactions.
Detection of aberrant splicing events in RNA-seq data with FRASER
Authors: Mertes Christian , Scheller Ines , Yépez Vicente A. , Çelik Muhammed H. , Liang Yingjiqiong , Kremer Laura S. , Gusic Mirjana , Prokisch Holger , Gagneur Julien 
Published: December 2019

AbstractAberrant splicing is a major cause of rare diseases, yet its prediction from genome sequence remains in most cases inconclusive. Recently, RNA sequencing has proven to be an effective complementary avenue to detect aberrant splicing. Here, we developed FRASER, an algorithm to detect aberrant splicing from RNA sequencing data. Unlike existing methods, FRASER captures not only alternative splicing but also intron retention events. This typically doubles the number of detected aberrant events and identified a pathogenic intron retention inMCOLN1. FRASER automatically controls for latent confounders, which are widespread and substantially affect sensitivity. Moreover, FRASER is based on a count distribution and multiple testing correction, reducing the number of calls by two orders of magnitude over commonly applied z score cutoffs, with a minor sensitivity loss. The application to rare disease diagnostics is demonstrated by reprioritizing a pathogenic aberrant exon truncation inTAZfrom a published dataset. FRASER is easy to use and freely available.
A PI3K-WIPI2 positive feedback loop allosterically activates LC3 lipidation in autophagy
Authors: Fracchiolla Dorotea , Chang Chunmei , Hurley James H. , Martens Sascha 
Published: December 2019

AbstractAutophagy degrades cytoplasmic cargo by its delivery to lysosomes within double membrane autophagosomes. Synthesis of the phosphoinositide PI(3)P by the autophagic PI 3-kinase complex I (PI3KC3-C1) and conjugation of ATG8/LC3 proteins to phagophore membranes by the ATG12–ATG5-ATG16L1 (E3) complex are two critical steps in autophagosome biogenesis, connected by WIPI2. Here we present a complete reconstitution of these events. On giant unilamellar vesicles (GUVs), LC3 lipidation is strictly dependent on the recruitment of WIPI2, which in turn depends on PI(3)P. Ectopically targeting E3 to membranes in the absence of WIPI2 is insufficient to support LC3 lipidation, demonstrating that WIPI2 allosterically activates the E3 complex. PI3KC3-C1 and WIPI2 mutually promote the recruitment of each other in a positive feedback loop. When both PI 3-kinase and LC3 lipidation reactions were carried out simultaneously, positive feedback between PI3KC3-C1 and WIPI2 led to rapid LC3 lipidation with kinetics similar to those seen in cellular autophagosome formation.SummaryAutophagy requires the synthesis of PI(3)P and the conjugation of LC3 to the phagophore membrane. We reconstituted these two reactions and their coupling by WIPI2, and showed that positive feedback between PI3KC3-C1 and WIPI2 leads to rapid LC3 lipidation by the ATG16L1 complex.
Prophylactic host behaviour discourages pathogen exploitation
Authors: Mitchell Evan , Wild Geoff 
Published: December 2019

SummaryMuch work has considered the evolution of pathogens, but little is known about how they respond to changes in host behaviour. We build a model where hosts are able to choose to engage in prophylactic measures that reduce the likelihood of disease transmission. This choice is mediated by costs and benefits associated with prophylaxis, but the fraction of hosts engaged in prophylaxis is also affected by population dynamics. We identify a critical cost threshold above which hosts do not engage in prophylaxis. Below the threshold, prophylactic host behaviour does occur and pathogen virulence, measured by the extent to which it exploits its host, is reduced by the action of selection relative to the level that would otherwise be predicted in the absence of prophylaxis. Our work emphasizes the significance of the dual nature of the trade-off faced by the pathogen between balancing transmission and recovery, and creating new infections in hosts engaging or not engaging in prophylaxis.
A Role for the Locus Coeruleus in the Modulation of Feeding
Authors: Sciolino Natale R. , Hsiang Madeline , Mazzone Christopher M. , Wilson Leslie R. , Plummer Nicholas W. , Amin Jaisal , Smith Kathleen G. , McGee Christopher A. , Fry Sydney A. , Yang Cindy X. , Powell Jeanne M. , Bruchas Michael R. , Kravitz Alexxai V. , Cushman Jesse D. , Krashes Michael J. , Cui Guohong , Jensen Patricia 
Published: December 2019

AbstractRecent data suggest that LC-NE neurons play a role in fear-induced suppression of feeding, but their endogenous activity in naturally behaving animals has not been explored. We found that endogenous activity of LC-NE neurons was enhanced during food approach and suppressed during food consumption, and that these food-evoked LC-NE responses were attenuated in sated mice. Interestingly, visual-evoked LC-NE activity was also attenuated in sated mice, demonstrating that internal satiety state modulates LC-NE encoding of multiple behavioral states. We also found that food intake could be attenuated by brief or longer durations of LC-NE activation. Lastly, we demonstrated that activation of LC neurons suppresses feeding and enhances avoidance and anxiety-like responding through a projection to the lateral hypothalamus. Collectively, our data suggest that LC-NE neurons modulate feeding by integrating both external cues (e.g., anxiogenic environmental cues) and internal drives (e.g., nutritional state).
BioFabric Visualization of Network Alignments
Authors: Desai Rishi M. , Longabaugh William J.R. , Hayes Wayne B. 
Published: December 2019

AbstractBackgroundDozens of global network alignment algorithms have been developed over the past fifteen years. Effective network visualization tools are lacking and would enhance our ability to gain an intuitive understanding of the strengths and weaknesses of these algorithms.ResultsWe have created a plugin to the existing network visualization tool BioFabric, calledVISNAB: Visualization of Network Alignments using BioFabric. We leverage BioFabric’s unique approach to layout (nodes are horizontal lines connected by vertical lines representing edges) to improve understanding of network alignment performance. Our visualization tool allows the user to clearly spot deficiencies in alignments that cannot be detected through simply evaluating and comparing standard numerical topological measures such as the Edge Coverage (EC) or Symmetric Substructure Score (S3). Furthermore, we provide new automatic layouts that allow researchers to identify problem areas in an alignment. Finally, our new definitions ofnode groupsandlink groupsthat arise from our visualization technique allows us to also introduce novel numeric measures for assessing alignment quality.ConclusionsOur new approach to visualize network alignments will allow researchers to gain a new, and better, understanding of the strengths and shortcomings of the many available network alignment algorithms.
Wash and the WASH Regulatory Complex function in Nuclear Envelope budding
Authors: Verboon Jeffrey M. , Nakamura Mitsutoshi , Decker Jacob R. , Davidson Kerri A. , Nandakumar Vivek , Parkhurst Susan M. 
Published: December 2019

SUMMARYNuclear envelope budding is a recently described phenomenon wherein large macromolecular complexes can be packaged inside the nucleus and be extruded through the nuclear membranes, completely bypassing nuclear pores. While factors have been identified both as cargos or actively involved in this process, much remains unknown about the molecules that generate the forces and membrane deformations which appear inherent. Using fluorescence and electron microscopy, biochemical and cell biological assays, and genetic perturbations in theDrosophilamodel, we identify Wash, its regulatory complex, and Arp2/3 as novel players in NE-budding. Surprisingly, Wash’s role in this process is bipotent and, independent of SHRC/Arp2/3, its perturbation disrupts the normal homotypic Lamin A/B meshworks that are necessary for NE-budding to occur. In addition to NE-budding emerging as important in additional cellular processes and organisms, its incredible similarity to herpesvirus egress suggests new avenues for exploration in both normal and disease biology.
Webina: An Open-Source Library and Web App that Runs AutoDock Vina Entirely in the Web Browser
Authors: Kochnev Yuri , Hellemann Erich , Cassidy Kevin C. , Durrant Jacob D. 
Published: December 2019

1AbstractMolecular docking is a computational technique for predicting how a small molecule might bind a macromolecular target. Among docking programs, AutoDock Vina is particularly popular. Like many docking programs, Vina requires users to download/install an executable file and to run that file from a Unix- or DOS-like command-line interface. Choosing proper configuration parameters and analyzing Vina output is also sometimes challenging. These issues are particularly problematic for students and novice researchers. We have created Webina, a new version of Vina, to address these challenges. Webina is a JavaScript/WebAssembly library that runs AutoDock Vina entirely in a web browser. To use Webina, users need only visit a Webina-enabled webpage. The docking calculations take place on the user’s own computer rather than a remote server. To encourage use, we have incorporated the Webina library into our own Webina web app. The app includes a convenient interface so users can easily setup their docking runs and analyze the results. Webina will be a useful open-source tool for the research and educational communities. A working version of the app can be accessed free of charge fromhttp://durrantlab.com/webina.
Implications ofTP53Allelic State for Genome Stability, Clinical Presentation and Outcomes in Myelodysplastic Syndromes
Authors: Bernard Elsa , Nannya Yasuhito , Hasserjian Robert P. , Devlin Sean M. , Tuechler Heinz , Medina-Martinez Juan S. , Yoshizato Tetsuichi , Shiozawa Yusuke , Saiki Ryunosuke , Malcovati Luca , Levine Max F. , Arango Juan E. , Zhou Yangyu , Sole Francesc , Cargo Catherine A. , Haase Detlef , Creignou Maria , Germing Ulrich , Zhang Yanming , Gundem Gunes , Sarian Araxe , van de Loosdrecht Arjan A. , Jädersten Martin , Tobiasson Magnus , Kosmider Olivier , Follo Matilde Y. , Thol Felicitas , Pinheiro Ronald F. , Santini Valeria , Kotsianidis Ioannis , Boultwood Jacqueline , Santos Fabio P.S. , Schanz Julie , Kasahara Senji , Ishikawa Takayuki , Tsurumi Hisashi , Takaori-Kondo Akifumi , Kiguchi Toru , Polprasert Chantana , Bennett John M. , Klimek Virginia M. , Savona Michael R. , Belickova Monika , Ganster Christina , Palomo Laura , Sanz Guillermo , Ades Lionel , Porta Matteo Giovanni Della , Smith Alexandra G , Werner Yesenia , Patel Minal , Viale Agnès , Vanness Katelynd , Neuberg Donna S. , Stevenson Kristen E. , Menghrajani Kamal , Bolton Kelly L. , Fenaux Pierre , Pellagatti Andrea , Platzbecker Uwe , Heuser Michael , Valent Peter , Chiba Shigeru , Miyazaki Yasushi , Finelli Carlo , Voso Maria Teresa , Shih Lee-Yung , Fontenay Michaela , Jansen Joop H. , Cervera José , Atsuta Yoshiko , Gattermann Norbert , Ebert Benjamin L. , Bejar Rafael , Greenberg Peter L. , Cazzola Mario , Hellström-Lindberg Eva , Ogawa Seishi , Papaemmanuil Elli 
Published: December 2019

ABSTRACTTP53mutations are associated with poor clinical outcomes and treatment resistance in myelodysplastic syndromes. However, the biological and clinical relevance of the underlying mono- or bi-allelic state of the mutations is unclear. We analyzed 3,324 MDS patients forTP53mutations and allelic imbalances of theTP53locus and found that 1 in 3TP53-mutated patients had mono-allelic targeting of the gene whereas 2 in 3 had multiple hits consistent with bi-allelic targeting. The established associations forTP53with complex karyotype, high-risk presentation, poor survival and rapid leukemic transformation were specific to patients with multi-hit state only.TP53multi-hit state predicted risk of death and leukemic transformation independently of the Revised International Prognostic Scoring System, while mono-allelic patients did not differ fromTP53wild-type patients. The separation by allelic state was retained in therapy-related MDS. Findings were validated in a cohort of 1,120 patients. Ascertainment ofTP53allelic state is critical for diagnosis, risk estimation and prognostication precision in MDS, and future correlative studies of treatment response should considerTP53allelic state.
Thyroid and androgen receptor signaling are antagonized by CRYM in prostate cancer
Authors: Aksoy Osman , Pencik Jan , Hartenbach Markus , Moazzami Ali A. , Schlederer Michaela , Balber Theresa , Mazumder Bismoy , Whitchurch Jonathan B , Roberts Christopher J. , Susani Martin , Mitterhauser Markus , Marculescu Rodrig , Kramer Gero , Turner Suzanne D. , Hartenbach Sabrina , Tangermann Simone , Egger Gerda , Neubauer Heidi A. , Moriggl Richard , Culig Zoran , Hoermann Gregor , Hacker Marcus , Heery David M. , Merkel Olaf , Kenner Lukas 
Published: December 2019

AbstractAndrogen deprivation therapy (ADT) remains a key approach in the treatment of prostate cancer (PCa). However, PCa inevitably relapses and becomes ADT resistant. Besides androgens, there is evidence that thyroid hormone thyroxine (T4) and its active form 3,5,3’-triiodo-L-thyronine (T3) are involved in the progression of PCa. Epidemiologic evidence indicates a higher incidence of PCa in men with elevated thyroid hormone levels. The thyroid hormone binding protein μ-Crystallin (CRYM) mediates intracellular thyroid hormone action by sequestering T3 and blocks its binding to cognate receptors (TRa/TRb) in target tissues. We show in this study that low CRYM expression levels in PCa patient samples are associated with early BCR and poor prognosis. Moreover, we found a disease stage-specific expression of CRYM in PCa. CRYM counteracted thyroid and androgen signaling and blocked intracellular choline uptake. CRYM inversely correlated with [18F]fluoromethylcholine (FMC) levels in PET/MRI imaging of PCa patients. Our data suggest CRYM as a novel antagonist of T3 and androgen-mediated signalling. The role of CRYM could therefore be an essential control mechanism for the prevention of aggressive PCa growth.HighlightsThyroid and androgen hormone driven pathways in prostate cancer (PCa) are antagonized by μ- Crystallin (CRYM).[18F]fluoromethylcholine uptake and prognostic values in PCa correlate with CRYM protein levels.Reduced CRYM expression predicts early biochemical recurrence (BCR) in PCa patients.