bluuebunny/crossref_metadata_2025_split huggingface dataset:
Calpain Activation and Organ Failure in Sepsis: Molecular Insights and Therapeutic Perspectives
Authors: Huang Yifan , Wang Grace , Peng Tianqing 
Published: October 2020

ABSTRACT
Sepsis is a severe systemic response to infection; its ensuing organ failure commonly portends an unfavorable prognosis. Despite the fact that sepsis has been studied for decades, the molecular mechanisms underlying sepsis-induced organ dysfunction remain elusive and more complex than previously thought, and effective therapies are extremely limited. Calpain is a type of calcium-dependent cysteine protease that includes dozens of isoforms. Calpain, as well as its endogenous-specific inhibitor calpastatin, have been implicated in the pathogenesis of sepsis-induced organ dysfunction. Further, there is an accumulating body of evidence supporting the beneficial effect of calpain inhibition or regulation on multiple organ failure in sepsis. Better understanding of the underlying molecular mechanisms is helpful in the development of calpain/calpastatin-targeted therapeutic strategies to protect against sepsis-induced organ injury. The aim of this review is to summarize the recent literature and evidence surrounding the role of the calpain/calpastatin system in the process of organ dysfunction caused by sepsis—including regulation of cell death, modulation of inflammatory response, and disruption of critical proteins—to provide guidance for future research and therapy development.
Model Adequacy Tests for Likelihood Models of Chromosome-Number Evolution
Authors: Rice Anna , Mayrose Itay 
Published: October 2020

SummaryChromosome number is a central feature of eukaryote genomes. Deciphering patterns of chromosome-number change along a phylogeny is central to the inference of whole genome duplications and ancestral chromosome numbers. ChromEvol is a probabilistic inference tool that allows the evaluation of several models of chromosome-number evolution and their fit to the data. However, fitting a model does not necessarily mean that the model describes the empirical data adequately. This vulnerability may lead to incorrect conclusions when model assumptions are not met by real data.Here, we present a model adequacy test for likelihood models of chromosome-number evolution. The procedure allows to determine whether the model can generate data with similar characteristics as those found in the observed ones.We demonstrate that using inadequate models can lead to inflated errors in several inference tasks. Applying the developed method to 200 angiosperm genera, we find that in many of these, the best-fitted model provides poor fit to the data. The inadequacy rate increases in large clades or in those in which hybridizations are present.The developed model adequacy test can help researchers to identify phylogenies whose underlying evolutionary patterns deviate substantially from current modelling assumptions and should guide future methods developments.
A dense linkage map for a large repetitive genome: discovery of the sex-determining region in hybridising fire-bellied toads (Bombina bombinaandB. variegata)
Authors: Nürnberger Beate , Baird Stuart J.E. , Čížková Dagmar , Bryjová Anna , Mudd Austin B. , Blaxter Mark L. , Szymura Jacek M. 
Published: October 2020

AbstractHybrid zones that result from secondary contact between diverged populations offer unparalleled insight into the genetic architecture of emerging reproductive barriers and so shed light on the process of speciation. Natural selection and recombination jointly determine their dynamics, leading to a range of outcomes from finely fragmented mixtures of the parental genomes that facilitate introgression to a situation where strong selection against recombinants retains large unrecombined genomic blocks that act as strong barriers to gene flow. In the hybrid zone between the fire-bellied toadsBombina bombinaandB. variegata(Anura: Bombinatoridae), two anciently diverged and ecologically distinct taxa meet and produce abundant, fertile hybrids. The dense linkage map presented here enables genomic analysis of the selection-recombination balance that keeps the two gene pools from merging into one. We mapped 4,775 newly developed marker loci from bait-enriched genomic libraries in F2 crosses. The enrichment targets were selected from a draft assembly of theB. variegatagenome, after filtering highly repetitive sequences. We developed a novel approach to infer the most likely diplotype per sample and locus from the raw read mapping data, which is robust to over-merging and obviates arbitrary filtering thresholds. Large-scale synteny betweenBombinaandXenopus tropicalissupports the resulting linkage map. By assessing the sex of late-stage F2 tadpoles from histological sections, we also identified the sex-determining region in theBombinagenome to 7 cM on LG5, which is homologous toX. tropicalischromosome 5, and inferred male heterogamety, suggestive of an XY sex determination mechanism. Interestingly, chromosome 5 has been repeatedly recruited as a sex chromosome in anurans with XY sex determination.
Hearing loss is associated with gray matter differences in older adults at risk for and with Alzheimer’s disease
Authors: Giroud N. , Pichora-Fuller M. K. , Mick P. , Wittich W. , Al-Yawer F. , Rehan S. , Orange J.B. , Phillips N. A. 
Published: October 2020

AbstractUsing data from the COMPASS-ND study we investigated associations between hearing loss and hippocampal volume as well as cortical thickness in older adults with subjective cognitive decline (SCD), mild cognitive impairment (MCI), and Alzheimer’s dementia (AD). SCD participants with greater pure-tone HL exhibited lower hippocampal volume, but more cortical thickness in the left superior temporal gyrus and right pars opercularis. Greater speech-in-noise reception thresholds were associated with lower cortical thickness bilaterally across much of the cortex in AD. The AD group also showed a trend towards worse speech-in-noise thresholds compared to the SCD group.HighlightsIn SCD, greater pure-tone hearing loss was associated with lower right hippocampal volume.Pure-tone hearing loss was not associated with brain atrophy in MCI or AD.Individuals with AD exhibited a trend towards poorer speech-in-noise (SiN) thresholds than SCD.In AD, greater atrophy across large portions of the cortex was associated with greater SiN thresholds.
Near-Fibre Electromyography
Authors: Piasecki Mathew , Estruch Oscar Garnés C. , Stashuk Daniel W 
Published: October 2020

AbstractNear fibre electromyography (NFEMG) is the use of specifically high-pass filtered motor unit potential (MUPs) (i.e. near fibre MUPs (NFMs)) extracted from needle-detected EMG signals for the examination of changes in motor unit (MU) morphology and electrophysiology caused by neuromuscular disorders or ageing. The concepts of NFEMG, the parameters used, including NFM duration and dispersion, which relates to fibre diameter variability and/or endplate scatter, and a new measure of neuromuscular junction transmission (NMJ) instability, NFM segment jitter, and the methods for obtaining their values are explained. Evaluations using simulated needle-detected EMG data and exemplary human data are presented, described and discussed. The data presented demonstrate the ability of using NFEMG parameters to detect changes in MU fibre diameter variability, end plate scatter, and neuromuscular transmission time variability. These changes can be detected prior to alterations of MU size, numbers or muscle recruitment patterns.
Modelling testing and response strategies for COVID-19 outbreaks in remote Australian Aboriginal communities
Authors: Hui Ben B. , Brown Damien , Chisholm Rebecca H. , Geard Nicholas , McVernon Jodie , Regan David G. 
Published: October 2020

AbstractBackgroundRemote Australian Aboriginal and Torres Strait Islander communities have potential to be severely impacted by COVID-19, with multiple factors predisposing to increased transmission and disease severity. Our modelling aims to inform optimal public health responses.MethodsAn individual-based simulation model represented communities ranging from 100 to 3,500 people, comprised of large interconnected households. A range of strategies for case finding, quarantining of contacts, testing, and lockdown were examined, following the silent introduction of a case.ResultsMultiple secondary infections are likely present by the time the first case is identified. Quarantine of close contacts, defined by extended household membership, can reduce peak infection prevalence from 60-70% to around 10%, but subsequent waves may occur when community mixing resumes. Exit testing significantly reduces ongoing transmission.Concurrent lockdown of non-quarantined households for 14 days is highly effective for epidemic control and reduces overall testing requirements; peak prevalence of the initial outbreak can be constrained to less than 5%, and the final community attack rate to less than 10% in modelled scenarios. Lockdown also mitigates the effect of a delay in the initial response. Compliance with lockdown must be at least 80-90%, however, or epidemic control will be lost.ConclusionsA SARS-CoV-2 outbreak will spread rapidly in remote communities. Prompt case detection with quarantining of extended-household contacts and a 14-day lockdown for all other residents, combined with exit testing for all, is the most effective strategy for rapid containment. Compliance is crucial, underscoring the need for community supported, culturally sensitive responses.
Genome-scale identification of SARS-CoV-2 and pan-coronavirus host factor networks
Authors: Schneider William M. , Luna Joseph M. , Hoffmann H.-Heinrich , Sánchez-Rivera Francisco J. , Leal Andrew A. , Ashbrook Alison W. , Le Pen Jérémie , Michailidis Eleftherios , Ricardo-Lax Inna , Peace Avery , Stenzel Ansgar F. , Lowe Scott W. , MacDonald Margaret R. , Rice Charles M. , Poirier John T. 
Published: October 2020

SUMMARYThe COVID-19 pandemic has claimed the lives of more than one million people worldwide. The causative agent, SARS-CoV-2, is a member of theCoronaviridaefamily, which are viruses that cause respiratory infections of varying severity. The cellular host factors and pathways co-opted by SARS-CoV-2 and other coronaviruses in the execution of their life cycles remain ill-defined. To develop an extensive compendium of host factors required for infection by SARS-CoV-2 and three seasonal coronaviruses (HCoV-OC43, HCoV-NL63, and HCoV-229E), we performed parallel genome-scale CRISPR knockout screens. These screens uncovered multiple host factors and pathways with pan-coronavirus and virus-specific functional roles, including major dependency on glycosaminoglycan biosynthesis, SREBP signaling, and glycosylphosphatidylinositol biosynthesis, as well as an unexpected requirement for several poorly characterized proteins. We identified an absolute requirement for the VTT-domain containing protein TMEM41B for infection by SARS-CoV-2 and all other coronaviruses. This humanCoronaviridaehost factor compendium represents a rich resource to develop new therapeutic strategies for acute COVID-19 and potential future coronavirus spillover events.HIGHLIGHTSGenome-wide CRISPR screens for SARS-CoV-2, HCoV-OC43, HCoV-NL63, and HCoV-229E coronavirus host factors.Parallel genome-wide CRISPR screening uncovered host factors and pathways with pan-coronavirus and virus-specific functional roles.Coronaviruses co-opt multiple biological pathways, including glycosaminoglycan biosynthesis, SREBP signaling, and glycosylphosphatidylinositol biosynthesis and anchoring, among others.TMEM41B - a poorly understood factor with roles in autophagy and lipid mobilization - is a critical pan-coronavirus host factor.
Interactions among mTORC, AMPK, and SIRT: A Computational Model for Cell Energy Balance and Metabolism
Authors: Sadria Mehrshad , Layton Anita T. 
Published: October 2020

AbstractKey proteins such as mTORC, AMPK, and sirtuins are known to play an essential role in the management of metabolic stress and ageing mechanisms. An impairment in these mechanisms is commonly associated with cellular ageing and degenerative diseases. To understand the complex interactions of ageing□related signalling pathways and environmental signals, and the impacts on lifespan and health-span, we developed a computational model of ageing signalling pathways. The model includes (i) the insulin/IGF-1 pathway, which couples energy and nutrient abundance to the execution of cell growth and division, (ii) mTORC1 and amino acid sensors, (iii) the Preiss-Handler and salvage pathways, which regulate the metabolism of NAD+ and the NAD+-consuming factor SIRT1, (iv) the energy sensor AMPK, and (v) transcription factors FOXO and PGC-1α. Key findings include the clinically important role of PRAS40, sestrin2, and diet in the treatment of cancers and other diseases, and a potential link between SIRT1-activating compounds and premature autophagy. The model can be used as an essential component to simulate gene manipulation, therapies (e.g., rapamycin and wortmannin), calorie restrictions, and chronic stress, and to assess their functional implications on longevity and ageing□related diseases.Author SummaryIn cellular ageing, mitochondrial function declines over time, which affects normal mechanisms of cells and organisms and leads to myriad of degenerative diseases and other health problems. To investigate the mechanisms that affect the ageing process, we focus on pathways that play a key role in the management of metabolic stress: the mTORC, AMPK, and sirtuins pathways. Our goal is to understand the complex interactions of ageing and metabolism related signalling pathways and environmental signals, and the impacts on lifespan and health-span. To accomplish that goal, we developed a computational model of signalling pathways related to ageing and metabolism. By conducting model simulations, we have unraveled the clinically important role of PRAS40, sestrin2, and diet in the treatment of cancers and other diseases, and a double-edged sword effect of SIRT1-activating compounds in their use as a health remedy. We view this model as an essential step towards a tool for studying metabolism, longevity, and ageing-related diseases. By extending the present model as appropriate, we can simulate gene manipulation, therapies (e.g., rapamycin and wortmannin), calorie restrictions, and chronic stress,.
Mutations in SKI in Shprintzen-Goldberg syndrome lead to attenuated TGF-β responses through SKI stabilization
Authors: Gori Ilaria , George Roger , Purkiss Andrew G. , Strohbuecker Stephanie , Randall Rebecca A. , Ogrodowicz Roksana , Carmignac Virginie , Faivre Laurence , Joshi Dhira , Kjaer Svend , Hill Caroline S. 
Published: October 2020

ABSTRACTShprintzen-Goldberg syndrome (SGS) is a multisystemic connective tissue disorder, with considerable clinical overlap with Marfan and Loeys-Dietz syndromes. These syndromes have commonly been associated with enhanced TGF-β signaling. In SGS patients, heterozygous point mutations have been mapped to the transcriptional corepressor SKI, which is a negative regulator of TGF-β signaling that is rapidly degraded upon ligand stimulation. The molecular consequences of these mutations, however, are not understood. Here we use a combination of structural biology, genome editing and biochemistry to show that SGS mutations in SKI abolish its binding to phosphorylated SMAD2 and SMAD3. This results in stabilization of SKI and consequently attenuation of TGF-β responses, in both knockin cells expressing an SGS mutation, and in fibroblasts from SGS patients. Thus, we reveal that SGS is associated with an attenuation of TGF-β-induced transcriptional responses, and not enhancement, which has important implications for other Marfan-related syndromes.
Creating Clear and Informative Image-based Figures for Scientific Publications
Authors: Jambor Helena , Antonietti Alberto , Alicea Bradly , Audisio Tracy L. , Auer Susann , Bhardwaj Vivek , Burgess Steven J. , Ferling Iuliia , Gazda Małgorzata Anna , Hoeppner Luke H. , Ilangovan Vinodh , Lo Hung , Olson Mischa , Mohamed Salem Yousef , Sarabipour Sarvenaz , Varma Aalok , Walavalkar Kaivalya , Wissink Erin M. , Weissgerber Tracey L. 
Published: October 2020

AbstractScientists routinely use images to display data. Readers often examine figures first; therefore, it is important that figures are accessible to a broad audience. Many resources discuss fraudulent image manipulation and technical specifications for image acquisition; however, data on the legibility and interpretability of images are scarce. We systematically examined these factors in non-blot images published in the top 15 journals in three fields; plant sciences, cell biology and physiology (n=580 papers). Common problems included missing scale bars, misplaced or poorly marked insets, images or labels that were not accessible to colorblind readers, and insufficient explanations of colors, labels, annotations, or the species and tissue or object depicted in the image. Papers that met all good practice criteria examined for all image-based figures were uncommon (physiology 16%, cell biology 12%, plant sciences 2%). We present detailed descriptions and visual examples to help scientists avoid common pitfalls when publishing images. Our recommendations address image magnification, scale information, insets, annotation, and color and may encourage discussion about quality standards for bioimage publishing.
NOX4 links metabolic regulation in pancreatic cancer to endoplasmic reticulum redox vulnerability and dependence on PRDX4
Authors: Jain Pallavi , Dvorkin-Gheva Anna , Mollen Erik , Xie Michael , Jessa Fatima , Dhavarasa Piriththiv , Chung Stephen , Brown Kevin R. , Jang Gun Ho , Notta Faiyaz , Moffat Jason , Hedley David , Boutros Paul C. , Wouters Bradly G. , Koritzinsky Marianne 
Published: October 2020

AbstractPancreatic ductal adenocarcinoma (PDAC) is an almost universally fatal malignancy and there is an urgent need for new therapeutic targets. PDAC cells harbor genetic alterations and display metabolic changes that render them vulnerable to perturbations in redox homeostasis. Peroxiredoxin 4 (PRDX4) supports redox homeostasis by metabolizing H2O2 in the endoplasmic reticulum (ER). Based on functional genomics, we found that PDAC cell lines are dependent on PRDX4 for their growth and survival. We validated this dependency in established and primary PDAC cells, as well as 3D models and orthotopic xenografts. Cell death induced by PRDX4 depletion was accompanied by increased levels of reactive oxygen species (ROS), DNA damage and a DNA-PKcs-governed DNA damage response. As such, PRDX4 depletion also sensitized cells and tumors to ionizing radiation. The source of ROS that created a dependency on PRDX4 was attributed to NADPH oxidase 4 (NOX4), which localizes to the ER membrane. The functional requirement for PRDX4 was correlated with cellular NADPH levels across different models of PDAC and could be rescued by depletion of NOX4 or NADPH. As such, this study has identified NOX4 as a link between metabolic deregulation and ER-specific redox vulnerability in PDAC. Since PRDX4 is not an essential gene in normal tissues, our work also suggests that PRDX4 represents a novel therapeutic target for pancreatic cancer that may be particularly potent in combination with radiotherapy.
The Hippo pathway controls myofibril assembly and muscle fiber growth by regulating sarcomeric gene expression
Authors: Kaya-Çopur Aynur , Marchiano Fabio , Hein Marco Y. , Alpern Daniel , Russeil Julie , Luis Nuno Miguel , Mann Matthias , Deplancke Bart , Habermann Bianca H. , Schnorrer Frank 
Published: October 2020

AbstractSkeletal muscles are composed of gigantic cells called muscle fibers, packed with force-producing myofibrils. During development the size of individual muscle fibers must dramatically enlarge to match with skeletal growth. How muscle growth is coordinated with growth of the contractile apparatus is not understood. Here, we use the largeDrosophilaflight muscles to mechanistically decipher how muscle fiber growth is controlled. We find that regulated activity of core members of the Hippo pathway is required to support flight muscle growth. Interestingly, we identify Dlg5 and Slmap as regulators of the STRIPAK phosphatase, which negatively regulates Hippo to enable post-mitotic muscle growth. Mechanistically, we show that the Hippo pathway controls timing and levels of sarcomeric gene expression during development and thus regulates the key components that physically mediate muscle growth. Since Dlg5, STRIPAK and the Hippo pathway are conserved a similar mechanism may contribute to muscle or cardiomyocyte growth in humans.
Accounting for epistasis improves genomic prediction of phenotypes with univariate and bivariate models across environments
Authors: Vojgani Elaheh , Pook Torsten , Martini Johannes W.R. , Hölker Armin C. , Mayer Manfred , Schön Chris-Carolin , Simianer Henner 
Published: October 2020

AbstractWe compared the predictive ability of various prediction models for a maize dataset derived from 910 doubled haploid lines from European landraces (Kemater Landmais Gelb and Petkuser Ferdinand Rot), which were tested in six locations in Germany and Spain. The compared models were Genomic Best Linear Unbiased Prediction (GBLUP) as an additive model, Epistatic Random Regression BLUP (ERRBLUP) accounting for all pairwise SNP interactions, and selective Epistatic Random Regression BLUP (sERRBLUP) accounting for a selected subset of pairwise SNP interactions. These models have been compared in both univariate and bivariate statistical settings within and across environments. Our results indicate that modeling all pairwise SNP interactions into the univariate/bivariate model (ERRBLUP) is not superior in predictive ability to the respective additive model (GBLUP). However, incorporating only a selected subset of interactions with the highest effect variances in univariate/bivariate sERRBLUP can increase predictive ability significantly compared to the univariate/bivariate GBLUP. Overall, bivariate models consistently outperform univariate models in predictive ability. Over all studied traits, locations, and landraces, the increase in prediction accuracy from univariate GBLUP to univariate sERRBLUP ranged from 5.9 to 112.4 percent, with an average increase of 47 percent. For bivariate models, the change ranged from −0.3 to +27.9 percent comparing the bivariate sERRBLUP to the bivariate GBLUP. The average increase across traits and locations was 11 percent. This considerable increase in predictive ability achieved by sERRBLUP may be of interest for “sparse testing” approaches in which only a subset of the lines/hybrids of interest is observed at each location.Key MessageThe prediction accuracy of genomic prediction of phenotypes can be increased by only including top ranked pairwise SNP interactions into the prediction models.