bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor cell-derived lymphotoxin alpha triggers metastatic extravasation through TNFRs/cIAP1
Authors: Vasilikos Lazaros , Hänggi Kay , Spilgies Lisanne M. , Wong W. Wei-Lynn 
Published: September 2019

AbstractMetastasis involves the interaction of the tumor, immune and endothelial cells. Cell death proteins, such as inhibitors of apoptosis proteins (IAPs), are critical players in survival, inflammation and permeability. Whether the use of Smac mimetics, which target cIAP1/2 for degradation would affect metastasis is unknown. We show Smac mimetics reduced metastasis due to the loss of cIAP1 but not cIAP2 in experimental metastasis models. The endothelial compartment rather than the immune cells was responsible for reduction of extravasation upon loss of cIAP1. Loss of cIAP1 in primary endothelial cells did not lead to cell death but resulted in an unresponsive endothelium barrier to permeability factors causing a reduction in tumor cell extravasation. Unexpectedly, the co-loss of TNFR1 and cIAP1 restored the tumor load. We were surprised to find lymphotoxin alpha (LTA), and not TNF, secreted by the tumor cells was critical for the extravasation. Using TCGA data, we found high levels of LTA mRNA expression correlated with decreased survival in kidney carcinoma and associated with advance disease stage. Our data suggest that Smac mimetics, targeting cIAP1/2, may reduce metastasis to the lung through a LTA/TNFR mechanism by altering the endothelial barrier and inhibiting the ability of tumor cells to extravasate.
Inosine is an alternative carbon supply that supports effector T cell proliferation and antitumor function under glucose restriction
Authors: Wang Tingting , Gnanaprakasam JN Rashida , Chen Xuyong , Kang Siwen , Xu Xuequn , Sun Hua , Liu Lingling , Miller Ethan , Cassel Teresa A. , Sun Qiushi , Vicente-Muñoz Sara , Warmoes Marc O. , Lane Andrew N. , Song Xiaotong , Fan Teresa W.-M. , Wang Ruoning 
Published: September 2019

AbstractT cells undergo a characteristic metabolic rewiring that fulfills the dramatically increased bioenergetic, biosynthetic, and redox demands following antigen stimulation. A robust adaptive immune system requires effector T cells to respond and adapt to fluctuations in environmental nutrient levels imposed by infectious and inflammatory sites in different tissues. Inevitably, such responsiveness and adaptation reflect metabolic plasticity, allowing T cells to elicit immune functions by using a wide range of nutrient substrates. Here, we show that effector T cells utilize inosine, as an alternative substrate, to support cell growth and function in the absence of glucose. T cells metabolize inosine into hypoxanthine and phosphorylated ribose by purine nucleoside phosphorylase (PNP). Using Stable Isotope-Resolved Metabolomics (SIRM), we demonstrated that ribose moiety of inosine can enter into central metabolic pathways to provide ATP and biosynthetic precursors. Accordingly, the dependence of T cells on extracellular glucose for growth and effector functions can be relieved by inosine. On the other hand, cancer cells display diverse capacity to utilize inosine as a carbon resource. Moreover, the supplement of inosine enhances the anti-tumor efficacy of immune-checkpoint blockade or adoptive T cell transfer, reflecting the capability of inosine in relieving tumor-imposed metabolic restrictions on T cellsin vivo.
A Bayesian implementation of the multispecies coalescent model with introgression for comparative genomic analysis
Authors: Flouris Thomas , Jiao Xiyun , Rannala Bruce , Yang Ziheng 
Published: September 2019

AbstractRecent analyses suggest that cross-species gene flow or introgression is common in nature, especially during species divergences. Genomic sequence data can be used to infer introgression events and to estimate the timing and intensity of introgression, providing an important means to advance our understanding of the role of gene flow in speciation. Here we implement the multispecies-coalescent-with-introgression (MSci) model, an extension of the multispecies-coalescent (MSC) model to incorporate introgression, in our Bayesian Markov chain Monte Carlo (MCMC) program BPP. The MSci model accommodates deep coalescence (or incomplete lineage sorting) and introgression and provides a natural framework for inference using genomic sequence data. Computer simulation confirms the good statistical properties of the method, although hundreds or thousands of loci are typically needed to estimate introgression probabilities reliably. Re-analysis of datasets from the purple cone spruce confirms the hypothesis of homoploid hybrid speciation. We estimated the introgression probability using the genomic sequence data from six mosquito species in theAnopheles gambiaespecies complex, which varies considerably across the genome, likely driven by differential selection against introgressed alleles.
The nuclear to cytoplasmic ratio directly regulates zygotic transcription inDrosophilathrough multiple modalities
Authors: Syed Sahla , Wilky Henry , Raimundo João , Lim Bomyi , Amodeo Amanda A. 
Published: September 2019

AbstractEarly embryos must rapidly generate large numbers of cells to form an organism. Many species accomplish this through a series of rapid, reductive, and transcriptionally silent cleavage divisions. Previous work has demonstrated that the number of divisions before both cell cycle elongation and zygotic genome activation (ZGA) is regulated by the ratio of nuclear content to cytoplasm (N/C). To understand how the N/C ratio affects the timing of ZGA, we directly assayed the behavior of several previously identified N/C-ratio-dependent genes using the MS2-MCP reporter system in livingDrosophilaembryos with altered ploidy and cell cycle durations. For every gene that we examined, we found that nascent RNA output per cycle is delayed in haploid embryos. Moreover, we found that the N/C ratio influences transcription through three separate modes of action. For some genes (knirpsandsnail) the effect of ploidy can be entirely accounted for by changes in cell cycle duration. However, for other genes (giant, bottleneck and fruhstart) the N/C ratio directly affects ZGA. Forgiantandbottleneck,the N/C ratio regulates the kinetics of transcription activation, while forfruhstartit controls the probability of transcription initiation. Our data demonstrate that the regulatory elements of N/C-ratio-dependent genes respond directly to the N/C ratio, through multiple modes of regulation, independent of interphase length.
Real-time dynamics of Plasmodium NDC80 reveals unusual modes of chromosome segregation during parasite proliferation
Authors: Zeeshan Mohammad , Pandey Rajan , Ferguson David J.P. , Tromer Eelco C. , Markus Robert , Abel Steven , Brady Declan , Daniel Emilie , Limenitakis Rebecca , Bottrill Andrew R. , Le Roch Karine G. , Holder Anthony A. , Waller Ross F. , Guttery David S. , Tewari Rita 
Published: September 2019

AbstractEukaryotic cell proliferation requires chromosome replication and precise segregation to ensure daughter cells have identical genomic copies. The genus Plasmodium, the causative agent of malaria, displays remarkable aspects of nuclear division throughout its lifecycle to meet some peculiar and unique challenges of DNA replication and chromosome segregation. The parasite undergoes atypical endomitosis and endoreduplication with an intact nuclear membrane and intranuclear mitotic spindle. To understand these diverse modes of Plasmodium cell division, we have studied the behaviour and composition of the outer kinetochore NDC80 complex, a key part of the mitotic apparatus that attaches the centromere of chromosomes to microtubules of the mitotic spindle. Using NDC80-GFP live-cell imaging in Plasmodium berghei we observe dynamic spatiotemporal changes during proliferation, including highly unusual kinetochore arrangements during sexual stages. We identify a very divergent candidate for the SPC24 subunit of the NDC80 complex, previously thought to be missing in Plasmodium, which completes a canonical, albeit unusual, NDC80 complex structure. Altogether, our studies reveal the kinetochore as an ideal tool to investigate the non-canonical modes of chromosome segregation and cell division in Plasmodium.Summary StatementThe dynamic localization of kinetochore marker NDC80 protein complex during proliferative stages of the malaria parasite life cycle reveals unique modes of chromosome segregation.
The Wnt pathway scaffold protein Axin promotes signaling specificity by suppressing competing kinase reactions
Authors: Gavagan Maire , Fagnan Erin , Speltz Elizabeth B. , Zalatan Jesse G. 
Published: September 2019

AbstractGSK3β is a multifunctional kinase that phosphorylates β-catenin in the Wnt signaling network and also acts on other protein targets in response to distinct cellular signals. To test the long-standing hypothesis that the scaffold protein Axin specifically accelerates β-catenin phosphorylation, we measured GSK3β reaction rates with multiple substrates in a minimal, biochemically-reconstituted system. We observed an unexpectedly small, ~2-fold Axin-mediated rate increase for the β-catenin reaction. The much larger effects reported previously may have arisen because Axin can rescue GSK3β from an inactive state that occurs only under highly specific conditions. Surprisingly, Axin significantly slows the reaction of GSK3β with CREB, a non-Wnt pathway substrate. When both β-catenin and CREB are present, Axin accelerates the β-catenin reaction by preventing competition with CREB. Thus, while Axin alone does not markedly accelerate the β-catenin reaction, in physiological settings where multiple GSK3β substrates are present, Axin can promote signaling specificity by suppressing interactions with competing, non-Wnt pathway targets.
Claudin-12 deficiency causes nerve barrier breakdown, mechanical hypersensitivity and painfulness in polyneuropathy
Authors: Chen Jeremy Tsung-Chieh , Hu Xiawei , Doppler Kathrin , Breitkreuz-Korff Olga , Otto Isabel U. C. , Schwabe Joachim , Reinhold Ann-Kristin , Günzel Dorothee , Dithmer Sophie , Hankir Mohammed K. , Fallier-Becker Petra , Winkler Lars , Blasig Rosel , Sommer Claudia , Brack Alexander , Blasig Ingolf E. , Rittner Heike L. 
Published: September 2019

AbstractPeripheral nerves and their axons are shielded by the blood-nerve and the myelin barrier, but understanding of how these barriers impact nociception is limited. Here, we identified a regulatory axis of the tight junction protein claudin-12, sex-dependently controlling perineurial and myelin barrier integrity. In nerve biopsies, claudin-12 in Schwann cells was lost in male and postmenopausal female patients with painful but not painless polyneuropathy. Global Cldn12 gene-knockout selectively increased perineurial/myelin barrier leakage, damaged tight junction protein expression and morphology, increased proinflammatory cytokines and induced mechanical hypersensitivity in naïve and neuropathic male mice, respectively. Other barriers and neurological function remained intact. In vitro transfection studies documented claudin-12 plasma membrane localisation without interaction with other tight junction proteins or intrinsic sealing properties. Rather, claudin-12 had a regulatory tight junction protein function on the myelin barrier via the morphogen SHH in vivo in Cldn12-KO and after local siRNA knockdown. Fertile female mice were completely protected. Collectively, these studies reveal the critical role of claudin-12 maintaining the myelin barrier and highlight restoration of the claudin-12/SHH pathway as a potential target for painful neuropathy.
Hyaluronic acid particle hydrogels decrease cerebral atrophy and promote pro-reparative astrocyte/axonal infiltration in the core after ischemic stroke
Authors: Sideris Elias , Yu Aaron , Chen Jun , Carmichael S Thomas , Segura Tatiana 
Published: September 2019

AbstractThe death rate due to stroke is decreasing, resulting in more individuals living with stroke related disabilities. Following stroke, dying cells contribute to the large influx of highly reactive astrocytes and pro-inflammatory microglia that release cytokines and lead to a cytotoxic environment that causes further brain damage and prevents endogenous repair. Paradoxically, these same cells also activate pro-repair mechanisms that contribute to endogenous repair and brain plasticity. Here, we show that the direct injection of a hyaluronic acid based microporous annealed particle (HA-MAP) hydrogel into the stroke core reduces the percent of highly reactive astrocytes and increases the percent of alternatively activated microglia in and around the lesion. Further, we show that HA-MAP hydrogel promotes reparative astrocyte infiltration into the lesion, which directly coincides with axonal penetration into the lesion. Additionally, HA-MAP injection decreases cerebral atrophy and preserves nigrostriatal bundles after stroke. This work shows that the injection of a porous scaffold into the stroke core can lead to clinically relevant decrease in cerebral atrophy and modulates the phenotype of astrocytes and microglia towards a pro-repair phenotype.
Deviations from Hardy Weinberg Equilibrium at CCR5-Δ32 in Large Sequencing Data Sets
Authors: Wei Xinzhu , Nielsen Rasmus 
Published: September 2019

AbstractPrevious analyses of the UK Biobank (UKB) genotyping array data in the CCR5-Δ32 locus show evidence for deviations from Hardy-Weinberg Equilibrium (HWE) and an increased mortality rate of homozygous individuals, consistent with a recessive deleterious effect of the deletion mutation. We here examine if similar deviations from HWE can be observed in the newly released UKB Whole Exome Sequencing (WES) data and in the sequencing data of the Genome Aggregation Database (gnomAD). We also examine the reliability of the genotype calls in the UKB array data. The UKB genotyping array probe targeting CCR5-Δ32 (rs62625034) and the WES of Δ32 are strongly correlated (r2 = 0.97). This contrasts to tag SNPs of CCR5-Δ32 in the UKB which have high missing data rates and imputation errors rates. We also show that, while different data sets are subject to different biases, both the UKB-WES and the gnomAD data have a deficiency of homozygous CCR5-Δ32 individuals compared to the HWE expectation (combined P-value < 0.01), consistent with an increased mortality rate in homozygotes. Finally, we perform a survival analysis on data from parents of UKB volunteers, that, while underpowered, is also consistent with the original report of a deleterious effect of CCR5-Δ32 in the homozygous state.
Automated quality control of next generation sequencing data using machine learning
Authors: Albrecht Steffen , Andrade-Navarro Miguel A. , Fontaine Jean-Fred 
Published: September 2019

AbstractControlling quality of next generation sequencing (NGS) data files is a necessary but complex task. To address this problem, we statistically characterized common NGS quality features and developed a novel quality control procedure involving tree-based and deep learning classification algorithms. Predictive models, validated on internal data and external disease diagnostic datasets, are to some extent generalizable to data from unseen species. The derived statistical guidelines and predictive models represent a valuable resource for users of NGS data to better understand quality issues and perform automatic quality control. Our guidelines and software are available at the following URL:https://github.com/salbrec/seqQscorer.
RAD51 promotes non-homologous genetic rearrangements that are prevented by 53BP1
Authors: Guirouilh-Barbat Josée , Yu Wei , Babin Loelia , Galende Elisa Yaniz , Popova Tatiana , So Ayeong , Lescale Chloé , Stern Marc-Henri , Brunet Erika , Deriano Ludovic , Lopez Bernard S. 
Published: September 2019

AbstractHomologous recombination (HR), which requires long sequence homologies, is considered a high fidelity mechanism, preserving genome stability. In contrast, we show here that the central HR players RAD51 or BRCA2, promote genetic instability, fostering translocations and capture of ectopic chromosomal sequences when joining distant DNA breaks. Surprisingly, these events do not involve sequence homologies. Moreover, our data reveal that 53BP1 protects against RAD51-mediated non-homologous genetic rearrangements. Finally, analysis of a large panel of breast tumors revealed that BRCA2 proficiency is associated with increased frequency of capture of non-homologous sequences at junctions of structural variants (translocations, duplications, inversions, deletions). These data reveal that HR proteins (RAD51, BRCA2) possess the intrinsic capacity to generate genetic instability through sequence homology-independent processes, and that 53BP1 protects against it. We propose that BRCA2/RAD51-mediated genome instability occurs in the course of sequence homology search for HR.
On the effect of asymmetrical trait inheritance on models of trait evolution
Authors: Duchen Pablo , Alfaro Michael L. , Rolland Jonathan , Salamin Nicolas , Silvestro Daniele 
Published: September 2019

AbstractCurrent phylogenetic comparative methods modeling quantitative trait evolution generally assume that, during speciation, phenotypes are inherited identically between the two daughter species. This, however, neglects the fact that species consist of a set of individuals, each bearing its own trait value. Indeed, because descendent populations after speciation are samples of a parent population, we can expect their mean phenotypes to randomly differ from one another potentially generating a “jump” of mean phenotypes due to asymmetrical trait inheritance at cladogenesis. Here, we aim to clarify the effect of asymmetrical trait inheritance at speciation on macroevolutionary analyses, focusing on model testing and parameter estimation using some of the most common models of quantitative trait evolution. We developed an individual-based simulation framework in which the evolution of species phenotypes is determined by trait changes at the individual level accumulating across generations and cladogenesis occurs then by separation of subsets of the individuals into new lineages. Through simulations, we assess the magnitude of phenotypic jumps at cladogenesis under different modes of trait inheritance at speciation. We show that even small jumps can strongly alter both the results of model selection and parameter estimations, potentially affecting the biological interpretation of the estimated mode of evolution of a trait. Our results call for caution when interpreting analyses of trait evolution, while highlighting the importance of testing a wide range of alternative models. In the light of our findings, we propose that future methodological advances in comparative methods should more explicitly model the intra-specific variability around species mean phenotypes and how it is inherited at speciation.
Finding differentially expressed sRNA-Seq regions with srnadiff
Authors: Zytnicki Matthias , González Ignacio 
Published: September 2019

AbstractSmall RNAs (sRNAs) encompass a great variety of different molecules of different kinds, such as micro RNAs, small interfering RNAs, Piwi-associated RNA, among other. These sRNA have a wide range of activities, which include gene regulation, protection against virus, transposable element silencing, and have been identified as a key actor to study and understand the development of the cell. Small RNA sequencing is thus routinely used to assess the expression of the diversity of sRNAs, usually in the context of differentially expression, where two conditions are compared. Many tools have been presented to detect differentially expressed micro RNAs, because they are well documented, and the associated genes are well defined. However, tools are lacking to detect other types of sRNAs, which are less studied, and have an imprecise “gene” structure. We present here a new method, called srnadiff, to find all kinds of differentially expressed sRNAs. To the extent of our knowledge, srnadiff is the first tool that detects differentially expressed sRNAs without the use of external information, such as genomic annotation or reference sequence of sRNAs.Author summaryWe present here a new method for the ab initio discovery of differentially expressed small RNAs. The standard method, sometimes named annotate-then-identify, first finds possible genes, and tests for differential expression. In contrast, our method skips the first step and scans the genome for potential differentially expressed regions (the identify-then-annotate strategy). Since our method is the first one to use the identify-then-annotate strategy on sRNAs, we compared our method against a similar method, developed for long RNAs (derfinder), and to the annotate-then-identify strategy, where the sRNAs have been identified beforehand using a segmentation tool, on three published datasets, and a simulated one. Results show that srnadiff gives much better results than derfinder, and is also better than the annotate-then-identify strategy on many aspects. srnadiff is available as a Bioconductor package, together with a detailed manual: https://bioconductor.org/packages/release/bioc/html/srnadiff.html
Feasibility of Remotely Supervised Transcranial Direct Current Stimulation and Cognitive Remediation: A Systematic Review
Authors: Gough Nicole , Brkan Lea , Subramaniam Ponnusamy , Chiuccariello Lina , De Petrillo Alessandra , Mulsant Benoit H. , Bowie Christopher R. , Rajji Tarek K. 
Published: September 2019

ABSTRACTWith technological advancements and an aging population, there is growing interest in delivering interventions at home. Transcranial Direct Current Stimulation (tDCS) and Cognitive Remediation (CR) have been widely studied, but mainly in laboratories or hospitals. Thus, the objectives of this review are to examine feasibility and the interventions components to support the domiciliary administration of tDCS and CR. We performed a systematic search of electronic databases, websites and reference lists of included articles from the first date available until October 31, 2018. Articles included had to meet the following criteria: original work published in English using human subjects, majority of tDCS or CR intervention administered remotely. A total of 39 studies were identified (16 tDCS, 23 CR/cognitive training, 5 using both tDCS & cognitive training). Four studies were single case studies and two were multiple case studies. The remaining 33 studies had a range of 9 – 135 participants. Five tDCS and nine CR/cognitive training studies were double blind randomized controlled trials. Most studies focused on schizophrenia (8/39) and multiple sclerosis (8/39). Literature examined suggests the feasibility of delivering tDCS or CR remotely with the support of information and communication technologies.
ChIP-Hub: an Integrative Platform for Exploring Plant Regulome
Authors: Chen Dijun , Fu Liang-Yu , Zhang Peijing , Chen Ming , Kaufmann Kerstin 
Published: September 2019

AbstractPlant genomes encode a complex and evolutionary diverse regulatory grammar that forms the basis for most life on earth. A wealth of regulome and epigenome data have been generated in various plant species, but no common, standardized resource is available so far for biologists. Here we present ChIP-Hub, an integrative web-based platform in the ENCODE standards that bundles publicly available datasets reanalyzed from >40 plant species, allowing visualization and meta-analysis.