bluuebunny/crossref_metadata_2025_split huggingface dataset:
We think what we eat: Animal-based diet influences cerebral and microbiota networks connectivity in early ages. A study case of an indigenous community in Mexico
Authors: Elvia Ramirez-Carrillo , Isaac G-Santoyo , Oliver López-Corona , Rojas-Ramos Olga A. , Falcón Luisa I. , Gaona Osiris , Cerqueda-García Daniel , Sánchez-Quinto Andrés , de la Fuente Rodríguez Rosa María , Castillo Ariatna Hernández , Javier Nieto 
Published: July 2020

AbstractWe are not individuals, we are much better described as ecosystems due to trillions of bacteria and other microorganisms that inhabit us. We now know that gut microbiota can greatly influence many physiological parameters that in turn may impact several cognitive functions, such as learning, memory, and decision making processes. This mutualistic symbiotic relation known as the gut-brain axis is also constrained by external factors such as dietary habits such as animal protein and lipids intake. Using a novel combination of Machine Learning and Network Theory techniques, we provide evidence from an indigenous population in Guerrero Mexico, that both brain and gut-microbiota connectivity, evaluated by Minimum Spanning Tree as the critical backbone of information flow, diminish under either low protein or lipids intake. We discuss then how this loss of connectivity may translate into a reduction of the individual’s capacity to cope with perturbations as loss of connectivity may be linked with losses in antifragility.
Identification of clinical combination therapies to induce durable responses in kidney cancers
Authors: Lue Hui-wen , Derrick Daniel S. , Rao Soumya , Van Gaest Anna , Cheng Larry , Podolak Jennifer , Lawson Samantha , Xue Changhui , Garg Devin , White Ralph , Ryan Christopher W. , Drake Justin M. , Ritz Anna , Heiser Laura M. , Thomas George V. 
Published: July 2020

AbstractThe lack of effective treatment options for advanced non-clear cell renal cell carcinoma (NCCRCC) is a critical unmet clinical need. Applying a high throughput drug screen to multiple human kidney cancer cells, we identified the combination of the VEGFR-MET inhibitor cabozantinib and the SRC inhibitor dasatinib acted synergistically in cells to markedly reduce cell viability. Importantly, the combination was well tolerated and caused tumor regressionin vivo. Transcriptional and phosphoproteomic profiling revealed that the combination converged to downregulate the MAPK-ERK signaling pathway, a result not predicted by single agent analysis alone. Correspondingly, the addition of a MEK inhibitor synergized with either dasatinib or cabozantinib to increase its efficacy. This study, by employing approved, clinically relevant drugs provides the rationale for the design of effective combination treatments in NCCRCC that can be rapidly translated to the clinic.
Structure and function of a novel osmoregulated periplasmic fiber-forming high-molecular-weight carbohydrate ofMyxococcus xanthus
Authors: Agrawal Sapeckshita , Heiss Christian , Zuckerman David M. , So Jeffery M. T. , Semeijn Koen , Naran Radnaa , Azadi Parastoo , Hoiczyk Egbert 
Published: July 2020

AbstractOsmoregulation is of central importance for living cells. In Gram-negative bacteria, strategies for osmoregulation and turgor maintenance in hypotonic environments include the synthesis, accumulation, and modification of periplasmic oligosaccharides. These osmoregulated periplasmic glucans (OPGs, formerly known as membrane-derived oligosaccharides or MDOs) promote water uptake and retention, keeping the cells in an optimal state of hydration. While our understanding of OPG-dependent osmoregulation in a number of model organisms likeEscherichia coliis quite detailed, less is known about these processes in bacteria that live in environments characterized by strongly fluctuating osmolarity, such as soil. Here we describe that the soil bacteriumMyxococcus xanthuslacks a canonical low-molecular-weight OPG, but instead possesses a novel high-molecular-weight, fiber-forming polysaccharide. Chemical analysis reveals that this polysaccharide is several thousand kilodaltons in size, composed of a highly branched decasaccharide repeat unit containing mannose, glucose, N-acetylglucosamine, and rhamnose. Physiological experiments indicate that the polysaccharide is osmoregulated thereby functionally replacing the canonical OPG. Moreover, experiments indicate that this high-molecular-weight periplasmic polysaccharide forms a fibrillar meshwork that stabilizes the cell envelope during glycerol spore formation, a process during which the entire peptidoglycan of the cell is degraded and the rod-shaped vegetative cells convert into spherical spores.SignificanceOsmoprotection is a necessity for every living cell, particularly in an environment with fluctuating osmolarity. In Gram-negative bacteria, low-molecular-weight osmoregulated periplasmic glucans (OPGs) are an important component of the osmotic stress response in hypotonic environments. Here, we describe that the soil bacteriumMyxococcus xanthusdoes not possess such an OPG but instead accumulates a novel high-molecular-weight fiber-forming polysaccharide in the periplasm in response to hypotonic conditions. This polymer is important for osmoprotection of the cells and plays a key role in the stabilization of the cell envelope during the conversion of rod-shaped vegetative cells into spherical spores. These results indicate that bacteria may use non-OPG carbohydrates for osmoprotection and cell wall stabilization during processes like cellular differentiation.
Cell-free DNA as a biomarker for prostate cancer: elevated concentration and decreased fragment size
Authors: Chen Emmalyn , Cario Clinton L. , Leong Lancelote , Lopez Karen , Márquez César P. , Chu Carissa , Li Patricia S. , Oropeza Erica , Tenggara Imelda , Cowan Janet , Simko Jeffry P. , Chan June M. , Friedlander Terence , Wyatt Alexander W. , Aggarwal Rahul , Paris Pamela L. , Carroll Peter R. , Feng Felix , Witte John S. 
Published: July 2020

AbstractPurposeProstate cancer is the most commonly diagnosed neoplasm in American men. Although existing biomarkers may detect localized prostate cancer, additional strategies are necessary for improving detection and identifying aggressive disease that may require further intervention. One promising, minimally invasive biomarker is cell-free DNA (cfDNA), which consist of short DNA fragments released into circulation by dying or lysed cells that may reflect underlying cancer. Here we investigated whether differences in cfDNA concentration and cfDNA fragment size could improve the sensitivity for detecting more advanced and aggressive prostate cancer.Materials and MethodsThis study included 268 individuals: 34 healthy controls, 112 men with localized prostate cancer who underwent radical prostatectomy (RP), and 122 men with metastatic castration-resistant prostate cancer (mCRPC). Plasma cfDNA concentration and fragment size were quantified with the Qubit 3.0 and the 2100 Bioanalyzer. The potential relationship between cfDNA concentration or fragment size and localized or mCRPC prostate cancer was evaluated with descriptive statistics, logistic regression, and area under the curve analysis with cross-validation.ResultsPlasma cfDNA concentrations were elevated in mCRPC patients in comparison to localized disease (OR5 ng/mL= 1.34, P = 0.027) or to being a control (OR5 ng/mL= 1.69, P = 0.034). Decreased average fragment size was associated with an increased risk of localized disease compared to controls (OR5bp= 0.77, P = 0.0008).ConclusionThis study suggests that cfDNA concentration and average cfDNA fragment size may provide a quick, cost-effective approach to help determine which patients will benefit most from further screening and/or disease monitoring to help improve prostate cancer outcomes.
Variants atRNF212andRNF212Bare associated with recombination rate variation in Soay sheep (Ovis aries)
Authors: Johnston Susan E. , Stoffel Martin A. , Pemberton Josephine M. 
Published: July 2020

AbstractMeiotic recombination is a ubiquitous feature of sexual reproduction, ensuring proper disjunction of homologous chromosomes, and creating new combinations of alleles upon which selection can act. By identifying the genetic drivers of recombination rate variation, we can begin to understand its evolution. Here, we revisit an analysis investigating the genetic architecture of gamete autosomal crossover counts (ACC) in a wild population of Soay sheep (Ovis aries) using a much larger dataset (increasing from 3,300 to 7,235 gametes and from ∼39,000 to ∼415,000 SNPs for genome-wide association analysis). Animal models fitting genomic relatedness confirmed that ACC was heritable in both females (h2= 0.18) and males (h2= 0.12). Genome-wide association studies identified two regions associated with ACC variation. A region on chromosome 6 containingRNF212explained 46% of heritable variation in female ACC, but was not associated with male ACC, confirming the previous finding. A region on chromosome 7 containingRNF212Bexplained 20-25% of variation in ACC in both males and females. BothRNF212andRNF212Bhave been repeatedly associated with recombination rate in other mammal species. These findings confirm that moderate to large effect loci can underpin ACC variation in wild mammals, and provide a foundation for further studies on the evolution of recombination rates.
Dynamic control over feedback regulation identifies pyruvate-ferredoxin oxidoreductase as a central metabolic enzyme in stationary phaseE. coli
Authors: Li Shuai , Ye Zhixia , Lebeau Juliana , Moreb Eirik A. , Lynch Michael D. 
Published: July 2020

AbstractWe demonstrate the use of two-stage dynamic metabolic control to manipulate feedback regulation in central metabolism and improve stationary phase biosynthesis in engineeredE. coli. Specifically, we report the impact of dynamic control over two enzymes: citrate synthase, and glucose-6-phosphate dehydrogenase, on stationary phase fluxes. Firstly, reduced citrate synthase levels lead to a reduction inα-ketoglutarate, which is an inhibitor of sugar transport, resulting in increased stationary phase glucose uptake and glycolytic fluxes. Reduced glucose-6-phosphate dehydrogenase activity activates the SoxRS regulon and expression of pyruvate-ferredoxin oxidoreductase, which is in turn responsible for large increases in acetyl-CoA production. The combined reduction in citrate synthase and glucose-6-phosphate dehydrogenase, leads to greatly enhanced stationary phase metabolism and the improved production of citramalic acid enabling titers of 126±7g/L. These results identify pyruvate oxidation via the pyruvate-ferredoxin oxidoreductase as a “central” metabolic pathway in stationary phaseE. coli, which coupled with ferredoxin reductase comprise a pathway whose physiologic role is maintaining NADPH levels.HighlightsDynamic reduction inα-keto-glutarate pools alleviate inhibition of PTS dependent transport improving stationary phase sugar uptake.Dynamic reduction in glucose-6-phosphate dehydrogenase activates pyruvate flavodoxin/ferredoxin oxidoreductase and improves stationary acetyl-CoA flux.Pyruvate flavodoxin/ferredoxin oxidoreductase is responsible for large stationary phase acetyl-CoA fluxes under aerobic conditions.Production of citramalate to titers 126 ± 7g/L at > 90 % of theoretical yield.
Transposable Element-Gene Splicing Modulates the Transcriptional Landscape of Human Pluripotent Stem Cells
Authors: Babarinde Isaac A. , Ma Gang , Li Yuhao , Deng Boping , Luo Zhiwei , Liu Hao , Abdul Mazid Md. , Ward Carl , Chen Minchun , Fu Xiuling , Duttlinger Martha , He Jiangping , Sun Li , Li Wenjuan , Zhuang Qiang , Frampton Jon , Cazier Jean-Baptiste , Chen Jiekai , Jauch Ralf , Esteban Miguel A. , Hutchins Andrew P. 
Published: July 2020

AbstractTransposable elements (TEs) occupy nearly 50% of mammalian genomes and are both potential dangers to genome stability and functional genetic elements. TEs can be expressed and exonised as part of a transcript, however, their full contribution to the transcript splicing remains unresolved. Here, guided by long and short read sequencing of RNAs, we show that 26% of coding and 65% of non-coding transcripts of human pluripotent stem cells (hPSCs) contain TEs. Different TE families have unique integration patterns with diverse consequences on RNA expression and function. We identify hPSC-specific splicing of endogenous retroviruses (ERVs) as well as LINE L1 elements into protein coding genes that generate TE-derived peptides. Finally, single cell RNA-seq reveals that proliferating hPSCs are dominated by ERV-containing transcripts, and subpopulations express SINE or LINE-containing transcripts. Overall, we demonstrate that TE splicing modulates the pluripotency transcriptome by enhancing and impairing transcript expression and generating novel transcripts and peptides.
partR2: Partitioning R2in generalized linear mixed models
Authors: Stoffel Martin A. , Nakagawa Shinichi , Schielzeth Holger 
Published: July 2020

AbstractThe coefficient of determinationR2quantifies the amount of variance explained by regression coefficients in a linear model. It can be seen as the fixed-effects complement to the repeatabilityR(intra-class correlation) for the variance explained by random effects and thus as a tool for variance decomposition. TheR2of a model can be further partitioned into the variance explained by a particular predictor or a combination of predictors using semi-partial (part)R2and structure coefficients, but this is rarely done due to a lack of software implementing these statistics. Here, we introducepartR2, an R package that quantifies partR2for fixed effect predictors based on (generalized) linear mixed-effect model fits. The package iteratively removes predictors of interest from the model and monitors the change in the variance of the linear predictor. The difference to the full model gives a measure of the amount of variance explained uniquely by a particular predictor or a set of predictors.partR2also estimates structure coefficients as the correlation between a predictor and fitted values, which provide an estimate of the total contribution of a fixed effect to the overall prediction, independent of other predictors. Structure coefficients can be converted to the total variance explained by a predictor, here called ‘inclusive’R2, as the square of the structure coefficients times totalR2. Furthermore, the package reports beta weights (standardized regression coefficients). Finally,partR2implements parametric bootstrapping to quantify confidence intervals for each estimate. We illustrate the use ofpartR2with real example datasets for Gaussian and binomial GLMMs and discuss interactions, which pose a specific challenge for partitioning the explained variance among predictors.
Cytokinetic abscission is part of the mid-blastula transition switch in early zebrafish embryogenesis
Authors: Adar-Levor Shai , Nachmias Dikla , Gal-Oz Shani T. , Jahn Yarden M. , Peyrieras Nadine , Zaritsky Assaf , Birnbaum Ramon Y. , Elia Natalie 
Published: July 2020

ABSTRACTAnimal cytokinesis ends with the formation of a thin intercellular membrane bridge connecting the two newly formed sibling cells that is ultimately resolved by abscission. While mitosis is completed within 15 minutes, the intercellular bridge can persist for hours, maintaining a physical connection between sibling cells and allowing exchange of cytosolic components. Although cell-cell communication is fundamental for development, the potential role of intercellular bridges during embryogenesis have not been fully elucidated. Here, we found that in early zebrafish (Danio rerio) embryogenesis, abscission is delayed and cells do not resolve their intercellular bridges until midblastula transition (MBT), giving rise to the formation of small inter-connected cell clusters. Interestingly, abscission commences during the MBT switch, which is manifested by cell cycle elongation, loss of synchronized divisions and genome activation. Moreover, depletion of Chmp4bb which is an essential ESCRT-III component for scission, delayed abscission beyond the MBT switch. Hallmark features of MBT, including transcription onset and cell shape changes, were similar in sibling cells connected by intercellular bridges, proposing a role for intercellular bridges in maintaining cell-cell communication in the embryo. Taken together, our data suggest that abscission is part of the cellular changes that occur during MBT and that cells coordinate their behavior during this critical embryonic phase through persisted intercellular bridges.Significance StatementIn this work we show that the last step of cytokinesis, termed abscission, is inhibited in early zebrafish embryos. As a result, sibling cells remain connected to one another for several cycles and mutually time their developmental progress including transcription onset. Abscission commences at the 10thcell cycle, when embryos enter the midblastula transition (MBT) switch in which embryonic cells become individualized and exhibit the characteristics of mature cells. Our data suggest that abscission is part of the MBT switch and that embryonic sibling cells mutually time their developmental progress by maintaining physical connections between them in the early embryo.
COVID-19 and Rheumatoid Arthritis share myeloid pathogenic and resolving pathways
Authors: MacDonald Lucy , Otto Thomas D. , Elmesmari Aziza , Tolusso Barbara , Somma Domenico , McSharry Charles , Gremese Elisa , McInnes Iain B. , Alivernini Stefano , Kurowska-Stolarska Mariola 
Published: July 2020

AbstractBackgroundWe recently delineated the functional biology of pathogenic and inflammation resolving synovial tissue macrophage clusters in rheumatoid arthritis (RA). Whilst RA is not a viral respiratory syndrome, it represents a pro-inflammatory cytokine-driven chronic articular condition often accompanied by cardiovascular and lung pathologies. We hypothesised that functionally equivalent macrophage clusters in the lung might govern inflammation and resolution of COVID-19 pneumonitis.MethodsTo provide insight into the targetable functions of COVID-19 bronchoalveolar lavage (BALF) macrophage clusters, a comparative analysis of BALF macrophage single cell transcriptomics (scRNA-seq) with synovial tissue (ST) macrophage scRNA-seq and functional biology was performed. The function of shared BALF and ST MerTK inflammation-resolving pathway was confirmed with inhibitor in primary macrophage-synovial fibroblast co-cultures.Results. Distinct BALF FCNposand FCNposSPP1posmacrophage clusters emerging in severe COVID-19 patients were closely related to ST CD48highS100A12posand CD48posSPP1posclusters driving synovitis in active RA. They shared transcriptomic profile and pathogenic mechanisms. Healthy lung resident alveolar FABP4posmacrophages shared a regulatory transcriptomic profile, including TAM (Tyro, Axl, MerTK) receptors pathway with synovial tissue TREM2posmacrophages that govern RA remission. This pathway was substantially altered in BALF macrophages of severe COVID-19. In vitro dexamethasone inhibited tissue inflammation via macrophages’ MerTK function.ConclusionPathogenesis and resolution of COVID-19 pneumonitis and RA synovitis might be driven by similar macrophage clusters and pathways. The MerTK-dependent anti-inflammatory mechanisms of dexamethasone, and the homeostatic function of TAM pathways that maintain RA in remission advocate the therapeutic MerTK agonism to ameliorate the cytokine storm and pneumonitis of severe COVID-19.
Perinatal exposure to fluoxetine and maternal adversity affect myelin-related gene expression and epigenetic regulation in the corticolimbic circuit of juvenile rats
Authors: Ramsteijn Anouschka S. , Verkaik-Schakel Rikst Nynke , Houwing Danielle J. , Plösch Torsten , Olivier Jocelien D.A. 
Published: July 2020

AbstractMany pregnant women experience symptoms of depression, and are often treated with selective serotonin reuptake inhibitor (SSRI) antidepressants, such as fluoxetine.In uteroexposure to SSRIs and maternal depressive symptoms is associated with sex-specific effects on the brain and behavior. However, knowledge about the neurobiological mechanisms underlying these sex differences is limited. In addition, most animal research into developmental SSRI exposure neglects the influence of maternal adversity. Therefore, we used a rat model relevant to depression to investigate the molecular effects of perinatal fluoxetine exposure in male and female juvenile offspring. We performed RNA sequencing and targeted DNA methylation analyses on the prefrontal cortex and basolateral amygdala; key regions of the corticolimbic circuit. Perinatal fluoxetine enhanced myelin-related gene expression in the prefrontal cortex, while inhibiting it in the basolateral amygdala. SSRI exposure and maternal adversity interacted to affect expression of genes such as myelin−associated glycoprotein (Mag) and myelin basic protein (Mbp). We speculate that altered myelination reflects altered brain maturation. In addition, these effects are stronger in males than in females, resembling known behavioral outcomes. Finally,MagandMbpexpression correlated with DNA methylation, highlighting epigenetic regulation as a potential mechanism for developmental fluoxetine-induced changes in myelination.
The impact of microclimate and soil on the ecology and evolution of an arctic plant
Authors: Wickander Niklas J. , Rasmussen Pil U. , Marteinsdóttir Bryndís , Ehrlén Johan , Tack Ayco J. M. 
Published: July 2020

AbstractThe arctic and alpine regions are predicted to experience one of the highest rates of climate change, and the arctic vegetation is expected to be especially sensitive to such changes. Understanding the ecological and evolutionary responses of arctic plant species to changes in climate is therefore a key objective. Geothermal areas, where temperature gradients naturally occur over small spatial scales, and without many of the confounding environmental factors present in latitudinal and other gradient studies, provide a natural experimental setting to examine the impact of temperature on the response of arctic-alpine plants to increasing temperatures. To test the ecological and evolutionary response of the circumpolar alpine bistort (Bistorta vivipara) to temperature, we collected plant material and soil from areas with low, intermediate, and high soil temperatures and grew them in all combinations at three different temperatures. At higher experimental soil temperatures, sprouting was earlier, and plants had more leaves. Sprouting was earlier in soil originating from intermediate temperature and plants had more leaves when grown in soil originating from low temperatures. We did not find evidence of local adaptation or genetic variation in reaction norms among plants originating from areas with low, intermediate, and high soil temperature. Our findings suggest that the alpine bistort has a strong plastic response to warming, but that differences in soil temperature have not resulted in genetic differentiation. The lack of an observed evolutionary response may, for example, be due to the absence of temperature-mediated selection onB. vivipara, or high levels of gene flow balancing differences in selection. When placed within the context of other studies, we conclude that arctic-alpine plant species often show strong plastic responses to spring warming, while evidence of evolutionary responses varies among species.