bluuebunny/crossref_metadata_2025_split huggingface dataset:
Capturing the dynamics of microbiomes using individual-specific networks
Authors: Yousefi Behnam , Melograna Federico , Galazzo Gianluca , van Best Niels , Mommers Monique , Penders John , Schwikowski Benno , van Steen Kristel 
Published: January 2023

AbstractBackgroundLongitudinal analysis of multivariate individual-specific microbiome profiles over time or across conditions remains a daunting task. The vast majority of statistical tools and methods available to study the microbiota are based upon cross-sectional data. Over the past few years, several attempts have been made to model the dynamics of bacterial species over time or across conditions. However, the field needs novel views on how to incorporate individual-specific microbial associations in temporal analyses when the focus lies on microbial interactions.ResultsHere, we propose a novel data analysis framework, called MNDA, to uncover taxon neighbourhood dynamics that combines representation learning and individual-specific microbiome co-occurrence networks. We show that tracking local neighbourhood dynamics in microbiome interaction or co-occurrence networks can yield complementary information to standard approaches that only use microbial abundances or pairwise microbial interactions. We use cohort data on infants for whom microbiome data was available at 6 and 9 months after birth, as well as information on mode of delivery and diet changes over time. In particular, MNDA-based prediction models outperform traditional prediction models based on individual-specific abundances, and enable the detection of microbes whose neighbourhood dynamics are informative of clinical variables. We further show that similarity analyses of individuals based on microbial neighbourhood dynamics can be used to find subpopulations of individuals with potential relevance to clinical practice. The annotated source code for the MNDA framework can be downloaded from:https://github.com/H2020TranSYS/microbiome_dynamicsConclusionsMNDA extracts information from matched microbiome profiles and opens new avenues to personalized prediction or stratified medicine with temporal microbiome data.
Mitochondrial citrate metabolism and efflux regulates trophoblast differentiation
Authors: Mahr Renee M. , Jena Snehalata , Nashif Sereen K. , Nelson Alisa B. , Rauckhorst Adam J. , Rome Ferrol I. , Sheldon Ryan D. , Hughey Curtis C. , Puchalska Patrycja , Gearhart Micah D. , Taylor Eric B. , Crawford Peter A. , Wernimont Sarah A. 
Published: January 2023

AbstractCytotrophoblasts fuse to form and renew syncytiotrophoblasts necessary to maintain placental health throughout gestation. During cytotrophoblast to syncytiotrophoblast differentiation, cells undergo regulated metabolic and transcriptional reprogramming. Mitochondria play a critical role in differentiation events in cellular systems, thus we hypothesized that mitochondrial metabolism played a central role in trophoblast differentiation. In this work, we employed static and stable isotope tracing untargeted metabolomics methods along with gene expression and histone acetylation studies in an established cell culture model of trophoblast differentiation. Trophoblast differentiation was associated with increased abundance of the TCA cycle intermediates citrate and α-ketoglutarate. Citrate was preferentially exported from mitochondria in the undifferentiated state but was retained to a larger extent within mitochondria upon differentiation. Correspondingly, differentiation was associated with decreased expression of the mitochondrial citrate transporter (CIC). CRISPR/Cas9 disruption of the mitochondrial citrate carrier showed that CIC is required for biochemical differentiation of trophoblasts. Loss of CIC resulted in broad alterations in gene expression and histone acetylation. These gene expression changes were partially rescued through acetate supplementation. Taken together, these results highlight a central role for mitochondrial citrate metabolism in orchestrating histone acetylation and gene expression during trophoblast differentiation.
Modeling of African population history usingf-statistics can be highly biased and is not addressed by previously suggested SNP ascertainment schemes
Authors: Flegontov Pavel , Işıldak Ulaş , Maier Robert , Yüncü Eren , Changmai Piya , Reich David 
Published: January 2023

Abstractf-statistics have emerged as a first line of analysis for making inferences about demographic history from genome-wide data. These statistics can provide strong evidence for either admixture or cladality, which can be robust to substantial rates of errors or missing data.f-statistics are guaranteed to be unbiased under “SNP ascertainment” (analyzing non-randomly chosen subsets of single nucleotide polymorphisms) only if it relies on a population that is an outgroup for all groups analyzed. However, ascertainment on a true outgroup that is not co-analyzed with other populations is often impractical and uncommon in the literature. In this study focused on practical rather than theoretical aspects of SNP ascertainment, we show that many non-outgroup ascertainment schemes lead to false rejection of true demographic histories, as well as to failure to reject incorrect models. But the bias introduced by common ascertainments such as the 1240K panel is mostly limited to situations when more than one sub-Saharan African and/or archaic human groups (Neanderthals and Denisovans) or non-human outgroups are co-modelled, for example,f4-statistics involving one non-African group, two African groups, and one archaic group. Analyzing panels of SNPs polymorphic in archaic humans, which has been suggested as a solution for the ascertainment problem, cannot fix all these problems since for some classes off-statistics it is not a clean outgroup ascertainment, and in other cases it demonstrates relatively low power to reject incorrect demographic models since it provides a relatively small number of variants common in anatomically modern humans. And due to the paucity of high-coverage archaic genomes, archaic individuals used for ascertainment often act as sole representatives of the respective groups in an analysis, and we show that this approach is highly problematic. By carrying out large numbers of simulations of diverse demographic histories, we find that bias in inferences based onf-statistics introduced by non-outgroup ascertainment can be minimized if the derived allele frequency spectrum in the population used for ascertainment approaches the spectrum that existed at the root of all groups being co-analyzed. Ascertaining on sites with variants common in a diverse group of African individuals provides a good approximation to such a set of SNPs, addressing the great majority of biases and also retaining high statistical power for studying population history. Such a “pan-African” ascertainment, although not completely problem-free, allows unbiased exploration of demographic models for the widest set of archaic and modern human populations, as compared to the other ascertainment schemes we explored.
A dual sgRNA library design to probe genetic modifiers using genome-wide CRISPRi screens
Authors: Guna Alina , Page Katharine R. , Replogle Joseph M. , Esantsi Theodore K. , Wang Maxine L. , Weissman Jonathan S. , Voorhees Rebecca M. 
Published: January 2023

AbstractMapping genetic interactions is essential for determining gene function and defining novel biological pathways. We report a simple to use CRISPR interference (CRISPRi) based platform, compatible with Fluorescence Activated Cell Sorting (FACS)-based reporter screens, to query epistatic relationships at scale. This is enabled by a flexible dual-sgRNA library design that allows for the simultaneous delivery and selection of a fixed sgRNA and a second randomized guide, comprised of a genome-wide library, with a single transduction. We use this approach to identify epistatic relationships for a defined biological pathway, showing both increased sensitivity and specificity than traditional growth screening approaches.
Dynamics of Changes in Cadmium Levels in Environmental Objects and its Impact on the Bio-Elemental Composition of Living Organisms
Authors: Nechytailo Larysa , Danyliv Svitlana , Kuras Liliia , Shkurashivska Svitlana , Buchko Aleksandra 
Published: January 2023

AbstractAs a result of intensive anthropogenic impact in the biosphere there is a rapid process of accumulation of heavy metal salts. They have led to the aggravation of problems associated with the pollution of ecosystems and basic food products of plant and animal origin. Environmental pollution by these compounds is caused by their persistence in environmental objects, migration ability, accumulation by plants. This contributes to their accumulation in the human environment. A number of studies have shown that heavy metals have mutagenic, toxic effects and affect the intensity of biochemical processes. Therefore, the presence of heavy metals in the environment is extremely undesirable. Moreover, the ecological state of the environment is directly related to changes in the human internal environment. Deficiency or excess of certain bioelements in soils and drinking water or non-compliance with its stable chemical composition causes the development of dysmicroelementosis. The ecological situation of the Carpathian region is closely related to the state of soils and water resources. In this regard, it is advisable to study and control the level of cadmium compounds in the environment of the region. The study of the effect of cadmium intoxication on the macro- and microelement composition of the brain and myocardium of experimental animals is also worthwhile.Materials and methodsSoils and drinking water of the plain, foothill and mountainous zones of the region, as well as organs and tissues of experimental animals served as the object of research. Cadmium levels in drinking water and myocardial tissues and brain of experimental animals have been measured by atomic absorption spectroscopy.Results and discussionThe study of soils in the Prykarpattia region has revealed an increase in the toxic element cadmium. Its content is 1.1-1.5 times higher than background levels. The analysis of drinking water allowed to establish that a significant number of people living in the plain and foothill zone of the region consume water with a high content of cadmium. The main stages of cadmium intake and accumulation in plants have been analyzed.Significant disorders in the body of experimental animals under conditions of excessive intake of cadmium compounds have been revealed. It was accompanied by the accumulation of cadmium in the myocardium and brain, on the background of redistribution of vital macronutrients calcium and magnesium along with micronutrients copper and zinc. Thus, excessive intake of cadmium salts causes the development of dysmicroelementosis, which is accompanied by a violation of the homeostasis of a living organism. It is suggested to conduct continuous monitoring of the level of toxicants in the ecosystem as an integral component of environmental monitoring.
Division and Spreading of Attention across Colour
Authors: Martinovic Jasna , Boyanova Antoniya , Andersen Søren K. 
Published: January 2023

AbstractBiological systems must allocate limited perceptual resources to relevant elements in their environment. This often requires simultaneous selection of multiple elements from the same feature dimension (e.g., colour). To establish the determinants of divided attentional selection of colour, we conducted an experiment that used multicoloured displays with four overlapping random dot kinematograms that differed only in hue. We manipulated (1) requirement to focus attention to a single colour or divide it between two colours; (2) distances of distractor hues from target hues in a perceptual colour space. We conducted a behavioural and an electroencephalographic experiment, in which each colour was tagged by a specific flicker frequency and driving its own steady-state visual evoked potential. Behavioural and neural indices of attention showed several major consistencies. Concurrent selection halved the neural signature of target enhancement observed for single targets, consistent with an approximately equal division of limited resources between two hue-selective foci. Distractors interfered with behavioural performance in a context-dependent fashion but their effects were asymmetric, indicating that perceptual distance did not adequately capture attentional distance. These asymmetries point towards an important role of higher-level mechanisms such as categorisation and grouping-by-colour in determining the efficiency of attentional allocation in complex, multi-coloured scenes.
Using inbreeding to test the contribution of non-additive genetic effects to additive genetic variance: a case study inDrosophila serrata
Authors: Dugand Robert J. , Blows Mark W. , McGuigan Katrina 
Published: January 2023

AbstractAdditive genetic variance,VA, is the key parameter for predicting adaptive and neutral phenotypic evolution. Changes in demography (e.g., increased close-relative inbreeding) can alterVA, but how depends on the, typically unknown, gene action and allele frequencies across many loci. For example,VAincreases proportionally with the inbreeding coefficient when allelic effects are additive, but larger (or smaller) increases can occur when allele frequencies are unequal at causal loci with dominance effects. Here, we describe an experimental approach to assess the potential for rare, recessive alleles to inflateVAunder inbreeding. Applying a powerful paired pedigree design inDrosophila serrata, we measured 11 wing traits on half-sibling families bred via either random or sibling mating, differing only in homozygosity (not allele frequency). Despite close inbreeding and substantial power to detect smallVA, we detected no deviation from the expected additive effect of inbreeding on genetic (co)variances. Our results suggest the average dominance coefficient is very small relative to the additive effect, or that allele frequencies are relatively equal at loci affecting wing traits. We outline the further opportunities for this paired pedigree approach to reveal the characteristics ofVA, providing insight into historical selection and future evolutionary potential.
Solution-state NMR Assignment and Secondary Structural Propensities of the Full-Length and Minimalistic-Truncated Prefibrillar Monomeric Form of Biofilm-Forming Functional-Amyloid FapC fromPseudomonas aeruginosa
Authors: Byeon Chang-Hyeock , Wang Pang C. , Byeon In-Ja L. , Akbey Ümit 
Published: January 2023

AbstractFunctional bacterial amyloids provide structural scaffolding to bacterial biofilms. In contrast to the pathological amyloids, they have a rolein vivoand are tightly regulated. Their presence is essential to the integrity of the bacterial communities surviving in biofilms and may cause serious health complications. Targeting amyloids in biofilms could be a novel approach to prevent chronic infections. However, structural information is very scarce on them in both soluble monomeric and insoluble fibrillar forms, hindering our molecular understanding and strategies to fight biofilm related diseases. Here, we present solution-state NMR assignment of 250 amino acid long biofilm-forming functional-amyloid FapC fromPseudomonas aeruginosa. We studied the full-length and shorter minimalistic-truncated FapC constructs without signal-sequence that is required for secretion. 91% and 100% backbone NH resonance assignment for FL and short constructs, respectively, indicates that soluble monomeric FapC is predominantly disordered, with sizeable secondary structural propensities mostly as PP2 helices, but also as α-helices and β-sheets highlighting hotspots for fibrillation initiation interface. Shorter construct showing almost identical NMR chemical shifts highlights the promise of utilizing it for more demanding solid-state NMR studies that requires methods to alleviate signal redundancy due to almost identical repeat units. This study provides key NMR resonance assignment for future structural studies of soluble, pre-fibrillar and fibrillar forms of FapC.
Accurate and interpretable gene expression imputation on scRNA-seq data using IGSimpute
Authors: Xu Ke , Cheong ChinWang , Veldsman Werner Pieter , Lyu Aiping , Cheung William K. , Zhang Lu 
Published: January 2023

AbstractSingle-cell RNA-sequencing (scRNA-seq) enables the quantification of gene expression at the transcriptomic level with single-cell resolution, enhancing our understanding of cellular heterogeneity. However, the excessive missing values present in scRNA-seq data (termed dropout events) hinder downstream analysis. While numerous imputation methods have been proposed to recover scRNA-seq data, high imputation performance often comes with low or no interpretability. Here, we present IGSimpute, an accurate and interpretable imputation method for recovering missing values in scRNA-seq data with an interpretable instance-wise gene selection layer. IGSimpute outperforms ten other state-of-the-art imputation methods on nine tissues of the Tabula Muris atlas with the lowest mean squared error as the chosen benchmark metric. We demonstrate that IGSimpute can give unbiased estimates of the missing values compared to other methods, regardless of whether the average gene expression values are small or large. Clustering results of imputed profiles show that IGSimpute offers statistically significant improvement over other imputation methods. By taking the heart-and-aorta and the limb muscle tissues as examples, we show that IGSimpute can also denoise gene expression profiles by removing outlier entries with unexpected high expression values via the instance-wise gene selection layer. We also show that genes selected by the instance-wise gene selection layer could indicate the age of B cells from bladder fat tissue of the Tabula Muris Senis atlas. IGSimpute has linear time-complexity with respect to cell number, and thus applicable to large datasets.
Antithetic effects of agonists and antagonists on the structural fluctuations of TRPV1 channel
Authors: Sumino Ayumi , Zhao Yimeng , Mukai Daichi , Sumikama Takashi , Puppulin Leonardo , Hattori Motoyuki , Shibata Mikihiro 
Published: January 2023

AbstractTransient receptor potential vanilloid member 1 (TRPV1) is a heat and capsaicin receptor that allows cations to permeate and cause pain. As the molecular basis for temperature sensing, the heat capacity (ΔCp) model (D. E. Clapham, C. Miller,Proc. Natl. Acad. Sci. U. S. A.108, 19492–19497 (2011).) has been proposed and experimentally supported. Theoretically, heat capacity is proportional to a variance in enthalpy, presumably related to structural fluctuation; however, the fluctuation of TRPV1 has not been directly visualized. In this study, we directly visualized single-molecule structural fluctuations of the TRPV1 channels in a lipid bilayer with the ligands resiniferatoxin (RTX: agonist, 1000 times hotter than capsaicin) and capsazepine (CPZ: antagonist) by high-speed atomic force microscopy (HS-AFM). We observed the structural fluctuations of TRPV1 in an apo state and found that RTX binding enhances structural fluctuations, while CPZ binding suppresses fluctuations. These ligand-dependent differences in structural fluctuation would play a key role in the gating of TRPV1.
Correcting dilated cardiomyopathy with fibroblast-targeted p38 deficiency
Authors: Bretherton Ross C. , Reichardt Isabella M. , Zabrecky Kristin A. , Goldstein Alex J. , Bailey Logan R.J. , Bugg Darrian , McMillen Timothy S. , Kooiker Kristina B. , Flint Galina V. , Martinson Amy , Gunaje Jagdambika , Koser Franziska , Plaster Elizabeth , Linke Wolfgang A. , Regnier Michael , Moussavi-Harami Farid , Sniadecki Nathan J. , DeForest Cole A. , Davis Jennifer 
Published: January 2023

AbstractInherited mutations in contractile and structural genes, which decrease cardiomyocyte tension generation, are principal drivers of dilated cardiomyopathy (DCM)– the leading cause of heart failure1,2. Progress towards developing precision therapeutics for and defining the underlying determinants of DCM has been cardiomyocyte centric with negligible attention directed towards fibroblasts despite their role in regulating the best predictor of DCM severity, cardiac fibrosis3,4. Given that failure to reverse fibrosis is a major limitation of both standard of care and first in class precision therapeutics for DCM, this study examined whether cardiac fibroblast-mediated regulation of the heart’s material properties is essential for the DCM phenotype. Here we report in a mouse model of inherited DCM that prior to the onset of fibrosis and dilated myocardial remodeling both the myocardium and extracellular matrix (ECM) stiffen from switches in titin isoform expression, enhanced collagen fiber alignment, and expansion of the cardiac fibroblast population, which we blocked by genetically suppressing p38α in cardiac fibroblasts. This fibroblast-targeted intervention unexpectedly improved the primary cardiomyocyte defect in contractile function and reversed ECM and dilated myocardial remodeling. Together these findings challenge the long-standing paradigm that ECM remodeling is a secondary complication to inherited defects in cardiomyocyte contractile function and instead demonstrate cardiac fibroblasts are essential contributors to the DCM phenotype, thus suggesting DCM-specific therapeutics will require fibroblast-specific strategies.
Novel Pipeline for Large-Scale Comparative Population Genetics
Authors: Majoros S.E. , Adamowicz S.J. , Cottenie K. 
Published: January 2023

AbstractThis study determined population genetic structure measures, compared these measures across species with different biological traits; and created efficient, reproducible, reusable programming modules that are publicly available for future research. Cytochrome C Oxidase subunit I gene sequences from Diptera (true fly) species from Greenland and Canada were used as a case study and proof of concept. We hypothesized that population genetic structure measures will be influenced by the biological traits of organisms. Data were pulled from public databases, as well as taxon-specific literature. The R pipeline includes fifteen modules that can be adapted and applied to a diverse set of animal groups, geographic regions, genes, and traits. Habitat, larval diet, geographical distance, latitude, and longitude were all significantly related to population genetic structure in Diptera. Overall, this study has created efficient, reusable bioinformatics modules, as well as provided insight into the factors affecting population genetic structure in Northern fly communities.