bluuebunny/crossref_metadata_2025_split huggingface dataset:
A syngeneic spontaneous zebrafish model oftp53-deficient, EGFRvIII, and PI3KCAH1047R-driven glioblastoma reveals inhibitory roles for inflammation during tumor initiation and relapsein vivo
Authors: Weiss Alex , D’Amata Cassandra , Pearson Bret J. , Hayes Madeline N. 
Published: October 2023

AbstractHigh-throughput vertebrate animal model systems for the study of patient-specific biology and new therapeutic approaches for aggressive brain tumors are currently lacking, and new approaches are urgently needed. Therefore, to build a patient-relevantin vivomodel of human glioblastoma, we expressed common oncogenic variants including activated human EGFRvIIIand PI3KCAH1047Runder the control of the radial glial-specific promoterher4.1in syngeneictp53loss-of-function mutant zebrafish. Robust tumor formation was observed prior to 45 days of life, and tumors had a gene expression signature similar to human glioblastoma of the mesenchymal subtype, with a strong inflammatory component. Within early stage tumor lesions, and in anin vivoand endogenous tumor microenvironment, we visualized infiltration of phagocytic cells, as well as internalization of tumor cells bympeg1.1:EGFP+ microglia/macrophages, suggesting negative regulatory pressure by pro-inflammatory cell types on tumor growth at early stages of glioblastoma initiation. Furthermore, CRISPR/Cas9-mediated gene targeting of master inflammatory transcription factorsirf7orirf8led to increased tumor formation in the primary context, while suppression of phagocyte activity led to enhanced tumor cell engraftment following transplantation into otherwise immune-competent zebrafish hosts. Altogether, we developed a genetically relevant model of aggressive human glioblastoma and harnessed the unique advantages of zebrafish including live imaging, high-throughput genetic and chemical manipulations to highlight important tumor suppressive roles for the innate immune system on glioblastoma initiation, with important future opportunities for therapeutic discovery and optimizations.
Enhanced local cooling effects of forests across the globe
Authors: Verbiest William W. M. , Smith Gabriel Reuben , Mirzagholi Leila , Lauber Thomas , Zohner Constantin M. , Maynard Daniel S. , Schemm Sebastian , Crowther Thomas W. 
Published: October 2023

SummaryForests cool the land surface in warm regions and warm the land surface in cool regions. Because these local temperature buffering effects depend on background climate1,2, increasingly large areas might experience forest cooling effects as the climate warms3–5. Here, using statistical modeling, we quantified changes in the sensitivity of land surface temperatures6to forest cover change7from 1988 – 2016, across 15 million km2of land area. Forests had a local cooling effect on day and night surface temperatures in 86.3% (72 million km2) and 61.6% (5,108 million km2) of the forest area, respectively. This area has increased by 0.3% (0.2 million km2) at day and 4.7% (2 million km2) at night over recent decades. Our study indicates that climate change is enhancing the cooling effect of forests in the short term, underscoring the importance of protecting natural, diverse forest ecosystems in the face of rising global temperatures that threaten ecosystems8,9, human health10,11, and food production12.
Enhancer-driven local 3D chromatin domain folding modulates transcription in human mammary tumor cells
Authors: Kocanova Silvia , Raynal Flavien , Goiffon Isabelle , Oksuz Betul Akgol , Baú Davide , Kamgoué Alain , Cantaloube Sylvain , Zhan Ye , Lajoie Bryan , Marti-Renom Marc A. , Dekker Job , Bystricky Kerstin 
Published: October 2023

AbstractThe genome is organized in functional compartments and structural domains at the sub-megabase scale. How within these domains interactions between numerous cis-acting enhancers and promoters regulate transcription remains an open question. Here, we determined chromatin folding and composition over several hundred kb around estrogen responsive genes in human breast cancer cell lines following hormone stimulation. Modeling of 5C data at 1.8 kb resolution was combined with quantitative 3D analysis of multicolor FISH measurements at 100 nm resolution and integrated with ChIP-seq data on transcription factor binding and histone modifications. We found that rapid estradiol induction of the progesterone gene (PGR) expression occurs in the context of pre-existing, cell type specific chromosomal architectures encompassing the 90 kb PGR coding region and an enhancer-spiked 5’ 300 kb upstream genomic region. In response to estradiol, interactions between estrogen-receptor α (ERα) bound regulatory elements are re-enforced. While initial enhancer – gene contacts coincide with RNA Pol 2 binding and transcription initiation, sustained hormone stimulation promotes ER accumulation creating a regulatory hub stimulating transcript synthesis. In addition to implications for estrogen receptor signaling, we uncover that preestablished chromatin architectures efficiently regulate gene expression upon stimulation without the need for de-novo extensive rewiring of long-range chromatin interactions.
Maximizing Efficiency in SedaDNA Analysis: A Novel Extract Pooling Approach
Authors: Oberreiter Victoria , Gelabert Pere , Brück Florian , Franz Stefan , Zelger Evelyn , Szedlacsek Sophie , Cheronet Olivia , Tenorio Cano Fernanda , Exler Florian , Zagorc Brina , Karavanić Ivor , Banda Marko , Gasparyan Boris , Straus Lawrence Guy , Gonzalez Morales Manuel R. , Kappelman John , Stahlschmidt Mareike , Rattei Thomas , Kraemer Stephan M. , Sawyer Susanna , Pinhasi Ron 
Published: October 2023

AbstractIn recent years, the field of ancient DNA (aDNA) has taken a new direction toward studying human population dynamics through sedimentary DNA (sedaDNA), enabling the study of past ecosystems. However, the screening of numerous sediment samples from archaeological sites remains a time-consuming and costly endeavor, particularly when targeting hominin DNA. Here, we present a novel high-throughput method that facilitates the fast and efficient analysis of sediment samples by applying a pooled testing method. Our approach involves combining multiple extracts, allowing users to parallelize laboratory procedures early in the sample preparation pipeline while effectively screening for the presence of aDNA. Pooled samples that exhibit aDNA signals can then undergo detailed analysis, while empty pools are discarded. We have successfully applied our extract pooling method to various sediment samples from Middle and Upper Paleolithic sites in Europe, Asia, and Africa. Notably, our results reveal that an aDNA signal remains discernible even when pooled with four negative samples. We also demonstrate that the DNA yield of double-stranded libraries increases significantly when reducing the extract input, potentially mitigating the effects of inhibition. By embracing this innovative approach, researchers can analyze large numbers of sediment samples for aDNA preservation, achieving significant cost reductions of up to 70% and reducing hands-on laboratory time to one-fifth.
Niche Availability and Competitive Facilitation Control Proliferation of Bacterial Strains Intended for Soil Microbiome Interventions
Authors: Čaušević Senka , Dubey Manupriyam , Morales Marian , Salazar Guillem , Sentchilo Vladimir , Carraro Nicolas , Ruscheweyh Hans-Joachim , Sunagawa Shinichi , van der Meer Jan Roelof 
Published: October 2023

ABSTRACTMicrobiome engineering, the rational manipulation of microbial communities and their habitats, is considered a crucial strategy to revert dysbiosis. However, the concept is in its infancy and lacks experimental support. Here we study the ecological factors controlling the proliferation of focal bacterial inoculants into taxa-complex soil communities and their impact on resident microbiota. We demonstrate using standardized soil microbiomes with different growth phases that the proliferation of typical soil inoculants depends on niche competition. By adding an artificial, inoculant selective niche to soil we improve inoculant proliferation and show by metatranscriptomics to give rise to a conjoint metabolic network in the soil microbiome. Furthermore, using random paired growth assays we demonstrate that, in addition to direct competition, inoculants lose competitiveness with soil bacteria because of metabolite sharing. Thus, the fate of inoculants in soil is controlled by niche availability and competitive facilitation, which may be manipulated by selective niche generation.TeaserTypical bacterial inoculants for soil microbiome engineering suffer from facilitating growth of native resident microorganisms
SEM: sized-based expectation maximization for characterizing nucleosome positions and subtypes
Authors: Yang Jianyu , Yen Kuangyu , Mahony Shaun 
Published: October 2023

ABSTRACTGenome-wide nucleosome profiles are predominantly characterized using MNase-seq, which involves extensive MNase digestion and size selection to enrich for mono-nucleosome-sized fragments. Most available MNase-seq analysis packages assume that nucleosomes uniformly protect 147bp DNA fragments. However, some nucleosomes with atypical histone or chemical compositions protect shorter lengths of DNA. The rigid assumptions imposed by current nucleosome analysis packages ignore variation in nucleosome lengths, potentially blinding investigators to regulatory roles played by atypical nucleosomes.To enable the characterization of different nucleosome types from MNase-seq data, we introduce the Size-based Expectation Maximization (SEM) nucleosome calling package. SEM employs a hierarchical Gaussian mixture model to estimate the positions and subtype identity of nucleosomes from MNase-seq fragments. Nucleosome subtypes are automatically identified based on the distribution of protected DNA fragment lengths at nucleosome positions. Benchmark analysis indicates that SEM is on par with existing packages in terms of standard nucleosome-calling accuracy metrics, while uniquely providing the ability to characterize nucleosome subtype identities.Using SEM on a low-dose MNase H2B MNase-ChIP-seq dataset from mouse embryonic stem cells, we identified three nucleosome types: short-fragment nucleosomes, canonical nucleosomes, and dinucleosomes. The short-fragment nucleosomes can be divided further into two subtypes based on their chromatin accessibility. Interestingly, the subset of short-fragment nucleosomes in accessible regions exhibit high MNase sensitivity and display distribution patterns around transcription start sites (TSSs) and CTCF peaks, similar to the previously reported “fragile nucleosomes”. These SEM-defined accessible short-fragment nucleosomes are found not just in promoters, but also in enhancers and other regulatory regions. Additional investigations reveal their co-localization with the chromatin remodelers Chd6, Chd8, and Ep400.In summary, SEM provides an effective platform for distinguishing various nucleosome subtypes, paving the way for future exploration of non-standard nucleosomes.
Population variability in X-chromosome inactivation across 9 mammalian species
Authors: Werner Jonathan M. , Hover John , Gillis Jesse 
Published: October 2023

AbstractOne of the two X chromosomes in female mammals is epigenetically silenced in embryonic stem cells by X chromosome inactivation (XCI). This creates a mosaic of cells expressing either the maternal or the paternal X allele. The XCI ratio, the proportion of inactivated parental alleles, varies widely among individuals, representing the largest instance of epigenetic variability within mammalian populations. While various contributing factors to XCI variability are recognized, namely stochastic and/or genetic effects, their relative contributions are poorly understood. This is due in part to limited cross-species analysis, making it difficult to distinguish between generalizable or species-specific mechanisms for XCI ratio variability. To address this gap, we measured XCI ratios in nine mammalian species (9,143 individual samples), ranging from rodents to primates, and compared the strength of stochastic models or genetic factors for explaining XCI variability. Our results demonstrate the embryonic stochasticity of XCI is a general explanatory model for population XCI variability in mammals, while genetic factors play a minor role.
A multiscale model of immune surveillance in micrometastases: towards cancer patient digital twins
Authors: Rocha Heber L. , Aguilar Boris , Getz Michael , Shmulevich Ilya , Macklin Paul 
Published: October 2023

AbstractMetastasis is the leading cause of death in patients with cancer, driving considerable scientific and clinical interest in immunosurveillance of micrometastases. We investigated this process by creating a multiscale mathematical model to study the interactions between the immune system and the progression of micrometastases in general epithelial tissue. We analyzed the parameter space of the model using high-throughput computing resources to generate over 100,000 virtual patient trajectories. We demonstrated that the model could recapitulate a wide variety of virtual patient trajectories, including uncontrolled growth, partial response, and complete immune response to tumor growth. We classified the virtual patients and identified key patient parameters with the greatest effect on the simulated immunosurveillance. We highlight the lessons derived from this analysis and their impact on the nascent field of cancer patient digital twins (CPDTs). While CPDTs could enable clinicians to systematically dissect the complexity of cancer in each individual patient and inform treatment choices, our work shows that key challenges remain before we can reach this vision. In particular, we show that there remain considerable uncertainties in immune responses, dysfunctional data stratification, and unpredictable personalized treatment. Nonetheless, we also show that in spite of these challenges, patient-specific models suggest strategies to increase control of clinically undetectable micrometastases even without complete parameter certainty.
Scale-dependent hierarchical resolution: applications to atomic resolution and model validation in cryoEM
Authors: Ray Korak Kumar , Kinz-Thompson Colin D. 
Published: October 2023

AbstractThe recent cryoEM resolution revolution has had a tremendous impact on our ability to investigate biomolecular structure and function. However, outstanding questions about the reliability of using a cryoEM-derived molecular model for interpreting experiments and building further hypotheses limit its full impact. Significant amounts of research have been focused on developing metrics to assess cryoEM model quality, yet no consensus exists. This is in part because the meaning of cryoEM model quality is not well defined. In this work, we formalize cryoEM model quality in terms of whether a cryoEM map is better described by a model with localized atomic coordinates or by a lower-resolution model that lacks atomic-level information. This approach emerges from a novel, quantitative definition of image resolution based upon the hierarchical structure of biomolecules, which enables computational selection of the length scale to which a biomolecule is resolved based upon the available evidence embedded in the experimental data. In the context of cryoEM, we develop a machine learning-based implementation of this framework, called hierarchical atomic resolution perception (HARP), for assessing local atomic resolution in a cryoEM map and thus evaluating cryoEM model quality in a theoretically and statistically well-defined manner. Finally, using HARP, we perform a meta-analysis of the cryoEM-derived structures in the Protein Data Bank (PDB) to assess the state of atomic resolution in the field and quantify factors that affect it.Significance StatementInformation about biomolecular structure is very useful to researchers investigating the mechanistic basis of biomolecular function. To enable researchers to assess the reliability of biomolecular structural information that is derived from experimental data, a new theoretical definition of atomic resolution has been developed. This definition forms the basis of a machine learning-based tool called HARP that can be used to measure the local atomic resolution of cryoEM maps, as well as the quality of the biomolecular structural models derived from such cryoEM maps. To demonstrate the power and utility of these conceptually novel approaches, this work demonstrates how they may be used to investigate the scientific and social factors that have historically affected the quality of cryoEM experiments.
Skimming genomes for systematics and DNA barcodes of corals
Authors: Quattrini Andrea M. , McCartin Luke J. , Easton Erin E. , Horowitz Jeremy , Wirshing Herman H. , Bowers Hailey , Mitchell Kenneth , Sei Makiri , McFadden Catherine S. , Herrera Santiago 
Published: October 2023

Abstract1:Numerous genomic methods developed over the past two decades have enabled the discovery and extraction of orthologous loci to help resolve phylogenetic relationships across various taxa and scales. Genome skimming (or low-coverage whole genome sequencing) remains a low-cost, promising method to not only extract high-copy loci, but also 100s to 1000s of phylogenetically informative single-copy nuclear loci (e.g., ultraconserved elements [UCEs] and exons) from contemporary and historical museum samples. The subphylum Anthozoa, which includes important ecosystem engineers (e.g., stony corals, black corals, anemones and octocorals) in the marine environment, is in critical need of phylogenetic resolution and thus might benefit from a genome-skimming approach.2:Genome skimming was conducted on 242 hexacorals and octocorals collected from 1890 to 2022. Using previously developed target-capture baitsets, we bioinformatically obtained UCEs and exons from the genome-skimming data and incorporated them with data from previously published target-capture studies. We also extracted partial to whole mitogenomes and nuclear rRNA genes from the skim data.3:The mean number of UCE and exon loci extracted from the genome skimming data was 1,837 ± 662 SD for octocorals and 1,422 ± 720 loci for hexacorals; phylogenetic relationships were well resolved within each class. A mean of 1,422 ± 720 loci were obtained from the historical museum specimens, with 1,253 loci recovered from the oldest specimen collected in 1886 and 1,336 loci recovered from a holotype. The nuclearrRNAgenes and the majority of mitochondrial genes were successfully obtained from >95% of samples. Out of 99 circularized mitogenomes, 88% were recovered in samples from which we obtained >15M paired-end (PE) reads (>30M total reads); there was more variability in whether mitogenomes were circularized or not in samples with <15M PE reads.4:Bioinformatically pulling UCEs, exons, mitochondrial genomes, and nuclear rRNA genes from genome skimming is a viable and low-cost option for phylogenetic studies. This approach can be used to review and support taxonomic revisions and reconstruct evolutionary histories, including historical museum and type specimens.
TARO: tree-aggregated factor regression for microbiome data integration
Authors: Mishra Aditya K. , Mahmud Iqbal , Lorenzi Philip L. , Jenq Robert R. , Wargo Jennifer A. , Ajami Nadim J. , Peterson Christine B. 
Published: October 2023

AbstractMotivationAlthough the human microbiome plays a key role in health and disease, the biological mechanisms underlying the interaction between the microbiome and its host are incompletely understood. Integration with other molecular profiling data offers an opportunity to characterize the role of the microbiome and elucidate therapeutic targets. However, this remains challenging to the high dimensionality, compositionality, and rare features found in microbiome profiling data. These challenges necessitate the use of methods that can achieve structured sparsity in learning cross-platform association patterns.ResultsWe propose Tree-Aggregated factor RegressiOn (TARO) for the integration of microbiome and metabolomic data. We leverage information on the phylogenetic tree structure to flexibly aggregate rare features. We demonstrate through simulation studies that TARO accurately recovers a low-rank coefficient matrix and identifies relevant features. We applied TARO to microbiome and metabolomic profiles gathered from subjects being screened for colorectal cancer to understand how gut microrganisms shape intestinal metabolite abundances.Availability and implementationThe R packageTAROimplementing the proposed methods is available online athttps://github.com/amishra-stats/taro-package.
Resting state changes in aging and Parkinson’s disease are shaped by underlying neurotransmission – a normative modeling study
Authors: Kasper Jan , Caspers Svenja , Lotter Leon D. , Hoffstaedter Felix , Eickhoff Simon B. , Dukart Juergen 
Published: October 2023

AbstractHuman healthy and pathological aging is linked to a steady decline in brain resting state activity and connectivity measures. The neurophysiological mechanisms underlying these changes remain poorly understood. Making use of recent developments in normative modeling and availability of in vivo maps for various neurochemical systems, we test in the UK Biobank cohort (N=25,917) if and how age- and Parkinson’s disease related resting state changes in commonly applied local and global activity and connectivity measures co-localize with underlying neurotransmitter systems. We find the distributions of several major neurotransmitter systems including serotonergic, dopaminergic, noradrenergic and glutamatergic neurotransmission to explain age-related changes as observed across functional activity and connectivity measures. Co-localization patterns in Parkinson’s disease deviate from normative aging trajectories for these, as well as for cholinergic and GABAergic neurotransmission. The deviation from normal co-localization of brain function and GABAa correlates with disease duration. These findings provide new insights into molecular mechanisms underlying age- and Parkinson’s related brain functional changes. Combining normative modeling and neurotransmitter mapping may aid future research and drug development through deeper understanding of neurophysiological mechanisms underlying specific clinical conditions.
Neuronal activity modulates the incorporation of newly translated PSD-95 into a robust structure as revealed by STED and MINFLUX
Authors: Gürth Clara-Marie , do Rego Barros Fernandes Lima Maria Augusta , Palacios Victor Macarrón , Hubrich Jasmine , Cereceda Delgado Angel Rafael , Mougios Nikolaos , Opazo Felipe , D’Este Elisa 
Published: October 2023

AbstractThe postsynaptic density component PSD-95 undergoes activity-dependent plasticity mechanisms that rely on protein synthesis and structural remodeling. How synaptic activity can influence these dynamics at the single synapse level remains unclear. Here we combine genome-editing, pulse-chase experiments, STED and 3D MINFLUX nanoscopy on hippocampal neuronal cultures to study the integration of newly translated PSD-95 molecules at postsynaptic sites and their rearrangement within individual clusters at near-molecular resolution. We show that the amount of newly translated PSD-95 recruited to individual synapses scales with synaptic size, and modulates in a bidirectional manner, resulting in less new protein following excitatory and more new protein following inhibitory stimulation. Furthermore, we show that within synaptic clusters PSD-95 has a dispersed organization that is largely robust to long-lasting changes in activity. Altogether, this work sheds new light on the mechanisms underlying plasticity at the single synapse level, adding previously inaccessible information.