bluuebunny/crossref_metadata_2025_split huggingface dataset:
Biobank-scale inference of ancestral recombination graphs enables genealogy-based mixed model association of complex traits
Authors: Zhang Brian C. , Biddanda Arjun , Palamara Pier Francesco 
Published: November 2021

AbstractAccurate inference of gene genealogies from genetic data has the potential to facilitate a wide range of analyses. We introduce a method for accurately inferring biobank-scale genome-wide genealogies from sequencing or genotyping array data, as well as strategies to utilize genealogies within linear mixed models to perform association and other complex trait analyses. We use these new methods to build genome-wide genealogies using genotyping data for 337,464 UK Biobank individuals and to detect associations in 7 complex traits. Genealogy-based association detects more rare and ultra-rare signals (N= 133, frequency range 0.0004% - 0.1%) than genotype imputation from ∼65,000 sequenced haplotypes (N= 65). In a subset of 138,039 exome sequencing samples, these associations strongly tag (averager= 0.72) underlying sequencing variants, which are enriched for missense (2.3×) and loss-of-function (4.5×) variation. Inferred genealogies also capture additional association signals in higher frequency variants. These results demonstrate that large-scale inference of gene genealogies may be leveraged in the analysis of complex traits, complementing approaches that require the availability of large, population-specific sequencing panels.
PGC-1α in the myofibers regulates the balance between myogenic and adipogenic progenitors affecting muscle regeneration
Authors: Beltrà Marc , Pin Fabrizio , Costamagna Domiziana , Duelen Robin , Renzini Alessandra , Ballarò Riccardo , Garcia-Castillo Lorena , Iannuzzi Ambra , Moresi Viviana , Coletti Dario , Sampaolesi Maurilio , Penna Fabio , Costelli Paola 
Published: November 2021

ABSTRACTSkeletal muscle repair is accomplished by satellite cells (MuSC) in cooperation with interstitial stromal cells (ISCs). So far, the relationship between the function of these cells and the metabolic state of myofibers remains unclear. The present study reports alterations in the proportion of both MuSCs and adipogenesis regulators (Aregs) induced by overexpression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in the myofibers (MCK-PGC-1α mice). Although PGC-1α–driven increase of MuSCs does not accelerate muscle regeneration, myogenic progenitors isolated from MCK-PGC-1α mice and transplanted into intact and regenerating muscles are more prone to fuse with recipient myofibers than those derived from WT donors. Moreover, both young and aged MCK-PGC-1α animals show reduced perilipin-positive areas when challenged with an adipogenic stimulus, demonstrating low propensity to accumulate adipocytes within the muscle. These results provide new insights on the role played by PGC-1α in promoting myogenesis and hindering adipogenesis in the skeletal muscle.
A multi-species co-occurrence index to avoid type II errors in null model testing
Authors: Lagat Vitalis K. , Latombe Guillaume , Hui Cang 
Published: November 2021

AbstractCommunity structure is determined by the interplay among different processes, including biotic interactions, abiotic filtering and dispersal. Their effects can be detected by comparing observed patterns of co-occurrence between different species (e.g. C-score and the natural metric) to patterns generated by null models based on permutations of species-by-site matrices under constraints on row or column sums. These comparisons enable us to detect significant signals of species association or dissociation, from which the type of biotic interactions between species (e.g. facilitative or antagonistic) can be inferred. Commonly used patterns are based on the levels of co-occurrence between randomly paired species. The level of co-occurrence for three or more species is rarely considered, ignoring the potential existence of functional guilds or motifs composed of multiple species within the community. Null model tests that do not consider multi-species co-occurrence could therefore generate false negatives (Type II error) in detecting non-random forces at play that would only be apparent for such guilds. Here, we propose a multi-species co-occurrence index (hereafter, joint occupancy) that measures the number of sites jointly occupied by multiple species simultaneously, of which the pairwise metric of co-occurrence is a special case. Using this joint occupancy index along with standard permutation algorithms for null model testing, we illustrate nine archetypes of multi-species co-occurrence and explore how frequent they are in the seminal database of 289 species-by-site community matrices published by Atmar and Patterson in 1995. We show that null model testing using pairwise co-occurrence metrics could indeed lead to severe Type II errors in one specific archetype, accounting for 2.4% of the tested community matrices.
A novel hybrid protein promotes Aβ clearance and reduces inflammatory response through MerTK
Authors: Samentar Lorena P. , Salazar Arnold , Pan Pei-Pei , Etebar Kayvon , Choy Kelly , Uddin Durin , Eliseeff Pauline , Bugayong Adrienne Marrie , Garrido Jose Antonio Ma. G. , Emini Aurora , Rock Nicole , Caberoy Nora Blanca 
Published: November 2021

AbstractAlzheimer’s disease (AD) is the world’s leading cause of dementia and the most common neurodegenerative disorder. Its major pathological features are amyloid beta (Aβ) plaques, tau tangles, and neuroinflammation that eventually leads to massive death of nerve cells. Even with the multifactorial aspect of AD, the most accepted theory is that Aβ is the driving force of AD pathogenesis. We engineered a novel hybrid protein that facilitates the phagocytosis of Aβ and redirect its clearance to the noninflammatory Mer tyrosine kinase (MerTK) pathway. The novel hybrid protein facilitates robust uptake and clearance of Aβ in BV2 microglia through MerTK receptor with reduced production of inflammatory factors and oxidative products. In APP/PS1 transgenic AD mouse model, intraperitoneal administration of the hybrid protein for two months results in significant reduction of Aβ burden in the brain and protection of nerve cells from dying. Taken together, our results suggest that the novel hybrid may have the potential for AD treatment by targeting both Aβ clearance and reduction of inflammation.
Meta-Analysis of cortical inhibitory interneurons markers landscape and their performances in scRNA-seq studies
Authors: Martini Lorenzo , Bardini Roberta , Di Carlo Stefano 
Published: November 2021

AbstractThe mammalian cortex contains a great variety of neuronal cells. In particular, GABAergic interneurons, which play a major role in neuronal circuit function, exhibit an extraordinary diversity of cell types. In this regard, single-cell RNA-seq analysis is crucial to study cellular heterogeneity. To identify and analyze rare cell types, it is necessary to reliably label cells through known markers. In this way, all the related studies are dependent on the quality of the employed marker genes. Therefore, in this work, we investigate how a set of chosen inhibitory interneurons markers perform. The gene set consists of both immunohistochemistry-derived genes and single-cell RNA-seq taxonomy ones. We employed various human and mouse datasets of the brain cortex, consequently processed with the Monocle3 pipeline. We defined metrics based on the relations between unsupervised cluster results and the marker expression. Specifically, we calculated the specificity, the fraction of cells expressing, and some metrics derived from decision tree analysis like entropy gain and impurity reduction. The results highlighted the strong reliability of some markers but also the low quality of others. More interestingly, though, a correlation emerges between the general performances of the genes set and the experimental quality of the datasets. Therefore, the proposed method allows evaluating the quality of a dataset in relation to its reliability regarding the inhibitory interneurons cellular heterogeneity study.
Endothelial Rap1B mediates T-cell exclusion to promote tumor growth – a novel mechanism underlying vascular immunosuppression
Authors: Sharma Guru Prasad , Kosuru Ramoji , Lakshmikanthan Sribalaji , Zheng Shikan , Chen Yao , Burns Robert , Xin Gang , Cui Weiguo , Chrzanowska Magdalena 
Published: November 2021

AbstractOvercoming vascular immunosuppression: lack of endothelial cell (EC) responsiveness to inflammatory stimuli in the proangiogenic environment of tumors, is essential for successful cancer immunotherapy. The mechanisms through which Vascular Endothelial Growth Factor (VEGF) modulates tumor EC response to exclude T cells are not well understood. The goal was to determine the role of EC Rap1B, a small GTPase that positively regulates VEGF- angiogenesis during development, in tumor growth in vivo. Using mouse models of Rap1B deficiency, Rap1B+/- and EC-specific Rap1B KO (Rap1BiΔEC) we demonstrate that EC Rap1B restricts tumor growth and angiogenesis. More importantly, EC-specific Rap1B deletion leads to an altered tumor microenvironment with increased recruitment of leukocytes and increased activity of tumor CD8+ T cells. We find that tumor growth, albeit not angiogenesis, is restored in Rap1BiΔEC mice by depleting CD8+ T cells. Mechanistically, global transcriptome analysis indicated upregulation of the tumor cytokine, TNF-α, -induced signaling and NFκB transcriptional activity in Rap1B-deficient ECs. Functionally, EC Rap1B deletion led to upregulation of NFκB activity and enhanced Cell Adhesion Molecules (CAMs) expression in TNF-α stimulated ECs. Importantly, CAM expression was upregulated also in tumor ECs from Rap1BiΔEC mice, vs. controls. Significantly, deletion of Rap1B abrogated VEGF immunosuppressive downregulation of CAM expression, demonstrating that Rap1B is essential for VEGF-suppressive signaling. Thus, our studies identify a novel endothelial-endogenous mechanism underlying VEGF-dependent desensitization of EC to pro-inflammatory stimuli. Significantly, they identify EC Rap1 as a potential novel vascular target in cancer immunotherapy.
Biofabrication of development-inspired scaffolds for regeneration of the annulus fibrosus macro- and microarchitecture
Authors: Kluser Nadine , Sprecher Christoph , Alig Gion Ursin , Häckel Sonja , Albers Christoph E. , Alini Mauro , Grad Sibylle , Eglin David , Vernengo Andrea 
Published: November 2021

AbstractAnnulus fibrosus (AF) tissue engineering is a promising strategy for repairing the degenerated intervertebral disc (IVD) and a research area that could benefit from improved tissue models to drive translation. AF tissue is composed of concentric layers of aligned collagen bundles arranged in an angle-ply pattern, an architecture which is challenging to recapitulate with current scaffold design strategies. In response to this need, we developed a strategy to print 3D scaffolds that induce cell and tissue organization into oriented patterns mimicking the AF. Polycaprolactone (PCL) was printed in an angle-ply macroarchitecture possessing microscale aligned topographical cues. The topography was achieved by extrusion through custom-designed printer nozzles which were either round or possessing circumferential sinusoidal peaks. Whereas the round nozzle produced extruded filaments with a slight uniaxial texture, patterned nozzles with peak heights of 60 or 120 μm produced grooves, 10.87 ± 3.09 μm or 17.77 ± 4.91 μm wide, respectively. Bone marrow derived mesenchymal stem cells (BM-MSCs) cultured on the scaffolds for four weeks exhibited similar degrees of alignment within ± 10 ° of the printing direction and upregulation of outer AF markers (COL1, COL12, SFRP, MKX, MCAM, SCX and TAGLN), with no statistically significant differences as a function of topography. Interestingly, the grooves generated by the patterned nozzles induced longitudinal end-to-end alignment of cells, capturing the arrangement of cells during fibrillogenesis. In contrast, topography produced from the round nozzle induced a continuous web of elongated cells without end-to-end alignment. Extracellular collagen I, decorin and fibromodulin were detected in patterns closely following cellular organization. Taken together, we present a single-step biofabrication strategy to induce anisotropic cellular alignments in x-, y-, and z-space, with potential application as anin vitromodel for studying AF tissue morphogenesis and growth.
Effects of chlorpyrifos on early development and anti-predator behavior of agile frogs
Authors: Mikó Zsanett , Bókony Veronika , Ujhegyi Nikolett , Nemesházi Edina , Erös Réka , Orf Stephanie , Hettyey Attila 
Published: November 2021

AbstractThe widespread application of pesticides makes it important to understand the impacts of these chemicals on wildlife populations. Chlorpyrifos is an organophosphate insecticide which can affect the development and behavior of aquatic organisms and may thereby alter predator-prey interactions. To investigate how environmentally relevant, sublethal concentrations of chlorpyrifos affect anti-predator behavior and larval development of the agile frog (Rana dalmatina), we exposed tadpoles to one of three concentrations (0, 0.5 and 5 μg chlorpyrifos / L) either for a brief period of three days (acute exposure) or throughout larval development (chronic exposure). We observed tadpole activity and space use in the presence or absence of chemical cues of predatory fish. We also assessed mortality, time to metamorphosis, mass at metamorphosis, brain morphology and sex ratio. We found that tadpoles chronically exposed to 5 μg/L chlorpyrifos swam distances that were longer by more than 20 % and exhibited body masses at metamorphosis that were lower by ca. 7 % than in control individuals, but the other fitness-related traits remained unaffected. The lower concentration of chlorpyrifos applied chronically, and either one of the acute chlorpyrifos treatments did not influence any measured trait. Our results demonstrate that exposure to chlorpyrifos can induce changes in locomotor activity and may result in lowered body mass of agile frog tadpoles, but only if the insecticide is present chronically at concentrations which are rarely reached in natural waterbodies. Thus, agile frog tadpoles appear to be relatively tolerant to chlorpyrifos, but may nonetheless suffer from its presence in situations of repeated high-dose application.
Singlet oxygen-induced signalling depends on the metabolic status of the Chlamydomonas cell
Authors: Al Youssef Waeil , Feil Regina , Saint-Sorny Maureen , Johnson Xenie , Lunn John E. , Grimm Bernhard , Brzezowski Pawel 
Published: November 2021

AbstractUsing a novel mutant screen, we identified TREHALOSE 6-PHOSPHATE PHOSPHATASE 1 (TSPP1) as a functional enzyme dephosphorylating trehalose 6-phosphate (Tre6P) to trehalose in Chlamydomonas reinhardtii. The tspp1 knock-out results in reprogramming of the cell metabolism via significantly altered transcriptome. As a secondary effect, tspp1 also shows impairment in 1O2-induced chloroplast retrograde signalling. From transcriptomic analysis and metabolite profiling, we conclude that accumulation or deficiency of certain metabolites directly affect 1O2-signalling. 1O2-inducible GLUTATHIONE PEROXIDASE 5 (GPX5) gene expression is suppressed by increased content of fumarate, an intermediate in the tricarboxylic acid cycle (TCA cycle) in mitochondria and dicarboxylate metabolism in the cytosol, while it is promoted by another TCA cycle intermediate, aconitate. Furthermore, genes encoding known essential components of chloroplast-to-nucleus 1O2-signalling, PSBP2, MBS, and SAK1, show decreased transcript levels in the tspp1 mutant, which can be rescued by exogenous application of aconitate. We demonstrate that chloroplast retrograde signalling involving 1O2 depends on mitochondrial and cytosolic processes and that the metabolic status of the cell determines the response to 1O2.
The promotion of stress tolerant Symbiodiniaceae dominance in juveniles of two coral species due to simulated future conditions of ocean warming and acidification
Authors: Terrell Alyx P. , Marangon Emma , Webster Nicole S. , Cooke Ira , Quigley Kate M. 
Published: November 2021

SummaryThe symbiotic relationship between coral and its endosymbiotic algae, Symbiodiniaceae, greatly influences the hosts’ potential to withstand environmental stress. To date, the effects of climate change on this relationship has primarily focused on adult corals. Uncovering the effects of environmental stress on the establishment and development of this symbiosis in early life stages is critical for predicting how corals may respond to climate change. To determine the impacts of future climate projections on the establishment of symbionts in juvenile corals, ITS2 amplicon sequencing of single coral juveniles was applied to Goniastrea retiformis and Acropora millepora before and after exposure to three climate conditions of varying temperature and pCO2 levels (current and RCP8.5 in 2050 and 2100). Compared to ambient conditions, juvenile corals experienced shuffling in the relative abundance of Cladocopium (C1m, reduction) to Durusdinium (D1 and D1a, increase) over time. We calculated a novel risk metric incorporating functional redundancy and likelihood of impact on host physiology to identify the loss of D1a as a ‘low risk’ to the coral compared to the loss of “higher risk” taxa like D1 and C1m. Although the increase in stress tolerant Durusdinium under future warming was encouraging for A. millepora, by 2100, G. retiformis communities displayed signs of symbiosis de-regulation, suggesting this acclimatory mechanism may have species-specific thresholds. These results emphasize the need for understanding of long-term effects of climate change induced stress on coral juveniles and their potential for increased acclimation to heat tolerance through changes in symbiosis.Originality StatementHere we assessed changes in the uptake and establishment of Symbiodiniaceae in the early lifehistory stages of two coral species under future climate scenarios. Our study represents the first such assessment of future climate change projections (increased temperature and pCO2) influencing Symbiodiniaceae acquisition and specifically shows a community structure dominated by the stress tolerant genus Durusdinium. We also develop a novel risk metric that includes taxonomic function and redundancy to estimate the impact of symbiont taxa changes on coral physiology. Through the risk metric, we relate the stress-induced changes in symbiont community structure to the likelihood of functional loss to better understand the extent to which these changes may lead to a decrease in coral health.
Transcription factor induction of vascular blood stem cell niches in vivo
Authors: Hagedorn Elliott J. , Perlin Julie R. , Freeman Rebecca J. , Wattrus Samuel J. , Han Tianxiao , Mao Clara , Kim Ji Wook , Fernández-Maestre Inés , Daily Madeleine L. , D’Amato Christopher , Fairchild Michael J. , Riquelme Raquel , Li Brian , Ragoonanan Dana A.V.E. , Enkhbayar Khaliun , Henault Emily L. , Wang Helen G. , Redfield Shelby E. , Collins Samantha H. , Lichtig Asher , Yang Song , Zhou Yi , Kunar Balvir , Gomez-Salinero Jesus Maria , Dinh Thanh T. , Pan Junliang , Holler Karoline , Feldman Henry A. , Butcher Eugene C. , van Oudenaarden Alexander , Rafii Shahin , Philipp Junker J. , Zon Leonard I. 
Published: November 2021

AbstractThe hematopoietic niche is a supportive microenvironment comprised of distinct cell types, including specialized vascular endothelial cells that directly interact with hematopoietic stem and progenitor cells (HSPCs). The molecular factors that specify niche endothelial cells and orchestrate HSPC homeostasis remain largely unknown. Using multi-dimensional gene expression and chromatin accessibility analyses, we define a conserved gene expression signature and cis-regulatory landscape unique to sinusoidal endothelial cells in the HSPC niche. Using enhancer mutagenesis and transcription factor overexpression, we elucidate a transcriptional code involving members of the Ets, Sox and Nuclear Hormone Receptor families that is sufficient to induce ectopic niche endothelial cells that associate with mesenchymal stromal cells and support the recruitment, maintenance and division of HSPCs in vivo. These studies set forth an approach for generating synthetic HSPC niches, in vitro or in vivo, and for effective therapies to modulate the endogenous niche.
Leishmania amazonensis sabotages host cell SUMOylation for intracellular survival
Authors: Okuda Kendi , Costa Franco Miriam Maria Silva , Yasunaga Ari , Gazzinelli Ricardo , Rabinovitch Michel , Cherry Sara , Silverman Neal 
Published: November 2021

AbstractLeishmania parasites use elaborate virulence mechanisms to invade and thrive in macrophages. These virulence mechanisms inhibit host cell defense responses and generate a specialized replicative niche, the parasitophorous vacuole. In this work, we performed a genome-wide RNAi screen in Drosophila macrophage-like cells to identify host factors necessary for Leishmania amazonensis infection. This screen identified 52 conserved genes required specifically for parasite entry, including several components of the SUMOylation machinery. Further studies in mammalian macrophages found that L. amazonensis infection inhibited SUMOylation within infected macrophages and this inhibition enhanced parasitophorous vacuole growth and parasite proliferation through modulation of multiple genes especially ATP6V0D2, which in turn effects CD36 expression and cholesterol levels. Together, these data suggest that parasites actively sabotage host SUMOylation and alter host transcription to improve their intracellular niche and enhance their replication.
Reciprocal zebrafish-medaka hybrids reveal maternal control of zygotic genome activation timing
Authors: Gert Krista R. , Quio Luis Enrique Cabrera , Novatchkova Maria , Guo Yixuan , Cairns Bradley R. , Pauli Andrea 
Published: November 2021

AbstractAfter fertilization, the sperm and egg contribute unequally to the newly formed zygote. While the sperm contributes mainly paternal DNA, the egg provides both maternal DNA and the bulk of the future embryonic cytoplasm. Most embryonic processes (like the onset of zygotic transcription) depend on maternally-provided cytoplasmic components, and it is largely unclear whether paternal components besides the centrosome play a role in the regulation of early embryogenesis. Here we report a reciprocal zebrafish-medaka hybrid system as a powerful tool to investigate paternal vs. maternal influence during early development. By combining expression of zebrafish Bouncer on the medaka egg with artificial egg activation, we demonstrate the in vitro generation of paternal zebrafish x maternal medaka (reripes) hybrids. These hybrids complement the previously established paternal medaka x maternal zebrafish (latio) hybrids (Herberg et al., 2018). As proof of concept, we investigated maternal vs. paternal control of zygotic genome activation (ZGA) timing using this reciprocal hybrid system. RNA-seq analysis of the purebred fish species and hybrids revealed that the onset of ZGA is primarily governed by the egg. Overall, our study establishes the reciprocal zebrafish-medaka hybrid system as a versatile tool to dissect parental control mechanisms during early development.