bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intronic enhancers regulate the expression of genes involved in tissue-specific functions and homeostasis
Authors: Borsari Beatrice , Villegas-Mirón Pablo , Laayouni Hafid , Segarra-Casas Alba , Bertranpetit Jaume , Guigó Roderic , Acosta Sandra 
Published: August 2020

AbstractTissue function and homeostasis reflect the gene expression signature by which the combination of ubiquitous and tissue-specific genes contribute to the tissue maintenance and stimuli-responsive function. Enhancers are central to control this tissue-specific gene expression pattern. Here, we explore the correlation between the genomic location of enhancers and their role in tissue-specific gene expression. We found that enhancers showing tissue-specific activity are highly enriched in intronic regions and regulate the expression of genes involved in tissue-specific functions, while housekeeping genes are more often controlled by intergenic enhancers. Notably, an intergenic-to-intronic active enhancers continuum is observed in the transition from developmental to adult stages: the most differentiated tissues present higher rates of intronic enhancers, while the lowest rates are observed in embryonic stem cells. Altogether, our results suggest that the genomic location of active enhancers is key for the tissue-specific control of gene expression.
Connectomic Alterations Linked to Transdiagnostic Risk for Psychopathology at the Transition to Adolescence
Authors: Sripada Chandra , Angstadt Mike , Rutherford Saige , Taxali Aman , Greathouse Tristan , Clark D. Angus , Hyde Luke , Weigard Alex , Brislin Sarah , Hicks Brian , Heitzeg Mary 
Published: August 2020

AbstractBACKGROUNDConvergent research identifies a general factor (“P factor”) that confers transdiagnostic risk for psychopathology. However, brain functional connectivity patterns that underpin the P factor remain poorly understood, especially at the transition to adolescence when many serious mental disorders have their onset.OBJECTIVEIdentify a distributed connectome-wide neurosignature of the P factor and assess the generalizability of this neurosignature in held out samples.DESIGN, SETTING, AND PARTICIPANTSThis study used data from the full baseline wave of the Adolescent Brain and Cognitive Development (ABCD) national consortium study, a prospective, population-based study of 11,875 9- and 10-year olds. Data for this study were collected from September 1, 2016 to November 15, 2018 at 21 research sites across the United States.MAIN OUTCOMES AND MEASURESWe produced whole brain functional connectomes for 5,880 youth with high quality resting state scans. We then constructed a low rank basis set of 250 components that captures interindividual connectomic differences. Multi-level regression modeling was used to link these components to the P factor, and leave-one-site-out cross-validation was used to assess generalizability of P factor neurosignatures to held out subjects across 19 ABCD sites.RESULTSThe set of 250 connectomic components was highly statistically significantly related to the P factor, over and above nuisance covariates alone (ANOVA nested model comparison, incremental R-squared 6.05%, χ2(250) =412.1,p<4.6×10−10). In addition, two individual connectomic components were statistically significantly related to the P factor after Bonferroni correction for multiple comparisons (t(5511)= 4.8,p<1.4×10−06; t(5121)= 3.9, p<9.7×10−05). Functional connections linking control networks and default mode network were prominent in the P factor neurosignature. In leave-one-site-out cross-validation, the P factor neurosignature generalized to held out subjects (average correlation between actual and predicted P factor scores across 19 held out sites=0.13;pPERMUTATION<0.0001). Additionally, results remained significant after a number of robustness checks.CONCLUSIONS AND RELEVANCEThe general factor of psychopathology is associated with connectomic alterations involving control networks and default mode network. Brain imaging combined with network neuroscience can identify distributed and generalizable signatures of transdiagnostic risk for psychopathology during emerging adolescence.
Oviduct epithelial cells constitute two developmentally distinct lineages that are spatially separated along the distal-proximal axis
Authors: Ford Matthew J , Harwalkar Keerthana , Pacis Alain S , Maunsell Helen , Wang Yu Chang , Badescu Dunarel , Teng Katie , Yamanaka Nobuko , Bouchard Maxime , Ragoussis Jiannis , Yamanaka Yojiro 
Published: August 2020

SummaryOwing to technical advances in single cell biology, the appreciation of cellular heterogeneity has increased, which has aided our understanding of organ function, homeostasis and disease progression. The oviduct (also known as the fallopian tube in humans) is the distal-most portion of the female reproductive tract. It is essential for reproduction and the proposed origin of high grade serous ovarian carcinoma (HGSOC). In mammals, the oviduct is morphologically segmented along the ovary-uterus axis into four evolutionally conserved regions. It is unknown however if there is a diversification of epithelial cell characteristics between these regions. In this study, we identified transcriptionally distinct populations of secretory and multiciliated cells restricted to the distal and proximal regions of the oviduct. We demonstrated that these distal and proximal populations are distinct lineages specified early in Müllerian duct development and are maintained separately. These results aid our understanding of epithelial development, homeostasis and initiation of disease from the oviduct.
Loss of Polycomb Protein EZH2 causes major depletion of H3K27 and H3K9 tri-methylation and developmental defects in the fungusPodospora anserina
Authors: Carlier F , Debuchy R , Maroc L , Souaid C , Noordermeer D , Grognet P , Malagnac F 
Published: August 2020

AbstractSelective gene silencing is key to development. The H3K27me3 enriched heterochromatin maintains transcription repression established during early development and regulates cell fate. Conversely, H3K9me3 enriched heterochromatin prevents differentiation but constitutes a permanent protection against transposable element. We exploited the fungusPodospora anserina, a valuable alternative to higher eukaryote models to question the biological relevance and interplay of these two distinct heterochromatin conformations. We found that H3K27me3 and H3K9me3 modifications are mutually exclusive within gene-rich regions but not within repeats. Lack of PaKmt6 EZH2-like enzyme resulted in loss of H3K27me3 and in significant H3K9me3 reduction, whereas lack of PaKmt1 SU(VAR)3-9-like enzyme caused loss of H3K9me3 only. We established thatP. anserinadevelopmental programs require H3K27me3 mediated silencing unlike most fungi studied to date. Our findings provide new insight into roles of these histone marks and into the relationship between chromatin modifications and development.
SOX11 is a lineage-dependency factor and master epigenetic regulator in neuroblastoma
Authors: Decaesteker Bieke , Louwagie Amber , Loontiens Siebe , De Vloed Fanny , Roels Juliette , Vanhauwaert Suzanne , De Brouwer Sara , Sanders Ellen , Denecker Geertrui , D’haene Eva , Van Haver Stéphane , Van Loocke Wouter , Van Dorpe Jo , Creytens David , Van Roy Nadine , Pieters Tim , Van Neste Christophe , Fischer Matthias , Van Vlierberghe Pieter , Roberts Stephen S , Schulte Johannes , Ek Sara , Versteeg Rogier , Koster Jan , van Nes Johan , De Preter Katleen , Speleman Frank 
Published: August 2020

ABSTRACTThe pediatric extra-cranial tumor neuroblastoma (NB) is characterised by a low mutation burden while copy number alterations are present in most high-risk cases. We identified SOX11 as a strong lineage dependency transcription factor in adrenergic NB based on recurrent chromosome 2p focal gains and amplifications, its specific expression in the normal sympatho-adrenal lineage and adrenergic NBs and its regulation by multiple adrenergic specific cis-interacting (super-)enhancers. Adrenergic NBs are strongly dependent on highSOX11expression levels for growth and proliferation. Through genome-wide DNA-binding and transcriptome analysis, we identified and validated functional SOX11 target genes, several of which implicated in chromatin remodeling and epigenetic modification. SOX11 controls chromatin accessibility predominantly affecting distal adrenergic lineage-specific enhancers marked by binding sites of the adrenergic core regulatory circuitry. During normal sympathoblast differentiation we find expression of SOX11 prior to members of the adrenergic core regulatory circuitry. Given the broad control of SOX11 of multiple epigenetic regulatory complexes and its presumed pioneer factor function, we propose that adrenergic NB cells have co-opted the normal role of SOX11 as a crucial regulator of chromatin accessibility and cell identity.
CASP microdomain formation requires cross cell wall stabilization of domains and non-cell autonomous action of LOTR1
Authors: Kolbeck Andreas , Marhavý Peter , De Bellis Damien , Li Baohai , Kamiya Takehiro , Fujiwara Toru , Kalmbach Lothar , Geldner Niko 
Published: August 2020

SummaryEfficient uptake of nutrients in both animal and plant cells requires tissue-spanning diffusion barriers separating inner tissues from the outer lumen/soil. However, we poorly understand how such contiguous three-dimensional superstructures are formed in plants. Here, we show that correct establishment of the plant Casparian Strip (CS) network relies on local neighbor communication. We show that positioning of Casparian Strip membrane domains (CSDs) is tightly coordinated between neighbors in wild-type and that restriction of domain formation involves the putative extracellular protease LOTR1. Impaired domain restriction inlotr1leads to fully functional CSDs at ectopic positions, forming “half strips” LOTR1 action in the endodermis requires its expression in the stele. LOTR1 endodermal expression cannot complement, while cortex expression causes a dominant-negative phenotype. Our findings establishLOTR1as a crucial player in CSD positioning acting in a directional, non-cell-autonomous manner to restrict and coordinate CS positioning.
Ubiquitous Forbidden Order in R-group classified protein sequence of SARS-CoV-2 and other viruses
Authors: Pratibha  , Shaju C. , Kamal  
Published: August 2020

AbstractEach amino acid in a polypeptide chain has a distinctive R-group associated with it. We report here a novel method of species characterization based upon the order of these R-group classified amino acids in the linear sequence of the side chains associated with the codon triplets. In an otherwise pseudo-random sequence, we search for forbidden combinations ofkth order. We applied this method to analyze the available protein sequences of various viruses including SARS-CoV-2. We found that these ubiquitous forbidden orders (UFO) are unique to each of the viruses we analyzed. This unique structure of the viruses may provide an insight into viruses’ chemical behavior and the folding patterns of the proteins. This finding may have a broad significance for the analysis of coding sequences of species in general.
Characterization of Viral Insulins Reveals White Adipose Tissue Specific Effects in Mice
Authors: Chrudinová Martina , Moreau Francois , Noh Hye Lim , Páníková Terezie , Žáková Lenka , Friedline Randall H. , Valenzuela Francisco A. , Kim Jason K. , Jiráček Jiří , Kahn C. Ronald , Altindis Emrah 
Published: August 2020

ABSTRACTMembers of the insulin/IGF superfamily are well conserved across the evolutionary tree. We recently showed that four viruses in theIridoviridaefamily possess genes that encode proteins highly homologous to human insulin/IGF-1. Using chemically synthesized single chain (sc), i.e. IGF-1-like, forms of the viral insulin/IGF-1 like peptides (VILPs), we previously showed that they can stimulate human receptors. Because these peptides possess potential cleavage sites to form double chain (dc), i.e. more insulin-like, VILPs, in this study, we have characterized dc forms of VILPs for Grouper iridovirus (GIV), Singapore grouper iridovirus (SGIV) and Lymphocystis disease virus-1 (LCDV-1). GIV and SGIV dcVILPs bind to both isoforms of human insulin receptor (IR-A, IR-B) and to the IGF1R, and for the latter show higher affinity than human insulin. These dcVILPs stimulate IR and IGF1R phosphorylation and post-receptor signaling in vitro and in vivo. Both GIV and SGIV dcVILPs stimulate glucose uptake in mice. In vivo infusion experiments in awake mice revealed that while insulin (0.015 nmol/kg/min) and GIV dcVILP (0.75nmol/kg/min) stimulated a comparable glucose uptake in heart, skeletal muscle and brown adipose tissue, GIV dcVILP stimulated ~2 fold higher glucose uptake in white adipose tissue (WAT) compared to insulin. This was associated with increased Akt phosphorylation and glucose transporter type 4 (GLUT4) gene expression compared to insulin. Taken together, these results show that GIV and SGIV dcVILPs are active members of the insulin superfamily with unique characteristics. Elucidating the mechanism of tissue specificity for GIV dcVILP will help us to better understand insulin action, design new analogues that specifically target the tissues, and provide new insights into their potential role in disease.
Covidex: an ultrafast and accurate tool for virus subtyping
Authors: Cacciabue Marco , Aguilera Pablo , Gismondi María Inés , Taboga Oscar 
Published: August 2020

SummaryCovidex is an open-source, alignment-free machine learning subtyping tool for viral species. It is a shiny app that allows a fast and accurate classification in pre-defined clusters for SARS-CoV-2 and FMDV genome sequences. The user can also build its own classification models with the Covidex model generator.AvailabilityCovidex is open-source, cross-platform compatible, and is available under the terms of the GNU General Public License v3 (http://www.gnu.org/licenses/gpl.txt). Covidex is available via SourceForgehttps://sourceforge.net/projects/covidexor the web applicationhttps://cacciabue.shinyapps.io/shiny2/Contactcacciabue.marco@inta.gob.ar;marcocacciabue@yahoo.com
Bark from avocado trees of different geographic locations have consistent microbial communities
Authors: Aguirre-von-Wobeser Eneas , Alonso-Sánchez Alexandro , Méndez-Bravo Alfonso , Espino Luis Alberto Villanueva , Reverchon Frédérique 
Published: August 2020

AbstractBark is a permanent surface for microbial colonization at the interface of trees and the surrounding air. However, little is known about the microbial communities harbored on these tissues. Studies on bark microbial ecology show a dominance of bacteria from a few phyla. Bark microbial communities of avocado (Persea americana) could have implications for tree health, as a first barrier for defense against certain pests and diseases in this economically important species. We used shotgun metagenomic sequencing to analyze the bark microbial communities of avocado trees from two orchards, and compared one of them to rhizospheric soil. Our results show that the microbial communities of avocado bark have a well-defined taxonomic structure, with consistent patterns of abundance of bacteria, fungi and archaea, even in trees from two different locations. Bacteria in avocado bark were dominated by Proteobacteria (particularly Alphaproteobacteria), Actinobacteria and Bacteroidetes, consistently with bark communities in other trees. Fungal members were dominated by Ascomycota and Basidiomycota, while most Archaea in bark were Euryarchaeota. We can conclude that avocado bark is a well-defined environment, providing niches for specific taxonomic groups. The present in-depth characterization of bark microbial communities can form a basis for their future manipulation for agronomical purposes.
Single-pixel epiretinal stimulation with a wide-field and high-density retinal prosthesis for artificial vision
Authors: Ludmilla Chenais Naïg Aurelia , Airaghi Leccardi Marta Jole Ildelfonsa , Ghezzi Diego 
Published: August 2020

AbstractRetinal prostheses hold the promise of restoring artificial vision in profoundly and totally blind people. However, a decade of clinical trials highlighted quantitative limitations hampering the possibility to reach this goal. A key obstacle to suitable retinal stimulation is the ability to independently activate retinal neurons over a large portion of the subject’s visual field. Reaching such a goal would significantly improve the perception accuracy in the users of retinal implants, along with their spatial cognition, attention, ambient mapping and interaction with the environment. Here we show a wide-field, high-density and high-resolution photovoltaic epiretinal prosthesis for artificial vision. The prosthesis embeds 10,498 physically and functionally independent photovoltaic pixels allowing for both wide retinal coverage and high-resolution stimulation. Single-pixel illumination reproducibly induced network-mediated responses from retinal ganglion cells at safe irradiance levels. Furthermore, the prosthesis enables a sub-receptive field response resolution for retinal ganglion cells having a dendritic tree larger than the pixel’s pitch. This approach could allow the restoration of mid-peripheric artificial vision in patients with retinitis pigmentosa.
Ivermectin converts cold tumors hot and synergies with immune checkpoint blockade for treatment of breast cancer
Authors: Draganov Dobrin , Han Zhen , Bennett Nitasha , Irvine Darrell J. , Lee Peter P. 
Published: August 2020

AbstractWe show that treatment with the FDA-approved anti-parasitic drug ivermectin induces immunogenic cancer cell death (ICD) and robust T cell infiltration into breast tumors. As an allosteric modulator of the ATP/P2×4/P2×7 axis which operates in both cancer and immune cells, ivermectin also selectively targets immunosuppressive populations including myeloid cells and Tregs, resulting in enhanced Teff/Tregs ratio. While neither agent alone showed efficacyin vivo, combination therapy with ivermectin and checkpoint inhibitor anti-PD1 antibody achieved synergy in limiting tumor growth (p=0.03) and promoted complete responses (p<0.01), also leading to immunity against contralateral re-challenge with demonstrated anti-tumor immune responses. Going beyond primary tumors, this combination achieved significant reduction in relapse after neoadjuvant (p=0.03) and adjuvant treatment (p<0.001), and potential cures in metastatic disease (p<0.001). Statistical modeling confirmed bona fide synergistic activity in both the adjuvant (p=0.007) and metastatic settings (p<0.001). Ivermectin has dual immunomodulatory and ICD-inducing effects in breast cancer, converting ‘cold’ tumors ‘hot’, thus represents a rational mechanistic partner with checkpoint blockade.
A complex of distal appendage-associated kinases linked to human disease regulates ciliary trafficking and stability
Authors: Loukil Abdelhalim , Barrington Chloe , Goetz Sarah C. 
Published: August 2020

ABSTRACTCilia biogenesis is a complex, multi-step process involving the coordination of multiple cellular trafficking pathways. Despite the importance of ciliogenesis in mediating the cellular response to cues from the microenvironment, we have only a limited understanding of the regulation of cilium assembly. We previously identified a kinase that acts as a key regulator of ciliogenesis, TTBK2. Here, using CRISPR kinome screening, we identify the CK2 subunit CSNK2A1 as an important modulator of TTBK2 function in cilia trafficking. Super-resolution microscopy reveals that CSNK2A1 is a centrosomal protein concentrated at the mother centriole and associated with the distal appendages where it physically interacts with TTBK2. Further,Csnk2a1knockout partially corrects defects in cilia formation and length inTtbk2hypomorphic cells.Csnk2a1mutant cilia are longer than those of control cells and exhibit instability, particularly at the tip.Csnk2a1mutant cilia also abnormally accumulate key cilia assembly and SHH-related proteins including IFT, GLI2, KIF7, and Smoothened (SMO).De novomutations ofCsnk2a1were recently linked to the human genetic disorder Okur-Chung neurodevelopmental syndrome (OCNDS). Consistent with the role of CSNK2A1 in cilium stability, we find that expression of OCNDS-associatedCsnk2a1variants in wild-type cells cause ciliary structural defects. Our findings provide new insights into mechanisms involved in ciliary length regulation, trafficking, and stability that in turn shed light on the significance and implications of cilia instability in human disease.SIGNIFICANCE STATEMENTPrimary cilia (PC) are sensory organelles that play essential roles during development and adulthood. Abnormal functioning of PC causes human disorders called ciliopathies. Hence, a thorough understanding of the molecular regulation of PC is critical. Our findings highlight CSNK2A1 as a novel modulator of cilia trafficking and stability, tightly related to TTBK2 function. Enriched at the centrosome, CSNK2A1 prevents abnormal accumulation of key ciliary proteins, instability at the tip, and aberrant activation of the Sonic Hedgehog pathway. Further, we establish thatCsnk2a1mutations associated with Okur-Chung neurodevelopmental disorder (OCNDS) alter cilia morphology. Thus, we report a potential linkage between CSNK2A1 ciliary function and OCNDS.
Limited window for donation of convalescent plasma with high live-virus neutralizing antibodies for COVID-19 immunotherapy
Authors: Gontu Abhinay , Srinivasan Sreenidhi , Salazar Eric , Nair Meera Surendran , Nissly Ruth H. , Greenawalt Denver , Bird Ian M. , Herzog Catherine , Ferrari Matthew J. , Poojary Indira , Katani Robab , Lindner Scott E. , Minns Allen M. , Rossi Randall , Christensen Paul A. , Castillo Brian , Chen Jian , Eagar Todd N. , Yi Xin , Zhao Picheng , Leveque Christopher , Olsen Randall J. , Bernard David W. , Gollihar Jimmy , Kuchipudi Suresh V. , Musser James M. , Kapur Vivek 
Published: August 2020

ABSTRACTThe optimal timeframe for donating convalescent plasma to be used for COVID-19 immunotherapy is unknown. To address this important knowledge deficit, we determinedin vitrolive-virus neutralizing capacity and persistence of IgM and IgG antibody responses against the receptor-binding domain and S1 ectodomain of the SARS-CoV-2 spike glycoprotein in 540 convalescent plasma samples obtained from 175 COVID-19 plasma donors for up to 142 days post-symptom onset. Robust IgM, IgG, and viral neutralization responses to SARS-CoV-2 persist, in the aggregate, for at least 100 days post-symptom onset. However, a notable acceleration in decline in virus neutralization titers ≥160, a value suitable for convalescent plasma therapy, was observed starting 60 days after first symptom onset. Together, these findings better define the optimal window for donating convalescent plasma useful for immunotherapy of COVID-19 patients and reveal important predictors of an ideal plasma donor, including age and COVID-19 disease severity score.One Sentence SummaryEvaluation of SARS-CoV-2 anti-spike protein IgM, IgG, and live-virus neutralizing titer profiles reveals that the optimal window for donating convalescent plasma for use in immunotherapy is within the first 60 days of symptom onset.