bluuebunny/crossref_metadata_2025_split huggingface dataset:
Severe dysregulation of TNF expression leads to multiple inflammatory diseases and embryonic death
Authors: Clayer Elise , Dalseno Destiny , Kueh Andrew , Lacey Derek , Tsai Minhsuang , Carr Elysa , Wimmer Verena C. , Bouillet Philippe 
Published: May 2020

AbstractPost-transcriptional regulation mechanisms regulate mRNA stability or translational efficiency via ribosomes and recent evidence indicates that it is a major determinant of the accurate levels of cytokine mRNAs. While transcriptional regulation ofTnfhas been well studied and found to be important for the rapid induction ofTnfmRNA and regulation of the acute phase of inflammation, study of its post-transcriptional regulation has been largely limited to the role of the AU-rich element (ARE), and to a lesser extent, that of the constitutive decay element (CDE). We have identified a new regulatory element (NRE) in the 3’ untranslated region (3’UTR) ofTnf, and demonstrate that ARE, CDE and NRE cooperate to efficiently down regulateTnfexpression and prevent autoimmune inflammatory diseases. We also show for the first time that excessive TNF may lead to embryonic death.
Agile workflow for interactive analysis of mass cytometry data
Authors: Casado Julia , Lehtonen Oskari , Rantanen Ville , Kaipio Katja , Pasquini Luca , Häkkinen Antti , Petrucci Elenora , Carpén Olli , Biffoni Mauro , Färkkilä Anniina , Hautaniemi Sampsa 
Published: May 2020

AbstractMotivationSingle-cell proteomics technologies, such as mass cytometry, have enabled characterization of cell-to-cell variation and cell populations at a single cell resolution. These large amounts of data, however, require dedicated, interactive tools for translating the data into knowledge.ResultsWe present a comprehensive, interactive method calledCytoto streamline analysis of large-scale cytometry data.Cytois a workflow-based open-source solution that automatizes the use of of state-of-the-art single-cell analysis methods with interactive visualization. We show the utility ofCytoby applying it to mass cytometry data from peripheral blood and high-grade serous ovarian cancer (HGSOC) samples. Our results show that Cyto is able to reliably capture the immune cell sub-populations from peripheral blood as well as cellular compositions of unique immune- and cancer cell subpopulations in HGSOC tumor and ascites samples.AvailabilityThe method is available as a Docker container athttps://hub.docker.com/r/anduril/cytoand the user guide and source code are available athttps://bitbucket.org/anduril-dev/cytoContactsampsa.hautaniemi@helsinki.fiSupplementary informationSupplementary material is available and FCS files are hosted at flowrepository.org/id/FR-FCM-Z2LW
Heterogeneous somatostatin-expressing neuron population in mouse ventral tegmental area
Authors: Nagaeva Elina , Zubarev Ivan , Gonzales Carolina Bengtsson , Forss Mikko , Nikouei Kasra , de Miguel Elena , Elsilä Lauri , Linden Anni-Maija , Hjerling-Leffler Jens , Augustine George J. , Korpi Esa R. 
Published: May 2020

AbstractThe cellular architecture of the ventral tegmental area (VTA), the main hub of the brain reward system, remains only partially characterized. To extend the characterization to inhibitory neurons, we have identified three distinct subtypes of somatostatin (Sst)-expressing neurons in the mouse VTA. These neurons differ in their electrophysiological and morphological properties, anatomical localization, as well as mRNA expression profiles. Importantly, similar to cortical Sst-containing interneurons, most VTA Sst neurons express GABAergic inhibitory markers, but some of them also express glutamatergic excitatory markers and a subpopulation even express dopaminergic markers. Furthermore, only some of the proposed marker genes for cortical Sst neurons were expressed in the VTA Sst neurons. Physiologically, one of the VTA Sst neuron subtypes locally inhibited neighboring dopamine neurons. Overall, our results demonstrate the remarkable complexity and heterogeneity of VTA Sst neurons and suggest that these cells are multifunctional players in the midbrain reward circuitry.
The anterior insular cortex in the rat exerts an inhibitory influence over the loss of control of heroin intake and subsequent propensity to relapse
Authors: Joshi Dhaval D. , Puaud Mickaël , Fouyssac Maxime , Belin-Rauscent Aude , Everitt Barry , Belin David 
Published: May 2020

AbstractThe anterior insular cortex (AIC) has been implicated in addictive behaviour, including the loss of control over drug intake, craving and the propensity to relapse. Evidence suggests that the influence of the AIC on drug-related behaviours is complex since in rats exposed to extended access to cocaine self-administration, the AIC was shown to exert a state-dependent, bidirectional influence on the development and expression of loss of control over drug intake, facilitating the latter but impairing the former. However, it is unclear whether this influence of the AIC is confined to stimulant drugs that have marked peripheral sympathomimetic and anxiogenic effects or whether it extends to other addictive drugs, such as opiates, that lack overt acute aversive peripheral effects. Thus, we investigated in outbred rats the effects of bilateral excitotoxic lesions of AIC, induced both prior to or after long-term exposure to extended access heroin self-administration, on the development and maintenance of escalated heroin intake and the subsequent vulnerability to relapse following abstinence. Compared to sham-surgeries, pre-exposure AIC lesions had no effect on the development of loss of control over heroin intake, but lesions made after a history of escalated heroin intake potentiated escalation and also enhanced responding at relapse. These data show that the AIC inhibits or limits the loss of control over heroin intake and propensity to relapse, in marked contrast to its influence on the loss of control over cocaine intake.
Analysis of gene network bifurcation during optic cup morphogenesis in zebrafish
Authors: Buono Lorena , Naranjo Silvia , Moreno-Marmol Tania , de la Cerda Berta , Polvillo Rocío , Díaz-Corrales Francisco-Javier , Bogdanovic Ozren , Bovolenta Paola , Martínez-Morales Juan-Ramón 
Published: May 2020

SummarySight depends on the tight cooperation between photoreceptors and pigmented cells. Both derive from common progenitors in which a single gene regulatory network (GRN) bifurcates into the neural retina (NR) and retinal-pigmented epithelium (RPE) programs. Although genetic studies have identified upstream nodes controlling these networks, their regulatory logic remains poorly investigated. Here, we characterize transcriptome dynamics (RNA-seq) and chromatin accessibility (ATAC-seq) in segregating NR/RPE populations in zebrafish. Analysis of active cis-regulatory modules and enriched transcription factor (TF) motives suggest extensive network redundancy and context-dependent TF activity. Downstream targets identification highlights an early recruitment of desmosomal genes in the flattening RPE, revealing Tead factors as upstream regulators. Investigation of GRNs dynamics uncovers an unexpected sequence of TF recruitment during RPE specification, which is conserved in humans. This systematic interrogation of the NR/RPE bifurcation should improve both genetic counselling for eye disorders and hiPSCs-to-RPE differentiation protocols for cell-replacement therapies in degenerative diseases.
Overlapping connectivity gradients in the anterior temporal lobe underlie semantic cognition
Authors: Faber Myrthe , Przeździk Izabela , Fernández Guillén , Haak Koen V. , Beckmann Christian F. 
Published: May 2020

AbstractConvergent evidence from neuroimaging, computational, and clinical research has shown that the anterior temporal lobe (ATL) is critically involved in two key aspects of semantic cognition: the representation of semantic knowledge, and the executive regulation of this knowledge. Both are necessary for integrating features to understand concepts, and to integrate concepts to understand discourse. Here, we tested the hypothesis that these differential aspects of integration map onto different patterns of ATL connectivity. Specifically, we hypothesized that there are two overlapping modes of functional connectivity of the ATL that each predict distinct aspects of semantic cognition on an individual level. We used a novel analytical approach (connectopic mapping) to identify the first two dominant modes connection topographies (i.e. maps of spatially varying connectivity) in the ATL in 766 participants (Human Connectome Project), and summarized these into 16 parameters that reflect inter-individual differences in their functional organization. If these connection topographies reflect the ATL’s functional multiplicity, then we would expect to find a dissociation where one mode (but not the other) correlates with cross-modal matching of verbal and visual information (picture vocabulary naming), and the other (but not the former) correlates with how quickly and accurately relevant semantic information is retrieved (story comprehension). Our analysis revealed a gradient of spatially varying connectivity along the inferior-superior axis, and secondly, an anterior to posterior gradient. Multiple regression analyses revealed a double dissociation such that individual differences in the inferior-superior gradient are predictive of differences in story comprehension, whereas the anterior-posterior gradient maps onto differences in picture vocabulary naming, but not vice versa. These findings indicate that overlapping gradients of functional connectivity in the ATL are related to differential behaviors, which is important for understanding how its functional organization underlies its multiple functions.
The Atypical Fibrin Fibre Network in Rheumatoid Arthritis and its Relation to Autoimmunity, Inflammation and Thrombosis
Authors: Bezuidenhout Johannes A. , Venter Chantelle , Roberts Timothy , Tarr Gareth , Kell Douglas B. , Pretorius Etheresia 
Published: May 2020

AbstractObjectiveThe risk of cardiovascular events in patients with RA is disproportionately heightened as a result of systemic inflammation. The relative effect of autoimmune-associated citrullination on the structure and thrombotic potential of fibrin(ogen) remains unknown. We therefore compared indices of vascular function, inflammation, coagulation and fibrin clot composition in RA patients with healthy controls and evaluated inter-parameter relationships.MethodsBlood samples were collected from 30 RA patients and 25 age- and gender-matched healthy volunteers. Levels of SAA, CRP, ICAM-1 and VCAM-1 was measured using a sandwich immunoassay. Whole blood coagulation was assessed using Thromboelastography. Fibrin clot networks and fiber structure was investigated using Scanning Electron Microscopy. The detection and quantification of citrullination in formed fibrin clots were performed using a fluorescently labeled Citrulline monoclonal antibody with Confocal Microscopy.ResultsConcentrations of SAA, CRP and ICAM-1 were significantly elevated in RA patients compared to controls. TEG parameters relating to coagulation initiation (R and K), rate of fibrin cross-linking (α-Angle), and time to reach maximum thrombus generation (TMRTG) were attenuated in RA patients. Parameters relating to clot strength (MA, MRTG, TGG) did not statistically differ between RA and controls. Logistic regression modelling revealed stronger association between acute phase reactants (CRP, SAA) with TEG parameters than endothelial function markers. Microscopic analysis revealed denser networks of thicker fibrin fibers in RA patients compared to controls [median (interquartile range) 214 (170-285)vs120 (100-144) nm respectively, p<0.0001, Odds ratio=22.7). Detection of multiple citrullinated regions within fibrin clot structures in RA patients, which was less prevalent in control samples (p<0.05, OR=2.2).ConclusionPatients with active RA display a coagulation profile that is dissimilar to general findings associated with other inflammatory conditions. The alteration of protein structures by autoimmune linked citrullination could play a role in determining the structure of fibrin and the potential of conferring a heightened thrombotic risk in RA patients.
Scaffolding protein IQ motif containing GTPase activating protein 2 (IQGAP2) regulates glycogen metabolism
Authors: Sen Anushna , Youssef Sara , Wendt Karen , Anakk Sayeepriyadarshini 
Published: May 2020

AbstractThe liver is critical in maintaining metabolic homeostasis, regulating both anabolic and catabolic processes of fats, proteins, and carbohydrates. The IQ motif containing GTPase activating protein 2 (IQGAP2) is a member of the IQGAP family. Of the three homologous isoforms, the IQGAP2 scaffolding protein is predominantly found in the liver. To characterize its role in regulating metabolism, Iqgap2−/− female and male mice, and their WT controls, were fed ad libitum or fasted for 24 hours. Hepatic gene expression, protein levels, and the metabolic response were compared between WT and Iqgap2−/− mice, using RT-qPCR, western blot analysis, and histological stains. We found that loss of IQGAP2 alters the phosphorylation of active glycogen synthase kinase 3 (GSK3) expression, a known regulator of glycogen synthesis and lipogenesis. Consistent with this result, Iqgap2−/− female mice displayed depletion of periportal glycogen even in the fed state. We also observed the blunted expression of genes involved in glycogenesis and lipogenesis when IQGAP2 was deleted. Since GSK3 is known to regulate the activity of β-catenin, we examined and found it to be reduced in Iqgap2−/− mice. Our findings demonstrate that IQGAP2 plays an important role in regulating glycogen synthesis.
Structure-function relationship ofGossypium hirsutumNAC transcription factor, GhNAC4 with regard to ABA and abiotic stress responses
Authors: Trishla Vikas Shalibhadra , Kirti Pulugurtha Bharadwaja 
Published: May 2020

AbstractOur previous study demonstrated that the expression ofGhNAC4, a NAC transcription factor from cotton, was induced by abiotic stresses and abscisic acid (ABA) treatment. In the present study, we investigated the molecular mechanisms underlying ABA and stress response of GhNAC4. Over-expression ofGhNAC4in transgenic tobacco conferred tolerance to salinity and drought treatments with associated enhanced expression of several stress-responsive marker genes. GhNAC4 is a nuclear protein that exhibits transcriptional activation property, and the C-terminal transcriptional regulatory (TR) domain is responsible for it. GhNAC4 also forms homo-dimers and the N-terminal NAC-domain is essential for this activity. The structure-function relationship of NAC transcription factors, particularly with respect to abiotic stress tolerance remains largely unclear. In this study, we investigated the domains essential for the biochemical functions of GhNAC4. We developed transgenic tobacco plants overexpressing the GhNAC4 NAC-domain and the TR-domain separately. NAC-domain transgenics showed hypersensitivity to exogenous ABA while TR-domain transgenics exhibited reduced sensitivity. Abiotic stress assays indicated that transgenic plants expressing both the domains separately were more tolerant than wild-type plants with the NAC-domain transgenics showing increased tolerance as compared to TR-domain transgenics. Expression analysis revealed that various stress-responsive genes were upregulated in both NAC-domain and TR-domain transgenics as compared to wild-type under salinity and drought treatments. These results suggest that the stress tolerance ability of GhNAC4 is associated with both the component domains while the ABA responsiveness is largely associated with N-terminal NAC-domain.Key MessageNAC and transcriptional regulatory domains are responsible for the abiotic stress tolerance ability of the cotton NAC transcription factor GhNAC4 while the ABA-responsiveness is largely associated with the NAC-domain.
Quantifying multi-species microbial interactions in the larval zebrafish gut
Authors: Sundarraman Deepika , Hay Edouard A. , Martins Dylan M. , Shields Drew S. , Pettinari Noah L. , Parthasarathy Raghuveer 
Published: May 2020

AbstractThe microbial communities resident in animal intestines are composed of multiple species that together play important roles in host development, health and disease. Due to the complexity of these communities and the difficulty of characterizing them in situ, the determinants of microbial composition remain largely unknown. Further, it is unclear for many multi-species consortia whether their species-level makeup can be predicted based on an understanding of pairwise species interactions, or whether higher-order interactions are needed to explain emergent compositions. To address this, we examine commensal intestinal microbes in larval zebrafish, initially raised germ-free to allow introduction of controlled combinations of bacterial species. Using a dissection and plating assay, we demonstrate the construction of communities of one to five bacterial species and show that the outcomes from the two-species competitions fail to predict species abundances in more complex communities. With multiple species present, inter-bacterial interactions become weaker and more cooperative, suggesting that higher-order interactions in the vertebrate gut may stabilize complex communities.
Sonic Hedgehog is not a limb morphogen but acts as a trigger to specify all digits
Authors: Zhu Jianjian , Patel Rashmi , Trofka Anna , Harfe Brian D. , Mackem Susan 
Published: May 2020

SummaryLimb patterning by Sonic hedgehog (Shh) has served as a paradigm of “morphogen” function, acting either by graded spatial or temporal signal integration. Yet how Shh instructs distinct digit identities remains controversial. Here, we bypassed the requirement for Shh in cell survival during limb bud outgrowth and demonstrate that a transient, early Shh pulse is both necessary and sufficient for normal limb development. Our analysis of Shh-responding cells shows signaling acts at only short-range during this time window and that Shh patterns digits indirectly, via a relay mechanism, rather than by direct spatial or temporal signal integration. Using a genetic assay for relay signaling, we unexpectedly discovered Shh also specifies digit 1 (the thumb; previously thought to be exclusively Shh-independent) indirectly, thus implicating Shh in a unique regulatory hierarchy for digit 1 evolutionary adaptations, such as opposable thumbs. This study illuminates Shh as a trigger for a relay network that becomes rapidly self-sustaining, with mechanistic relevance for limb development, regeneration, and evolution.
An atlas of robust microbiome associations with phenotypic traits based on large-scale cohorts from two continents
Authors: Rothschild Daphna , Leviatan Sigal , Hanemann Ariel , Cohen Yossi , Weissbrod Omer , Segal Eran 
Published: May 2020

SummaryNumerous human conditions are associated with the microbiome, yet studies are inconsistent as to the magnitude of the associations and the bacteria involved, likely reflecting insufficiently employed sample sizes. Here, we collected diverse phenotypes and gut microbiota from 34,057 individuals from Israel and the U.S.. Analyzing these data using a much-expanded microbial genomes set, we derive an atlas of robust and numerous unreported associations between bacteria and physiological human traits, which we show to replicate in cohorts from both continents. Using machine learning models trained on microbiome data, we predict human traits with high accuracy across continents. Subsampling our cohort to smaller cohort sizes yielded highly variable models and thus sensitivity to the selected cohort, underscoring the utility of large cohorts and possibly explaining the source of discrepancies across studies. Finally, many of our prediction models saturate at these numbers of individuals, suggesting that similar analyses on larger cohorts may not further improve these predictions.
A deep intronic variant activates a pseudoexon in theMTM1gene in a family with X-linked myotubular myopathy
Authors: Fitzgerald Jamie , Feist Cori , Dietz Paula , Moore Stephen , Basel Donald 
Published: May 2020

AbstractWe report a novel intronic variant in theMTM1gene in four males in a family with severe X-linked myotubular myopathy. The A>G variant in deep intronic space activates a cryptic 5’ donor splice site resulting in the inclusion of a 48bp pseudoexon into the matureMTM1mRNA. The variant is present in all affected males, absent in unaffected males and heterozygous in the mother of the affected males. The included intronic sequence contains a premature stop codon and experiments using a translational inhibitor indicate that the mutant mRNAs undergo nonsense-mediate decay. We conclude that affected males produce no, or low, levels of myotubularin-1 protein leading to a severe neonatal myopathy. The study highlights the need to consider non-coding variants in genomic screening in families with X-linked myotubular myopathy.
Natural selection in the evolution of SARS-CoV-2 in bats, not humans, created a highly capable human pathogen
Authors: MacLean Oscar A. , Lytras Spyros , Weaver Steven , Singer Joshua B. , Boni Maciej F. , Lemey Philippe , Kosakovsky Pond Sergei L. , Robertson David L. 
Published: May 2020

AbstractRNA viruses are proficient at switching host species, and evolving adaptations to exploit the new host’s cells efficiently. Surprisingly, SARS-CoV-2 has apparently required no significant adaptation to humans since the start of the COVID-19 pandemic, with no observed selective sweeps since genome sampling began. Here we assess the types of natural selection taking place inSarbecovirusesin horseshoe bats versus SARS-CoV-2 evolution in humans. While there is moderate evidence of diversifying positive selection in SARS-CoV-2 in humans, it is limited to the early phase of the pandemic, and purifying selection is much weaker in SARS-CoV-2 than in related batSarbecoviruses. In contrast, our analysis detects significant positive episodic diversifying selection acting on the bat virus lineage SARS-CoV-2 emerged from, accompanied by an adaptive depletion in CpG composition presumed to be linked to the action of antiviral mechanisms in ancestral hosts. The closest bat virus to SARS-CoV-2, RmYN02 (sharing an ancestor ∼1976), is a recombinant with a structure that includes differential CpG content in Spike; clear evidence of coinfection and evolution in bats without involvement of other species. Collectively our results demonstrate the progenitor of SARS-CoV-2 was capable of near immediate human-human transmission as a consequence of its adaptive evolutionary history in bats, not humans.
Single-molecule long-read sequencing reveals a conserved selection mechanism determining intact long RNA and miRNA profiles in sperm
Authors: Sun Yu H. , Wang Anqi , Song Chi , Srivastava Rajesh K. , Au Kin Fai , Li Xin Zhiguo 
Published: May 2020

AbstractSperm contributes diverse RNAs to the zygote. While sperm small RNAs have been shown to be shaped by paternal environments and impact offspring phenotypes, we know little about long RNAs in sperm, including mRNAs and long non-coding RNAs. Here, by integrating PacBio single-molecule long reads with Illumina short reads, we found 2,778 sperm intact long transcript (SpILT) species in mouse. The SpILTs profile is evolutionarily conserved between rodents and primates. mRNAs encoding ribosomal proteins are enriched in SpILTs, and in mice they are sensitive to early trauma. Mouse and human SpILT profiles are determined by a post-transcriptional selection process during spermiogenesis, and are co-retained in sperm with base pair-complementary miRNAs. In sum, we have developed a bioinformatics pipeline to define intact transcripts, added SplLTs into the “sperm RNA code” for use in future research and potential diagnosis, and uncovered selection mechanism(s) controlling sperm RNA profiles.