bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hippocampal hypothyroidism in mice promotes glial cell activation and spatial memory deficits
Authors: Chamas Lamis , Seugnet Isabelle , Poirier Roseline , Clerget-Froidevaux Marie-Stéphanie , Enderlin Valérie 
Published: April 2022

AbstractAdult-onset hypothyroidism is associated with learning and cognitive dysfunctions, which may be related to alterations in synaptic plasticity. Local reduced levels of thyroid hormones (THs) may impair glia morphology and activity, and promote the increase of pro-inflammatory cytokine levels mainly in the hippocampus. Given that neuroinflammation induces memory impairments, hypothyroidism-related glia dysfunction may participate in brain disorders. Thus, we investigated the mechanisms linking hypothyroidism, neuroinflammation and spatial memory, from a protective prospective. We induced hypothyroidism in adult C57BL/6J and wild-derived WSB/EiJ male mice by a seven-week propylthiouracil (PTU) treatment. We previously showed that WSB/EiJ mice were resistant to high-fat diet (HFD)-induced obesity, showing no neuroinflammatory response through adaptive abilities, unlike C57BL/6J. As PTU and HFD treatments are known to induce comparable inflammatory responses, we hypothesized WSB/EiJ mice might also be protected against hypothyroidism-induced neuroinflammation. We showed that hypothyroid WSB/EiJ mice depicted no hippocampal neuroinflammatory response and were able to maintain their hippocampal thyroid signalling despite low circulating TH levels. In contrast, C57BL/6J mice exhibited disturbed hippocampal TH signalling, accompanied by neuroinflammation and memory impairment. Our results reinforce the preponderance of local TH levels over circulating levels and the major role of hippocampal glia reactivity in the establishment of memory deficits.
Abstinence-dependent effects of long-access cocaine self-administration on nucleus accumbens astrocytes are observed in male, but not female rats
Authors: Kim Ronald , Testen Anze , Harder Eden V. , Brown Natalie E. , Witt Emily A. , Bellinger Tania J. , Franklin Janay P. , Reissner Kathryn J. 
Published: April 2022

AbstractAccumulating evidence indicates significant consequences for astrocytes associated with drug abuse. For example, reductions in structural features and synaptic colocalization of male rat nucleus accumbens (NAc) astrocytes are observed following short-access (ShA, 2 hours/day) self-administration and extinction from cocaine, methamphetamine, and heroin. However, it is unknown whether these observations extend to other rodent models of drug abuse, how enduring these effects may be, and whether similar effects are observed in female rats. Here we assess the effects of long-access (LgA, 6 hours/day) cocaine self-administration and abstinence on NAc astrocytes separately in male and female rats, a commonly used behavioral approach to investigate the incubation of cocaine craving. NAc astrocytes from male rats exhibit extensive (∼40%) reductions in surface area, volume, and postsynaptic colocalization 45 days, but not 24 hours after the last self-administration session. In contrast, no effect of self-administration was observed in astrocytes from female rats. Moreover, no effect of LgA self-administration and abstinence was observed on NAc GLT-1 expression in female rats, an effect that has been well described in males. The results indicate striking and sexually dimorphic effects of abstinence subsequent to LgA self-administration on astrocytes. Taken together, these results indicate a pivotal role of prolonged abstinence in the effects of cocaine self-administration on NAc astrocytes, and extend a growing body of evidence regarding sex differences in the cellular consequences of drug self-administration in the brain.
Functional recovery from tactile stimulation after perinatal cortical injury is mediated by FGF-2
Authors: Gibb Robbin , Kolb Bryan 
Published: April 2022

AbstractThe consequences of perinatal brain injury can be devastating but currently there are few effective treatments. We sought to determine if tactile stimulation (TS) or exogenous application of fibroblast growth factor-2 (FGF-2) following injury could reverse the behavioral loss. Infant rats received frontal cortex removals on postnatal day 4 (P4) or a sham surgery. The TS animals received thrice-daily 15-minute bouts of stimulation (Experiment 1) on the day following surgery until weaning. In Experiment 2, treated animals received subcutaneous injections of FGF-2 once daily for one week, postsurgery. Behavioral testing began on postnatal day 60. Brains were later processed for Golgi analysis. We show in Experiment 1, that tactilely stimulating infant rats with perinatal cortical injury stimulates functional recovery and reverses injury-related changes in neuronal morphology in the cerebral cortex. The TS induction of recovery is associated with changes in expression of FGF-2 in both the skin and brain. Direct administration of FGF-2 (Experiment 2) is also effective in facilitating recovery, although not as completely as TS. These results suggest that early behavioral intervention after perinatal cortical injury can stimulate plastic neuronal changes that can underlie functional recovery and that these changes are mediated, in part, through an upregulation of FGF-2.
Proteome-wide identification of amino acid substitutions deleterious for protein function
Authors: Rodriguez-Mias Ricard A. , Hess Kyle N. , Ruiz Bianca Y. , Smith Ian R. , Barente Anthony S. , Zimmerman Stephanie M. , Lu Yang Y. , Noble William S. , Fields Stanley , Villén Judit 
Published: April 2022

AbstractDNA sequencing has led to the discovery of millions of mutations that change the encoded protein sequences, but the impact of nearly all of these mutations on protein function is unknown. We addressed this scarcity of functional data by developing Miro, a proteomic technology that uses mistranslation to introduce amino acid substitutions and biochemical assays to quantify functional differences of thousands of protein variants by mass spectrometry. We apply this technology to the proteome of yeast to reveal amino acid substitutions that impact protein structure, ligand binding, protein-protein interactions, protein post-translational modifications, and protein thermal stability. Adapting Miro to human cells will provide a means to efficiently accelerate our mechanistic interpretation of genomic mutations to predict disease risk.
Plastic loss of motile cilia in the gills ofPolypterusin response to high CO2or terrestrial environments
Authors: Kimura Yuki , Nakamuta Nobuaki , Nikaido Masato 
Published: April 2022

AbstractThe evolutionary transition of vertebrates from water to land during the Devonian period was accompanied by major changes in animal respiratory systems in terms of physiology and morphology. Indeed, the fossil record of the early tetrapods has revealed the existence of internal gills, which are vestigial fish-like traits used underwater. However, the fossil record provides only limited data on the process of the evolutionary transition of gills from fish to early tetrapods. This study investigated the gills ofPolypterus senegalus, a basal ray-finned/amphibious fish which shows many ancestral features of stem Osteichthyes. Based on scanning electron microscopy observations and transcriptome analysis, the existence of motile cilia in the gills was revealed which may create a flow on the gill surface leading to efficient ventilation or remove particles from the surface. Interestingly, these cilia were observed to disappear after rearing in terrestrial or high CO2environments, which mimics the environmental changes in the Devonian period. The cilia re-appeared after being returned to the original aquatic environment. The ability of plastic changes of gills inPolypterusrevealed in this study may allow them to survive in fluctuating environments, such as shallow swamps. The ancestor of Osteichthyes is expected to have possessed such plasticity in the gills, which may be one of the driving forces behind the transition of vertebrates from water to land.
Evaluation of in silico predictors on short nucleotide variants in HBA1, HBA2 and HBB associated with haemoglobinopathies
Authors: Tamana Stella , Xenophontos Maria , Minaidou Anna , Stephanou Coralea , Harteveld Cornells L. , Bento Celeste , Traeger-Synodinos Joanne , Fylaktou Irene , Yasin Norafiza Mohd , Hamid Faidatul Syazlin Abdul , Esa Ezalia , Halim-Fikri Hashim , Zilfalil Bin Alwi , Kakouri Andrea C. ,   ClinGen Hemoglobinopathy VCEP, Kleanthous Marina , Kountouris Petros 
Published: April 2022

AbstractIntroductionHaemoglobinopathies are the commonest monogenic diseases worldwide and are caused by variants in the globin gene clusters. With over 2400 variants detected to date, their interpretation using the ACMG/AMP guidelines is challenging, with computational evidence able to provide valuable input about their functional annotation. While many in silico predictors have already been developed, their performance varies for different genes and diseases.Materials and MethodsWe evaluate 31 in silico predictors using a dataset of 1627 variants in HBA1, HBA2, and HBB. Through varying the decision threshold for each tool, we analyse their performance (a) as binary classifiers of pathogenicity, and (b) using different nonoverlapping pathogenic and benign thresholds for their optimal use in the ACMG/AMP framework.ResultsCADD, Eigen-PC, and REVEL are the overall top performers, with the former reaching moderate strength level for pathogenic prediction. Eigen-PC and REVEL achieve the highest accuracies for missense variants, while CADD is also a reliable predictor of nonmissense variants. Moreover, SpliceAl is the top performing splicing predictor, reaching strong level of evidence, while GERP++ and phyloP are the most accurate conservation tools.DiscussionThis study provides evidence about the optimal use of computational evidence in globin gene clusters under the ACMG/AMP framework.
A six-months, long acting, one-shot injectable formulation of Ivermectin as a complementary malaria vector control tool to target zoophagic Anopheles : laboratory and model-based proofs of concept
Authors: Pooda Sié Hermann , Moiroux Nicolas , Porciani Angélique , Courgeault Anne-Laure , Roberge Christophe , Gaudriault Georges , Sidibé Issa , Belem Adrien Marie Gaston , Rayaissé Jean-Baptiste , Dabiré Roch K. , Mouline Karine 
Published: April 2022

SummaryContextIn the current context of residual plasmodium transmission where zoophagic proclivities of Anopheles intervene, we propose to treat peridomestic animals using the endectocide Ivermectin as a complementary approach to bednets. As Ivermectin remanence with classic veterinary compounds is insufficient to induce a significant decrease in vectors’ populations, we developed a long-lasting injectable formulation of ivermectin from the BEPO® technology designed to release insecticidal concentrations of the molecule for 6 months. The work reported here is a proof of concept that using this new technology could help decrease field Anopheles populations.MethodsEight calves were injected with Ivermectin therapeutic doses of 1.2 mg/kg body weight using 2 long lasting formulations (A and B). Efficacy of the product at killing wild derivedAn. coluzziihas been evaluated by direct-skin feeding assays from 1 to 210 days after injection (DAI). Efficacy on survival was estimated with Cox proportional hazards mixed models and Kaplan meier estimates. To predict efficacy in field-based scenarii, we used a transmission model fed with an entomological model considering different levels for the Anopheles’ zoophagic preference, calves vs humans ratios, and bed net use variables.ResultsThe release at mosquitocidal plasmatic concentrations of Ivermectin during 6 months is confirmed for both formulations (Hazard ratios > 1 for both formulations against their vehicle for 210 days). The Ivermectin concentration allowing to kill 90% of the mosquitoes before the extrinsic incubation period of the parasite is achieved (10 days) are 11 and 9 ng/ml for formulations A and B if the blood meal is taken before the infectious one, and 15 and 13 ng/ml if it was taken after. Modeling showed that Ivermectin treatment of calves using BEPO® technology would reduce infectious vector populations, from at least 35% for most anthropophagic Anopheles in villages where cattle to human ratio is the lowest, to more than 75% if vectors were zoophagic and calves numbers superior to humans’.ConclusionOur study gives the proof of concept that a long-lasting formulation of Ivermectin administered to calves could help decrease field malaria vectors’ populations, which may, ultimately, have an impact at the epidemiological level.
The molecular mechanism and physiological role of silent nociceptor activation
Authors: Nees Timo A. , Wang Na , Adamek Pavel , Verkest Clement , La Porta Carmen , Schaefer Irina , Virnich Julie , Balkaya Selin , Prato Vincenzo , Morelli Chiara , Zeitzschel Nadja , Begay Valerie , Lee Young Jae , Tappe-Theodor Anke , Lewin Gary R. , Heppenstall Paul A. , Taberner Francisco J. , Lechner Stefan G. 
Published: April 2022

SummarySilent nociceptors are sensory afferents that are insensitive to noxious mechanical stimuli under normal conditions but become sensitized to such stimuli during inflammation. Using RNA-sequencing and quantitative RT-PCR we demonstrate that inflammation selectively upregulates the expression of the transmembrane protein TMEM100 in silent nociceptors and electrophysiology revealed that over-expression of TMEM100 is required and sufficient to un-silence silent nociceptors. Moreover, we show that mice lacking TMEM100 do not develop secondary allodynia – i.e. pain hypersensitivity that spreads beyond the site of inflammation – in a mouse model of knee joint inflammation and that AAV-mediated overexpression of TMEM100 in articular afferents in the absence of inflammation is sufficient to induce allodynia in remote skin regions without causing knee joint pain. Thus, our work identifies TMEM100 as a key regulator of silent nociceptor un-silencing and reveals a physiological role for this hitherto enigmatic afferent subclass in triggering spatially remote secondary allodynia during inflammation.
Resetting H3K4me3, H3K27ac, H3K9me3 and H3K27me3 during the maternal-to-zygotic transition and blastocyst lineage specification in bovine embryos
Authors: Zhou Chuan , Halstead Michelle M. , Bonnet-Garnier Amèlie , Schultz Richard M. , Ross Pablo J. 
Published: April 2022

AbstractIt remains poorly understood how histone modifications regulate changes in gene expression during preimplantation development. Using a bovine model, we profiled changes in two activating (H3K4me3 and H3K27ac) and two repressive (H3K9me3 and H3K27me3) marks in oocytes, 2-, 4- and 8-cell embryos (that developed in the presence or absence of the transcription inhibitor a-amanitin), morula, blastocysts, inner cell mass cells and trophectoderm. In oocytes, we find that broad bivalent domains of H3K4me3 and H3K27me3 mark developmental genes, and that prior to genome activation, H3K9me3 and H3K27me3 co-occupy gene bodies. During genome activation, chromatin accessibility is established before canonical H3K4me3 and H3K27ac, and although embryonic transcription is required for this active remodeling, it is dispensable for maintenance of pre-established histone marks. Finally, blastocyst lineages are defined by differential Polycomb repression and transcription factor activity. Overall, these results further support the use of bovine as a more appropriate model system than the mouse to study genome activation and cell lineage specification during human preimplantation development.
Global disparity of research allocation and the Aichi biodiversity conservation targets
Authors: Mugerwa Badru , Niedballa Jürgen , Planillo Aimara , Sheil Douglas , Kramer-Schadt Stephanie , Wilting Andreas 
Published: April 2022

AbstractTracking progress towards global biodiversity conservation targets requires appropriate allocation of research and monitoring efforts. We conducted a global review of camera trap research on mammals as a proxy for biodiversity research and monitoring over the last two decades. We assessed how 3395 research locations from 2324 studies tracked priority regions for attaining the 2020 Aichi Biodiversity Targets. We used a geospatial distribution modelling approach to predict the spatial allocation of biodiversity research and to identify its key drivers. We show that conservation research in the past two decades has often failed to target areas important for conservation, and that 76.8% of the global research allocation can be attributed to country income, biome, mammal richness and accessibility. We predicted lowest probabilities of research allocation in low income countries. The Amazon and Congo Forest basins — two highly biodiverse ecosystems facing unprecedented human alteration — received inadequate research attention. Even in the most researched regions, an average of 51.4% of the research locations were outside the top 20% most important areas for the global biodiversity Aichi Targets. To support biodiversity conservation targets, policy and practice, more research and monitoring is required in regions with high importance for conservation.
Recovery of 447 Eukaryotic bins reveals major challenges for Eukaryote genome reconstruction from metagenomes
Authors: Saraiva Joao Pedro , Bartholomäus Alexander , Toscan Rodolfo Brizola , Baldrian Petr , da Rocha Ulisses Nunes 
Published: April 2022

AbstractAn estimated 8.7 million eukaryotic species exist on our planet. However, recent tools for taxonomic classification of eukaryotes only dispose of 734 reference genomes. As most Eukaryotic genomes are yet to be sequenced, the mechanisms underlying their contribution to different ecosystem processes remain untapped. Although approaches to recover Prokaryotic genomes have become common in genome biology, few studies have tackled the recovery of Eukaryotic genomes from metagenomes. This study assessed the reconstruction of Eukaryotic genomes using 215 metagenomes from diverse environments using the EukRep pipeline. We obtained 447 eukaryotic bins from 15 classes (e.g., Saccharomycetes, Sordariomycetes, and Mamiellophyceae) and 16 orders (e.g., Mamiellales, Saccharomycetales, and Hypocreales). More than 73% of the obtained eukaryotic bins were recovered from samples whose biomes were classified as host-associated, aquatic and anthropogenic terrestrial. However, only 93 bins showed taxonomic classification to (9 unique) genera and 17 bins to (6 unique) species. A total of 193 bins contained completeness and contamination measures. Average completeness and contamination were 44.64% (σ=27.41%) and 3.97% (σ=6.53%), respectively. Micromonas commoda was the most frequent taxa found while Saccharomyces cerevisiae presented the highest completeness, possibly resulting from a more significant number of reference genomes. However, mapping eukaryotic bins to the chromosomes of the reference genomes suggests that completeness measures should consider both single-copy genes and chromosome coverage. Recovering eukaryotic genomes will benefit significantly from long-read sequencing, intron removal after assembly, and improved reference genomes databases.
Less is more - loss of EGFL7 improves memory by upregulation of VEGF-D
Authors: Vasić Verica , Barth Kathrin , Bicker Frank , Schumann Ulrike , Maurer Christine , Heinig Nora , Röhlecke Cora , Nimtschke Ute , Schumann Lana , Meinhardt Matthias , Mittmann Thomas , Radyushkin Konstantin , Baumgart Jan , Tenzer Stefan , Zipp Frauke , Tegeder Irmgard , Schmidt Mirko HH 
Published: April 2022

AbstractNeural stem cells reside in a specialized neurogenic niche of the hippocampus termed the subgranular zone. Throughout life, they give rise to adult-born neurons in the dentate gyrus thereby contributing to learning and memory. Here, we report that neurons together with neural stem and precursor cells secrete the neurovascular protein epidermal growth factor-like protein 7 (EGFL7) to shape this niche. EGFL7 knock-out in vivo promoted adult neurogenesis generating neurons forming additional spines which permanently integrated into the neural circuit until old age. RNA-sequencing identified the cytokine VEGF-D as a major molecular driver of this process in vivo. In behavioral studies EGFL7 knock-out mice displayed stronger maintenance of memory suggesting longer-lasting spatial memory and improved memory consolidation in the hippocampus by modulation of pattern separation in young and aged mice. Taken together, EGFL7 is an upstream regulator of the VEGF-D in adult neurogenesis and a key regulator of learning and memory.
Statistical learning for sparser fine-mapped polygenic models: the prediction of LDL-cholesterol
Authors: Maj Carlo , Staerk Christian , Borisov Oleg , Klinkhammer Hannah , Yeung Ming Wai , Krawitz Peter , Mayr Andreas 
Published: April 2022

AbstractPolygenic risk scores quantify the individual genetic predisposition regarding a particular trait. We propose and illustrate the application of existing statistical learning methods to derive sparser models for genome-wide data with a polygenic signal. Our approach is based on three consecutive steps. First, potentially informative loci are identified by a marginal screening approach. Then, fine-mapping is independently applied for blocks of variants in linkage disequilibrium, where informative variants are retrieved by using variable selection methods including boosting with probing and stochastic searches with the Adaptive Subspace method. Finally, joint prediction models with the selected variants are derived using statistical boosting. In contrast to alternative approaches relying on univariate summary statistics from genome-wide association studies, our three-step approach enables to select and fit multivariable regression models on large-scale genotype data. Based on UK Biobank data, we develop prediction models for LDL-cholesterol as a continuous trait. Additionally, we consider a recent scalable algorithm for the Lasso. Results show that statistical learning approaches based on fine-mapping of genetic signals result in a competitive prediction performance compared to classical polygenic risk approaches, while yielding sparser risk models that tend to be more robust regarding deviations from the target population.