bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ambient Temperature and Dengue Hospitalisation in Brazil: A 10-year period two-stage case-design time series analysis
Authors: Lopes Rafael , Basagaña Xavier , Bastos Leonardo S. L. , Bozza Fernando A. , Ranzani Otavio T. 
Published: April 2022

AbstractClimate factors are known to influence seasonal patterns of dengue transmission. However, little is known about the effect of extremes of temperature on the severity of dengue infection, such as hospital admission. We aimed to quantify the effect of ambient temperature on dengue hospitalisation risk in Brazil. We retrieved daily dengue hospitalisation counts by each of 5,565 municipalities across the 27 states of Brazil from 1st of January 2010 to 31st of December 2019, from the Brazilian Public Hospital Admission System (“SIH”). We obtained average daily ambient temperature for each municipality from the ERA5-land product reanalysis. We combined distributed lag non-linear models with time stratified design model framework to pool a relative risk (RR) estimate for dose-response and lag-response structures for the association of temperature and Dengue hospitalisation. We estimate the overall dengue hospitalisation RR for the whole country as well for each of the five macro-regions by meta-analysing state level estimates. 579,703 hospital admissions due to dengue occurred over the 10 years’ period of 2010 to 2019. We observed a positive association between high temperatures and high risk of hospitalisation for Brazil. The overall RR for dengue hospitalisation was 2.185 (95% CI 1.457-3.276) at the 50th percentile of temperature and 2.385 (95% CI 1.556-3.655) at 95th percentile of temperature for Brazil. We also found lag effects of heat on hospitalisation, particularly an immediate augmented risk to hospitalisation, both at the 50th percentile and 95th. High temperatures are associated with an increase in the risk of hospitalisation by dengue. These findings may guide preparedness and mitigation policies during dengue season outbreaks, particularly on the health-care demand.
α1 adrenoreceptor antagonism mitigates extracellular mitochondrial DNA accumulation in lung fibrosis models and in patients with IPF
Authors: Ishikawa Genta , Peng Xueyan , McGovern John , Woo Sam , Perry Carrighan , Liu Angela , Yu Sheeline , Ghincea Alexander , Sun Huanxing , Ryu Changwan , Herzog Erica L. 
Published: April 2022

ABSTRACTIdiopathic Pulmonary Fibrosis is increasingly associated with adrenergic innervation and endogenous innate immune ligands such as mitochondrial DNA (mtDNA). Interestingly, a connection between these entities has not been explored. Here we report that noradrenaline (NA) derived from the lung’s adrenergic nerve supply drives the accumulation of αSMA-expressing fibroblasts via a mechanism involving α1 adrenoreceptors and mtDNA. Using the bleomycin model of lung fibrosis we compared the effect of lung specific adrenergic denervation achieved via the inhalational administration of the sympathetic neurotoxin 6-hydroxydopamine to surgically mediated adrenal ablation and found that NA derived from local but not adrenal sources drives lung fibrosis. Bleomycin induced the appearance of a αSMA+ fibroblast population co-expressing the adrenoreceptor alpha-1D (ADRA1D). Therapeutic delivery of the α1 adrenoreceptor antagonist terazosin reversed these changes and suppressed the accumulation of extracellular mtDNA. TGFβ1-stimulated normal human lung fibroblasts treated with TGFβ1 and Noradrenaline expressed ADRA1D and developed reduced αSMA expression and extracellular mtDNA concentrations when treated with terazosin. IPF patients prescribed α1 adrenoreceptor antagonists for non-pulmonary indications showed improved survival and reduced concentrations of plasma mtDNA. These findings link nerve-derived NA and α1 adrenoreceptor antagonism with mtDNA accumulation and lung fibrogenesis in mouse models, cultured cells, and humans with IPF. Further study of this neuro-innate connection may yield new avenues for investigation in the clinical and basic science realms.
Localization of Abnormal Brain Regions in Parkinsonian Disorders: An ALE Meta-Analysis
Authors: Ellis Elizabeth G. , Joutsa Juho , Morrison-Ham Jordan , Caeyenberghs Karen , Corp Daniel T. 
Published: April 2022

AbstractParkinsonism is a feature of several neurodegenerative disorders, including Parkinson’s disease (PD), progressive supranuclear palsy (PSP), corticobasal degeneration syndrome (CBS) and multiple system atrophy (MSA). Neuroimaging studies have yielded insights into parkinsonism; however it remains unclear whether there is a common neural substrate amongst disorders. The aim of the present meta-analysis was to identify consistent brain alterations in parkinsonian disorders (PD, PSP, CBS, MSA) both individually, and combined, to elucidate the shared substrate of parkinsonism. 33,505 studies were systematically screened following searches of MEDLINE Complete and Embase databases. A series of whole-brain activation likelihood estimation meta-analyses were performed on 126 neuroimaging studies (64 PD; 25 PSP; 18 CBS; 19 MSA) utilizing anatomical MRI, perfusion or metabolism positron emission tomography and single photon emission computed tomography. Abnormality of the caudate, thalamus, middle frontal and temporal gyri was common to all parkinsonian disorders. Localizations of commonly affected brain regions in individual disorders aligned with current diagnostic imaging markers, localizing the midbrain in PSP, putamen in MSA-parkinsonian variant and brainstem in MSA-cerebellar variant. Regions of the basal ganglia and precuneus were most commonly affected in PD, while CBS was characterized by caudate abnormality. To our knowledge, this is the largest meta-analysis of neuroimaging studies in parkinsonian disorders. Findings support the notion that parkinsonism may share a common neural substrate, independent of the underlying disease process, while also highlighting characteristic patterns of brain abnormality in each disorder.
Evolution and co-evolution of the suck behaviour, a postcopulatory female resistance trait that manipulates received ejaculate
Authors: Singh Pragya , Brand Jeremias N. , Schärer Lukas 
Published: April 2022

AbstractSexual conflicts over the post-mating fate of received ejaculate can favour traits in one sex that are costly to the other. Reciprocally mating hermaphrodites face unique challenges as they mate simultaneously in both the male and female role, potentially leading to receipt of unwanted ejaculate. Reciprocal mating can then give rise to postcopulatory female resistance traits that allow manipulation of received ejaculate. A putative example is the suck behaviour, observed in the flatworm genusMacrostomum. It involves the sperm recipient placing its pharynx over its own female genital opening and appearing to suck, likely removing received ejaculate after mating. The genus also contains hypodermically-inseminating species that presumably exhibit unilateral mating and have not been observed to suck. Here, we examine the evolution of the suck behaviour inMacrostomum, aiming to document the mating behaviour in 64 species. First, we provide videographic evidence that ejaculate is indeed removed during the suck behaviour in a reciprocally mating species,Macrostomum hamatum. Next, we show evolutionary positive correlations between the presence, duration and frequency of reciprocal mating behaviour and the suck behaviour, providing clear evidence that the suck behaviour co-evolves with reciprocal mating behaviour. Finally, we show an association between reproductive behaviour and reproductive morphology, suggesting that reproductive morphology can be used for inferring the behavioural mating strategy of a species. Together our study demonstrates sexual antagonistic coevolution leading to the evolution of a postcopulatory behavioural trait that functions as a female counter-adaptation allowing individuals to gain control over received ejaculate in a hermaphroditic sexual system.
Spinosaurids as ‘subaqueous foragers’ undermined by selective sampling and problematic statistical inference
Authors: Myhrvold Nathan , Sereno Paul C. , Baumgart Stephanie L. , Formoso Kiersten K. , Vidal Daniel , Fish Frank E. , Henderson Donald M. 
Published: April 2022

AbstractFabbri et al.1 claim that the huge sail-backed dinosaur Spinosaurus aegyptiacus and the spinosaurid Baryonyx were “subaqueous foragers,” diving underwater in pursuit of prey, based on their measure of bone “compactness.” Using thin-sections and computed tomographic (CT) scans of thigh bone (femur) and trunk rib from various living and extinct vertebrates, they claim to be able to distinguish taxa with “aquatic habits” from others. Their conclusions are undermined by selective bone sampling, inaccuracies concerning spinosaurid bone structure, faulty statistical inferences, and novel redefinition of the term “aquatic.”
Onlinemeta: A Web Server for Meta-Analysis Based on Shiny Framework
Authors: Dai Weiyuntian , Yi Yonglin , Lin Anqi , Zhou Chaozheng , Zhang Jian , Wang Shixiang , Sun Min , Luo Peng 
Published: April 2022

ABSTRACTMeta-analysis is a common statistical method used to summarize multiple studies that cover the same topic. It can provide less biased results and explain heterogeneity between studies. Although there exists a variety of meta-analysis softwares, they are rarely both convenient to use and capable of comprehensive analytical functions. As a result, we are motivated to establish a meta-analysis web tool called Meta-Analysis Online (Onlinemeta). Onlinemeta includes three major modules: risk bias analysis, meta-analysis and network meta-analysis. The risk bias analysis module can produce heatmaps and histograms, whereas the meta-analysis module accepts many types of data as input, including dichotomous variables, single-armed dichotomous variables, continuous variables, single-armed continuous variables, survival data, deft method and diagnostic experiments, and outputs well-tuned forest plots, sensitivity analysis forest plots, funnel plots, comparison table of effects, SROC curve, and crosshair plots. For network meta-analysis module, the tool can process dichotomous variables or continuous variables, and generate network plots, forest plots, SUCRA (Surface Under the Cumulative Ranking) plots, rank plots and heatmaps. Onlinemeta is available athttps://smuonco.Shinyapps.io/Onlinemeta/.
Catecholaminergic cell type-specific expression of Cre recombinase in knock-in transgenic rats generated by the Combi-CRISPR technology
Authors: Matsushita Natsuki , Nishizawa Kayo , Kato Shigeki , Iguchi Yoshio , Fukabori Ryoji , Takeuchi Kosei , Miyasaka Yoshiki , Mashimo Tomoji , Kobayashi Kazuto 
Published: April 2022

ABSTRACTBackgroundCell groups containing catecholamines provide a useful model to study the molecular and cellular mechanisms underlying the morphogenesis, physiology, and pathology of the central nervous system. For this purpose, it is necessary to establish a system to induce catecholaminergic group-specific expression of Cre recombinase. Recently, we introduced a gene cassette encoding 2A peptide fused to Cre recombinase into the site between the C-terminus and translational termination codons of the rat tyrosine hydroxylase (TH) open reading frame by the Combi-CRISPR technology, which is a genomic editing method to enable an efficient knock-in (KI) of long DNA sequence into a target site. However, the expression patterns of the transgene and its function as well as the effect of the mutation on the biochemical and behavioral phenotypes in the KI strains have not been characterized yet.New MethodWe aimed to evaluate the usefulness of TH-Cre KI rats as an experimental model for investigating the structure and function of catecholaminergic neurons in the brain.ResultsWe detected cell type-specific expression of Cre recombinase and site-specific recombination activity in the representative catecholaminergic groups in the TH-Cre KI rat strains. In addition, we measured TH expression level and catecholamine accumulation in the brain regions, and spontaneous locomotion, indicating that catecholamine metabolism and general behavior are apparently normal in these KI rats.ConclusionsTH-Cre KI rat strains produced by the Combi-CRISPR system offer a beneficial model to study the molecular and cellular mechanics for the morphogenesis, physiology, and pathology of catecholamine-containing neurons in the brain.
Extensive diversity and rapid turnover of phage defense repertoires in cheese-associated bacterial communities
Authors: Somerville Vincent , Schowing Thibault , Chabas Hélène , Schmidt Remo S. , von Ah Ueli , Bruggmann Rémy , Engel Philipp 
Published: April 2022

AbstractPhages are key drivers of genomic diversity in bacterial populations as they impose strong selective pressure on the evolution of bacterial defense mechanisms across closely related strains. The pan-immunity model suggests that such diversity is maintained because the effective immune system of a bacterial species is the one distributed across all strains present in the community. However, only few studies have analyzed the distribution of bacterial defense systems at the community-level, mostly focusing on CRISPR and comparing samples from complex environments. Here, we studied 2’778 bacterial genomes and 158 metagenomes from cheese-associated communities, which are dominated by a few bacterial taxa and occur in relatively stable environments. We find that nearly identical strains of cheese-associated bacteria contain diverse and highly variable arsenals of innate and adaptive (i.e CRISPR-Cas) immunity suggesting rapid turnover of defense mechanisms in these communities. CRISPR spacer abundance correlated with the abundance of matching target sequences across the metagenomes providing evidence that the identified defense repertoires are functional and under selection. While these characteristics align with the pan-immunity model, the detected CRISPR spacers only covered a subset of the phages previously identified in cheese, suggesting that CRISPR does not provide complete immunity against all phages, and that the innate immune mechanisms may have complementary roles. Our findings show that the evolution of bacterial defense mechanisms is a highly dynamic process and highlight that experimentally tractable, low complexity communities such as those found in cheese, can help to understand ecological and molecular processes underlying phage-defense system relationships.ImportanceBacteria are constantly exposed to phage predation and hence harbor highly diverse defense arsenals. According to the pan-immunity hypothesis the effective immune system of a bacterial species is not the one encoded in a single genome but in the entire community. However, few studies have investigated how defense systems are distributed within communities. Here, we carried out (meta)genomic analyses of bacterial communities used in cheesemaking. These are tractable communities of biotechnological interest which house few bacterial species and are exposed to high phage pressure. In line with the pan-immunity hypothesis, we find that nearly identical strains of cheese-associated bacteria contain highly variable arsenals of innate and adaptive immunity. We provide evidence for the functional importance of this diversity, and reveal that CRISPR alone does not provide complete immunity against all phages. Our findings can have implications for the design of robust synthetic communities used in biotechnology and the food industry.
Prenatal development of neonatal vocalizations
Authors: Narayanan Darshana Z. , Takahashi Daniel Y. , Kelly Lauren M. , Hlavaty Sabina I. , Huang Junzhou , Ghazanfar Asif A. 
Published: April 2022

AbstractHuman and non-human primates produce rhythmical sounds as soon as they are born. These early vocalizations are important for soliciting the attention of caregivers. How they develop, remains a mystery. The orofacial movements necessary for producing these vocalizations have distinct spatiotemporal signatures. Therefore, their development could potentially be tracked over the course of prenatal life. We densely and longitudinally sampled fetal head and orofacial movements in marmoset monkeys using ultrasound imaging. We show that orofacial movements necessary for producing rhythmical vocalizations differentiate from a larger movement pattern that includes the entire head. We also show that signature features of marmoset infant contact calls emerge prenatally as a distinct pattern of orofacial movements. Our results establish that aspects of the sensorimotor development necessary for vocalizing occur prenatally, even before the production of sound.
A novel PNGase Rc for improved protein N-deglycosylation in bioanalytics and HDX-MS epitope mapping under challenging conditions
Authors: Gramlich Marius , Maier Sandra , Kaiser Philipp D. , Traenkle Bjoern , Wagner Teresa R. , Voglmeir Josef , Stoll Dieter , Rothbauer Ulrich , Zeck Anne 
Published: April 2022

AbstractN-linked glycosylation is a ubiquitous posttranslational modification of proteins. While it plays an important role in the biological function of proteins, it often poses a major challenge for their analytical characterization. Currently available peptide N-glycanases (PNGases) are often inefficient at deglycosylating proteins due to sterically inaccessible N-glycosylation sites. This usually leads to poor sequence coverage in bottom-up analysis using liquid chromatography with tandem mass spectrometry (LC-MS) and makes it impossible to obtain an intact mass signal in top-down MS analysis. In addition, most PNGases operate optimally only in the neutral to slightly acidic pH range and are severely compromised in the presence of reducing and denaturing substances, which limits their use for advanced bioanalysis based on hydrogen-deuterium exchange in combination with mass spectrometry (HDX-MS).Here, we present a novel peptide N-glycanase from Rudaea cellulosilytica (PNGase Rc) for which we demonstrate broad substrate specificity for N-glycan hydrolysis from multiply occupied and natively folded proteins. Our results show that PNGase Rc is functional even under challenging, HDX quench conditions (pH 2.5, 0 °C) and in the presence of 0.4 M Tris(2-carboxyethyl)phosphine (TCEP), 4 M urea and 1 M guanidinium chloride (GdmCl). Most importantly, we successfully applied the PNGase Rc in an HDX-MS workflow to determine the epitope of a nanobody targeting the extracellular domain of human signal-regulating protein alpha (SIRPα).
Molecular basis of indispensable accuracy of mammalian miRNA biogenesis
Authors: Zapletal David , Taborska Eliska , Pasulka Josef , Malik Radek , Kubicek Karel , Zanova Martina , Much Christian , Sebesta Marek , Buccheri Valeria , Horvat Filip , Jenickova Irena , Prochazkova Michaela , Prochazka Jan , Pinkas Matyas , Novacek Jiri , Joseph Diego F. , Sedlacek Radislav , O’Carroll Dónal , Stefl Richard , Svoboda Petr 
Published: April 2022

AbstractMammalian Dicer is the gatekeeper into the essential gene-regulating miRNA pathway. What is committing mammalian Dicer to the miRNA pathway remains unknown. We report that Dicer’s highly conserved DExD/H helicase domain is the key structural element supporting accurate miRNA biogenesis. While ATPase activity of the domain is non-essential, its loss is lethal in mice. It is required during canonical miRNA biogenesis for efficient recognition, high-fidelity cleavage, and strand selection. Structure of Dicer-miRNA precursor complexes showed that the DExD/H domain acquired helicase-unrelated function defining Dicer conformations, which affect substrate loading and facilitate pre-selection of miRNA precursors. Dicer lacking the DExD/H domain favors conformations enabling reduced substrate selectivity and supporting RNA interference, a different small RNA pathway. Therefore, Dicer’s DExD/H domain ensures indispensable high-fidelity precursor processing of mammalian miRNAs, which constitutes a structural “mold” for adaptive miRNA evolution.
Melanocortin receptor agonist melanotan-II microinjected in the nucleus accumbens decreases appetitive and consumptive responding for food
Authors: Eliason Nicole , Martin Lynne , Low Malcolm J. , Sharpe Amanda L. 
Published: April 2022

ABSTRACTRationale. Obesity is a major health problem worldwide. An understanding of the factors that drive feeding behaviors is key to the development of pharmaceuticals to decrease appetite and consumption. Proopiomelanocortin (POMC), the melanocortin peptide precursor, is essential in the regulation of body weight and ingestive behaviors. Deletion of POMC or impairment of melanocortin signaling in the brain results in hyperphagic obesity. Neurons in the hypothalamic arcuate nucleus produce POMC and project to many areas including the nucleus accumbens (NAcc), which is well established in the rewarding and reinforcing effects of both food and drugs of abuse.ObjectiveThese studies sought to determine the role of melanocortins in the NAcc on consumption of and motivation to obtain access to standard rodent chow.MethodsMale, C57BL/6J mice were microinjected bilaterally into the NAcc (100 nl/side) with the melanocortin receptor 3/4 agonist melanotan-II (MT-II; 0.1, 0.3, and 1 nmol), and ingestive behaviors were examined in both home cage and operant food self-administration experiments. In addition, the ability of MT-II in the NAcc to produce aversive properties or affect metabolic rate were tested.ResultsMT-II injected into the NAcc significantly decreased consumption in both home cage and operant paradigms, and furthermore decreased appetitive responding to gain access to food. There was no development of conditioned taste avoidance or change in metabolic parameters following anorexic doses of MT-II. Conclusions. MT-II in the NAcc decreased both the motivation to eat and the amount of food consumed without inducing an aversive state or affecting metabolic rate, suggesting a role for melanocortin signaling in the ventral striatum that is selective for appetite and satiety without affecting metabolism or producing an aversive state.
A complete allosteric map of a GTPase switch in its native network
Authors: Mathy Christopher J.P. , Mishra Parul , Flynn Julia M. , Perica Tina , Mavor David , Bolon Daniel N.A. , Kortemme Tanja 
Published: April 2022

AbstractAllosteric regulation is central to protein function in cellular networks1. However, despite technological advances2,3 most studies of allosteric effects on function are conducted in heterologous environments2,4,5, limiting the discovery of allosteric mechanisms that rely on endogenous binding partners or posttranslational modifications to modulate activity. Here we report an approach that enables probing of new sites of allosteric regulation at residue-level resolution in essential eukaryotic proteins in their native biological context by comprehensive mutational scanning. We apply our approach to the central GTPase Gsp1/Ran. GTPases are highly regulated molecular switches that control signaling, with switching occurring via catalyzed GTP hydrolysis and nucleotide exchange. We find that 28% of 4,315 assayed mutations in Gsp1/Ran are highly deleterious, showing a toxic response identified by our assay as gain-of-function (GOF). Remarkably, a third of all positions enriched for GOF mutations (20/60) are outside the GTPase active site. Kinetic analysis shows that these distal sites are allosterically coupled to the active site, including a novel cluster of sites that alter the nucleotide preference of Gsp1 from GDP to GTP. We describe multiple distinct mechanisms by which allosteric mutations alter Gsp1/Ran cellular function by modulating GTPase switching. Our systematic discovery of new regulatory sites provides a functional map relevant to other GTPases such as Ras that could be exploited for targeting and reprogramming critical biological processes.