bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impaired intracellular Ca2+signaling contributes to age-related cerebral small vessel disease inCol4a1mutant mice
Authors: Yamasaki Evan , Thakore Pratish , Ali Sher , Solano Alfredo Sanchez , Wang Xiaowei , Gao Xiao , Labelle-Dumais Cassandre , Chaumeil Myriam M. , Gould Douglas B. , Earley Scott 
Published: August 2022

AbstractHumans and mice with mutations inCOL4A1andCOL4A2manifest hallmarks of cerebral small vessel disease (cSVD), but the pathogenic mechanisms are largely unknown. Mice with a missense mutation inCol4a1at amino acid 1344 (Col4a1+/G1344D) exhibited age-dependent intracerebral hemorrhage (ICH) and brain lesions. Here we report that this pathology was associated with the loss of myogenic vasoconstriction, an intrinsic vascular response essential for the autoregulation of cerebral blood flow. Electrophysiological analyses showed that the loss of myogenic constriction resulted from blunted pressure-induced smooth muscle cell (SMC) membrane depolarization. Further, we found that dysregulation of membrane potential was associated with impaired Ca2+-dependent activation of large-conductance Ca2+-activated K+(BK) and transient receptor potential melastatin 4 (TRPM4) cation channels linked to disruptions in sarcoplasmic reticulum (SR) Ca2+signaling. TreatingCol4a1+/G1344Dmice with 4-phenylbutyrate, a compound that promotes the trafficking of misfolded proteins and alleviates SR stress, restored SR Ca2+signaling, BK and TRPM4 channel activity, prevented loss of myogenic tone, and reduced ICH. We conclude that alterations in SR Ca2+handling that impair membrane potential regulating ion channel activity result in dysregulation of SMC membrane potential and loss of myogenic tone contributing to age-related cSVD inCol4a1+/G1344Dmice.Graphical Abstract
Detection of Domestication Signals through the Analysis of the Full Distribution of Fitness Effects
Authors: Castellano David , Vourlaki Ioanna-Theoni , Gutenkunst Ryan N. , Ramos-Onsins Sebastian E. 
Published: August 2022

ABSTRACTDomestication is a process marked by complex interactions between demographic changes and selective pressures, which together shape genetic diversity. While the phenotypic outcomes of domestication are well documented, its genetic basis—particularly the dynamics of selection— remain less well understood. To investigate these dynamics, we performed simulations designed to approximate the demographic history of large domestic mammals. These simulations used selection coefficients as a modeling tool to represent changes in selection pressures, recognizing that such coefficients are abstractions rather than direct representations of biological reality. Specifically, we analyzed site frequency spectra (SFS) under varying distributions of fitness effects (DFE) and proportions of mutations with divergent selective pressures. Our results show that the discretized deleterious DFE can be reliably inferred from the SFS of a single population, but reconstructing the beneficial DFE and demographic history remains challenging, even when using the joint SFS of both populations. We further developed a novel joint DFE inference model to estimate the proportion of mutations with divergent selection coefficients (pc), although we found that signals of classic hard sweeps can mimic increases inpc, complicating interpretation. These findings underscore both the utility and limitations of DFE inference and highlight the need for caution when interpreting demographic histories in domesticated populations based on such modeling assumptions.
Ecdysone acts through cortex glia to regulate sleep in Drosophila
Authors: Li Yongjun , Haynes Paula , Zhang Shirley L. , Yue Zhifeng , Sehgal Amita 
Published: August 2022

SummarySteroid hormones are attractive candidates for transmitting long-range signals to affect behavior. These lipid-soluble molecules derived from dietary cholesterol easily penetrate the brain and act through nuclear hormone receptors (NHRs) that function as transcription factors. To determine the extent to which NHRs affect sleep: wake cycles, we knocked down each of the 18 highly conserved NHRs found in Drosophila adults and report that the ecdysone receptor (EcR) and its direct downstream NHR Eip75B (E75) act in glia to regulate the rhythm and amount of sleep. Halloween genes, a set of ecdysone synthesis genes, have little to no expression in the fly brain, while mRNA levels of the ecdysone target E75 cycle in the fly head, suggesting that glial ecdysone comes from the periphery and may enter the brain more at night. Anti-EcR staining localizes to the cortex glia in the brain and functional screening of glial subtypes revealed that EcR functions in adult cortex glia to affect sleep. Cortex glia are implicated in lipid metabolism, which appears to be relevant for actions of ecdysone as ecdysone treatment reduces lipid droplet size in these cells. In addition, sleep-promoting effects of exogenous ecdysone are diminished in Lsd-2 mutant flies, which are lean and deficient in lipid accumulation. We propose that ecdysone is a systemic secreted factor that modulates sleep by stimulating lipid metabolism in cortex glia.Graphical AbstractHighlightsGlial knockdown of ecdysone inducible NHRs reduces sleep.The ecdysone receptor (EcR) and its downstream target E75 function in cortex glia to modulate sleep.Ecdysone synthesis genes are not expressed in the fly brain, suggesting that glial ecdysone comes from the periphery.Ecdysone promotes sleep by mobilizing lipid droplets stored mainly in glia.
langevitour: smooth interactive touring of high dimensions, demonstrated with scRNA-Seq data
Authors: Harrison Paul 
Published: August 2022

Abstractlangevitour displays interactive animated 2D projections of high-dimensional datasets. Langevin Dynamics is used to produce a smooth path of projections. Projections are initially explored at random. A “guide” can be activated to look for an informative projection, or variables can be manually positioned. After a projection of particular interest has been found, continuing small motions provide a channel of visual information not present in a static scatter-plot. langevitour is implemented in Javascript, allowing for a high frame rate and responsive interaction, and can be used directly from the R environment or embedded in HTML documents produced using R. The widget is demonstrated using single-cell RNA sequencing (scRNA-Seq) data. langevitour’s linear projections provide a less distorted view of this data than commonly used non-linear dimensionality reductions such as UMAP.
UltraSEQ: a universal bioinformatic platform for information-based clinical metagenomics and beyond
Authors: Gemler Bryan T , Mukherjee Chiranjit , Howland Carrie , Fullerton Patrick A , Spurbeck Rachel R , Catlin Lindsay A , Smith Anthony , Minard-Smith Angela T , Bartling Craig 
Published: August 2022

AbstractApplied metagenomics is a powerful emerging capability enabling untargeted detection of pathogens, and its application in clinical diagnostics promises to alleviate the limitations of current targeted assays. While metagenomics offers a hypothesis-free approach to identify any pathogen, including unculturable and potentially novel pathogens, its application in clinical diagnostics has so far been limited by workflow-specific requirements, computational constraints, and lengthy expert review requirements. To address these challenges, we developed UltraSEQ, a first-of its kind metagenomics-based clinical diagnostics and biosurveillance tool that is accurate and scalable.Here we present results for evaluation of our novel UltraSEQ pipeline using anin silicosynthesized metagenome, mock microbial community datasets, and publicly available clinical datasets from samples of different infection types, and both short-read and long-read sequencing data. Our results show that UltraSEQ successfully detected all expected species across the tree of life in thein silicosample and detected all 10 bacterial and fungal species in the mock microbial community dataset. For clinical datasets, even without requiring dataset-specific configuration settings changes, background sample subtraction, or prior sample information, UltraSEQ achieved an overall accuracy of 91%. Further, we demonstrated UltraSEQ’s ability to provide accurate antibiotic resistance and virulence factor genotypes that are consistent with phenotypic results.Taken together, the above results demonstrates that the UltraSEQ platform offers a transformative approach to microbial and metagenomic sample characterization, employing a biologically informed detection logic, deep metadata, and a flexible system architecture for classification and characterization of taxonomic origin, gene function, and user-defined functions, including disease-causing infection.
The Iron Content of Human Serum Albumin Modulates the Susceptibility of Acinetobacter baumannii to Cefiderocol
Authors: Escalante Jenny , Nishimura Brent , Tuttobene Marisel R. , Subils Tomás , Mezcord Vyanka , Actis Luis A. , Tolmasky Marcelo E. , Bonomo Robert A. , Ramirez María Soledad 
Published: August 2022

ABSTRACTMortality rates of patients infected with Acinetobacter baumannii treated with cefiderocol (CFDC) were not as favorable as the best available treatment for pulmonary and bloodstream infections. Previous studies showed that the presence of human serum albumin (HSA) or HSA-containing fluids like human pleural fluid (HPF) or human serum (HS) in the growth medium is correlated with a decrease in the expression of genes associated with high-efficiency iron uptake systems. These observations may explain the less-than-ideal performance of CFDC in pulmonary and bloodstream infections because ferric siderophore transporters enhance penetration of CFDC into the cell’s cytosol. Removal of HSA from HPF or HS resulted in a reduction of the minimal inhibitory concentration of CFDC. Concomitant with these results, there was an enhancement of the expression of genes associated with high-efficiency iron uptake systems. In addition to inducing modifications in iron-uptake gene expression, removal of HSA also decreased the expression of β-lactam resistance genes. Taken together, these observations indicate that environmental HSA has a role in the expression levels of selected A. baumannii. Furthermore, removal of iron from HSA had the same effect as removal of HSA on the expression of genes associated with high-efficiency iron uptake systems, suggesting that at least one of the mechanisms by which HSA regulates the expression of selected genes is through acting as an iron supplier.IMPORTANCECefiderocol (CFDC) is a new antibiotic that combines its major bactericidal activity, i.e., inhibition of the Gram-negative bacterial cell wall synthesis, with a first in its class mechanism of cell penetration. The siderophore-like moiety facilitates entry through receptors that recognize ferric-siderophore complexes. Recent trials showed that treating pulmonary and bloodstream Acinetobacter baumannii infections with CFDC did not result in the same outcomes as treating other pathogens. Our studies indicated that exposure to human fluids that contain human serum albumin (HSA) increases the MIC values of CFDC. Results described in this work show that HSA is responsible for a reduction in susceptibility of A. baumannii to CFDC. Furthermore, the presence of HSA in the milieu produces a reduction in levels of expression of proteins associated with high-affinity iron uptake systems and enhanced expression of β-lactam resistance-associated genes. Deferration of HSA was accompanied by a loss of the ability to modify these genes’ expression levels. These results indicate that the microbiological activity of CFDC towards A. baumannii is attenuated in the presence of HSA-containing fluids. This unique insight opens up new avenues of investigation. Understanding this phenomenon’s molecular mechanism will help define methodologies to increase treatment efficiency.
Use of whole genome sequencing to estimate the contribution of immune evasion and waning immunity to decreasing COVID-19 vaccine effectiveness during alpha and delta variant waves
Authors: Lind Margaret L , Copin Richard , McCarthy Shane , Coppi Andreas , Warner Fred , Ferguson David , Duckwall Chelsea , Borg Ryan , Muenker M Catherine , Overton John , Hamon Sara , Zhou Anbo , Cummings Derek AT , Ko Albert I. , Hamilton Jennifer D , Schulz Wade , Hitchings Matt T. 
Published: August 2022

AbstractBackgroundThe decline in COVID-19 mRNA vaccine effectiveness (VE) is well established, however the impact of variant-specific immune evasion and waning protection remains unclear. Here, we use whole-genome-sequencing (WGS) to tease apart the contribution of these factors on the decline observed following the introduction of the Delta variant. Further, we evaluate the utility of calendar-period-based variant classification as an alternative to WGS.MethodsWe conducted a test-negative-case-control study among people who received SARS-CoV-2 RT-PCR testing in the Yale New Haven Health System between April 1 and August 24, 2021. Variant classification was performed using WGS and secondarily by calendar-period. We estimated VE as one minus the ratio comparing the odds of infection among vaccinated and unvaccinated people.ResultsOverall, 2,029 cases (RT-PCR positive, sequenced samples) and 343,985 controls (negative RT-PCRs) were included. VE 14-89 days after 2nd dose was significantly higher against WGS-classified Alpha infection (84.4%, 95% confidence interval: 75.6-90.0%) than Delta infection (68.9%, CI: 58.0-77.1%, p-value: 0.013). The odds of WGS-classified Delta infection were significantly higher 90-149 than 14-89 days after 2nd dose (Odds ratio: 1.6, CI: 1.2-2.3). While estimates of VE against calendar-period-classified infections approximated estimates against WGS-classified infections, calendar-period-based classification was subject to outcome misclassification (35% during Alpha period, 4% during Delta period).ConclusionsThese findings suggest that both waning protection and variant-specific immune evasion contributed to the lower effectiveness. While estimates of VE against calendar-period-classified infections mirrored that against WGS-classified infections, our analysis highlights the need for WGS when variants are co-circulating and misclassification is likely.Summary of main pointsUsing whole genome sequencing, we provide direct evidence of waning vaccine effectiveness and variant-specific immune evasion during the Delta wave. Effectiveness estimates against calendar-period-classified infections approximated estimates against WGS-classified infections, however, calendar-period classification was associated with a variant misclassification.
Homologous and heterologous boosting with CoronaVac and BNT162b2: a randomized trial (the Cobovax study)
Authors: Leung Nancy H. L. , Cheng Samuel M. S. , Cohen Carolyn A. , Martín-Sánchez Mario , Au Niki Y. M. , Luk Leo L. H. , Tsang Leo C. H. , Kwan Kelvin K. H. , Chaothai Sara , Fung Lison W. C. , Cheung Alan W. L. , Chan Karl C. K. , Li John K. C. , Ng Yvonne Y. , Kaewpreedee Prathanporn , Jia Janice Z. , Ip Dennis K. M. , Poon Leo L. M. , Leung Gabriel M. , Peiris J. S. Malik , Valkenburg Sophie A. , Cowling Benjamin J. 
Published: August 2022

ABSTRACTBackgroundThere are few trials comparing homologous and heterologous third doses of COVID-19 vaccination with inactivated vaccines and mRNA vaccines.MethodsWe conducted an open-label randomized trial in adults >=18 years of age who received two doses of inactivated vaccine (CoronaVac) or mRNA vaccine (BNT162b2) >=6 months earlier, randomised in 1:1 ratio to receive a third dose of either vaccine. We compared the reactogenicity, immunogenicity and cell-mediated immune responses, and assessed vaccine efficacy against infections during follow-up.ResultsWe enrolled 219 adults who previously received two doses of CoronaVac and randomised to CoronaVac (“CC-C”, n=101) or BNT162b2 (“CC-B”, n=118) third dose; and 232 adults who previously received BNT162b2 and randomised to CoronaVac (“BB-C”, n=118) or BNT162b2 (“BB-B”, n=114). There were more frequent reports of mild reactions in recipients of third-dose BNT162b2, which generally subsided within 7 days. Antibody responses against the ancestral virus, Omicron BA.1 and BA.2 subvariant by surrogate neutralization and PRNT50were stronger for the recipients of a third dose of BNT162b2 over CoronaVac irrespective of prior vaccine type. CD4+T cells boost only occurred in CoronaVac-primed arms. We did not identify differences in CD4+and CD8+T cell responses between arms. When Omicron BA.2 was circulating, we identified 58 infections with cumulative incidence of 15.3% and 15.4% in the CC-C and CC-B (p=0.93), and 16.7% and 14.0% in the BB-C and BB-B arms, respectively (p=0.56).ConclusionsSimilar levels of incidence of infection in each arm suggest all third dose combinations may provide similar degrees of protection against prevalent Omicron BA.2 infection, despite very weak antibody responses to BA.2 in the recipients of a CoronaVac third dose. Further research is warranted to identify appropriate correlates of protection for inactivated COVID-19 vaccines.
Assessing glucose-6-phosphate dehydrogenase (G6PD) during COVID-19 requires caution: evidence on the impact of the infection upon enzyme activity
Authors: de Almeida Rodrigues Maria Gabriela , de Melo Gisely Cardoso , Barros Dias Ádila Liliane , Sartim Marco Aurélio , Xavier Mariana Simão , Abreu Netto Rebeca Linhares , Almeida Val Fernando Fonseca , Baía-da-Silva Djane Clarys , Brito-Sousa José Diego , Monteiro Wuelton Marcelo , de Lacerda Marcus Vinicius Guimarães , de Souza Sampaio Vanderson 
Published: August 2022

ABSTRACTGlucose-6 phosphate dehydrogenase deficiency (G6PDd) was suggested as a risk factor of severity in patients with COVID-19. In this article, we assessed the influence of G6PDd on the infection, severity, and clinical progression of patients with COVID-19. This prospective cohort study included adult participants (≥18 years old) who had clinical and/or radiological COVID-19 findings or positive RT-PCR results. Epidemiological and clinical data were extracted from electronic medical records. G6PD activity was measured in SD Biosensor STANDARD G6PD® equipment at admission and one year after discharge. Samples were genotyped for the three most common single nucleotide polymorphisms (SNPs) for G6PDd in the Brazilian Amazon s1050828, rs1050829 and rs5030868, corresponding to G6PD African A-(G202A, A376G), G6PD African A+(A376G) and G6PD Mediterranean(C563T), respectively. Seven hundred fifty-three patients were included, of which 123 (16.3%) were G6PDd. The G6PDd group had a higher mean hemoglobin, and lower values of C-reactive protein and leukocytes at admission. There was no association between G6PDd and COVID-19 severity, considering that the frequency of G6PDd who needed to be hospitalized (1.9%) or demanding invasive mechanical ventilation (16.0%) or died (21.1%) was lower than G6PD normal patients. Only 29 out of 116 (25%) participants carried the African genotype. Out of 30 participants tested as G6PDd during disease, only 11 (36.7%) results agreed one year after discharge. In conclusion, caution must be taken when G6PDd screening in patients with acute COVID-19.
Gold Nanourchins Improve Virus Targeting and Plasmonic Coupling for Virus Diagnosis on a Smartphone Platform
Authors: Liu Yaning , Ye Haihang , Bayram Abdullah , Zhang Tingting , Cai Qi , Xie Chen , Huynh HoangDinh , Peerzade Saquib Ahmed M. A. , Kahn Jeffrey S. , Qin Zhenpeng 
Published: August 2022

AbstractPoint-of-care detection of pathogens is critical to monitor and combat viral infections. Here, we demonstrate a plasmonic coupling assay (PCA) using gold nanourchins (AuNUs) as labels for the colorimetric quantification of viruses. The antibody functionalized AuNUs allow for rapid and highly specific identification of viruses and provide strong color change for sensitive detection. Using respiratory syncytial virus (RSV) as a target, we demonstrate that the AuNU-based PCA achieves a detection limit of 1,402 PFU/mL (equivalent to 17 copies/μL) that is 3.1- and 5.7-times lower than the rod- and sphere-based counterparts, respectively. The improved detection sensitivity arises from the higher virus binding capability and stronger plasmonic coupling at long distances (∼10 nm) by AuNU probes. The detection can be performed with a portable smartphone-based spectrometer and is validated by testing RSV-spiked nasal swab clinical samples. Our study reports a rapid and sensitive approach for intact virus detection and provides a potential toolkit at the point of care.Graphical abstract
Predicting the efficacy of variant-modified COVID-19 vaccine boosters
Authors: Khoury David S. , Docken Steffen S. , Subbarao Kanta , Kent Stephen J. , Davenport Miles P. , Cromer Deborah 
Published: August 2022

AbstractAs a result of the emergence and circulation of antigenically distinct SARS-CoV-2 variants, a number of variant-modified COVID-19 vaccines have been developed. Here we perform a meta-analysis of the available data on neutralisation titres from clinical studies comparing booster vaccination with either the current ancestral-based vaccines or variant-modified vaccines. We then use this to predict the relative efficacies of these booster vaccines under different scenarios.
Progression and trajectory network of age-related functional impairments and their associations with mortality: a two-decade prospective study
Authors: Chen Hui , Wang Binghan , Lv Rongxia , Zhou Tianjing , Shen Jie , Song Huan , Xu Xiaolin , Ma Yuan , Yuan Changzheng 
Published: August 2022

ABSTRACTObjectiveTo characterize the progression and trajectory network of age-related functional impairments and assess their associations with mortality.DesignProspective cohort study.SettingThe Health and Retirement Study (HRS, 2000-2020).ParticipantsA total of 17 914 HRS participants aged from 51 to 90 years in 2000.Main outcome measureAge-related functional impairments including visual impairment, hearing impairment, cognitive impairment, physical frailty, restless sleep, and depression, all measured using structural questionnaires biennially or quadrennially. All-cause mortality was ascertained from multiple sources.ResultsDuring follow-up (median=12 years), the incidence rates of visual impairment (59.3 cases/1000 person years), hearing impairment (52.1 cases/1000 person years), physical frailty (31.7 cases/1000 person years), and cognitive impairment (42.5 cases/1000 person years) increased exponentially with age (P-trend <0.001), while those of restless sleep (75.6 cases/1000 person years) and depression (35.6 cases/1000 person years) increased relatively slowly. We detected bidirectional associations among all ARFIs (P <0.001). Overall, each additional ARFI was associated with 13% (11%-15%) higher risk of mortality, with independent associations observed for physical frailty (hazard ratio: 1.59, 95% confidence interval: 1.49-1.69), depression (1.38, 1.30-1.46), visual impairment (1.19, 1.13-1.26), and cognitive impairment (1.13, 1.06-1.21).ConclusionsARFIs were highly interconnected as a network and were associated with mortality, which highlighted the importance of integrated strategies to monitor and manage the ARFIs to achieve healthy longevity.SUMMARY BOXESWHAT IS ALREADY KNOWN ON THIS TOPICAging is characterized by changes in multiple functions, such as visual, hearing, and cognitive impairments.Specific age-related functional impairments are associated bidirectionally.WHAT THIS STUDY ADDSIn a prospective study, the incidence rates of visual impairment, hearing impairment, physical frailty, and cognitive impairment increased exponentially as age increased, while incidence rates of restless sleep and depression increased relatively slowly with age.The six ARFIs are bidirectionally related to each other and predicted higher risk of mortality in a dose-response manner, with independent associations observed for visual impairment, cognitive impairment, physical frailty, and depression.