bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early Initiation of Fast-Track Care for Persons Living with HIV Initiating Dolutegravir-Based Regimens during a Period of Severe Civil Unrest in Port-au-Prince, Haiti
Authors: Marc Jean Bernard , Pierre Samuel , Ducatel Othnia , Homeus Fabienne , Zion Abigail , Rivera Vanessa R. , Dorvil Nancy , Severe Patrice , Guiteau Colette , Rouzier Vanessa , Katz Ingrid T. , Duchatelier Carl Frederic , Louis Forestal Guyrlaine Pierre , Jean Josette , Bernadin Guirlaine , Dumont Emelyne Droit , Riche Rose Cardelle B. , Pape Jean William , Koenig Serena P 
Published: August 2024

ABSTRACTIntroductionDifferentiated service delivery (DSD) models have been widely implemented for patients who are established in HIV care. However, DSD has rarely been offered to those newly diagnosed with HIV. We conducted a study to assess the effectiveness of early fast-track care during the COVID-19 pandemic and a period of severe civil unrest at GHESKIO, in Haiti.MethodsWe conducted a pilot randomized trial among adults presenting with World Health Organization Stage 1 or 2 disease at HIV diagnosis to determine whether early fast-track care (at eight to 12 weeks after same-day HIV testing and ART initiation) was associated with superior outcomes, compared with standard care (deferred eligibility for fast-track care). All participants received tenofovir disoproxil fumarate/lamivudine/dolutegravir (TLD), and HIV-1 RNA <200 copies/mL was required prior to initiating fast-track care. The primary outcome was 48-week HIV-1 RNA <200 copies/mL, with intention-to-treat analysis.ResultsFrom December 13, 2020, to August 19, 2022, 247 participants were randomized; 2 met protocol-specified criteria for late exclusions, leaving a study population of 245 (standard: 116; early fast-track: 129). All participants initiated TLD on the day of HIV diagnosis. In the standard group, 2 (1.7%) died, 106 (91.4%) were retained in care, and 78 (67.2%) received 48-week viral load testing; 66 (84.6% of those tested; 56.9% of those randomized) had HIV-1 RNA <200 copies/mL. In the early fast-track group, 1 (0.8%) died, 112 (86.8%) were retained in care, and 87 (67.4%) received 48-week viral load testing; 79 (90.8% of those tested; 61.2% of those randomized) had 48-week HIV-1 RNA <200 copies/mL. There was no difference in primary outcome (48-week HIV-1 RNA <200 copies/mL) between the early fast-track and standard groups (61.2% vs. 56.9%; RD: 0.043; 95% CI: -0.080, 0.167).ConclusionsThe provision of fast-track care as early as 8 weeks after TLD initiation is associated with high levels of retention in care and viral suppression in a setting of severe civil unrest, with no difference in outcome compared to deferred eligibility for fast-track care. Completion of 48-week viral load testing was suboptimal; low-cost point-of-care testing capacity may facilitate completion of viral load testing in this setting.
Analysis of Stochastic COVID-19 and Hepatitis B Co-infection Model with Brownian and Lévy Noise
Authors: Pobbi Michael A. , Moore Stephen E. 
Published: August 2024

AbstractIn this article, we formulate and analyze a mathematical model for the coinfection of HBV and COVID-19 that incorporates the effects of Brownian and Lévi noise. We studied the dynamics and effects of these diseases in a given population. First, we establish the basic reproduction number of the disease-free equilibrium point of the stochastic model by means of a suitable Lyapunov function. Additionally, we provided sufficient conditions for the stability of the model around the disease-free equilibrium points. Finally, using a few simulation studies, we demonstrate our theoretical results. In particularly, we derived threshold values for HBV only, COVID-19 only,, and coinfectionfor the stochastic model around disease-free equilibrium point. Next, the conditions for stability in the stochastic sense for HBV only, COVID-19 only submodels, and the full model are established. Furthermore, we devote our concentrated attention to sufficient conditions for extinction and persistence using each of these reproductive numbers. Finally, by using the Euler–Murayama scheme, we demonstrate the dynamics of the coinfection by means of numerical simulations.
An atlas of genetic effects on the monocyte methylome across European and African populations
Authors: Zhang Wanheng , Zhang Xiao , Qiu Chuan , Zhang Zichen , Su Kuan-Jui , Luo Zhe , Liu Minghui , Zhao Bingxin , Wu Lang , Tian Qing , Shen Hui , Wu Chong , Deng Hong-Wen 
Published: August 2024

AbstractElucidating the genetic architecture of DNA methylation is crucial for decoding complex disease etiology. However, current epigenomic studies are often limited by incomplete methylation coverage and heterogeneous tissue samples. Here, we present the first comprehensive, multi-ancestry human methylome atlas of purified human monocytes, generated through integrated whole-genome bisulfite sequencing and whole-genome sequencing from 298 European Americans (EA) and 160 African Americans (AA). By analyzing over 25 million methylation sites, we identified 1,383,250 and 1,721,167 methylation quantitative trait loci (meQTLs) incis-regions for EA and AA populations, respectively, revealing both shared (880,108 sites) and population-specific regulatory patterns. Furthermore, we developed population-specific DNAm imputation models, enabling methylome-wide association studies (MWAS) for 1,976,046 and 2,657,581 methylation sites in EA and AA, respectively. These models were validated through multi-ancestry analysis of 41 complex traits from the Million Veteran Program. The identified meQTLs, MWAS models, and data resources are freely available atwww.gcbhub.organdhttps://osf.io/gct57/.
Structural variants linked to Alzheimer’s Disease and other common age-related clinical and neuropathologic traits
Authors: Vialle Ricardo A , de Paiva Lopes Katia , Li Yan , Ng Bernard , Schneider Julie A , Buchman Aron S , Wang Yanling , Farfel Jose M , Barnes Lisa L , Wingo Aliza P , Wingo Thomas S , Seyfried Nicholas T , De Jager Philip L , Gaiteri Chris , Tasaki Shinya , Bennett David A 
Published: August 2024

ABSTRACTAdvances have led to a greater understanding of the genetics of Alzheimer’s Disease (AD). However, the gap between the predicted and observed genetic heritability estimates when using single nucleotide polymorphisms (SNPs) and small indel data remains. Large genomic rearrangements, known as structural variants (SVs), have the potential to account for this missing genetic heritability. By leveraging data from two ongoing cohort studies of aging and dementia, the Religious Orders Study and Rush Memory and Aging Project (ROS/MAP), we performed genome-wide association analysis testing around 20,000 common SVs from 1,088 participants with whole genome sequencing (WGS) data. A range of Alzheimer’s Disease and Related Disorders (AD/ADRD) clinical and pathologic traits were examined. Given the limited sample size, no genome-wide significant association was found, but we mapped SVs across 81 AD risk loci and discovered 22 SVs in linkage disequilibrium (LD) with GWAS lead variants and directly associated with AD/ADRD phenotypes (nominalP< 0.05). The strongest association was a deletion of anAluelement in the 3’UTR of theTMEM106Bgene. This SV was in high LD with the respective AD GWAS locus and was associated with multiple AD/ADRD phenotypes, including tangle density, TDP-43, and cognitive resilience. The deletion of this element was also linked to lower TMEM106B protein abundance. We also found a 22 kb deletion associated with depression in ROSMAP and bearing similar association patterns as AD GWAS SNPs at theIQCKlocus. In addition, genome-wide scans allowed the identification of 7 SVs, with no LD with SNPs and nominally associated with AD/ADRD traits. This result suggests potentially new ADRD risk loci not discoverable using SNP data. Among these findings, we highlight a 5.6 kb duplication of coding regions of the geneC1orf186at chromosome 1 associated with indices of cognitive impairment, decline, and resilience. While further replication in independent datasets is needed to validate these findings, our results support the potential roles of common structural variations in the pathogenesis of AD/ADRD.
How does policy modelling work in practice? A global analysis on the use of epidemiological modelling in health crises
Authors: Hadley Liza , Rich Caylyn , Tasker Alex , Restif Olivier , Funk Sebastian 
Published: August 2024

AbstractThis study examines the use of epidemiological modelling to policymakers in Covid-19 outbreak response. Prior to Covid-19, there was little readiness of global health systems and many science-policy networks were assembled ad-hoc. Moreover, in the field of epidemiological modelling, one with significant sudden influence, there is still no international guidance or standard of practice on how modelled evidence should guide policy during major health crises. Here we use a multi-country case study on the use of epidemiological modelling in emergency Covid-19 response, to examine the effective organisation of crisis science-and-policy at different scales. We investigate Covid-19 modelling-policy systems and practices in 13 different countries, spanning all six UN geographic regions. Data collection takes the form of expert interviews with a range of national decision makers, scientific advisors, and modellers. We examine the use and organisation of modelling in health policy on a global scale, introducing a classification framework for modelling-policy systems and recommendations for future practice. Full analysis and interpretation of the breadth of interview responses is presented, providing evidence for the current and future use of modelling in health crises. We argue that long-standing relationships are fundamental to effective science-to-policy pathways and outline activities that scientists and policy actors could action in their own countries. This article serves as a first evidence base for the current use of modelling in a recent major health crisis.
Selecting sites for strategic surveillance of zoonotic pathogens: a case study in Panamá
Authors: Cobos Marlon E. , Dunnum Jonathan L. , Armién Blas , González Publio , Juárez Enós , Salazar Jacqueline R. , Cook Joseph A. , Colella Jocelyn P. 
Published: August 2024

AbstractSurveillance and monitoring of zoonotic pathogens is key to identifying and mitigating emerging public health threats. Surveillance is often designed to be taxonomically targeted or systematically dispersed across geography, however, those approaches may not represent the breadth of environments inhabited by a host, vector, or pathogen, leaving significant gaps in our understanding of pathogen dynamics in their natural reservoirs and environments. As a case study on the design of pathogen surveillance programs, we assess how well 20 years of small mammal surveys in Panamá have sampled available environments and propose a multistep approach to selecting survey localities in the future. We use >8,000 georeferenced mammal specimen records, collected as part of a long-term hantavirus surveillance program, to test the completeness of country-wide environmental sampling. Despite 20 years of surveillance, our analyses identified a few key environmental sampling gaps. To refine surveillance strategies, we selected a series of core historically sampled localities, supplemented with additional environmentally distinct sites to more completely represent Panama’s environments. Based on lessons learned through decades of surveillance, we propose a series of recommendations to improve strategic sampling for zoonotic pathogen surveillance.
Aerolysin nanopore structure revealed at high resolution in lipid environment
Authors: Anton Jana S. , Iacovache Ioan , Juarez Juan F. Bada , Abriata Luciano A. , Perrin Louis W. , Cao Chan , Marcaida Maria J. , Zuber Benoit , Peraro Matteo Dal 
Published: August 2024

AbstractAerolysin is a β-pore-forming toxin produced by mostAeromonasbacteria which has attracted large attention in the field of nanopore sensing due to its narrow and charged pore lumen. Structurally similar proteins, belonging to the aerolysin-like family, are present throughout all kingdoms of life, but very few of them have been structurally characterized in a lipid environment. Here we present the first high-resolution atomic cryo-EM structures of aerolysin pre-pore and pore in a membrane-like environment. These structures allow the identification of key interactions, which are relevant for the pore formation and for positioning the pore barrel into the membrane with the anchoring β-turn motif now finally observed. Moreover, we elucidate at high resolution the architecture of key mutations and precisely identify four constriction rings in the pore lumen that are highly relevant for nanopore sensing experiments.
Identification ofCNTN2as a genetic modifier of PIGA-CDG through pedigree analysis of a family with incomplete penetrance and functional testing inDrosophila
Authors: Thorpe Holly J. , Pedersen Brent S. , Dietze Miranda , Link Nichole , Quinlan Aaron R. , Bonkowsky Joshua L. , Thomas Ashley , Chow Clement Y. 
Published: August 2024

AbstractLoss of function mutations in the X-linkedPIGAgene lead to PIGA-CDG, an ultra-rare congenital disorder of glycosylation (CDG), typically presenting with seizures, hypotonia, and neurodevelopmental delay. We identified two brothers (probands) with PIGA-CDG, presenting with epilepsy and mild developmental delay. Both probands carryPIGAS132C, an ultra-rare variant predicted to be damaging. Strikingly, the maternal grandfather and a great-uncle also carryPIGAS132C, but neither presents with symptoms associated with PIGA-CDG. We hypothesized genetic modifiers may contribute to this reduced penetrance. Using whole genome sequencing and pedigree analysis, we identified possible susceptibility variants found in the probands and not in carriers and possible protective variants found in the carriers and not in the probands. Candidate variants included heterozygous, damaging variants in three genes also involved directly in GPI-anchor biosynthesis and a few genes involved in other glycosylation pathways or encoding GPI-anchored proteins. We functionally tested the predicted modifiers using aDrosophilaeye-based model of PIGA-CDG. We found that loss ofCNTN2, a predicted protective modifier, rescues loss ofPIGAinDrosophilaeye-based model, like what we predict in the family. Further testing found that loss ofCNTN2also rescues patient-relevant phenotypes, including seizures and climbing defects inDrosophilaneurological models of PIGA-CDG. By using pedigree information, genome sequencing, andin vivotesting, we identifiedCNTN2as a strong candidate modifier that could explain the incomplete penetrance in this family. Identifying and studying rare disease modifier genes in human pedigrees may lead to pathways and targets that may be developed into therapies.
Altering translation allowsE. colito overcome chemically stabilized G-quadruplexes
Authors: Cueny Rachel R , Voter Andrew F , McKenzie Aidan M , Morgenstern Marcel , Myers Kevin S , Place Michael M , Peters Jason M. , Coon Joshua J , Keck James L 
Published: August 2024

AbstractG-quadruplex (G4) structures can form in guanine-rich DNA or RNA and have been found to modulate cellular processes including replication, transcription, and translation. Many studies on the cellular roles of G4s have focused on eukaryotic systems, with far fewer probing bacterial G4s. Using a chemical-genetic approach, we identified genes inEscherichia colithat are important for growth in G4-stabilizing conditions. Reducing levels of elongation factor Tu or slowing translation elongation with chloramphenicol suppress the effects of G4 stabilization. In contrast, reducing expression of certain translation termination or ribosome recycling proteins is detrimental to growth in G4-stabilizing conditions. Proteomic and transcriptomic analyses demonstrate that ribosome assembly factors and other proteins involved in translation are less abundant in G4-stabilizing conditions. Our integrated systems approach allowed us to propose a model for how RNA G4s can present barriers toE. coligrowth and that reducing the rate of translation can compensate for G4-related stress.
Phosphate-dependent nuclear export via a novel NES class recognized by exportin Msn5
Authors: Fung Ho Yee Joyce , Mittal Sanraj R. , Niesman Ashley B , Jiou Jenny , Shakya Binita , Yoshizawa Takuya , Cansizoglu Ahmet E , Rout Michael P. , Chook Yuh Min 
Published: August 2024

SummaryGene expression in response to environmental stimuli is dependent on nuclear localization of key signaling components, which can be tightly regulated by phosphorylation. This is exemplified by the phosphate-sensing transcription factor Pho4, which requires phosphorylation for nuclear export by the yeast exportin Msn5. Unlike the traditional hydrophobic nuclear export signal (NES) utilized by the Exportin-1/XPO1 system, cryogenic-electron microscopy structures reveal that Pho4 presents a novel, phosphorylated 35-residue NES that interacts with the concave surface of Msn5 through two Pho4 phospho-serines that align with two Msn5 basic patches, unveiling a previously unknown mechanism of phosphate-specific recognition. Furthermore, the discovery that unliganded Msn5 is autoinhibited explains the positive cooperativity of Pho4/Ran-binding and proposes a mechanism for Pho4’s release in the cytoplasm. These findings advance our understanding of the diversity of signals that drive nuclear export and how cargo phosphorylation is crucial in regulating nuclear transport and controlling cellular signaling pathways.
Spontaneous calcium transients in hair cell stereocilia
Authors: Hussain Saman , Sedlacek Miloslav , Cui Runjia , Zhang-Hooks Wendy , Bergles Dwight , Bum-Shin Jung , Kindt Katie S. , Kachar Bechara 
Published: August 2024

AbstractThe hair bundle of auditory and vestibular hair cells converts mechanical stimuli into electrical signals through mechanoelectrical transduction (MET). The MET apparatus is built around a tip link that connects neighboring stereocilia that are aligned in the direction of mechanosensitivity of the hair bundle. Upon stimulation, the MET channel complex responds to changes in tip-link tension and allows a cation influx into the cell. Ca2+influx in stereocilia has been used as a signature of MET activity. Using genetically encoded Ca2+sensors (GCaMP3, GCaMP6s) and high-performance fluorescence confocal microscopy, we detect spontaneous Ca2+transients in individual stereocilia in developing and fully formed hair bundles. We demonstrate that this activity is abolished by MET channel blockers and thus likely originates from putative MET channels. We observe Ca2+transients in the stereocilia of mice in tissue explants as well asin vivoin zebrafish hair cells, indicating this activity is functionally conserved. Within stereocilia, the origin of Ca2+transients is not limited to the canonical MET site at the stereocilia tip but is also present along the stereocilia length. Remarkably, we also observe these Ca2+transients in the microvilli-like structures on the hair cell surface in the early stages of bundle development, prior to the onset of MET. Ca2+transients are also present in the tallest rows of stereocilia in auditory hair cells, structures not traditionally thought to contain MET channels. We hypothesize that this newly described activity may reflect stochastic and spontaneous MET channel opening. Localization of these transients to other regions of the stereocilia indicates the presence of a pool of channels or channel precursors. Our work provides insights into MET channel assembly, maturation, function, and turnover.
Addressing the problem of lysine glycation prediction in proteins via Recurrent Neural Networks
Authors: Que-Salinas Ulices , Martinez-Peon Dulce , Mendez Gerardo Maximiliano , Argüelles-Lucho P. , Reyes-Figueroa Angel D. , Scheckhuber Christian Quintus 
Published: August 2024

AbstractA distinguishing feature of the metabolic disorder diabetes involves elevated damage to cellular proteins. The primary form of alteration arises from the chemical interaction between glycating agents such as methylglyoxal and proteinaceous arginine/lysine residues, causing structural and functional disruptions in target proteins. In this study, a curated version of the CPLM database to implement a recurrent neural network strategy for the classification of lysine glycation has been utilized. By using one physical property for the characterization of amino acids next to lysine sites (i.e., isoelectric point), it was possible to obtain a 59.6% accuracy for correctly predicting lysine glycation. When two properties were combined, i.e., mass and torsion angle, the accuracy increased to 59.9%. Overall, this approach can aid the task of narrowing down possible sites of lysine glycation in protein targets for further analysis.
Chromatin remodeler CHD4 establishes chromatin states required for ovarian reserve formation, maintenance, and germ cell survival
Authors: Munakata Yasuhisa , Hu Mengwen , Kitamura Yuka , Bynder Adam L. , Fritz Amelia S. , Schultz Richard M. , Namekawa Satoshi H. 
Published: August 2024

AbstractThe ovarian reserve defines female reproductive lifespan, which in humans spans decades due to the maintenance of meiotic arrest in non-growing oocytes (NGO) residing in primordial follicles. Unknown is how the chromatin state of NGOs is established to enable long-term maintenance of the ovarian reserve. Here, we show that a chromatin remodeler, CHD4, a member of the Nucleosome Remodeling and Deacetylase (NuRD) complex, establishes chromatin states required for formation and maintenance of the ovarian reserve. Conditional loss of CHD4 in perinatal mouse oocytes results in acute death of NGOs and depletion of the ovarian reserve. CHD4 establishes closed chromatin at regulatory elements of pro-apoptotic genes to prevent cell death and at specific genes required for meiotic prophase I to facilitate the transition from meiotic prophase I oocytes to meiotic arrested NGOs. In addition, CHD4 establishes closed chromatin at the regulatory elements of pro-apoptotic genes in male germ cells, allowing male germ cell survival. These results demonstrate a role for CHD4 in defining a chromatin state that ensures germ cell survival, thereby enabling the long-term maintenance of both female and male germ cells.