bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stay or go? Outcomes of lower limb arthroplasty in patients travelling away from home for surgery: A cross-sectional analysis of the AOANJRR comparing patient residence and hospital remoteness
Authors: Scholes Corey , Holder Carl , Vertullo Christopher , Broadhead Matthew 
Published: August 2024

AbstractPurposeThe relationship between remoteness of patient residence and post-surgical outcomes, such as early implant revision, has yet to be examined. The aim of this study was to assess whether the incidence of all-cause revision at up to 2 years following primary hip or knee total joint arthroplasty varies with the remoteness of a person’s place of residence at the time of the primary procedure.MethodsAn analysis was performed of data from the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) from 1 Sept 1999 to 31 Dec 2022. The Modified Monash Model (2015) of remoteness classification was used to categorise patient residence and hospital location into metro-regional (MM 1-2) and rural-remote (MM 3-7). All-cause revision within the two-year period after surgery for primary total knee arthroplasty (TKA) and primary total hip arthroplasty (THA) for osteoarthritis as the primary diagnosis was selected as the primary outcome. A directed-acyclic graph approach was used to prioritise covariates for inclusion in a Cox proportional hazards regression model. Cumulative percent revision (CPR) rates with 95% confidence intervals was reported with hazard ratios between subgroups of residential and hospital remoteness.ResultsThe two-year CPR for primary TKA ranged from 1.8% (95% CI 1.7 - 1.9) to 2.2% (95% CI 1.8 - 2.7). Patients residing in rural-remote areas who travelled to a metro-regional hospital displayed a significantly higher rate of revision following TKA compared to patients that were treated at a rural-remote hospital (HR: 1.11, 95% CI 1.05 - 1.18, P = 0.001) within two-year follow-up of the primary procedure. Patients residing in rural-remote areas that stayed in these areas for their operation displayed a significantly reduced revision rate compared to metro-regional patients that stayed in-area for their joint replacement (HR=0.90, 95%CI 0.85 - 0.95, P <0.001). Infection was the dominant reason for TKA revision for patients in the follow-up period. No discernible differences in revision risk were observed between patient and hospital combinations for primary total hip replacement.ConclusionsTravel distance, but not remoteness of a patient’s place of residence may be associated with cumulative risk of early revision (within 2 years) of primary TKA, particularly in regional/remote patients travelling out of area, but not for patients undergoing THA. Further work linking service utilisation prior to a revision procedure is required to clarify whether differences in revision between remoteness and travel distances are due to variability in the clinical threshold for offering revision arthroplasty between regional and metropolitan surgeons or improved outcomes of the primary procedure.
Multi-trait and multi-ancestry genetic analysis of comorbid lung diseases and traits improves genetic discovery and polygenic risk prediction
Authors: He Yixuan , Lu Wenhan , Jee Yon Ho , Wang Ying , Tsuo Kristin , Qian David C. , Diao James A. , Huang Hailiang , Patel Chirag J. , Byun Jinyoung , Pasaniuc Bogdan , Atkinson Elizabeth G. , Amos Christopher I. , Moll Matthew , Cho Michael H. , Martin Alicia R. 
Published: August 2024

AbstractWhile respiratory diseases such as COPD and asthma share many risk factors, most studies investigate them in insolation and in predominantly European ancestry populations. Here, we conducted the most powerful multi-trait and -ancestry genetic analysis of respiratory diseases and auxiliary traits to date. Our approach improves the power of genetic discovery across traits and ancestries, identifying 44 novel loci associated with lung function in individuals of East Asian ancestry. Using these results, we developed PRSxtra (cross TRait and Ancestry), a multi-trait and -ancestry polygenic risk score approach that leverages shared components of heritable risk via pleiotropic effects. PRSxtra significantly improved the prediction of asthma, COPD, and lung cancer compared to trait- and ancestry-matched PRS in a multi-ancestry cohort from the All of Us Research Program, especially in diverse populations. PRSxtra identified individuals in the top decile with over four-fold odds of asthma and COPD compared to the first decile. Our results present a new framework for multi-trait and -ancestry studies of respiratory diseases to improve genetic discovery and polygenic prediction.
Repetitive neonatal pain increases spinal cord DNA methylation of the µ-opioid receptor
Authors: Baudat Mathilde , Joosten Elbert A.J , Simons Sinno H.P. , van den Hove Daniël L.A. , Riemens Renzo J.M. 
Published: August 2024

AbstractRepetitive neonatal painful procedures experienced in the neonatal intensive care unit (NICU) are known to alter the development of the nociceptive system and have long-lasting consequences, notably lower post-operative µ-opioid receptor levels in the spinal cord. Given the influence of the NICU on the epigenome, the present study hypothesized that neonatal procedural pain alters the DNA methylation status of the opioid receptor mu 1 encoding gene (Mor-1) in the spinal cord and dorsal root ganglions (DRGs). To this end, the needle prick model of repetitive neonatal pain was used, and methylation ofMor-1promotor was assessed in the spinal cord and the DRG using bisulfite pyrosequencing. Our findings demonstrated that neonatal procedural pain increased spinal cordMor-1promotor DNA methylation in the ipsilateral side as compared to the contralateral side, an effect that was not observed in the control animals, nor in the DRG. We also identified a behaviorally-associated CpG site following neonatal needle pricks. This study is the first to highlight a localized and noxious-stimuli-dependent effect of repetitive neonatal procedural pain onMor-1promotor methylation and emphasizes the need to explore the effects of repetitive neonatal procedural pain on the epigenome.ImpactThis study reveals that repetitive neonatal procedural pain increases DNA methylation of the Mor-1 promoter in the spinal cord of neonatal rats.This is the first study to identify an effect of neonatal procedural pain on DNA methylation, emphasizing the critical need for further investigation into the epigenetic consequences of neonatal procedural pain.These insights could lead to better management and treatment strategies to mitigate the long-term impacts of early pain exposure on neurodevelopment and behavior.
Extensive exploration of structure activity relationships for the SARS-CoV-2 macrodomain from shape-based fragment merging and active learning
Authors: Correy Galen J. , Rachman Moira , Togo Takaya , Gahbauer Stefan , Doruk Yagmur U. , Stevens Maisie , Jaishankar Priyadarshini , Kelley Brian , Goldman Brian , Schmidt Molly , Kramer Trevor , Ashworth Alan , Riley Patrick , Shoichet Brian K. , Renslo Adam R. , Walters W. Patrick , Fraser James S. 
Published: August 2024

AbstractThe macrodomain contained in the SARS-CoV-2 non-structural protein 3 (NSP3) is required for viral pathogenesis and lethality. Inhibitors that block the macrodomain could be a new therapeutic strategy for viral suppression. We previously performed a large-scale X-ray crystallography-based fragment screen and discovered a sub-micromolar inhibitor by fragment linking. However, this carboxylic acid-containing lead had poor membrane permeability and other liabilities that made optimization difficult. Here, we developed a shape- based virtual screening pipeline - FrankenROCS - to identify new macrodomain inhibitors using fragment X-ray crystal structures. We used FrankenROCS to exhaustively screen the Enamine high-throughput screening (HTS) collection of 2.1 million compounds and selected 39 compounds for testing, with the most potent compound having an IC50value equal to 130 μM. We then paired FrankenROCS with an active learning algorithm (Thompson sampling) to efficiently search the Enamine REAL database of 22 billion molecules, testing 32 compounds with the most potent having an IC50equal to 220 μM. Further optimization led to analogs with IC50values better than 10 μM, with X-ray crystal structures revealing diverse binding modes despite conserved chemical features. These analogs represent a new lead series with improved membrane permeability that is poised for optimization. In addition, the collection of 137 X-ray crystal structures with associated binding data will serve as a resource for the development of structure-based drug discovery methods. FrankenROCS may be a scalable method for fragment linking to exploit ever-growing synthesis-on- demand libraries.
AcrIF11 is a potent CRISPR-specific ADP-ribosyltransferase encoded by phage and plasmid
Authors: Chen Daphne F. , Roe Leah T. , Li Yuping , Borges Adair L. , Zhang Jenny Y. , Babbar Palak , Maji Sourobh , Stevens Maisie G.V. , Correy Galen J. , Diolaiti Morgan E. , Smith Dominique H. , Ashworth Alan , Stroud Robert M. , Kelly Mark J.S. , Bondy-Denomy Joseph , Fraser James S. 
Published: August 2024

AbstractPhage-encoded anti-CRISPR (Acr) proteins inhibit CRISPR-Cas systems to allow phage replication and lysogeny maintenance. Most of the Acrs characterized to date are stable stoichiometric inhibitors, and while enzymatic Acrs have been characterized biochemically, little is known about their potency, specificity, and reversibility. Here, we examine AcrIF11, a widespread phage and plasmid-encoded ADP-ribosyltransferase (ART) that inhibits the Type I-F CRISPR-Cas system. We present an NMR structure of an AcrIF11 homolog that reveals chemical shift perturbations consistent with NAD (cofactor) binding. In experiments that model both lytic phage replication and MGE/lysogen stability under high targeting pressure, AcrIF11 is a highly potent CRISPR-Cas inhibitor and more robust to Cas protein level fluctuations than stoichiometric inhibitors. Furthermore, we demonstrate that AcrIF11 is remarkably specific, predominantly ADP-ribosylating Csy1 when expressed inP. aeruginosa. Given the reversible nature of ADP-ribosylation, we hypothesized that ADPr eraser enzymes (macrodomains) could remove ADPr from Csy1, a potential limitation of PTM-based CRISPR inhibition. We demonstrate that diverse macrodomains can indeed remove the modification from Csy1 inP. aeruginosalysate. Together, these experiments connect thein vitroobservations of AcrIF11’s enzymatic activity to its potent and specific effectsin vivo, clarifying the advantages and drawbacks of enzymatic Acrs in the evolutionary arms race between phages and bacteria.
COA5 has an essential role in the early stage of mitochondrial complex IV assembly
Authors: Tang Jia Xin , Cabrera-Orefice Alfredo , Meisterknecht Jana , Taylor Lucie S. , Monteuuis Geoffray , Stensland Maria Ekman , Szczepanek Adam , Stals Karen , Davison James , He Langping , Hopton Sila , Nyman Tuula A. , Jackson Christopher B. , Pyle Angela , Winter Monika , Wittig Ilka , Taylor Robert W. 
Published: August 2024

AbstractPathogenic variants in cytochromecoxidase assembly factor 5 (COA5), a proposed complex IV (CIV) assembly factor, have been shown to cause clinical mitochondrial disease with two siblings affected by neonatal hypertrophic cardiomyopathy manifesting a rare, homozygousCOA5missense variant (NM_001008215.3: c.157G>C, p.Ala53Pro). The most striking observation in the affected individuals was an isolated impairment in the early stage of mitochondrial CIV assembly. In this study, we report an unrelated family in who we have identified the sameCOA5variant with patient-derived fibroblasts and skeletal muscle biopsies replicating an isolated CIV deficiency. A CRISPR/Cas9-edited homozygousCOA5knockout U2OS cell line with similar biochemical profile was generated to interrogate the functional role of the human COA5 protein. Mitochondrial complexome profiling pinpointed a role for COA5 in early CIV assembly, more specifically, its involvement in the stage between MTCO1 maturation and the incorporation of MTCO2. We therefore propose that the COA5 protein plays an essential role for the biogenesis of MTCO2 and its integration into the early CIV assembly intermediate for downstream assembly of the functional holocomplex.
Visuomotor paired associative stimulation for post-stroke hand motor impairments
Authors: Picardi Michela , Guidali Giacomo , Caronni Antonio , Rota Viviana , Corbo Massimo , Bolognini Nadia 
Published: August 2024

ABSTRACTObjectivesWe assess the effectiveness of a visuomotorpaired associative stimulation(vm-PAS) protocol targeting the Action Observation Network (AON) in patients with chronic post-stroke upper-limb hemiparesis. Vm-PAS consisted of hand-grasping action observation stimuli repeatedly paired with transcranial magnetic stimulation (TMS) pulses over the ipsilesional primary motor cortex (M1).MethodsFifteen post-stroke patients underwent a session of the vm-PAS and, as a control, of the standard excitatory PAS (M1-PAS), during which slow-rate electrical stimulation of the paretic limb was paired with M1-TMS. Before and after each PAS, we assessed corticospinal excitability (CSE), short-interval intracortical inhibition (SICI), and paretic wrist’s voluntary movements.ResultsThe two protocols induce distinct muscle-specific CSE enhancements: vm-PAS increases motor- evoked potentials (MEPs) recorded from the pareticfirst dorsal interosseousmuscle. Conversely, M1-PAS increases MEPs recorded from the electrically stimulatedextensor carpi radialismuscle. Vm-PAS efficacy correlates with hemiparesis chronicity: the higher the time elapsed since the stroke, the greater vm-PAS effects on CSE. Neither protocol affected SICI or wrist movements.ConclusionVm-PAS leads to muscle-specific enhancements of CSE in post-stroke patients, highlighting its potential for driving post-stroke motor recovery.SignificanceOur findings show the efficacy of a cross-modal PAS protocol targeting the AON in an injured motor system.
Break-induced replication drives large-scale genomic amplifications in cancer cells
Authors: Benamar Mouadh , Eki Rebeka , Du Kang-Ping , Abbas Tarek 
Published: August 2024

AbstractDNA double-strand breaks (DSBs) are highly toxic lesions that underly the efficacy of ionizing radiation (IR) and a large number of cytotoxic chemotherapies1–3. Yet, abnormal repair of DSBs is associated with genomic instability and may contribute to cancer heterogeneity and tumour evolution. Here, we show that DSBs induced by IR, by DSB-inducing chemotherapeutics, or by the expression of a rare-cutting restriction endonuclease induce large-scale genomic amplification in human cancer cells. Importantly, the extent of DSB-induced genomic amplification (DIGA) in a panel of melanoma cell lines correlated with the degree of cytotoxicity elicited by IR, suggesting that DIGA contributes significantly to DSB-induced cancer cell lethality. DIGA, which is mediated through conservative DNA synthesis, does not require origin re-licensing, and is enhanced by the depletion or deletion of the methyltransferases SET8 and SUV4-20H1, which function sequentially to mono- and di-methylate histone H4 lysine 20 (H4K20) at DSBs to facilitate the recruitment of 53BP1-RIF1 and its downstream effector shieldin complex to DSBs to prevent hyper-resection4–11. Consistently, DIGA was enhanced in cells lacking 53BP1 or RIF1, or in cells that lacked components of the shieldin complex or of other factors that help recruit 53BP1 to DSBs. Mechanistically, DIGA requires MRE11/CtIP and EXO1, factors that promote resection and hyper-resection at DSBs, and is dependent on the catalytic activity of the RAD51 recombinase. Furthermore, deletion or depletion of POLD3, POLD4, or RAD52, proteins involved in break-induced replication (BIR), significantly inhibited DIGA, suggesting that DIGA is mediated through a RAD51-dependent BIR-like process. DIGA induction was maximal if the cells encountered DSBs in early and mid S-phase, whereas cells competent for homologous recombination (in late S and G2) exhibited less DIGA induction. We propose that unshielded, hyper-resected ends of DSBs may nucleate a replication-like intermediate that enables cytotoxic long-range genomic DNA amplification mediated through BIR.
Applying Prospective Tree-Temporal Scan Statistics to Genomic Surveillance Data to Detect Emerging SARS-CoV-2 Variants and Salmonellosis Clusters in New York City
Authors: Greene Sharon K. , Latash Julia , Peterson Eric R. , Levin-Rector Alison , Luoma Elizabeth , Wang Jade C. , Bernard Kevin , Olsen Aaron , Li Lan , Waechter HaeNa , Mattias Aria , Rohrer Rebecca , Kulldorff Martin 
Published: August 2024

AbstractGenomic surveillance data are used to detect communicable disease clusters, typically by applying rule-based signaling criteria, which can be arbitrary. We applied the prospective tree-temporal scan statistic (TreeScan) to genomic data with a hierarchical nomenclature to search for recent case increases at any granularity, from large phylogenetic branches to small groups of indistinguishable isolates. Using COVID-19 and salmonellosis cases diagnosed among New York City (NYC) residents and reported to the NYC Health Department, we conducted weekly analyses to detect emerging SARS-CoV-2 variants based on Pango lineages and clusters ofSalmonellaisolates based on allele codes. The SARS-CoV-2 Omicron subvariant EG.5.1 first signaled as locally emerging on June 22, 2023, seven weeks before the World Health Organization designated it as a variant of interest. During one year of salmonellosis analyses, TreeScan detected fifteen credible clusters worth investigating for common exposures and two data quality issues for correction. A challenge was maintaining timely and specific lineage assignments, and a limitation was that genetic distances between tree nodes were not considered. By automatically sifting through genomic data and generating ranked shortlists of nodes with statistically unusual recent case increases, TreeScan assisted in detecting emerging communicable disease clusters and in prioritizing them for investigation.
JYNNEOS vaccination induced short-lived neutralizing antibody responses to monkeypox virus in naïve individuals
Authors: Phipps Kara , Yates Jennifer , Machowski Jessica , Bialosuknia Sean , Hunt Danielle , DuPuis Alan , Payne Anne , Lee William , McDonough Kathleen A. 
Published: August 2024

AbstractCurrent studies of the JYNNEOS-induced neutralizing antibody response to monkeypox virus (MPXV) are limited by either short-term durability data, quantification in an endemic population, or lack of an infectious MPXV neutralization assay. We used plaque reduction neutralization test (PRNT) with authentic MPXV and vaccinia viruse (VACV) to assess antibody responses over twelve months of eight donors vaccinated with two doses of JYNNEOS. One donor previously received the ACAM2000 vaccine; seven donors were smallpox-vaccine naïve. The IgG response of the donors to VACV (L1R, B5R, and A33R) and MPXV (E8L, H3L, A35R) antigens and PRNT titers to both viruses peaked at eight weeks post-vaccination and waned thereafter in naïve donors. MPXV PRNT titers were especially low; no naïve donors produced a detectable PRNT90 titer. Our results suggest the MPXV humoral response produced by JYNNEOS is limited in naïve donors and invites further investigation into current mpox vaccination strategies and correlates of protection.
CAR-based therapeutic targets in pediatric high-grade glioma
Authors: Griffioen Myrthe M.M.R. , Metselaar Dennis S. 
Published: August 2024

AbstractHigh-grade glioma (HGG) patients have a dismal prognosis, due to a lack of effective treatments. In order to change the fate of HGG patients and decrease the current treatment-related side effects, therapy focus has shifted in the past years to immunotherapy, such as chimeric antigen receptor (CAR)-based treatments. Recent developments in CAR-based therapy show promising results in adult glioma patients, and the first clinical trials for pediatric patients with HGG are in progress. However, there are significant differences between pediatric HGG (pHGG) and their adult counterparts, including the composition of the tumor immune microenvironment (TIME), which strongly influences CAR treatment responsiveness. Therefore, we here provide a systematic overview of CAR-based therapeutic targets in pHGG entities, focusing on clinical trials and preclinical research, and comparing them to adult glioma. We conclude that target expression, TIME and CAR treatment-related toxicities vary across pHGG entities and differ from adult HGG, which suggests the need for more tailored immunotherapeutic CAR approaches in pHGG. Overall, we provide a target roadmap for future development of CAR-based therapeutic strategies for pediatric HGG patients, who are in desperate need for novel therapies.Graphical abstractThe number of potential CAR-based therapeutic targets for glioblastoma and pHGG.CAR: Chimeric antigen receptor; pHGG: pediatric high-grade glioma; DHG: H3 G34-mutant diffuse hemispheric glioma; DMG: H3 K27-altered diffuse midline glioma; PFA: posterior fossa ependymoma type A. Image was created inBiorender.com.
SLC30A8 rare variant modify contribution of common genetic and lifestyle factors toward type 2 diabetes
Authors: Jang Hye-Mi , Hwang Mi Yeong , Park Yi Seul , Kim Bong-Jo , Kim Young Jin 
Published: August 2024

AbstractThis study aimed to investigate the modifying effects of rare genetic variants on the risk of type 2 diabetes in the context of common genetic and lifestyle factors. We conducted a comprehensive analysis of genetic and lifestyle factors associated with type 2 diabetes in a cohort of 146,284 Korean individuals. Among them, 4,603 individuals developed type 2 diabetes during the follow-up period of up to 18 years. We calculated a polygenic risk score (PRS) for type 2 diabetes and identified carriers of the rare allele I349F at SLC30A8. A Healthy Lifestyle Score (HLS) was also derived from physical activity, obesity, smoking, diet, and sodium intake levels. Using Cox proportional hazards models, we analyzed how PRS, HLS, and I349F influenced type 2 diabetes incidence. Results showed that high PRS and poor lifestyle were associated with increased risk. Remarkably, I349F carriers exhibited a lower type 2 diabetes prevalence (5.4% compared to 11.7% in non-carriers) and reduced the impact of high PRS from 23.18% to 12.70%. This trend was consistent across different HLS categories, with I349F carriers displaying a lower risk of type 2 diabetes. The integration of common and rare genetic variants with lifestyle factors enhanced type 2 diabetes predictability in the Korean population. Our findings highlight the critical role of rare genetic variants in risk assessments and suggest that standard PRS and HLS metrics alone may be inadequate for predicting type 2 diabetes risk among carriers of such variants.Author summaryIn our study, we investigated how rare genetic variants affect the risk of developing type 2 diabetes, particularly when combined with common genetic and lifestyle factors. We analyzed data from over 146,000 Korean individuals, following their health outcomes for up to 18 years. During this time, 4,603 participants developed type 2 diabetes. We calculated a polygenic risk score (PRS) based on common genetic variants and examined lifestyle factors such as physical activity, diet, and smoking. We also identified individuals carrying a rare genetic variant (I349F) in the SLC30A8 gene, which appeared to have a protective effect against type 2 diabetes. Our findings show that individuals with high PRS and unhealthy lifestyles are at increased risk for the disease. However, those carrying the I349F variant had a significantly lower risk, even among those with high PRS and poor lifestyle habits. This suggests that rare genetic variants can play a crucial role, and that combining genetic and lifestyle factors provides a more accurate prediction of diabetes risk. Our work highlights the importance of including rare genetic variants in personalized risk assessments for type 2 diabetes.