bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structure-based discovery of highly bioavailable, covalent, broad-spectrum coronavirus-MProinhibitors with potent in vivo efficacy
Authors: Detomasi Tyler C. , Degotte Gilles , Huang Sijie , Suryawanshi Rahul K. , Diallo Amy , Lizzadro Luca , Zaptero-Belinchón Francisco J. , Taha Taha Y. , Li Jiapeng , Richards Alicia , Hantz Eric R. , Alam Zain , Mantano Mauricio , McCavitt-Malvido Maria , Gumpena Rajesh , Partridge James R. , Correy Galen J. , Charvat Annemarie F. , Glenn Isabella S. , Rosecrans Julia , Revalde Jezrael L. , Anderson Dashiell , Hultquist Judd F. , Arkin Michelle R. , Neitz R. Jeffrey , Swaney Danielle L. , Krogan Nevan J. , Shoichet Brian K. , Verba Kliment A. , Ott Melanie , Renslo Adam R. , Craik Charles S. 
Published: January 2025

AbstractThe main protease (MPro) of SARS-CoV-2 is crucial for viral replication and is the target of nirmatrelvir (the active ingredient of Paxlovid) and ensitrelvir. The identification of new agents with differentiated pharmacokinetic and drug resistance profiles will increase therapeutic options for COVID-19 patients and bolster pandemic preparedness generally. Starting with a lead-like dihydrouracil chemotype from a large-library docking campaign, we improved MProinhibition >1,000-fold by engaging additional sub-sites in the MProactive site, most notably by employing a latent propargyl electrophile to engage the catalytic Cys145. Advanced leads from this series, includingAVI-4516andAVI-4773show pan-coronavirus antiviral activity in cells, very low clearance in mice, and forAVI-4773a rapid reduction in viral titers more than a million-fold after just three doses, more rapidly and effectively than the approved drugs, nirmatrelvir and ensitrelvir. BothAVI-4516andAVI-4773 are well distributed in mouse tissues, including brain, where concentrations ten or fifteen-thousand times the EC90, respectively, are observed eight hours after an oral dose. As exemplar of the series,AVI-4516shows minimal inhibition of major CYP isoforms and human cysteine and serine proteases, likely due to its latent–electrophilic warhead.AVI-4516also exhibits synergy in cellular infection models in combination with the RdRp inhibitor molnupiravir, while related analogs strongly inhibit nirmatrelvir-resistant MPromutant virus in cells. Thein vivoand antiviral properties of this new chemotype are differentiated from existing clinical and pre-clinical MProinhibitors, and will advance new therapeutic development against emerging SARS-CoV-2 variants and other coronaviruses.One sentence summaryThis manuscript describes the discovery of a new class of potent inhibitors of the SARS-CoV-2 major proteases (MPro) with a unique mechanism of inhibition, pan coronaviral activityin cellulo, exquisite selectivity vs. the human proteome, and exceptionalin vivoefficacy in SARS-CoV-2 infection models that surpasses that of currently approved agents.
Self-Reported Fitness (IFIS) in Adults with Type 2 Diabetes Mellitus: Validity and Associations with Cardiometabolic and Body Composition Outcomes
Authors: Herraiz-Adillo Ángel , Rådholm Karin , Iredahl Fredrik , Carlhäll Carl-Johan , Roemkens Nahuel , Forsgren Mikael , Leinhard Olof Dahlqvist , Lundberg Peter , Kechagias Stergios , Dahlström Nils , Nasr Patrik , Ekstedt Mattias , Henriksson Pontus 
Published: January 2025

ABSTRACTThis study aimed to assess the validity of the International Fitness Scale (IFIS) for evaluating cardiorespiratory fitness compared to the 6-minute walk test (criterion validity) and to examine their associations with cardiometabolic and body composition outcomes (construct validity) in adults with type 2 diabetes mellitus (T2DM). A cross-sectional analysis was conducted on 282 adults with T2DM (mean age 63.6 ± 8.1 years, 37.9% women). Self-reported fitness was assessed using IFIS, including overall fitness and cardiorespiratory fitness scores. Objective cardiorespiratory fitness was assessed using the 6-minute walk test. Associations with cardiometabolic (i.e., cardiovascular health score, metabolic dysfunction-associated steatotic liver disease [MASLD], high-sensitive C-reactive protein) and body composition outcomes (i.e., body mass index [BMI], visceral adipose tissue volume, and thigh fat-free muscle volume) were analyzed using ANCOVA and ROC curves, which were compared using DeLong tests.Both IFIS overall and cardiorespiratory fitness strongly correlated with performance in the 6-minute walk test (p<0.001 for ANCOVA models) and were associated with all cardiometabolic and body composition outcomes. ROC analyses showed at least similar predictive performance for IFIS overall and cardiorespiratory fitness scores compared to the 6-minute walk test. Furthermore, IFIS overall outperformed the 6-minute walk test for predicting poor cardiovascular health (AUCs: 0.678 [95% CI: 0.618-0.737] versus 0.586 [95% CI: 0.517-0.654]) as well as MASLD (AUCs: 0.630 [95% CI: 0.563-0.696] versus 0.519 [95% CI: 0.443-0.595]).This study proves that IFIS is a valid tool for assessing physical fitness in T2DM patients and that it conveys cardiometabolic and body composition outcomes at least as well as the 6-minute walk test.
Physical therapists’ perceptions of telerehabilitation for patients with musculoskeletal conditions in a post-pandemic world
Authors: McLaughlin Kevin , Minick Kate I. , Fritz Julie M. , Tannahill Nicole , Spar Anne , Feinsilver Marissa , Weber Matthew , Opoku Erika , Adams Jeff , Skolasky Richard L. 
Published: January 2025

AbstractObjectiveTo examine physical therapists’ experience providing telerehabilitation and their perceptions of telerehabilitation for patients with musculoskeletal conditions.MethodsSurvey of members of the Academy of Orthopaedic Physical TherapyResultsWe received 208 completed responses to our survey invitation. Most physical therapists responding to our survey reported using little to no telerehabilitation prior to the pandemic but increased use during the pandemic, followed by decreased use of telerehabilitation after the pandemic. Respondents reported using telerehabilitation slightly more after the pandemic than beforehand. Physical therapists reported that they believed they could deliver effective care using telerehabilitation but that it was not as effective as in-clinic care and they would prefer to use telerehabilitation as part of a hybrid care model versus using only telerehabilitation. Physical therapists suggested that certain patients were more likely than others to benefit from telerehabilitation and identified specific factors (e.g., patient preference, self-efficacy, postoperative status) that influenced whom they would consider to be most appropriate for telerehabilitation. “Patient issues with technology” was identified as the most common barrier to telerehabilitation use. Most physical therapists reported that they planned to use telerehabilitation in the future and agreed that telerehabilitation plays an important role in expanding access to physical therapy in the United States.ConclusionsPhysical therapists believed that telerehabilitation continues to play an important role in a post-pandemic world. Although physical therapists reported that they considered telerehabilitation to be an effective method for delivering care, they did not consider it to be a replacement for in-clinic care and believed that certain patients are more likely than others to benefit from this approach.Impact StatementPhysical therapists consider telerehabilitation to be a viable care option for patients with musculoskeletal pain.
Abdominal Myosteatosis and Cognitive Decline in a Biracial Cohort: Insights from CARDIA Study
Authors: Acevedo-Fontánez Adrianna , Rosano Caterina , Yaffe Kristine , Carr J Jeffrey , Terry James G. , Nair Sangeeta , Barinas-Mitchell Emma , Cvejkus Ryan K. , Miljkovic Iva 
Published: January 2025

ABSTRACTObjectiveSkeletal muscle fat infiltration (myosteatosis) increases with age and is an emerging risk factor for dementia. We aimed to determine the association between myosteatosis and cognitive decline among middle-aged White and Black Americans.MethodsData were on men (n=1,080; 41.9% Black) and women (n=1,432; 49.0% Black) from the CARDIA study. CT-measured abdominal intermuscular fat (IMAT) volume was assessed at baseline. Cognition was assessed by Digit Symbol Substitution (DSST), Rey Auditory Verbal Learning (RAVLT), and Stroop Test at baseline and 5-year follow-up. Multivariable linear regression was used to assess associations of IMAT with cognitive change.ResultsParticipants were aged 50.2 (3.6) years and had IMAT of 2.3 (1.6) cm3, 5-year change in DSST of -2.8% (21.8), RAVLT 2.8% (17.5) and Stroop 6.5% (49.5). Greater IMAT was associated with steeper DSST decline (β =-0.52 points per SD, p-value=0.035), but not with Stroop or RAVLT. Stratified by race, greater IMAT predicted DSST decline among White (β =-0.73, p =0.044), but not Black (β =-0.44, p =0.195), participants.ConclusionsAbdominal myosteatosis may be a novel risk factor for decline in psychomotor speed, especially in middle-aged Whites. Further research on mechanisms, including metabolic mediators, is warranted to understand myosteatosis’s role in mid-life cognitive decline.
Vaccine demands to achieve outbreak control for MPXV Clade I with one-time mass campaign in sub-Saharan Africa: scenario-based modelling study
Authors: Jin Shihui , Asakura Toshiaki R , Murayama Hiroaki , Niyukuri David , Saila-Ngita Diafuka , Lim Jue Tao , Endo Akira , Dickens Borame L 
Published: January 2025

AbstractBackgroundDeclining cross-protection from historical smallpox vaccination campaigns and persistent zoonotic reservoirs leave many sub-Saharan countries susceptible to mpox outbreaks. With millions of vaccine doses made available to the region since late 2024, estimating the country specific impact of one-time mass vaccination strategies is crucial for ongoing outbreaks and for other countries at future risk.MethodsWe adapted a next generation matrix model to incorporate vaccination which was calibrated using mpox datasets from the Democratic Republic of Congo. We projected the effective reproduction number,Reff, for 47 sub-Saharan countries from 2025 to 2050 under four transmission scenarios with different contributions of community vs sexual contacts, informed by Clade Ia and Ib outbreaks. We then calculated country-specific minimum vaccine coverages required for outbreak control and evaluated one-time age-specific mass vaccination strategies for reducingReff.FindingsFor all 47 countries,Reffs are projected to rise. At least 20 are estimated to require vaccination in 2025, and 36 in 2050, in the event of national outbreaks. For eleven clade I-affected countries, the minimum required coverage is estimated to range from 0%–4.8% to 14.5%–19.5% in 2025 with increasing sexual transmission, increasing to 0%–10.8% and 22.6%–26.0% in 2050, respectively. The prioritised age group for vaccination shifts from 0–4 to 20–29 with additional sexual transmission.InterpretationWith diminishing smallpox-vaccination-induced immunity, increasingReffs and potential for persistent outbreaks are expected for mpox. Policymakers may face increasing vaccine demand, which will necessitate coordinated efforts to prioritise high-risk groups under supply constraints.
Data-driven workflow for comprehensive gene expression analysis in complex microbiomes
Authors: Mameda Ryo , Bono Hidemasa 
Published: January 2025

AbstractComplex microbiomes, characterized by highly diverse microbial species, are ubiquitous in the environment. However, the genomes of many constituent microbes remain uncharacterized, complicating the use of publicly available genome sequences as reference data for gene expression analysis based on next-generation sequencing (NGS) data. Consequently, selecting suitable reference sequences is critical for accurate gene expression analysis in complex microbiomes. Additionally, such analyses require precise quantitative evaluation of the genes within each microorganism. In this study, we identified appropriate reference sequences and developed a data-driven analytical workflow for gene expression analysis in complex microbiomes. Utilizing metagenomic and metatranscriptomic NGS reads from these microbiomes, the workflow evaluates gene abundance and transcriptional levels, addressing key analytical challenges. The findings demonstrate that metagenomic contigs are more suitable than conventional reference sequences for mapping both metagenomic and metatranscriptomic data. Moreover, this workflow facilitates not only the assessment of transcriptional activity but also the evaluation of gene expression potential.
Integrated analysis of protein sequence and structure redefines viral diversity and the taxonomy of theFlaviviridae
Authors: Simmonds Peter , Butković Anamarija , Grove Joe , Mayne Richard , Mifsud Jonathon C. O. , Beer Martin , Bukh Jens , Drexler J. Felix , Kapoor Amit , Lohmann Volker , Smith Donald B. , Stapleton Jack T. , Vasilakis Nikos , Kuhn Jens H. 
Published: January 2025

AbstractTheFlaviviridaeare a family of non-segmented positive-sense enveloped RNA viruses containing significant pathogens including hepatitis C virus and yellow fever virus. Recent large-scale metagenomic surveys have identified many diverse RNA viruses related to classical orthoflaviviruses and pestiviruses but quite different genome lengths and configurations, and with a hugely expanded host range that spans multiple animal phyla, including molluscs, cnidarians and stramenopiles,, and plants. Grouping of RNA-directed RNA polymerase (RdRP) hallmark gene sequences of flavivirus and ‘flavi-like’ viruses into four divergent clades and multiple lineages within them was congruent with helicase gene phylogeny, PPHMM profile comparisons, and comparison of RdRP protein structure predicted by AlphFold2. These results support their classification into the established order,Amarillovirales, in three families (Flaviviridae, Pestiviridae, andHepaciviridae), and 14 genera. This taxonomic framework informed by RdRP hallmark gene evolutionary relationships provides a stable reference from which major genome re-organisational events can be understood.
Electrophysiological resting-state signatures link polygenic scores to general intelligence
Authors: Engler Rebecca , Stammen Christina , Arnau Stefan , Schneider Penate Javier , Metzen Dorothea , Digutsch Jan , Gajewski Patrick D. , Getzmann Stephan , Fraenz Christoph , Reinders Jörg , Streit Fabian , Ocklenburg Sebastian , Schneider Daniel , Burke Michael , Hengstler Jan G. , Watzl Carsten , Nitsche Michael A. , Kumsta Robert , Wascher Edmund , Genꞔ Erhan 
Published: January 2025

AbstractIntelligence is associated with important life outcomes. Behavioral, genetic, structural, and functional brain correlates of intelligence have been studied for decades, but questions remain as to how genetics are related to trait expression and what intermediary role brain properties play. This study investigated these mediations in a representative sample of 434 individuals, comprising young and older adults. Polygenic scores (PGS) for intelligence were calculated. Resting-state EEG recordings were analyzed using graph theory quantifying functional connectivity across different frequencies. We tested whether global and local graph metrics like efficiency and clustering mediated the association between PGS and intelligence. PGS significantly predicted variance in intelligence and were related to frequency-specific graph metrics in areas predominantly located in parieto-frontal regions, which in turn were associated with intelligence. These findings, which are based on the first study linking PGS to intelligence using EEG-derived graph metrics, advance our understanding of the neurogenetics of intelligence.
Systematic Determination of the Impact of Structural Edits on Accumulation into Mycobacteria
Authors: Dash Rachita , Liu Zichen , Lepori Irene , Chordia Mahendra D. , Ocius Karl , Holsinger Kadie , Zhang Han , Kenyon Ryan , Im Wonpil , Siegrist M. Sloan , Pires Marcos M. 
Published: January 2025

ABSTRACTThe mycomembrane of mycobacteria has long been regarded as the primary barrier to the accumulation of molecules within these bacteria. Understanding accumulation beyond the mycomembrane ofMycobacterium tuberculosis(Mtb) is crucial for developing effective antimycobacterial agents. This study investigates two design principles commonly found in natural products and mammalian cell-permeable peptides – backboneN-methylation and macrocyclization – aimed at enhancing accumulation. To assess the impact of these structural edits on accumulation, we employed our recently described Peptidoglycan Accessibility Click-Mediated Assessment (PAC-MAN) assay for live-cell analysis. Our findings indicate that peptide macrocyclization generally enhances permeability and metabolic stability, whileN-methylation modifies accumulation in a context-dependent manner. Furthermore, we applied these design principles to the peptide antibiotic Tridecaptin A1, demonstrating improved permeability and efficacy against mycobacteria, in specific contexts. This work suggests that strategic structural modifications can enhance accumulation past the mycomembrane and provide the first systematic governing rules for the rational redesign of potential antimycobacterial agents. Most importantly, our results broadly challenge the notion that large hydrophilic molecules (e.g., peptides) cannot readily bypass the mycomembrane to reach the cytosolic space.
The reasonable effectiveness of domain adaptation for inference of introgression
Authors: Cobb Kerry A. , Smith Megan L. 
Published: January 2025

AbstractSupervised machine learning approaches have proven powerful in population genetics. To use such approaches, training data with known inputs and outputs are required. Since such data are generally unavailable in population genetics, researchers typically rely on simulations under the models of interest to train machine learning algorithms. While powerful, this approach depends heavily on the models used to generate training data. Because of the variety and complexity of processes shaping genetic variation, it is inevitable that not all processes important in an empirical system will be included when generating training data. This leads to a mismatch between the data used to train a machine learning algorithm and the data to which the trained model is ultimately applied–i.e., a domain shift– and can negatively impact inference. Here, we train a Convolutional Neural Network (CNN) to detect introgression between sister populations and demonstrate that it has near perfect accuracy when applied to data generated under the models used for training. To evaluate the impacts of domain shifts on inference, we generated new data with introgression from a third, unsampled population into one of the two focal populations (i.e., ghost introgression), and accuracy was substantially reduced on these data. Finally, we used domain adaptation, which aims to train a network that performs well in the presence of a domain shift. Notably, this requires no knowledge of the target or empirical domain. Our domain adaptation network was able to accurately detect introgression, even in the presence of unmodelled ghost introgression. We also applied this approach to empirical data to detect introgression between ABC Island brown bears and other populations of brown bears. Previous work has suggested that introgression between ABC Island bears and polar bears can mislead tests of introgression between populations of brown bears. We found that using domain adaptation reduced support for introgression between geographically isolated populations of brown bears, suggesting that our approach reduces false inferences of introgression due to ghost introgression.
Partial Wwox Loss of Function Increases Severity of Murine Sepsis and Neuroinflammation
Authors: De La Cruz Priscilla , Gomes Marta , Lockett Angelia , Fisher Amanda , Cook Todd , Smith Patricia , Lloyd Christopher , Twigg Homer L , Oblak Adrian , Aldaz C. Marcelo , Machado Roberto F. 
Published: January 2025

AbstractRationaleWW domain-containing oxidoreductase (WWOX) is a gene associated implicated in both neurologic and inflammatory diseases and is susceptible to environmental stressors. We hypothesize partial loss of Wwox function will result in increased sepsis severity and neuroinflammation.MethodsWwoxWT/P47Tmice, generated by CRISPR/Cas9, andWwoxWT/WTmice were treated with intraperitoneal PBS vs LPS (10mg/kg) and euthanized 12 hours post-injection. Open Field Testing (OFT) and Murine Sepsis Severity Scores (MSS) were utilized to measure sickness behavior and sepsis severity, respectively. Brain tissue was analyzed using immunohistochemistry and PCR to measure neuroinflammation and apoptosis.ResultsWwoxWT/P47TLPS mice demonstrated a more significant response to sepsis with an increase in sickness behavior, sepsis severity, gliosis, and apoptosis compared toWwowWT/WTLPS littermates.ConclusionsPartial loss of Wwox function increases risk for severe sepsis and neuroinflammation. Given the susceptibility ofWWOXto environmental stressors, this may be a target for future therapeutic interventions.
Differential regulation of brain-specific molecular pathways is the reason for curcumin’s adult life-phase specific DAergic neuroprotection: Insights from ALSS Drosophila model of Parkinson’s disease
Authors: Das Abhik , Yenisetti Sarat Chandra 
Published: January 2025

AbstractCurcumin (CU), a bioactive compound of turmeric, has been put forward as a “golden molecule” due to its anti-inflammatory, antioxidant, hepatoprotective, neuroprotective, and anti-cancer ability, as proven by research conducted over the decade and more. Our laboratory, developed an adult life stage specific (ALSS)Drosophilamodel of sporadic Parkinson’s disease (PD), and for first time demonstrated that dopaminergic (DAergic) neuroprotective efficacy of curcumin is limited to health phase viz. adult-young life stage and is absent during transition phase viz. adult senior life stages when PD set in. This observation suggests the limitation of curcumin as a therapeutic agent for late-onset disorders like PD. Further, our laboratory also demonstrated that despite curcumin’s ability to sequester oxidative stress during both the adult life stages, neuroprotection and brain dopamine replenishment is granted only in health stages but not in a vulnerable transition stage, which prompted to put forward the hypothesis that the molecular target(s) of CU, may be absent or inadequate in the transition stage of aging brain. With this insight, the current study was implemented to analyse the life stage-specific differential regulation of multiple molecular players of neuro-integral pathways in brain of ALSSDrosophilamodel of PD with curcumin intervention. It is discovered that curcumin-mediated health phase-specific neuroprotection underlies the correction of an altered expression of 1.dFOXO, GADD45, PucofBsk-dFOXOstress response pathway, 2.Mfn2of Mitochondrial dynamics 3.CncC, GCLC, Prx 2540 -1,2, Jafrac1, Prx3of Phase II antioxidant defense system pathway. Further, it is discovered that significant aging-associated naturally altered expression of certain molecular targets exists, that may contribute to the limitation of curcumin’s DAergic neuroprotective efficacy during the adult-transition stage. This knowledge will help in developing altered therapeutic strategies for PD as molecular targets of curcumin are conserved among fly, mice and human.