bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hepatitis A virus whole genome sequencing strategy using NGS/Illumina technology
Authors: Sicilia Paola , Fantilli Anabella C. , Cuba Facundo , Di Cola Guadalupe , Barbás María Gabriela , Poklepovich Tomás , Ré Viviana E. , Castro Gonzalo , Pisano María Belén 
Published: May 2024

AbstractBackgroundMolecular epidemiology of hepatitis A virus (HAV) plays a critical role in identifying outbreak origin and conducting surveillance. Although it is mostly carried out using short partial VP1/2A genomic sequences, utilizing whole-genome sequences (WGS) provides more accurate and robust information.Objectivewe aimed to develop an amplicon-based next-generation sequencing (NGS) strategy to obtain complete HAV genomes utilizing the COVIDSeq Test (Illumina), available in surveillance laboratories after the COVID19 pandemic.Study design25 primer pairs were designed and used to amplify partial genomic fragments (400bp) that comprise the entire HAV genome sequence from HAV previously positive serum and stool samples from Argentina. The DNA library was prepared using the Illumina COVIDSeq Test and sequenced in a MiSeq equipment. Phylogenetic analyses were performed with IQ-Tree using WGS and VP1/2A partial sequences of 1084pb and 422pb.Results11 samples could be successfully amplified and sequenced, with horizontal coverage between 79.3%-100% (>90% in 9 samples). Individual RT-PCRs and Sanger sequencing with specific primers had to be performed in 6 samples to cover gaps of Ns. Phylogenetic analyses of WGS and VP1/2A partial sequences yielded similar results (clustering with genotype IA), although 422pb fragments showed low accurate grouping definition.Conclusionthe amplicon-based NGS whole genome sequencing tool developed by adapting the COVIDSeq test to HAV, proved to be efficient in generating new complete and near-complete viral sequences. The study of the 1084bp fragment of the VP1/2A region would constitute a useful alternative option for outbreak investigation with public health impact.
Retrospective Comparison of Outcomes and Cost of a Virtual vs. Center-Based Cardiac Rehabilitation Program
Authors: Shah Neil D. , Banta Conor W. , Berger Andrea L. , Hattenberger Andrea , Zimmerman Alex , Martin Bryan E. , Wu Edward , Majumdar Usnish , Kirchner H. Lester , Matsumura Martin E. 
Published: May 2024

ABSTRACTBackgroundDespite robust evidence supporting an association with improved outcomes in eligible patients, cardiac rehabilitation (CR) remains underutilized, with a minority of eligible patients participating. Virtual cardiac rehabilitation (VCR) has been proposed as an alternative to traditional center-based CR (CBCR) to improve utilization rates. However, data supporting the efficacy and cost-effectiveness of VCR is limited. In the present study, we compared the outcomes and cost of a VCR vs. traditional CBCR program.MethodsRetrospective cohort study comparing VCR vs. CBCR. CBCR data were collected from a period of January 2018 to September 2023. VCR data were collected from program initiation in July 2021 to September 2023. Primary health outcomes measured were 1-year mortality rates, recurrent MI, all-cause hospital readmission, and emergency department visits. Primary cost outcomes were analyzed as cost ratios related to VCR vs. CBCR assessing total medical costs allowed, pharmacy costs, and total costs of care over the 12 months post-CR enrollment.ResultsVCR was associated with a significant reduction in 1-year all-cause hospital readmission (incident rate ratio (IRR)=0.616, 95% confidence interval (CI): 0.489, 0.777, p<0.001) and ED admission (IRR=0.557, 95% CI: 0.452, 0.687, p<0.001) at 1 year. The IRR of MI and all-cause mortality did not significantly differ between VCR and CBCR. In addition, VCR was associated with significant reductions in medically related (cost ratio=0.814, 95% CI: 0.690, 0.960, p=0.0144) and total costs (cost ratio=0.838, 95% CI: 0.725, 0.970, p=0.0176).ConclusionVCR is a viable alternative to CBCR with at least comparable efficacy and cost, and as such, represents a key mechanism for improving access to and participation in CR for eligible patients.
Universal protection of allogeneic cell therapies from natural killer cells via CD300a agonism
Authors: Zhang Shu-Qi , Thomas Faith , Fang Justin , Austgen Kathryn , Cowan Chad , Welstead G. Grant 
Published: May 2024

AbstractImmunogenicity limits the persistence of off-the-shelf, allogeneic cell therapies and transplants. While ablation of human leukocyte antigen (HLA) removes most T cell and humoral alloreactivity, no solution has enabled universal protection against the resulting natural killer (NK) cell response. Here, we engineered Trans Antigen Signaling Receptors (TASR) as a new class of NK inhibitory ligands and discovered CD300a, a previously inaccessible receptor, as a functional target. CD300a TASR outperformed leading alternative strategies in focused screens, including CD47 and HLA-E, and was solely capable of universally protecting allogeneic T cells against a large human cohort (45/45 donors), spanning diverse demographics and NK cell phenotypes. A model allogeneic T cell therapy co-expressing an anti-CD19 Chimeric Antigen Receptor (CAR) and CD300a TASR, produced using multiplexed non-viral integration, exhibited enhanced B cell killing potency under allogeneic immune pressure. CD300 TASR represents a universal solution to NK alloreactivity, broadening the population that could be effectively treated by next-generation allogeneic cell therapies.CategoryImmunobiology and ImmunotherapyKey PointsAn engineered CD300a agonist ligand (CD300a TASR) universally protects HLA-deficient allogeneic T cells from NK-mediated rejection.CD300a TASR is more protective in CMV seropositive hosts than HLA-E ligand and enhances CAR-T efficacy under allogeneic immune pressure.
Gym-Based Modified Powerlifting Exercises for People with Early Onset Parkinson’s Disease: Study Protocol
Authors: Harris Dale M , Thwaites Claire , Callisaya Michelle L , Blazé Richard , Morris Meg E 
Published: May 2024

ABSTRACTBackgroundAlthough powerlifting has been shown to increase strength and function in some adults, the safety and feasibility of powerlifting exercises modified for people with early onset Parkinson’s disease is not known.MethodsPeople with early onset Parkinson’s disease (age <50 years) will be invited to engage in eight consecutive weeks of twice-weekly modified powerlifting exercises in a community gymnasium. The primary outcome is the feasibility of powerlifting exercises modified for people with early onset Parkinson’s disease, quantified by measures of safety, adverse events, adherence, access, and cost. Secondary outcomes include motor disability, quality of life, psychosocial status, and strength. Semi-structured interviews with participants and exercise trainers will capture experiences, beliefs, and attitudes towards this type of community-based strength training.DiscussionPowerlifting may be beneficial for those with early onset Parkinson’s disease as it can improve muscle strength, coordination, and balance, and may have neuroprotective effects, potentially slowing down the progression of the disease. However, there is a need to first measure feasibility and safety of modified powerlifting in a small number of individuals before the efficacy can be tested in larger randomised controlled trials.Ethics and disseminationWe will publish the findings in peer-reviewed journals and presentations at conferences. The consumer engagement council will guide communication of findings to individuals with early onset Parkinson’s disease, ensuring information is accessible and actionable for the target audience.
The African American Dementia and Aging Project (AADAPt): An Oregon-based Longitudinal Study
Authors: Lindauer Allison , Croff Raina , Duff Kevin , Mattek Nora , Fuller Patrice , Pierce Aimee , Bonds Kalisha , Kaye Jeffrey 
Published: May 2024

AbstractObjectivesThe vast majority of studies on aging, cognition, and dementia focus on non-Hispanic white subjects. This paper adds to the extant literature by providing insight into the African American aging experience. Here we describe the study design and baseline characteristics of the African American Dementia and Aging Project (AADAPt) study, which is exploring aging and cognition in African American older adults in Oregon.MethodsAfrican American older adults (n=177) participated in AADAPt, a longitudinal study that collected data on cognitive, physical, and social functioning in annual visits since 2000.ResultsAADAPt participants had risk factors for developing dementia in future, such as hypertension and hyperlipidemia, but also reported protective factors such as high social engagement.ConclusionsThe AADAPt project offers new insights into aging in older African Americans that includes data on cognition, social engagement, and physical health, which are crucial for understanding the experience of under-represented groups and making future studies more inclusive. These findings reflect a window of time for a geographically-focused cohort, and the lessons learned from this study likely have broader implications for shaping the health of these older African American adults. Keywords: African American, Dementia, Observational Study
Filling the gaps: leveraging large language models for temporal harmonization of clinical text across multiple medical visits for clinical prediction
Authors: Choi Inyoung , Long Qi , Getzen Emily 
Published: May 2024

AbstractElectronic health records offer great promise for early disease detection, treatment evaluation, information discovery, and other important facets of precision health. Clinical notes, in particular, may contain nuanced information about a patient’s condition, treatment plans, and history that structured data may not capture. As a result, and with advancements in natural language processing, clinical notes have been increasingly used in supervised prediction models. To predict long-term outcomes such as chronic disease and mortality, it is often advantageous to leverage data occurring at multiple time points in a patient’s history. However, these data are often collected at irregular time intervals and varying frequencies, thus posing an analytical challenge. Here, we propose the use of large language models (LLMs) for robust temporal harmonization of clinical notes across multiple visits. We compare multiple state-of-the-art LLMs in their ability to generate useful information during time gaps, and evaluate performance in supervised deep learning models for clinical prediction.
Functional and multi-omic aging rejuvenation with GLP-1R agonism
Authors: Huang Junzhe , Kwok Andrew J. , Li Jason Chak Yan , Chiu Clement Lek Hin , Ip Bonaventure Y. , Tung Lok Yi , Zheng Xianyi , Chow Hoi Tung , Lo Michelle P. S. , Li Zhongqi , Chan Roy C. H. , Lin Nenghan , Wang Ziyu , Wang Manyu , Yan Leo Y. C. , Chan Danny C. W. , Wu William K. K. , Chow Kim Hei-Man , Lin Wei-Jye , Tang Yamei , Ng Billy Wai-Lung , Wong Sunny H. , Leung Thomas W. , Mok Vincent C. T. , Ko Ho 
Published: May 2024

AbstractIdentifying readily implementable methods that can effectively counteract aging is urgently needed for tackling age-related degenerative disorders. Here, we conducted functional assessments and deep molecular phenotyping in the aging mouse to demonstrate that glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment attenuates body-wide age-related changes. Apart from improvements in physical and cognitive performance, the age-counteracting effects are prominently evident at multiple omic levels. These span the transcriptomes and DNA methylomes of various tissues, organs and circulating white blood cells, as well as the plasma metabolome. Importantly, the beneficial effects are specific to aged mice, not young adults, and are achieved with a low dosage of GLP-1RA which has a negligible impact on food consumption and body weight. The molecular rejuvenation effects exhibit organ-specific characteristics, which are generally heavily dependent on hypothalamic GLP-1R. We benchmarked the GLP-1RA age-counteracting effects against those of mTOR inhibition, a well-established anti-aging intervention, observing a strong resemblance across the two strategies. Our findings have broad implications for understanding the mechanistic basis of the clinically observed pleiotropic effects of GLP-1RAs, the design of intervention trials for age-related diseases, and the development of anti-aging-based therapeutics.
Autologous ovarian tissue transplantation and longevity improvement (experimental mice model)
Authors: Ruhliada Nikolai 
Published: May 2024

AbstractIn the study we showed the improvement in life longevity in mice after step-by step autologous ovarian transplantation. This has proven to be more efficient than “traditional” hormonal replacement therapy. Despite the highest speed and effectiveness of estradiol replacement deficiency in blood by its oral or transdermal use, one did not receive a significant increase in the life longevity in animals and possibly in women (Canderelli R., Leccesse L. et al. 2007). The function of transplanted fragment is usually limited to 6-12 months. This is enough for oncofertility purposes, sometimes, but not for longevity improvement. We performed periodical tissue return (autologous transplantation), containing both cortex and medulla in mice experimental model, that resulted in statistically reliable improvement of longevity. The experimental model we suggested could be projected and to other mammals or humans, as the cortical transplantation gives the same results for reproduction restoration in mice and humans and even on hormone levels normalization, but there is still lack of information about anti-ageing factors containing in ovarian medulla and cortex. That is why we consider that the most important factor for anti-ageing transplantation technology is to preserve both medulla and cortex.SummaryStep-by step autologous ovarian transplantation provides the improvement in life longevity in female mice. This technology could be even more efficient, compared to estrogen hormonal replacement therapy in hormone levels improvement (FSH, estradiol). While menopausal hormonal therapy (MHT) with estrogens doesn’t improve longevity in mice, step-by-step autologous transplantation of ovarian cryopreserved tissue statistically reliably prolongs lifespan in mice.
The TWK-26 potassium channel governs nutrient absorption in theC. elegansintestine
Authors: Torzone Sarah K. , Breen Peter C. , Cohen Natalie R. , Simmons Kaylee N. , Dowen Robert H. 
Published: May 2024

ABSTRACTIon channels are necessary for proper water and nutrient absorption in the intestine, which supports cellular metabolism and organismal growth. While a role for Na+co-transporters and pumps in intestinal nutrient absorption is well defined, how individual K+uniporters function to maintain ion homeostasis is poorly understood. UsingCaenorhabditis elegans, we show that a gain-of-function mutation intwk-26, which encodes a two-pore domain K+ion channel orthologous to human KCNK3, facilitates nutrient absorption and suppresses the metabolic and developmental defects displayed by impaired intestinal MAP Kinase (MAPK) signaling. Mutations indrl-1andflr-4,which encode two components of this MAPK pathway, cause severe growth defects, reduced lipid storage, and a dramatic increase in autophagic lysosomes, which mirror dietary restriction phenotypes. Additionally, these MAPK mutants display structural defects of the intestine and an impaired defecation motor program. We find that activation of TWK-26 reverses the dietary restriction-like state of the MAPK mutants by restoring intestinal nutrient absorption without correcting the intestinal bloating or defecation defects. This study provides unique insight into the mechanisms by which intestinal K+ion channels support intestinal metabolic homeostasis.
Local structural dynamics of Rad51 protomers revealed by cryo-electron microscopy of Rad51-ssDNA filaments
Authors: Liu Jie , Gore Steven , Heyer Wolf-Dietrich 
Published: May 2024

ABSTRACTHomologous recombination (HR) is a high-fidelity repair mechanism for double-strand breaks. Rad51 is the key enzyme that forms filaments on single-stranded DNA (ssDNA) to catalyze homology search and DNA strand exchange in recombinational DNA repair. In this study, we employed single-particle cryo-electron microscopy (cryo-EM) to ascertain the density map of the budding yeast Rad51-ssDNA filament bound to ADP-AlF3, achieving a resolution of 2.35 Å without imposing helical symmetry. The model assigned 6 Rad51 protomers, 24 nt of DNA, and 6 bound ADP-AlF3. It shows 6-fold symmetry implying monomeric building blocks, unlike the structure of the Rad51-I345T mutant filament with three-fold symmetry implying dimeric building blocks, for which the structural comparisons provide a satisfying mechanistic explanation. This image analysis enables comprehensive comparisons of individual Rad51 protomers within the filament and reveals local conformational movements of amino acid side chains. Notably, Arg293 in Loop1 adopts multiple conformations to facilitate Leu296 and Val331 in separating and twisting the DNA triplets. We also analyzed the predicted structures of yeast Rad51-K342E and two tumor-derived human RAD51 variants, RAD51-Q268P and RAD51-Q272L, using the Rad51-ssDNA structure from this study as a reference.
Interleukin 21 is a marker of Human African Trypanosomiasis Infection and a contributor to pathology in mice
Authors: Capewell Paul , Ilboudo Hamidou , Cooper Anneli , Kaboré Windingoudi Justin , Noyes Harry , Neill Kerry O’ , Camara Mamadou , Jamonneau Vincent , MacLeod Annette , Bucheton Bruno ,   TrypanoGEN+ research group of the H3Africa consortium
Published: May 2024

AbstractBackgroundHuman African trypanosomiasis (HAT) is an important disease of sub-Saharan Africa that is approaching elimination in many regions. However, the disease has previously returned from similarly low case numbers in the past, making it important to identify issues that hinder elimination efforts. One important factor is likely to be the recent characterization of individuals with latent HAT infections that are able to tolerate HAT with few symptoms and to control blood parasitaemia to levels that are undetectable by microscopy. Although animal trypanotolerance has been examined in detail, it is unclear how the latent phenotype is maintained in humans.MethodsTo identify immune components involved in latent HAT, we used targeted RNASeq to examine the expression of 495 immune-related transcripts in blood collected from 287 individuals at active disease foci in Guinea. These samples included latent infections, HAT clinical cases, and uninfected controls. Thein vivoeffects of IL21 functional blockade was investigated using a murine model of trypanosomiasis.ResultsDifferential expression analysis revealed transcripts involved in T cell activation and B cell development that associated with trypanosome infection, includingPD1,CD70, andCD80. In particular,IL21was found to be elevated in infected individuals, although it was significantly higher in clinical cases relative to latent infections. This pattern was replicated at the protein level when patient sera were examined by ELISA. Reducing IL21 pathway activity in mice infected withTrypanosoma bruceiled to increased survivorship and reduced parasitaemia in the model animals.ConclusionOur data show that IL21 is a potential biomarker of Human African Trypanosomiasis and is a cause rather than a consequence of symptoms severity. Further investigation of IL21 will contribute to understanding the factors involved in developing latent HAT, improving control efforts to identify and predict such infections. In the future, the factors identified in this study may also serve as intervention targets to control the symptoms of trypanosomiasis.
In uteroadeno-associated virus (AAV)-mediated gene delivery targeting sensory and supporting cells in the embryonic mouse inner ear
Authors: Barbosa-Spinola Carla Maria , Boutet de Monvel Jacques , Safieddine Saaid , Lahlou Ghizlène , Etournay Raphaël 
Published: May 2024

AbstractIn vivo gene delivery to tissues using adeno-associated vector (AAVs) has revolutionized the field of gene therapy. Yet, while sensorineural hearing loss is one of the most common sensory disorders worldwide, gene therapy applied to the human inner ear is still in its infancy. Recent advances in the development recombinant AAVs have significantly improved their cell tropism and transduction efficiency across diverse inner ear cell types to a level that renders this tool valuable for conditionally manipulating gene expression in the context of developmental biology studies of the mouse inner ear. Here, we describe a protocol forin uteromicro-injection of AAVs into the embryonic inner ear, using the AAV-PHP.eB and AAV-DJ serotypes that respectively target the sensory hair cells and the supporting cells of the auditory sensory epithelium. We also aimed to standardize procedures for imaging acquisition and image analysis to foster research reproducibility and allow accurate comparisons between studies. We find that AAV-PHP.eB and AAV-DJ provide efficient and reliable tools for conditional gene expression targeting cochlear sensory and supporting cells in the mouse inner ear, from late embryonic stages on.
Age-specific dynamics of neutralizing antibodies, cytokines, and chemokines in response to La Crosse virus infection in mice
Authors: Alatrash Reem , Vaidya Varun , Herrera Bobby Brooke 
Published: May 2024

AbstractLa Crosse virus (LACV) is a primary cause of pediatric arboviral encephalitis in the United States, particularly affecting children aged 16 years or younger. This age-related susceptibility extends to murine models, where weanling mice (3 weeks old) succumb to LACV infection, while adults (≥6 weeks old) demonstrate resistance. Despite its clinical relevance, the host immune response to LACV is not fully understood. In this study, we investigated the roles of neutralizing antibodies (nAbs), cytokines, and chemokines in weanling and adult mice following infection with 5x105plaque forming units (PFU) of LACV. We observed significant age-related differences in viral titers and survival. Weanling mice demonstrated early disease onset with elevated peripheral viremia, but passive transfer of adult serum, confirmed to have nAbs, to naïve weanlings prior to infection completely rescued them from death. Cytokine and chemokine profiling revealed distinct kinetics and age-specific immune responses. Adult mice had increased Th1 cytokines, Th9/Th17/Th22/Treg cytokines, and many chemokines. In contrast, weanlings had higher Th2 cytokines, correlating with symptoms onset. Flow cytometry and intracellular cytokine staining further demonstrated that weanling mice produced higher levels of IL-4 by CD4+and CD8+T cells compared to adults, regardless of infection status. Conversely, LACV-infected adult mice had increased IFN-γ production by CD8+T cells compared to uninfected adults. Finally, adoptive transfer of splenocytes from immune adult mice to naïve weanlings delayed neurological symptoms and improved survival, highlighting the protective role of immune adult cells against LACV. In conclusion, this study links nAbs and cytokine and chemokine responses to protective immunity in adult mice, contrasting with the pathogenesis seen in weanlings. These findings underscore the importance of further research into innate and adaptive immune mechanisms in LACV infection.