bluuebunny/crossref_metadata_2025_split huggingface dataset:
Investigation of the causative pathogen in the 2023 conjunctivitis outbreak of Nepal using unbiased metagenomic next generation sequencing
Authors: Shrestha Eliya , Katuwal Nishan , Kharel Sitaula Ranju , Gurung Harimaya , Shrestha Aastha , Karki Pratap , Shrestha Rajeev 
Published: April 2024

AbstractIn mid-2023, Nepal experienced a significant outbreak of conjunctivitis, affecting over 60% of outpatients in eye hospitals and prompting school closures. The outbreak, peaking in August, predominantly impacted children and individuals with compromised immunity. Clinical manifestations included sudden-onset redness, foreign body sensation, watery discharge, and occasional lid swelling. A majority of cases exhibited acute hemorrhagic conjunctivitis, with management involving ocular lubricants, personal hygiene, and topical antibiotics. This study details the genomic epidemiology and clinical characteristics of conjunctivitis cases during the outbreak. To understand the causative agents, conjunctival swabs from patients were evaluated using unbiased metagenomic next-generation sequencing (mNGS) in Illumina iSeq100 at Dhulikhel Hospital Kathmandu University Hospital. This case series revealed the presence of Enterovirus C (coxsackievirus strain A24) as the major pathogen responsible for the outbreak. This case series contributes valuable insights into the genomic diversity of conjunctivitis-associated viruses, highlighting the potential of mNGS in enhancing diagnostic capabilities and guiding public health responses.
Human iPSCs from aged donors retain their mitochondrial aging signature
Authors: Lejri Imane , Cader Zameel , Grimm Amandine , Eckert Anne 
Published: April 2024

AbstractAging represents the main risk factor for developing neurodegenerative disorders. One of the hallmarks of aging is mitochondrial dysfunction. Age-related mitochondrial alterations have been shown to affect mitochondrial energy metabolism and redox homeostasis as well as mitochondrial dynamics. In the present study, we addressed the question of whether or not, induced pluripotent stem cells (iPSCs) may be used as a model of “aging in a dish” to identify therapies at alleviating the aging of mitochondria. Notably, we could demonstrate that compared to human iPSCs from young donors, those from aged donors show impaired mitochondrial bioenergetics and exhibit a rise in reactive oxygen species generation. Furthermore, we demonstrate that iPSCs from aged donors present low mitochondrial mass and alterations of the morphology of the mitochondrial network. This study provides evidence that the aging phenotype is present at the mitochondrial level in iPSCs from aged donors, ranging from bioenergetics to dynamics. Thus, this model can be used for high through put screening to identify drugs that improve mitochondrial function.Graphical abstract
Identification and characterization of innate immunity inActinidia melanandrain response toPseudomonas syringaepv.actinidiae
Authors: Hemara Lauren M. , Chatterjee Abhishek , Yeh Shin-Mei , Chen Ronan K.Y. , Hilario Elena , Le Lievre Liam , Crowhurst Ross N. , Bohne Deborah , Arshed Saadiah , Patterson Haileigh R. , Barrett-Manako Kelvina , Thomson Susan , Allan Andrew C. , Brendolise Cyril , Chagné David , Templeton Matthew D. , Jayaraman Jay , Tahir Jibran 
Published: April 2024

AbstractPseudomonas syringaepv.actinidiaebiovar 3 (Psa3) has decimated kiwifruit orchards growing susceptible kiwifruitActinidia chinensisvarieties. Effector loss has occurred recently in Psa3 isolates from resistant kiwifruit germplasm, resulting in strains capable of partially overcoming resistance present in kiwiberry vines (A. arguta, A. polygama, andA. melanandra). Diploid maleA. melanandrarecognises several effectors, sharing recognition of at least one avirulence effector (HopAW1a) with previously studied tetraploid kiwiberry vines. Sequencing and assembly of theA. melanandragenome enabled the characterisation of the transcriptomic response of this non-host to wild-type and genetic mutants of Psa3.A. melanandraappears to mount a classic effector-triggered immunity (ETI) response to wildtype Psa3 V-13, as expected. Surprisingly, the type III secretion (T3S) system-lackingPsa3 V-13 ΔhrcCstrain did not appear to trigger pattern-triggered immunity (PTI) despite lacking the ability to deliver immunity-suppressing effectors. Contrasting theA. melanandraresponses to an effectorless Psa3 V-13 Δ33Estrain and to Psa3 V-13 ΔhrcCsuggested that PTI triggered by Psa3 V-13 was based on the recognition of the T3S itself. The characterisation of both ETI and PTI branches of innate immunity responses withinA. melanandrafurther enables breeding for durable resistance in future kiwifruit cultivars.
Brain and Blood Transcriptome-Wide Association Studies Identify Five Novel Genes Associated with Alzheimer’s Disease
Authors: Mews Makaela A. , Naj Adam C. , Griswold Anthony J. ,   Alzheimer’s Disease Genetics Consortium, Below Jennifer E. , Bush William S. 
Published: April 2024

ABSTRACTINTRODUCTIONTranscriptome-wide Association Studies (TWAS) extend genome-wide association studies (GWAS) by integrating genetically-regulated gene expression models. We performed the most powerful AD-TWAS to date, using summary statistics fromcis-eQTL meta-analyses and the largest clinically-adjudicated Alzheimer’s Disease (AD) GWAS.METHODSWe implemented the OTTERS TWAS pipeline, leveragingcis-eQTL data from cortical brain tissue (MetaBrain; N=2,683) and blood (eQTLGen; N=31,684) to predict gene expression, then applied these models to AD-GWAS data (Cases=21,982; Controls=44,944).RESULTSWe identified and validated five novel gene associations in cortical brain tissue (PRKAG1,C3orf62,LYSMD4,ZNF439,SLC11A2) and six genes proximal to known AD-related GWAS loci (Blood:MYBPC3; Brain:MTCH2,CYB561,MADD,PSMA5,ANXA11). Further, using causal eQTL fine-mapping, we generated sparse models that retained the strength of the AD-TWAS association forMTCH2,MADD,ZNF439,CYB561, andMYBPC3.DISCUSSIONOur comprehensive AD-TWAS discovered new gene associations and provided insights into the functional relevance of previously associated variants.
Latiné immigrant heterogeneity: Striking health differences among Cuban refugee/migration waves to the United States
Authors: Hernandez M. , Perry G.H. 
Published: April 2024

AbstractLatiné people differ markedly in our lived experiences in ways that are underappreciated. Meanwhile, variations in social experiences are known to be associated with differential health outcomes. We test whether immigration history is associated with health differences among U.S.-based Cuban refugees. Cubans from the circum-1980 Mariel Boatlift migration wave reported significantly higher instances of disability than Early Cuban Exiles, Freedom Flight refugees, and Special Period refugees. We also interviewed Miami-based Cubans. Participants described heightened discrimination in 1980s Cuba and U.S., which we hypothesize contributed to higher instances of disability refugees of that era. By understanding how differential social experiences shape health, we aim to provide a nuanced understanding of the social determinants of health and the ways adverse experiences can be combated.One-Sentence SummaryEven within a Latiné community from a single country of origin, we find that differential social experiences of immigrating to the U.S. are associated with variation in health outcomes.
Leveraging transformers and large language models with antimicrobial prescribing data to predict sources of infection for electronic health record studies
Authors: Yuan Kevin , Yoon Chang Ho , Gu Qingze , Munby Henry , Walker A Sarah , Zhu Tingting , Eyre David W 
Published: April 2024

AbstractBackgroundElectronic health records frequently contain extensive unstructured free-text data, but extracting information accurately from these data and at scale is challenging. Using free-text from antibiotic prescribing data as an example, we investigate the performance of modern natural language processing methods (NLP) and large language models (LLMs) as tools for extracting features from medical records.MethodsWe used 938,150 hospital antibiotic prescriptions from Oxfordshire, UK. The 4000 most frequently used free-text indications justifying antibiotic use were labelled by clinical researchers into 11 categories describing the infection source/clinical syndrome being treated and used for model training. Traditional classification methods, fuzzy regex matching and n-grams with XGBoost, were compared against modern transformer models: we fine-tuned generic and domain-specific BERT models, fine-tuned GPT3.5, and investigated few-shot learning with GPT4. Models were evaluated on internal and external test datasets (2000 prescriptions each). Infection sources determined from ICD10 codes were also used for comparisons.ResultsIn internal and external test datasets, the fine-tuned domain-specific Bio+Clinical BERT model averaged an F1 score of 0.97 and 0.98 respectively across the classes and outperformed the traditional regex (F1=0.71 and 0.74) and n-grams/XGBoost (F1=0.86 and 0.84). OpenAI’s GPT4 model achieved F1 scores of 0.71 and 0.86 without using labelled training data and a fine-tuned GPT3.5 model F1 scores of 0.95 and 0.97. Comparing infection sources extracted from ICD10 codes to those parsed from free-text indications, free-text indications revealed 31% more specific infection sources.ConclusionModern transformer-based models can efficiently and accurately categorise semi-structured free-text in medical records, such as prescription free-text. Finetuned local transformer models outperform LLMs currently for structured tasks. Few shot LLMs match the performance of traditional NLP without the need for labelling. Transformer-based models have the potential to be used widely throughout medicine to analyse medical records more accurately, facilitating beter research and patient care.
Barriers and facilitators to physical activity among Black women: a qualitative systematic review and thematic synthesis
Authors: Howard Sherron L. , Bartholomew John B. 
Published: April 2024

AbstractAmerican Black women are less physically active than other American women. While several qualitative studies have investigated this issue, there has been no effort to synthesize this literature.PurposeThis study aimed to utilize qualitative thematic synthesis to employ an intersectionality framework in synthesizing existing published qualitative studies on barriers to and facilitators of physical activity for Black women and reflect constructs related to (a) all American women, (b) Black Americans, and (c) Black women. This qualitative thematic synthesis included 18 studies published from 2011 to the present. Studies were coded for quality and then reviewed with their themes identified and inductively integrated across the studies. The resulting themes were then deductively placed within a broader structure of an intersectionality framework. Reflecting this framework, three categories were identified: (1) general experience of physical activity for women, regardless of race, with themes of (a) motivation, (b) structured support, (c) overall health, (d) environment; (2) general experiences of physical activity for Black Americans, with a sub-theme of (a) low access; and (3) specific, intersectional experiences of physical activity for Black women, with sub-themes of (a) black hair, and (b) body ideal. Our synthesis of the existing qualitative research revealed that Black women experience PA related to being a woman, to being Black, and to the intersectional nature of being a Black woman. Interventions might target these intersectional themes to tailor interventions to support PA in Black women.
Genome-Wide CRISPR-Cas9 Screening Identifies a Synergy between Hypomethylating Agents and SUMOylation Blockade in MDS/AML
Authors: Truong Peter , Shen Sylvie , Joshi Swapna , Islam Md Imtiazul , Zhong Ling , Raftery Mark J. , Afrasiabi Ali , Alinejad-Rokny Hamid , Nguyen Mary , Zou Xiaoheng , Bhuyan Golam Sarower , Sarowar Chowdhury H. , Ghodousi Elaheh S. , Stonehouse Olivia , Mohamed Sara , Toscan Cara E. , Connerty Patrick , Kakadia Purvi M. , Bohlander Stefan K. , Michie Katharine A. , Larsson Jonas , Lock Richard B. , Walkley Carl R. , Thoms Julie A. I. , Jolly Christopher J. , Pimanda John E. 
Published: April 2024

ABSTRACTHypomethylating agents (HMAs) are frontline therapies effective at altering the natural course of Myelodysplastic Neoplasms (MDS) and Acute Myeloid Leukemia (AML).However, acquired resistance and treatment failure are hallmarks of HMA therapy. To address this clinical need, we performed a genome-wide CRISPR-Cas9 screen in a human MDS-derived cell line, MDS-L, and identified TOPORS as a highly ranked loss-of-function target that synergizes with HMAs, reducing leukemic burden and improving survival in xenograft models. We demonstrate that the depletion of TOPORS mediates sensitivity to HMAs by predisposing leukemic blasts to an impaired DNA damage response (DDR) accompanied by an accumulation of SUMOylated DNMT1 in HMA-treated TOPORS-depleted cells. Importantly, the combination of HMAs with targeting of TOPORS did not functionally impair healthy hematopoiesis. While inhibitors of TOPORS are currently unavailable, we show that inhibition of protein SUMOylation (upstream of TOPORS functions) with TAK-981 partially phenocopies HMA-sensitivity and DDR impairment. Overall, our data suggest that the combination of HMAs with the inhibition of SUMOylation or TOPORS demonstrates a favourable therapeutic index and is a rational treatment framework for High-Risk MDS (HR-MDS) or AML.
Pangenomes of Human Gut Microbiota Uncover Links Between Genetic Diversity and Stress Response
Authors: Shoer Saar , Reicher Lee , Pilpel Yitzhak , Segal Eran 
Published: April 2024

AbstractThe human gut microbiota has been the subject of many studies, establishing its central role in host health and disease. Interplay between mutations, horizontal gene transfer, natural selection, and genetic drift, lead to genetic diversity within these species, resulting in different phenotypes and effects on the host. Pangenome represents the collective gene pool of different strains of the same species. Here, we created pangenomes for 728 human gut prokaryotic species, holding four times more genes than the highest quality individual genome, showcasing the genetic diversity inherent in the human gut population. We find these species have a core set of about a thousand genes that defines them, distinct even between closely related species, and an accessory set of genes that are unique to the different strains. Furthermore, we show a spectrum of microbial behavior, while some species exhibit a saturated or “closed” pangenome, suggesting a limited set of genetic capabilities, others maintain an “open” pangenome, indicating elevated adaptability through genetic diversity. We discover that high strain variability is associated with the capacity of species to undergo sporulation, whereas low strain variability is associated with carrying genes that facilitate antibiotic resistances, suggesting different evolutionary strategies for survival taken by these microbes. We further map the landscape of antibiotic resistance genes across the human gut population, and find 237 cases of extreme resistance, predominantly of Enterobacteriaceae species, even to last resort antibiotics kept for cases where traditional treatments have failed. Lastly, we associate microbial strain level differences with human age and sex, exemplifying how the presence of specific genes inAkkermansia muciniphilaandPhocaeicola vulgatusrelate to host characteristics. Overall, our research provides a comprehensive overview of the evolution, genetic complexity and functional potential of the human gut microbiota, emphasizing its significant implications for human health and disease. The pangenomes and the antibiotic resistances map constitute a valuable resource for further scientific research and therapeutic advancements.
Genetic mechanisms underlying the structural elaboration and dissemination of viral internal ribosomal entry sites
Authors: Abaeva Irina S. , Pestova Tatyana V. , Hellen Christopher U. T. 
Published: April 2024

AbstractViral internal ribosomal entry sites (IRESs) form several classes that use distinct mechanisms to mediate end-independent initiation of translation. The origin of viral IRESs is a longstanding question. The simplest IRESs comprise tandem pseudoknots and occur in the intergenic region (IGR) ofDicistroviridaegenomes (orderPicornavirales). Larger IGR IRESs contain additional elements that determine specific properties such as binding to the head of the ribosoma l 40S subunit. Metagenomic analyses reported here identified novel groups of structurally distinct IGR-like IRESs. The smallest of these (∼120nt long) comprise three pseudoknots and bind directly to the ribosomal P site. Others are up to 260nt long: insertions occurred at specific loci, possibly reflecting non-templated nucleotide insertion during replication. Various groups can be arranged in order, differing by the cumulative addition of single structural elements, suggesting an accretion mechanism for the structural elaboration of IRESs. Identification of chimeric IRESs implicates recombinational exchange of domains as a second mechanism for the diversification of IRES structure. Recombination likely also accounts for the presence of IGR-like IRESs at the 5’-end of some dicistrovirus-like genomes (e.g. Hangzhou dicistrovirus 3) and in the RNA genomes ofTombusviridae(orderTolivirales),Marnaviridae(orderPicornavirales), and the ‘Ripiresk’ picorna-like clade (orderPicornavirales).
The variable genomic landscape during osteosarcoma progression: insights from a longitudinal WGS analysis
Authors: Meijer Debora M. , Ruano Dina , Briaire-de Bruijn Inge H. , Wijers-Koster Pauline M. , van de Sande Michiel A.J. , Gelderblom Hans , Cleton-Jansen Anne-Marie , de Miranda Noel F.C.C. , Kuijjer Marieke L. , Bovée Judith V.M.G. 
Published: April 2024

AbstractOsteosarcoma is a primary bone tumor that exhibits a complex genome characterized by gross chromosomal abnormalities. Osteosarcoma patients often develop metastatic disease, resulting in limited therapeutic options and poor survival rates. To gain knowledge on the mechanisms underlying osteosarcoma heterogeneity and metastatic process, it is important to obtain a detailed profile of the genomic alterations that accompany osteosarcoma progression. We performed WGS on multiple tissue samples from six patients with osteosarcoma, including the treatment naïve biopsy of the primary tumor, resection of the primary tumor after neoadjuvant chemotherapy, local recurrence and distant metastases. SNVs and structural variants were found to accumulate over time, contributing to an increased complexity of the genome of osteosarcoma during progression. Phylogenetic trees based on SNVs and structural variants reveal distinct evolutionary patterns between patients, including linear, neutral and branched patterns. The majority of osteosarcomas showed variable copy number profiles or gained whole genome doubling in later occurrences. Additionally, chromothripsis is not confined to a single early event, as multiple other chromothripsis events may appear in later occurrences. Together, we provide a detailed analysis of the complex genome of osteosarcomas and show that five out of six osteosarcoma genomes are highly dynamic and variable during progression.
Differential risk of cardiovascular complications in patients with adult type-2 diabetes mellitus in Ghana using clustering analysis: A hospital-based cross-sectional study
Authors: Obirikorang Christian , Adu Evans Asamoah , Afum-Adjei Awuah Anthony , Darko Samuel Nkansah , Ghartey Frank Naku , Ametepe Samuel , Nyarko Eric NY , Anto Enoch Odame 
Published: April 2024

AbstractAimTo characterize clinically relevant subgroups of patients with T2DM based on adiposity, insulin secretion, and resistance indices.MethodsA cross-sectional study was conducted at Eastern Regional Hospital in Ghana from July to October 2021 to investigate long-term patients with T2DM. To select participants, a systematic random sampling method was employed. Demographic data was collected using a structured questionnaire and fasting blood samples were taken to measure glycemic and lipid levels. Blood pressure and adiposity indices were measured during recruitment. The risk of cardiovascular disease (CVD) was defined using Framingham scores and standard low-density lipoprotein thresholds. To analyze the data, k-means clustering algorithms and regression analysis were used.ResultsThe study identified three groups in female patients according to body mass index, relative fat mass, glycated hemoglobin, and triglyceride-glucose index. These groups included the obesity-related phenotype, the severe insulin resistance phenotype, and the normal weight phenotype with improved insulin resistance. Among male patients with T2DM, two groups were identified, including the obesity-related phenotype with severe insulin resistance and the normal weight phenotype with improved insulin sensitivity. The severe insulin resistance phenotype in female patients was associated with an increased risk of high CVD (OR=5.34, 95%CI:2.11-13.55) and MetS (OR=7.07; 95%CI:3.24-15.42). Among male patients, the obesity-related phenotype with severe insulin resistance was associated with an increased intermediate (OR=21.78, 95%CI:4.17-113.78) and a high-risk CVD (OR=6.84, 95%CI:1.45-32.12).ConclusionsThe findings suggest that there are specific subgroups of patients with T2DM characterized by obesity and uncontrolled insulin resistance leading to poor glycemic control. This underscores the importance of considering differences in adiposity, insulin secretion, and sensitivity indices when making clinical decisions for patients with T2DM.