bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neurotoxic Methamphetamine Doses Alter CDCel-1 Levels and Its Interaction with Vesicular Monoamine Transporter-2 in Rat Striatum
Authors: Chauhan Heli , Carruthers Nick , Stemmer Paul , Schneider Bernard P. , Moszczynska Anna 
Published: July 2024

AbstractIn recent years, methamphetamine METH misuse in the US has been rapidly increasing and there is no FDA-approved pharmacotherapy for METH use disorder (MUD). In addition to being dependent on the drug, people with MUD develop a variety of neurological problems related to the toxicity of this drug. A variety of molecular mechanisms underlying METH neurotoxicity has been identified, including dysfunction of the neuroprotective protein parkin. However, it is not known whether parkin loss of function within striatal dopaminergic (DAergic) terminals translates into a decrease in DA storage capacity. This study examined the relationship between parkin, its substrate cell division cycle related-1 (CDCrel-1), and vesicular monoamine transporter-2 (VMAT2) in METH neurotoxicity in male Sprague Dawley rats. To also assess individual differences in response to METH’s neurotoxic effects, a large group of rats was treated with binge METH or saline and sacrificed 1h or 24h later. This study is the first to show that binge METH alters the levels and subcellular localization of CDCrel-1 and that CDCrel-1 interacts with VMAT2 and increases its levels at the plasma membrane. Furthermore, we found wide individual differences in the responses of measured indices to METH. Proteomic analysis of VMAT-2-associated proteins revealed upregulation of several proteins involved in the exocytosis/endocytosis cycle. The results suggest that at 1h after METH binge, DAergic neurons are engaged in counteracting METH-induced toxic effects, including oxidative stress- and hyperthermia-induced inhibition of synaptic vesicle cycling, with the responses varying between individual rats. Studying CDCrel-1, VMAT2, and other proteins in large groups of outbred rats can help define individual genetic and molecular differences in responses to METH neurotoxicity which, in turn, will aid treating humans suffering from METH use disorder and its neurological consequences.
Tiberius: End-to-End Deep Learning with an HMM for Gene Prediction
Authors: Gabriel Lars , Becker Felix , Hoff Katharina J. , Stanke Mario 
Published: July 2024

AbstractMotivationFor more than 25 years, learning-based eukaryotic gene predictors were driven by hidden Markov models (HMMs), which were directly inputted a DNA sequence. Recently, Holst et al. demonstrated with their program Helixer that the accuracy ofab initioeukaryotic gene prediction can be improved by combining deep learning layers with a separate HMM postprocessor.ResultsWe present Tiberius, a novel deep learning-basedab initiogene predictor that end-to-end integrates convolutional and long short-term memory layers with a differentiable HMM layer. Tiberius uses a custom gene prediction loss and was trained for prediction in mammalian genomes and evaluated on human and two other genomes. It significantly outperforms existingab initiomethods, achieving F1-scores of 62% at gene level for the human genome, compared to 21% for the next bestab initiomethod. Inde novomode, Tiberius predicts the exon-intron structure of two out of three human genes without error. Remarkably, even Tiberius’sab initioaccuracy matches that of BRAKER3, which uses RNA-seq data and a protein database. Tiberius’s highly parallelized model is the fastest state-of-the-art gene prediction method, processing the human genome in under 2 hours.Availability and Implementationhttps://github.com/Gaius-Augustus/TiberiusContact{lars.gabriel@uni-greifswald.de,mario.stanke@uni-greifswald.de}
Single-cell transcriptomic profiling of the whole colony ofBotrylloides diegensis: Insights into tissue specialization and blastogenesis
Authors: Temiz Berivan , Meier Michael , Wilson Megan J. 
Published: July 2024

AbstractBotrylloides diegensisis a colonial ascidian that has been the focus of developmental, evolutionary, and regeneration research. In this study, we performed single-cell RNA sequencing (scRNA-seq) of an entireB. diegensiscolony, including zooids, buds, and vascular tunics, to resolve cellular heterogeneity and identify cell and tissue markers. We identified 29 major cell clusters within the colony and usedin situhybridization to examine the spatial expression of cluster marker genes. Numerous tissue types were identified at the molecular level, including blood cells and zooid tissues such as the branchial epithelium, stomach, and endostyle. Distinct cluster markers were identified for specific regions of the stomach epithelium, highlighting the specialization of these regions and the strength of using scRNA-seq to explore their functionality. Cell trajectory projections highlighted the early appearance of progenitor clusters, whereas more differentiated zooid-related tissues appeared later in the developmental path. This study provides a valuable resource for understanding the development, tissue function, and regeneration ofB. diegensis.This demonstrates the power of scRNA-seq to define cell types and tissues in complex colonial organisms.Summary statementSingle-cell RNA sequencing ofBotrylloides diegensisrevealed cellular heterogeneity, identified 29 major cell clusters, and provided insights into tissue specialization and blastogenesis.
Experiences of Indigenous peoples living with pelvic health conditions: A scoping review
Authors: Brown Kaeleigh , Choi Katherine , Kim Esther , Campbell Sandra M , Schulz Jane , Moffitt Pertice , Chatwood Susan 
Published: July 2024

AbstractBackgroundPelvic health conditions significantly impact quality of life and are prevalent in the general population. Urinary and fecal incontinence, pelvic organ prolapse, and pelvic pain are examples of pelvic health conditions. A scoping review was conducted to understand what is currently known about pelvic health conditions experienced by Indigenous populations worldwide. To date, no such review has been reported.MethodsA scoping review methodology was used. In June 2023, a search was conducted, and then updated in February 2024, capturing both primary and grey literature. An iterative process of abstract and full text screening was conducted by two reviewers before proceeding to data extraction. Inclusion criteria focused on English publications and reports of pelvic health conditions experienced by Indigenous peoples. Data was collected in Google Sheets, and then underwent descriptive statistical analysis. Publications that provided qualitative data were analyzed using thematic analysis.ResultsA total of 203 publications were included in the analysis. Several patterns emerged regarding publication region, gender and age representation, pelvic health conditions reported, and representation of Indigenous peoples. Notable gaps were a lack of publications from China, Russia, and Nordic countries, minimal representation of gender diverse populations, few publications reporting on auto-immune and bowel conditions, and limited mention of trauma-informed and culturally safe approaches.ConclusionsThis study highlights gaps in the current literature around gender representation, bowel and auto-immune conditions, regional representation, and the use of safety frameworks, which may inform future research initiatives. It also summarizes the existing literature, which may inform clinical and health system-level decision making.
ATRIP deficiency impairs the replication stress response and manifests as microcephalic primordial dwarfism and immunodeficiency
Authors: Duthoo Evi , Beyls Elien , Backers Lynn , Gudjónsson Thorkell , Huang Peiquan , Jonckheere Leander , Riemann Sebastian , Parton Bram , Du Likun , Debacker Veronique , De Bruyne Marieke , Hoste Levi , Baeyens Ans , Vral Anne , Van Braeckel Eva , Staal Jens , Mortier Geert , Kerre Tessa , Pan-Hammarström Qiang , Sørensen Claus Storgaard , Haerynck Filomeen , Claes Kathleen BM , Tavernier Simon J 
Published: July 2024

ABSTRACTATR (Ataxia Telangiectasia and Rad3-related) kinase and its interacting protein ATRIP orchestrate the replication stress response. Two patients of independent ancestry with microcephaly, primordial dwarfism, and recurring infections were found to be homozygous for splice donor site variants ofATRIPexon 5, resulting in ATRIP deficiency. The c.829+5G>T patient exhibited autoimmune hemolytic anemia, lymphopenia, poor vaccine response, and intermittent neutropenia. Immunophenotyping revealed reduced CD16+NK cells and absent naïve T cells, mucosal-associated invariant T cells (MAITs), and invariant natural killer T cells (iNKTs). Lymphocytic defects were characterized by T cell receptor (TCR) oligoclonality, abnormal class switch recombination (CSR), and impaired T cell proliferation. ATRIP deficiency resulted in low-grade ATR activation but impaired CHK1 phosphorylation upon genotoxic stress. Consequently, ATRIP deficient cells inadequately regulated DNA replication, leading to chromosomal instability, compromised cell cycle control, and impaired cell viability. CRISPR-SelectTIMEconfirmed reduced cell fitness induced by both variants. This study establishes ATRIP deficiency as a monogenic cause of microcephalic primordial dwarfism, highlights ATRIP’s critical role in protecting immune cells from replication stress, and brings a renewed perspective to the canonical functions of ATRIP.
The Effects of Heart Rate Variability Biofeedback on Functional Gastrointestinal Disorders: A Scoping Review
Authors: Pereira Ashley G , Fu Lily , Xu William , Gharibans Armen A , O’Grady Greg 
Published: July 2024

AbstractFunctional Gastrointestinal Disorders (FGID) are a group of symptom-based disorders that occur across the alimentary tract and have a high prevalence globally in both adults and children. These symptoms are chronic and/or recurrent and often have substantial effects on quality of life. Their incidence is tied to multiple factors, including gut-brain axis imbalance, which includes autonomic dysregulation related to a relative withdrawal of vagal activity. Heart rate variability biofeedback (HRVB) is a non-invasive intervention that can influence autonomic activity and has shown benefit for diverse conditions including depression and anxiety, however the evidence of its effect has not yet been systematically assessed in FGIDs. This scoping review aimed to collate and evaluate the available literature regarding HRVB and FGIDs. We systematically searched four medical databases. Four articles met inclusion criteria for being interventional studies using HRVB in FGIDs. These were heterogeneous, including both paediatric and adult as well different subtypes of FGID. Two of the four studies demonstrated significant improvements from HRVB interventions in FGID symptoms while the other two found no significant difference. Scoping evaluation indicated this inconsistency likely reflects heterogeneous populations and study designs. Further scoping review of the broader HRVB literature also discovered that at least six weeks of HRVB is required to observe an impact on FGID symptoms and defined recommended guidance for performing future evaluations of HRVB in FGIDs. Evidence on HRVB for FGID is emergent, however HRVB appears a promising intervention when administered optimally. Further studies using best-practice techniques are required.
Systematic benchmarking demonstrates large language models have not reached the diagnostic accuracy of traditional rare-disease decision support tools
Authors: Reese Justin T , Chimirri Leonardo , Bridges Yasemin , Danis Daniel , Caufield J Harry , Wissink Kyran , McMurry Julie A , Graefe Adam SL , Casiraghi Elena , Valentini Giorgio , Jacobsen Julius OB , Haendel Melissa , Smedley Damian , Mungall Christopher J , Robinson Peter N 
Published: July 2024

AbstractLarge language models (LLMs) show promise in supporting differential diagnosis, but their performance is challenging to evaluate due to the unstructured nature of their responses. To assess the current capabilities of LLMs to diagnose genetic diseases, we benchmarked these models on 5,213 case reports using the Phenopacket Schema, the Human Phenotype Ontology and Mondo disease ontology. Prompts generated from each phenopacket were sent to three generative pretrained transformer (GPT) models. The same phenopackets were used as input to a widely used diagnostic tool, Exomiser, in phenotype-only mode. The best LLM ranked the correct diagnosis first in 23.6% of cases, whereas Exomiser did so in 35.5% of cases. While the performance of LLMs for supporting differential diagnosis has been improving, it has not reached the level of commonly used traditional bioinformatics tools. Future research is needed to determine the best approach to incorporate LLMs into diagnostic pipelines.
Predicted failure of common Mpox PCR testing on a recent DRC clade I variant: Persistent genomic surveillance is critically important for accurate diagnostics
Authors: Gratalo Dawn , Morley Valerie J. , Oppenheim Ben , Philipson Casandra W. , Rush Sarah , Sureka Swati , Wolfe Mitchell I. , Simen Birgitte B. 
Published: July 2024

AbstractPathogens can rapidly evolve to evade detection via existing diagnostic testing capabilities, creating blind spots for health care and security systems. Persistent genomic surveillance of pathogens can help identify and address these gaps. Here, we present a case study of a new lineage of Monkeypox virus Clade I that emerged during an outbreak in the Democratic Republic of the Congo, in which a genomic deletion allowed the virus to evade detection by current diagnostic assays. We rapidly developed and validated an updated assay. Availability of pathogen genomic data is a critical input, and often a bottleneck, to response efforts.
Exploring Temperature Effects on Large Language Models Across Various Clinical Tasks
Authors: Patel Dhavalkumar , Timsina Prem , Raut Ganesh , Freeman Robert , levin Matthew A , Nadkarni Girish N , Glicksberg Benjamin S , Klang Eyal 
Published: July 2024

AbstractLarge Language Models (LLMs) are becoming integral to healthcare analytics. However, the influence of the temperature hyperparameter, which controls output randomness, remains poorly understood in clinical tasks. This study evaluates the effects of different temperature settings across various clinical tasks. We conducted a retrospective cohort study using electronic health records from the Mount Sinai Health System, collecting a random sample of 1283 patients from January to December 2023. Three LLMs (GPT-4, GPT-3.5, and Llama-3-70b) were tested at five temperature settings (0.2, 0.4, 0.6, 0.8, 1.0) for their ability to predict in-hospital mortality (binary classification), length of stay (regression), and the accuracy of medical coding (clinical reasoning). For mortality prediction, all models’ accuracies were generally stable across different temperatures. Llama-3 showed the highest accuracy, around 90%, followed by GPT-4 (80-83%) and GPT-3.5 (74-76%). Regression analysis for predicting the length of stay showed that all models performed consistently across different temperatures. In the medical coding task, performance was also stable across temperatures, with GPT-4 achieving the highest accuracy at 17% for complete code accuracy. Our study demonstrates that LLMs maintain consistent accuracy across different temperature settings for varied clinical tasks, challenging the assumption that lower temperatures are necessary for clinical reasoning.
A Specialized Reference Panel with Structural Variants Integration for Improving Genotype Imputation in Alzheimer’s Disease and Related Dementias (ADRD)
Authors: Cheng Po-Liang , Wang Hui , Dombroski Beth A , Farrell John J , Horng Iris , Chung Tingting , Tosto Giuseppe , Kunkle Brian W , Bush William S , Vardarajan Badri , Schellenberg Gerard D , Lee Wan-Ping 
Published: July 2024

SummaryWe developed an imputation panel for Alzheimer’s disease (AD) and related dementias (ADRD) using whole-genome sequencing (WGS) data from the Alzheimer’s Disease Sequencing Project (ADSP). Recognizing the significant associations between structural variants (SVs) and AD, and their underrepresentation in existing public reference panels, our panel uniquely integrates single nucleotide variants (SNVs), short insertions and deletions (indels), and SVs. This panel enhances the imputation of disease susceptibility, including rare AD-associated SNVs, indels, and SVs, onto genotype array data, offering a cost-effective alternative to whole-genome sequencing while significantly augmenting statistical power. Notably, we discovered 10 rare indels nominal significant related to AD that are absent in the TOPMed-r2 panel and identified three suggestive significant (p-value < 1E-05) AD-associated SVs in the genesEXOC3L2andDMPK, were identified. These findings provide new insights into AD genetics and underscore the critical role of imputation panels in advancing our understanding of complex diseases like ADRD.
Microvascular dysfunction induces a hyperdynamic circulation; a mathematical exploration
Authors: Popovich Ivor 
Published: July 2024

AbstractBackgroundThe discordance between the macrocirculation and microcirculation in septic shock has been recognised but never explained. I present a novel mathematical hypothesis as to how heterogenous microcirculatory flow distribution directly induces a hyperdynamic circulation and how elevated central venous pressure induces microcirculatory dysfunction.MethodsI explore the tube law and modified Poiseuille resistance for compliant blood vessels. Using these equations a new equation is developed incorporating time constants, elastance of the vessel, unstressed volume and wave reflections that demonstrates the relationship between volume of a microcirculatory vessel and total flow through it.ResultsThe relationship is demonstrated to be constant at zero until the unstressed volume is reached after which it increases exponentially. By considering n of these vessels in parallel, I demonstrate that the summed flow is minimised when flow is equally distributed among the n vessels, while it is maximised when all flow goes through one vessel alone, thereby demonstrating that heterogenous microvascular perfusion leads to increased total flow. It is shown that if conditions of wave reflection are right then a hyperdynamic circulation with high cardiac output develops. It is also demonstrated that high central venous pressure increases wave reflections and necessarily leads to microvascular perfusion heterogeneity if cardiac output is to be maintained.ConclusionsMicrovascular impairment in septic shock directly leads to a hyperdynamic circulation with high cardiac output. High central venous pressures impair the microcirculation. Decades of clinical findings can now be explained mathematically. Implications for hemodynamic therapy for septic shock are discussed.Clinical PerspectiveResearch in septic shock has focussed on two main components of the circulation; the macrocirculation and microcirculation. Very discordant findings have been observed between the two, to the point that the term ‘uncoupling’ has appeared in the literature in reference to these two circulations. Thus far nobody has put forward a satisfactory physiological explanation as to the mechanism of this discordance. There is a need to understand the physiological mechanisms to guide future attempts and research into methods of resuscitating the septic patient in order to improve circulatory function.This work provides the first theoretical mathematical groundwork as to not only how these circulations are linked, but how they directly influence one another. This sets the framework for future clinical and basic science research and helps us understand how our current resuscitation strategies may work to restore the microcirculation, and when they may start to impair it.
Prognostic Nutritional Index in Risk of Mortality Following Fulminant Myocarditis
Authors: Doi Shunichi , Ishibashi Yuki , Suzuki Norio , Miyahara Daisuke , Sato Yukio , Kuwata Shingo , Kida Keisuke , Izumo Masaki , Onoue Kenji , Kanaoka Koshiro , Saito Yoshihiko , Akashi Yoshihiro J. ,   Japanese Registry of Fulminant Myocarditis Investigators
Published: July 2024

AbstractBackgroundFulminant myocarditis (FM) is an acute fatal inflammation disease, but its chronic phase is unclear. A Japanese nationwide registry evaluated the long-term mortality in FM patients using a prognostic nutritional index (PNI).Methods and ResultsThe retrospective cohort study included patients with clinically suspected or histologically proven FM available for PNI. PNI was assessed on admission and at discharge. We divided patients into two groups based on PNI at discharge (PNI ≤40 or PNI >40) and analyzed the change in PNI and mortality between the groups. Of 323 patients (the median [first-third quartiles] age of this cohort was 50 [37–64] years, and 143 [44%] were female), PNI ≤40 at discharge was in 99 (31%) patients. The median PNI in all patients increased from 41 (36– 46) on admission to 43 (39–48) at discharge (P<0.0001). Patients with PNI ≤40 had a lower event-free rate of death or rehospitalization with cardiovascular causes than those with PNI >40 (log-rankP=0.0001). When the PNI at discharge, age, sex, left ventricular ejection fraction, and Barthel index were evaluated in a multivariable Cox regression analysis, PNI ≤40 had an independent association with the death or rehospitalization with cardiovascular causes (hazard ratio, 2.14 [95% confidence interval, 1.14–4.01];P=0.0289).ConclusionsOne-third of FM patients with low PNI at discharge had a higher risk of mortality than those with high PNI in the chronic phase. This study provokes clinical insight into the phenotype of chronic inflammation in FM and optimal follow-up management with low PNI.
Who Grows There? A Course-based Undergraduate Research Experience to explore the human microbiome through 16S DNA metabarcoding
Authors: Sellers Graham S , Freiheit Merideth , Winter Michael R , Joyce Domino A , Cullen Darron A , Lunt David H , Hubbard Katharine E 
Published: July 2024

AbstractWe describe a two week Course-based Undergraduate Research Experience (CURE) to introduce students to next-generation DNA sequencing, molecular biology methods and a bioinformatic workflow. The CURE is designed to take students with little to no technical and bioinformatic experience through key steps of the protocol through scaffolded laboratory and computational practicals. Our students extract and amplify human microbiome DNA using 16S ribosomal RNA specific primers, then construct a sequencing library for Oxford Nanopore based sequencing. They taxonomically assign the sequencing reads, and determine the ecological community composition using relevant software packages. Our students were able to successfully prepare sequencing libraries and analyse the data to produce relevant figures, demonstrating they met the learning objectives of the CURE. Students identified that they had developed higher level learning as defined by Bloom’s taxonomy, and that their confidence in practical work significantly increased as a result of doing the CURE. We share recommendations for implementation of the CURE in undergraduate curricula, and adaptations of the methods for use in schools outreach. Our CURE successfully provides training for students in genetic analysis in an enjoyable and relatively time and cost efficient manner, preparing them for future research or careers in modern molecular biology techniques.