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SLC7A8 is essential for metabolic fitness and function of Th2 cells
No full textAmino acids are essential for the activation and function of CD4 T helper (Th) cells, which differentiate into Th1, Th2, Th17, and Treg subsets to coordinate immune responses. While specific amino acid transporters have been identified for Th1, Th17, and Tregs, a transporter regulating Th2 cells remains unknown. This study identifies SLC7A8 as a Th2-specific amino acid transporter in the Th compartment. We found that Slc7a8 expression is upregulated in Th2 cells compared with other T helper subsets, and Slc7a8 deficiency impairs Th2 cell proliferation and cytokine production. Furthermore, SLC7A8 was found to be crucial for an effective type 2 immune response to helminth infection and allergen-induced lung inflammation. Mechanistically, Slc7a8 deficiency disrupted Th2 cell metabolism, leading to reduced mTOR activation and, consequently, diminished mitochondrial function along with an impaired c-Myc pathway; these defects cumulatively induced cellular stress that curtailed cell growth and survival. Collectively, these findings highlight a previously unknown role for SLC7A8 in Th2 cells, with potential implications for understanding and treating type 2 immune-related diseases
Lightweight open-source large language models versus cTAKES for information extraction from discharge summaries: Tobacco smoking status test case
No full textOBJECTIVES: To compare lightweight open-source large language models (LLMs) with cTAKES, a state-of-the-art natural language processing (NLP) system, in an information extraction task from hospitalization discharge summaries.
MATERIALS AND METHODS: Two readers annotated 250 randomly sampled adult discharge summaries (BJC HealthCare, 2018-2023) for tobacco smoking status as Smoker, Never smoker, Unknown. Six LLMs (Llama-3 [1B-70B], gpt-oss-20B, MedGemma-27B) and cTAKES extracted smoking status from summaries. Performance was benchmarked against consensus annotations using weighted F1-score, macro F1-score, and per-class F1-scores and a noninferiority test.
RESULTS: Inter-reader agreement was excellent (κ = 0.91). LLM size (2.3-47.3 GB) and inference time (2.5-14.5 s/note) varied. gpt-oss-20B achieved non-inferior performance vs cTAKES (F1 = 0.99 vs 0.97;
DISCUSSION: The high accuracy and efficiency of gpt-oss-20B support its potential as a practical, open-source alternative to traditional NLP for clinical information extraction.
CONCLUSION: Lightweight LLMs can be applied for use across diverse clinical information extraction tasks without the need for task-specific fine-tuning
Accurate chromatin marks peak calling with Omnipeak
No full textChromatin immunoprecipitation sequencing (ChIP-seq) is a widely used technique for identifying transcription-factor binding and histone modifications across the genome. Peaks in ChIP-seq data vary in length depending on the biological context, from narrow transcription factor binding sites to broad histone modification domains. However, commonly used peak-calling tools are tailored to the specific types of data and struggle to consistently handle various peak lengths, datasets of varying quality, and missing control tracks-common issues in comparative or meta-analyses. These limitations are addressed with Omnipeak, a universal unsupervised peak-calling algorithm based on a constrained three-state hidden Markov model. Omnipeak accurately models global genomic read coverage, capturing structure patterns in the data of all length scales and variable quality. We benchmarked Omnipeak versus eight different peak calling methods using over 550 public and 300 synthetic datasets, including conventional, ultra-low-input ChIP-seq, and ATAC-seq. Omnipeak produced consistent peaks across narrow, broad, and variable mark lengths, with the best agreement between replicates and robustness against noise and lack of control tracks. Together with a variety of supported input formats and peak calling capabilities within the genome browser, Omnipeak is well-positioned for processing various ChIP-seq and ATAC-seq datasets
Mapping the transcriptional regulatory network of a fungal pathogen by exploiting transcription factor perturbation
No full textUNLABELLED:
IMPORTANCE
Clinical performance of a novel point-of-care high-sensitivity cardiac troponin I assay
No full textBACKGROUND: High-sensitivity cardiac troponin (hs-cTn) assays performed in the central laboratory have long turnaround times. This study evaluates the clinical performance of a novel bedside point-of-care (POC) hs-cTnI assay (i-STAT® hs-TnI) to aid in the diagnosis of myocardial infarction (MI).
METHODS: A prospective multisite cohort study involving emergency department (ED) patients with symptoms suggestive of acute coronary syndrome was conducted at 28 sites across the United States. Serial whole blood samples were collected at 0-1 h and \u3e1-3 h from ED presentation. Primary outcome was MI or non-MI. Sensitivity, specificity, and negative predictive value (NPV) for MI were calculated with 97.5% lower confidence limits (LCL) using the female, male, and overall 99th percentile upper reference limit (URL, 13, 28, and 21 ng/L, respectively). Post hoc analysis was also conducted for initial measurements below the limit of quantification (LoQ, 2.9 ng/L) and \u3c 5.0 ng/L.
RESULTS: The cohort included 3582 patients, median age 59 y, 64% female. MI incidence was 8.6%. Sensitivity and specificity at \u3e1-3 h were 96.6% (LCL 91.7%) and 82.1% (80.2%) using the female URL; 90.7% (LCL 84.1%) and 83.9% (LCL 81.4%) using the male URL; and 92.4% (LCL 88.3%) and 85.6% (LCL 84.2%) using the overall URL. NPVs for MI of initial hs-cTnI measurements
CONCLUSIONS: The whole blood POC i-STAT hs-TnI assay demonstrated performance characteristics similar to other hs-cTn assays and achieved high sensitivity and NPV for initial measurements
CLINICALTRIALS.GOV REGISTRATION NUMBER: NCT05629572
St. Louis Children\u27s Hospital Publications Collection
No full texthttps://digitalcommons.wustl.edu/homepage_slideshow/1005/thumbnail.jp
Amyloidosis of bridging veins is a pathologic feature of Alzheimer\u27s disease
No full textAlzheimer\u27s disease (AD) is characterized by the accumulation of extracellular aggregated amyloid beta, resulting from impaired waste clearance. We recently identified new cerebrospinal fluid (CSF) efflux structures termed arachnoid cuff exit (ACE) points and speculated that these may be impacted in AD, leading to impaired waste clearance function. Using 5XFAD mice, we found progressive amyloidosis of bridging veins at ACE points. Indeed, in 5XFAD mice, there is impaired CSF efflux to the dura mater, impaired CSF flow along bridging veins, and impaired blood flow through bridging veins. These observations suggest that ACE point amyloidosis plays a role in waste clearance dysfunction in AD. In postmortem human samples, we also found striking amyloidosis of the bridging veins of individuals with AD. Moreover, in human AD specimens, there was prominent bridging vein structural degeneration, indicating advanced pathology and stronger deficits in humans. We propose that bridging vein amyloidosis is an underrecognized pathophysiological correlate of AD that may impair CSF efflux, intracranial pressure, vascular reactivity, and vascular integrity
The IGVF Catalog-From genetic variation to function
No full textGenomic variation between individuals is essential for understanding how differences in the genome sequence affect molecular and cellular processes. The Impact of Genomic Variation on Function (IGVF) Consortium aims to uncover the relationships among genomic variation, genome function, and phenotypes by combining experimental techniques, such as single-cell mapping and genomic perturbation assays, with computational approaches such as machine learning-based predictive modeling. The IGVF Data and Administrative Coordinating Centers collect, analyze, and disseminate data and results from across the consortium through an open-source platform called the IGVF Catalog. This resource includes, but is not limited to, data on the effects of coding variants on protein abundance and function, noncoding variants on enhancer activity (measured by MPRA or predicted computationally), and associations between variants and quantitative traits. All data are organized within a graph database comprising over 50 types of data collections with nearly 3 billion nodes and over 7.5 billion edges. The Catalog offers public API endpoints (https://api.catalogkg.igvf.org/) and a user-friendly interface for exploring, querying, and visualizing the data at https://catalog.igvf.org. We expect that this open-access platform will support the broader scientific community to advance our understanding of how genomic variation influences biology and disease
Towards a unified gating scheme for the CNBD ion channel family
No full textCyclic nucleotide-binding domain (CNBD) channels are critical components of numerous bioelectrical processes, including cardiac pacemaking, neuronal signaling, phototransduction in the eye, and stomatal regulation in plants. While members of this channel family share a conserved overall structure, they exhibit striking differences in voltage sensitivity. Hyperpolarization-activated cyclic nucleotide-gated channels are activated by membrane hyperpolarization, whereas ether-à-go-go channels open upon depolarization. Mutagenesis and chimeragenesis studies have revealed that some mutants display bipolar gating behavior-remaining closed at intermediate membrane potentials but capable of opening in response to both hyperpolarization and depolarization. Remarkably, in certain cases, just a few mutations are sufficient to reverse the intrinsic gating polarity of the channel. This degree of diversity and plasticity in voltage-dependent gating appears to be unique to the CNBD clade and is not adequately explained by existing models. In this study, we systematically evaluate current models and propose a revised framework that better accounts for the full range of voltage-gating behaviors observed in CNBD channels