Effects of commonly used antibiotics on children's developing gut microbiomes and resistomes in peri-urban Lima, Peru.

Background: The effects of antibiotic use on children's gut microbiomes and resistomes are not well characterized in middle-income countries, where pediatric antibiotic consumption is exceptionally common. We characterized the effects of antibiotics commonly used by Peruvian children (i.e.

Prioritizing Parkinson's disease risk genes in genome-wide association loci.

Recent advancements in Parkinson's disease (PD) drug development have been significantly driven by genetic research. Importantly, drugs supported by genetic evidence are more likely to be approved. While genome-wide association studies (GWAS) are a powerful tool to nominate genomic regions associated with certain traits or diseases, pinpointing the causal biologically relevant gene is often challenging.

InTraSeq: A Multimodal Assay that Uncovers New Single-Cell Biology and Regulatory Mechanisms.

Single-cell RNA sequencing (scRNA-seq) has revolutionized cell biology by enabling the profiling of transcriptomes at a single-cell resolution, leading to important discoveries that have advanced our understanding of cellular and tissue heterogeneity, developmental trajectories, and disease progression. Despite these important advances, scRNA-seq is limited to measuring the transcriptome providing a partial view of cellular function. To address this limitation, multimodal scRNA-seq assays have emerged, allowing for the simultaneous measurement of RNA expression and protein.

Transcriptional profile of the rat cardiovascular system at single-cell resolution.

We sought to characterize cellular composition across the cardiovascular system of the healthy Wistar rat, an important model in preclinical cardiovascular research. We performed single-nucleus RNA sequencing (snRNA-seq) in 78 samples in 10 distinct regions, including the four chambers of the heart, ventricular septum, sinoatrial node, atrioventricular node, aorta, pulmonary artery, and pulmonary veins, which produced 505,835 nuclei. We identified 26 distinct cell types and additional subtypes, with different cellular composition across cardiac regions and tissue-specific transcription for each cell type.

Stress reactivity moderates the association between stressful life events and depressive symptoms in adolescents: Results from a population-based study.

Background: A large body of evidence links stressful life events with depression. However, little is understood about the role of perceived impact in this association.

Methods: We performed regression analysis to investigate whether self-reported stress reactivity (derived by regressing the impact-weighted life event score on the unweighted score) moderated the association between stressful life events and depressive symptoms in adolescents from the Avon Longitudinal Study of Parents and Children cohort (n = 4791), controlling for age at outcome, sex, ethnicity, and maternal education.

Deep profiling deconstructs features associated with memory CD8 T cell tissue residence.

Tissue-resident memory CD8 T (Trm) cells control infections and cancer and are defined by their lack of recirculation. Because migration is difficult to assess, residence is usually inferred by putative residence-defining phenotypic and gene signature proxies. We assessed the validity and universality of residence proxies by integrating mouse parabiosis, multi-organ sampling, intravascular staining, acute and chronic infection models, dirty mice, and single-cell multi-omics.

Putative looping factor ZNF143/ZFP143 is an essential transcriptional regulator with no looping function.

Interactions between distal loci, including those involving enhancers and promoters, are a central mechanism of gene regulation in mammals, yet the protein regulators of these interactions remain largely undetermined. The zinc-finger transcription factor (TF) ZNF143/ZFP143 has been strongly implicated as a regulator of chromatin interactions, functioning either with or without CTCF. However, how ZNF143/ZFP143 functions as a looping factor is not well understood.

Potassium/sodium cation carriers robustly up-regulate CD20 antigen by targeting MYC, and synergize with anti-CD20 immunotherapies to eliminate malignant B cells.

Our investigation uncovers that nanomolar concentrations of salinomycin, monensin, nigericin, and narasin (a group of potassium/sodium cation carriers) robustly enhance surface expression of CD20 antigen in B-cell-derived tumor cells, including primary malignant cells of chronic lymphocytic leukemia and diffuse large B-cell lymphoma. Experiments in vitro, ex vivo, and animal model reveal a novel approach of combining salinomycin or monensin with therapeutic anti-CD20 monoclonal antibodies or anti-CD20 CAR-T cells, significantly improving non- Hodgkin lymphoma (NHL) therapy. The results of RNA-seq, genetic editing, and chemical inhibition delineate the molecular mechanism of CD20 upregulation, at least partially, to the downregulation of MYC, the transcriptional repressor of the MS4A1 gene encoding CD20.

Assembling Ancestors: the manipulation of Neolithic and Gallo-Roman skeletal remains from Pommerœul, Belgium.

The ancient cemetery of Pommerœul, Belgium, was classified as Gallo-Roman in the 1970s', yielding 76 cremation graves and one inhumation. However, subsequent radiocarbon analyses dated the inhumation to the Late Neolithic (4-3 millennium calBC). We report osteoarchaeological analysis indicating that the inhumation was composed of bones from multiple individuals, afterwards buried as "one".

Probabilistic medical predictions of large language models.

Large Language Models (LLMs) have shown promise in clinical applications through prompt engineering, allowing flexible clinical predictions. However, they struggle to produce reliable prediction probabilities, which are crucial for transparency and decision-making. While explicit prompts can lead LLMs to generate probability estimates, their numerical reasoning limitations raise concerns about reliability.

Bridging silicon and carbon worlds with digital twins and on-chip systems in drug discovery.

This perspective discusses the convergence of digital twin (DT) technology and on-the-chip systems as pivotal innovations in precision medicine, substantially advancing drug discovery. DT leverages extensive health data to create dynamic virtual patient models, enabling predictive insights and optimized treatment strategies. Concurrently, on-the-chip systems from the Carbon world replicate human biological processes on microfluidic platforms, providing detailed insights into disease mechanisms and pharmacological interactions.

HGVS Nomenclature 2024: improvements to community engagement, usability, and computability.

Background: The Human Genome Variation Society (HGVS) Nomenclature is the global standard for describing and communicating variants in DNA, RNA, and protein sequences in clinical and research genomics. This manuscript details recent updates to the HGVS Nomenclature, highlighting improvements in governance, community engagement, website functionality, and underlying implementation of the standard.

Methods: The HGVS Variant Nomenclature Committee (HVNC) now operates under the Human Genome Organization (HUGO), facilitating broader community feedback and collaboration with related standards organizations.

The landscape of primary mismatch repair deficient gliomas in children, adolescents, and young adults: a multi-cohort study.

Background: Gliomas are a major cause of cancer-related death among children, adolescents, and young adults (age 0-40 years). Primary mismatch repair deficiency (MMRD) is a pan-cancer mechanism with unique biology and therapeutic opportunities. We aimed to determine the extent and impact of primary MMRD in gliomas among children, adolescents, and young adults.

Exome and Genome Sequencing to Diagnose the Genetic Basis of Neonatal Hypotonia: An International Consortium Study.

Background And Objectives: Hypotonia is a relatively common finding among infants in the neonatal intensive care unit (NICU). Consideration of genetic testing is recommended early in the care of infants with unexplained hypotonia. We aimed to assess the diagnostic yield and overall impact of exome and genome sequencing (ES and GS).

Circulating cytokine associations with clinical outcomes in melanoma patients treated with combination nivolumab plus ipilimumab.

Nivolumab plus ipilimumab (aCTLA-4/aPD-1) combination therapy has significantly improved clinical outcomes in patients with metastatic melanoma, with 50%-60% of patients responding to treatment, but predictors of response are poorly characterized. We hypothesized that circulating cytokines and peripheral white blood cells may predict response to therapy and evaluated 15 cytokines and complete blood counts (CBC with differentials) from 89 patients with advanced melanoma treated with combination therapy from three points in time: pre-treatment, one month and approximately three months after starting therapy. Clinical endpoints evaluated included durable clinical benefit (DCB), progression-free survival (PFS), and overall survival (OS).

Historical and Archaeogenomic Identification of High-Status Englishmen at Jamestown, Virginia.

Ancient DNA (aDNA) data are reported for two human skeletons buried within the chancel of the 1608-1616 church at the North American colonial settlement of Jamestown, Virginia. The men are suspected kinsmen of the colony's first Governor, Thomas West, 3 Baron De La Warr based on archaeological, osteological, and documentary evidence. Genomic analyses of these men, Sir Ferdinando Wenman and Captain William West, identify a shared mitochondrial haplogroup, H10e, inferring maternal relatedness.

Type 2 diabetes genetic risk and incident diabetes across diabetes risk enhancers.

Aims: To evaluate the predictive value of a contemporary type 2 diabetes (T2D) polygenic score (PGS) in detecting incident diabetes across a range of diabetes risk factors.

Materials And Methods: We analysed participants in the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial (ClinicalTrials.gov, number NCT0176463), which compared the efficacy of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab versus placebo in lowering cardiovascular outcomes in participants with stable atherosclerotic cardiovascular disease and LDL cholesterol levels of 70 mg/dL (1.

Evaluation of imputation performance of multiple reference panels in a Pakistani population.

Genotype imputation is crucial for GWAS, but reference panels and existing benchmarking studies prioritize European individuals. Consequently, it is unclear which publicly available reference panel should be used for Pakistani individuals, and whether ancestry composition or sample size of the panel matters more for imputation accuracy. Our study compared different reference panels to impute genotype data in 1814 Pakistani individuals, finding the best performance balancing accuracy and coverage with meta-imputation with TOPMed and the expanded 1000 Genomes (ex1KG) reference.

Advancements in Immunity and Dementia Research: Highlights from the 2023 AAIC Advancements: Immunity Conference.

The immune system is a key player in the onset and progression of neurodegenerative disorders. While brain resident immune cell-mediated neuroinflammation and peripheral immune cell (eg, T cell) infiltration into the brain have been shown to significantly contribute to Alzheimer's disease (AD) pathology, the nature and extent of immune responses in the brain in the context of AD and related dementias (ADRD) remain unclear. Furthermore, the roles of the peripheral immune system in driving ADRD pathology remain incompletely elucidated.

Count Me In: patient-partnered research to address disparities for rare cancer patients.

Background: Approximately 25% of cancer patients are diagnosed with rare cancers and face unique challenges. Decentralized patient-partnered research efforts, like Count Me In provide an avenue for patients to participate in research that overcomes key barriers to address disparities in rare cancer research to accelerate discovery.

Objectives: Projects in metastatic breast cancer (The Metastatic Breast Cancer Project; MBCproject) and angiosarcoma (The Angiosarcoma Project; ASCproject) highlight disparities that exist for all cancer patients and underscore those that are compounded for rare cancer patients.