Expansion and revision of the genus and proposal of gen. nov.

The nitrogen-fixing, chemolithoautotrophic genus is found across numerous diverse environments worldwide and is an important member of many ecosystems. These species serve as model systems for their metabolic properties and have industrial applications in bioremediation and sustainable protein, food and fertilizer production. Despite their abundance and utility, the majority of strains are without a genome sequence, and only eight validly published species are known to date.

The RNA-binding protein TRIM71 is essential for hearing in humans and mice and times auditory sensory organ development.

The RNA-binding protein TRIM71 is essential for brain development, and recent genetic studies in humans have identified as a risk gene for congenital hydrocephal-us (CH). Here, we show that monoallelic missense mutations in are associated with hearing loss (HL) and inner ear aplasia in humans. Utilizing conditional knockout mice carrying a CH and HL-associated mutation, we demonstrate that loss of TRIM71 function during early otic development (embryonic day 9 to 10) causes severe HL.

TIGER: A tdTomato in vivo genome-editing reporter mouse for investigating precision-editor delivery approaches.

In vivo genome editing has the potential to address many inherited and environmental disorders. However, a major hurdle for the clinical translation of genome editing is safe, efficient delivery to disease-relevant tissues. A modality-agnostic reporter animal model that facilitates rapid, precise, and quantifiable assessment of functional delivery and editing could greatly enhance the evaluation and translation of delivery technologies.

Efficiently quantifying dependence in massive scientific datasets using InterDependence Scores.

Large-scale scientific datasets today contain tens of thousands of random variables across millions of samples (for example, the RNA expression levels of 20,000 protein-coding genes across 30 million single cells). Being able to quantify dependencies between these variables would help us discover novel relationships between variables of interest. Simple measures of dependence, such as Pearson correlation, are fast to compute, but limited in that they are designed to detect linear relationships between variables.

Genetic and Epigenetic Reprogramming of Transposable Elements Drives ecDNA-Mediated Metastatic Prostate Cancer.

Extrachromosomal DNAs (ecDNAs), which replicate and segregate in a non-Mendelian manner, serve as vectors for accelerated tumor evolution. By integrating chromatin accessibility, whole-genome sequencing, and Hi-C-based genome topology data from a cohort of metastatic Castration-Resistant Prostate Cancer (mCRPC) cases, we show that epigenetically activated repeat DNA, amplified in ecDNAs, drive oncogene overexpression. Specifically, we identify a subgroup of mCRPCs (20%) characterized by clusters of accessible LINE1 repeat DNA elements flanking the androgen receptor (AR) gene.

Mitochondrial genome copy number variation across tissues in mice and humans.

The mammalian mitochondrial genome (mtDNA) is multicopy and its copy number (mtCN) varies widely across tissues, in development and in disease. Here, we systematically catalog this variation by assaying mtCN in 52 human tissues across 952 donors (10,499 samples from the Genotype-Tissue Expression project) and 20 murine tissues using qPCR, capturing 50- and 200-fold variation, respectively. We also estimate per cell mtCN across 173 human cell lines from the Cancer Cell Line Encyclopedia using whole-genome sequencing data and observe >50-fold variation.

Plasma Metabolomics Profiles in Prodromal and Clinical Parkinson's Disease.

Background: The long prodromal phase of Parkinson's disease (PD) and the link the disease has with metabolic factors suggest that metabolomics could help identify affected individuals at early stages.

Objective: The goal was to examine whether plasma metabolomic profiles could identify individuals in the prodromal and clinical phase of PD.

Methods: We quantified and compared the plasma metabolomic profiles of 922 individuals with PD who provided blood samples at a median of 11 years before (n = 809) or 2 years after (n = 113) disease diagnosis to that of matched controls, all selected from three established cohort studies (Nurses' Health Study, Health Professionals Follow-up Study, and Cancer Prevention Study II).

Endogenous gene editing of alveolar organoids reveals that expression of pathogenic variant SFTPC-I73T disrupts endosomal function, epithelial polarity and wound healing.

Background: Idiopathic pulmonary fibrosis is a fatal lung disease of progressive lung parenchymal scarring caused by the aberrant response of an alveolar epithelium repeatedly exposed to injury. Understanding epithelial dysfunction has been hampered by the lack of physiological alveolar type 2 (AT2) cell models and defined disease triggers. Monogenic forms of familial pulmonary fibrosis (FPF) caused by toxic gain-of-function variants provide an opportunity to investigate early pathogenic events.

Circling in on plasmids: benchmarking plasmid detection and reconstruction tools for short-read data from diverse species.

The ability to detect and reconstruct plasmids from genome assemblies is crucial for studying the evolution and spread of antimicrobial resistance and virulence in bacteria. Though long-read sequencing technologies have made reconstructing plasmids easier, most (97%) of the bacterial genome assemblies in the public domain are generated from short-read data. Work to compare plasmid reconstruction tools has focused primarily on , leaving gaps in our understanding of how well these tools perform on other, less well-characterized, taxa.

Lessons learned from experience of phosphatidylinositol 3-kinase inhibitors in chronic lymphocytic leukemia and lymphoma.

The development of phosphoinositide 3-kinase (PI3K) pathway inhibitors for the treatment of lymphoma and chronic lymphocytic leukemia (CLL) has been a journey characterized by significant promise and important challenges1, 2. Starting as a very rational targeted approach for B- and T-cell lymphoproliferative disorders, the development of PI3K inhibitors faced regulatory setbacks due to class-specific adverse events and complex interpretation of the survival outcomes3. The recently published CHRONOS-4 clinical trial4, a randomized placebocontrolled study comparing copanlisib in combination with bendamustine plus rituximab and placebo with bendamustine plus rituximab, demonstrated that adding copanlisib to the standard-of-care bendamustine plus rituximab did not improve survival and increased toxicity.

In vivo prime editing rescues alternating hemiplegia of childhood in mice.

Alternating hemiplegia of childhood (AHC) is a neurodevelopmental disorder with no disease-modifying treatment. Mutations in ATP1A3, encoding an Na/K ATPase subunit, cause 70% of AHC cases. Here, we present prime editing (PE) and base editing (BE) strategies to correct ATP1A3 and Atp1a3 mutations in human cells and in two AHC mouse models.

Regulation of inflammatory responses by pH-dependent transcriptional condensates.

Inflammation is an essential defense response but operates at the cost of normal tissue functions. Whether and how the negative impact of inflammation is monitored remains largely unknown. Acidification of the tissue microenvironment is associated with inflammation.

Cell-type-informed genotyping of mosaic focal epilepsies reveals cell-autonomous and non-cell-autonomous disease-associated transcriptional programs.

While it is widely accepted that somatic variants that activate the PI3K-mTOR pathway are a major cause of drug-resistant focal epilepsy, typically associated with focal cortical dysplasia (FCD) type 2, understanding the mechanism of epileptogenesis requires identifying genotype-associated changes at the single-cell level, which is technically challenging with existing methods. Here, we performed single-nucleus RNA-sequencing (snRNA-seq) of 18 FCD type 2 samples removed surgically for treatment of drug-resistant epilepsy, and 17 non-FCD control samples, and analyzed additional published data comprising >400,000 single nuclei. We also performed simultaneous single-nucleus genotyping and gene expression analysis using two independent approaches: 1) a method that we called genotyping of transcriptomes enhanced with nanopore sequencing (GO-TEN) that combines targeted cDNA long-read sequencing with snRNA-seq, 2) ResolveOME snRNA-seq and DNA genotyping.

Spatially defined multicellular functional units in colorectal cancer revealed from single cell and spatial transcriptomics.

While advances in single cell genomics have helped to chart the cellular components of tumor ecosystems, it has been more challenging to characterize their specific spatial organization and functional interactions. Here, we combine single cell RNA-seq, spatial transcriptomics by Slide-seq, and multiplex RNA analysis, to create a detailed spatial map of healthy and dysplastic colon cellular ecosystems and their association with disease progression. We profiled inducible genetic CRC mouse models that recapitulate key features of human CRC, assigned cell types and epithelial expression programs to spatial tissue locations in tumors, and computationally used them to identify the regional features spanning different cells in the same spatial niche.

Clusterin drives myeloid bias in aged hematopoietic stem cells by regulating mitochondrial function.

Aged hematopoietic stem cells (HSCs) exhibit diminished self-renewal and myeloid-biased differentiation with a decline in hematopoiesis and adaptive immune function. However, the molecular regulation of this impaired function remains largely unknown. Here, through an in vivo CRISPR-Cas9-based screen, we uncovered clusterin (Clu) as a driver of biased differentiation.

In vivo directed evolution of an ultrafast Rubisco from a semianaerobic environment imparts oxygen resistance.

Carbon dioxide (CO) assimilation by the enzyme Ribulose-1,5-bisphosphate Carboxylase/Oxygenase (Rubisco) underpins biomass accumulation in photosynthetic bacteria and eukaryotes. Despite its pivotal role, Rubisco has a slow carboxylation rate ([Formula: see text]) and is competitively inhibited by oxygen (O). These traits impose limitations on photosynthetic efficiency, making Rubisco a compelling target for improvement.

Urinary C-X-C-motif ligand 9 (CXCL9) in immune checkpoint inhibitor-associated acute interstitial nephritis.

Introduction: Immune checkpoint inhibitor-associated acute interstitial nephritis presents significant clinical challenges. There are no reliable non-invasive biomarkers and kidney biopsy remains the gold standard for diagnosis. Prior studies have shown that urinary C-X-C-motif ligand 9 (CXCL9) is upregulated in patients with acute interstitial nephritis.

Resident memory T cell development is gradual and shows AP-1 gene expression in mature cells.

Tissue-resident memory T (TRM) cells play a central role in immune responses across all barrier tissues after infection. However, the mechanisms that drive TRM differentiation and priming for their recall effector function remains unclear. In this study, we leveraged newly generated and publicly available single-cell RNA-seq data generated across 10 developmental time points to define features of CD8+ TRM across both skin and small-intestine intraepithelial lymphocytes (siIEL).

A single dose of a CD137 antibody-drug conjugate protects rhesus macaque allogeneic HCT recipients against acute GVHD.

Rapid CD137 upregulation on alloreactive T cells upon allogeneic stimulation suggests that their selective elimination could prevent acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (HCT). Here, we developed a novel aGVHD prophylactic regimen consisting of a single dose of an anti-CD137 antibody-drug conjugate (CD137-ADC) administered on the day of transplant without additional immunosuppression. The CD137-ADC depleted both human and nonhuman primate (NHP) activated T cells and proved highly effective in preventing xenogeneic aGVHD in mice receiving human peripheral blood mononuclear cells, as well as in NHP undergoing major histocompatibility complex (MHC)-haploidentical HCT.

Diverse modes of T cell receptor sequence convergence define unique functional and cellular phenotypes.

Single-cell techniques allow concurrent study of gene activity and T cell receptor (TCR) sequences, identifying connections between TCR structure and cell traits. Expanding on our CoNGA software, we present a "metaCoNGA" analysis of 6 million T cells from 91 diverse studies, mapping TCR sequence similarity across tissues and diseases. This approach exposes shared TCR features within specific T cell subsets, including those associated with infection, cancer, and autoimmunity.

Proteogenomic analysis of the CALGB 40601 (Alliance) HER2+ breast cancer neoadjuvant trial reveals resistance biomarkers.

Proteogenomic analysis is applied to samples from the CALGB 40601 (Alliance) randomized neoadjuvant trial of trastuzumab, lapatinib, or the combination to identify biomarkers associated with pathological response status. Absence of ERBB2 gene amplification and human epidermal growth factor receptor 2 (HER2) protein overexpression by proteogenomics is associated with non-pathological compete response (pCR) (p < 0.05), highlighting potential false positives from standard diagnostics.

Burden of Cardiovascular Outcomes After SARS-CoV-2 Infection in South Korea and Japan: A Binational Population-Based Cohort Study.

Background: Despite the significant global impact of the COVID-19 pandemic, limited studies have investigated the long-term cardiovascular sequelae of SARS-CoV-2 infection, particularly among Asian populations. This large-scale, population-based binational cohort study with long-term follow-up aimed to investigate the association between SARS-CoV-2 infection and the risk of cardiovascular events.

Methods: We used binational, large-scale, and population-based cohorts, including a Korean nationwide cohort (K-CONV-N [Korea Disease Control and Prevention Agency-COVID-19-National Health Insurance Service cohort]; discovery cohort; n=18 989 129) and a Japanese nationwide cohort (Japan Medical Data Center; validation cohort; n=12 218 680).