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Exhaustion is a functional state that hampers anti-cancer and antiviral CD8 T cell activity, and is preceded by a stem-like state, maintained by the transcription factor TCF1. Here authors develop mouse models that allow a precise understanding of the developmental trajectory between the stem-cell-like and exhausted states of CD8 T cells and find that while constitutive overexpression of TCF1 expands the stem-like T cell pool, TCF1 expression specifically in already exhausted cells is unable to promote dedifferentiation.

Large-effect variants in autism remain elusive. Here, the authors use long-read sequencing to assemble phased genomes for 189 individuals, identifying pathogenic variants in TBL1XR1, MECP2, and SYNGAP1, plus nine candidate structural variants missed by short-read methods.

Genomic analyses applied to 14 childhood- and adult-onset psychiatric disorders identifies five underlying genomic factors that explain the majority of the genetic variance of the individual disorders.

Despite improving therapeutic options, the prognosis for patients with metastatic castration-resistance prostate cancer (mCRPC) remains poor. Here, the authors identify MCL1 copy number alterations as a prognostic and predictive biomarker, demonstrating its therapeutic potential as a drug target, either alone or in combination, in patients with mCRPC.

A study of several longitudinal birth cohorts and cross-sectional cohorts finds only moderate overlap in genetic variants between autism that is diagnosed earlier and that diagnosed later, so they may represent aetiologically different conditions.

Targeting CD8⁺ T cell exhaustion is a strategy to enhance immune checkpoint inhibition and to fight cancer. Here the authors show a NRF2-dependent role for the prostaglandin I₂ receptor PTGIR in controlling T cell exhaustion.

Combination radiotherapy (RT) + αPD-L1 enhances tumor control via a tumor-draining lymph node (TdLN)-derived CD8+ PD-1+ TCF-1+ T cells. RT + αPD-L1 induces a novel LY6A+ subset in the TdLN that migrates to the tumor and differentiates into effectors.

A cell-sorting method leveraging leucine zippers allows for the generation of T cells displaying multiple chimaeric antigen receptors as well as receptors converting inhibitory signals into stimulatory signals.

An integrated analysis of de novo and inherited coding variants in 42,607 individuals with autism spectrum disorder identifies 60 risk genes of which five have not previously been associated with neurodevelopmental disorders.

A high-resolution, global atlas of mortality of children under five years of age between 2000 and 2017 highlights subnational geographical inequalities in the distribution, rates and absolute counts of child deaths by age.

The authors identify thousands of genetic variants affecting RNA splicing in primary human chondrocytes and link several of them to osteoarthritis risk using genome editing and computational approaches.

Analysis of a human isolate of the A/Texas/37/2024 strain of highly pathogenic avian influenza A(H5N1) virus in the ferret model demonstrates its pathogenicity and transmission in both direct and indirect contact settings, including airborne transmission.

Authors provide analysis of starch-binding protein Sas6, from Ruminococcus bromii, a bacterium that degrades resistant starch granules in the human gut, and demonstrate how carbohydrate-binding modules recognize different moieties within starch.

Using well-calibrated statistical methods the authors jointly analyze Undiagnosed Diseases Network genomes, identifying known and novel disease genes. Software is publicly available to support future cross-cohort rare disease discovery efforts.

Multi-ancestry genome-wide analyses identify 95 loci associated with post-traumatic stress disorder and implicate candidate genes, pathways and neurobiological systems underlying its pathophysiology.

Study shows PTSD predisposition shares distinct genes and genomic regions with several cardiovascular conditions. Here the findings reveal neuronal, immune, and metabolic pathways, and repurposed drug targets that further the understanding of the comorbidity.

Antibodies targeting the HIV-1 fusion peptide rarely achieve more than 60% neutralization breadth. Here, the authors develop an anti-FP antibody enhancing its potency to 80% and structurally resolve the expanded FP-binding site that allows the antibody to target diverse viral variants.

Astrocyte diversity is greatly influenced by local environmental modulation. Wang et al. report a critical role for astrocytic primary cilia in transmitting local cues that drive the region-specific diversification of astrocytes within the developing mouse brain.

Tonic and burst-like locus coeruleus firing distinctly tune brain topology toward associative and sensory regions, recruiting both astrocytic and neuronal inhibitory activity.

The association of telomere length with age and mortality across racially diverse pulmonary fibrosis populations is unknown. Here, the authors show that leukocyte telomere length associates with chronologic age and is predictive of mortality in pulmonary fibrosis across racial groups.

Samples of different body regions from hundreds of human donors are used to study how genetic variation influences gene expression levels in 44 disease-relevant tissues.

The role of IgG glycosylation in the immune response has been studied, but less is known about IgM glycosylation. Here the authors characterize glycosylation of SARS-CoV-2 spike specific IgM and show that it correlates with COVID-19 severity and affects complement deposition.

The STEP HIV-1 vaccine trial failed to protect volunteers from infection, but whether vaccine-driven immune responses affected the profile of viral variants in infected individuals was unknown. By analyzing nucleotide sequences and predicted T cell epitopes in viruses from newly infected trial participants, Rolland et al. now report that the degree of viral divergence from vaccine-encoded inserts suggests that vaccine-induced T cell responses indeed influenced the viral repertoire, a finding that might be harnessed in future vaccine design.

The intracellular domain (ICD) of Cys-loop receptors mediates many of their functions, but no complete structure of a Cys-loop receptor ICD is available to date. Here, the authors combine NMR and ESR spectroscopy to determine the full-length ICD structures of the human α7 nicotinic acetylcholine receptor (α7nAChR).

The growth plate cartilage supports long bone growth. Here the authors identify FoxA2+ long term stem cells in the growth plate that are stratified with short term PTHrP+ cells, participate in production of hyaline cartilage, expand in response to trauma, and whose ablation impairs cartilage regeneration.

A randomized trial in patients hospitalized with COVID-19 showed no benefit and potentially increased harm associated with the use of convalescent plasma, with subgroup analyses suggesting that the antibody profile in donor plasma is critical in determining clinical outcomes.

Bhattacharjee and Schaeffer et al. map exclusive breastfeeding (EBF) in 94 low- and middle-income countries (LMICs), finding increased EBF practice and reduced subnational variation across the majority of LMICs from 2000 to 2018. However, only six LMICs will meet WHO’s target of ≥70% EBF by 2030 nationally, and only three will achieve this in all districts.

Crystal structures of HIV-1 Env V1V2 in complex with human broadly neutralizing antibodies and ontogeny analyses allow the engineering of Env trimers that are recognized by ancestor and intermediate antibody forms.

Although progress in the coverage of routine measles vaccination in children in low- and middle-income countries was made during 2000–2019, many countries remain far from the goal of 80% coverage in all districts by 2019.

Jayavelu, Samaha et al., apply machine learning models on hospital admission data, including antibody titers and viral load, to identify patients at high risk for Long COVID. Low antibody levels, high viral loads, chronic diseases, and female sex are key predictors, supporting early, targeted interventions.

Fine-scale geospatial mapping of overweight and wasting (two components of the double burden of malnutrition) in 105 LMICs shows that overweight has increased from 5.2% in 2000 to 6.0% in children under 5 in 2017. Although overall wasting decreased over the same period, most countries are not on track to meet the World Health Organization’s Global Nutrition Target of <5% in over half of LMICs by 2025.

Comprehensive integration of gene expression with epigenetic features is needed to understand the transition of kidney cells from health to injury. Here, the authors integrate dual single nucleus RNA expression and chromatin accessibility, DNA methylation, and histone modifications to decipher the chromatin landscape of the kidney in reference and adaptive injury cell states, identifying a transcription factor network of ELF3, KLF6, and KLF10 which regulates adaptive repair and maladaptive failed repair.

A longitudinal study of an individual patient developing neutralizing antibodies against HIV-1 (targeting the V1V2 region of gp120) reveals how such neutralizing antibodies develop and evolve over time, providing important insights relevant to vaccine development.

Electricity can be used to stimulate the nervous system to treat diseases, and computer models are powerful tools for designing these therapies. Here, authors develop a model of neurons’ responses to electricity that is accurate and thousands of times faster than the current industry standard.

The authors summarize the data produced by phase III of the Encyclopedia of DNA Elements (ENCODE) project, a resource for better understanding of the human and mouse genomes.

Solid organ transplant recipients are at increased risk of infectious disease and have unique molecular pathophysiology. Here the authors use host-microbe profiling to assess SARS-CoV-2 infection and immunity in solid organ transplant recipients, showing enhanced viral abundance, impaired clearance, and increased expression of innate immunity genes.

Most tumours associated with germline BRCA1/BRCA2 loss of function mutations respond to DNA damaging agents, however, some do not. Herein, the authors identify that a subset of breast/ovarian tumors retain a normal allele, which is associated with decreased overall survival after DNA damage-inducing platinum chemotherapy.

High-resolution subnational mapping of child growth failure indicators for 105 low- and middle-income countries between 2000 and 2017 shows that, despite considerable progress, substantial geographical inequalities still exist in some countries.

Post-acute sequelae of SARS-CoV-2 (PASC) is still not well understood. Here the authors provide patient reported outcomes from 590 hospitalized COVID-19 patients and show association of PASC with higher respiratory SARS-CoV-2 load and circulating antibody titers, and in some an elevation in circulating fibroblast growth factor 21.

The authors report that the protein Flotillin-1/Reggie-2 (Flot1) is required for PKC-regulated internalization of the dopamine transporter (DAT) and the glial glutamate transporter EAAT2. Flot1 was required to localize DAT within plasma membrane microdomains in stable cell lines, and for amphetamine-induced reverse transport of dopamine in neurons.

Human ALS/FTD patient iPSC-derived neurons are used to uncover mechanisms by which C9ORF72 mutations cause neurodegeneration.

Highly recurrent hotspot r.3A>G mutations are identified in U1 splicesomal small nuclear RNAs in about 50% of Sonic hedgehog medulloblastomas, which result in disrupted RNA splicing and the activation of oncogenes.

Phenotypic variation and diseases are influenced by factors such as genetic variants and gene expression. Here, Barbeira et al. develop S-PrediXcan to compute PrediXcan results using summary data, and investigate the effects of gene expression variation on human phenotypes in 44 GTEx tissues and >100 phenotypes.

Exclusive breastfeeding in Africa is highly varied within and between countries, with many countries unlikely to reach World Health Organization 2025 targets without urgent action.

Cas9-specific antibodies and reactive T cells are found in the majority of healthy adult human serum samples analyzed. Such preexisting adaptive immunity should be taken into consideration as the CRISPR–Cas9 system moves toward clinical trials.

Using the GTEx data and others, a comprehensive analysis of adenosine-to-inosine RNA editing in mammals is presented; targets of the various ADAR enzymes are identified, as are several potential regulators of editing, such as AIMP2.

Multiple transcriptome approaches, including single-cell sequencing, demonstrate that escape from X chromosome inactivation is widespread and occasionally variable between cells, chromosomes, and tissues, resulting in sex-biased expression of at least 60 genes and potentially contributing to sex-specific differences in health and disease.