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Prior hypoglycemia alters the paracrine interaction between islet α and δ cells, leading to impaired counter-regulatory glucagon secretion through somatostatin hypersecretion, increasing the risk of recurrent hypoglycemia.

Here, the authors present an update to a widely used curatedMetagenomicData (cMD) database and use it to create a catalog of microbiome-phenotype associations (age, sex, body mass index), and develop an oral enrichment score in the gut microbiome independently of age.

Variation in responses to bacterial and viral stimuli between Batwa rainforest hunter-gatherers and Bakiga agriculturalists from Uganda suggests population-level divergence under natural selection, with hunter-gatherers disproportionately showing signatures of positive selection.

A combination of biochemical, cell biological and electron microscopy analyses reveal a ‘nucleotide code’ that coordinates Lis1–dynein binding stoichiometry, which in turn governs Lis1’s ability to relieve dynein autoinhibition.

Vaccines inducing mucosal immunity may provide better protection from respiratory viruses. Here, Ykema et al. demonstrate the utility of a bivalent, mucosally delivered nanostructured lipid carrier-replicon vaccine for induction of mucosal and systemic immunity and protection against morbidity and mortality from H5N1 and H7N9 influenza.

Chronic stress is a risk factor for depression, yet the mechanisms are unclear. Here, the authors show in mice that stress drives interferon-mediated neutrophil recruitment from the skull to the brain’s outer membranes, contributing to depressive behaviors.

The microbiota may mediate the differential responses to oral cholera vaccine (OCV). Here, the authors reveal that the presence of sphingolipid-producing bacteria is associated with the development of protective immune responses after OCV.

The International Brain Laboratory presents a brain-wide electrophysiological map obtained from pooling data from 12 laboratories that performed the same standardized perceptual decision-making task in mice.

A single-cell sequencing study using more than 30,000 tumour genomes from human ovarian cancers shows that whole-genome doubling is an ongoing mutational process that drives tumour evolution and disrupts immunity.

Mulholland et al. identify progenitor exhausted T cells, expressing intermediate levels of PD-1 (PD-1^int), as a prominent source of pro-inflammatory cytokines in the murine atherosclerotic aorta and potential cellular targets driving checkpoint inhibition-elicited pro-atherosclerotic immune responses. They further demonstrate elevated levels of circulating PD-1-expressing T cells in individuals with subclinical cardiovascular disease.

Here the authors use a range of approaches to examine the interplay between genetic variants linked to risk for polygenic skin diseases and transcription factors (TFs) important for skin homeostasis. The findings implicate dysregulated binding of specific TF families in risk for diverse skin diseases.

Here the authors perform longitudinal sampling of lymphoid organs along with fate mapping and matched single-cell RNA sequencing and TCR sequencing to define the developmental dynamics of follicular regulatory T (T_FR) cells. They find that T_FR cells undergo clonal expansion and progressive differentiation in a process that requires follicular helper T cells.

Approximately 17% of meningiomas remain genomically uncharacterized. Here, the authors analyze 105 meningiomas without known driver mutations or significant copy number alterations and identify a subgroup of meningiomas, defined by FOS/FOSB gene fusions with distinctive transcriptomic and histopathological features.

Oncogenic driver mutations can influence the tumour biology of lung adenocarcinomas. Here, authors analyse 157 LUAD samples using imaging mass cytometry to reveal how these mutations impact the tumour microenvironment and clinical outcomes.

There’s an emerging body of evidence to show how biological sex impacts cancer incidence, treatment and underlying biology. Here, using a large pan-cancer dataset, the authors further highlight how sex differences shape the cancer genome.

The INTIMET study is a randomized 26-week double-blind clinical trial to assess whether metformin can reduce insulin resistance in adults with type 1 diabetes. Metformin did not reduce insulin resistance in type 1 diabetes, but lowered insulin dose versus placebo – a secondary outcome.

Transcranial ultrasound stimulation (TUS) is a non-invasive method to modulate deep brain activity. Using direct recordings from implanted electrodes, we showed that TUS engages the human globus pallidus internus, with effects on neural oscillations and behavior.

Hyperglycaemia leads to impaired costimulatory molecule expression, antigen transport and T cell priming in distinct lung dendritic cell subsets, driving a defective antiviral adaptive immune response, delayed viral clearance and enhanced mortality.

Boyle et al. show that ROCK upregulates PERK signalling in epithelia of breast cancer, thereby enhancing recruitment and function of cancer-associated fibroblasts through CRELD2 to promote tumourigenesis.

An analysis of 2,954 genomes from 38 cancer subtypes identified 19,166 retrotransposition events in 35% of samples. Aberrant LINE-1 retrotranspositions can lead to the deletion of tumor-suppressor genes as well as the amplification of oncogenes.

Anagnostou et al. present an improved predictor of response to immune checkpoint blockade that integrates estimates of tumor mutational burden corrected for tumor purity, RTK genomic alterations, a smoking-related mutational signature and HLA status.

The flagship paper of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium describes the generation of the integrative analyses of 2,658 cancer whole genomes and their matching normal tissues across 38 tumour types, the structures for international data sharing and standardized analyses, and the main scientific findings from across the consortium studies.

ProteinGenerator simultaneously generates protein sequences and structures using sequence space diffusion.

CD4⁺ T cells promote immunity to tuberculosis infection via macrophages. Here the authors show upregulation of SLAMF1/CD150 on infected macrophages after interaction with CD4⁺ T cells and that the presence of SLAMF1 promotes ROS production by macrophages and the absence of Slamf1 in macrophages results in higher mycobacterial loads in infected mice.

Arya et al. report that migrating neutrophils resolve acute inflammation by releasing exosomes associated with nuclear DNA. This process is distinct from the release of neutrophil extracellular traps, and relies on the lamin B receptor.

High-depth sequencing of non-cancerous tissue from patients with metastatic cancer reveals single-base mutational signatures of alcohol, smoking and cancer treatments, and reveals how exogenous factors, including cancer therapies, affect somatic cell evolution.

With the generation of large pan-cancer whole-exome and whole-genome sequencing projects, a question remains about how comparable these datasets are. Here, using The Cancer Genome Atlas samples analysed as part of the Pan-Cancer Analysis of Whole Genomes project, the authors explore the concordance of mutations called by whole exome sequencing and whole genome sequencing techniques.

Analyses of in vivo models, cell lines and patient-derived samples show that apolipoprotein B mRNA-editing catalytic subunit 3B (APOBEC3B) not only restrains lung tumor initiation but also that its upregulation is associated with resistance to targeted therapies. This study highlights the complex and context-dependent role of APOBEC3B in lung cancer.

Group 3 medulloblastoma is an aggressive pediatric brain tumour that disseminates through the leptomeningeal cerebral spinal fluid. Here, the authors show that in Group 3 medulloblastoma NOTCH1 activates BMI1 through the activation of TWIST1, driving metastasis and self-renewal, and in mouse models a NOTCH1 blocking antibody decreased spinal metastases.

Post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS) is a disabling disorder, yet the clinical phenotype is poorly defined and the pathophysiology unknown. Here, the authors conduct deep phenotyping of a cohort of PI-ME/CFS patients.

Identifying the metabolic interactions that underlie microbial communities is challenging. Here, the authors combine Tara Oceans -omics data with co-activity networks and genome-scale metabolic models to predict biotic interactions among planktonic prokaryotes in the upper ocean.

Chromosomal instability in cancer is linked to endoplasmic reticulum stress signalling, immune suppression and metastasis, which is mediated by the cGAS–STING pathway, suppression of which can reduce metastasis.

A large brain imaging study of over 2000 people worldwide shows that fear conditioning engages brain regions linked to emotion and attention, with differences in individuals with anxiety or depression and strong influences from task design.

Autophagy in CD11c⁺ phagocytes prevents myeloid-derived suppressor cell recruitment and promotes protective T cell responses during high-dose Mycobacterium tuberculosis infection in mice.

Areas of aquatic vegetation have expanded in northern lakes between 1984 and 2021, and this expansion is probably an additional climate feedback that enhances methane emissions, according to a monitoring study using Landsat imagery.

Autoimmune encephalitis (AIE) may involve neuron-specific cytotoxic T cells, but evidence is still lacking. Here the authors use induced pluripotent stem cells from patients with AIE and single cell RNA-sequencing of ex vivo CD8 T cells to find neuron-specific, KIR⁺CD8⁺ T cells with altered transcriptome that potentially contribute to AIE etiology.

The molecular basis for differences in immune response to SARS-CoV-2 in children and adults is still unclear. Here, the authors show that antibodies are of high binding and functional quality in children with mild or asymptomatic infection, but antibody response is delayed as compared to adults.

The authors show that LARP4 drives T cell dysfunction in tumors by promoting hypertranslation of oxidative phosphorylation-related mRNAs, resulting in mitochondrial dysfunction. They also target LARP4 to enhance T cell persistence and anti-tumor activity and provide a CAR T cell strategy for treating solid and liquid tumors.

HRGM2 is a catalogue of 155,211 high-quality metagenome-assembled genomes spanning 41 countries that allows improved genome-scale metabolic modelling and functional characterization of human gut microbes.

Stress-associated catecholamines promote CD8⁺ T cell exhaustion through the β₁-adrenergic receptor, and blocking β-adrenergic signalling may help restore anti-tumour functions.

Mixed responses to targeted therapy within a patient are a clinical challenge. Here the authors show that TP53 loss-of-function cooperates with whole genome doubling which increases chromosomal instability. This leads to greater cellular diversity and multiple routes of resistance, which in turn promotes mixed responses to treatment.

Sleeve gastrectomy is a common bariatric surgery in which most of the gastric corpus is removed. Here, the authors show the adaptation of the gastric mucosa to surgery in patients, and how it facilitates maintenance of gastric pH homeostasis through a proportional-integral feedback control.

The processes that regulate melanoblast migration during development are also thought to be involved in melanoma metastasis. Here, Prex1 null mice are shown to have a melanoblast migration defect and, when crossed to a mouse model of melanoma, are resistant to metastasis, suggesting a role for Prex1 in metastatic melanoma.

A pan-cancer genomic analysis reports the effects of structural variations on chromatin domains (TADs). Most TAD disruptions do not result in appreciable changes in expression of nearby genes.

In this study, the authors present antimalarial drug resistance surveillance data from Uganda over the period 2019-2024. They measure ex vivo susceptibility to nine standard antimalarials in 1,114 isolates and characterise sequences of markers of drug susceptibility.

A comprehensive single-cell RNA sequencing study delineates cell-type-specific transcriptomic changes in the brain associated with normal ageing that will inform the investigation into functional changes and the interaction of ageing and disease.

Why children are generally less susceptible than adults to COVID-19 is unclear and has not extensively been examined longitudinally. Here the authors compare antibodies, cytokines and immune cell responses in adults and children over 6 months post-infection showing, among other things, a reduced CD4+ and CD8+ T cell response in children.