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The Mre11-Rad50 (MR) complex has key functions in the detection, signaling and repair of DNA breaks. Here the authors use transmission electron microscopy to show MR oligomerization is governed by a small beta-sheet protruding from the head domain of Rad50 at the base of the MR structure, and reveal MR head domain oligomerization is required for efficient DNA end resection.

ER⁺ breast cancer patients treated with endocrine therapies often acquire resistance and develop metastasis. In this study, the authors demonstrate that endocrine therapies can promote the self-renewal of CD133^hi/ER^lodrug resistant cells with metastatic potential driven through the IL6-Notch3 axis activation.

Zeiser and colleagues show that CAR T cell therapy results in upregulation of the TGFβ-activated kinase-1 (TAK1)–NF-κB–p38 MAPK pathway in microglia, causing neurocognitive defects, and find that TAK1 inhibition can reduce immune effector cell-associated neurotoxicity syndrome.

Vγ9Vδ2 (Vδ2) T cells have been proposed as cell carriers for off-the-shelf CAR therapies. Here the authors describe CD16 as a biomarker for the selection of Vδ2 T cells with high levels of cytotoxicity and report the anti-tumor activity of engineered CD16high Vδ2 T cells in ovarian cancer preclinical models.

Indigenous agroecosystems often balance food production with environmental concerns better than industrial approaches, but they are rarely considered for meeting modern food needs. This study uses spatial models and climate scenarios to find indigenous production in Hawaiʻi’s past could meet significant population demands then and, potentially, now, but with lower capacity in the warmest end-of-century scenario.

This study found higher RSV antibody levels were associated with lower RSV risk in children outside the hospital. An earlier rise in incidence and higher incidence rates were observed among children <5 years compared to older children and adults.

The tumour microenvironment is low in glucose and high in the alternative metabolite lactate, which regulatory T cells are shown here to use, maintaining their ability to suppress effector immune cells.

Polygenic scores for body mass index and obesity constructed using data from 5 million people with different ancestries were associated with distinct weight gain trajectories from early childhood to adulthood.

Classes of autism are uncovered with a generative mixture modeling approach leveraging matched phenotypic and genetic data from a large cohort, revealing different genetic programs underlying their phenotypic and clinical traits.

Whole genome sequences enable discovery of rare variants which may help to explain the heritability of common diseases. Here the authors find that ultra-rare variants explain ~50% of coronary artery disease (CAD) heritability and highlight several functional processes including cell type-specific regulatory mechanisms as key drivers of CAD genetic risk.

A global network of researchers was formed to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity; this paper reports 13 genome-wide significant loci and potentially actionable mechanisms in response to infection.

Viral infection of the respiratory system induces exuberant fibroblast activity, resulting in extensive remodelling of the extracellular matrix and cytokine release, which promote immune cell infiltration of the affected area at the expense of respiratory function.

Glucocorticoids (GC) are commonly used to suppress undesirable inflammatory responses. Here the authors show, using hi-dimensional flow cytometry data, that GC treatment following major surgeries alters adaptive immunity without significant modulation of innate immune responses or pain/functional impairment.

Distinguishing glioblastoma and primary central nervous system lymphoma (PCNSL) remains challenging due to their overlapping pathology features. Here, the authors develop a computational tool, PICTURE, for differentiating similar pathological features enabling improved diagnosis of CNS tumours.

Sanz and colleagues examine B cell subsets in a cohort of patients with COVID-19. Severely ill patients have higher frequencies of activated extrafollicular T-bet⁺ B cells that form antibody-secreting cells, the majority of which express germline sequences and are reminiscent of antibody responses observed in patients with systemic lupus erythematosus during flares.

Transgenerational transmission of acquired immunological traits has been demonstrated in invertebrates and plants but not mammals. Katzmarski et al. demonstrate that trained immunity that protects against heterologous infections can be transmitted to F2 offspring.

Openshaw and colleagues find myeloid inflammation and complement activation signatures in patients with long COVID who were previously hospitalized.

In three mouse models of breast cancer, we show reduced responses to neoadjuvant chemotherapy when treatment is initiated during the dioestrus stage, when compared with initiation during the oestrus stage.

This cross-sectional study in two independent middle-aged and aged cohorts investigates whether psychological characteristics associated with varying dementia risk aggregate into psychological profiles and relate to aging brain health.

Mesenchymal stromal cells (MSCs) demonstrate therapeutic benefits in multiple diseases, but the mechanisms remain unclear as infused MSCs do not persist in the body. Here, the authors show that MSC apoptosis is an important mechanistic element, as MSCs rendered genetically incapable of apoptosis lose their ability to ameliorate disease.

The CTLA-4–Ig fusion protein (abatacept) can have beneficial effects in autoimmune disease. Walker and colleagues show in mouse and human type 1 diabetes that abatacept targets pathogenic follicular helper T cells, and the frequencies of these cells at baseline can be used to stratify treatment responses in patients.

Mammary gland resident macrophages are known to be crucial components of the mammary stem cell niche. Here, the authors show that CXCR4⁺ macrophages form a niche that regulates the tumor-initiating activity of breast cancer cells and induces early immune evasion through the recruitment of regulatory T cells.

Hayday and colleagues show that the responsiveness of mouse and human γδ IELs to Btnl or BTNL proteins is mediated by germline-encoded motifs within the cognate TCR V_γ chains, while V_γ chain motifs generated by somatic gene rearrangement remain available for nominal antigen binding.

Single-cell technologies are increasingly prominent in clinical applications, but predictive modelling with such data in large cohorts has remained computationally challenging. We developed a new algorithm, ‘VoPo’, for predictive modelling and visualization of single cell data for translational applications.

Whole-genome sequencing, transcriptome-wide association and fine-mapping analyses in over 7,000 individuals with critical COVID-19 are used to identify 16 independent variants that are associated with severe illness in COVID-19.

Microglia are CNS-resident macrophages, but studying their functions in health and disease has been challenging due to a lack of specific markers. Greter and colleagues identify the transcription factor Sall1 as being uniquely associated with microglia in the CNS, where it is important for defining their fate and homeostatic function.

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.

Antigenic activation induces the generation of effector and memory CD8⁺ T cells. Goldrath and colleagues profile gene expression at various times after infection to identify transcriptional networks unique to each population.

Myelination by Schwann cells (SC) in the peripheral nervous system is essential for motor function, and dysregulation of SC myelination can lead to various neuropathies. Here the authors describe a critical role of CCCTC-binding factor (CTCF)-dependent chromatin reorganization in peripheral myelination and myelin regeneration after injury.

Structural changes mediated by advanced glycation end-products enhance extracellular matrix viscoelasticity, and that viscoelasticity can promote cancer progression in vivo, independent of stiffness.

The biological functions of WSX1, the alpha subunit of the interleukin-27 receptor, in non-immune cells are largely unknown. Here, the authors propose an IL-27-independent tumor suppressor role for WSX1 in hepatocytes, showing that WSX1 restricts tumor progression by down-regulating PD-L1 expression in tumour cells and maximizing T cell mediated antitumor immune responses.

A large genome-wide association study of more than 5 million individuals reveals that 12,111 single-nucleotide polymorphisms account for nearly all the heritability of height attributable to common genetic variants.

An updated analysis of the DYNAMIC biomarker-driven trial, including mature survival data at 5 years, supports a ctDNA-guided approach to adjuvant chemotherapy for stage II colon cancer.

Seronegative healthcare workers with an innate signature of infection preferentially expand pre-existing T cells targeting the conserved replication transcription complex of SARS-CoV-2 in abortive infection.

This study presents results from a SARS-CoV-2 genomic surveillance study at a university campus in which ~2,000 samples were sequenced over five months. The authors document the replacement of Delta with Omicron as the dominant variant, and describe clinical characteristics and transmission dynamics.

Characterizing EBV and host gene expression profiles of spontaneous lymphoblastoid cell lines isolated from multiple sclerosis (MS) patients with acute or stable disease, as well as healthy donors, suggests antivirals as a potential road to treat MS.

A genome-wide association meta-analysis study of blood lipid levels in roughly 1.6 million individuals demonstrates the gain of power attained when diverse ancestries are included to improve fine-mapping and polygenic score generation, with gains in locus discovery related to sample size.

A study reports whole-genome sequences for 490,640 participants from the UK Biobank and combines these data with phenotypic data to provide new insights into the relationship between human variation and sequence variation.

Rudloff et al. examine the kinetics of CD8⁺ T cell dysfunction/exhaustion. Tumor-specific CD8⁺ T cells in the tumor environment exhibit epigenetic modifications within hours, before cell division. The findings suggest a temporal relationship between tumor antigen exposure, chromatin remodeling and dysfunction ‘imprinting’.

PREGCARE is a new strategy for families who had a child with a pathogenic de novo mutation, that efficiently identifies couples at higher recurrence risk due to parental mosaicism, while reassuring many others that their recurrence risk is negligible.

STING agonists are often limited by low circulation time and cellular uptake. The conjugation of STING agonists with polymer nanoparticles is shown to enhance stability, circulation time and cellular uptake, increasing the immunotherapeutic activity.

Dimethyl fumarate (DMF) is an anti-inflammatory drug proposed as a treatment for COVID19. Here the results are reported from a randomised trial testing DMF treatment in 713 patients hospitalised with COVID-19. DMF was not associated with any improvement in day 5 outcomes.

Circulating tumour DNA profiling in early-stage non-small-cell lung cancer can be used to track single-nucleotide variants in plasma to predict lung cancer relapse and identify tumour subclones involved in the metastatic process.

Systemic lupus erythematosus (SLE) is associated with altered B cell responses but the underlying aetiology is still unclear. Here the authors show that a CD11c^hiT-bet⁺ B cell subset with a unique phenotype and transcriptome is increased in patients with SLE, can be expanded by IL-21, and may contribute to autoimmune responses in SLE.

Immunoglobulin gene rearrangements occur in an organized, temporal way. Skok and colleagues show that immunoglobulin alleles 'pair' to coordinate cleavage and allelic availability.