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Excised signal circles are circular DNA by-products of V(D)J recombination that form a complex with the V(D)J recombinase, and when increased in abundance, result in increased mutagenesis, causing adverse outcomes in cancer.

Androgen receptor in prostate cancer (PCa) transcriptionally represses multiple genes including MYC. Here, the authors suggest that increased MYC in response to androgen deprivation contributes to castration-resistant PCa, while decreased MYC may contribute to responses to supraphysiological androgen therapy.

The lowest-frequency gravitational wave background may be shaped by supermassive black hole binaries that scatter nearby stars or dark matter. In this case, the NANOGrav 15-year dataset favours dense galactic centres with 10⁶ solar masses per cubic parsec.

The calvarial stem cell niche is populated by a cathepsin K-expressing cell lineage and a newly identified discoidin domain-containing receptor 2-expressing lineage, both of which are required for proper calvarial mineralization.

Spinal cord injury (SCI) often leads to immune dysfunction, but mechanistic insights are still lacking. Here the authors show that SCI alters chemokine signaling and induces long, persisting defects in hematopoietic stem and progenitor cell migration, thereby entrapping them in the bone marrow and disrupting peripheral immune homeostasis.

African dust from the Saharan desert makes its way to the Eastern Equatorial Pacific Ocean in greater proportions during cold millennial pulses of the last deglacial. The pulsing of African-sourced dust may be indicative of large climate-related shifts in the Intertropical Convergence Zone.

Estimates from the Global Burden of Disease study reveal declines in chronic respiratory disease mortality between 1990 and 2023—especially during the COVID-19 pandemic—but the burdens on people affected remain substantial.

Determinants of WEE1 inhibitor sensitivity in cancer cells are largely undefined. Here, the authors show that WEE1 inhibitors beyond their cell cycle perturbing effects also lead to paradoxical activation of the integrated stress response kinase GCN2.

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.

Polyamines produced by gut bacteria have been proposed to contribute to inflammatory bowel diseases. Here, Nauta et al. show that bacteria can produce a noncanonical polyamine intermediate that functions similarly to deoxyhypusine synthase inhibitors, activates mitochondrial stress responses, and inhibits nematode development and mouse macrophage differentiation.

Genomic analysis of Plasmodium DNA from 36 ancient individuals provides insight into the global distribution and spread of malaria-causing species during around 5,500 years of human history.

Chronic care manages long-term, progressive conditions, while acute care handles short-term ones. Here, authors show chronic conditions account for most of the global health burden, with 68% of DALYs and 93% of YLDs attributed to chronic care needs.

A study of retrotransposon activity repurposes a retroelement called R2Tocc to create a programmable system called STITCHR that enables diverse genome edits including efficient, scarless large payload insertions.

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.

Adipose immune cells contribute to obesity-related disease, but less is known about weight cycling. Here, authors show that weight loss reduces diabetes risk, but inflammatory adipose immune cell populations persist and may contribute to worsened diabetes risk upon weight regain.

Deaminases of the APOBEC3 family contribute to the mutagenesis of various cancers, including urothelial carcinoma (UC) of the bladder. Here, the authors use functional studies and transcriptomics to demonstrate that APOBEC3 promotes tumour progression and squamous trans-differentiation in UC through IL-1α and downstream activation of the AP-1 transcription factor.

Here, the authors leverage whole-genome sequencing from >88,000 diverse individuals to uncover 18 BMI-related genetic signals, including novel variants in participants of African genetic ancestry, highlighting the value of diversity in genetic discovery.

Sadhu et al. identify and functionally validate ferredoxin-1 (FDX1) as a determinant of cholesterol metabolism and cardiovascular risk in Asian populations.

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.

Changes in agricultural practices have led to the expansion of tree plantations across the tropics, but this expansion is poorly characterized. Nearly 7 million unique patches of observed tree cover gain are classified through satellite imagery to report on tropical tree plantation expansion between 2000 and 2012.

Psoriasis is a partially heritable skin disorder, the genetic basis of which is not fully understood. Here, the authors use genome-wide association meta-analysis to discover psoriasis susceptibility loci and genes, which encode existing and potential new drug targets.

The MmpL5/MmpS5 efflux system is crucial for drug extrusion and siderophore export in M. tuberculosis. Here, the authors report its high-resolution cryo-EM structures, revealing a unique trimeric assembly and a flexible extracellular stalk.

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.

Genome-wide association studies (GWAS) have improved our understanding of the genetic basis of lung adenocarcinoma but known susceptibility variants explain only a small fraction of the familial risk. Here, the authors perform a two-stage GWAS and report 12 novel genetic loci associated with lung adenocarcinoma in East Asians.

Direct dark matter searches need to take into account whether the total observation time is lower than the characteristic coherence time of the DM field. Analysing this generally overlooked scenario, here the authors quantify the impact on DM limits of the stochastic nature of the virialised ultralight field.

Cognitive function is associated with health and important life outcomes. Here, the authors perform a genome-wide association study for general cognitive function in 300,486 individuals and identify genetic loci that implicate neural and cell developmental pathways in this trait.

A genome-wide association study including over 76,000 individuals with schizophrenia and over 243,000 control individuals identifies common variant associations at 287 genomic loci, and further fine-mapping analyses highlight the importance of genes involved in synaptic processes.

Prospective assessment of a T-cell-inflamed gene signature and tumor mutational burden is feasible in patients with non-small cell lung cancer randomized to receive various anti-PD-1-based treatment combinations, with an encouraging objective response rate for first-line pembrolizumab + lenvatinib in one biomarker-defined group.

Similarities in cancers can be studied to interrogate their etiology. Here, the authors use genome-wide association study summary statistics from six cancer types based on 296,215 cases and 301,319 controls of European ancestry, showing that solid tumours arising from different tissues share a degree of common germline genetic basis.

Sox9 is an important transcription factor in the formation of cartilage chondrogenesis that occurs during skeletal development. Nakamuraet al.show that Sox9 interacts with Wwp2 and Med25 to form a complex and that loss of either protein in zebrafish results in altered palate chondrogenesis.

The goal of the 1000 Genomes Project is to provide in-depth information on variation in human genome sequences. In the pilot phase reported here, different strategies for genome-wide sequencing, using high-throughput sequencing platforms, were developed and compared. The resulting data set includes more than 95% of the currently accessible variants found in any individual, and can be used to inform association and functional studies.

Analysis of rare coding variants in the UK Biobank identifies eight genes associated with adult cognitive function, including KDM5B. Rare and common variant signals overlap and contribute additively to the phenotype.

An unbiased approach for the genome-wide detection of off-target cleavage by CRISPR-Cas9 RNA–guided nucleases reveals wide variability in the off-target activity of different guide RNAs.

A cross-ancestry meta-analysis of genome-wide association studies identifies association signals for stroke and its subtypes at 89 (61 new) independent loci, reveals putative causal genes, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as potential drug targets, and provides cross-ancestry integrative risk prediction.

In lung cancer, relatively few germline mutations are known to impact risk. Here the authors looked at rare variants in 39,146 individuals and find novel germline mutations associated with risk, as well as implicating ATM and a new candidate gene for lung cancer risk.

The first phase 2 gene therapy trial for HIV-1 has shown some promising signs. There's a long way to go before this would be a viable approach in people with HIV—this trial did not show a statistically significant difference in viral load at the primary end point–but other analyses did reveal that the gene therapy seemed to have a modest, but statistically significant, effect at reducing viral load in the treated subjects versus the placebo arm. The study also provides some clues about what to improve in the future.

Acquired radioresistance is a challenge for the cure of glioblastoma. Here, the authors show that radioresistant glioblastoma boosts mitochondrial fatty acid oxidation that fuels cell proliferation and induces immunosuppression via CD47 mediated anti-phagocytosis. Inhibition of FAO by etomoxir combined with anti-CD47 antibodies sensitizes glioblastoma to radiotherapy.

Few biomaterials are suitable for long-term tissue engineering applications and these examples usually possess limited property scope, can be difficult to process, and are non-responsive to external stimuli. Here, the authors overcome these issues by developing a class of easily processable polyamides with stereo-controlled mechanical properties and high-fidelity shape memory behaviour.

By examining neural responses from tree shrews performing hierarchical decision tasks with rule reversals, the authors identify a thalamocortical mechanism for regulating cognitive flexibility.

A chip-integrated laser with 7.5 × 10⁻¹⁴ fractional frequency instability is demonstrated by active stabilization to an on-chip 6.1-m-long spiral resonator. By using this laser to interrogate the narrow-linewidth transition of ⁸⁸Sr⁺, a clock instability averaging down as \(3.9\times 1{0}^{-14}/\sqrt{\tau }\) is achieved.

A multi-ancestry genome-wide association meta-analysis of kidney cancer identifies 63 regions associated with disease susceptibility including one locus that was associated with increased risk in individuals with African ancestry.

Alterations in the tumour suppressor genes STK11 and/or KEAP1 can identify patients with advanced non-small-cell lung cancer who are likely to benefit from combinations of PD-(L)1 and CTLA4 immune checkpoint inhibitors added to chemotherapy.

Combination of epidemiology, preclinical models and ultradeep DNA profiling of clinical cohorts unpicks the inflammatory mechanism by which air pollution promotes lung cancer

The ability of Mycobacterium leprae to upregulate miRNA-21 provides an effective mechanism for the pathogen to escape from the vitamin D–dependent antimicrobial pathway.