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The ocean carbon sink strengthened in previous warm El Niño years due to reduced CO₂ outgassing in the tropics. Here the authors show that the ocean carbon sink declined in 2023 despite record-high sea surface temperatures (SSTs), primarily due to SST-driven outgassing of CO₂ in the subtropics.

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.

Eusociality evolved independently in Hymenoptera and in termites. Here, the authors sequence genomes of the German cockroach and a drywood termite and provide insights into the evolutionary signatures of termite eusociality.

Natural products have historically made a major contribution to pharmacotherapy, but also present challenges for drug discovery, such as technical barriers to screening, isolation, characterization and optimization. This Review discusses recent technological developments — including improved analytical tools, genome mining and engineering strategies, and microbial culturing advances — that are enabling a revitalization of natural product-based drug discovery.

Despite being an important driver of a subset of medulloblastomas, efforts to therapeutically target Sonic Hedgehog (SHH) signaling, such as with the use of Smoothened (SMO) inhibitors, have had limited success. Here, the authors find that SHH medulloblastomas are sensitive to netrin-1 inhibition and investigate netrin-1 as a mechanism of resistance to SMO inhibition.

An analysis of 24,202 critical cases of COVID-19 identifies potentially druggable targets in inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

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.

An analysis of 2,173 individuals from the MetaCardis cohort quantifies the individual and combinatorial effects of a range of drugs on host health, metabolome and gut microbiome in cardiometabolic disease.

An investigation using various methods reports an association between adeno-associated virus 2 and paediatric hepatitis of unknown aetiology.

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.

Here, the authors show that reactivating motor memories during sleep at moments of high (vs. low) neuronal excitability (up vs. down phases of slow oscillations) enhances their consolidation. Up-reactivation strengthens sleep markers of plasticity and the neural responses supporting memory consolidation.

Competition is fierce in the microbial world, making evolutionary training and fitness essential for a microorganism to survive and thrive. To honour this spirit, in this Essay an expert panel has selected seven special events to make up the inaugural Microbial Olympics.

Results from the PRADO extension cohort of the OpACIN-neo trial show that pathologic response rate to neoadjuvant ipilimumab and nivolumab can be used as a criterion for personalization of further treatment in stage III nodal melanoma, with the potential to reduce treatment morbidity and increase patient quality of life.

A case–control study investigating the causes of recent cases of acute hepatitis of unknown aetiology in 32 children identifies an association between adeno-associated virus infection and host genetics in disease susceptibility.

Gut microbial metabolism of nutrients contributes to metabolic diseases, and the histidine metabolite imidazole propionate (ImP) is produced by type 2 diabetes (T2D) associated microbiome. Here the authors report that circulating ImP levels are increased in subjects with prediabetes or T2D in three European populations, and this increase associates with altered gut microbiota rather than dietary histidine.

TMAO is known to be atherothrombotic. Here the authors show that i) kidney function is the main determinant of serum TMAO, ii) TMAO increases kidney scarring with TGF-β1 signalling and iii) anti-diabetic drugs with reno-protective properties such as GLP1R agonists reduce plasma TMAO.

A cross-sectional analysis of participants in the MetaCardis Body Mass Index Spectrum cohort finds that the higher prevalence of gut microbiota dysbiosis in individuals with obesity is not observed in those who take statin drugs.

By studying individuals along a spectrum of cardiometabolic disease and adjusting for effects of lifestyle and medication, this investigation identifies alterations of the metabolome and microbiome from dysmetabolic conditions, such as obesity and type 2 diabetes, to ischemic heart disease.

A hybrid approach reconciles discrepancies between observation-based and ocean model estimates of the ocean CO₂ sink. It shows that ocean models underestimate variability, while observation-based methods tend to overestimate the 2010s trend.

Although termites are major human pests, they have an important role in maintaining ecosystem function and biodiversity. Here, the authors sequence the genome and transcriptomes of a dampwood termite and highlight genes that may be involved in the mechanisms underlying insect social behaviour.

BRCA1 mutations located within the BRCT domain result in proteasomal degradation and sensitivity to PARP inhibitors (PARPi). Here, the authors report genetic rearrangements in the BRCA1 gene that generate a BRCT-less BRCA1 protein isoform, which avoids degradation and leads to PARPi resistance.

Analysis of the phase 3 CheckMate 816 trial shows that the depth of pathologic response as assessed by percent residual viable tumor is correlated with event-free survival following neoadjuvant immunotherapy plus chemotherapy, supporting pathologic response as a biomarker of survival.

Trastuzumab deruxtecan, an anti-HER2–drug conjugate, exhibits the highest objective response rate in patients with HER2-overexpressing metastatic breast cancer, but clinical activity is also observed in patients with HER2-low or non-expressing tumors, potentially pointing to additional determinants of drug efficacy.

Methylation of CHMP2B regulates abscission timing by modulating ESCRT-III dynamics during cytokinesis. This methylation also plays a role in HIV-1 budding, highlighting the broader significance of ESCRT-III methylation.

In this immunological ancillary study of the PREVAC trial, the authors show that approved Ebola virus vaccines induce memory T-cell responses that persist during the five year follow-up after initial vaccination.

Fine-mapping of causal variants and integration of epigenetic and chromatin conformation data identify likely target genes for 150 breast cancer risk regions.

Hsp90s, molecular chaperones critically involved in many essential cellular processes, were the focus of a recent international conference held in Seeon, Germany. The scope of the conference ranged from structural and mechanistic insights all the way to medical applications.

The co-repressor GPS2 acts in macrophages to regulate their activation in obesity-induced inflammation, and appropriate GPS2 function is required to maintain insulin sensitivity in mice and humans with obesity.

Carbon uptake by the ocean has increased alongside rising atmospheric CO₂ concentrations, but with substantial variability. This Review examines trends in ocean CO₂ uptake and the internal and external factors driving its variability, finding an ocean uptake of –2.7 ± 0.3 Pg C year^–1 for the period 1990 through 2019.

Hepatitis C virus utilizes flavin adenine dinucleotide as a non-canonical initiating nucleotide for the viral RNA polymerase, resulting in 5′ capping of viral RNA, which provides protection against the host innate immune response.

Wartewig et al. show that PDCD1 in T cell lymphoma restricts glycolytic energy and acetyl-CoA production. Inhibition of PD-1 signaling enforces ACLY activity and generates extramitochondrial acetyl-CoA for histone acetylation to enable AP-1 hyperactivation.

Deletion of the transcription factor Irf5 in macrophages leads to expansion of the subcutaneous fat depot but restriction of the visceral fat during obesity, resulting in improved insulin sensitivity

A global dataset of the satellite-tracked movements of pelagic sharks and fishing fleets show that sharks—and, in particular, commercially important species—have limited spatial refuge from fishing effort.

Mammalian genomes are scattered with repetitive sequences, but their biology remains largely elusive. Here, the authors show that transcription can initiate from short tandem repetitive sequences, and that genetic variants linked to human diseases are preferentially found at repeats with high transcription initiation level.

Known genetic loci account for only a fraction of the genetic contribution to Alzheimer’s disease. Here, the authors have performed a large genome-wide meta-analysis comprising 409,435 individuals to discover 6 new loci and demonstrate the efficacy of an Alzheimer’s disease polygenic risk score.

Luis Pérez-Jurado, Stephen Chanock and colleagues detect clonal chromosomal abnormalities in peripheral blood or buccal samples from individuals in the general population. They show that the frequency of such events increases with age and is associated with elevated risk of developing subsequent hematological cancers.

Paul Pharoah and colleagues report the results of a large genome-wide association study of ovarian cancer. They identify new susceptibility loci for different epithelial ovarian cancer histotypes and use integrated analyses of genes and regulatory features at each locus to predict candidate susceptibility genes, including OBFC1.

Stig Bojesen, Georgia Chenevix-Trench, Alison Dunning and colleagues report common variants at the TERT-CLPTM1L locus associated with mean telomere length measured in whole blood. They also identify associations at this locus to breast or ovarian cancer susceptibility and report functional studies in breast and ovarian cancer tissue and cell lines.

Clinical, genomic and transcriptomic analyses of paired samples of synchronous bilateral female breast cancer identify associations between tumor concordance and immune infiltrates levels and response to neoadjuvant treatment.

Breast cancer risk for BRCA1/BRCA2 mutation carriers varies depending on other genetic factors. Here, the authors perform a case-only genome-wide association study and highlight novel loci associated with breast cancer risk for BRCA1/BRCA2 mutation carriers.

Epidermal homeostasis requires long term stem cell function. Here, the authors apply transcriptional circuitry analysis based on integrated epigenomic profiling of primary human keratinocytes with high and low stem cell function to identify IRF2 as a negative regulator of stemness.