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Humanity’s Last Exam, a multi-modal benchmark at the frontier of human knowledge, is designed to be an expert-level closed-ended academic benchmark with broad subject coverage.

While inequalities in science are common, most efforts to understand them treat scientists as isolated individuals, ignoring the network effects of collaboration. Here, the authors develop models that untangle the network effects of productivity and prominence of individual scientists from their collaboration networks.

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.

Ventures focusing on drug testing or therapies against rare disease, cancer, gastrointestinal disease, fibrosis and pain are among those selected by the editors in 2014's crop of startups.

Many premalignant colorectal polyps in familial adenomatous polyposis arise polyclonally rather than from a single mutated cell, showing diverse early evolutionary trajectories that frequently occur without clonal APC or KRAS driver events.

Age-related macular degeneration (AMD) is a common cause of vision loss with a large genetic risk in older individuals. Here, for a high-risk AMD subtype, the authors identify an association with a chromosome 10 risk region containing a long non-coding RNA.

While anti-PD-1 therapy can be effective in patients with breast cancer, response varies and is often limited by the development of resistance. Here, the authors investigate molecular determinant of response and resistance using multiomic single nucleus sequencing of longitudinal biopsies taken from breast cancer patients on a phase II clinical trial investigating neoadjuvant chemotherapy and pembrolizumab (anti-PD-1).

Ventures focusing on gene therapy, adoptive T-cell therapy, protein homeostasis and the microbiome are among those selected by the editors in 2013's crop of startups.

Academic leaders must audit departments for flaws and strengths, then tailor practices to build good behaviour, say C. K. Gunsalus and Aaron D. Robinson.

A computational null model is proposed to study the gender and racial diversity-association effects in academia. Researchers’ early training in diverse environments is strongly correlated with nurturing diverse groups in the established period.

Our annual survey highlights several academic startups developing immunotherapies as well as ventures focusing on microbiomes, proteostasis, integrin biology, nucleic acid delivery and subcellular imaging.

Immuno-oncology was hotly pursued by investors in 2015, along with drug delivery platforms. In the agbiotech world, a systems biology company set up shop.

In a randomized phase 3 trial, the combination of the BET inhibitor pelabresib with the JAK inhibitor ruxolitinib resulted in a significantly higher spleen volume reduction from baseline versus placebo with ruxolitinib in patients with JAK inhibitor-naive myelofibrosis.

Cisplatin is the most frequently used chemotherapeutic agent for the treatment of patients with oral cavity squamous cell carcinoma (OCSCC), however, systemic administration is often associated with dose limiting side effects. Here the authors design and test a nano-engineered patch system (PRV111) for the local delivery of cisplatin-loaded chitosan nanoparticles and report the results of a phase 1/2 clinical trial of PRV111 in patients with OCSCC.

RETFound, a foundation model for retinal images that learns generalizable representations from unlabelled images, is trained on 1.6 million unlabelled images by self-supervised learning and then adapted to disease detection tasks with explicit labels.

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.

Last year, President Clinton made clear the urgent need for an effective HIV vaccine, and suggested that it should be possible to create one within ten years. The authors agree. Although recent progress should not be underestimated, many obstacles remain some technical, others not. Here, Dennis Burton (Scripps Research Institute) and John Moore (Aaron Diamond AIDS Research Center) outline their views on the state of development of an HIV vaccine and the areas in which more effort should be focused.

Rare variant analyses identify a new type 2 diabetes risk allele near the LEP gene, which encodes leptin, and other risk alleles of intermediate penetrance in genes previously implicated in monogenic forms of diabetes.

Structural variants (SVs) in human genomes contribute diversity and diseases. Here, the authors use a multi-platform strategy to generate haplotype-resolved SVs for three human parent–child trios.

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).

Sex differences in fasting glucose and insulin have been identified, but the genetic loci underlying these differences have not. Here, the authors perform a meta-analysis of genome-wide association studies to detect sex-specific and sex-dimorphic loci associated with fasting glucose and insulin.

Two below-threshold surface code memories on superconducting processors markedly reduce logical error rates, achieving high efficiency and real-time decoding, indicating potential for practical large-scale fault-tolerant quantum algorithms.

Epigenetic variation is most strongly associated with genetic variation at the iPSC stage. That relationship weakens as epigenetic variation increases in differentiated cells.

Genome-wide association analyses of blood glucose measurements under nonstandardized conditions provide insights into the biology of glucose regulation, diabetes complications and pathways for treatment stratification.

A molecular tumor board (MTB) is often used as a platform that integrates clinical and molecular parameters for clinical decision making. Here, the authors review the outcome of 715 cancer patients presented at their institution’s MTB, and demonstrate that patients who received a MTB-recommended regimen received therapy that was better matched to their alterations and achieved better clinical outcomes.

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.

The base-calling algorithm SNPSeeker detects single-nucleotide polymorphisms with frequencies that are below the error rate of the sequencing platform. It is thus well suited to analyze data from large pooled samples and find rare variants that may contribute to diseases or complex traits.

Why joints are highly responsive to systemic inflammation is unknown. Hasegawa et al. sought to address this question, developing a whole-mount imaging system of the entire synovium to profile the vascular, neuronal and immune components.

By analyzing bulk and single-cell RNA-sequencing datasets generated from left atrial appendages of individuals with atrial fibrillation and non-affected controls, Leblanc and Yiu identify cell-type-specific genes and transcriptomic programs implicated in atrial fibrillation, a cardiomyocyte-specific androgen receptor signaling signature and an anti-fibrotic effect of NR4A1 inhibition in atrial cardiofibroblasts.

Chronic infection with SARS-CoV-2 leads to the emergence of viral variants that show reduced susceptibility to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma.

We show the evolution of a case of EGFR mutant lung cancer treated with a combination of erlotinib, osimertinib, radiotherapy and a personalized neopeptide vaccine targeting somatic mutations, including EGFR exon 19 deletion.

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 authors show that machine learning derives the degree of background retinal pigmentation with more nuance than self-described ethnicity. Retinal pigment scores are associated with genes linked to melanin and may improve algorithmic fairness.

Given the lack of global legislation, nations should work hard to establish cross-border protections for vulnerable species, says Aaron M. Ellison.

To protect endangered species from extinction, the ecological community must become more politically involved, argues Aaron M. Ellison.

Sera from vaccinated individuals and some monoclonal antibodies show a modest reduction in neutralizing activity against the B.1.1.7 variant of SARS-CoV-2; but the E484K substitution leads to a considerable loss of neutralizing activity.

Intratumoural heterogeneity in high-grade serous ovarian carcinoma (HGSOC) remains to be explored. Here, the authors perform spatial transcriptomics and reveal a high degree of subclonal heterogeneity in HGSOC.

The complicated and labor-intensive manufacturing of novel cell and gene therapies requires efforts to improve workforce development programs for the nascent cell therapy industry broadly, and for cell manufacturing more specifically.

Fibroblasts play critical roles in tissue homeostasis, but in pathologic states they can drive fibrosis, inflammation, and tissue destruction. Here, Faust et al. find that healthy human synovial fibroblasts under the influence of adjacent adipocytes have altered lipid metabolism driven by cortisol signaling. Both adipocytes and these characteristics are lost in inflammatory arthritis.

Uveal melanoma has a propensity to metastasise. Here, the authors report the whole genome sequence of 103 uveal melanomas and find that the tumour mutational burden is variable and that two subsets of tumours are characterised by MBD4 mutations and a UV exposure signature.

Case report of an individual heterozygous for a rare RELN-COLBOS variant that confers resilience, via a gain-of-function mechanism, to Alzheimer’s disease.