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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.

The ExoSloNano system facilitates nanogold probe-based labeling of specific proteins of a wide range of sizes in live cells for cryo-electron tomography and correlative light and electron microscopy studies.

This study shows that the 2025 Mw 7.7 Myanmar earthquake ruptured 500 km of the Sagaing Fault with nearly no shallow slip deficit, revealing that mature, linear strike-slip faults can release strain efficiently, unlike less mature faults.

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.

A proteomic risk score for cardiorespiratory fitness, comprising as few as 21 proteins, is dynamic with exercise training and helps predict the risk of mortality and a range of cardiovascular, metabolic and neurological conditions.

Expression of VIM-2 leads to physiological trade-offs for bacterial pathogens that can be exploited to treat infections caused by multidrug-resistant bacteria.

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.

Sexual dimorphism in genetic vulnerability to schizophrenia, systemic lupus erythematosus and Sjögren’s syndrome is linked to differential protein abundance from alleles of complement component 4.

Medulloblastoma is the most common malignant brain tumour in children; having assembled over 1,000 samples the authors report that somatic copy number aberrations are common in medulloblastoma, in particular a tandem duplication of SNCAIP, a gene associated with Parkinson’s disease, which is restricted to subgroup 4α, and translocations of PVT1, which are restricted to Group 3.

Inborn errors of the alternative NF-κB pathway in humans impair the development of AIRE-expressing medullary thymic epithelial cells, thereby underlying the production of autoantibodies against type I IFNs and predisposition to viral diseases

For many neurodevelopmental disorder (NDD) risk genes, the significance for mutational burden is unestablished. Here, the authors sequence 125 candidate NDD genes in over 16,000 NDD cases; case-control mutational burden analysis identifies 48 genes with a significant burden of severe ultra-rare mutations.

Using data from a phase 3 efficacy trial, the authors here show that post-boost Omicron BA.1 spike-specific binding and neutralizing antibodies inversely correlate with Omicron COVID-19 and booster efficacy for naive and non-naive participants, supporting the continued use of antibody as a surrogate endpoint.

Rheumatoid arthritis patients respond differently to anti-TNF treatment. Using community-based challenge, the authors show that currently available data does not reveal meaningful genetic predictors of response to anti-TNF therapy, thus confirming clinical observations.

A phase 1/2a study shows that human neural progenitor cells modified to release the growth factor GDNF are safely transplanted into the spinal cord of patients with ALS, with cell survival and GDNF production for over 3 years.

Dense calcium imaging combined with co-registered high-resolution electron microscopy reconstruction of the brain of the same mouse provide a functional connectomics map of tens of thousands of neurons of a region of the primary cortex and higher visual areas.

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.

Coastal cities face a compound threat from relative sea-level rise and land subsidence; however, local land subsidence rates are spatially variable and can be difficult to quantify. Remote interferometric radar observations allow high-resolution estimations of local land subsidence to better inform the future of major coastal cities.

Pak et al. show that prolonged fasting is required for the effects of calorie restriction on insulin sensitivity, fuel utilization and ageing in mice.

Ghajar and colleagues report that astrocyte-deposited laminin-211 promotes the quiescence of disseminated tumor cells in the brain, in a manner dependent on the cytoplasmic sequestration of YAP by dystroglycan.

A spatially resolved transcriptional atlas of the mid-gestational developing human brain has been created using laser-capture microdissection and microarray technology, providing a comprehensive reference resource which also enables new hypotheses about the nature of human brain evolution and the origins of neurodevelopmental disorders.

The 2007 Mw 8.4 Bengkulu earthquake promoted the subsequent 2010 Mw 7.8 Mentawai earthquake by loading the shallow, velocity-weakening area that ruptured in the latter, according to hybrid postseismic modelling that integrates forward and inverse methods

Alpine valleys and lineated bedforms imaged with swath radar suggest that ice flowed quickly into a fault-bounded basin during the initial nucleation of the West Antarctic Ice Sheet near Hercules Dome.

Inhibition of fatty acid biosynthesis re-sensitizes colistin-resistant clinically relevant bacteria in vivo by inducing stress responses and altering membrane composition.

Hypermutation and microsatellite burden determine responses and long-term survival following PD-1 blockade in children and young adults with refractory cancers resulting from germline DNA replication repair deficiency.

To address the question of whether a recurrent tumour is genetically similar to the tumour at diagnosis, the evolution of medulloblastoma has been studied in both an in vivo mouse model of clinical tumour therapy as well as in humans with recurrent disease; targeted tumour therapies are usually based on targets present in the tumour at diagnosis but the results from this study indicate that post-treatment recurring tumours (compared with the tumour at diagnosis) have undergone substantial clonal divergence of the initial dominant tumour clone.

A first-in-human phase I clinical trial demonstrates the feasibility and safety of non-viral precision genome-engineering of a personalized adoptive cell transfer anticancer therapeutic.

Shallow parts of megathrusts up-dip of locked patches generally have a high slip rate deficit, which could mean tsunami hazard has been underestimated, according to a stress-constrained inversion of geodetic data.

Genetic and testing data from England show that the SARS-CoV-2 variant of concern B.1.1.7 has a transmission advantage over other lineages.

The plasmid-borne mcr-1 gene confers resistance to the antibiotic colistin. Here, MacNair et al. show that mcr-1 positive bacteria are however susceptible to colistin-mediated disruption of the outer membrane, and can be killed in vitro and in vivo by combining colistin with other antibiotics.

A 32-year-long slow-slip event occurred on a shallow part of the Sunda megathrust, perhaps because of stress accumulation after fluid expulsion, according to an analysis of the deformation history of the area and physics-based simulations.

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.

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.

In this study, Aggarwal and colleagues perform prospective sequencing of SARS-CoV-2 isolates derived from asymptomatic student screening and symptomatic testing of students and staff at the University of Cambridge. They identify important factors that contributed to within university transmission and onward spread into the wider community.

In a randomized placebo-controlled trial in rural Niger, biannual azithromycin distribution to children 1-59 months reduced all-cause mortality. Based on serology, Arzika et al. here report a reduction of Campylobacter infection, supporting one mechanism for the intervention’s impact on mortality.

A study of the evolution of the SARS-CoV-2 virus in England between September 2020 and June 2021 finds that interventions capable of containing previous variants were insufficient to stop the more transmissible Alpha and Delta variants.

The Human Microbiome Project Consortium has established a population-scale framework to study a variety of microbial communities that exist throughout the human body, enabling the generation of a range of quality-controlled data as well as community resources.

Post-international travel quarantine has been widely implemented to mitigate SARS-CoV-2 transmission, but the impacts of such policies are unclear. Here, the authors used linked genomic and contact tracing data to assess the impacts of a 14-day quarantine on return to England in summer 2020.

Better analytical methods are needed to extract biological meaning from genome-wide association studies (GWAS) of psychiatric disorders. Here the authors take GWAS data from over 60,000 subjects, including patients with schizophrenia, bipolar disorder and major depression, and identify common etiological pathways shared amongst them.

The Omicron variant evades vaccine-induced neutralization but also fails to form syncytia, shows reduced replication in human lung cells and preferentially uses a TMPRSS2-independent cell entry pathway, which may contribute to enhanced replication in cells of the upper airway. Altered fusion and cell entry characteristics are linked to distinct regions of the Omicron spike protein.

A high-resolution gene expression atlas of prenatal and postnatal brain development of rhesus monkey charts global transcriptional dynamics in relation to brain maturation, while comparative analysis reveals human-specific gene trajectories; candidate risk genes associated with human neurodevelopmental disorders tend to be co-expressed in disease-specific patterns in the developing monkey neocortex.

The insect IMD signalling pathway detects invading pathogens. Here the authors show that ticks have an alternative IMD system that lacks peptidoglycan receptors, IMD and FADD, and is instead reliant on interaction of the E3 ligase XIAP with the E2 conjugating enzyme Bendless.

A genome-wide association study for attention deficit/hyperactivity disorder (ADHD) identifies 12 loci and implicates neurodevelopmental pathways and conserved regions of the genome as being involved in underlying ADHD biology.

In this study the authors identify a possible link between the gene FAM222A and brain atrophy. The protein it encodes is found to accumulate in plaques seen in Alzheimer’s disease, and functional analysis suggests it interacts with amyloid-beta.

This Perspective discusses some of the challenges that pharmaceutical companies face in the use of lipid excipients at each stage of development, and proposes recommendations on how to streamline regulatory expectations.

The deubiquitinase A20 is a negative regulator of transcription factor NF-κB signaling pathways. Ma and colleagues show that mice lacking A20 expression in dendritic cells have defective lymphocyte homeostasis and develop spontaneous inflammatory disease.

In a new study including 200 families who experienced perinatal death, adding genomic analyses to standard autopsies improved the identification of underlying pathogenic causes and informed genetic counseling.