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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.

A purpose-built implantable system based on biomimetic epidural electrical stimulation of the spinal cord reduces the severity of hypotensive complications in people with spinal cord injury and improves quality of life.

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 neuronal architecture that develops after spinal cord injury and causes autonomic dysreflexia is uncovered.

EchoNext, a deep learning model for electrocardiograms trained and validated in diverse health systems, successfully detects many forms of structural heart disease, supporting the potential of artificial intelligence to expand access to heart disease screening at scale.

An epidural spinal cord stimulation system regulates blood pressure in the acute and chronic phases of spinal cord injury.

p14ARF drives NPM1 phase separation and forms meso-scale assemblies that limit NPM1 dynamics. Here the authors show that p14ARF hydrophobic residues enhance NPM1 phase separation, promote p14ARF nucleolar partitioning, nucleolar NPM1 immobilization, and reduce cell viability.

Aaron Beck's influential cognitive model of depression posits that cognitive biases lead to depressive symptoms. In this Review, Beck and colleagues discuss neuroimaging findings suggesting that both top-down and bottom-up neural mechanisms underlie these biases, and propose a neurobiological architecture of the cognitive model of depression.

Silane, which is a precursor to the sandy surfaces of rocky planets and dusty clouds on gas giants, is seen directly in another world—a low-metallicity brown dwarf in which oxidation is slow and gas mixing is fast.

Combined patch clamp recording, biocytin staining and single-cell RNA-sequencing of human neurocortical neurons shows an expansion of glutamatergic neuron types relative to mouse that characterizes the greater complexity of the human neocortex.

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).

Warm-rain and ice crystal pathways of precipitation formation can co-exist in storms and the balance between each is determined by cloud base temperature and solute aerosol conditions, suggest numerical simulations of aerosol-cloud processes in convective storms.

This study demonstrates that the MKK3b/6 signalling pathway drives the skeletal muscle growth-promoting effects of resistance exercise.

Using well-calibrated statistical methods the authors jointly analyze Undiagnosed Diseases Network genomes, identifying known and novel disease genes. Software is publicly available to support future cross-cohort rare disease discovery efforts.

A study identifies public neoantigens generated by tumor-wide aberrant mRNA splicing activity across distinct cancer types.

Comprehensive genomic and transcriptomics analyses of more than 1,300 cases of childhood T-lineage acute lymphoblastic leukaemia identify 15 distinct subtypes that are associated with specific outcomes.

Using an exploratory phenome-wide association study of polygenic risk scores (PRS) in children aged 9–13 from the Adolescent Brain Cognitive Development Study cohort, the authors identify neurodevelopmental and internalizing PRS associations with multiple phenotypes similar to the constituent GWAS indicators (for example, neurodevelopmental and internalizing traits) as well as cross-trait phenotypes (for example, screen time, cortical volume).

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.

RNA-sequencing analysis of cells in the human cortex enabled identification of diverse cell types, revealing well-conserved architecture and homologous cell types as well as extensive differences when compared with datasets covering the analogous region of the mouse brain.

The authors used data from the ABCD Study to examine the effects of prenatal cannabis exposure on neuroimaging metrics and mental health in adolescents.

A combined-ancestry GWAS of diabetic retinopathy, comprising 68,169 cases and 129,188 controls, revealed nine previously unreported loci associated with the condition, including an evolutionarily adaptive genetic variant alongside a potential functional mechanism that influences racial disparities in diabetes complications among individuals of non-Hispanic African ancestry.

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.

Chromosomal instability occurs frequently in cancer, making it an attractive therapeutic target. Here, the authors identify KIF18A as a targetable vulnerability of cancer cells with chromosomal instability and target this using VLS-1272, a selective KIF18A inhibitor.

PtRu nanoparticles are the state-of-the-art catalysts for methanol electrooxidation—the anodic reaction in direct methanol fuel cells. Now, a method of dispersing single Pt atoms over Ru nanoparticles is presented and monitored in situ, thereby boosting the catalytic performance in the methanol oxidation reaction.

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

Data collected from more than 2,000 taxa provide an unparalleled opportunity to quantify how extreme wildfires affect biodiversity, revealing that the largest effects on plants and animals were in areas with frequent or recent past fires and within extensively burnt areas.

Using mouse lines in which subsets of neurons are genetically labelled, the authors provide generalized anatomical rules for connections within and between the cortex and thalamus.

Phylogenomic analysis of 7,923 angiosperm species using a standardized set of 353 nuclear genes produced an angiosperm tree of life dated with 200 fossil calibrations, providing key insights into evolutionary relationships and diversification.

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 use small angle neutron scattering and coarse-grained molecular dynamics simulations to demonstrate that condensates based on the granular components of nucleoli are network fluids.

Safely opening university campuses has been a major challenge during the COVID-19 pandemic. Here, the authors describe a program of public health measures employed at a university in the United States which, combined with other non-pharmaceutical interventions, allowed the university to stay open in fall 2020 with limited evidence of transmission.

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.

ABCC4 is a chemotherapeutic drug exporter highly expressed in acute myeloid leukemia. Here, the authors demonstrate that MPP1 anchors ABCC4 to the outer cell membrane mediating drug resistance in leukemic cells and identify antimycin A as a chemical probe that disrupts such interaction and restores sensitivity.

Severe cutaneous adverse reactions (SCAR) is a T cell-mediated, potentially lethal drug hypersensitivity (DH). Here, the authors identify a carbamazepine-specific TCR common among patients with carbamazepine-induced SCAR that confers SCAR-like pathology in mice upon carbamazepine exposure, thereby implicating specific TCRs in DH etiology.

Gouwens et al. established a morpho-electrical taxonomy of cell types for the mouse visual cortex via unsupervised clustering analysis of multiple quantitative features from 1,938 neurons available online at the Allen Cell Types Database.

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.

A study generates a clinicogenomics dataset resource, MSK-CHORD, that combines natural language processing-derived clinical annotations with patient medical data from various sources to improve models of cancer outcome.

The nucleolus is a membrane-less organelle formed through liquid–liquid phase separation (LLPS). Here the authors use biophysical methods and show that the nucleolar protein nucleophosmin (NPM1) also undergoes LLPS through homotypic, inter-NPM1 interactions and discuss implications for the ribosome biogenesis process.

Cardiomyocytes derived from human induced pluripotent stem cells could be used to generate cardiac tissues for regenerative purposes. Here the authors describe a method to obtain large bioengineered heart tissues showing advanced maturation, functional features and engraftment capacity.

The presence of strong inter-layer interactions has hindered the synthesis efforts towards large-area and highly crystalline monolayer SnS. Here, the authors report synthesis of large-area monolayer SnS using a liquid metal-based technique, and fabricate piezoelectric nano-generators with average peak output voltage of 150 mV at 0.7% strain.

Functional diversity and phylogenetic diversity are expected to be positively correlated. Here the authors show that the covariation between these metrics in vascular plant communities around the world is often either inconsistent or negative.

Piperidine heterocycles are widely prevalent in drug molecules; however, their synthesis remains challenging. Now, a general approach for N-(hetero)aryl piperidine synthesis using isolable iminium salts is reported. A variety of substituents are installed at the C2 and C3 positions, giving access to densely functionalized piperidines that are challenging to obtain using other methods.