Search

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.

De novo and inherited dominant variants in genes encoding U4 and U6 small nuclear RNAs are identified in individuals with retinitis pigmentosa. The variants cluster at nucleotide positions distinct from those implicated in neurodevelopmental disorders.

Alström syndrome (AöS) is a rare genetic disorder characterized by metabolic problems. Here, the authors show that in AöS models, defects in cilia and autophagy lead to ACBP accumulation, which drives obesity. An anti-ACBP antibody reduces weight gain and metabolic dysfunction, highlighting ACBP as a therapeutic target for this ciliopathy.

Cannabis exposure is a critical concern, particularly during adolescence. This study shows that tetrahydrocannabinol-induced cognitive deficits are mediated by a specific astrocytic ensemble in the nucleus accumbens whose manipulation prevents and reverses these effects.

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).

Recent evidence suggests that astrocytes, through coordinated activation in sparse ensembles, contribute to memory traces — termed ‘astro-neuronal engrams’. In this Perspective, Sánchez Romero and Navarrete discuss supporting evidence for astro-neuronal engrams and how these findings challenge traditional neurocentric models of memory.

Non-alcoholic fatty liver disease (NAFLD) is a potentially serious liver disease with a substantial burden worldwide. In this Consensus Statement, a global multidisciplinary group of experts develop consensus statements and recommendations addressing a broad range of topics on NAFLD to raise awareness and spur action.

Individuals with schizophrenia show reduced structural similarity in temporal, cingulate, and insular lobes, especially those with worse cognition and symptoms, affecting late maturing association areas with low metabolism and high neurotransmission.

Cells respond to redox changes by shifting their protein thiol–disulfide balance. Here, the authors show that this balance is spatially regulated and varies widely across individuals, challenging the concept that glutathione acts as the main cellular redox buffer.

People of Mexico have diverse historical and genetic background. Here, Romero-Hidalgo and colleagues sequence whole genomes of Native Americans of Mexico, and show demographic history and genetic variation shared among subgroups of Native Americans.

Using the AstroLight system, the authors reveal that astrocytic ensembles in the nucleus accumbens regulate cue-motivated reward behavior, demonstrating that selective manipulation of tagged astrocytes can influence specific behavioral choices.

The human germinal centre-associated lymphoma gene is expressed in germinal centre B-lymphocytes; however, its function is unknown. Here the authors show that human germinal centre-associated lymphoma activates Syk kinase, leading to lymphoid hyperplasia and systemic reactive amyloid A amyloidosis in transgenic mice.

The crystal structure of apo flavodoxin from Anabaena displays a compact fold and suggests possible mechanisms for FMN binding.

Genotype and exome sequencing of 150,000 participants and whole-genome sequencing of 9,950 selected individuals recruited into the Mexico City Prospective Study constitute a valuable, publicly available resource of non-European sequencing data.

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.

The molecular mechanisms underlying metastasis in pheochromocytoma/paraganglioma (mPPGL) remain to be explored. Here, the authors perform genomic and immunogenomic profiling of mPPGL tumors and suggest potential biomarkers for risk of metastasis and immunotherapy response.

In neurons, brain-derived neurotrophic factor (BDNF) transcription is activated by synaptic activity, in part by epigenetic regulation of its promoter regions. Here the authors characterize histone modifications in response to NMDA treatment that result in different kinetics of Bdnf activation from its different promoter regions.

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

Genome-wide association analyses of intracranial and nine subcortical brain volumes in 74,898 participants of European ancestry identify 254 independent loci and yield polygenic scores accounting for brain variation across ancestries.

A transcriptome-wide association study identifies associations of genetically predicted gene expression with breast cancer risk. This analysis finds 48 candidate genes implicated in breast cancer susceptibility, including 14 at novel loci.

Microglia can help clear amyloid β plaques in the Alzheimer’s disease brain but may also become dysfunctional and can contribute to disease progression. March-Diaz et al. reveal that hypoxia, a potentially modifiable risk factor for Alzheimer’s disease, disrupts the metabolism and function of microglia near plaques, which may contribute to neuropathology.

How adipose mitochondria activity is fine-tuned in response to obesity is an active area of study. Here, the authors show that mitochondrial protein MCJ can block thermogenesis and that silencing this gene can correct obesity-related comorbidities.

Microglia rely on mitochondrial complex I during development, suggesting that complex I deficiency in microglia may have a role in primary mitochondrial diseases.

Single-cell gene expression analysis reveals phenotypic heterogeneity to enable bacterial specialization over the course of plant colonization.

Type 1 diabetes mellitus (T1DM) is characterized by beta cell loss because of an autoimmune attack. Here the authors show that an agonist for LRH-1/NR5A2, a nuclear receptor known to be protective against beta cell apoptosis, inhibits immune-mediated inflammation and hyperglycemia in T1DM mouse models.

The pathways that underlie the effects of exercise on metabolism remain incompletely described. Here, the authors perform a meta-analysis of transcriptomic data from 66 published datasets of human skeletal muscle. They identify pathways selectively activated by inactivity, aerobic or resistance exercise, and characterize NR4A3 as one of the genes responsive to inactivity.

The bacterium Helicobacter pylori, often found in the human stomach, can be classified into distinct subpopulations associated with the geographic origin of the host. Here, the authors provide insights into H. pylori population structure by collecting over 1,000 clinical strains from 50 countries and generating and analyzing high-quality bacterial genome sequences.

Sarcomas are morphologically heterogeneous tumours rendering their classification challenging. Here the authors developed a classifier using DNA methylation data from several soft tissue and bone sarcoma subtypes, which has the potential to improve classification for research and clinical purposes.

The molecular diversity of microglia has been described. Here the authors show that ARG1-expressing microglia are enriched in phagocytic inclusions and are involved in hippocampal innervation and spine maturation in mice. ARG1-expressing microglia also modulate cognition in a sex-dependent manner.

Tumor-secreted midkine modulates immune tolerance in the melanoma tumor microenvironment and determines resistance to immune checkpoint blockade.

Latin Americans trace their ancestry to the admixture of Native Americans, Europeans and Sub-Saharan Africans. Here, the authors develop a novel haplotype-based approach and analyse over 6,500 Latin Americans to infer the geographically-detailed genetic structure of this population.

Meta-analysis of genome-wide association studies on Alzheimer’s disease and related dementias identifies new loci and enables generation of a new genetic risk score associated with the risk of future Alzheimer’s disease and dementia.

Genetic factors that cause cardiac angiosarcoma are unknown. Calveteet al. show that a missense mutation in protection of telomeres1 (POT1) gene causes cardiac angiosarcoma by affecting the POT1 function and, consequently, telomere length and stability.

Seagrass meadows are important but one of the most threatened ecosystems globally. Here the authors analyse data about extent and density of seagrasses in Europe from 1869 to 2016, and find evidence of recent trend reversal for declining European seagrass meadows.

Humans show great diversity in facial appearance and this variation is highly heritable. Here, Andres Ruiz-Linares and colleagues examined facial features in admixed Latin Americans and identify genome-wide associations for 14 facial traits, including four gene loci (RUNX2, GLI3, DCHS2 and PAX1) influencing nose morphology.

The use of templates to achieve ordered material architectures over long length scales is challenging. Here, the authors use single-wall carbon nanotubes as scaffolds to macroscopically control the ordering of n/pthree-dimensional supramolecularly assembled materials.

In breast cancer the contribution of different genetic variants to disease heritability is complex and not fully understood. Here, the authors present a network-based analysis in 84,567 patients studying ~7.3 million variants, identifying gene modules associated with breast cancer survival.

Ankylosing spondylitis is a common, highly inheritable inflammatory arthritis with poorly understood biology. Here Brown, Cortes and colleagues use fine mapping of the major histocompatibility complex and identify novel associations, and identify other HLA alleles that like HLA-B27 interact with ERAP1 variants to influence disease risk.

The shape of the pinna varies widely in the general human population but the genetic basis of this variation is unknown. Here Adhikari et al. conduct a genome-wide association study in Latin Americans and discover seven gene regions influencing pinna morphology, including EDAR and TBX15.