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A mass spectrometry-based approach globally identifies protein regulators of metabolism and reveals the role of LRRC58 in controlling cysteine catabolism.

Genome-wide analyses identify 30 independent loci associated with obsessive–compulsive disorder, highlighting genetic overlap with other psychiatric disorders and implicating putative effector genes and cell types contributing to its etiology.

Long-term effects of fetal SSRI exposure—commonly prescribed to pregnant mothers who suffer from depression and anxiety—are unknown. Here, authors finds increased fear-related behaviors and matching brain circuit activation in both mice and humans.

Mice expressing humanized mutant tau exhibit synaptic loss and behavioral abnormalities in the absence of abnormal tau conformers, suggesting that hyperphosphorylated tau can be pathological, at least in tauopathies caused by tau isoform imbalance.

The study advances the use of serological surveys to guide trachoma elimination program decisions and provides a way to set thresholds for whether or not to continue an intervention program.

The authors present PIONEAR–seq technology to assay in vitro binding of pioneer transcription factors to nucleosomes. The PIONEAR–seq data reveal that a nucleosome’s broader sequence context regulates the interactions of pioneer transcription factors via DNA bendability.

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.

Using cryo-electron tomography (cryo-ET) and proteomics, this study identifies the tethering of pathological tau filaments within defined brain extracellular vesicles in Alzheimer’s disease, shining light on the link between these vesicles and tau pathology.

Here the authors use single cell profiling of T cells across the human lifespan to show that a suboptimal TCR shift in T cells as we enter older age results in a molecular signature that resembles that of T cells from newborns and children.

SARS-CoV-2 evolution poses a risk to vaccine and antiviral drug efficacy. Here, Gagne et al. report the development of a variant-agnostic protein, RBD-62, with enhanced ACE2 binding obtained through in vitro evolution and show that RBD-62 inhalation protects nonhuman primates against SARS-CoV-2 Delta challenge.

This study employs a functional genomic approach to identify a synthetic lethal interaction between CDS1 and CDS2 in uveal melanoma and other cancers, which may represent a potential therapeutic target.

Whether multimorbidity accelerates brain Aβ deposition in humans remains largely unknown. Here, the authors demonstrate that higher self-reported multimorbidity burden predicts increased brain Aβ accumulation rates in the ADNI cohort.

This manuscript evaluates forecasts of laboratory-confirmed influenza hospital admissions, a new target for influenza forecasting in the United States. Across two influenza seasons, the FluSight ensemble is robust compared to submitted models.

This study finds that sST2 is a disease-causing factor for Alzheimer’s disease. Higher sST2 levels impair microglial Aβ clearance in APOE4⁺ female individuals. A genetic variant, rs1921622, is associated with a reduction in sST2 level and protects against AD in APOE4⁺ female individuals.

Sun et al. report human lifespan changes in the brain’s functional connectome in 33,250 individuals, which highlights critical growth milestones and distinct maturation patterns and offers a normative reference for development, aging and diseases.

A 50 microRNA-based dynamic risk score for stratifying individuals with and without type 1 diabetes was developed using samples obtained from multicenter and multiethnic cohorts.

AI decision support system non-homogenously influences clinical decisions in dynamic treatment regimen, as it depends on several factors including prior knowledge, preference, disease type, treatment modality, and AI’s learned behavior and inherent biases.

Artificial intelligence (AI) system is known to improve dermatologists’ diagnostic accuracy for melanoma. This group applies the eye-tracking technology on dermatologists when diagnosing dermoscopic images of melanomas and reports improved balanced diagnostic accuracy when using an X(explainable) AI system comparing to the standard one.

How sensory systems are organized during development remains unclear. Here, the authors used electron microscopy to examine the gravity-sensing system in zebrafish, finding that directional tuning and developmental age are organizing principles of the transformation from vestibular sensation to motor control.

During Plasmodium intra-erythrocytic developmental, parasites compromise the structural integrity of host red-blood cells. Here, Clark et al. develop a flow cytometric osmotic stability assay to show that P. vivax infection destabilizes host reticulocytes, which are less stable than P. falciparum-infected normocytes.

Susan Slager and colleagues report a meta-analysis of genome-wide association studies for chronic lymphocytic leukemia (CLL). They identify nine loci newly associated with CLL.

The cellular functions of arrestins are determined in part by the pattern of phosphorylation on the G protein-coupled receptors (GPCRs) to which arrestins bind. Here, authors use a library of synthetic phosphopeptide analogues of the GPCR rhodopsin C-terminus and determine the ability of these peptides to bind and activate arrestins using a variety of biochemical and biophysical methods.

Similarities in cancers can be studied to interrogate their etiology. Here, the authors use genome-wide association study summary statistics from six cancer types based on 296,215 cases and 301,319 controls of European ancestry, showing that solid tumours arising from different tissues share a degree of common germline genetic basis.

The beta variant (B.1.351) is to date the most resistant to neutralization of the SARS-CoV-2 variants. Using nonhuman primates, Seder and colleagues demonstrate that double vaccination with a high dose of the lipid nanoparticle vaccine mRNA-1273 protects against infection with the beta variant.

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.

Calcineurin — the Ca2+ regulated phosphatase and target of immunosuppressants — regulates GPCR-mediated phospholipid signaling at the plasma membrane. Here the authors show that CNAβ1 (a poorly studied isoform of the calcineurin catalytic subunit) is targeted to the plasma membrane through palmitoylation to dephosphorylate and promote PI4KA complex activity.

The BIN1 SNP rs744373 is associated with higher CSF tau and phosphorylated tau levels. Here the authors show, using PET imaging, that this SNP is associated with tau accumulation in the brain as well as impaired memory in older individuals without dementia.

The KL-VS haplotype of the Klotho gene has been associated with reduced risk of Alzheimer’s disease and dementia. Here the authors show an association between the KL-VS haplotype and amyloid-dependent tau accumulation using PET data.

Long-lived, self-renewing ‘progenitor-like’ CD8⁺ T cells can arise during chronic viral infection or in cancer. Wu and colleagues identify the transcription factor TOX as essential to endow ‘stemness’ and long-term persistence in the face of chronic infection.

In this largest whole-exome sequencing study of epilepsies to date, the Epi25 Collaborative identified extremely rare variants that confer risk for diverse epilepsy subtypes, highlighting roles in synaptic transmission and neuronal excitability.

In a biomarker-driven, outcome-adaptive platform trial for patients with metastatic castration-resistant prostate cancer, androgen receptor pathway inhibitors showed longer survival with respect to taxanes and physician’s choice treatment.

White-tailed deer are an important reservoir of SARS-CoV-2 in the USA and continued monitoring of the virus in deer populations is needed. In this genomic epidemiology study from Ohio, the authors show that the virus has been introduced multiple times to deer from humans, and that it has evolved faster in deer.

Aging is the most important risk factor for breast cancer in women without genetic mutations. Shalabi and colleagues now show that histologically normal mammary epithelial cells genetically predisposed to cancer exhibit features of accelerated aging, such as the loss of cell lineage markers, differentiation defects and transcriptome-wide enrichment of expression of genes related to aging and inflammation.

Isolating the neural mechanisms of consciousness is complicated by task report and other irrelevant signals. Here, the authors removed report and eye movement confounds to uncover large scale cortical-subcortical networks specific for human visual consciousness.

Alzheimer’s disease is heterogeneous in its neuroimaging and clinical phenotypes. Here the authors present a semi-supervised deep learning method, Smile-GAN, to show four neurodegenerative patterns and two progression pathways providing prognostic and clinical information.

X-linked adrenoleukodystophy (X-ALD) is a highly variable, progressive neurodegenerative disorder. In this study, neurofilament light chain protein (NfL) was identified as a potential early distinguishing biomarker.

This paper shows that integrating diverse stakeholders into management plans results in better protection, especially for those most vulnerable to the impacts of natural resource depletion.

A mutation leading to ubiquitous ectopic expression of agouti signaling protein, which is not picked up in conventional genetic screenings, is reported in patients with severe childhood obesity.

Class IIa histone deacetylases (HDACs) are generally viewed as noncatalytic readers of acetylated lysines within proteins. Specific inhibitors of class IIa HDACs, based on a new zinc-binding scaffold, offer chemical probes to explore the biological function and potential druggability of this enzyme subclass.

X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases such as chronic kidney disease (CKD). Here, the authors perform a sex-stratified, cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits, with results including identification of four novel loci associated with the CKD-defining trait eGFR.

Spatiotemporal sampling gaps in existing pathogen genomic data limits their use in understanding epidemiological patterns. Here, the authors apply a phylogeographic approach with SARS-CoV-2 genomes to accurately reproduce pathogen spread by accounting for spatial biases and travel history of the individual.

Here the authors propose an RNA interference-based switch for dynamic control of AAV transgene expression. In this approach, transgene expression may be silenced by RNAi and subsequently recovered using REVERSIR oligonucleotides.

Glutaminase is a mitochondrial complex that deaminates glutamine to form glutamate. Here the authors investigate inorganic-phosphate-induced enzyme filamentation, revealing an allosteric mechanism and roles of filamentous glutaminase in mitochondrial morphology and recycling.

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.

Sortilin is an endocytosis receptor with a luminal β-propeller domain. Here the authors present the structures of the β-propeller domain at neutral and acidic pH, which reveal that sortilin dimerises and undergoes conformational changes at low pH and further propose a model for low pH-induced ligand release by endocytosis receptors.