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Neuropathic pain is commonly treated with opioids due to limited alternatives. Here, authors determine cryo-EM structures of the neuronal glycine transporter GlyT2 and develop a reversible inhibitor that provides analgesia in vivo without side effects.

Genome-wide association meta-analysis identifies 58 independent risk loci for major anxiety disorders among individuals of European ancestry and implicates GABAergic signaling as a potential mechanism underlying genetic risk for these disorders.

This study introduces a semi-automated, scalable whole-brain mapping workflow that enables unbiased comparisons across cohorts, revealing widespread temporally and sexually distinct regional activation patterns after acute morphine exposure in mice.

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.

MultiSuSiE is an extension of the Sum of Single Effects fine-mapping model that allows causal effect sizes to vary across ancestries. Applying MultiSuSiE to quantitative traits in All of Us identifies fine-mapped variants not implicated by other methods.

Networks with higher order interactions, relevant to social groups, ecosystems and human brain, require new tools and instruments for their analysis. Gambuzza et al. propose an analytical approach which allows to find conditions for stable synchronization in many-body interaction networks.

Genomic analyses applied to 14 childhood- and adult-onset psychiatric disorders identifies five underlying genomic factors that explain the majority of the genetic variance of the individual disorders.

Analyses of genome and exome sequencing data identify rare coding and structural variants associated with atrial fibrillation and highlight genetic links between atrial fibrillation and cardiomyopathies.

Glutathione has pleiotropic functions in different organs. Here the authors specifically examine deletion of a glutathione synthetic enzyme in the liver of adult mice and show that lack of glutathione affects lipid abundance through repressing NRF2.

TIRTL-seq is a high-throughput method for paired T cell receptor sequencing at the cohort scale.

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.

This multi-omic longitudinal analysis of the healthy human peripheral immune system constructs the Human Immune Health Atlas and assembles data on immune cell composition and state changes with age, including responses to cytomegalovirus infection and influenza vaccination.

MultiSTAAR provides a general and flexible statistical framework for functionally informed multi-trait rare variant analysis of biobank-scale sequencing studies by jointly analyzing multiple traits and incorporating annotation information.

Regional differences in SARS-CoV-2 variants may affect treatment outcome. Here, the authors show that near-sourced convalescent plasma has higher efficacy, as defined by death within 30 days of transfusion, than plasma sourced more than 150 miles away.

The preparation of conjugates between proteins and small molecules is often challenging and requires several synthetic steps to functionalize each component for conjugation. Now, a conjugation methodology that leverages an electrophilic Se–S bond of selenocysteine to create bioconjugates between polypeptides and complex small molecules has been described.

The Convention on the Conservation of Migratory Species of Wild Animals (CMS) provides a global framework for protecting migratory species, yet freshwater fishes remain underrepresented in the CMS appendices. Strengthening links between research, science communications, policy development and CMS implementation can generate synergistic effects that enhance conservation of migratory freshwater fishes.

Tunable polarization control and a two-colour X-ray pump–X-ray probe operating mode are demonstrated at the Linac Coherent Light Source (LCLS).

Neural progenitor cell transplantation shows promise for treating spinal cord injury. However, here, the authors show that graft-derived neurons form limited synaptic connections with host spinal motor circuits after injury, constraining functional motor recovery.

Genome editing tools can precisely introduce a specified lesion into the DNA, but ultimately rely on the cell’s DNA repair machinery to determine the editing outcome. Here, authors demonstrate how neurons’ unique DNA repair pathways impact the safety, efficiency, and precision of CRISPR edits.

Reframing of arousal as a latent dynamical system can reconstruct multidimensional measurements of large-scale spatiotemporal brain dynamics on the timescale of seconds in mice.

CAR-T cell therapy has been shown to be effective in immunotherapy for treatment of several different tumours. Here the authors show pre-specified interim outcomes from a P-BCMA-ALLO1 trial with BCMA targeted CAR-T therapy in multiple myeloma.

An ‘intracrine’ signaling mechanism is proposed whereby a G-protein-coupled receptor (free fatty acid receptor 4) senses locally released fatty acids on intracellular membranes associated with lipid droplets to efficiently regulate lipolysis in adipocytes.

Dysregulation of mTORC1 function is linked to various pathological conditions, including addiction. In this study, the authors show that mTORC1 activation in the nucleus accumbens of mice consuming excessive alcohol triggers translational repression through microRNA machinery, which in turn suppresses glycolysis and increases alcohol intake.

A horizon scan of international respondents identifies and discusses ten developing challenges in Antarctic conservation, revealing an increased emphasis on challenges related to governance, geopolitics and economics compared to a similar scan from 2012.

Materials typically break down in response to the repeated mechanical forces that they experience during use. Now, it has been shown that a mechanochemically active polymer can respond to shear forces by forming more bonds than are broken, leading to improved mechanical properties under conditions that would otherwise be destructive.

Directional Solvent Extraction is an emerging non-membrane desalination technology for sea water desalination but is limited by throughput and energy efficiency. Here, the authors demonstrate that the production rate and energy efficiency can be increased by using ionic liquids as directional solvent.

Self-assembled multidomain supramolecular peptide hydrogels that engage in dynamic covalent bonding with small-molecule drugs and biologics are shown to offer sustained release, extend the activity, and maintain safe and potent drug levels in vivo.

Building synthetic chromosomes from natural components is an unexplored alternative to de novo chromosome synthesis that may have many potential applications. In this paper, the authors report CReATiNG, a method for constructing synthetic chromosomes from natural components in yeast.

Deep-sea hydrothermal plumes support an array of microbial metabolisms, but the fate of organic carbon in these systems is unknown. Here, the authors used metabolic rate assays and metagenomic data to show that heterotrophic bacteria contribute significantly to carbon cycling in the deep sea.

Theoretical models and structures recovered from measured data serve for analysis of complex networks. The authors discuss here existing gaps between theoretical methods and real-world applied networks, and potential ways to improve the interplay between theory and applications.

Bicyclo[1.1.1]pentanes are of interest to the pharmaceutical and chemical communities, due largely to their metabolic stability and potential as bioisosteres. Here the enantioselective C–H activation of these carbocycles is reported, giving access to enantioenriched, substituted products while maintaining the carbocyclic framework.

Polymer mechanochemistry can trigger a wide range of often unanticipated reactivity, but the focus of these systems typically falls on the structure of the mechanophore rather than the intervening polymer backbone. Now, it has been shown that a poly(norbornene) backbone has a substantial impact on a mechanochemical ring-opening reaction, despite having only a minor effect on the force-free reaction.

Here, the authors leverage whole-genome sequencing from >88,000 diverse individuals to uncover 18 BMI-related genetic signals, including novel variants in participants of African genetic ancestry, highlighting the value of diversity in genetic discovery.

Researchers experimentally demonstrate the first joint-detection receiver capable of performing a joint measurement over pulse-position-modulation codewords. This result — the largest improvement over the standard quantum limit reported to date — is accomplished by using a conditional nulling receiver, which uses optimized-amplitude coherent pulse nulling, single-photon detection and quantum feedforward.

Circulating cell-free DNA (cfDNA) assays for monitoring individuals with cancer typically use tumor-specific mutations that may not be detected in many patients. Here, the authors develop a tumor-independent and mutation-independent approach (DELFI-TF) to estimate tumor burden in cfDNA for treatment response monitoring and clinical outcome prediction.

The goals, resources and design of the NHLBI Trans-Omics for Precision Medicine (TOPMed) programme are described, and analyses of rare variants detected in the first 53,831 samples provide insights into mutational processes and recent human evolutionary history.

A unified realization of the volt, ohm and ampere can be achieved by integrating a quantum anomalous Hall resistor and a programmable Josephson voltage standard in a single cryostat.

Zachary Lippman and colleagues report mutations in the tomato ortholog of CLV1 and a gene encoding a hydroxyproline O-arabinosyltransferase enzyme that modifies CLV3, both of which cause fasciated flowers and fruits owing to increased meristem size. They also find that a natural mutation in CLV3 was a major target of selection during tomato domestication.

Radiation and steroid dosing can affect the immune composition of brain metastasis (BM). The authors have designed a pilot study of pre-operative stereotactic radiosurgery with low or high dose of peri-operative dexamethasone for resectable brain metastases, here reporting clinical outcomes and characterization of intratumor TCF1+ CD8+ stem-like T cell immune niches in the brain.

Jeppesen, Sanchez et al. identify blebbisomes as large membrane-enclosed vesicles containing organelles and secreted by cells. Blebbisomes can both secrete and internalize exosomes and microvesicles.

Treatment with neoadjuvant BRAF/MEK-targeted therapy results in higher rates of major pathological response in female compared with male patients with melanoma, and pharmacological inhibition of androgen receptor signalling improved the responses of male and female mice to BRAF/MEK-targeted therapy.

De novo designed interleukin-4 mimetics were engineered that induce biased signaling activation and exhibit high thermal stability. These mimetics offer insight into cytokine signaling and can be directly incorporated into 3D-printed biomaterials

The authors present a characterization of complex X-linked lncRNA loci with sex- and allele-specific epigenetic signatures that serve as a platform for the largest chromatin structures in mammals, thereby elucidating diverse phenotypes and combinatorial effects on autosomes.

How signaling pathways recruit SWI/SNF chromatin remodeling complexes is not known. Here the authors suggest a ubiquitin directed mechanism targeting SWI/SNF for Wnt pathway dependent transcription, important for development and cancer.

A novel personalized phage therapy strategy that selects phages for a predicted evolutionary trade-off may represent a viable alternative approach for the treatment of antimicrobial-resistant bacterial infections.