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The Evo2 Variant Effect Database (Evo2VED; https://dnallmved.org/) is a publicly accessible resource cataloging precomputed Evo2-derived variant effect scores, defined as allelic score differences, for 6.48 million human variants common in the gnomAD non-Finnish European population. Evo2VED includes scores from the 7B and 40B models under three scoring schemes, alongside annotations of variant function, evolutionary constraint, allele age, and disease associations. It integrates genome-wide...

The basal ganglia (BG) are conserved brain regions essential for motor control, learning, emotion, and cognition and are implicated in neurological and psychiatric disease, yet a unified cross-species taxonomy of BG cell types is lacking. We present a multiomic consensus atlas of 1.8 million nuclei from humans, macaques, and marmosets spanning eight BG structures, integrating gene expression, open chromatin, and spatial profiling. Alignment across species and to mouse and human whole-brain...

Rich-club organization is a topographical property of functional brain networks where highly connected regions are more densely interconnected. The rich-club has been shown to be vital for supporting cognitive functioning, and differences have been associated with a wide range of mental health and developmental conditions. This type of organization undergoes complex changes across development, and we have previously shown that males and females have strikingly distinct age-related changes. While...

The Chemical Probes Portal (https://www.chemicalprobes.org) is an open, international, resource empowering scientific robustness by supporting responsible research using chemical probes. The Portal informs best-practice in the selection and application of small-molecule chemical probes through expert review, manual curation, and community engagement. Used correctly, high-quality chemical probes are powerful, versatile research tools enabling the fundamental study of protein function, target...

Voltage-gated sodium channels regulate neuronal excitability and synaptic transmission in the postnatal and adult brain. The gene SCN2A, encoding the sodium channel Na(v)1.2, regulates synaptic development and variants in SCN2A are associated with autism spectrum disorders (ASD) and a broad spectrum of epilepsy phenotypes, including early-onset developmental and epileptic encephalopathies. The expression pattern of SCN2A begins during prenatal cortical development, prior to the onset of synaptic...

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The Mirror Neuron System (MNS) underlies important neurocognitive functions, such as imitation learning, social cognition and empathy, and may facilitate the recognition of emotional expressions via motor simulation. However, its development remains poorly understood. This study investigated functional connectivity maturation of MNS-related areas between early childhood and adulthood during an emotional faces task. Using the innovative magnetoencephalography approach of optically pumped...

BACKGROUND: Efinopegdutide is a pharmacologically distinct once-weekly GLP-1-glucagon receptor co-agonist with a relative receptor potency balance of approximately 2:1 under development for metabolic dysfunction-associated steatohepatitis (MASH). We aimed to investigate the efficacy and safety of efinopegdutide in adults with non-cirrhotic MASH.

Stroboscopic light stimulation (SLS) is a candidate non-pharmacological intervention that induces transient visual and affective experiences, with potential application in depression. Before efficacy testing, clinical development requires safety, tolerability, and feasibility data. We report a staged, single-site programme in adults reporting depressive symptoms. Study 1 tested 11 SLS parameter sets for safety and tolerability. Study 2 assessed whether an active comparator reduced subjective...

Clinical interventions for cancer treatment toxicities can reduce morbidity, mortality, and healthcare cost, if high risk patients can be identified. We developed SPARC, a transformer-based foundation model, using real-world, longitudinal, routinely collected health measurements, to predict adverse event risk. Pre-training and fine-tuning SPARC on 101,920,379 measurements from 224,047 patients with cancer led to state-of-the-art performance at predicting cancer-related adverse events on (i)...

The construction of accurate enzyme-constrained genome-scale models (ecGEMs) remains a critical challenge in systems biology, limited by sparse kinetic data and the need for biologically meaningful representations. This work presents an integrated framework combining CPI-Pred, a deep learning model to predict kinetic parameters (kcat) from sequence and compound embeddings, with kinGEMs, a pipeline to incorporate these uncertainty-aware parameters into ecGEMs for metabolic optimization. By...

CONCLUSIONS: Humoral responses declined significantly within six months of vaccination. Cellular responses were comparable across vaccine status groups, yet vaccinated children tended to maintain higher levels for more than one-year post-vaccination. Hybrid immunity could contribute to a more robust and durable cellular response.

CONCLUSIONS: Over a decade, the proportion of children with CCCs needing PICU care has grown, with trends toward increasing prevalence in the clinically dominant categories of respiratory and hematology, immunodeficiency, and immunology, and the subcategories respiratory malformations, hereditary hemostasis anomalies, and home ventilation, and trends toward higher mortality rates following treatment withdrawal.

In this study, we employ Bayesian optimization to identify conditions for enzyme-catalyzed, site-selective esterifications of pyranoside derivatives. Our findings indicate that Bayesian algorithms facilitate these challenging optimizations, which involve simultaneous variation of enzyme identity, solvent, acyl donor loading, time and temperature, across a range of substrates with various configurations, protective groups and anomeric substituents. Using the experimental optimization data...

A common approach for detecting rare variants (RVs) associated with complex human diseases is to perform a gene-based analysis or a region-based test of association. Typically, in a gene-based analysis, all the RVs pertaining to the gene considered are included in the statistical test, which potentially reduces its power since most RVs are likely not associated with the outcome of interest. As paradigm shift, we propose to add a variable selection step to choose the RVs that compose the...

The phytopathogen Pseudomonas syringae must enter the leaf interior through natural openings such as stomata to cause disease. Plants restrict pathogen entry into the leaf through non-self-recognition-driven stomatal closure. P. syringae counters this stomatal immunity by deploying a range of toxins and effectors. Here, we show that stomatal immunity in Arabidopsis thaliana is reinforced upon recognition of the ubiquitous P. syringae type III effector AvrE1 by the resistance protein CAR1. CAR1...

CONCLUSIONS: Structural brain aging in MDD is age-dependent and most pronounced in a neuroanatomical phenotype associated with poorer key clinical outcomes. The findings are consistent with, but do not establish, neuroprogression models of MDD and demonstrate that cBAG is not a uniform feature of MDD, being more strongly expressed in a specifically clinically vulnerable disease phenotype.

CONCLUSIONS: Career sustainability requires reducing avoidable occupational load while preserving physical capacity and restoring function through recognition, modification, conditioning, recovery, assessment, and rehabilitation.

CONCLUSIONS: The C2PS is a pragmatic and reliable tool to harmonize heterogeneous neuropsychiatric phenotypic data for large multi-national studies. Observations in 1,325 individuals with CNVs at 16p11.2 or 22q11.2 reveal variant-specific psychiatric profiles, emphasize burden and impact of psychiatric multimorbidity, and provide insights beyond categorical diagnoses.

CONCLUSIONS: Proton re-RT demonstrated encouraging locoregional control and survival in heavily pretreated patients, although late toxicities remain important concerns (ClinicalTrials.gov identifier: NCT03217188).