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Proteomic data from natural isolates of Saccharomyces cerevisiae provide insight into how these cells tolerate aneuploidy (an imbalance in the number of chromosomes), and reveal differences between lab-engineered aneuploids and diverse natural yeasts.

This study estimates the green cooling distribution and the population most exposed to heat in 14 major European areas. It found that lower-income residents, immigrants and unemployed residents are more vulnerable compared with upper-income residents, nationals and homeowners.

Efforts to apply targeted protein degradation for antibiotic development are limited by our understanding of prokaryotic protein degradation. Here, the authors establish a chemical-genetic platform and predictive model to determine the degradation potential of essential mycobacterial proteins.

The epigenetic changes underlying the heterogeneity of RA disease presentation have been the subject of intense scrutiny. In this study, the authors use multiple single-cell sequencing datasets to define ‘chromatin superstates’ in patients with RA, which associate with distinct transcription factors and disease phenotypes.

Temporal multi-omic analysis of tissues from rats undergoing up to eight weeks of endurance exercise training reveals widespread shared, tissue-specific and sex-specific changes, including immune, metabolic, stress response and mitochondrial pathways.

Human cortical maturation is organized along the sensorimotor-association axis. Here, the authors investigate in multiple cohorts if the development of functional connectivity during adolescence conforms to this hierarchy.

Dengue is a major public health concern in the Americas, and the Caribbean can be a source for reintroduction and spread. Here, the authors use travel surveillance data and genomic epidemiology to reconstruct Dengue epidemic dynamics in the Caribbean from 2009-2022.

Jacobsen and colleagues elucidate the nonhierarchical relationship between two types of stem cells: Vwf⁻ hematopoietic stem cells that stably replenish all blood cell lineages without a platelet bias, and Vwf⁺ stem cells that replenish almost exclusively platelets, and demonstrate that the two types utilize cellularly and molecularly distinct progenitor trajectories for replenishment of platelets.

The tuning properties of ventral stream neurons for object shape and category are not fully understood. Here the authors carry out multi-electrode array recordings in lateral occcipital complex and find that object properties are largely shape-based.

Type 2 inflammation drives the formation of pathologic mucus in patients with asthma. Here, authors reveal a role for intelectin-1 in IL-13-induced mucus properties, and that an ITLN1 eQTL is associated with protection from the formation of mucus plugs in T2-high asthma.

Inflammatory and degenerative processes are thought to play a role in the pathophysiology of multiple sclerosis. Here, the authors identified twenty serum proteins associated with increased clinical and radiographic disease activity.

Interleukin-33 (IL-33) is a master initiator of cancer-prone chronic inflammation. Here, the authors show that TLR3/4-TBK1-IRF3 pathway activation induces IL-33, and the cholesterol-lowering drug, statin, blocks this pathway to suppress chronic inflammation and its cancer sequela.

SCENT is a nonparametric method that models association between chromatin accessibility and gene expression in single-cell multimodal datasets, enabling construction of cell-type-specific enhancer–gene maps to aid mapping of candidate causal variants and genes for common diseases.

A survey of sharks and rays on coral reefs within 66 marine protected areas across 36 countries showcases that the conservation benefits of full MPA protection to sharks almost double when accompanied by effective fisheries management.

BEAN is a Bayesian approach for analyzing base editing screens with improved effect size quantification and variant classification. Applied to low-density lipoprotein (LDL)-associated common variants and saturation base editing of LDLR, BEAN identifies new LDL uptake genes and offers insights into variant structure–pathogenicity mechanisms.

Here, using a dynamic modelling approach, the authors find that the spread of dengue through Mexico and Brazil is shaped by specific interactions between human mobility, climate, and the environment. Their models can also be applied to predict future spread in these geographic areas.

Recent protein design methods rely on large neural networks, yet it is unclear which dependencies are critical for determining function. Here, authors show that learning the per residue mutation preferences, without considering interactions, enables design of functional and diverse protein variants.

Polypharmacology drugs are compounds designed to inhibit multiple protein targets. Here, authors use recent advances in AI to rapidly generate polypharmacology compounds against any pair of protein targets, experimentally validating numerous compounds targeting MEK1 and mTOR.

Patient-derived xenografts are important tools for cancer drug development. Here, the authors develop models from 22 non-small cell lung cancer patients. They show genomic differences between models created from different spatial regions of tumours and a bottleneck on model establishment.

Precise mass and radius measurements of giant planet WASP-193 b find an extremely low density of 0.059 ± 0.014 g cm⁻³. Current evolutionary models cannot fully explain such a low density, but the extended atmosphere makes WASP-193 b very suitable for high-precision characterization via JWST.

Genome-wide association analysis in over one million individuals of European ancestry identifies 2,103 independent genetic signals (including 113 new loci) associated with blood pressure traits.

A neural epigenetic signature detectable via plasma analyses is prognostic in patients with glioblastoma, resembling an oligodendrocyte-progenitor- and neuronal-progenitor-cell-like state and showing increased neuro-to-glioma synapse formation.

Understanding the complex relationships between enzyme sequence, folding stability and catalytic activity is essential for applications, but current technologies cannot simultaneously resolve both stability and activity phenotypes and couple these to gene sequences at large scale. Here, the authors report Enzyme Proximity Sequencing (EP-Seq), a deep mutational scanning method to assay both expression level and catalytic activity of thousands of oxidoreductase variants from a cellular pool in a single experiment.

Here, the authors suggest that molecular dysregulation on three axes may play a critical role in asthma within the African Diaspora. RNASeq and DNA methylation data are generated from nasal epithelium including cases and controls from seven different geographic sites.

Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus with unclear immune cell involvement. Here the authors generate a single cell transcriptomic dataset with 400k cells from the esophageal mucosa of active EoE patients, remission EoE patients, and healthy individuals to characterise esophageal cellular composition, phenotype and interaction in this disease.

Asymmetry is a key organising principle of the brain. Here the authors leveraged rare genetic mutations to revisit structural brain asymmetry showing the planum temporale is susceptible to deletions & duplications of specific gene sets.

Rich and colleagues show that glioblastoma stem cells have increased global protein translation, which is achieved via the tRNA modifier YRDC. They show that targeting it or reducing its substrate threonine suppresses tumor growth.

GWAS in difficult-to-recruit populations identifies variants associated with Lassa fever outcome and susceptibility at loci proximal to LIF, GRM7 and LARGE1.

Translocations and copy number variations that affect multiple myeloma (MM) have not been investigated at the single cell level. Here, single cell multi-omics reveal the relationship between epigenetic regulation and cytogenetic events that lead to the increase of cell proliferation in MM.

Here, the authors identify a small molecule degrader (XL44) for hRpn13 and solve the XL44-hRpn13 structure. XL44 induces apoptosis in myeloma cells with hRpn13 dependency and also targets KEN box proteins PCLAF and RRM2. Loss of hRpn13 and PCLAF abrogates XL44 restriction of cell viability.

Analysis of EZH2 separation-of-function mutants indicates that part of the RNA-binding surface of EZH2 is necessary for histone modification independently of RNA. A specific RNA-binding-defective mutant shows normal enzymatic activity in vitro and in lineage-committed cells.

COVID-19 can be associated with neurological complications. Here the authors show that markers of brain injury, but not immune markers, are elevated in the blood of patients with COVID-19 both early and months after SARS-CoV-2 infection, particularly in those with brain dysfunction or neurological diagnoses.

Amyotrophic Lateral Sclerosis (ALS) is highly heritable but the mechanisms of sporadic ALS are not fully understood. In this study, the authors identify drivers of variation and disease-relevant changes in the epigenomic profile of iPSC-derived motor neuron lines generated from ALS patients and healthy controls as part of the Answer ALS program.

Cyst growth in autosomal dominant polycystic kidney disease (ADPKD) is driven by unknown molecular signals that require the presence of intact primary cilia in the absence of the PKD gene products. Here, the authors show that the transcription factor Glis2 is a key effector of this cilia dependent cyst growth pathway and a potential target for therapy in ADPKD

Faecal microbiota transplantation (FMT) can be used to treat established colitis. Here the authors profile transcriptional changes in humans after FMT and how this relates to colitis remission identifying a role for GBP5, and this protein is validated in a loss-of-function mouse model.

Proteome-wide measurements of dose–response curves for 144 drugs reveal drug mechanisms of action.

Analysing camera-trap data of 163 mammal species before and after the onset of COVID-19 lockdowns, the authors show that responses to human activity are dependent on the degree to which the landscape is modified by humans, with carnivores being especially sensitive.

The factors that determine the direction of traveling waves in the brain are not well understood. Here, the authors show that the sum of incoming structural connection strengths shape both traveling wave direction and frequency gradients.

Whole-genome sequencing of 962 clear cell renal cell carcinomas from 11 countries shows geographic variations in somatic mutation profiles, including a mutational signature of unknown cause in 70% of cases from Japan.

Processing of coherent motion has been extensively studied in the primate visual system, but has not been well characterized in mice. Here, the authors use widefield calcium imaging to reveal that coherent motion responses are organized anisotropically both across and within visual areas in mice.

Cancer biomarkers are often continuous measurements, which poses challenges for their prediction using classification-based deep learning. Here, the authors develop a regression-based deep learning method to predict continuous biomarkers - such as the homologous repair deficiency score - from cancer histopathology images.

The mechanistic link between cortical activity and behaviors remains largely unclear. Here authors show that targeted holographic photostimulation of mouse visual cortex during a detection task alters performance based on the animal’s state and visual stimulus conditions, highlighting the dynamic influence of cortical activity on perception and behavior.

Short tandem repeat mutations in a primate Alu element on chromosome 15q cause activation of a thyroid-specific enhancer, upregulating MIR7-2/MIR1179. This results in defective thyroid proliferation and thyrotropin resistance.

IFNγ signaling is important in the pathogenesis and immune response, emphasizing the need for investigation of its role. Here, the authors show that IFNγ plays a key role in shaping immune microenvironment in AML and developing resistance, providing insights for potential therapeutic strategies.

Recent years have seen many advances in deep learning models for protein design, usually involving a large amount of training data. Focusing on potential clinical impact, Garton et al. develop a variational autoencoder approach trained on sparse data of natural sequences of adenoviruses to generate large proteins that can be used as viral vectors in gene therapy.

Generative models for chemical structures are often trained to create output in the common SMILES notation. Michael Skinnider shows that training models with the goal of avoiding the generation of incorrect SMILES strings is detrimental to learning other chemical properties and that allowing models to generate incorrect molecules, which can be easily removed post hoc, leads to better performing models.

Schief and colleagues show that germline-targeting epitope scaffolds can elicit responses from rare broadly neutralizing antibody precursor B cells with predefined binding specificities and genetic features.

Analysis of copy number alterations in 1,451 patient-derived xenografts (PDXs) and matched patient tumor samples shows strong conservation from patient tumors through late-passage PDXs and a lack of systematic copy number evolution driven by the mouse host.

In a tumor-agnostic phase 2 basket trial, the oral FGFR1–FGFR3 inhibitor pemigatinib elicits responses in tumor types beyond cholangiocarcinoma and bladder cancer and in tumor types with rarer FGFR alterations, with insights provided into resistance mechanisms.