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McGrail and colleagues report that high intratumoral bacteria abundance is associated with an immunosuppressive microenvironment and resistance to immune checkpoint blockade in head and neck squamous cell carcinoma.

The authors show how Vγ1⁺ γδ T cells produce IL-4 to drive early CD8⁺ T cell and dendritic cell responses to malaria infection in mice.

The viscosity of tumour cells is shown to govern their ability to disseminate through the bloodstream and extravasate, establishing a key biomechanical factor of metastasis.

C-COMPASS is an open-source software designed to predict the spatial cellular distribution of proteins and lipids from cellular organelle profiling using a neural network-based regression model.

Engineered carbon nanotube sensors enable the detection of intracranial tumours in blood, identify low-abundance biomarkers and amplify cancer detection by capturing secreted factors from the entire tumour ecosystem for early-stage disease diagnosis.

Risk associated with genetically defined forms of autism spectrum disorder (ASD) can propagate by means of transcriptional regulation to affect convergently dysregulated pathways, providing insight into the convergent impact of ASD genetic risk on human neurodevelopment.

Ni, Wei, Vona and colleagues use human brain organoids to dissect patient AIRIM variants associated with neurodevelopmental features. A subset of variants impaired ribosome production and protein synthesis, and delayed radial glial cell specification.

Lymphatics maintain lipid transport, immunity, and fluid balance. Kim J and Chaudhary S et al. reveal an AIBP-driven cholesterol efflux mechanism that regulates lymphangiogenesis via VEGF signaling.

TCR-engineered T cells have shown limited efficacy in part due to the absence of co-stimulation leading to limited accumulation in solid tumors. The authors here show engineering the CD8β coreceptor with an intracellular CD28 domain enhances cytokine production, persistence, and tumor control in vivo independent of tumor-associated co-stimulatory ligand encounter.

Analysis of a placebo-controlled trial of a BCMA-targeting CAR-T cell therapy in patients with myasthenia gravis shows that CAR-T cell infusion selectively remodels the systemic immune environment, with elimination of BCMA-high plasma cells and activated plasmacytoid dendritic cells and changes in the autoreactive B cell repertoire.

Chromogranin A (CgA) ablation in Tauopathy mice reduces toxic Tau buildup, reverses cognitive decline and improves lifespan. Mechanistically, the deletion of CgA normalizes the adrenergic signaling axis in the brain.

Cas9 DNA targeting is inherently sequence specific but not temporally controlled. Here, authors spatiotemporally couple Cas9 activity to target site transcription in eukaryotes and exploit this to preferentially edit the more highly transcribed of two alleles that harbor identical Cas9 targets.

Genetically encoded sensors are generally optimized to function during exponential growth rather than stationary phase, which limits their potential value for metabolic engineering and bioproduction. Here, authors engineer a stationary phase green light sensor and use pulsatile light to optimize production of industrially relevant small molecules.

Understanding the mechanisms underlying the survival of drug tolerant persister cells following chemotherapy remains elusive. Here, multi-omics analysis and experimental approaches show that the germ-cell-specific H3K4 methyltransferase PRDM9 promotes metabolic rewiring in glioblastoma stem cells.

Affinity-proteomics platforms often yield poorly correlated measurements. Here, the authors show that protein-altering variants drive a portion of inter-platform inconsistency and that accounting for genetic variants can improve concordance of protein measures and phenotypic associations across ancestries.

cSplotch compares spatial transcriptomics data across ages and regions of mouse colon tissue.

Intratumor heterogeneity (ITH) has been mainly studied at the genomic level. Here, the authors integrate multi-region proteomics of 280 tumor regions from 33 patients, exome sequencing, and imaging-based immune and stromal profiling to investigate functional spatial proteomic ITH in breast cancer and the interactions of cancer cells and the tumor microenvironment during cancer progression.

Relatively few lncRNAs have been shown to regulate animal behavior. Here, Saha et al. use mouse genetic methods to show that the lncRNA Pnky can underlie specific mouse behavior by functioning in trans.

Dietary n-6 PUFAs enhance adipose tissue expandability through the PPARγ–LPCAT3 membrane remodelling axis.

Mesocosm experiments revealed that both phytoplankton community composition and cellular acclimation influence marine particulate C:N:P ratios, with community shifts more sensitive to nitrogen supply and acclimation to the nutrient N:P supply ratio

Ramachandran et al. identify a previously unappreciated function for transcriptional repressor B cell lymphoma 6 (BCL6) in muscle proteostasis and strength, and provide mechanistic insight into the molecular underpinnings of this function.

Brain-restricted allogeneic transplantation of myeloid progenitors enables microglia replacement without the need for genetic engineering or systemic cytotoxic preconditioning.

This work presents a degradable ionizable lipid, AMG1541, for mRNA vaccines that significantly enhances potency and enables similar protective immunity at doses 100-fold lower than current standards, while also reducing toxicity and improving clearance in vivo.

In an arm of an ongoing multicenter phase 2 trial testing different therapies in patients with genetically profiled grade 2 or 3 meningiomas, treatment with an oral CDK4/6 inhibitor met the primary endpoint for progression-free survival at 6 months in patients with CDK or NF2 alterations.

Traumatic brain injury is associated with changes to the metabolome. Here the authors show that acute traumatic brain injury has distinctive serum metabolic patterns which may suggest protective changes of systemic lipid metabolism aiming to maintain lipid homeostasis in the brain.

Interact-omics, a high-throughput cytometry-based framework, resolves the cellular interaction landscape.

In a phase 2 trial evaluating healthy donor fecal microbial transplantation plus either anti-PD-1 in patients with non-small cell lung cancer or anti-PD-1 and anti-CTLA-4 in patients with melanoma, encouraging efficacy was seen in both cohorts, with responses linked to significantly greater loss of baseline bacterial species.

Hepatocyte organoids derived directly from human tissue enable long-term hepatocyte expansion and can be combined with portal mesenchyme and cholangiocyte organoids to form a donor-specific periportal liver assembloid system.

Colorectal cancer is often diagnosed at later stages, leading to poor prognosis. Here, the authors utilise analysis of rectal mucus specimens using host and microbial analysis to detect cancer lesions.

Drug resistance in bacteria often involves drug-tolerant persisters. Mycobacterium tuberculosis uses trehalose catalytic shift to promote persister formation, thereby developing multidrug resistant-TB (MDR-TB). Authors show that inhibiting this shift reduces MDR-TB, highlighting a potential therapeutic target for new treatments.

In patients with advanced cancer, the development of brain metastasis (BM) often signals a worsening prognosis with limited therapeutic options. Here, the authors assemble a large, open-source neuroimaging dataset of BM and perform spatial and morphological analysis which they use to develop a framework for function-sparing brain radiotherapy design.

mRNA vaccines targeting SARS-CoV-2 also sensitize tumours to immune checkpoint inhibitors.

Children born to women living with HIV suffer increased morbidity and, in low-income settings, have two to three times the mortality of infants born to women without HIV. Here, we profile the milk metabolome of 326 women living with and without HIV sampled longitudinally for 18 months postpartum using global metabolomics. Our findings demonstrate that milk tryptophan content and availability decrease among WLWH, which may indicate perturbations in milk tryptophan catabolism.

The complex processes guiding mammalian cortical folding are incompletely understood. Here authors report that cortical folding was enhanced in mice by combining mutations affecting neuron adhesion and progenitor expansion, producing both sulci and gyri.

The relationship between metabolomic and behavioral changes is not well understood. Here, the authors analyze metabolome changes in D. melanogaster heads and bodies during hunger and satiety, and develop the Flyscape tool to visualize the resulting metabolic networks and integrate them with other omics data.

The multidomain scaffold protein SH3 and multiple ankyrin repeat domain 3 (SHANK3) can bind GTP-bound Ras and Rap small GTPases. Here the authors show that, by binding active KRAS, SHANK3 maintains oncogenic KRAS/MAPK/ERK signaling at an optimal level while its depletion in KRAS-mutant cancer cell lines results in ERK signalling overdose and impaired cell proliferation.

The relationship between striatal vascular and neural activity is not fully understood. Here the authors found neuronal activity inadequately explains striatal hemodynamic polarity, challenging classic fMRI interpretations.

This study maps the connections of layer 5 pyramidal neurons in the mouse cortex, revealing distinct local and intercortical wiring patterns, and provides an open framework for exploring the connectivity of cell types.

During mitosis, the chromatin undergoes a dynamic reorganization important for faithful chromosome segregation. Here the authors show that the DEAD-box RNA helicase eIF4A1/2 regulates the perichromatin layer’s composition required for chromatin decondensation during cell division.

In this work, authors utilise a prefractionation natural product extract screening platform, which uncovers coniotins, lipopeptaibiotics with broad antifungal activity and a mechanism of action that targets fungal cell wall β-glucan.

Molecular recorders based on kinase activity-dependent protein labeling track specific kinase activities to understand their link to cellular phenotypes in heterogeneous cell populations and in vivo.

The authors show that astrocytes produce high levels of the adenosine receptor A2A in Alzheimer brains. Reducing the levels of astrocytic A2A boosted memory in young and aging mice and mouse models of Alzheimer disease, whereas activating a related molecular pathway impaired memory. Thus, astrocytes regulate memory and abnormal receptor activity in these cells may contribute to memory disorders.

Single-nucleus and single-cell RNA sequencing plus spatial profiling with four methods of core biopsies from 60 patients with metastatic breast cancer reveal patient-specific gene expression programs of breast cancer metastases that are maintained across time, site of metastasis and spatial profiling method, with spatial phenotypes correlating with microenvironmental features.

Here the authors reveal how an incoherent feedforward C/EBPα–Notch circuit times lung cell fate, guiding alveolar development, repair after injury, and shifts between protective and reparative states.

Non-syndromic orofacial cleft is a relatively common congenital anomaly. Many non-coding genetic variants are associated with this disorder but only a subset is functional. Here the authors use reporter assays and stem cells to reveal members of this subset.

C9orf72 ALS/FTD polyGR and polyPR knock-in mice show cortical hyperexcitability and motor neuron loss accompanied by an increase in extracellular matrix proteins in the spinal cord that is conserved in patient iPS cell-derived neurons and is neuroprotective.

CaMKII is a key enzyme in brain, heart, and egg cells, regulated by calcium signals. Here, authors show that charged residues in the variable linker tune CaMKII activity, a mechanism that may underlie cell type–specific responses.

Human activities affect marine predators in complex ways, yet we lack spatial understanding of cumulative impacts across key habitats. Here the authors analyse distribution and movements of eight marine predators, and find that species and human impacts vary across space and overlap within marine sanctuaries.

Using brain organoids models, Prigione and colleagues uncovered the impact of Huntington’s disease on human brain developmental and identified early dysregulation of CHCHD2, which disrupted mitochondria and might serve as a therapeutic target.