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This study shows that C9orf72 mutations impair immune activation in ALS, affecting how brain cells communicate, and highlights key differences in the cellular and molecular pathways underlying sporadic and genetic forms of the disease.

Klein and colleagues characterize 04_A06, a new V_H1-2-encoded broadly neutralizing antibody that has marked breadth and potency against extended multiclade HIV-1 pseudovirus panels and can maintain full viral suppression in HIV-1-infected humanized mice.

HistoPlexer, a deep learning model, generates multiplexed protein expression maps from H&E images, capturing tumour–immune cell interactions. It outperforms baselines, enhances immune subtyping and survival prediction and offers a cost-effective tool for precision oncology.

Conway et al. show that integrin β1 phosphorylation is regulated through balanced activities of tyrosine kinases, such as Src and Arg, and phosphatases, such as PTP-PEST and Shp2, facilitating invadopodia formation and invasion of breast cancer cells.

Montoliu-Gaya, Salvadó et al. develop a blood-based model using tau biomarkers measured in a single analysis enabling biological staging of Alzheimer’s disease to support the diagnosis, prognosis and identification of patients likely to benefit from targeted therapies.

varVAMP is open-source software for designing primers for tiled-amplicon sequencing and qPCR. It simplifies primer design for viral pathogens with high genomic variability by including sequence variations into primer sequences.

Olfactomedin-2 is a pleiotropic glycoprotein emerging as a regulator of energy homeostasis via the hypothalamus. The present findings functionally connect adipose-specific OLFM2 to obesity, and highlight its significance in maintaining adipocyte commitment to avoid metabolic disease.

Many protein–protein interactions depend on Short Linear Motifs (SLiMs). In this study, the authors use large-scale binding assays, deep mutational scanning, and structural analysis to map SLiMs recognised by human cyclins and uncover the rules that determine their specificity and affinity.

Heart failure with preserved ejection fraction (HFpEF), which can be driven by obesity and hypertension, has a high prevalence but limited treatment options. Here, the authors show that nitro-oleic acid restores mitochondrial function and improves heart failure symptoms in a mouse model of HFpEF.

Analysis of single nuclei RNA-sequencing data across eight major brain cell types identifies putative causal associations between cell-type-specific expression and brain phenotypes.

The neoantigen discovery pipeline NeoDisc incorporates mass spectrometry immunopeptidomics data.

Mechanical forces modulate tumor cell phenotype, which in turn shapes the tumor microenvironment and contributes to downstream processes such as invasion and metastasis. Here authors show in primary patient-derived breast cancer explant cultures that low compression changes the tumour cells to a less differentiated state, leading to secretion of immunosuppressive cytokines, which impacts the tumor resident immune cells.

In the Tumor Profiler proof-of-concept observational study, a multiomics approach for profiling tumors from patients with melanoma was feasible, returning data within 4 weeks and informing treatment recommendations in 75% of cases.

Melanoma cells can switch between proliferative and invasive phenotypes. Here the authors show that the embryonic stem cell factor Sall4 is a negative regulator of melanoma phenotype switching where its loss leads to the acquisition of an invasive phenotype, due to derepression of invasiveness genes.

Here, the authors present and characterise a collection of human gut bacteria including novel taxa associated with health conditions and a large diversity of plasmids. All isolates, their genomes and metadata are publicly available, facilitating research by others (www.hibc.rwth-aachen.de).

Human brain morphodynamics are explored using organoids.

Lilja et al. find that SHANK proteins inhibit the signalling of Ras and Rap G-proteins by restricting their availability at the plasma membrane. This leads to restricted integrin activation, affecting cell spreading, migration and invasion.

Time-resolved electron microscopy reveals that intersectin-1 and endophilin A1 condensates hold replacement synaptic vesicles close to release sites. Without this, replacement vesicles are unavailable for immediate use, causing synaptic depression in response to stimulation trains.

Here they reveal how DNA methylation and chromatin accessibility shape how stem cells respond to differentiation signals and uncover an ERK-driven mechanism that guides the formation of diverse tissues during mammalian development.

Therapeutic interference with the immune response after myocardial infarction holds the potential to close a clinically relevant gap. Here, the authors show that inhibition of a cardiomyocyte-specific ADAM10 / CX3CL1 axis improves post infarction survival and cardiac function by attenuating neutrophil-mediated myocardial damage.

In the non-randomized phase 3b/4 DESTINY-Breast12 study, trastuzumab deruxtecan (T-DXd) treatment of patients with HER2⁺ advanced breast cancer and active or stable brain metastases showed consistent intracranial activity and systemic efficacy of T-DXd.

The EGF receptor HER2 is an oncogene protein thought to reside at the plasma membrane, but its endosomal trafficking is currently unclear. Here, the authors report that HER2 is endocytosed and that sortillin-related receptor 1 (SORLA) promotes endosomal HER2 recycling and HER2 oncogenic signalling.

Down syndrome causes extensive Alzheimer’s disease pathology in all individuals and has been instrumental in development of the amyloid hypothesis in AD. Here, the authors use proteomics on Down syndrome spinal fluid and brain tissues to illustrate the common and unique changes in DSAD compared to other genetic forms of AD and the more common late-onset form of the disease.

Vallentgoed et al. integrate clinical and multiomic data from persons with matched initial and recurrent IDH-mutant astrocytomas to identify progression-associated mechanisms and report a DNA methylation-based signature associated with survival.

Patients with MMR-proficient, microsatellite stable (MSS) colorectal cancer (CRC) are highly resistant to immune-checkpoint inhibitors. Here the authors report that tumor intrinsic expression of the autophagy gene ATG16L1 is associated with resistance to anti-tumor immunity in preclinical CRC models and that elevated ATG16L1 expression predicts poor immunotherapy response in Kras-mutant CRC patients.

Deep understanding of mechanisms of resistance to active therapies in metastatic colorectal cancer is crucial for developing more effective treatments. Here, the authors investigate the genomic landscape of 254 patients receiving anti-VEGF and anti-EGFR treatment, identify potential therapeutic vulnerabilities and suggest combination therapies.

How much the environment influences inherited adaptive traits is debated and challenging to demonstrate in mammals. Here the authors performed a multigeneration study that failed to morphologically replicate enhanced wound healing response following ancestral liver injury in rats. However, heritable transcriptional effects suggest transmission at the molecular level, albeit of unclear functional relevance.

A neoadjuvant treatment regimen of anti-PD-L1 monotherapy followed by anti-PD-L1 plus chemotherapy was well tolerated and led to a major pathologic response rate of 70% in patients with resectable gastric or gastroesophageal junction adenocarcinoma.

Deubiquitinases are proteases that cleave after the C-terminus of ubiquitin to hydrolyze ubiquitin chains and cleave ubiquitin from substrates. Here the authors describe a reactive-site-centric chemoproteomics approach to studying deubiquitinase activity, and expand the repertoire of known deubiquitinases.

Large genome-wide meta-analysis of clinically diagnosed late-onset Alzheimer’s disease (LOAD) from 94,437 individuals identifies new LOAD risk loci and implicates Aβ formation, tau protein binding, immune response and lipid metabolism.

Metabolic processes may be different in immune cells between neonates and adults. Here the authors measure metabolic changes in human monocytes from different aged donors and find enhanced oxidative phosphorylation fueling myeloid differentiation in neonates which contrasts glycolytic responses in early childhood and more effective inflammatory response.

Leukemias with ambiguous lineage require further characterisation. Here, the authors perform epigenomic and transcriptomic analysis of a subgroup of such leukemias with CpG Island Methylator Phenotype and propose that epigenetic dysregulation and not genetic lesions explains their mixed phenotype.

The CCR4-NOT complex is a key regulator of eukaryotic mRNA deadenylation. Here the authors identified the E3 ubiquitin ligase RNF219 as an acetylation-regulated cofactor of the complex, which inhibits mRNA decay through a direct interaction with NOT9.

Rubinstein-Taybi syndrome (RSTS) is a neurodevelopmental disorder with unclear underlying mechanisms. Here, the authors unravel the contribution of a stress-responsive pathway to RSTS where impaired HSF2 acetylation, due to RSTS-associated CBP/EP300 mutations, alters the expression of neurodevelopmental players, in keeping with hallmarks of cell-cell adhesion defects.

The molecular mechanisms underlying drug resistance in relapsed or refractory (rr) acute myeloid leukemia (AML) remain to be explored. Here, the use of bulk and single cell multi-omics and ex vivo drug profiling for 21 rrAML patients reveals mechanisms of resistance to the Bcl-2 inhibitor venetoclax and treatment vulnerabilities.

Vaccination is effective in protecting from COVID-19. Here the authors report immune responses and breakthrough infections in twice-vaccinated patients receiving anti-TNF treatments for inflammatory bowel disease, and find dampened vaccine responses that implicate the need of adapted vaccination schedules for these patients.

Olfactory deficits occur early in Alzheimer’s disease (AD). Here, the authors identify that loss of locus coeruleus axons in the olfactory bulb underlies impaired olfaction in an AD mouse model and provide translational evidence for similar deficits in humans.

A meta-analysis of genome-wide association studies of type 2 diabetes (T2D) identifies more than 600 T2D-associated loci; integrating physiological trait and single-cell chromatin accessibility data at these loci sheds light on heterogeneity within the T2D phenotype.

Genome-wide association and fine-mapping analyses in ancestrally diverse populations implicate candidate causal genes and mechanisms underlying type 2 diabetes. Trans-ancestry genetic risk scores enhance transferability across populations.

Metabolites are indicators of health and disease; genetic studies can reveal variants influencing their levels. Here, the authors investigate the contribution of rare, exonic variants on the levels of urine metabolites and generate predictions on metabolic consequences underlying metabolic disease.

Long-read single-cell RNA sequencing is capable of detecting isoform-level gene expression and genomic alterations such as mutations and gene fusions, thereby providing cell-specific genotype-phenotype information. Here, the authors use long-read scRNA-seq on metastatic ovarian cancer samples and detect cell-type specific isoforms and gene fusions that may otherwise be misclassified in short-read data.

Combination of TCR or CAR T cells expressing the engineered CD47 variant 47_E with anti-CD47 antibody therapy results in synergistic antitumour efficacy due to T cell resistance to clearance by macrophages, while maintaining macrophage recruitment into the tumour microenvironment.

This study presents an analytic framework to link imaging-derived brain phenotypes to gene expression. In the future, this approach may facilitate in vivo pharmacotranscriptomics and the development of personalized (pharmacological) interventions.

Obesity is linked to cancer risk in post-menopausal breast cancer. At the molecular level this is governed by cellular adaption to palmitic acid through epigenetic activation of a C/EBPB-dependent transcriptional network that drives tumor formation.

Aberrant redox homeostasis links lipid metabolism and cell death programs. Here, authors reveal how cell stress reduces growth factor signaling, enriching polyunsaturated fatty acids in phospholipids and sensitizing membranes to oxidative damage.

Peroxisomes are essential but their role in cell fate regulation remains understudied. Here, the authors reveal that young and old peroxisomes are not equally distributed in asymmetrically dividing stem cells, and peroxisome inheritance influences daughter cell fate.

Somatic heterozygous TET2 loss drives clonal hematopoiesis, which is linked to malignant cell degeneration and potentially cardiovascular disease. Here, the authors investigate the molecular impact of a germline TET2 mutation in a lymphoma family, finding elevated blood DNA methylation levels and no predisposition to atherosclerosis