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Targeted ablation of prostaglandin E₂ (PGE₂) signalling in CAR T cells enhances their activity in PGE₂-rich solid tumours, with demonstrations of efficacy in vitro, in mouse xenografts and in patient-derived organotypic tumour spheroids.

Large-scale computational and in vitro analyses identify commensal type III secretion systems and substrates in the human gut microbiome that can interact with human proteins to modulate immune pathways.

Multidrug-resistant pathogens have become increasingly common in hospital settings. Here, the authors investigate the efficacy of adjunctive antibiotic and phage therapy in a human cell model and a murine model of ventilator-associated pneumonia.

Task paradigms allowing studies on the core ethological function of the whiskers are lacking. Authors here present a task for freely moving mice that enables the study of how the brain processes touch and learns. The setup combines behavior, electrophysiology, and imaging, offering insights into naturalistic sensory and decision-making processes.

Pathology-oriented multiplexing (PathoPlex) represents a framework for widespread access to multiplexed imaging and computational image analysis of clinical specimens at a relatively high throughput and subcellular resolution.

Authors utilise a murine model of infection to provide mechanistic insight into how antimicrobial therapy may be a predisposing risk factor for hospital-acquired pneumonia. They show that antibiotic-induced microbiota perturbations compromise inflammatory monocytes and thereby impair antibacterial defence.

Zeiser and colleagues show that CAR T cell therapy results in upregulation of the TGFβ-activated kinase-1 (TAK1)–NF-κB–p38 MAPK pathway in microglia, causing neurocognitive defects, and find that TAK1 inhibition can reduce immune effector cell-associated neurotoxicity syndrome.

IκBζ is a rather unknown transcriptional co-factor of NF-κB. Here, the authors show that constitutive IκBζ expression in a subgroup of patients with melanoma drives immunotherapy resistance and enhanced tumor growth.

Zhang et al. show that bone marrow fatty acid metabolism fuels expanded leukocyte production after myocardial infarction and, based on mouse, pig and human data, suggest that lipolysis in marrow adipocytes provides fatty acids to hematopoietic stem cells.

Inbreeding depression has been observed in many different species, but in humans a systematic analysis has been difficult so far. Here, analysing more than 1.3 million individuals, the authors show that a genomic inbreeding coefficient (FROH) is associated with disadvantageous outcomes in 32 out of 100 traits tested.

In glioblastoma (GBM), tumour microtubes (TM) connect tumour cells to a broader cellular network, with roles in tumour progression and therapy resistance. Here, the authors combine a dye uptake method in GBM xenograft models with subsequent scRNA-seq to infer a TM connectivity signature, finding CHI3L1 as a marker of connectivity.

The acidic tumour microenvironment in melanoma drives immune evasion by cAMP in tumor-infiltrating monocytes. Here, the authors show that the release of an adenylate cyclase inhibitor from micelles restores antitumor immunity and, when combined with regulatory T cell depletion, leads to remission of established B16-F10-OVA tumors.

In somatic cells the mechanisms maintaining the chromosome ends are normally inactivated; however, cancer cells can re-activate these pathways to support continuous growth. Here, the authors characterize the telomeric landscapes across tumour types and identify genomic alterations associated with different telomere maintenance mechanisms.

Invasive pulmonary aspergillosis is a life-threatening fungal lung disease devoid of specific rapid diagnosis and with limited therapeutic options. Here, the authors show how state-of-the-art imaging approaches can enable specific diagnosis and therapy monitoring of this infection.

Adipose tissue is composed of a variety of cell types, including adipocyte precursor populations, that contribute to adipose tissue function upon differentiation. Here, using scRNA-sequencing of adolescent and adult mouse subcutaneous adipose tissue, the authors identify an Asc-1 positive preadipocyte population that is enriched in adolescent subcutaneous fat and demonstrate that loss of Asc-1 triggers spontaneous beige adipocyte differentiation.

Periventricular heterotopia (PH) is associated with neurodevelopmental delay. Here authors report patient-derived organoids with FAT4 and DCHS1 mutations mimic PH features, showing hyperactivity, synaptic changes and cell morphological alterations.

Peripheral stimuli can induce acute immune training and tolerance in the brain and lead to long-lasting epigenetic reprogramming of microglia; these changes alter pathology in mouse models of stroke and Alzheimer’s pathology .

Wnt signaling is necessary for colorectal cancer tumorigenesis and stem cell maintenance. Here, the authors identify MEK1/2 inhibitors as potent activators of Wnt/β-catenin signalling and show that clinically approved MEK inhibitors inadvertently induce stem cell plasticity in colorectal cancer

The accuracy of melanoma diagnosis can vary considerably among clinicians, impacting both patient outcomes and the performance of related AI tools. Here, the authors systematically assess interrater variability among expert pathologists reviewing histopathological images and clinical metadata of melanoma-suspicious lesions collected at eight German hospitals.

Lassé et al. show that genes involved in kidney organoid proteomic response to TNFα segregate a subset of individuals with poor outcomes in proteinuric kidney disease, demonstrating the relevance of kidney organoid modeling to human kidney disease.

Microenvironmental niches are instrumental to immune cell development via supporting soluble and contact-dependent differentiation signals. Here authors show that different bone marrow mesenchymal stromal cell subtypes modulate NK cell development via their different Il-15 expression capacities.

A SARS-CoV-2-human protein contactome map uncovers an inhibitor of viral replication.

A microfluidic approach allows spatiotemporal control of morphogen distribution in human pluripotent stem cell cultures. This approach recapitulates early developmental processes such as localized signaling and symmetry-breaking events.

Exploring benign and green methodologies for the synthesis of functionalized nitriles continues to attract the interest of academic and industrial chemists. Here, the authors efficiently synthesize various aryl, heterocyclic, allylic, and aliphatic nitriles from alcohols in water under very mild conditions using zeolitic imidazolate frameworks derived Fe₁-N-C catalysts.

Numerous disease-associated variants have been described in GWAS for atrial fibrillation. Here the authors integrate omics data to investigate the consequences of genetic variants for transcript and protein levels in the atrium of the human heart. With this multi-omics approach, authors reveal the regulatory network underlying atrial fibrillation and provide a resource for cardiac gene prioritization.

Macrophages are increasingly recognized as key drivers of lung damage in acute pneumonia including COVID-19. Here, the authors report on a first-in-class, inhalable, carbohydrate-coupled microRNA-inhibitor for selective targeting of macrophages and that prevents pulmonary hyperinflammation.

Here, Bachmann et al. provide data on long-term dynamics of the HIV-1 reservoir in 1,057 individuals on suppressive antiretroviral therapy and show that in 26.6% of individuals the reservoir increases. Viral blips and low-level viremia are significantly associated with a slower reservoir decay.

Zuend and colleagues show that an arousal-induced increase in cortical activity is accompanied by a surge in lactate in the extracellular space and a substantial lactate dip in astrocytes, followed by mobilization of lactate from glycogen stores and neuronal lactate increase.

A genome-wide association study including over 76,000 individuals with schizophrenia and over 243,000 control individuals identifies common variant associations at 287 genomic loci, and further fine-mapping analyses highlight the importance of genes involved in synaptic processes.

New biomarkers are required to improve the assessment of aortic wall integrity and risk of rupture. Here the authors report the development of an imaging probe for ADAMTS4, which they test in an abdominal aortic aneurysm mouse model and show in vivo prediction of aneurysm and rupture.

Pemphigus vulgaris is a life-threatening blistering skin disease caused by autoantibodies which destabilize cell adhesion of keratinocytes. The phosphodiesterase 4 inhibitor apremilast prevents skin blistering by stabilizing the keratin filament anchorage of desmosomes.

Here, the authors show that IFNγ binding to heparan sulfate is a mechanism to restrain IFNγ at the site of production, thereby preventing high systemic levels of this cytokine and associated immunopathology.

Shukla and colleagues study the genomic and transcriptomic data of exceptional responders to immunotherapy in renal cell carcinoma and find that such responses could be related to tertiary lymphoid structures, clonal neoantigen load and altered metabolism.

Artificial intelligence (AI) system is known to improve dermatologists’ diagnostic accuracy for melanoma. This group applies the eye-tracking technology on dermatologists when diagnosing dermoscopic images of melanomas and reports improved balanced diagnostic accuracy when using an X(explainable) AI system comparing to the standard one.

Benzodiazepines, used to treat anxiety and sleep disorders, may cause cognitive impairment. Shi et al. demonstrate that this is caused by interaction with the mitochondrial protein TSPO, which drives microglia to excessively remove synapses.

Broadly neutralizing antibodies (bnAbs) develop in a minority of HIV-infected individuals. Analyzing data from more than 4,000 infected individuals, Alexandra Trkola and colleagues identify viral, host and disease factors associated with the development of bNAbs that may inform future vaccine design.

The HIV reservoir is a major hurdle for a cure of HIV, but the factors determining its size and dynamics remain unclear. Here the authors show in a large cohort of 610 HIV-1 infected individuals, who are on suppressive ART for a median of 5.4 years, that viral genetic factors contribute substantially to the HIV-1 reservoir size.

Chronic obstructive pulmonary disease is a severe inflammatory lung disease characterized by obstructed airflow from the lungs. Here, Seimetz et al. show that NADPH oxidase subunit 1 (NOXO1) is responsible for peroxynitrite formation from nitric oxide and superoxide and drives the development of smoke-induced emphysema and pulmonary hypertension.

There is growing evidence that autophagy might serve specialized functions in neurons besides its role in protein homeostasis. In this study, authors demonstrate that axonal retrograde transport of BDNF/TrkB in neuronal amphisomes is involved in plasticity-relevant local signaling at presynaptic boutons and that SIPA1L2, a member of the SIPA1L family of neuronal RapGAPs, associates via LC3b to TrkB-containing amphisomes to regulate its motility and signaling at the axon terminals

In contrast to previously reported findings, M2-like polarized macrophages are not a source of catecholamines and do not contribute to browning of the fat.

The molecular mechanisms regulating remyelination are unclear. Here, the authors show that promoting deacetylation of eEF1A1 prevents the translocation of Sox10 outside the nucleus, contributing to maintaining the expression of Sox10 target genes and increasing remyelination efficiency.

Expression of HNF1A and KRT81 stratifies pancreatic ductal adenocarcinoma tumors into different subtypes, and expression of cytochrome P450 3A5 mediates basal and/or drug-induced therapy resistance in each subtype.

Interogation of mass-spectrometry-based proteomics of liver and plasma from a cohort of patients with alcohol-related liver disease identifies noninvasive biomarkers associated with early stages of disease progression, including significant fibrosis, inflammation and steatosis.

Similarity of antibody responses in HIV-1 transmission pairs reveals a significant impact of the virus genome on imprinting antibody responses.

Cancer cachexia is marked by a pathological loss of fat tissue, but preventing the degradation of AMPK in this tissue helps preserve its mass in mouse models.

Cre recombinase and tdTomato expressed from a neutrophil-specific promoter allow highly specific genetic manipulation and labeling of neutrophils.

Surgical weight-loss interventions improve insulin sensitivity via incompletely understood mechanisms. Here the authors assess skeletal muscle epigenetic changes in individuals with obesity following metabolic surgery and compare them with data from individuals without obesity.