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T-cell–mediated rejection (TCMR) remains a major cause of kidney transplant failure with incompletely understood mechanisms. Here the authors use single-nucleus RNA sequencing, spatial transcriptomics and immunofluorescence to show that injured kidney epithelial cell states associate with poor transplant outcomes after T-cell–mediated rejection.

The tolerogenic activity of type 1 conventional dendritic cells (cDC1s) is determined by EPOR, which is preferentially expressed in cDC1s and induces antigen-specific FOXP3-expressing regulatory T cells.

Spatial transcriptomic studies and lineage tracing reveal that, after brain injury, transient profibrotic fibroblasts develop from existing brain fibroblasts, infiltrate lesions, regulate the local immune response and lead to beneficial scar tissue formation.

Shark teeth have short lifespans yet can be subject to significant mechanical damage. Here, the authors report on a site-specific damage mechanism in shark teeth enameloid, which maintains tooth functional shape, providing experimental evidence that tooth architecture may have influenced the diversification of shark ecologies over evolution.

Hutchinson-Gilford Progeria Syndrome is characterized by premature aging with cardiovascular disease being the main cause of death. Here the authors show that inhibition of the NAT10 enzyme enhances cardiac function and fitness, and reduces age-related phenotypes in a mouse model of premature aging.

Targeted protein degradation using PROTACs doesn’t discriminate functional from disease-causing versions of the same protein. Here, we describe small molecule TRIMTACs that recruit the unique E3 ligase TRIM21 and allow state-selective protein degradation, including challenging substrates like tau.

Metformin may serve as a non-toxic intervention to inhibit mitochondrial metabolism and slow DNMT3A-R882 clonal haematopoiesis expansion, thus delaying or averting progression to acute myeloid leukaemia.

Mutations in pre-mRNA processing factors cause autosomal dominant retinitis pigmentosa. Here the authors provide insights into the pathophysiological mechanisms underlying non-syndromic retinal disease caused by heterozygous mutations in genes encoding ubiquitously expressed splicing factors.

Therapeutic checkpoint for acute myeloid leukemia requires further investigations. The authors here identify ST2⁺ Treg cells facilitate AML growth by inducing CD8⁺ T cell depletion and exhaustion, while targeting ST2 by antibodies depletes ST2⁺ Treg cells and improves AML prognosis.

Existence of 150–170 serologically distinct human rhinoviruses (HRV) has hampered vaccine development for this human pathogen. Here, the authors show that a prime-boost regimen with an inactivated 50-valent HRV vaccine induces neutralizing antibody responses to diverse HRV serotypes in rhesus macaques.

Non-neutralizing antibodies against the nucleoprotein (NP) of Crimean-Congo hemorrhagic fever virus are protective against lethal challenge in mice. Here, the authors show that these anti-NP antibodies protect through the intracellular antibody receptor TRIM21 and that protection is independent of T cells.

Understanding and tuning the transport properties of colloidal particles near deformable and patchy interfaces have implications for biophysical processes and designs of nanofluidic devices. This work introduces a minimal model that hydrodynamically couples a colloidal particle to a fluctuating elastic mode under a periodic potential, revealing how soft boundaries and rapid nanoscale surface deformations leave measurable imprints on colloidal transport.

Infection may induce multi-organ thrombosis, but the underlying inflammatory mechanism remains elusive. Here, using Salmonella Typhimurium infectious mouse model, the authors reveal organ specific and broad inflammatory events like TNF for thrombosis in liver and spleen.

Dean Sheppard and his colleagues show that genetic or pharmacological inhibition of α_v integrin signaling ameliorates fibrosis in several solid organs.

High IL1RL1 correlates with poor survival in acute myeloid leukemia. A stress-driven IL-33/IL1RL1 loop induces leukemogenesis and a tolerogenic immune environment. Targeting this axis with bispecific antibodies offers a promising treatment.

An analysis of 24,202 critical cases of COVID-19 identifies potentially druggable targets in inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

Collagen production by lung cells is critical to maintain organ architecture but can also drive pathological scarring. Here the authors perform single cell RNA sequencing of collagen-producing lung cells identifying a subset of pathologic fibroblasts characterized by Cthrc1 expression which are concentrated within fibroblastic foci in fibrotic lungs and show a pro-fibrotic phenotype.

Brain tumors are difficult to treat using existing immunotherapeutic strategies. Here, the authors show that in brain tumors resistant to PD-1 blockade, HSCs expressing CCR2⁺ can reverse treatment resistance and sensitizes mice to immunotherapy.

The APOE4 allele is a major genetic risk factor for the development of late-onset Alzheimer’s disease (AD). In this manuscript, Butovsky and colleagues suggest that APOE4 impairs the microglial response in AD by inducing TGFβ-mediated checkpoints.

Microglial states are dynamically regulated during development and disease. Here, the authors show that these changes are mediated by cell autonomous TGF-β signaling in microglia, which is developmentally regulated by ITGB8 in radial glia.

A γδ T cell–IL-3 signalling axis is defined that controls the allergen responsiveness of cutaneous sensory neurons, leading to evidence for an immune rheostat that governs sensory neuronal responses to allergens on first exposure.

Ju et al. show that during three-dimensional cell migration, compression recruits cytoplasmic linker-associated proteins to microtubules; these stabilized microtubules then coordinate nuclear positioning and contractility in confined migration.

It is demonstrated that the brain circuitry involved in regulating the motivation for physical activity is not strictly central nervous system autonomous but is shaped by peripheral influences that originate in the intestinal microbial community.

In this study authors use morphological profiling and CRISPR/Cas9 genetic screens to investigate the mechanisms by which BiDACs induce the degradation of plasma membrane receptor tyrosine kinases (RTKs) EGFR and Her2.

Rhee et al. demonstrates that the potent neuroprotective agent CNTF significantly impacts metabolism of degenerating retinas, thus revealing cellular mechanisms underlying enhanced neuronal viability and providing insight for the ongoing CNTF clinical trials.

The ATR inhibitor ceralasertib has shown clinical activity in combination with immune-checkpoint inhibitors in several cancer types. Here the authors report the anti-tumor activity and the immunomodulatory changes, dependent on up-regulation of type I interferon pathway, following intermittent ATR inhibition in preclinical cancer models.

Interferon alpha (IFNalpha) therapy is showing promising results to treat myeloproliferative neoplasms (MPNs). Here, the authors show that IFNalpha response requires ULK1 phosphorylation to induce p38-MAPK signalling but it is counteracted by ROCK1-2 activation suggesting combination therapy of IFNalpha-ROCK1-2 inhibition may improve MPNs treatment.

Single-cell RNA sequencing and imaging of macrophages in human non-small cell lung cancer and in a mouse model of lung adenocarcinoma show that tissue-resident macrophages have a key role in early tumour progression.

A large genome-wide association study of more than 5 million individuals reveals that 12,111 single-nucleotide polymorphisms account for nearly all the heritability of height attributable to common genetic variants.

Roy et al. describe a generalized method for computationally designing miniproteins selective for a single integrin heterodimer and conformational state. The designed αvβ6 inhibitor remains monomeric and maintains biological activity following aerosolization and shows excellent efficacy in bleomycin induced lung fibrosis.

How mutations in the microbial receptor NOD2 induce Blau syndrome in humans and related uveitis is unclear. Here the authors show, using Nod2-deficient mice and experimental uveitis, that Nod2 negatively regulates T cell activation and transcription of autoimmunity-related genes to suppress Th17 responses and uveitis.

Natural killer cells of acute myeloid leukaemia patients lack cytotoxic activity. Here the authors show that these cells have elevated GSK3β, and that its inhibition prolongs survival of mice transplanted with human AML and stimulates NK cytotoxicity via increased adhesion of NK cells to their targets.

Interim results from the low-dose cohort of the PROCLAIM trial show that AAV-based delivery of the progranulin gene in patients with frontotemporal dementia was safe and was associated with increased CSF progranulin.

The MYC oncogene is activated in the majority of human cancers and has proven challenging to target therapeutically. In this study, the authors identify genome-wide MYC synthetic-lethal interactions that could serve as potential alternative targets for the treatment of MYC-driven cancers.

Transition from premalignant lesion to cancer cell highlights tumor initiation. Here, the authors use a model of K-Ras-initiated lung cancer to document two successive asymmetric divisions, each driven by mitotic polarization of key transcription factors, which lead to generation of initial cancer cells.

Renal cell carcinoma (RCC) is a common and aggressive malignancy. Here, the authors generate two mouse models of the most common RCC subtypes: the human papillary RCC throughMYC activation and clear cell RCC through MYC activation combined with Vhl and Cdkn2adeletion.

Although the common genetic variants contributing to blood lipid levels have been studied, the contribution of rare variants is less understood. Here, the authors perform a rare coding and noncoding variant association study of blood lipid levels using whole genome sequencing data.

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.