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Muscularis macrophages, housekeepers of enteric nervous system integrity and intestinal homeostasis, modulate α-synuclein pathology and neurodegeneration in models of Parkinson’s disease, and understanding the accompanying mechanisms could pave the way for early-stage biomarkers.

MYC-driven medulloblastoma is highly aggressive and associated with poor survival. Here, the authors perform single nuclei multi-omic analysis of matched primary and recurrent tumours and identify potential resistance mechanisms and targetable pathways.

IL-17A, a cytokine important for tissue repair, can impair healing when increased, contributing to keratinocyte dysfunction in type 2 diabetic wounds. Here, the authors show that IL-17A drives this dysfunction via JMJD3-mediated epigenetic changes, and that blocking this pathway improves wound healing.

Research on sustainable diets has primarily focused on human and planetary health, neglecting workers in food value chains. This study quantifies the risk of forced labour embedded in five different diets in the USA, underscoring the need to integrate such risk in sustainable diet transition efforts.

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).

Pathogenic variants in UNC13A underlie a novel neurodevelopmental syndrome, with three subtypes defined by distinct genotypes with varying clinical and functional impacts characterized in cellular and animal models.

The role of autoantibodies in bullous pemphigoid (BP) and their impact on keratinocytes and the response to BP pathology remains underexplored. By leveraging transcriptomics analysis and large-scale protein assays, here the authors identify keratinocyte MyD88 as a regulator of the pro-inflammatory response in BP, uncovering the role of keratinocytes in this disease pathology.

Multiple myeloma (MM) cancer cells can develop different resistance mechanisms to therapies inducing DNA-damage. Here, the authors show that the mitochondrial DNA repair protein DNA2 promotes MM cells survival after DNA damage-induced metabolic reprogramming.

Using phenotypic screening followed by optimization of side activities, the authors here identify pyrazolopyrimidine phosphodiesterase (PDE) inhibitors as anti-cryptosporidial drug leads. Humanizing a Cryptosporidum PDE by CRISPR indicates they target the parasite enzyme.

Snell et al. examine the heterogeneity of CD4⁺ T cells in chronic viral infection, showing that PD-L1 blockade enhances a cytotoxic gene program in antigen-specific T_H1 cells and can restore antiviral CD4⁺ T cell killer function.

Neurofibromatosis type 1 (NF1) is a genetic disorder caused by mutations in neurofibromin and associated with disruptions in physiology and behavior. Here the authors show that neurofibromin regulates metabolic homeostasis via a discrete brain circuit in a Drosophila model of NF1.

A global network of researchers was formed to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity; this paper reports 13 genome-wide significant loci and potentially actionable mechanisms in response to infection.

O’Donnell and colleagues report that activation of the integrated stress response in non-small cell lung cancer cells by impairing heme production leads to enhanced PD-L1 translation in an eIF5B-dependent manner.

Here it is shown that the end products of lipid oxidation — ω-(2-carboxyethyl) pyrrole and other related pyrroles — are generated during inflammation and wound healing, and accumulate at high levels in ageing tissues in mice and in highly vascularized tumours in murine and human melanomas. These carboxyalkylpyrroles are recognized by Toll-like receptor 2 on endothelial cells, setting off a chain of events that leads to the growth of new blood vessels.

SARS-CoV-2 variants with mutations in spike have emerged during the pandemic. Magaret et al. show that in Latin America, efficacy of the Ad26.COV2.S vaccine against moderate to severe–critical COVID-19 varied by sequence features, antibody escape scores, and neutralization impacting features of the SARS-CoV-2 variant.

A national prospective study of patients requiring hospitalization for COVID-19 demonstrates global cognitive deficits at 1 year, associated with elevated brain injury markers and reduced gray matter volume.

High-energy diet triggers mild β cell proliferation to compensate for peripheral insulin resistance. Qi and colleagues show that TLR2 and TLR4 inhibit the diet-induced replication of β cells in mice and humans.

The Akt pathway integrates multiple signals, but whether it affects vasculature function is debatable. Here the authors show that Akt pathway shutdown in adult mouse endothelium causes destabilization of vasculature leading to cardiac and retinal dysfunction, due to decreased levels of Jagged1 and impaired Notch signaling.

The elimination of forced labour (Sustainable Development Goal 8.7) is a priority for the sustainability of food systems. Using data on production, trade, labour intensity and risk, this study estimates the risk of forced labour embedded in the US land-based food supply across product category, country of origin and supply chain stage.

Understanding the pathology and immunological response to SARS CoV2 infection in specific patient groups is essential for informing the scientific and clinical handling of infections within these patient populations. Here the authors characterise the adaptive immune response to SARS-CoV2 infection in people living with HIV.

Whole-genome sequencing, transcriptome-wide association and fine-mapping analyses in over 7,000 individuals with critical COVID-19 are used to identify 16 independent variants that are associated with severe illness in COVID-19.

Small RNAs targeted to gene promoters are known regulators of transcription in mammalian cells. Antigene RNAs complementary to non-coding transcripts localized to the 3′ termini of genes are now shown to regulate transcription across long genomic sequences.

Branched chain ketoacid dehydrogenase kinase (BDK) inhibits the activity of branched chain ketoacid dehydrogenase and branched chain amino acid degradation, implicated in several diseases. Here, the authors discover a BDK inhibitor and degrader that shows efficacy in rodent metabolism and heart failure models, as well as another class of BDK inhibitors that stabilizes BDK.

Placental dysfunction can affect heart development, but the prevalence of this causality has not been well established. Here, the authors use mouse genetic tools to show that the placenta may constitute a significant source of congenital heart defects.

Glass and colleagues show that the transcription factor SALL1-associated super-enhancer is exclusively activated in microglia, in part through SMAD4-mediated signaling, and that SALL1 subsequently enforces microglia-specific functions of SMAD4.

How ILC1s respond to cancer cells is somewhat controversial. Here, the authors show that IFNγ released by ILC1s can control acute myeloid leukemia by promoting leukemia stem cell apoptosis and favoring their differentiation into non-leukemic cells.

Human TNF is required for respiratory-burst-dependent immunity to Mycobacterium tuberculosis in macrophages but seems to be largely redundant physiologically.

Asthma is often characterized by Th2-mediated inflammatory responses, which are initiated by lung dendritic cells. Here, Williams et al.demonstrate that dendritic cell expression of transcription factor IRF4 drives Th2 differentiation through IL-33 and IL-10 activation.

Memory T cells are vital responders to skin inflammation, but cell localization and dynamics of exchange with the bloodstream are not clear. Here the authors use parabiosis and intravital microscopy to show that CD4⁺memory T cells equilibrate with the circulation and cluster around hair follicles in response to CCL5-dependent responses to viral infection or contact sensitization.

During an immune response naive CD8⁺ T cells can differentiate into either effector or memory T cells. Here the authors show that Akt-mediated phosphorylation of the epigenetic regulator Ezh2 is critical for the generation of an anti-tumor CD8 T cell response and promotes the expansion of memory-precursors.

Forced labour in agriculture is a threat to the sustainability of food systems. With distinct datasets and a new forced labour risk scoring method, this study demonstrates that while many commodities are at higher risk, a small number of commodities account for substantial fractions of the risk embedded in the US retail fruit and vegetable supplies.

Genome-wide association analyses based on whole-genome sequencing and imputation identify 40 new risk variants for colorectal cancer, including a strongly protective low-frequency variant at CHD1 and loci implicating signaling and immune function in disease etiology.

Single-cell RNAseq during initiation and progression of mouse glioblastoma reveals a dynamic immune microenvironment transitioning from pro-inflammatory microglia in early tumors towards an infiltrating macrophage and suppressor cell-centric immune landscape in late-stage tumors.

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.

Trujillo et al. identify scavenger receptor class B type I (SR-B1) as a keratinocyte marker of skin inflammation and a potential therapeutic target. Topically delivered HDL-like nanoparticles target SR-B1, reduce inflammatory signaling in keratinocytes, and improve imiquimod-induced inflammation in murine models.

Real world PM2.5 exposure promotes oxidative stress, proteinopathy and functional defects in the heart and brain revealing the impact of environmental modifiers on disease progression in both organs that is worsened in the presence of genetic risks.

H₂ roaming is associated with H₃⁺ formation when certain organic molecules are exposed to strong laser fields. Here, the mechanistic details and time-resolved dynamics of H₃⁺ formation from a series of alcohols were obtained and found that the product yield decreases as the carbon chain length increases.

Openshaw and colleagues find myeloid inflammation and complement activation signatures in patients with long COVID who were previously hospitalized.