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Vaccination provides protection from COVID-19, but optimization in design and route is an ever-ongoing process. Here the authors pursue an open-label, multi-arm phase I clinical trial to report the safety of a multi-valent, aerosol vaccine administered via inhalation, as well as superior mucosal immunity induced by ChAd over HuAd vectors.

Modifying the polyethylene glycol lipid ratio and phospholipids in the lipid nanoparticle component of nucleoside-modified mRNA–lipid nanoparticle vaccines is shown to have an impact on the elicited cellular and humoral immune responses.

Colobomatous microphthalmia often lacks a genetic diagnosis despite its developmental complexity. Here, the authors show that rare variants in NR6A1 cause a syndromic form with eye, kidney, and vertebral defects, supported by zebrafish functional validation.

Using viral barcode tracing to detect interactions between glioblastoma cells and non-malignant astrocytes in patient samples, investigators discovered a pathway that reduces tumour-specific immunity and identified potential therapeutic targets.

Neural networks fundamentally dictate function. Here, the authors show thirteen uniquely connected neuron populations within the anterior thalamic nuclei, suggesting multiple parallel subnetworks support its emotional and cognitive functions.

Rashan, Bartlett and colleagues show that mammalian 4-hydroxy fatty acids are primarily catabolized by ACAD10 and ACAD11 (atypical mitochondrial and peroxisomal acyl-CoA dehydrogenases, respectively) that use phosphorylation in their reaction mechanisms.

Here, the authors show that the skin microbiome of a remote hunter-gatherer Yanomami community harbors environmental microbes that help maintain skin barrier integrity and combat oxidative stress—functions that are reduced by industrial lifestyles.

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.

CREBBP mutations in B-cell acute lymphoblastic leukemia (B-ALL) are linked to poor prognosis and chemoresistance. Here, the authors show that genetic or pharmacological inactivation of CREBBP sensitizes B-ALL cells to the BCL2 inhibitor Venetoclax, inducing ferroptotic cell death and extending survival in B-ALL preclinical mouse models.

Single and multiple intravenous infusions with laromestrocel, an allogeneic cell therapy, is safe in patients with mild AD and may reduce the impact of cognitive decline and brain atrophy within 9 months of treatment.

Pashos et al. show that H3K36 methylation maintains intestinal epithelial fate commitment, whereas its suppression, which is also observed upon injury, induces a plastic state and expression of genes involved in regeneration.

Human airway contains physiologically relevant yet rare cells, but their scarcity prevents thorough profiling and differentiation studies. Here the authors use single cell RNA sequencing to identify rare ionocytes and tuft cells, as well as a potential progenitor population with cytokine-guided differentiation into either the ionocytes or tuft cell lineage.

A population of TRAIL-positive astrocytes in glioblastoma contributes to an immunosuppressive tumour microenvironment and this mechanism can be targeted with an engineered oncolytic virus to improve outcomes.

Bond et al. show that inducible PolG mutation in muscle causes mtDNA damage and muscle wasting. This is driven by the integrated stress response (ISR) and reduction in folate intermediates, linking impaired folate metabolism with ISR/disease induction.

Checkpoint inhibitor (CPI) therapy is modestly effective in Glioblastoma patients, with some patients not benefitting at all. Authors here present the outcomes of single arm prospective clinical trial employing combination CPI therapy in newly diagnosed GBM and identify the pre-treatment genetic, microbiome and immunological factors that might contribute to sensitivity.

A study of human and mouse models of pancreatic cancer finds that inhibiting the lipid kinase PIKfyve interferes with the cancer’s lipid homeostasis, making it a potential target for drug development.

An RNA-binding protein on leukemia cells provides an effective target in mouse models.

Collecting an extensive publicly available dataset on four inhibitory control tasks, Gratton et al. show that more than 1,000 trials per participant are necessary to reduce within-participant variability and improve the reliability of the congruency effect.

Using data from a single time point, passenger-approximated clonal expansion rate (PACER) estimates the fitness of common driver mutations that lead to clonal haematopoiesis and identifies TCL1A activation as a mediator of clonal expansion.

Anti-TNF CAR macrophages show anti-inflammatory efficacy in both acute and chronic inflammatory disease mouse models.

A comprehensive analysis of the cell-specific molecular regulatory mechanisms underlying post-traumatic stress disorder in the human prefrontal cortex.

In this mouse study, an adenine base editor shows potential as a durable therapy for glycogen storage disease type-Ia, correcting both the life-threatening lack of blood glucose control and metabolic abnormalities of this orphan disease.

A pangenome of the Cannabis genus including 193 genomes demonstrates high variability in most of the genome but low diversity in cannabinoid synthesis genes and provides a resource for future genetic studies and crop optimization.

Inhibiting glycogen synthase kinase 3 (GSK3) improves muscle function, metabolism, and bone health in many other diseases. Here, Marcella et al. found that inhibiting glycogen synthase kinase 3, alone or combined with exercise, improves muscle health and function in mouse models of Duchenne muscular dystrophy without negatively affecting insulin sensitivity or bone health.

EGF-induced recruitment of UPF1 adjacent to HNRNPC induces splicing surveillance of cell proliferation mRNAs.

This study, together with a companion manuscript, show that, in mice, weight loss as a result of GIP receptor antagonism requires, and potentiates, functional GLP-1 receptor signalling in the brain, explaining how both GIP receptor agonists and antagonists trigger weight loss through different mechanisms.

Toll-like receptor 7 (TLR7) normally recognizes exogenous single-stranded RNA for the activation of innate immunity. Here the authors show that TLR7 may also contribute, via the modulation of mast cell functions, to experimental, cigarette smoke-induced mouse models of emphysema, thereby hinting TLR7 as a potential therapeutic target for human lung inflammation.

The US COVID-19 Scenario Modeling Hub produced medium to long term projections based on different epidemic scenarios. In this study, the authors evaluate 14 rounds of projections by comparing them to the epidemic trajectories that occurred, and discuss lessons learned for future similar projects.

Impaired interleukin-2 production and regulatory T cell dysfunction is implicated in multiple autoimmune diseases. Here, in two phase lb trials, the authors show that rezpegaldesleukin, a Treg-selective pegylated IL-2, is safe and improves symptoms in patients with atopic dermatitis or psoriasis.

Mohanakrishnan et al. identify a distinct subset of post-arterial capillaries, termed type R. They show that type R capillaries contribute to trabecular bone formation in the diaphysis and respond to anti-osteoporosis treatments.

Small cell lung cancer presents high and multi-site metastatic potential. Here, the authors discover that FOXA2, regulated by ASCL1, promotes multi-site metastasis in small cell lung cancer by inducing a fetal neuroendocrine gene expression program.

DREDge is a software tool for motion correction of high-density electrophysiology recordings. It can handle action potential or local field potential data and is demonstrated on a variety of acute or chronic recordings from humans, nonhuman primates and mice.

In this phase 1 trial of a personalized, neoantigen-specific autologous T cell therapy, BNT221, when given as monotherapy in patients with metastatic melanoma refractory to PD-1 and CTLA-4 inhibitor regimens, the therapy was safe and showed preliminary clinical activity and neoantigen-specific T cell responses.

In the I-SPY2.2 trial, patients with high-risk stage 2/3 breast cancer received neoadjuvant datopotamab–deruxtecan, followed by sequential chemotherapy with or without targeted therapy, with the option of early surgical resection after each block of therapy. In a subgroup of patients, the sequential treatment strategy was superior to standard of care.

The heme degradation enzyme biliverdin IXβ reductase (BLVRB) is implicated in a redox-regulated thrombopoietic pathway. Here, the authors validate BLVRB as a cellular target by generating an orally-available small molecule inhibitor that retains platelet-enhancing functions that are mechanistically distinct from thrombopoietin receptor-targeted mimetics.

MultiSTAAR provides a general and flexible statistical framework for functionally informed multi-trait rare variant analysis of biobank-scale sequencing studies by jointly analyzing multiple traits and incorporating annotation information.

Administration of an antisense oligonuceotide in a preterm infant with severe early-onset SCN2A developmental and epileptic encephalopathy was well tolerated and led to a 60% decrease in seizure frequency.

In response to COVID-19, many states have implemented social distancing orders, but the effect of these orders on population mobility has not been fully quantified. Here, the authors use data from the US to show that state-level social distancing orders substantially reduced mobility and limited the spread of disease.

In the I-SPY2.2 trial, patients with high-risk stage 2/3 breast cancer received neoadjuvant datopotamab–deruxtecan plus durvalumab, followed by sequential chemotherapy with or without targeted therapy, with the option of early surgical resection after each block of therapy, showing that de-escalation of therapy is possible for several patient subgroups without compromising outcome and avoiding toxicity of standard chemotherapy.

Multisystem inflammatory syndrome in children (MIS-C) onsets in COVID-19 patients with manifestations similar to Kawasaki disease (KD). Here the author probe the peripheral blood transcriptome of MIS-C patients to find signatures related to natural killer (NK) cell activation and CD8+ T cell exhaustion that are shared with KD patients.

A study shows that clonal haematopoiesis of indeterminate potential is associated with an increased risk of chronic liver disease specifically through the promotion of liver inflammation and injury.

A large international panel of experts reach consensus on a new standard for reporting settings in psychedelic trials, identifying 30 key non-pharmacological factors to strengthen the rigor of psychedelic research.