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Bruton’s tyrosine kinase (BTK) is expressed in immune cells and microglia, where its role remains poorly understood. Here, the authors show that BTK modulates microglial neuroinflammatory pathways relevant to multiple sclerosis (MS) and report robust effects of BTK inhibition in human in vitro models and animal models of MS.

Distal gene regulation is increasingly recognised as a major contributor to complex trait variability. Here, the authors show that a heritable, biologically interpretable transcriptome signature driven by distal regulation predicts metabolic traits across mice and humans.

Cilia are composed of microtubule doublets, but how they assemble is unclear. Here, the authors show that the brain-specific MAP6d1, found in neuronal primary cilia, assembles doublet microtubules and forms protofilaments inside microtubules.

It remains unclear how rapid antibiotic switching affects the evolution of antibiotic resistance in individual patients. Here, Chung et al. combine short- and long-read sequencing and resistance phenotyping of 420 serial isolates of Pseudomonas aeruginosa collected from the onset of respiratory infection, and show that rare resistance mutations can increase by nearly 40-fold over 5–12 days in response to antibiotic changes, while mutations conferring resistance to antibiotics not administered diminish and even go to extinction.

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.

Building on evidence from the phase 3 COVE trial, the authors report the long-term safety and effectiveness of primary vaccination and boosting with mRNA-1273 against COVID-19, including during emergent variant waves.

Obesity impairs regulation of adipocyte lipolysis, which contributes towards development of insulin resistance. Here the authors report that adipocyte Gq signaling functions as a regulator of lipolysis and systemic glucose and lipid homeostasis in mice, suggesting that agents able to stimulate this pathway may prove useful as antidiabetic drugs.

Favipiravir has broad-spectrum antiviral activity against a variety of RNA viruses. Here the authors investigate the safety, pharmacokinetics and anti-SARS-CoV-2 efficacy of different drug dosage in the a Syrian hamster model of infection and, combined with genetic analyses, they show that Favipiravir at high doses decrease viral infectivity while inducing the emergence of mutations in viral genomes, decreasing fitness.

Tan and colleagues conducted a single-cell multiomic analysis of T cell acute lymphoblastic leukemia and identified a treatment-resistant subpopulation of bone marrow progenitor-like blasts associated with poor outcomes.

Desired cell-state transitions can be guided via the activation of gene expression through a constitutively expressed endoribonuclease whose translation is regulated by endogenous cell-state-specific miRNAs.

Regeneration of cardiac endothelial cells is challenging as these cells must receive proper cues for tissue formation and integrate in the pre-existing vasculature. Here, Farber et. al identify Sox17-Erg as an efficient combination to reprogram cardiac fibroblasts into endothelial-like cells both in vivo and in vitro.

JNJ-1802—a highly potent dengue virus inhibitor—blocks the NS3–NS4B interaction within the viral replication complex, and is highly effective against viral infection with DENV-1 or DENV-2 in non-human primates.

The lymphotoxin (LT) system has several defined roles in the regulation of immunity as well as vascular and lymphatic biology, however its role in cancer is less understood. Here the authors show that regulatory T cell-derived LTα1β2 promotes LTβ receptor-nonclassical NFκB signaling in tumor cells and lymphatic endothelial cells, accelerating tumor growth and metastasis.

Here, the authors show that base editing of CD33 and gamma globin genes in HSPCs results in the long-term engraftment of dual edited cells along with HbF reactivation and GO resistance in mice and nonhuman primates.

Mucopolysaccharidoses (MPS) are inherited metabolic disorders caused by enzyme deficiencies leading to glycosaminoglycan accumulation and systemic degenerative disease. Here, the authors show that iPSC-derived microglia progenitors can reduce glycosaminoglycan accumulation and prevent behavioral deficits in MPS mouse models.

Targeted protein degradation (TPD) can be employed to eliminate disease-causing proteins. Here, the authors present CYpHER, a TPD tool that uses molecules engineered for intracellular target release with drug recycling via transferrin receptor. CYpHER induces depletion of extracellular targets in vitro and in xenograft tumours.

Several exposures are required for protection from clinical malaria in endemic areas. Using the controlled human malaria infection model, Ferrer et al. here show that two exposures to Plasmodium falciparum infected mosquitoes induce partial preerythrocyte immunity in previously malaria naïve individuals. Immunity correlates positively with both anti-circumsporozoite protein antibody and CD69 + CD8 + T cell levels.

Saturation genome editing characterizes von Hippel–Lindau (VHL) coding variants and their associations with diseases. Function scores for 2,268 VHL single-nucleotide variants (SNVs) classify pathogenic alleles driving renal cell carcinoma and suggest new mechanisms by which variants impact function.

In preclinical studies, the FDA approved TSP-1 antagonist gabapentin has been shown to disrupt neuronal-glioma interactions, slowing glioblastoma progression. Here, authors report a retrospective cohort study demonstrating a survival benefit associated with gabapentin in patients with newly diagnosed glioblastoma.

Physicians face high rates of common mental disorders (CMDs) and suicidality, yet effective interventions remain underexplored. This systematic review and meta-analysis synthesizing the latest evidence on interventions finds that a range of physician-directed interventions reduces symptoms of CMD and that these moderate effects are maintained over time.

How Meckel-Gruber syndrome protein TMEM67 functions in ciliogenesis and Wnt signaling simultaneously is unknown. Here the authors show that TMEM67 is proteolytically cleaved by the matrix metalloproteinase ADAMTS9 generating two functional isoforms.

Alcohol use is commonplace and ischemic heart disease (IHD) the leading cause of death globally, yet their relationship is unclear. Here we show that study type determines whether research finds alcohol reduces IHD risk or is unrelated, arguing for new approaches to settle this critical debate.

In humans, ADPKD can develop from “second hit” mutations in the PKD1 gene. Here, the authors show that human PKD1 contains guanine quadruplex structures that cause mutagenic double stranded breaks.

In rodent models of type 2 diabetes, sustained remission of hyperglycemia can be induced by FGF1 action in the mediobasal hypothalamus. Here, the authors show that FGF1-injection is followed by marked changes in glial cell populations and that the sustained glycemic response is dependent on intact melanocortin signaling.

The IDG-DREAM Challenge carried out crowdsourced benchmarking of predictive algorithms for kinase inhibitor activities on unpublished data. This study provides a resource to compare emerging algorithms and prioritize new kinase activities to accelerate drug discovery and repurposing efforts.

Profiling the immune responses of 56 volunteers vaccinated with BNT162b2 reveals how this mRNA vaccine primes the innate immune system to mount a potent response to SARS-CoV-2 after booster immunization.

In this epidemiological analysis, Marcus et al. show that acute alcohol consumption is associated with a higher risk of discrete atrial fibrillation episodes, as well as for new-onset (incident) atrial fibrillation, in the general population.

Tools for gaining long-term genetic access to mu-opioid receptor (MOR) neural cell types are limited. Here, the authors develop a suite of adeno-associated viral tools allowing selective genetic access to MOR cell types, and showcase their use across species.

National implementation of a computed tomographic angiography and AI-diagnostic tool, CT-derived fractional flow reserve (FFR-CT), did not provide significant benefits in reducing mortality but led to fewer invasive coronary angiograms and downstream cardiac tests.

TGFβ superfamily proteins can affect cellular differentiation, thermogenesis, and fibrosis in mammalian adipose tissue. Here the authors described a role for the TGFβ superfamily protein GDF3 in the regulation of lipolysis, glucose tolerance and glycemic variability in mice.

Low formate dehydrogenase (FDH) activity limits formate assimilation via the synthetic reductive glycine pathway. In this study, the authors introduce a faster FDH in synthetic formatotrophic E. coli, which boosts growth rates and bioproduction titers from formate as sole carbon source.

Baculoviruses are large DNA virus widely used as biotechnological tools. Here, authors present the complete cryoEM structure of a circulating nucleocapsid, including the DNA packaging and exiting hub termed the apical cap.

Previously, OLIG2-expressing stems cells have been identified as having a role in medulloblastoma recurrence. Here, the authors investigate the effects of targeting this OLIG2+ stem cell population in Sonic Hedgehog (SHH) medulloblastoma using CT-179, an OLIG2 inhibitor.

Itkin et al. identify a role for Fli-1 in hematopoietic stem cell activation during regenerative hematopoiesis. They show that Fli-1 coordinates hematopoietic stem cells to stimulate niche-derived Notch1 feedback signals for demand-needed hematopoietic cell output.

Stojanov et al. updated and internally validated a prediction model for the occurrence of post-operative shoulder stiffness following primary arthroscopic rotator cuff repair in Switzerland. Their findings support the development of further prediction models for an evidence-based and individualized decision-making in orthopedics.

Previous work shows that a small population of quiescent SOX2⁺ medulloblastoma (MB) stem cells can drive tumour growth in early tumorigenesis and relapse. Here, the authors identify OLIG2 as a transcriptional mediator of the transition from quiescent to rapidly proliferating progenitor states and therapeutically target this axis in preclinical models of MB.

Accumulation of visceral fat, linked to adipocyte expansion and overgrowth, is the most detrimental aspect of obesity, and a major cause of obesity comorbidities. We develop a cationic nanomedicine based on polyamidoamine dendrimers that specifically targets visceral fat and shrinks adipocytes, inhibiting diet-induced obesity and improving metabolic health in murine models.