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Despite being an important driver of a subset of medulloblastomas, efforts to therapeutically target Sonic Hedgehog (SHH) signaling, such as with the use of Smoothened (SMO) inhibitors, have had limited success. Here, the authors find that SHH medulloblastomas are sensitive to netrin-1 inhibition and investigate netrin-1 as a mechanism of resistance to SMO inhibition.

Mutations in the RNA-binding protein FUS contribute to ALS. Here the authors use CLIP-seq on synaptoneurosomes to identify proteins associated with synapse organization and plasticity that are differentially regulated in a knock-in ALS mouse model.

Multiplexed editing using Cas12a transgenic mice facilitates the study of disease models with complex genotypes.

Factors controlling release of loaded cargo from polycationic gene delivery vectors are still poorly understood. Here, the authors report on a study of mechanisms of RNA release, highlighting the role of competitive binding, and characterise the interactome associated with vectors upon cytosolic entry.

It has been commonly believed that the driving force at the donor-acceptor heterojunction is vital to efficient charge separation in organic solar cells. Here Zhong et al. show that the driving force can be as small as 0.05 eV without compromising the charge transfer rate and efficiency.

Combined analysis of the connectome and transcriptome in the mouse cortex indicates that dynamic differences in expression levels of largely generic sets of genes regulate differential targeting within neuronal subtypes.

FZD₇ is a class F GPCR involved in intestinal epithelium homeostasis. Using cryo-EM, the authors determine the structure of inactive FZD₇ and compare it with the G-protein-bound form. They refine the FZD activation mechanisms and identify a water pocket and an allosteric cholesterol binding site.

The limited proliferative capacity of erythroid precursors complicates the production of red blood cells for clinical purposes in vitro. Here, the authors show that erythroid proliferative capacity can be vastly increased by BMI1 overexpression, which regulates erythroid self-renewal through both gene repression and activation.

The mechanisms regulating mitochondrial architecture in neurons remain unclear. The authors report that in dendrites, mitochondria structure is specified by the CAMKK2-AMPK pathway through compartment-specific and activity-dependent levels of fission.

Poly-ADP-ribosylation is a post-translational modification catalyzed by enzymes such as PARP1, which responds to metabolic and genotoxic stress. Now macrodomain-containing proteins are shown to rapidly move to PARP1 activation sites, and recruitment of the macrodomain-containing histone macroH2A1.1 results in local chromatin changes.

Breastfeeding confers lifelong benefits to both mother and child, yet women worldwide experience lactation insufficiency. Here, the authors show that DNA damage occurring in the breast during pregnancy drives the generation of milk-producing cells.

In this study, Marlin et al. provide insights into the potential use of subunit vaccines that induce a high level of protection against SARS-CoV-2 in animal models.

This overview of the ENCODE project outlines the data accumulated so far, revealing that 80% of the human genome now has at least one biochemical function assigned to it; the newly identified functional elements should aid the interpretation of results of genome-wide association studies, as many correspond to sites of association with human disease.

The underlying mechanism of acquired resistance to targeted therapy in cancer remains to be explored. Here, the authors show that upregulation of the FOSL1 transcription factor restores YAP/TEAD occupancy on chromatin to drive resistance to GNE-7883, an allosteric TEAD inhibitor.

PdCO is a switchable optogenetic tool for inhibiting synaptic transmission in neuronal terminals in vivo, as demonstrated in a variety of contexts mainly in the mouse.

The hetero-Diels–Alder reaction is a powerful strategy for constructing six-membered heterocycles, yet natural enzymatic hetero-Diels–Alder reactions are limited to a single heteroatom. Now a bifunctional enzyme, Abx₍₋₎F, is found to catalyse the dehydration and a dual-oxa Diels–Alder reaction to form the oxygen-bridged tricyclic acetal of (−)-anthrabenzoxocinones.

Vinyl polymers are appealing materials owing to their ease of synthesis and broad diversity. Their carbon–carbon backbones resist degradation, however, which limits the applications for which they can be used. This Review Article considers the most promising approaches to the design of degradable vinyl polymers and discusses the potential of these materials for biomedical applications.

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.

RNA Capture Long Seq (CLS) is a new method for transcript annotation that combines targeted RNA capture with long-read sequencing. CLS reannotates GENCODE lncRNAs and increases the number of validated splice junctions and transcript models for targeted loci.

A compound screen using zebrafish identified carbonic anhydrase (CA) as a modulator of tau toxicity. CA inhibition abrogates lysosomal acidification and causes tau secretion by lysosomal exocytosis without having a prion effect. This mechanism lowers intracellular tau and is neuroprotective in zebrafish and mouse models of tauopathy.

Epigenetic modifications of both DNA and histones undergo profound remodeling during early mammalian development. Epigenome editing demonstrates that DNA methylation can impact certain histone marks, helping control proper gene expression dynamics.

Here, the authors identify a third component of the outer membrane LPS translocon in Escherichia coli called LptM. Biochemical analysis and structural modelling reveal that LptM binds the LPS translocon by mimicking its native substrate, so stabilising an active conformation of the complex.

The authors summarize the data produced by phase III of the Encyclopedia of DNA Elements (ENCODE) project, a resource for better understanding of the human and mouse genomes.

The anti-aging intervention calorie restriction (CR) is thought to act via the nutrient-sensing multiprotein complex mTORC1. Here the authors show that the mTORC1-inhibitor rapamycin and CR use largely distinct mechanisms to slow mouse muscle aging.

Complete RNA isoforms are captured by a new single-nuclei sequencing method.

An investigation using various methods reports an association between adeno-associated virus 2 and paediatric hepatitis of unknown aetiology.

The authors identify ferritin light chain 1 (FTL1), an iron-associated protein, as a pro-aging neuronal factor that increases with age and promotes cognitive decline. Targeting FTL1 in the brain improved cognition in old mice.

Combined hepatocellular-cholangiocarcinomas (cHCC-CCA) are challenging to diagnose, as they exhibit features of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICCA). Here, the authors use deep learning to re-classify cHCC-CCA tumours into HCC or ICCA based on histopathology images.

Long-read sequencing has become a widely employed technology that enables a comprehensive view of RNA transcripts. Here, we discuss the importance of long-read sequencing in interpreting the variables along RNA molecules, such as polyadenylation sites, transcription start sites, splice sites and other RNA modifications. In addition, we highlight the history of short-read and long-read technologies and their advantages and disadvantages, as well as future directions in the field.

Growth hormone (GH) is a major modulator of physical growth and metabolism that is under tight regulatory control. Here the authors describe the signaling profile of GPR101, an orphan receptor that enhances GH secretion principally via constitutively activated Gs-PKA and Gq/11-PKC pathways.

Prime Editing is an advanced CRISPRCas9-based tool for precisely rewriting genes in living cells. Here, authors designed virus-like particles optimized to safely and efficiently introduce this technology into human cells of therapeutic interest.

Chromodomain Helicase DNA-binding (CHD) proteins have been implicated in neurodevelopmental processes. Here, the authors identify missense variants in CHD3 that disturb its chromatin remodeling activities and cause a neurodevelopmental disorder with macrocephaly and speech and language impairment.

Centrioles are broken down during oogenesis and are provided by the sperm during sexual reproduction, though how centriole numbers are regulated during asexual reproduction is unclear. Here they study two asexually reproducing nematodes and identify distinct mechanisms for maternal centrosome inheritance.

In this work, Planas et al. report that Omicron subvariants BA.2.75.2, BA.4.6, and BQ.1.1 escape neutralization from monoclonal antibodies, and sera from vaccinated individuals with or without Omicron BA.1/2 or BA.5 breakthrough infection.

The POU2F3–OCA-T complex is the master regulator of tuft cell identity and a prominent molecular vulnerability of tuft-cell-like small-cell lung cancer.

Long non-coding RNAs are increasingly recognised to be important factors in regulating cellular processes and comprise a large faction of the transcriptome, however most are uncharacterised. Here the authors present RACE-Seq, a tool to improve and extend the annotation of low-expression transcripts.

The BioID approaches takes advantage of the promiscuous biotinylation enzyme (BirA*) to identify proteins that closely interact. Here the authors improve the resolution of BioID using a protein fragment complementation approach that allows the assignment of protein-protein interactions to specific complexes within a common interactome.

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.

Prostaglandin E2 from the tumour microenvironment impairs interleukin-2 sensing by tumour-infiltrating lymphocytes, restricting proliferative response and promoting T cell death via metabolic impairment and ferroptosis. 

Ca²⁺ is an intracellular messenger that has a critical role in zebrafish development. Here Prudent et al. show that during gastrulation, the newly identified Bcl-2 homologue, Bcl-wav and the mitochondrial calcium uniporter regulate cell migration by controlling mitochondrial Ca²⁺storage.

Asthma is caused by hyperreactivity to benign antigens, with humoral immunity orchestrated by interleukin-4 (IL-4) and IL-13 being the key etiological factor. Here the authors show, in humanized mouse models, that dual vaccination against IL-4 and IL-13 induces their durable suppression ameliorate experimental asthma, and to hint clinical translation.

Mitochondria emerged as essential actors of neural circuits development. Here, the authors uncovered that the AMPK-related kinase NUAK1 controls axonal mitochondrial metabolism through the regulation of the mitochondrial microprotein BRAWNIN.

Studies in a mouse model of neurolisteriosis show that the effector protein InlB produced by Listeria monocytogenes protects infected monocytes in the host from T cell-mediated cell death, and thereby increases bacterial neuroinvasion, persistence and transmission.

Targeting cancer stem cells (CSCs) has great potential in anti-cancer treatment. Here this group reports the role of antibiotic Nifuroxazide as a potent anti-CSC compound and fabricates it into an anti-breast CSC prodrug using click chemistry strategy.

Reactive oxygen species (ROS) are metabolic by-products which in excess can be toxic for hematopoietic stem and progenitor cells (HSPCs). Here the authors show that toxic ROS are transferred by expanding HSPCs to the zebrafish developmental niche via connexin Cx41.8, where Ifi30 promotes their detoxification.

Radical SAM (rSAM) and 2-His-1-carboxylate enzymes are known to co-occur in RiPP biosynthetic pathways. Here we show the fusion of these enzymes in a single protein where the rSAM enzyme catalyzes cyclophane formation. The 2-His-1-carboxylate enzymes—termed αKG-HExxH—are α-ketoglutarate non-haem iron enzymes that harbour a distinct fold and catalyse β-hydroxylation.

Galectin-3 (Gal-3) has been proposed to have a pathogenic role in systemic sclerosis (SSc). Here, the authors identify a Gal-3-based transcriptomic signature associated with SSc severity in patients and demonstrate that Gal-3 blockade reduces the severity of SSc skin and lung lesions in murine models.

Bladder cancer treatment suffers from low therapeutic efficacy. Here the authors present radioactive ¹³¹I-labelled urease-powered nanobots that exhibit enhanced accumulation at the tumour site, enabling effective radionuclide therapy at low doses as an alternative treatment option for bladder cancer.