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Determinants of WEE1 inhibitor sensitivity in cancer cells are largely undefined. Here, the authors show that WEE1 inhibitors beyond their cell cycle perturbing effects also lead to paradoxical activation of the integrated stress response kinase GCN2.

Birds have evolved a unique sex chromosome dosage compensation mechanism involving the male-biased microRNA (miR-2954), which is essential for male survival by regulating the expression of dosage-sensitive Z-linked genes.

The study shows that the HIV-1 Nef protein stabilizes actin, thereby preventing R12C release and priming of RIG-I–like receptors. HIV-1 containing a mutant Nef unable to bind the actinmodulating kinase PAK2, triggers enhanced interferon responses.

Muscle mass is lost in patients with diabetes, which is associated with mitochondrial disfunction. Here they show that SLIRP maintains muscle mitochondria and that exercise training can compensate for SLIRP loss, improving mitochondrial function and quality control in muscle.

Arterial development is critical for proper blood flow, but the mechanisms mediating this process at the organ level remain unclear. Here, they show that a subpopulation of endothelial cells is important for formation of arterial endothelium in the intestine.

Activation of the mechanistic target of rapamycin (mTOR) is important in the metabolic function of proinflammatory T cells in autoimmunity. Here the authors characterise how Rab4A is involved with CD98 and endosome recycling which subsequently affects mTOR activation, autoimmunity and T cell expansion.

Ferroptosis is an iron-dependent lipid peroxidation-mediated form of cell death that holds promise for targeting treatment-resistant cancer cells. Here, the authors show that AMPK-mediated lipid droplet dynamics modulates the response to ferroptosis inducers in melanoma.

During development of eutherian females, one of the X-chromosomes is silenced. Here, authors show that alleles on the inactive X-chromosome are dynamically expressed along neural differentiation enhancing resilience of female neural tissue.

Centromere fragility can drive tumourigenesis, so protective mechanisms are important. Here, the authors suggest that the PBAF chromatin remodelling complex, which is frequently misregulated in cancer, helps to maintain the integrity of centromeres.

The authors found that VDAC2 plays a crucial role in influencing mitochondrial calcium dynamics and cellular calcium signalling. A VDAC2 agonist, efsevin, rescued the heart failure phenotype, identifying a new potential therapeutic target for heart failure.

Using chemical photoswitchable reagents to exert purely wavelength-dependent control over biological systems in deep tissue and in vivo requires a concentration-independent design paradigm. Here, such photoswitchable ligands are realized by ensuring that E/Z isomers have opposing efficacies yet similarly high affinity, allowing them to probe transient receptor potential C4 and C5 channel functions up to the tissue level.

CEBPA is frequently mutated in acute myeloid leukemia (AML), but the transcriptional impact of the AML-associated isoform remains unclear. Here, the authors show that CEBPA-mutant cells have reduced inflammatory expression and higher sensitivity to ER stress due to impaired function of AP1 factors.

A group of long non-coding RNAs (lncRNAs), Mammary Tumor Associated RNAs 1-30 (MaTARs 1-30), are differentially expressed between mammary tumor cells and normal mammary epithelial cells. Here the authors report that MaTAR25 plays a role in breast cancer cell proliferation, migration and invasion by regulating the expression of the Tensin1 gene in trans.

Death-inducer obliterator 3 (DIDO3) and PHD finger protein 3 (PHF3) are paralogue proteins that regulate transcription elongation by docking onto phosphorylated serine-2 in the C-terminal domain (CTD) of Pol II through their SPOC domains. Here the authors characterize the interplay of these proteins and show that they coregulate neuronal target genes.

The mechanisms of gliotransmitter release and their impact on neuronal signaling have remained largely elusive. The authors describe two functionally non-overlapping v-SNARE-dependent astrocytic release pathways that oppositely control synaptic strength at presynaptic sites. Thus, astrocytes are able to fine-tune fast glutamatergic neurotransmission and control fundamental processes of synaptic communication.

Savan and colleagues show that distinct isoforms of the RNA-binding protein ZAP function as an antiviral restriction factor or as an interferon-resolution factor, based on differences in their intracellular localization.

The cellular origins of lymphangioleiomyomatosis (LAM), a rare fatal lung disease, are poorly understood. Here the authors identify a mesenchymal cell hub coordinating the LAM phenotype and develop a LAM mouse model where they investigate the co-operative dysregulation of mTORC1 and WNT growth pathways in the sex- and age-specific changes leading to structural and functional decline.

People with mutations in ATGL, a gene involved in lipid catabolism, suffer from neutral lipid storage disease and often from cardiomyopathy. Rudolf Zechner and his colleagues now show in mice that Atgl activity in cardiac muscle produces key lipid ligands for PPAR-α, a transcription factor that regulates proper lipid metabolism and fuel burning in this tissue. These results may explain the mechanisms responsible for the cardiomyopathy and offer a potential target for treatment.

Khan et al. report a non-catalytic function of the methyltransferase SETD2 in regulating nuclear morphology and genome integrity. The SETD2 amino terminus functions as a scaffold helping CDK1 associate with lamins during nuclear-envelope disassembly

Martinez-Lopez et al. show that fasting or lipid availability stimulates mTORC2 activity in the liver, leading to phosphorylation of NDRG1 and NDRG1–CDC42-mediated mitochondrial fission.

Ronchese and colleagues show that IL-13 secreted homeostatically by dermal ILCs contributes to the differentiation of a CD11b^lo type 2 dendritic cell subset, which supports the development of T_H2 cells and curtails the development of T_H17 cells in the skin of mice and humans.

Ribbon synapses in our sensory nervous system are central to hearing and sight, yet little is known about how these synapses are assembled and maintained during development. In this study, authors use live imaging techniques to monitor ribbon appearance, loss and maintenance in a retinal circuit during development to show that nascent synapses comprising of both ribbons and PSD95 are more stable over time compared to contacts without ribbons.

The kinase RIPK3 initiates necroptosis, which has been reported to promote inflammation in various pathological conditions. Here, the authors show that genetic ablation of Ripk3results in adipocyte apoptosis and white adipose tissue inflammation in obese mice, which promotes glucose intolerance.

TP53 is mutated in many cancers, a system to detect and selectively eliminate p53 mutant cells is an attractive therapeutic strategy. Here, the authors present a genetic sensor that can detect p53 activity and is coupled to the thymidine kinase gene, which can activate the drug Ganciclovir, resulting in cell death.

Collagen can be a metabolic source to fuel cancer growth. Here the authors show that cell surface protein TEM8 mediates the binding and uptake of collagen in stromal cells and these cells processed the collagen to glutamine, providing an alternative energy source for tumour cells to grow.

Untargeted comparative metabolomics revealed N-acylspermidines as conserved metabolites downstream of mitochondrial sirtuins that provide direct evidence for their in vivo deacylation functions and may contribute to sirtuin-dependent phenotypes.

Pitulescu et al. and Hasan et al. show that Dll4–Notch signalling in endothelial tip cells regulates angiogenesis through control of artery formation, linking sprouting angiogenesis and artery formation.

Drug and target discovery for advanced liver disease are hampered by a lack of suitable models for clinical translation. Here the authors present a human liver cell-based system modeling a clinical prognostic signature allowing to propose nizatidine for treatment of advanced liver fibrosis and hepatocellular carcinoma prevention.

Gfi1b regulates cellularity of haematopoietic stem cells (HSCs) and megakaryocytes (MKs) as well as spreading of MKs on matrix. Here the authors show that Gfi1b regulates this behaviour by recruiting LSD1 and β-catenin to Wnt/β-catenin signalling targets.

Combination of TCR or CAR T cells expressing the engineered CD47 variant 47_E with anti-CD47 antibody therapy results in synergistic antitumour efficacy due to T cell resistance to clearance by macrophages, while maintaining macrophage recruitment into the tumour microenvironment.

Endothelial cells release extracellular matrix components that regulate inflammation. Here the authors demonstrate that the extracellular matrix component epidermal growth factor-like protein 7 regulates inflammation in experimental autoimmune encephalomyelitis in the mouse.

Innate immune mechanisms are critical for antiviral defense. Here, the authors developed a CRISPR/Cas9-based HIV-driven approach to identify cellular factors compromising viral transcription, assembly, release or infectivity in human T cells. They identify targets of the Nef protein as antiviral factors.

The adipose-specific phospholipase A2 (PLA2G16) has been identified as a pan-enterovirus host factor. Here, the authors show that the enterovirus EV-D68-947 can bypass PLA2G16 by using sulfated glycosaminoglycans as alternative glycan receptors and that the interaction induces structural changes promoting viral genome release.

The transcription factor GFI1 mediates the DNA damage response (DDR) of T cells through a yet unknown mechanism. Here the authors show that GFI1 can adopt non-transcriptional roles during DDR, enabling PRMT1 to bind and methylate the DNA repair proteins MRE11 and 53BP1.

A series of fluorescent probes is designed that act as dual agonists on both GLP1 and GIP receptors, and are used to image receptor binding activities in tissues and animals.

Neurological phenotypes of PTEN loss are driven by aberrant mTORC2 signaling, and therapeutic inhibition of the mTORC2 component Rictor by antisense oligonucleotides reverses seizures, social interaction deficits and memory impairments in rodents.

The basement membrane stiffness is shown to be a more dominant determinant than pore size in regulating cancer cell invasion, metastasis formation and patient survival. This stiffness is now known to be affected by the ratio of netrin-4 to laminin, with more netrin-4 leading to softer basement membranes.

Self-derived DNA may trigger interferon-driven autoinflammation mediated by the cGAS-STING axis. Here, the authors find that mutations in the GTPase ARF1 cause an interferonopathy by promoting aberrant mitochondrial DNA release and impairing STING recycling.

Angelman syndrome (AS) is characterized by developmental delay and intellectual disability, but the underlying pathophysiology is not well understood. Here the authors use induced pluripotent stem cell-derived neurons from AS patients and find impaired maturation of resting membrane potential and action potential firing, and defects in synaptic activity associated with the disease.

Phenotypic profiling of a phospho-deficient mutant library informs functional annotations of phosphosites.

Acquired resistance limits the efficacy of PARP inhibitors (PARPi) in high grade serous ovarian cancer (HGSOC). Here, the authors show that inhibition of RNA polymerase I transcription using CX-5461 increases the therapeutic efficacy of PARPi and overcomes PARPi resistance in PDX models of HGSOC.

A population of highly interconnected cells in glioblastoma makes these tumours resistant to general damage but vulnerable to targeted disruption of this small fraction of cells and their rhythmic Ca²⁺ oscillations.

T-cell function impairment is one of the major determinants of tumour immune evasion. Here, the authors show that the hostile conditions in the tumour microenvironment lead to C/EBP homologous-protein upregulation in T cells via ER stress, resulting in repression of T-bet and consequent inhibition of CD8⁺ T cell function.”

Promising clinical activity of Claudin (CLDN) 18.2-directed CAR-T cell therapy in patients with gastric cancer has been recently reported, however gastrointestinal toxicities have also been described. Here the authors recapitulate the on-target off-tumor toxicity of CLDN18.2-directed CAR-T cells due to gastric mucosa damage in preclinical models, suggesting an AND-gate strategy targeting CLDN18.2 and mesothelin to overcome CAR-T cell toxicity

The interferon-inducible RNA-binding protein N4BP1 binds to and degrades HIV-1 mRNAs, thus inhibiting viral degradation and promoting viral latency. However, metacaspase-mediated degradation of N4BP1 following activation of CD4⁺ T cells facilitates HIV-1 latency reversal.