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The insulin inhibitory receptor (inceptor) is found to bind to insulin and to regulate insulin stores by directing proinsulin and insulin towards lysosomal degradation.

The Li lab mapped molecularly distinct Purkinje cell (PC) subtypes in 3D and linked them to adult cerebellar architecture. They found that Foxp1/Foxp2 are essential for PC diversity and that Foxp1⁺ PCs are required for the formation of the cerebellar hemisphere.

The gut microbiome has been associated with pancreatic cancer. This Review summarizes the latest findings of microbiota association studies of tumours of the pancreas and outlines the mechanisms as to how the microbiome influences pancreatic cancer and the clinical potential of harnessing the microbiome in pancreatic cancer.

N-terminal protein acetylation is required for plant viability. Here the authors show that reducing N-terminal acetylation by NatA leads to an increase in global protein turnover that is facilitated by absent masking of a novel N-degron

Using a combination of bioinformatics, biochemistry, genetics, genomics and cell-based approaches, this study shows that the H3–H4 binding capacity of the histone chaperone SPT2 is required to preserve chromatin structure and function in Metazoa.

A chaperone complex containing CSPα, Hsc70 and SGT binds to monomeric SNAP-25 and prevents its aggregation and degradation. Loss of CSPα inhibits SNARE complex formation.

Mammalian DNA replication relies on various helicases and nucleases to ensure accurate genetic duplication, but how these enzymes are properly directed is unclear. Here, the authors identify USP50 as a key protein for promoting ongoing replication, restarting stalled forks, maintaining telomeres, and ensuring cell survival.

Whole-genome sequencing data for 2,778 cancer samples from 2,658 unique donors across 38 cancer types is used to reconstruct the evolutionary history of cancer, revealing that driver mutations can precede diagnosis by several years to decades.

Understanding deregulation of biological pathways in cancer can provide insight into disease etiology and potential therapies. Here, as part of the PanCancer Analysis of Whole Genomes (PCAWG) consortium, the authors present pathway and network analysis of 2583 whole cancer genomes from 27 tumour types.

Downregulation of estrogen receptor-α (ER-α) in breast tumors can mediate resistance to ER-α–targeted therapies such as tamoxifen. This report sheds light on a therapy resistance–conferring adaptation by identifying a new regulator of ER-α stability. CUE domain–containing protein-2 (CUEDC2) can bind to and promote degradation of ER-α, thereby driving tamoxifen resistance. Elevated CUEDC2 elevation in human breast cancers correlates with attenuated prognosis after tamoxifen treatment, thus suggesting its potential as a clinical predictor.

The sorting and assembly machinery (SAM) mediates mitochondrial β-barrel protein folding and membrane insertion. A cryo-EM structure of the yeast SAM complex bound to an early eukaryotic β-barrel intermediate reveals a multipoint guidance mechanism.

Mutations in the gene, GBA1, cause Gaucher’s disease, and are a strong risk factor for the development of Parkinson’s disease. Here the authors use cells derived from Parkinson’s patients with GBA1mutations to model the disease, and reveal changes in cellular recycling systems that may promote neurodegeneration.

Many bacterial toxins and viruses deform membranes prior to entering cells via clathrin independent endocytosis. Here the authors show that multivalent lipid binding by globular particles can exceed a threshold adhesion energy required for membrane deformation and that this is sufficient for internalization.

A small molecule can bypass the RNA-editing enzyme ADAR1 to directly activate the Z-form nucleic acid sensor ZBP1, induce necroptosis in tumour fibroblasts and reverse resistance to immune checkpoint blockade in mouse models of melanoma.

The mechanism by which ingested material accesses the cytosol for cross-presentation is unclear. Caetano Reis e Sousa and colleagues demonstrate that signaling via the lectin receptor DNGR-1 ruptures the phagosome and releases its contents to the cytosol for cross-presentation.

Acetylation of p53 is critical for its transcriptional activity and its tumour suppressive function. Here, the authors show that PBRM1 is a reader protein for p53′s C-terminal domain acetylation on lysine 382 through its bromodomain 4 and that mutations in this domain leads to compromised tumour suppressive function and renal tumour growth.

Visvader and colleagues report that in the mouse mammary gland, EGF and mTOR signalling induce expression of the anti-apoptotic Bcl2 family member Mcl-1 and show that this is required for the survival of milk-producing mammary epithelial cells.

Proteins are inserted into the outer mitochondrial membrane by the mitochondrial sorting and assembly machinery, two structural forms of which are presented here, suggesting the mechanism involved.

Analysis of cancer genome sequencing data has enabled the discovery of driver mutations. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium the authors present DriverPower, a software package that identifies coding and non-coding driver mutations within cancer whole genomes via consideration of mutational burden and functional impact evidence.

The authors present SVclone, a computational method for inferring the cancer cell fraction of structural variants from whole-genome sequencing data.

The identification of patient-specific disease mechanisms and druggable targets is crucial for precision medicine in glioblastoma. Here, the authors show that comparing patients-matched glioma-initiating cells with neural stem cells enables the discovery of patient-specific mechanisms of disease and the identification of effective drugs

The DCAF15 E3 ubiquitin ligase is targeted by aryl-sulfonamide molecular glues leading to neo-substrate proteasomal degradation. Here, the authors reveal DCAF15 as a cell autonomous acute myeloid leukemia dependency sustaining proliferation through control of cohesin complex recycling dynamics.

Lee et al. show that DMXL1, a regulator of V-ATPase assembly, is recruited to lysosomes upon TRPML1 activation in a manner dependent on conjugation of ATG8 proteins on lysosomal membranes (CASM) and promotes lysosomal function.

When injured, fish release an alarm substance produced by club cells in the skin that elicits fear in members of their shoal. Here, the authors show that mucus and bacteria are transported from the external surface into club cells, and bacterial components elicit alarm behaviour, acting in concert with a substance from fish.

In wildlife tagging, stress from capture and handling can alter post- release behavior and potentially study interpretations. This study of 42 mammal species shows that these effects diminish within 4–7 days, and quicker for animals in high human activity areas indicating adaptation to disturbance.

The field of regenerative medicine would greatly benefit from the study of a non-human primate model. Here, the authors prospectively isolated two quiescent stem cell populations from the non-human primate mouse lemur.

Under conditions such as hypoxia or starvation, an mTORC1-lipid signalling pathway initiates mitochondrial proteolysis by YME1L.

Phylogenomic analysis of 7,923 angiosperm species using a standardized set of 353 nuclear genes produced an angiosperm tree of life dated with 200 fossil calibrations, providing key insights into evolutionary relationships and diversification.

Viral pathogen load in cancer genomes is estimated through analysis of sequencing data from 2,656 tumors across 35 cancer types using multiple pathogen-detection pipelines, identifying viruses in 382 genomic and 68 transcriptome datasets.

Zimmermann et al. present OrgaPlexing, an imaging pipeline mapping metabolic organelles and their interactions. They find changes in mitochondria, ER, peroxisome and lipid droplet dynamics that impact macrophage inflammatory lipid mediator synthesis.

Mechanisms underlying tumor cell plasticity remain poorly understood. Here, the authors show the presence of a dormant-invasive SOX10- subpopulation in cutaneous melanoma that can be targeted by cIAP1/2 inhibitors.

It has been debated whether premature ageing in mitochondrial DNA mutator mice is driven by point mutations or deletions of mtDNA. Matic et al generate Mgme1 knockout mice and show here that these mice have tissue-specific replication stalling and accumulate deleted mtDNA, without developing progeria.

Homologous recombination (HR) gene mutations are thought to be synthetic lethal with DNA polymerase theta (Polθ) inhibition. Here, the authors reveal that Polθ addiction is determined by the functional impact of gene mutations on DNA end resection activity.

The flagship paper of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium describes the generation of the integrative analyses of 2,658 cancer whole genomes and their matching normal tissues across 38 tumour types, the structures for international data sharing and standardized analyses, and the main scientific findings from across the consortium studies.

Integrative analyses of transcriptome and whole-genome sequencing data for 1,188 tumours across 27 types of cancer are used to provide a comprehensive catalogue of RNA-level alterations in cancer.

Four decades after a test mining experiment that removed nodules, the biological impacts in many groups of organisms persist, although populations of several organisms have begun to re-establish despite persistent physical changes at the seafloor.

Asymmetric segregation of cell fate determinants during cell division governs daughter cell fate. Here the authors show that Sara endosomes, known to regulate Notch signalling, are targeted to the mitotic spindle and once phosphorylated are asymmetrically dispatched into a daughter cell to determine cell fate.