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Currently, there is limited knowledge about the spatial heterogeneity of glioma-driving molecular events. Here, the authors employ a multiomics approach to characterize the spatial transcriptomic heterogeneity of various types of gliomas and identify spatially distinct tumor subclones with genomic plasticity driven by mutations on extrachromosomal DNA.

A first-in-human phase I clinical trial demonstrates the feasibility and safety of non-viral precision genome-engineering of a personalized adoptive cell transfer anticancer therapeutic.

The early genetic evolution of uveal melanoma (UM) remains poorly understood. Here, the authors perform genetic profiling of 1140 primary UMs, including 131 small early-stage tumours, finding that most genetic driver aberrations have occurred by the time small tumours are biopsied; in addition, the15-gene expression profile discriminant score can predict the transition from low- to high-risk tumours.

Analysis of whole-genome sequencing data across 2,658 tumors spanning 38 cancer types shows that chromothripsis is pervasive, with a frequency of more than 50% in several cancer types, contributing to oncogene amplification, gene inactivation and cancer genome evolution.

Humanity’s Last Exam, a multi-modal benchmark at the frontier of human knowledge, is designed to be an expert-level closed-ended academic benchmark with broad subject coverage.

Together with a companion paper, the generation of a transcriptomic atlas for the mouse lemur and analyses of example cell types establish this animal as a molecularly tractable primate model organism.

Here they identify a short-lived vascular endothelial progenitor pool that predominantly vascularizes the mouse liver during postnatal growth and contributes to liver size control.

Patients with ovarium cancer frequently develop resistance to platinum chemotherapy and PARP inhibitors (PARPi). Here, the authors show that the combination of PARP and ATR inhibitors increases the therapeutic response in PARPi and platinum resistant ovarium cancer PDX models.

Yimiao Qu and Kyle Loh discuss a 2004 paper by Xie et al., who demonstrated that B cells can be reprogrammed into macrophages through the enforced expression of a single transcription factor, providing insights into cellular plasticity and lineage conversion.

Isakson et al. report a genetically engineered minipig model of Neurofibromatosis Type 1 (NF1) that exhibits clinical hallmarks of the disease, including neurofibromas and optic pathway glioma. This model may expedite the development of imaging methods, biomarkers, and therapies for NF1 patients.

Cancers evolve as they progress under differing selective pressures. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, the authors present the method TrackSig the estimates evolutionary trajectories of somatic mutational processes from single bulk tumour data.

Using large-scale exome sequencing, this study identifies a second (after VHL) frequently mutated gene in clear cell renal cell carcinomas, the most frequent type of kidney cancer. PBRM1, a member of the SWI/SNF complex involved in transcriptional regulation, is mutated in about 40% of cases and shown to function as tumour suppressor gene. PBRM1 was independently found as a putative cancer gene involved in pancreatic cancer in a mouse transposon screen.

WGS data were used from 347,630 individuals with European ancestry in the UK Biobank to obtain high-precision estimates of coding and non-coding rare variant heritability for 34 complex traits and diseases.

Mapping of the clonal structure of bone marrow cells in patients with acute myeloid leukemia treated with the IDH2 inhibitor enasidenib reveals heterogeneity in the cellular differentiation response and in mechanisms of relapse.

Elliot Stieglitz, Mignon Loh and colleagues report the whole-exome sequencing of diagnostic and relapsed samples from patients with juvenile myelomonocytic leukemia. They identify new recurrent mutations for this disease and find that the number of somatic alterations present at diagnosis may be predictive of clinical outcome.

Germline mutations in the Elongator complex gene ELP1 predispose individuals to the development of childhood medulloblastoma.

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.

Exome sequencing and copy number analysis are used to define genomic aberrations in early sporadic pancreatic ductal adenocarcinoma; among the findings are mutations in genes involved in chromatin modification and DNA damage repair, and frequent and diverse somatic aberrations in genes known as embryonic regulators of axon guidance.

Autosomal Recessive Renal Tubular Dysgenesis (AR-RTD) arises from mutations in Angiotensin II sensing genes, but how they impact the kidney was unclear. This study reveals that delayed angiogenesis at a critical developmental window underlies AR-RTD.

Intracranial germ cell tumours are rare tumours affecting mainly male adolescents, mainly in Asia; here the authors identify frequent mutations in the KIT/RAS and AKT/mTOR signalling pathways as well as rare germline variants in JMJD1C, suggesting potential therapeutic strategies focusing on the inhibition of KIT/RAS activation and the AKT1/mTOR pathway.

A chip-integrated laser with 7.5 × 10⁻¹⁴ fractional frequency instability is demonstrated by active stabilization to an on-chip 6.1-m-long spiral resonator. By using this laser to interrogate the narrow-linewidth transition of ⁸⁸Sr⁺, a clock instability averaging down as \(3.9\times 1{0}^{-14}/\sqrt{\tau }\) is achieved.

Human pluripotent stem cell derived therapies can have serious safety risks. Here the authors design two drug inducible genetic safeguards to deplete undifferentiated hPSCs and hPSC-derived cell types.

Genome-wide association and fine-mapping analyses in ancestrally diverse populations implicate candidate causal genes and mechanisms underlying type 2 diabetes. Trans-ancestry genetic risk scores enhance transferability across populations.

How changes in brain blood vessels lead to a chronic reduction in blood flow and, consequently, to vascular dementia is poorly understood. Here, the authors show that venous endothelial dysfunction driven by EPAS1 promotes abnormal vascular remodeling and contributes to cognitive decline.

Tatsuhiro Shibata, David Wheeler, Hiroyuki Aburatani and colleagues report the genomic, exomic and oncoviral sequencing of hundreds of liver cancers from the United States and Japan. The authors analyzed mutation patterns and identified signatures unique to the Asian cases.

Analyses of 2,658 whole genomes across 38 types of cancer identify the contribution of non-coding point mutations and structural variants to driving cancer.

A spatial transcriptomic analysis of healthy kidneys and those from individuals with chronic kidney disease characterizes the fibrotic microenvironment and highlights features that could be used to predict prognosis.

Bin Tean Teh and colleagues report exome sequencing of Opisthorchis viverrini–related cholangiocarcinoma, a fatal bile duct cancer associated with liver fluke infection.

Together with an accompanying paper presenting a transcriptomic atlas of the mouse lemur, interrogation of the atlas provides a rich body of data to support the use of the organism as a model for primate biology and health.

Generation of primordial germ cell-like cells (PGCLCs) from human pluripotent cells (hPSCs) offers insight into the mechanisms underlying human reproduction, but often requires complex methods. Here they describe a simplified monolayer protocol to differentiate and purify PGCLCs for further analysis.

An expanded GWAS of birth weight and subsequent analysis using structural equation modeling and Mendelian randomization decomposes maternal and fetal genetic contributions and causal links between birth weight, blood pressure and glycemic traits.

Direct reprogramming of closely-related lineages can generate hematopoietic stem cells. Here, the authors show hematopoietic transcription factors Scl, Lmo2, Runx1 and Bmi1 can reprogram fibroblasts into induced hematopoietic progenitors (iHPs), which are engraftable blood progenitors.

Live-cell single-molecule imaging of pioneer transcription factors revealed a ‘confined target search’ mechanism where they alternate between fast free diffusion in the nucleus and slower confined diffusion within compacted chromatin domains, leading to efficient pioneering on closed targets.

This paper describes methods for the 3D culture of mouse lung progenitor cells that can differentiate in vitro and in vivo along all epithelial lineages.

Madeleine Duvic, David Wheeler and colleagues present an integrated genomic analysis of Sézary syndrome. They identify recurrent alterations in key T cell signaling and differentiation genes and observe overexpression of IL32 and IL2RG in nearly all cases.

Sequencing data from two large-scale studies show that most of the genetic variation influencing the risk of type 2 diabetes involves common alleles and is found in regions previously identified by genome-wide association studies, clarifying the genetic architecture of this disease.

Hand grip strength as a proxy of muscular fitness is a clinical predictor of mortality and morbidity. In a large-scale GWA study, the authors find 16 robustly associated genetic loci that highlight roles in muscle fibre structure and function, neuronal maintenance and nervous system signal transduction.

The Cancer Genome Atlas Network describe their multifaceted analyses of primary breast cancers, shedding light on breast cancer heterogeneity; although only three genes (TP53, PIK3CA and GATA3) are mutated at a frequency greater than 10% across all breast cancers, numerous subtype-associated and novel mutations were identified.

Engineering of a high-affinity Delta-like variant, named Delta^MAX, potently activates Notch signaling when provided in a bead-bound or cellular format, while administration as a soluble decoy inhibits signaling.

How ribosomes differ in composition and function to regulate gene expression is poorly understood. Here, the authors show that ribosome composition changes during stem cell differentiation and identify a ribosomal protein that regulates production of the mesoderm lineage.

In this Review, Blum et al. summarize the current knowledge on sarcomatoid renal cell carcinoma, a diagnosis characterized by the presence of sarcomatoid dedifferentiation and a poor prognosis. They discuss the origin, presentation, molecular biology and treatment of this disease.

Conferring stem-cell potential on mature cells is not easy. A decisive impediment to this process has now been identified, and its elimination allows almost all mature cells to efficiently adopt a stem-cell identity. See Article p.65

The transformation of skin cells into stem cells is a fascinating but poorly understood process. At last, the molecular characters underlying the initial steps have been revealed. See Letter p.652

Pluripotent cells can produce all cell types in the body. It emerges that this state of potential is endowed by cues, including inhibition of Wnt signalling, that maintain a balance between diverse cellular outcomes. See Article p.316

A combination of gnotobiotic mouse models, transcriptomics, circuit tracing and chemogenetic manipulations identifies neuronal circuits that integrate microbial signals in the gut with regulation of the sympathetic nervous system.