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Neoadjuvant immunotherapy can induce promising response rates in patients with localised deficient mismatch repair (dMMR)/microsatellite instability-high (MSI-H) solid tumours but whether this translates to long term survival benefits is less clear. Here, the authors report long-term survival outcomes and ctDNA analysis of a phase II trial investigating neoadjuvant pembrolizumab in patients with dMMR/MSI-H solid tumours.

The epigenetic mechanisms underlying phenotypic diversity across different metastatic sites in castration-resistant prostate cancer (CRPC) remain to be characterised. Here, multi-omic profiling across metastatic lesions identifies regulatory networks driving tumour lineage programs and potential therapeutic targets.

Proteomic data from natural isolates of Saccharomyces cerevisiae provide insight into how these cells tolerate aneuploidy (an imbalance in the number of chromosomes), and reveal differences between lab-engineered aneuploids and diverse natural yeasts.

When hominins dispersed into Eurasia is unclear. Here, the authors present multiple cut-marked bones from Grăunceanu, Romania dated to at least 1.95 million years ago and suggest hominins would have lived in a temperate and seasonal environment.

The epigenetic and transcriptional roles of Nucleoporin 98 (NUP98) fusion oncoproteins in driving pediatric acute myeloid leukemia (AML) remain to be explored. Here, the authors identify a core set of genes regulated by NUP98::KDM5A and suggest CDK12 as a potential therapeutic vulnerability.

Certain antimetabolites used to treat cancer are more neurotoxic than others, and it is now shown that this is due to their greater tendency to generate DNA double-stranded breaks, whereas less neurotoxic agents induce single-stranded breaks.

Covalent histone modifications have been linked to many DNA processes. The repertoire of modifications is still growing, and histone H3K64 trimethylation is now shown to be localized to pericentric chromatin and its levels dynamically altered during developmental reprogramming in both embryos and primordial germ cells.

DNA methylation is associated with breast cancer risk. Here the authors measure DNA methylation in the blood of individuals from 25 Australian families with multiple cases of breast cancer but not known mutations associated with breast cancer risk to identify possible heritable methylation markers.

The outflow pathway of cerebrospinal fluid into lymph nodes in the neck and how non-invasive mechanical stimulation can enhance drainage and restore impaired outflow in aged mice are explored.

The authors perform meta-analysis of GWAS studies for asthma from multiancestral cohorts. They identify five new loci and find that the asthma-associated loci are enriched near enhancer marks in immune cells.

Cancer stem cells (CSCs) are thought to be the main drivers for disease progression and treatment resistance in liver cancer. This study identifies the LGR5+ compartment as an important CSC population, representing a viable therapeutic target for combating liver cancer.

A reinforcement learning-based virtual reality system, implementing a series of sport sessions with coaching, was as effective as standard physical activity in reducing fat mass in adolescents, with positive effects on cognition.

This study describes the integrative analysis of 111 reference human epigenomes, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression; the results annotate candidate regulatory elements in diverse tissues and cell types, their candidate regulators, and the set of human traits for which they show genetic variant enrichment, providing a resource for interpreting the molecular basis of human disease.

Using viral barcode tracing to detect interactions between glioblastoma cells and non-malignant astrocytes in patient samples, investigators discovered a pathway that reduces tumour-specific immunity and identified potential therapeutic targets.

Using pancreatic organoids and genetic mouse models, Antonucci et al. show that cellular stress activates an NRF2–EZH2 epigenetic axis leading to metabolic reprogramming and subsequent malignant transformation of KRAS-mutant benign lesions.

Nuclear quantum effects affect chemical processes and material properties. Here the authors use path-integral molecular dynamics simulation to analyze their effects on themophysical properties of 92 organic liquids across the chemical space.

Single particle cryo-electron microscopy of membrane proteins is limited by their small size and difficulty to orient. Here the authors generate recombinant antibodies against the 12 kDa fusion partner BRIL ___domain from apocytochrome b562 to use them as plug and play fiducial marks for structure determination of BRIL fused membrane proteins.

A subpopulation of adaptive immune cells patrols the brain and cerebrospinal fluid in people who have Alzheimer’s disease. This discovery should broaden our understanding of how the immune system can influence neurodegeneration.

Nshanian et al. investigate the differential effects of the short-chain fatty acids propionate and butyrate on chromatin remodelling and gain insight into the mechanisms that drive selective histone acylation.

This study reports on excavations of hearths and stone artefacts from 20,000-year-old deposits at Dargan Shelter, which at an elevation of 1,073 m is believed to be the oldest occupied high-altitude site in Australia.

Reagents that recognize specific chemical modifications while ignoring the surrounding protein offer valuable proteomic insights.

After a quarter of a century, the website remains an essential tool for navigating the genome and understanding its structure, function and clinical impact.

Basidiomycete fungi typically have two mating-type loci located on different chromosomes. Here, Lucotte et al. report the convergent loss-of-function of mating-type genes across several species of phytopathogenic fungi of the genus Microbotryum.

Kraft et al. identify TIE2 activation as a key driver of PIK3CA-related venous malformations and demonstrate that inhibiting TIE2 signaling can suppress the growth of advanced lesions.

Modifying the polyethylene glycol lipid ratio and phospholipids in the lipid nanoparticle component of nucleoside-modified mRNA–lipid nanoparticle vaccines is shown to have an impact on the elicited cellular and humoral immune responses.

Comprehensive integration of gene expression with epigenetic features is needed to understand the transition of kidney cells from health to injury. Here, the authors integrate dual single nucleus RNA expression and chromatin accessibility, DNA methylation, and histone modifications to decipher the chromatin landscape of the kidney in reference and adaptive injury cell states, identifying a transcription factor network of ELF3, KLF6, and KLF10 which regulates adaptive repair and maladaptive failed repair.

Routine breast MRI scans provide an opportunity to screen for thoracic aortic aneurysms, which are more fatal in women. Here, the authors show that a fully automated AI tool can screen for these aneurysms using routine breast MRI scans.

Macrophages are critical for granuloma formation, but the cell-intrinsic mechanisms remain unknown. Weichhart and colleagues demonstrate that chronic mTOR activity leads to macrophage-dependent granuloma formation, which may have relevance to sarcoidosis.

The physical organization of the genome in non-bilaterian animals and their closest unicellular relatives is characterized; comparative analysis shows chromatin looping is a conserved feature of genome architecture and spatial genome regulation emerged early in animal evolution.

Nerve injury activates microglia to remove spinal synapses, disrupting spinal sensory processing and contributing to chronic pain. Blocking complement protein C1q preserves synapses, highlighting a potential therapeutic target for neuropathic pain.

MPRAs and in vivo transgenic mouse assays are two potentially complementary ways to assay the impact of noncoding variants. Here, authors find a strong and specific correlation between the assays in neural cells. Mouse assays also reveal pleiotropic effects not observed in MPRA.

Genome-wide analyses identify 30 independent loci associated with obsessive–compulsive disorder, highlighting genetic overlap with other psychiatric disorders and implicating putative effector genes and cell types contributing to its etiology.

A study demonstrates a public generator of random numbers based on device-independent techniques, with the randomness being fully auditable and traceable.

An interconnect based on a low-loss detachable cable connection between two superconducting qubit devices can be used to create elementary quantum networks of interchangeable superconducting quantum devices.

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.

CREBBP mutations in B-cell acute lymphoblastic leukemia (B-ALL) are linked to poor prognosis and chemoresistance. Here, the authors show that genetic or pharmacological inactivation of CREBBP sensitizes B-ALL cells to the BCL2 inhibitor Venetoclax, inducing ferroptotic cell death and extending survival in B-ALL preclinical mouse models.

MaizeCODE maps active regulatory regions tied to maize domestication traits in a diverse panel of tissues and inbreds. It reveals bi-directional enhancer RNAs and the molecular conflicts between activity and silencing of non-coding regions.

The accelerated liquid–gel transition of collagen induced by an inert crowding agent enables the rapid and versatile fabrication of collagenous tissues under biocompatible and bioactive conditions for tissue engineering applications.

Integrated single-cell transcriptomic and genetic characterization of 121 adult glioblastomas identifies heterogeneity at cell type, cell state and baseline expression program levels associated with specific mutations that form three stereotypical ecosystems.

Current base editors cannot simultaneously edit multiple loci with base-pair level precision, hindering complex genotype generation. Here the authors describe optimized Cas12a gRNA array designs, enabling base-pair conversions at up to 15 loci and with reduced bystander editing rates in human cells.

Fine-mapping of causal variants and integration of epigenetic and chromatin conformation data identify likely target genes for 150 breast cancer risk regions.

Karpinska, Zhu and colleagues characterize the structure-function relationship of the genome during cellular differentiation and demonstrate a role for enhancer-promoter interactions in gene regulation that is independent of cooperative interactions in chromatin hubs.

A genome-wide study by the Long COVID Host Genetics Initiative identifies an association between the FOXP4 locus and long COVID, implicating altered lung function in its pathophysiology.

A new mechanism is identified for correct placement of the division machinery in Streptococcus pneumoniae that relies on the novel factor MapZ to form ring structures at the cell equator; these structures move apart as the cell elongates, acting as permanent markers of division sites.

This commentary provides a nuanced discussion on the conceptual framework to study epigenetic mechanisms that regulate brain function and plasticity. By drawing from examples in genomic imprinting, the authors highlight the challenges facing epigenetics research in the context of neuroscience.

A population of TRAIL-positive astrocytes in glioblastoma contributes to an immunosuppressive tumour microenvironment and this mechanism can be targeted with an engineered oncolytic virus to improve outcomes.

Distinguishing band and Mott insulators experimentally represents a longstanding challenge. Here, the authors demonstrate a momentum-resolved signature of a dimerized Mott-insulator in the out-of-plane spectral function of Nb₃Br₈.

Multiple types of cell elongation have been described in bacteria, but little is known about how these strategies vary across species. Here, the authors use fluorescent D-amino acids to track the spatiotemporal dynamics of bacterial cell elongation, revealing unsuspected diversity of elongation modes among closely related species of the family Caulobacteraceae.