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Goel and colleagues show that CDK4/6 inhibition induces global chromatin changes mediated by AP-1 factors, which mediate key biological and clinical effects in breast cancer.

Stem rust is an important disease of wheat and resistance present in some cultivars can be suppressed by the SuSr-D1 locus. Here the authors show that SuSr-D1 encodes a subunit of the Mediator Complex and that nonsense mutations are sufficient to abolish suppression and confer stem rust resistance.

Transport measurements of dual-gated devices constructed by slightly rotating a monolayer graphene sheet atop a thin bulk graphite crystal are performed, showing that moiré potential transforms the electronic properties of an entire graphitic thin film.

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

Analysis of copy number alterations in 1,451 patient-derived xenografts (PDXs) and matched patient tumor samples shows strong conservation from patient tumors through late-passage PDXs and a lack of systematic copy number evolution driven by the mouse host.

Using a three-pronged approach — spanning field-driven negative capacitance stabilization to increase intrinsic energy storage, antiferroelectric superlattice engineering to increase total energy storage, and conformal three-dimensional deposition to increase areal energy storage density — very high electrostatic energy storage density and power density are reported in HfO₂–ZrO₂-based thin film microcapacitors integrated into silicon.

Trencher and colleagues investigate the twenty companies making the largest purchases of offsets from the voluntary carbon market from 2020 to 2023. They find that 87% of the purchased offsets carry a high risk of not providing real and additional emissions reductions. Further, most offsets do not meet industry standards regarding age and country of implementation. The findings reinforce concerns that the voluntary carbon market is failing to support effective climate mitigation.

In a phase 2 trial, the combination of gemcitabine, cisplatin and anti-PD-1 led to a clinical complete response in 43% of patients with muscle-invasive bladder cancer, which facilitated bladder sparing and was associated with long-term bladder-intact metastasis-free survival.

Whole-exome analysis of individuals with developmental disorders shows that de novo mutations can equally cause loss or altered protein function, but that most mutations causing altered protein function have not yet been described.

Massively parallel DNA sequencing allows entire genomes to be screened for genetic changes associated with tumour progression. Here, the genomes of four DNA samples from a 44-year-old African-American patient with basal-like breast cancer were analysed. The samples came from peripheral blood, the primary tumour, a brain metastasis and a xenograft derived from the primary tumour. The findings indicate that cells with a distinct subset of the primary tumour mutation might be selected during metastasis and xenografting.

Connecting genomics and proteomics allows the development of more efficient and specific treatments for cancer. Here, the authors develop proteogenomic methods to defining cancer signaling in-vivo starting from core needle biopsies and with application to a HER2 breast cancer focused clinical trial.

A region on chromosome 19p13 is associated with the risk of developing ovarian and breast cancer. Here, the authors genotyped SNPs in this region in thousands of breast and ovarian cancer patients and identified SNPs associated with three genes, which were analysed with functional studies.

Whole-genome analysis of oestrogen-receptor-positive tumours in patients treated with aromatase inhibitors show that distinct phenotypes are associated with specific patterns of somatic mutations; however, most recurrent mutations are relatively infrequent so prospective clinical trials will require comprehensive sequencing and large study populations.

Aberrant thymocyte developmental programming results when interactions between thymic stroma and pre-T cell receptors occur in the absence of major histocompatibility complex bound to antigen peptide.

Severe febrile illnesses in children may be various in presentation and aetiology but involve immune dysfunction amenable to immunomodulation. Here, the authors identify shared neutrophil and T cell dysfunction and a distinct interferon signature in critically ill children with severe febrile illness.

Is there a precise end point that could enable us to compare neoadjuvant and adjuvant endocrine therapy outcomes? A reliable short-term surrogate to assess the potential of endocrine drugs in the adjuvant setting? In this Review, Goncalves et al. summarize the studies in which the proliferation marker Ki 67, measured during neoadjuvant treatment, has predicted accurately and consistently the results of much larger studies in the adjuvant setting.

A significant proportion of individuals with inherited neuromuscular disease do not receive a genetic diagnosis. Here, the authors establish CCG expansions in the 5’ untranslated region of ABCD3 as a cause of oculopharyngodistal myopathy (OPDM) in individuals of European ancestry and identify increased expression of expansion-containing ABCD3 transcripts as a possible disease mechanism underlying muscle degeneration.

Whole-genome sequencing of liver microdissections from five healthy individuals and nine with cirrhosis demonstrates the effects of liver disease on the genome, including increased rates of mutation, complex structural variation and different mutational signatures.

Expression of Cas9 and gRNA from viral vectors in vivo may cause off-target activity. Here the authors present NanoMEDIC, which uses nanovesicles to transiently deliver editing machinery to hard-to-transfect cells.

Upstream open reading frames (uORFs), located in 5’ untranslated regions, are regulators of downstream protein translation. Here, Whiffin et al. use the genomes of 15,708 individuals in the Genome Aggregation Database (gnomAD) to systematically assess the deleteriousness of variants creating or disrupting uORFs.

The One Thousand Plant Transcriptomes Initiative provides a robust phylogenomic framework for examining green plant evolution that comprises the transcriptomes and genomes of diverse species of green plants.

Developmental disorders (DDs) are more prevalent in males, thought to be due to X-linked genetic variation. Here, the authors investigate the burden of X-linked coding variants in 11,044 DD patients, showing that this contributes to ~6% of both male and female cases and therefore does not solely explain male bias in DDs.

Analyses of epigenomic datasets spanning transitions from normal prostate epithelium to localized prostate cancer to metastases show that latent developmental programs are reactivated in metastatic disease and that prostate lineage-specific regulatory elements are strongly enriched for prostate cancer risk heritability.

Multi-nucleotide variants (MNV) are genetic variants in close proximity of each other on the same haplotype whose functional impact is difficult to predict if they reside in the same codon. Here, Wang et al. use the gnomAD dataset to assemble a catalogue of MNVs and estimate their global mutation rate.

Low read depth sequencing of whole genomes and high read depth exomes of nearly 10,000 extensively phenotyped individuals are combined to help characterize novel sequence variants, generate a highly accurate imputation reference panel and identify novel alleles associated with lipid-related traits; in addition to describing population structure and providing functional annotation of rare and low-frequency variants the authors use the data to estimate the benefits of sequencing for association studies.

Vaccination is effective in protecting from COVID-19. Here the authors report immune responses and breakthrough infections in twice-vaccinated patients receiving anti-TNF treatments for inflammatory bowel disease, and find dampened vaccine responses that implicate the need of adapted vaccination schedules for these patients.

SMARCB1 is frequently lost in solid cancer and reported to support tumourigenesis through STAT3 activation. Here, the authors show in several preclinical models that targeting IL6/JAK/STAT3 molecular pathway is a potential therapeutic approach for SMARCB1-deficient bladder cancer.

By integrating healthcare and exome-sequencing data from parent–offspring trios of patients with developmental disorders, 28 genes that had not previously been associated with developmental disorders were identified.

An insertion of an Alu element into an intron of the TBXT gene is identified as a genetic mechanism of tail-loss evolution in humans and apes, with implications for human health today.

Development of comprehensive structure–activity relationships for coronatine has been a major goal in the agrochemical industry. Here, the authors report the gram-scale production and structure–activity relationship of parent coronafacic acid and ultimately rationalise the biological activity of analogues of this phytotoxin.

The spatiotemporal activation of phagocytosis by hair follicle cells is orchestrated by lipids released from surrounding apoptotic cells and retinoids released by healthy cells.

Baksh et al. show that oncogenic epidermal stem cells require extracellular serine to initiate squamous cell carcinoma via altering dioxygenases that remove H3K27me3.

Sarcomatoid and rhabdoid tumours are highly aggressive forms of renal cell carcinoma that are also responsive to immunotherapy. In this study, the authors perform a comprehensive molecular characterization of these tumours discovering an enrichment of specific alterations and an inflamed phenotype.

The molecular processes that lead to neuroendocrine prostate cancer after treating prostate adenocarcinoma (PRAD) are not well understood. Here the authors show that regulation by FOXA1 and changes in the epigenomic profile drive the transition from PRAD to a neuroendocrine phenotype.

The SARS-CoV-2 Alpha variant suppresses innate immune responses more effectively than isolates of first-wave SARS-CoV-2, and this is a result of mutations outside of the spike coding region that lead to upregulation of viral innate immune antagonists.

In this largest whole-exome sequencing study of epilepsies to date, the Epi25 Collaborative identified extremely rare variants that confer risk for diverse epilepsy subtypes, highlighting roles in synaptic transmission and neuronal excitability.

A strategy to improve the implementation of nature-based climate solutions in global forests for climate mitigation is described, comprising four key components to highlight notable science and policy considerations and providing solutions to improve rigour.

This Review discusses the mechanisms underlying resistance to aromatase inhibitor (AI) therapy of patients with oestrogen receptor-positive (ER⁺) breast cancer, and also assesses the possible therapeutic options for overcoming AI resistance.

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.

Malignant rhabdoid tumours (MRT) have been suggested to originate in the ectoderm-derived neural crest. Here, the authors analyse MRTs using phylogenetics, scRNA-seq, and patient-derived organoids; they find evidence for an MRT origin in the neural crest lineage and suggest differentiation treatment with HDAC/mTOR inhibitors.

A consortium reports the tripling of the number of genetic markers in Phase II of the International HapMap Project. This map of human genetic variation will continue to revolutionize discovery of susceptibility loci in common genetic diseases, and study of genes under selection in humans.