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IFT-A proteins and Kinesin-2 modulate canonical Wnt/Wg-signalling independent of their ciliary role, but how is unclear. Here, the authors show that Kinesin-2 and IFT-A act as a complex to promote nuclear translocation of β-catenin in Drosophila and mouse MEF Wnt signalling independent of its ciliary role.

A shallow slow-slip source region has laterally variable elastic properties and pore pressure, and near-velocity-neutral frictional properties, according to seismic imaging of part of the Hikurangi subduction margin and data-constrained modelling.

The induction of broadly neutralizing antibodies (bNAbs) is a goal of HIV-1 vaccine research. Here the authors demonstrate the ability of an HIV Env-derived immunogen to bind germline precursors of a class of bNAbs and to activate the corresponding B cells in a knock-in mouse model

Approximately 30% of psoriasis patients develop psoriatic arthritis (PsA) and early diagnosis is crucial for the management of PsA. Here, Patrick et al. develop a computational pipeline involving statistical and machine-learning methods that can assess the risk of progression to PsA based on genetic markers.

Mutagenic lesions such as those that give rise to cancer frequently segregate—unrepaired—during cell division, resulting in phasing of multiple alleles across generations of daughter cells and consequent tumour heterogeneity.

Osteoarthritis (OA) is associated with cartilage degeneration, and no effective therapy exists. Here, the authors show that the HPIP protein modulates OA progression by regulating Wnt signaling, and that its knockdown in joints via AAV-mediated gene silencing attentuates pathology.

The authors assess the growing field of climate change health impact attribution. They show literature bias towards direct heat effects and extreme weather in high-income countries, highlighting the lack of global representation in current efforts.

Inhibitors of CDK8 enhance IL-10 production during innate immune activation in human and mouse primary macrophages and dendritic cells via diminished phosphorylation of the c-Jun subunit of the AP-1 transcription regulatory complex.

Genome-wide data from ancient and modern individuals in Remote Oceania indicate population replacement but language continuity over the past 2,500 years. Papuan migrations led to almost complete genetic replacement of in situ East Asian-derived populations, but not replacement of Austronesian languages.

EZH2 and EED are components of the Polycomb repressive complex 2 (PRC2), a ‘writer’ complex involved in histone methylation. A stapled peptide that disrupts the EZH2-EED interaction arrests growth in PRC2-dependent leukemia cells and offers an alternative mode for EZH2 inhibition.

There is high prevalence of whole genome duplication (WGD) in high grade serous ovarian cancer. Here, the authors compare tumours with and without WGD and find that those that acquired WGD early during tumour evolution are associated with worse survival and have the lowest expression of MHC-II.

Whole-genome sequence analysis identifies five independent risk loci for Lewy body dementia and demonstrates overlapping genetic architecture with Alzheimer’s and Parkinson’s diseases.

Matthew Meyerson, Ramaswamy Govindan and colleagues examine the exome sequences and copy number profiles of 660 lung adenocarcinoma and 484 lung squamous cell carcinoma tumors. They identify novel significantly mutated genes and amplification peaks and find that around half of the tumors have at least five predicted neoepitopes.

Habituation is a learning mechanism that enables control over forgetting and learning. Zuo, Panda et al., demonstrate adaptive synaptic plasticity in SmNiO₃ perovskites to address catastrophic forgetting in a dynamic learning environment via hydrogen-induced electron localization.

The authors show that chronic neonatal hypoxia reduces GABA_A receptor–mediated signaling to oligodendrocyte precursor cells in the cerebellar white matter and enhances their proliferation, delays oligodendrocyte maturation and disrupts myelination. Following hypoxia, treatment with a GABA uptake blocker restores myelination.

The HPN-DREAM community challenge assessed the ability of computational methods to infer causal molecular networks, focusing specifically on the task of inferring causal protein signaling networks in cancer cell lines.

A selective, short-acting agonist for the sphingosine-1-phosphate receptor S1P₁ and GFP-S1P₁ knock-in mouse model are used to show that both receptor degradation and receptor reserve underlie the mechanisms of lymphocyte sequestration by agonists.

Huntington's disease is a neurodegenerative disorder associated with glutamate receptor dysfunction. Now Isabel Pérez-Otaño and colleagues report that the HTT protein that aggregates in the brains of individuals with the disease disrupts the ability of the adaptor protein PACSIN1 to keep the glutamate receptor subunit GluN3A away from the surface of neurons.

MSK-IMPACT is a clinical sequencing platform able to detect genomic mutations, copy number alterations and structural variants in a panel of cancer-related genes. This assay is implemented prospectively to inform patient enrollment in genomically matched clinical trials at Memorial Sloan Kettering Cancer Center (MSKCC). Sequencing results of tumor and matched normal tissue from a cohort of >10,000 patients with detailed clinical annotation provide an overview of the genomic landscape of advanced solid cancers and bring new insights into molecularly guided cancer therapy.

Kevin Brown and colleagues functionally characterize a melanoma risk locus encompassing PARP1, correlating the risk genotype to PARP1 gene expression levels in melanoma cells. They identify an intronic gene-regulatory variant in PARP1 and find that PARP1 can promote cell proliferation and rescue oncogene-induced senescence, likely through MITF.

Aminoadamantane compounds, delivered to cells via binding to viroporin channels, induce S-nitrosylation of the ACE2 protein, inhibiting binding to SARS-CoV-2 spike protein and viral infection.

TRACERx Lung: Intratumoral transcriptional heterogeneity, which often hinders the development of clinically useful RNA-expression-biased biomarkers for cancer, can now be overcome with an approach for the identification of clonal expression biomarkers.

Individuals over eighty years of age are less likely to mount a good immune response against SARS-CoV-2 (measured by neutralization titres) after the first dose of the BNT162b2 mRNA vaccine, but achieve good neutralization after the second dose.

Charles Mullighan, Stephen Hunger, Jinghui Zhang and colleagues report a genomic analysis of 264 pediatric and young adult T-lineage acute lymphoblastic leukemia (T-ALL) samples. They identify 106 candidate driver genes, 53 of which have not been described previously in pediatric T-ALL, as well as associations between mutations and disease stage or subtype.

Biophysical analyses based on the crystal structure of PHD2 in complex with HIF2α peptide show that the strength of the interaction between Pacak-Zhuang syndrome-causing HIF2α mutants and PHD2 correlates with disease severity.

Vaccines for SARS-COV-2 are needed in the ongoing pandemic. Here the authors characterize a vaccine candidate that presents the receptor-binding domain (RBD) of SARS-CoV-2 spike protein on a synthetic VLP platform using SpyTag/SpyCatcher technology and show immunogenicity of a prime-boost regimen in mice and pigs.

This analysis presents the results of a community-based evaluation of existing software for large-scale glycopeptide data analysis.

Charles Swanton and colleagues used multiregion exome sequencing to study the evolutionary histories of ten clear cell renal cell carcinomas. They observed marked intratumoral heterogeneity in all cases, with extensive evidence of parallel evolution of tumor subclones and only a small number of truncal driver events.

Evan Eichler and colleagues present a detailed characterization of the chromosome 15q13.3 microdeletion region. They identify complex structural polymorphisms and find that the rearrangement breakpoints cluster in palindromic GOLGA8 core duplicons, providing evidence that this repeat and its palindromic architecture underlie the evolutionary and disease-related instability of this region.

Host defense to bacterial infection and pulmonary inflammation is regulated by a circadian clock within lung epithelial cells and glucocorticoids.

Two genes controlling the transcriptional network involved in stomatal development in Arabidopsis thaliana have a conserved function in the non-vascular moss Physcomitrella patens. Moss mutants without stomata show delayed capsule dehiscence.

Endurance athletes and sedentary type 2 diabetes patients swapped their lifestyle for 8 weeks. Athletes store and utilise saturated fat intensely for performant physical activity, and type 2 diabetes patients reversed their dysmetabolic lipid state after endurance training.

The FANTOM4 study identified transcriptional start sites active during proliferation arrest and differentiation of the human monocytic cell line THP-1. Systematic knockdown of 52 transcription factors provide support for their model in which a complex transcriptional network regulates the differentiation process.

Mammalian cochlea inner hair cells (IHCs) can code a continuous grading of sound intensities. This is because neurotransmitter release at mature sensory ribbon synapses is linearly dependent on calcium influx, which has the effect of broadening the cells' dynamic range. Immature IHC neurotransmitter release is quite different. Here, the authors show that a switch from syanptogamin I and II to synaptogamin IV underlies this developmental change.

Telomere shortening, senescence and aging are connected, but how the signal at shortening telomeres is transmitted to the cell more globally is unclear. H3 and H4 synthesis is now shown to be reduced as cell cultures age. This alters expression of Asf1, a histone chaperone, compromising the ability of aging cells to restore chromatin after replication and DNA. In this way localized effects at shortening telomeres can be propagated throughout the cell.

Glaucoma is the most common cause of irreversible blindness worldwide. Here, the authors carry out a large meta-analysis of genetic data from individuals of European and Asian ancestry and identify 10 new loci associated with vertical cup-disc ratio, a key factor in the clinical assessment of patients with glaucoma.

Saliency maps have been proposed to guide visual attention, yet the underlying neural correlates remain undetermined. Here, the authors record from monkeys as they watch videos of natural scenes, and find superior colliculus superficial visual-layer neurons exhibit activity patterns consistent with a visual saliency map.

Analysis of data from over 400,000 UK Biobank participants shows that eGFR measured by cystatin C, but not serum creatinine, is strongly associated with cardiovascular disease outcomes and mortality.

The CTCF paralogue BORIS is upregulated in transcriptionally reprogrammed neuroblastoma cells rendered resistant to targeted therapy, in which it promotes regulatory chromatin interactions that maintain the resistance phenotype.

Tin Aung, Christopher Hammond and colleagues report the results of a large genome-wide association study of intraocular pressure. They identify four new loci associated with this trait and show that three of these loci are associated with risk of primary open-angle glaucoma.

Type 2 immune responses are often associated with the expression of chitinase-like Ym proteins, but their role is unclear. Allen and colleagues show that Ym1 and Ym2 act on γδ T cells to increase their expression of IL-17A and enhance the recruitment of neutrophils.

Circulating tumor cells from patients with small-cell lung cancer can form tumors in mice, and their derived explants recapitulate the patients' response to chemotherapy.

In this Resource article, the authors integrate genomic, bioinformatic and flow cytometric data from human bone marrow to provide an atlas of hematopoietic progenitor cell states in health and disease.

Cell-based and molecular exploration provide comparative characterization of currently developed PI3K inhibitors and structural insights for future inhibitor design.