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When 100 social and behavioural science claims were examined, 34% of reanalyses closely matched the original results, with 74% reaching the same conclusion, revealing limited robustness of single-path analyses and the need to address analytical uncertainty.

Natural product–inspired compounds are primed to interact with and manipulate biological processes, but obtaining these complex molecules poses synthetic challenges. The development of a 12-step, 1-pot cascade reaction leads to the 'centrocountins', tetrahydroindoloquinolizines that modulate mitosis by targeting the centrosome-associated proteins nucleophosmin and Crm1.

Endothelial-to-mesenchymal transition contributes to plaque progression in atherosclerosis. Here, Ayllon et al. show that the protein TWIST1 drives endothelial cell plasticity in atherosclerosis, promoting plaque growth and stability while reducing features linked to rupture, challenging the view that these cell changes always worsen disease.

How inflammation spreads from the skin to the joints in psoriatic disease is unclear. Here, the authors show that joint-resident fibroblasts can control differentiation of infiltrating skin-derived myeloid precursors that can become inflammatory macrophages.

T cells contribute to protection and pathogenesis in tuberculosis. Here the authors sequence T cell receptor repertoires in human skin biopsies from the site of the tuberculin skin test and show enrichment of clonotypes reactive to Mycobacterium tuberculosis using a computational pipeline metaclonotypist to identify distinct TCRs predicted to share peptide-MHC reactivity across participants, as an approach to explore T cell correlates of tuberculosis disease-risk stratification and vaccine efficacy.

Replicating the seminal reactions of transition metals with p-block species is often very challenging. Here, the authors present a step-for-step main-group replica of the historical Fischer carbene synthesis, providing bora-Fischer carbene species.

Familial adenomatous polyposis (FAP) is an inherited gastrointestinal syndrome associated with duodenal adenoma formation. Here the authors show that IL17A-producing NKp44- group 3 innate lymphoid cells accumulate in FAP duodenal tissue and are associated with duodenal adenoma formation in patients with FAP.

During SARS-CoV-2 infection caspase-8 fuels harmful inflammation independent of apoptosis. Genetic loss of caspase-8 reduces cytokine levels, lowers viral load and mitigates disease severity, revealing non-apoptotic caspase-8 as a key driver of severe COVID-19.

Across biological subdisciplines, the last decade has seen an explosion of high-dimensional datasets. At the ICTS workshop ‘Unifying Theories in High-Dimensional Biophysics’, we discussed whether this high dimensionality poses a challenge or an opportunity for theoretically describing, understanding and predicting biological systems. We discussed methods, models and frameworks that can be used for this purpose. This Comment summarizes our discussions from the perspectives of individual participants.

Deep Visual Proteomics combines machine learning, automated image analysis and single-cell proteomics.

Human endogenous retroviruses (HERV) normally remain quiescent, but can be reactivated by malignant transformation. Here the authors find, via HERV peptide library testing and tetramer validation, more profound HERV transcription and associated T cell recognition in myeloid cancer patients to implicate HERVs as potential therapeutic targets.

Truncated version of adenylyl cyclase 3 acts as a cold-induced rheostat during long-term brown adipose tissue activation.

How cancer cells engage the microenvironment to establish metastasis is poorly understood. Here, the authors show that CXCR3-expressing breast cancer cells secrete IL-1 to induce a paracrine crosstalk with fibroblasts in the lung, which involves CXCL9/10 production and results in colonization of the lung.

How translation of M-phase promoting factors is blocked in immature oocytes is poorly understood. Here, the authors show 4E-T suppresses cyclin-B and c-Mos translation, preventing oocytes from maturing spontaneously without hormonal stimulation.

Centromeres ensure chromosome segregation. Analyzed sister species with distinct centromere types show that kinetochore mutations, histone modifications, and centromeric DNA amplification underlie the process of mono- to holocentromere evolution.

An integrated high-resolution genetic, physical and shotgun sequence assembly of the barley genome, one of the earliest domesticated and most important crops, is described; it will provide a platform for genome-assisted research and future crop improvement.

What is the state of trust in scientists around the world? To answer this question, the authors surveyed 71,922 respondents in 68 countries and found that trust in scientists is moderately high.

Krisai et al. compare brain structure and cognitive function in elderly patients with and without atrial fibrillation using brain MRI and cognitive testing. They find that atrial fibrillation is associated with more brain lesions and lower cognitive function, but the cognitive impairment occurs primarily through direct effects of the arrhythmia rather than through brain damage.

Here the authors reveal that high-sensitive nascent transcript sequencing provides an extended high-resolution view on transcription, including lowly transcribed enhancers. Widespread transcription at enhancers and their target genes depends on the BET family protein BRD4.

For printed electronics to realize its potential as a sustainable ubiquitous technology, eco-friendly solvents that deliver excellent ink performance must be found. Here, the authors report a free online tool that identifies functional green solvents for solution-processed printed electronics.

Tethering proteins, known to mediate initial recognition and attachment during membrane fusion, are essential for driving the transition from the hemifused state to fusion pore formation.

Single-nucleus transcriptomes of frontal cortex and choroid plexus samples from patients with COVID-19 reveal pathological cell states that are similar to those associated with human neurodegenerative diseases and chronic brain disorders.

How cyclins contribute to CDK1 substrate specificity during cell division is poorly understood. Here, the authors show that a phosphate-binding pocket in cyclin B1 is critical for accurate CDK1 substrate phosphorylation ensuring mitotic fidelity.

Here the authors use positron emission tomography to visualize fibroblasts in patients with arthritis and combined with spatial transcriptomic data show that these cells undergo a phenotypic shift upon resolution of inflammation. A CD200⁺DKK3⁺ fibroblast subset promotes this resolution by inhibiting tumor necrosis factor and interleukin-17A.

A global network of researchers was formed to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity; this paper reports 13 genome-wide significant loci and potentially actionable mechanisms in response to infection.

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.

Retromer complex cooperates with Vps5 and Vps17 in yeast to traffic transmembrane proteins. Here, the authors present structural and functional studies that reveal the mechanism of Retromer and Vps5 interaction.

Citizen science taps the efforts of non-experts. Here, authors describe Drugit, an extension of the crowdsourcing game Foldit, and its use in designing a non-peptide binder of Von Hippel Lindau E3 ligase for use with proteolysis targeting chimeras.

The “anti-branching rule”, introduced in 1950, excludes branched polyphosphates from biological relevance due to their supposedly rapid hydrolysis. Here, the authors synthesize monodisperse branched polyphosphates and demonstrate their unexpected stability in water, as well as provide evidence for their competence in phosphorylation.

Optimizing COVID-19 vaccination strategies for patients under immunosuppressive medication is of high importance. In this clinical trial including non-seroconverted immunosuppressed patients, a homologous mRNA booster vaccination resulted in higher seroconversion rate than a switch to a vector-based vaccine.

A study describes the assembly and analysis of a haplotype-resolved pangenome of bulbous barley with the potential to improve domesticated barley and illustrates its use in evolutionary research and trait mapping.

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.

There’s an emerging body of evidence to show how biological sex impacts cancer incidence, treatment and underlying biology. Here, using a large pan-cancer dataset, the authors further highlight how sex differences shape the cancer genome.

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.

In somatic cells the mechanisms maintaining the chromosome ends are normally inactivated; however, cancer cells can re-activate these pathways to support continuous growth. Here, the authors characterize the telomeric landscapes across tumour types and identify genomic alterations associated with different telomere maintenance mechanisms.

With the generation of large pan-cancer whole-exome and whole-genome sequencing projects, a question remains about how comparable these datasets are. Here, using The Cancer Genome Atlas samples analysed as part of the Pan-Cancer Analysis of Whole Genomes project, the authors explore the concordance of mutations called by whole exome sequencing and whole genome sequencing techniques.

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.

Whole-genome sequencing data from more than 2,500 cancers of 38 tumour types reveal 16 signatures that can be used to classify somatic structural variants, highlighting the diversity of genomic rearrangements in cancer.

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.

A human SARS-CoV-2 challenge study in individuals without previous exposure to the virus or vaccines provides detailed profiles of local and systemic epithelial and immune cell response dynamics over time and infection status.

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.