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Random mutagenesis can uncover novel genes involved in phenotypic traits. Here the authors perform a large-scale phenotypic screen on over 100 mouse strains generated by ENU mutagenesis to identify mice with age-related diseases, which they attribute to specific mutations revealed by whole-genome sequencing.

The tumor suppressor p53 is the guardian of the genome. Here, the authors use comprehensive approaches to demonstrate that transient p53 activity induces revival stem cells to promote the regeneration of severely irradiated intestinal epithelium in mice.

Faced with an economic crisis as large and rapid as that precipitated by the COVID-19 pandemic, economists have turned to new ‘fast indicators’ based on big data, as Andy Haldane and Shiv Chowla of the Bank of England explain.

A study of the evolution of the SARS-CoV-2 virus in England between September 2020 and June 2021 finds that interventions capable of containing previous variants were insufficient to stop the more transmissible Alpha and Delta variants.

Opioids modulate pain, anxiety and stress by activating four subtypes of opioid receptors. The authors show that atypical chemokine receptor 3 (ACKR3) is a scavenger for various endogenous opioid peptides regulating their availability without activating downstream signaling.

The mechanisms that control the presynaptic abundance of GABAB receptors (GBRs) remains unclear. This study shows that sequence-related epitopes in APP, AJAP-1 and PIANP bind with nanomolar affinities to the N-terminal sushi-domain of presynaptic GBRs, and that selective loss of APP impaired GBR-mediated presynaptic inhibition and axonal GBR expression

Gao, Nowak-Imialek, Chen et al. generate porcine and human stem cells that possess expanded developmental potency for both embryonic and extra-embryonic cell lineages.

Penetrance of variants in monogenic disease and clinical utility of common polygenic variation has not been well explored on a large-scale. Here, the authors use exome sequencing data from 77,184 individuals to generate penetrance estimates and assess the utility of polygenic variation in risk prediction of monogenic variants.

An integrative genomic analysis of several hundred endometrial carcinomas shows that a minority of tumour samples carry copy number alterations or TP53 mutations and many contain key cancer-related gene mutations, such as those involved in canonical pathways and chromatin remodelling; a reclassification of endometrial tumours into four distinct types is proposed, which may have an effect on patient treatment regimes.

Elevated atmospheric CO₂ during the Palaeocene–Eocene Thermal Maximum coincided with substantial declines in the pH and carbonate saturation state of the ocean.

Warming-enhanced microbial respiration can explain marine anoxia patterns across depth, a key driver of the end-Permian mass extinction, according to biogeochemical modelling and geochemical proxy records.

High-affinity and isotype-switched antibodies arise from germinal center reactions. Goodnow and colleagues identify the Rho guanine nucleotide–exchange factor DOCK8 as being essential for sustained B cell immune synapse formation in germinal centers and mature antibody responses.

Compound climate events such as floods and droughts together can cause severe socio-economic impacts. Here, the authors analyse global hazard pairs from 1980–2014 and find global hotspots for the occurrence of compound events.

Here, the authors describe the global distribution of crAssphage, its presence in Old-World and New-World primates, and its association with gut bacterial communities and dietary factors, providing insights into the origin, evolution and epidemiology of human gut crAssphage.

Major depressive disorder is a major public health problem. Here, the authors illustrate that mesenchymal stromal cells exert antidepressant and anxiolytic effects through a pulmonary vagal→ nucleus tractus solitarius → 5-HT dorsal raphe nucleus neural pathway in murine depression models.

RNA sequencing data and tumour pathology observations of non-small-cell lung cancers indicate that the immune cell microenvironment exerts strong evolutionary selection pressures that shape the immune-evasion capacity of tumours.

A hypothesis for the permanent isolation of Britain from mainland Europe during interglacial high sea levels has been confirmed. Gupta et al. analysed a new regional bathymetric map of part of the area, finding a valley with landforms indicating large-scale subaerial erosion by high-magnitude water discharges. They suggest breaching of a rock dam at the Dover Strait instigated drainage of a large lake in the North Sea basin.

New fungicides are needed due to emerging resistance shown by crop pathogens. Here, the authors show that a mono-alkyl lipophilic cation protects plants from fungal pathogens by inhibiting fungal mitochondrial respiration, inducing production of reactive oxygen species, triggering fungal apoptosis, and activating innate plant defense.

Nail-patella syndrome (NPS) is characterized by nail dysplasia, absent/hypoplastic patellae, chronic kidney disease, and glaucoma and can be caused by haploinsufficiency of LMX1B; however, not all patients harbor pathogenic LMX1B mutations. Here the authors show that loss-of-function variations in upstream enhancer sequences are responsible for a limb specific form of human NPS.

The molecular mechanisms that underpin thymocyte selection remain incompletely defined. Groups led by Love, Gascoigne and Schwartz independently identify Themis, a signaling protein essential for the positive selection of thymocytes.

Cortical thickness is asymmetric, and cortical thinning occurs with age and in disease. Here the authors investigate if both cortices thin at the same rate or if the thicker hemisphere declines faster in aging and in Alzheimer’s disease.

Gilean McVean and colleagues report the results of a large-scale clinical genome sequencing project spanning a broad spectrum of disorders. They identify factors influencing successful genetic diagnosis and highlight the challenges of interpreting findings for genetically heterogeneous disorders.

A detailed reconstruction of the calcium carbonate compensation depth—at which calcium carbonate is dissolved—in the equatorial Pacific Ocean over the past 53 million years shows that it tracks ocean cooling, increasing as the ocean cools.

Whole-genome sequencing analysis of individuals with primary immunodeficiency identifies new candidate disease-associated genes and shows how the interplay between genetic variants can explain the variable penetrance and complexity of the disease.

A massive compliation of molecular data to shows that not only did mammalian evolution have deep roots, but that the extant Orders of mammals did not become established until many millions of years after the dinosaurs had headed for their last round-up. In other words, the great end-Creatceous mass extinction had relatively little effect on mammal evolution.

Soil-transmitted helminths (STHs) are major pathogens. Here the authors screen 480 structural families of natural products to find compounds that kill Caenorhabditis elegans specifically when they require rhodoquinone (RQ)-dependent metabolism: they identify several classes of compounds and show some compounds kill adult STHs.

A multi-cohort genome-wide association study of tau PET, a brain imaging-based marker of Alzheimer’s disease, identifies a CYP1B1-RMDN2 locus as associated with higher tau and faster cognitive decline. These results suggest a new genetic contribution to cerebral tau and target for Alzheimer’s disease research.

Tightly regulated promoters with strong inducibility and scalability are highly desirable for biological applications. Here the authors describe ‘Jungle Express’, a EilR repressor-based broad host system activated by cationic dyes.

The Greenland Ice Sheet is the largest land ice contributor to sea level rise and understanding the long-term glacier response to external forcing is key to improved projections. Here the authors show Greenland’s three largest outlet glaciers will likely exceed current worst-case scenario

Most of the archaeological record of the Middle to Later Stone Age transition comes from southern Africa. Here, Shipton et al. describe the new site Panga ya Saidi on the coast of Kenya that covers the last 78,000 years and shows gradual cultural and technological change in the Late Pleistocene.

Wansheng Jiang studies the endangered Chinese giant salamander to better protect its habitat.

The Paleocene–Eocene boundary coincided with runaway global warming possibly analogous to future climate change, but the sources of greenhouse gasses have remained unresolved. Here, the authors reveal volcanism triggered initial warming, and subsequent carbon was released after crossing a tipping point.

“Protein relocalisation plays a major role in the innate immune response but remains incompletely characterised. Here, the authors combine temporal proteomics with LOPIT, a spatial proteomic workflow, in a fully Bayesian framework to elucidate spatiotemporal proteomic changes during the LPS-induced immune response in THP-1 cells.

Cross-linking mass spectrometry (XLMS) allows mapping of protein-protein and protein-RNA interactions, but the analysis of protein-DNA complexes remains challenging. Here, the authors develop a UV light-based XLMS workflow to determine protein-DNA interfaces in reconstituted chromatin and isolated nuclei.

Understanding the genetics and physiology of domesticated species is important for crop improvement. By studying natural variation and the phenotypic traits of 413 diverse accessions of rice, Zhao et al. identify many common genetic variants that influence quantitative traits such as seed size and flowering time.

Shi et al. present a hybrid dependency map based on machine-learning analysis of gene essentiality data from the DEPMAP database, translated to data from TCGA. This application can be used to visualize other gene essentiality data.

Naturally acquired antibodies may inhibit Plasmodium survival in mosquitoes, alter malaria transmission dynamics, and form the basis for transmission-blocking vaccines. Here, using sera from malaria-exposed individuals, Stone et al. reveal novel antibody correlates of transmission-reducing activity.

Malaria transmission is effected by intra-erythrocytic parasites that commit to sexual development and form gametocytes. Here, the authors show that early reticulocytes in the major sites of haematopoiesis establish a cryptic asexual cycle; this cycle is characterised by early preferential commitment to gametocytogenesis, which initiates malaria transmission and drug resistance.

A genome-wide association study of critically ill patients with COVID-19 identifies genetic signals that relate to important host antiviral defence mechanisms and mediators of inflammatory organ damage that may be targeted by repurposing drug treatments.

Many researchers support open science, but how can they translate this view into behaviours to boost sharing?

Netie, a hierarchical Bayesian model to infer the neoantigen evolution and immune selection pressure during tumor progression.

A single-cell transcriptomic analysis of 63 patients with colorectal cancer classifies tumor cells into two epithelial subtypes. An improved tumor classification based on epithelial subtype, microsatellite stability and fibrosis reveals differences in pathway activation and metastasis.

Urban development in China has led to cropland loss and displacement over the past decades. This study uses a model-based approach to estimate spatial flows of grain, disaggregated by transport modal choices and routes, to explore the increase in carbon emission associated with the transport of cereals, tubers and soybean in China over 1990–2015.

Microfluidic chain reactions encode programs structurally in situ, and can form a frugal, versatile, bona fide lab-on-a-chip with wide-ranging applications in liquid handling and point-of-care diagnostics

Ionizing radiation may induce irreparable DNA damage leading to cancer. Here, the authors identify a specific signature of mutations arising in patients exposed to ionizing radiation and suggest that radiation-induced tumorigenesis is associated with higher rates of genome-wide deletions and balanced inversions.

Chronic infection with SARS-CoV-2 leads to the emergence of viral variants that show reduced susceptibility to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma.

Triple-negative breast cancers (TNBCs) tend to have poor prognosis; however, the mechanisms underlying TNBC pathology are not well understood. Here the authors utilize epidemiologic data and animal models to demonstrate an important role for BCL11A in the genesis and propagation of TNBCs.

Sera from vaccinated individuals and some monoclonal antibodies show a modest reduction in neutralizing activity against the B.1.1.7 variant of SARS-CoV-2; but the E484K substitution leads to a considerable loss of neutralizing activity.