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The 3CL protease of SARS-CoV-2 is inhibited by PF-00835231 in vitro. Here, the authors show that the prodrug PF-07304814 has broad spectrum activity, inhibiting SARS-CoV and SARS-CoV-2 in mice and its ADME and safety profile support clinical development.

Activated G protein–coupled receptors promote GDP release by their cognate G proteins, through an allosteric mechanism that remains to be fully determined. Now DEER analyses are integrated with previously available structural data and computational work, thus generating a unified model for receptor-mediated G-protein activation.

A systematic census at 1,636 sites around Australia from 2008 to 2021 finds that more than 30% of shallow invertebrate species in cool latitudes exhibit a high extinction risk due to declining populations and oceanic barriers, but tropical coral species remain relatively stable.

Identification of selective and effective anti-leishmanial compounds with potent in vitro and in vivo activity making them promising candidates for future drug development.

Here the authors investigate lipid nanodiscs as drug carriers for antitumour immunotherapy. They demonstrate that flexible lipid nanodiscs functionalized with STING-activating cyclic dinucleotides exhibit superior tumour penetration and tumour cell uptake compared with spherical liposomes, resulting in improved antitumour T-cell priming and tumour regression.

2-oxoglutarate links mitochondrial metabolism to oxygen sensing, gene transcription and epigenetic modifications. Here, the authors describe a mutagenesis screen to find genes that control 2-oxoglutarate levels, and identify ABHD11 as a mitochondrial regulator of 2-oxoglutarate abundance.

The characterization of 4,645 whole-genome and 19,184 exome sequences, covering most types of cancer, identifies 81 single-base substitution, doublet-base substitution and small-insertion-and-deletion mutational signatures, providing a systematic overview of the mutational processes that contribute to cancer development.

Here the authors conduct a multi-ancestry meta-analysis of telomere length, used diverse approaches to identify genes underlying association signals, and experimentally validated POP5 and KBTBD6 as regulators of telomere length in human cells.

Sun et al. report human lifespan changes in the brain’s functional connectome in 33,250 individuals, which highlights critical growth milestones and distinct maturation patterns and offers a normative reference for development, aging and diseases.

PRDM9 is a PR domain containing histone methyl transferase which expression is normally restricted to the germline that has also been linked to a number of somatic cancers. Here the authors describe the identification of a small molecule that selectivity inhibits the methyltransferase activity of PRDM9 in biochemical and cellular assays

In this study, the authors provide a global overview of SARS-CoV-2 genome sequencing, and estimate the proportion of cases sequenced and time to genome upload. They identify disparities and highlight the need to strengthen surveillance in lower and middle income countries.

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.

A cross-ancestry meta-analysis of genome-wide association studies identifies association signals for stroke and its subtypes at 89 (61 new) independent loci, reveals putative causal genes, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as potential drug targets, and provides cross-ancestry integrative risk prediction.

Pak et al. show that prolonged fasting is required for the effects of calorie restriction on insulin sensitivity, fuel utilization and ageing in mice.

Multi-omics profiling of 45 human lung samples highlights 80 different cell types along the proximal to distal axis of the lung with certain cell types showing enrichment for disease-associated genes. An immune niche for IgA-expressing plasma cells within airway submucosal glands (SMG) is also identified.

The ER chaperone BiP is regulated by FICD-mediated AMPylation and deAMPylation. Here, the authors characterise the structure of mammalian AMPylated BiP bound to FICD, by X-ray crystallography and neutron scattering, providing insights into the mechanism of BiP AMPylation and deAMPylation.

Openshaw and colleagues find myeloid inflammation and complement activation signatures in patients with long COVID who were previously hospitalized.

The design of highly oxidizing Earth-abundant transition metal complexes for photochemical applications is desirable, but progress in this area remains limited. Now a manganese(IV) diguanidylpyridine complex has been shown to photooxidize naphthalene, benzene and acetonitrile to their radical cations after excitation with near-infrared light. Experimental and theoretical studies indicate the presence of two distinct ligand-to-metal charge transfer excited states.

Adipogenesis associated Mth938 Domain Containing gene (AAMDC) is frequently amplified in the IntClus2 subgroup of ER + breast cancer. Here, the authors show that AAMDC drives tumourigenesis through activating PI3K-AKT-mTOR pathway for metabolic reprogramming.

The two cap methyltransferases (CMTrs) redundantly methylate riboses of first cap adjacent nucleotides in messenger RNAs in Drosophila. Here, CMTrs are required for reward learning and localization of untranslated messenger RNAs to synapses.

In this study, Aggarwal and colleagues perform prospective sequencing of SARS-CoV-2 isolates derived from asymptomatic student screening and symptomatic testing of students and staff at the University of Cambridge. They identify important factors that contributed to within university transmission and onward spread into the wider community.

One hundred and ten Zika virus genomes from ten countries and territories involved in the Zika virus epidemic reveal rapid expansion of the epidemic within Brazil and multiple introductions to other regions.

Catalysis with non-precious metals presents many advantages including ease of availability, security of supply and low cost. Here, the authors report a metal–organic framework with cobalt or iron sites for use as single-site solid catalysts in a number of chemoselective reactions.

Laser probing of integrated circuits using sub-bandgap photon energies remains a challenge. Here, the authors propose a super-resolution method capable of achieving probe placement accuracy to better than 10 nm; extraction of electro-optic waveforms from a node of a group of transistors and applied this to isolate and identify a fault on a defective device.

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.

The use of earth-abundant metals in catalysis is a prerequisite for the development of sustainable synthetic chemical processes for the future. Now, biomass-derived chemicals can be used in an efficient iron-catalysed reaction to make complex spirocycles. The resulting products contain two asymmetric centres that are furnished in high stereoselectivity.

Optical dating of sediments containing stone artefacts newly excavated at Madjedbebe, Australia, indicate that human occupation began around 65,000 years ago, thereby setting a new minimum age for the arrival of people in Australia.

This study finds that sST2 is a disease-causing factor for Alzheimer’s disease. Higher sST2 levels impair microglial Aβ clearance in APOE4⁺ female individuals. A genetic variant, rs1921622, is associated with a reduction in sST2 level and protects against AD in APOE4⁺ female individuals.

Analysis of exomes and transcriptomes from 100 African American patients with acute myeloid leukemia identifies ancestry-related variation in mutation profiles and survival. Refined risk classification suggests clinical relevance of these ancestry-associated differences.

It has been hypothesized that domestication can occur through the ‘commensal pathway’ in which the domesticate takes advantage of a niche created as a byproduct by the domesticator. Here, Brooker et al. provide evidence for a commensal domestication process between longfin damselfish and mysid shrimps.

A single-cell Poisson model is used to analyse eQTLs in memory T cells across continuous, dynamic cell states, revealing that the cell context is critical to understanding variation in eQTLs and their association with disease.

Pathological cardiac fibrosis is a hallmark of diseases leading to heart failure. Here, the authors used systems genetics to identify a pro-fibrotic gene network regulated by WWP2, a E3 ubiquitin ligase, which orchestrates the nucleocytoplasmic shuttling and transcriptional activity of SMAD2 in the diseased heart.

This study uses global datasets of marine prokaryotes to reveal that prokaryotic biomass varies by just under 3-fold across the global surface ocean, while metabolic activity increases by more than one order of magnitude from polar to tropical coastal and upwelling regions. The findings also suggest that shifts under climate change could lead to an increasingly microbial-dominated ocean.

Most genetic association studies have been done on single nucleotide polymorphisms and small indels, while other types of variants have been less studied. Here, the authors use whole genome sequencing in a diverse population to identify and provide experimental evidence for associations between structural variants and blood-cell traits.

The RNA endonuclease CPSF3 was identified as the cellular efficacy target of the small molecule JTE-607, revealing pre-mRNA processing as a vulnerability in cancers such as Ewing’s sarcoma that are characterized by aberrant transcription.

An integrated analysis of de novo and inherited coding variants in 42,607 individuals with autism spectrum disorder identifies 60 risk genes of which five have not previously been associated with neurodevelopmental disorders.

Semiconducting armchair graphene nanoribbons with sub-10 nm width are of great technological importance but yet to realize. Here, the authors report growth of such nanoribbons on germanium and controlled crystallographic orientation and well-defined armchair edges are obtained.

Magnetoelectric effect enables versatile electronic and spintronic devices. Here the authors demonstrate a different strategy to achieve magnetoelectric coupling in which the electric polarization is controlled by magnetic spin state transition instead of the traditional ferro- or antiferromagnetic order.

Therapeutic stress induces phenotypic plasticity in glioma stem cells although the mechanisms underlying this remain poorly understood. Here, the authors show that P300 mediates the radiation-induced vascular-like conversion of glioma stem cells to promote tumor recurrence.

Gene flow is classically thought to impede local adaptation via parallel evolution. However, a genomic study on Hawaiian crickets from different island populations finds evidence of parallel adaptation to the same lethal parasitoid in spite of strong ongoing gene flow.

Many individual genetic risk loci associate with multiple diseases, but the molecular basis of these loci often remains unclear. Here, the authors provide a framework to reveal the genetic cross-disease associations at the PROCR vascular disease locus.

STAARpipeline is a comprehensive framework for flexible and scalable rare-variant association analysis using whole-genome sequencing data and annotation information.

Genomic analysis of Plasmodium DNA from 36 ancient individuals provides insight into the global distribution and spread of malaria-causing species during around 5,500 years of human history.

Most studies of the genetics of the metabolome have been done in individuals of European descent. Here, the authors integrate genomics and metabolomics in Black individuals, highlighting the value of whole genome sequencing in diverse populations and linking circulating metabolites to human disease.

Glycomics can uncover important molecular changes but measured glycans are highly interconnected and incompatible with common statistical methods, introducing pitfalls during analysis. Here, the authors develop an approach to identify glycan dependencies across samples to facilitate comparative glycomics.

The combination of selective 2'-hydroxyl acylation of RNA with high-throughput sequencing of the transcribed cDNA allows identification of chemically modified sites as mutations in the sequence that then yield highly accurate secondary-structure models of the RNA.

NK-cell and γδ-T cell lymphoma share clinic-pathological features; however the driving mutations are largely unknown. Here the authors, using a combination of RNA-Seq analysis, targeted re-sequencing and functional analysis, identify frequent activating mutations in STAT3 and STAT5Bthat may be driver mutations in these diseases.