Search

The authors report PROTAC ternary complex structures involving the E3 ligase cIAP1 and target protein BTK, showing that cooperativity is not always correlated with degradation efficiency.

Vignali and colleagues show that the inhibitory receptor LAG3 interferes with TCR signaling and T cell activation by lowering the pH at the immune synapse, which causes the dissociation of the tyrosine kinase Lck from the CD4 or CD8 co-receptor.

The extent to which human bacterial pathogens broadly utilize ergothioneine as an antioxidant is unknown. Here, authors describe the discovery of a specific transporter for ergothioneine in a respiratory pathogen that is highly conserved among Firmicutes.

Using 1,854 routinely collected clinical samples from early in pregnancy, with validation in an external cohort, low-coverage cfDNA sequence data identified distinctive features among those who developed preeclampsia.

Venous tumour thrombus can occur within renal cell carcinoma, and can require complex additional surgery and treatment. Here, the authors analyse multiparametric data from patients treated with axitinib and develop a machine learning model to predict neoadjuvant treatment response.

Multiancestry genome-wide association analyses identify new risk loci for stroke and stroke subtypes. Fine mapping and bioinformatics analyses of these risk loci point to mechanisms not previously implicated in stroke pathophysiology.

Identification of the molecular features that define the kinetic stability of the clinically relevant NDM-1 metallo-β-lactamase in the bacterial periplasm links the cellular metabolism of this protein with its natural evolution.

Analysing camera-trap data of 163 mammal species before and after the onset of COVID-19 lockdowns, the authors show that responses to human activity are dependent on the degree to which the landscape is modified by humans, with carnivores being especially sensitive.

An analysis of 24,202 critical cases of COVID-19 identifies potentially druggable targets in inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

Building synthetic chromosomes from natural components is an unexplored alternative to de novo chromosome synthesis that may have many potential applications. In this paper, the authors report CReATiNG, a method for constructing synthetic chromosomes from natural components in yeast.

Biodiversity in established or proposed Antarctic Marine Protected Areas is threatened by climate change. The authors show that projected ocean acidification is severe in Antarctic coastal waters due to strong vertical mixing of anthropogenic carbon.

Classical toxin–antitoxin systems in bacteria are based on silencing of a toxin by an antitoxin that, when inactivated, releases the toxin, resulting in a change in metabolism. Here, the authors characterize an oxygen-sensitive toxin–antitoxin system and discuss the implications for the role of the Hha antitoxin.

There is growing need for ways to slow or prevent Alzheimer’s disease (AD). Here, the authors demonstrate that a low protein diet can protect against metabolic dysfunction, slow AD progression, and preserve cognitive function in a mouse model of AD.

Uroz et al. report that the distinct mechanical properties of brain vasculature versus parenchyma drive cancer cell migration through a talin-dependent mechanism, enabling vessel co-option and metastatic invasion in the brain.

Expanding the bacterial toxin-antitoxin system classes to a fifth class, GhoST was found to be involved in maintenance of persister cells, dormant cells that are tolerant of antibiotics. GhoS is the antitoxin, an endoribonuclease that cleaves the toxin mRNA ghoT, whose gene product is a membrane-lytic protein.

Changes in the Arctic could impact the oceanic carbon sequestration of the region. Here the authors consider regional biogeochemistry, including coastal erosion and river inputs, to show a 40% reduction in the biological carbon pump to 2100 under climate change.

Fungal Pdr1p family proteins bind directly to diverse drugs and xenobiotics, resulting in activation of transcription and induction of multidrug resistance. The mechanism has analogy to regulation of multidrug resistance in vertebrates by nuclear receptors.

Type three secretion systems consist of a multisubunit protein complex that crosses the bacterial membranes and an extracellular needle-shaped structure. New data show that the needle protomer partially refolds from alpha-helix into beta-strand conformation to extend the needle from the distal end. The closely related flagellar system also grows at the tip, but it is not known whether protomer refolding is required for its assembly.

Tsyben et al. study the spatial distribution of labelled metabolites in glioblastoma samples from patients infused with ¹³C-glucose, using mass spectrometry imaging.

A personalized antisense oligonucleotide developed for a female with a KIF1A-associated neurological disorder was well tolerated and led to preliminary improvements in mobility and behavioral arrest after 9 months of follow-up.

Whole genome sequences enable discovery of rare variants which may help to explain the heritability of common diseases. Here the authors find that ultra-rare variants explain ~50% of coronary artery disease (CAD) heritability and highlight several functional processes including cell type-specific regulatory mechanisms as key drivers of CAD genetic risk.

AFM and NMR are used to observe how the chaperones Skp and SurA work to fold a β-barrel outer-membrane protein, FhuA. Skp maintains FhuA in an unfolded state, and Sur A facilitates its folding.

The bacterial chaperone Trigger Factor (TF) is a dynamic protein and its dimer structure is unknown. Here the authors present a protocol combining NMR, computational and biophysical methods for the structural characterization of large dynamic protein complexes and show that TF forms a symmetric head-to-tail dimer.

The crystal structure of the RNA binding domains of Sxl and Unr with msl2 RNA shows that interwoven interactions establish cooperative assembly of the ternary complex, highlighting how binding of relatively general RNA binding domains to RNA can result in a unique and specific protein–RNA architecture.

GalNAc transferases’ (GalNAc-Ts) catalytic domains are connected to a lectin domain through a flexible linker. Here the authors present a structural analysis of GalNAc-T4 that implicates the linker region as modulator of the orientations of the lectin domain, which in turn imparts substrate specificity.

Multiplexed genome engineering with Cas9 can increase efficiency but also the risk of unintended alterations. Here the authors demonstrate the use of multiplexed base editors on primary T cells with reduced translocation frequency.

Current insecticide delivery practices are inefficient, with only a fraction reaching the intended target. This study developed carbon dot nanocarriers with molecular baskets to enhance the delivery of insecticides through stink bug tarsal pores, significantly increasing insecticide efficacy.

Skp is a bacterial chaperone that prevents aggregation of outer membrane proteins as they traverse the periplasmic space. The conformation and dynamics of Skp in complex with two OMPs are now examined by NMR spectroscopy. The analyses reveal that Skp provides a scaffold for its substrates, which in turn populate a dynamic conformational ensemble.

Using data from a single time point, passenger-approximated clonal expansion rate (PACER) estimates the fitness of common driver mutations that lead to clonal haematopoiesis and identifies TCL1A activation as a mediator of clonal expansion.

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.

Heterotropic ligand binding to Diaphanous 1 leads to negative cooperativity as a key element in controlling Diaphanous 1 activity to enable gradual responses to cellular processes that require prolonged and sustained regulation.

An orally bioavailable small-molecule active-site inhibitor of the phosphatases PTPN2 and PTPN1, ABBV-CLS-484, demonstrates immunotherapeutic efficacy in mouse models of cancer resistant to PD-1 blockade.

Hypomethylating agents (HMAs) are frontline therapy for Myelodysplasia, but their efficacy is limited. Here, the authors show that depleting the dual E3-ligase TOPORS synergizes with HMAs by enhancing DNA damage in leukemia cells, improving survival in mouse models without preventing healthy hematopoiesis.

Here, the authors show that DNA-PK and TRF2, via its iDDR, suppress MRN nucleolytic processing of leading-end blunt telomeres, which are instead processed by Apollo or, in its absence, are aberrantly fused by alternative end-joining.

Analysis of bronchoalveolar lavage fluid samples from patients with SARS-CoV-2-induced respiratory failure suggests that SARS-CoV-2 infects alveolar macrophages to cause release of T cell chemoattractants, thereby inducing local inflammatory cytokine release and further T cell activation, ultimately resulting in a positive feedback loop that drives alveolar inflammation.

Methods to demonstrate genomic linkages between pathogens across One Health compartments have not been established. Here, the authors compile a collection of E coli genomes from humans, animals, and the environment in Australia and investigate genomic evidence of cross-source clusters.

Recurrence of meningiomas is unpredictable by current methods based on surgically removed specimens, and identification of patients likely to recur could inform treatment strategy. Here, the authors analysed DNA methylation in liquid biopsy specimens from meningioma patients to help classify recurrence risk noninvasively even before surgery.

The authors identify a molecular switch that regulates the balance between neurotoxic and neuroprotective astrocyte populations, with potential application in the treatment of glaucoma and other optic neuropathies.