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Natural killer T cells (NKT cells) recognize lipid antigens presented by CD1d. Zajonc and Rossjohn and their colleagues describe molecular interactions between type II NKT cell antigen receptors and CD1d-ligand complexes, which demonstrate distinct modes of recognition used by the receptors.

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.

The function of TRPA1 channels in the mammalian cochlea is poorly understood. Here, the authors show that TRPA1 channels in supporting cells of the organ of Corti mediate contractile responses that may contribute to temporary shifts in hearing thresholds after noise exposure in mice.

Characterization of the polysaccharide utilization loci from two Bacteroides species from the human gut microbiota define biochemical and structural features underlying the catabolism of a hybrid algal polysaccharide found in edible seaweed.

Whole-genome sequencing, transcriptome-wide association and fine-mapping analyses in over 7,000 individuals with critical COVID-19 are used to identify 16 independent variants that are associated with severe illness in COVID-19.

How γδ TCRs bind antigen presented by antigen-presenting molecules remains unclear. Godfrey and colleagues describe a population of human γδ T cells that interacts with CD1d and provide a molecular basis for how a γδ TCR binds CD1d–α-GalCer.

Analyses of single-cell transcriptomic data from patients with VEXAS syndrome combined with xenotransplantation experiments in a mouse model of the disease provide insights on the mechanisms of clonal dominance of mutated cells leading to bone marrow failure

Germline-encoded mycolyl lipid-reactive (GEM) T cells recognize CD1b proteins presenting mycobacterial mycolates via their T-cell receptors (TCRs). Here, the authors present the structure of this interaction and provide a molecular basis for the co-recognition of CD1b and a mycobacterial glycolipid.

JmjC histone demethylases (KDMs) are cancer targets due to their links to cell proliferation, but selective inhibition remains a challenge. Here the authors identify potent inhibitors of KDM4A-C—viain vitroselection from a vast library of cyclic peptides—that show selectivity over other KDMs.

WalKR is an essential two-component regulator that controls peptidoglycan synthesis in the human pathogen Staphylococcus aureus. Here, the authors provide biochemical, structural, and functional evidence supporting that the binding of a zinc ion inhibits autophosphorylation and thus alters WalKR regulatory activity.

Multidomain RNA-binding proteins recognize specific target sequences through mechanisms that are not well understood. Here the authors present an integrated approach to define the RNA-binding specificity and RNP topology and apply it to the analysis of the prototypical multidomain RNA-binding protein IMP3.

The magnetosome-associated protein mamP is an iron oxidase that reveals a unique arrangement of a self-plugged PDZ domain fused to two magnetochrome domains, defining a new class of c-type cytochrome exclusively found in magnetotactic bacteria.

Human leukocyte antigen (HLA) presents peptides to activate T cells, but many aspects in the T cell receptor (TCR)/HLA interaction remain unclear. Here the authors show, via structural data, that two TCRs differentially recognize the same tumour peptide/HLA complex and induce contrasting conformation changes of the peptide.

Cross-reactivity to dengue virus serotypes can trigger life-threatening inflammation. Culshaw et al. show that germline-encoded components of dengue-virus-specific TCRs influence antigen engagament and suggest that ‘innate-like’ recognition of the virus might underpin harmful cross-reactivity.

Cytotoxic CD8+ T cells provide one level of protection against influenza infection. Here, the authors present evidence, in mice and humans, for the emergence and reversion of influenza A virus escape mutants associated with the immune pressure from cytotoxic CD8+ T lymphocytes.

HLA-C expression levels correlate with immune responses to pathogens and autoimmunity, and vary in an allele-specific manner across individuals. Here the authors identify factors that drive differential expression of HLA-C allomorphs at the cell surface, and influence the structure of the peptide-binding cleft and diversity of peptides bound by HLA-C molecules.

Much is known about crystal structures of MHC class II–autoreactive TCRs. Sewell and colleagues provide the structure of an MHC class I–autoreactive TCR and provide insight into the molecular basis of its diabetogenicity.

Bispecifics by orthogonal interfaces To improve correct antibody heavy-light chain pairing during bispecific antibody assembly, Lewis et al. design antibody heavy and light chains with orthogonal interfaces.

CD1 molecules present diverse lipid ligands to TCRs expressed by NKT cells. Rossjohn, Moody and colleagues show a unique form of autoreactivity with human CD1c molecules, whereby TCRs recognize a closed conformation of CD1c molecules, which are loaded with a diverse array of ‘headless’ glycolipids.

Genetic variants in ionotropic glutamate receptors have been implicated in neurodevelopmental disorders. Here, the authors report heterozygous de novo mutations in the GRIA2 gene in 28 individuals with intellectual disability and neurodevelopmental abnormalities associated with reduced Ca²⁺ transport and AMPAR currents.”

Genome-wide association meta-analyses identify 26 risk loci for epilepsy, including 19 loci specific to genetic generalized epilepsy. Prioritized candidate genes implicate synaptic processes and overlap with targets of antiseizure medications.

A dataset of coding variation, derived from exome sequencing of nearly one million individuals from a range of ancestries, provides insight into rare variants and could accelerate the discovery of disease-associated genes and advance precision medicine efforts.

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.

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.

The paper describes the mechanism by which small-molecule drugs such as abacavir affect antigen presentation and consequently T-cell response in immunologically based drug reactions such as abacavir hypersensitivity syndrome (AHS) and carbamazepine-induced Stevens–Johnson syndrome (SJS).

The BRAIN Initiative Cell Census Network has constructed a multimodal cell census and atlas of the mammalian primary motor cortex in a landmark effort towards understanding brain cell-type diversity, neural circuit organization and brain function.

Here, the authors perform a meta-analysis in 26,699 people with seizures and 492,324 controls to identify 25 genome-wide significant copy-number variants. The discovered loci point to known disease genes and associations with clinical annotations.

Hansen et al. compile and share an atlas of neurotransmitter receptor/transporter densities in the human cortex and show that receptor achitecture reflects brain structure, function, dynamics, cognitive specialization and disease vulnerability.