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Analysis of genotyping-by-sequencing data for more than 20,000 barley accessions from a German genebank provides a framework for genomics-assisted genebank management and analysis of large germplasm collections for important crops.

Pathology-oriented multiplexing (PathoPlex) represents a framework for widespread access to multiplexed imaging and computational image analysis of clinical specimens at a relatively high throughput and subcellular resolution.

The P2X4 receptor, an ATP-activated ion channel, plays a role in chronic pain, inflammation, and cancer. Authors in this work discover an extracellular allosteric binding site that interacts with anthraquinone derivatives, and is narrowed by ionic lock formation.

Leucine-rich repeat (LRR) domains are commonly present in immune regulatory proteins. Here the authors show that LRR exonic modularity and alternative splicing of an LRR-containing protein, NLRP3, modulate the ratio of functional/afunctional NLRP3 isoforms to instill a stochastic regulation of NLRP3-mediated inflammation and innate immunity.

Non-alcoholic steatohepatitis (NASH) is characterized by lipid accumulation within hepatocytes and fibrosis. Seitz et al. show that the GTPase protein Rab24 is increased in the livers of people who are obese or have NASH.

Characterization of RNA-binding proteins (RBPs) in tissues has been hampered by technical constraints. Here, the authors describe ex vivo eRIC, a method for global profiling of RBPs active in mammalian organs, and report comprehensive RBP atlases from mouse brain, kidney and liver.

Pyroptosis has been implicated in many diseases with aberrant inflammation. Here, Kopp et al. characterize single-chain nanobodies targeting the human gasdermin D protein as tools to inhibit pyroptosis.

Cyclin-dependent kinase 7 (Cdk7) is required in cell-cycle and transcriptional regulation. It is regulated by two phosphorylations in the activation segment. Here, the authors report a structure of the human Cdk7/Cyclin H/Mat1 complex containing both phosphorylations, with further insights into the regulatory mechanisms.

NLRP3 inflammasome activation is critical for the induction of protective immunity, but molecular insights are still lacking. Here, the authors express NLRP3 variants targeted to different cellular locations in NLRP3-deficient macrophages to show that membrane- or protein scaffold-induced NLRP3 clustering promotes NLRP3 inflammasome activation.

In glioblastoma (GBM), tumour microtubes (TM) connect tumour cells to a broader cellular network, with roles in tumour progression and therapy resistance. Here, the authors combine a dye uptake method in GBM xenograft models with subsequent scRNA-seq to infer a TM connectivity signature, finding CHI3L1 as a marker of connectivity.

RNA binding proteins are important regulators of RNA function. Here the authors describe a method for isolation of RNA-protein complexes that does not rely on a specific RNA sequence or motif, and demonstrate the approach by providing the global RNA-bound proteomes of human HEK293 cells and Salmonella Typhimurium.

An understudied subset of NOD-like receptors are involved in the reproductive system, and their dysfunction can cause infertility. The recently obtained structures of the core subcortical maternal complex assembled around one of them, NLRP5, provide important insight into this building block of early embryo cytoplasmic lattices.

Cryo-electron microscopy structures of human NLRP3 in its resting state and bound to the inhibitor CRID3 provide insight into the binding mechanism of CRID3 and its mode of antagonism.

Abemaciclib is a third generation CDK-directed drug used in the treatment of HR + /HER2 negative advanced or metastatic breast cancer. Here the authors demonstrate that members of the Homeodomain-interacting protein kinases (HIPKs) HIPK3 and DYRK1A are also targeted by Abemaciclib.

New biomarkers are required to improve the assessment of aortic wall integrity and risk of rupture. Here the authors report the development of an imaging probe for ADAMTS4, which they test in an abdominal aortic aneurysm mouse model and show in vivo prediction of aneurysm and rupture.

FMNL formins polymerize actin filaments to generate cellular protrusions such as lamellipodia and filopodia at the leading edge of a cell. Here the authors provide detailed mechanistic insights into the formation of actin-based protrusions through GTPase dependent activation and membrane localization of FMNL1 and FMNL2.

Dhamija et al. profile 3,412 nonstop mutations from 62 tumour entities and as proof of concept demonstrate that six such mutations cause degradation and loss of the tumour suppressor SMAD4.

Cyclin-dependent kinase 12 (Cdk12) phosphorylates the C-terminal domain (CTD) of RNA polymerase II to regulate transcription. Here, the authors solve the crystal structure of the Cdk12 kinase domain and show that Cdk12 has its highest activity on a CTD substrate that carries a serine 7 phosphorylation.

Phosphorylation of the carboxy-terminal domain of RNA polymerase II is important for controlling gene transcription. In this study, the transcription elongation factor Tefb is shown to phosphorylate serine-5 and its activity is enhanced when the polymerase is already phosphorylated on serine-7.

HIV and simian immunodeficiency virus (SIV) Nef proteins both stimulate the clathrin-mediated endocytosis of CD4 but differ in downmodulation of the immune receptor CD3. Here, the authors present the structure of SIV Nef bound to the ExxxLM motif of another Nef molecule, which allows them to propose a model how Nef recognizes these motifs in CD3 and CD4.

The replication of many retroviruses depends on interactions between the viral TAR RNA element and Tat as well as Cyclin T1, a component of the cellular transcriptional elongation complex. Structural insights into this ternary complex now suggest that the equine infectious anemia virus TAR is engaged by both proteins with Tat in a helical conformation and that binding depends on flipping out specific bases in the TAR loop region.

An advanced proteomics workflow is used to identify 340,000 proteins from 100 taxonomically diverse species, providing a comparative view of proteomes across the evolutionary range.

Chemical profiling in hyponeddylated cells coupled with multi-omics target deconvolution led to the identification of molecular glue degraders of cyclin K that function by inducing proximity between the CRL adaptor DDB1 and a CDK12–cyclin K complex.

Recognition of nucleic acids is a key strategy of the innate immune system to detect infectious organisms and tissue damage. Toll-like receptor (TLR) 8 was long assumed to be a receptor for single-stranded (ss) RNA. Unexpected findings now suggest that TLR8 recognizes RNA degradation products rather than ssRNA and that synergistic binding of two uridine-containing agonists at distinct sites of the receptor leads to activation of the innate immune response.

Inflammasome assembly promotes the cleavage and oligomerisation of gasdermin D (GSDMD) and subsequent pore formation. Here the authors raise nanobodies to human gasdermin and characterize the pore formation process mediated by GSDMD and how antagonistic nanobodies prevent pyroptosis.

Binding of HIV-1 Nef to host cell membranes is a biphasic process that involves electrostatic curvature-sensitive Nef-lipid interactions followed by a slower formation of an amphipathic helix. Nef action on the membrane may promote curvature and subsequent endocytosis of the host-cell proteins.

The solution structure of the Ras-binding domain (RBD) of Ral guanine-nucleotide exchange factor RalGEF was solved by NMR spectroscopy. The overall structure is similar to that of Raf-RBD, another effector of Ras, although the sequence identity is only 13%. 1SN chemical shifts changes in the complex of RalGEF-RBD with Ras indicate an interaction similar to the intermolecular β-sheet observed for the complex between Ras and Raf-RBD.

SARS-CoV-2 detection with LAMP-Seq combines isothermal amplification and barcoding with high-throughput sequencing.

The discovery of a specific CDK12 bivalent degrader, BSJ-4-116, reveals that chronic exposure of MOLT-4 and Jurkat cells to BSJ-4-116 leads to acquired resistance to the compound via point mutations in the CDK12 kinase domain.

Cdk12 is primarily involved in the regulation of DNA damage response (DDR) gene transcription as well as mRNA processing. Here, the authors demonstrate that CDK12 suppresses intronic polyadenylation, and that inhibition of this kinase primarily affects the expression of long genes with higher numbers of polyA sites, features common to many DDR genes.

Variations in microbial composition, phage induction, antimicrobial resistance genes and bile acid profiles are identified by using an ingestible device for site-specific sampling along the intestines.

A CalpL–CalpT–CalpS cascade mediated by cyclic oligoadenylates is identified as a mechanism to detect viral RNA and activate subsequent antivirus responses in microorganisms.

Tripartite ATP-independent periplasmic (TRAP) transporters are widespread in bacteria and archaea. Here, the authors used cryo-EM and a range of biophysical techniques to study the structure of function of the sialic acid TRAP transporter HiSiaQM.

Interogation of mass-spectrometry-based proteomics of liver and plasma from a cohort of patients with alcohol-related liver disease identifies noninvasive biomarkers associated with early stages of disease progression, including significant fibrosis, inflammation and steatosis.

Mutations in the coatomer complex I can result in endoplasmic reticulum stress and inflammatory consequences. Here authors define aberrant activation of the STING immunosensing pathway in a disturbed coatmer complex context and the therapeutic modulation of this axis to counter the associated immunopathology.

A knowledge graph platform integrates proteomics with other omics data and biomedical databases.

BoxCar, a mass spectrometry data acquisition method, greatly increases sensitivity and the detection of low-abundance peptides with a minimal amount of instrument time.

Latz et al. review the molecular mechanisms that drive NLRP3 inflammasome activation and regulation, and discuss emerging targeting strategies.

A small molecule inhibits CDK12 and CDK13 activity through covalent modification of Cys residues and reveals a role of the two kinases in regulating Pol II processivity and super-enhancer-driven transcription factor and DNA damage response gene expression.

Actin polymerization in lamellipodia of cells is regulated by the Arp2/3 complex and FMNL family formins. Here the authors show that both FMNL2 and FMNL3 contribute to lamellipodium protrusion and structure, and abolishing FMNL2/3 reduces protrusion force generation and migration, without affecting Arp2/3 incorporation.

Deposition and spreading of amyloid-β pathology in mice requires binding to microglia-released ASC specks.

Gain-of-function variants in the gene encoding NLRP3 lead to constitutive inflammasome activation and excessive IL-1β production. In this resource, authors perform functional screening of clinically relevant NLRP3 variants. Structural analysis suggested multiple mechanisms by which variants activate NLRP3 and the identification of pathogenic variants that can sensitize the activation of NLRP3 in response to nigericin and cold temperature exposure.