Aprocitentan for Blood Pressure Reduction in Black Patients.

Background: Black individuals frequently present with resistant hypertension and disproportionately increased cardiovascular risk. We investigated the blood pressure (BP)-lowering effect of the dual endothelin receptor antagonist aprocitentan in Black individuals enrolled in the PRECISION study (Parallel-Group, Phase 3 Study with Aprocitentan in Subjects with Resistant Hypertension).

Methods: Patients with confirmed resistant hypertension were randomized to aprocitentan 12.

Global Ion Suppression Limits the Potential of Mass Spectrometry Based Phosphoproteomics.

Mass spectrometry based proteomics has become the method of choice for pinpointing and monitoring thousands of post-translational modifications, predominately phosphorylation sites, in cellular signaling studies. Critical for achieving this analytical depth is the enrichment of phosphorylated peptides prior to liquid chromatography-mass spectrometry (MS) analysis. Despite the high prevalence of this modification, the numbers of identified phosphopeptides lag behind those achieved for unmodified peptides, and the cause for this still remains controversial.

The Inflammasome Drives GSDMD-Independent Secondary Pyroptosis and IL-1 Release in the Absence of Caspase-1 Protease Activity.

Inflammasomes activate the protease caspase-1, which cleaves interleukin-1β and interleukin-18 to generate the mature cytokines and controls their secretion and a form of inflammatory cell death called pyroptosis. By generating mice expressing enzymatically inactive caspase-1, we provide genetic evidence that caspase-1 protease activity is required for canonical IL-1 secretion, pyroptosis, and inflammasome-mediated immunity. In caspase-1-deficient cells, caspase-8 can be activated at the inflammasome.

Detecting Release of Bacterial dsDNA into the Host Cytosol Using Fluorescence Microscopy.

Recognition of pathogens by the innate immune system relies on germline-encoded pattern recognition receptors (PRRs) that recognize unique microbial molecules, so-called pathogen-associated molecular patterns (PAMPs). Nucleic acids and their derivatives are one of the most important groups of PAMPs, and are recognized by a number of surface-associated as well as cytosolic PRRs. Cyclic GMP-AMP synthase (cGAS) recognizes the presence of pathogen- or host-derived dsDNA in the cytosol and initiates type-I-IFN production.

Francisella requires dynamic type VI secretion system and ClpB to deliver effectors for phagosomal escape.

Francisella tularensis is an intracellular pathogen that causes the fatal zoonotic disease tularaemia. Critical for its pathogenesis is the ability of the phagocytosed bacteria to escape into the cell cytosol. For this, the bacteria use a non-canonical type VI secretion system (T6SS) encoded on the Francisella pathogenicity island (FPI).

Guanylate-binding proteins promote activation of the AIM2 inflammasome during infection with Francisella novicida.

The AIM2 inflammasome detects double-stranded DNA in the cytosol and induces caspase-1-dependent pyroptosis as well as release of the inflammatory cytokines interleukin 1β (IL-1β) and IL-18. AIM2 is critical for host defense against DNA viruses and bacteria that replicate in the cytosol, such as Francisella tularensis subspecies novicida (F. novicida).

Caspase-11 activation requires lysis of pathogen-containing vacuoles by IFN-induced GTPases.

Lipopolysaccharide from Gram-negative bacteria is sensed in the host cell cytoplasm by a non-canonical inflammasome pathway that ultimately results in caspase-11 activation and cell death. In mouse macrophages, activation of this pathway requires the production of type-I interferons, indicating that interferon-induced genes have a critical role in initiating this pathway. Here we report that a cluster of small interferon-inducible GTPases, the so-called guanylate-binding proteins, is required for the full activity of the non-canonical caspase-11 inflammasome during infections with vacuolar Gram-negative bacteria.

Systems-level overview of host protein phosphorylation during Shigella flexneri infection revealed by phosphoproteomics.

The enteroinvasive bacterium Shigella flexneri invades the intestinal epithelium of humans. During infection, several injected effector proteins promote bacterial internalization, and interfere with multiple host cell responses. To obtain a systems-level overview of host signaling during infection, we analyzed the global dynamics of protein phosphorylation by liquid chromatography-tandem MS and identified several hundred of proteins undergoing a phosphorylation change during the first hours of infection.