Mouse guanylate-binding proteins of the chromosome 3 cluster do not mediate antiviral activity in vitro or in mouse models of infection.

Dynamin-like GTPase proteins, including myxoma (Mx) and guanylate-binding proteins (GBPs), are among the many interferon stimulated genes induced following viral infections. While studies report that human (h)GBPs inhibit different viruses in vitro, few have convincingly demonstrated that mouse (m)GBPs mediate antiviral activity, although mGBP-deficient mice have been used extensively to define their importance in immunity to diverse intracellular bacteria and protozoa. Herein, we demonstrate that individual (overexpression) or collective (knockout (KO) mice) mGBPs of the chromosome 3 cluster (mGBPchr3) do not inhibit replication of five viruses from different virus families in vitro, nor do we observe differences in virus titres recovered from wild type versus mGBPchr3 KO mice after infection with three of these viruses (influenza A virus, herpes simplex virus type 1 or lymphocytic choriomeningitis virus).

Profiling the colonic mucosal response to fecal microbiota transplantation identifies a role for GBP5 in colitis in humans and mice.

Host molecular responses to fecal microbiota transplantation (FMT) in ulcerative colitis are not well understood. Here, we profile the human colonic mucosal transcriptome prior to and following FMT or placebo to identify molecules regulated during disease remission. FMT alters the transcriptome above the effect of placebo (n = 75 vs 3 genes, q < 0.

Ku70 senses cytosolic DNA and assembles a tumor-suppressive signalosome.

The innate immune response contributes to the development or attenuation of acute and chronic diseases, including cancer. Microbial DNA and mislocalized DNA from damaged host cells can activate different host responses that shape disease outcomes. Here, we show that mice and humans lacking a single allele of the DNA repair protein Ku70 had increased susceptibility to the development of intestinal cancer.

Impairing Gasdermin D-mediated pyroptosis is protective against retinal degeneration.

Background: Inflammasome activation and the subsequent release of pro-inflammatory cytokines including Interleukin 1β (IL-1β) have been widely reported to contribute to the progression of retinal degenerations, including age-related macular degeneration (AMD), the leading cause of blindness in the Western World. The role of Gasdermin D (GSDMD), a key executioner of pyroptosis following inflammasome activation, however, is less well-established. In this study we aimed to characterise the role of GSDMD in the healthy and degenerating retina, and uncover its role as a conduit for IL-1β release, including via extracellular vesicle (EV)-mediated release.

Clostridium perfringens virulence factors are nonredundant activators of the NLRP3 inflammasome.

Inflammasome signaling is a central pillar of innate immunity triggering inflammation and cell death in response to microbes and danger signals. Here, we show that two virulence factors from the human bacterial pathogen Clostridium perfringens are nonredundant activators of the NLRP3 inflammasome in mice and humans. C.

Immunity against Moraxella catarrhalis requires guanylate-binding proteins and caspase-11-NLRP3 inflammasomes.

Moraxella catarrhalis is an important human respiratory pathogen and a major causative agent of otitis media and chronic obstructive pulmonary disease. Toll-like receptors contribute to, but cannot fully account for, the complexity of the immune response seen in M. catarrhalis infection.

Pathogen-selective killing by guanylate-binding proteins as a molecular mechanism leading to inflammasome signaling.

Inflammasomes are cytosolic signaling complexes capable of sensing microbial ligands to trigger inflammation and cell death responses. Here, we show that guanylate-binding proteins (GBPs) mediate pathogen-selective inflammasome activation. We show that mouse GBP1 and GBP3 are specifically required for inflammasome activation during infection with the cytosolic bacterium Francisella novicida.

Predominant Bacterial and Viral Otopathogens Identified Within the Respiratory Tract and Middle Ear of Urban Australian Children Experiencing Otitis Media Are Diversely Distributed.

Background: Otitis media (OM) is one of the most common infections in young children, arising from bacterial and/or viral infection of the middle ear. Globally, and non-typeable (NTHi) are the predominant bacterial otopathogens. Importantly, common upper respiratory viruses are increasingly recognized contributors to the polymicrobial pathogenesis of OM.

Bacillus cereus: Epidemiology, Virulence Factors, and Host-Pathogen Interactions.

The toxin-producing bacterium Bacillus cereus is an important and neglected human pathogen and a common cause of food poisoning. Several toxins have been implicated in disease, including the pore-forming toxins hemolysin BL (HBL) and nonhemolytic enterotoxin (NHE). Recent work revealed that HBL binds to the mammalian surface receptors LITAF and CDIP1 and that both HBL and NHE induce potassium efflux and activate the NLRP3 inflammasome, leading to pyroptosis.

MicroRNA-223 Regulates Retinal Function and Inflammation in the Healthy and Degenerating Retina.

Introduction: MicroRNAs (miRNAs) are small, non-coding RNA molecules that have powerful regulatory properties, with the ability to regulate multiple messenger RNAs (mRNAs) and biological pathways. MicroRNA-223-3p (miR-223) is known to be a critical regulator of the innate immune response, and its dysregulation is thought to play a role in inflammatory disease progression. Despite miR-223 upregulation in numerous neurodegenerative conditions, largely in cells of the myeloid lineage, the role of miR-223 in the retina is relatively unexplored.

Visible Light Mediated Bidirectional Control over Carbonic Anhydrase Activity in Cells and Using Azobenzenesulfonamides.

Two azobenzenesulfonamide molecules with thermally stable configurations resulting from fluorination of positions to the azo group are reported that can differentially regulate the activity of carbonic anhydrase in the and configurations. These fluorinated probes each use two distinct visible wavelengths (520 and 410 or 460 nm) for isomerization with high photoconversion efficiency. Correspondingly, the isomer of these systems is highly stable and persistent (as evidenced by structural studies in solid and solution state), permitting regulation of metalloenzyme activity without continuous irradiation.

Bacillus cereus non-haemolytic enterotoxin activates the NLRP3 inflammasome.

Inflammasomes are important for host defence against pathogens and homeostasis with commensal microbes. Here, we show non-haemolytic enterotoxin (NHE) from the neglected human foodborne pathogen Bacillus cereus is an activator of the NLRP3 inflammasome and pyroptosis. NHE is a non-redundant toxin to haemolysin BL (HBL) despite having a similar mechanism of action.

A multicomponent toxin from Bacillus cereus incites inflammation and shapes host outcome via the NLRP3 inflammasome.

Host recognition of microbial components is essential in mediating an effective immune response. Cytosolic bacteria must secure entry into the host cytoplasm to facilitate replication and, in doing so, liberate microbial ligands that activate cytosolic innate immune sensors and the inflammasome. Here, we identified a multicomponent enterotoxin, haemolysin BL (HBL), that engages activation of the inflammasome.

Pull-Down of Metalloproteins in Their Native States by Using Desthiobiotin-Based Probes.

One-third of all proteins are estimated to require metals for structural stability and/or catalytic activity. Desthiobiotin probes containing metal binding groups can be used to capture metalloproteins with exposed active-site metals under mild conditions so as to prevent changes in metallation state. The proof-of-concept was demonstrated with carbonic anhydrase (CA), an open active site, Zn -containing protein.

Cytosolic Recognition of Microbes and Pathogens: Inflammasomes in Action.

Infection is a dynamic biological process underpinned by a complex interplay between the pathogen and the host. Microbes from all domains of life, including bacteria, viruses, fungi, and protozoan parasites, have the capacity to cause infection. Infection is sensed by the host, which often leads to activation of the inflammasome, a cytosolic macromolecular signaling platform that mediates the release of the proinflammatory cytokines interleukin-1β (IL-1β) and IL-18 and cleavage of the pore-forming protein gasdermin D, leading to pyroptosis.

A new probe for detecting zinc-bound carbonic anhydrase in cell lysates and cells.

We report the synthesis and application of a small molecule probe for carbonic anhydrase (CA) to track holo-CA in cell lysates and live-cell models of zinc dyshomeostasis. The probe displays a 12-fold increase in fluorescence upon binding to bovine CA and also responds to human CA isoforms.

Mechanisms and functions of guanylate-binding proteins and related interferon-inducible GTPases: Roles in intracellular lysis of pathogens.

Guanylate-binding proteins (GBPs) are a group interferon-inducible GTPases within the constellation of the dynamin GTPase superfamily. These proteins restrict the replication of intracellular pathogens in both immune and non-immune cells. GBPs and their related family members immunity-related GTPases target and lyse the membrane of the pathogen-containing vacuole, destroying the residential niche of vacuolar protozoal and bacterial pathogens.

NLRP9b: a novel RNA-sensing inflammasome complex.

Inflammasome sensors recognize pathogens and danger signals and assemble an immune signaling complex, which induces the secretion of pro-inflammatory cytokines IL-1β and IL-18, and pyroptosis. A new study published in Nature now describes a new inflammasome sensor NLRP9b in intestinal epithelial cells, which in concert with the RNA sensor DHX9, recognize short dsRNA from Rotavirus.

Predominant Bacteria Detected from the Middle Ear Fluid of Children Experiencing Otitis Media: A Systematic Review.

Background: Otitis media (OM) is amongst the most common childhood diseases and is associated with multiple microbial pathogens within the middle ear. Global and temporal monitoring of predominant bacterial pathogens is important to inform new treatment strategies, vaccine development and to monitor the impact of vaccine implementation to improve progress toward global OM prevention.

Methods: A systematic review of published reports of microbiology of acute otitis media (AOM) and otitis media with effusion (OME) from January, 1970 to August 2014, was performed using PubMed databases.

Diastereo- and Enantioselective Iridium Catalyzed Coupling of Vinyl Aziridines with Alcohols: Site-Selective Modification of Unprotected Diols and Synthesis of Substituted Piperidines.

The chiral cyclometalated π-allyliridium ortho-C,O-benzoate complex (R)-Ir-VIb derived from [Ir(cod)Cl]2, allyl acetate, 4-cyano-3-nitro-benzoic acid, and (R)-MeO-BIPHEP catalyzes the coupling of N-(p-nitrophenylsulfonyl) protected vinyl aziridine 3a with primary alcohols 1a-1l to furnish branched products of C-C bond formation 4a-4l with good levels of anti-diastereo- and enantioselectivity. In the presence of 2-propanol, but under otherwise identical conditions, vinyl aziridine 3a and aldehydes 2a-2l engage in reductive coupling to furnish an equivalent set of adducts 4a-4l with roughly equivalent levels of anti-diastereo- and enantioselectivity. Using enantiomeric iridium catalysts, vinyl aziridine 3a reacts with unprotected chiral 1,3-diols 1m-1o in a site-selective manner to deliver the diastereomeric products of C-allylation syn-4m, -4n, -4o and anti-4m, -4n, -4o, respectively, with good isolated yields and excellent levels of catalyst-directed diastereoselectivity.

Instantaneous adhesion of Cuvierian tubules in the sea cucumber Holothuria forskali.

The peculiar Cuvierian tubules of sea cucumbers function as a defense mechanism. They thwart attacks by creating a sticky network composed of elongated tubules within which the potential predator is entangled in a matter of seconds and thus immobilized. Cuvierian tubules are typical instantaneous adhesive organs in which tissue integrity is destroyed during the release of the adhesive secretion.

Modification of the adhesive properties of silicone-based coatings by block copolymers.

The improvement of the (bio)adhesive properties of elastomeric polydimethylsiloxane (PDMS) coatings is reported. This is achieved by a surface modification consisting of the incorporation of block copolymers containing a PDMS block and a poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA) block in a PDMS matrix, followed by matrix cross-linking and immersion of the obtained materials in water. Contact angle measurements (CA), X-ray photoelectron spectroscopy (XPS), and atomic force microscopy (AFM) showed the presence of the PDMAEMA block at the surface, drastic morphology changes, and improved adhesion properties after immersion in water.