44 research outputs found
A Yersinia Effector with Enhanced Inhibitory Activity on the NF-κB Pathway Activates the NLRP3/ASC/Caspase-1 Inflammasome in Macrophages
A type III secretion system (T3SS) in pathogenic Yersinia
species functions to translocate Yop effectors, which modulate cytokine
production and regulate cell death in macrophages. Distinct pathways of
T3SS-dependent cell death and caspase-1 activation occur in
Yersinia-infected macrophages. One pathway of cell death
and caspase-1 activation in macrophages requires the effector YopJ. YopJ is an
acetyltransferase that inactivates MAPK kinases and IKKβ to cause
TLR4-dependent apoptosis in naïve macrophages. A YopJ isoform in Y.
pestis KIM (YopJKIM) has two amino acid substitutions,
F177L and K206E, not present in YopJ proteins of Y.
pseudotuberculosis and Y. pestis CO92. As compared
to other YopJ isoforms, YopJKIM causes increased apoptosis, caspase-1
activation, and secretion of IL-1β in Yersinia-infected
macrophages. The molecular basis for increased apoptosis and activation of
caspase-1 by YopJKIM in Yersinia-infected
macrophages was studied. Site directed mutagenesis showed that the F177L and
K206E substitutions in YopJKIM were important for enhanced apoptosis,
caspase-1 activation, and IL-1β secretion. As compared to
YopJCO92, YopJKIM displayed an enhanced capacity to
inhibit phosphorylation of IκB-α in macrophages and to bind IKKβ in
vitro. YopJKIM also showed a moderately increased ability to inhibit
phosphorylation of MAPKs. Increased caspase-1 cleavage and IL-1β secretion
occurred in IKKβ-deficient macrophages infected with Y.
pestis expressing YopJCO92, confirming that the
NF-κB pathway can negatively regulate inflammasome activation.
K+ efflux, NLRP3 and ASC were important for secretion of
IL-1β in response to Y. pestis KIM infection as shown using
macrophages lacking inflammasome components or by the addition of exogenous KCl.
These data show that caspase-1 is activated in naïve macrophages in
response to infection with a pathogen that inhibits IKKβ and MAPK kinases
and induces TLR4-dependent apoptosis. This pro-inflammatory form of apoptosis
may represent an early innate immune response to highly virulent pathogens such
as Y. pestis KIM that have evolved an enhanced ability to
inhibit host signaling pathways
Exploring the genetics underpinning dynamic laryngeal collapse associated with poll flexion in Norwegian-Swedish Coldblooded Trotter racehorses
BACKGROUND: Dynamic laryngeal collapse (DLC) associated with poll flexion is the most common disorder of the upper respiratory tract (URT) in the Norwegian-Swedish Coldblooded Trotter (NSCT). The disorder, which has also been diagnosed in other breeds of trotters and gaited horses, appears to be related to anatomic phenotypes and only occurs during poll flexion when the horse is exercised 'on the bit'. OBJECTIVES: Identify genomic regions associated with DLC in the NSCT by combining a rigorous phenotyping protocol with genomic data from a high-density equine genotyping array. STUDY DESIGN: Prospective case/control study. METHODS: High-speed treadmill endoscopy was used to phenotype horses (n = 61) for DLC, distinguishing between cases and controls. Genome-wide association (GWA) analysis of DLC status was then performed using a principal component approach (PCA) with haplotype analyses subsequently performed for regions containing single-nucleotide polymorphisms (SNPs) above the suggestive genome-wide significance (GWS) threshold (P<1.0 × 10-5 ). RESULTS: One region containing 10 SNPs (Equus caballus chromosome [ECA] 7: 89,601,935-94,647,192) was above the suggestive GWS threshold. Two inferred haplotypes in this region demonstrated significant differences (P<0.001) between cases and controls, with the most frequent haplotype resulting in a significantly increased risk of DLC. MAIN LIMITATIONS: Small sample size as a result of stringent phenotyping protocols. CONCLUSIONS: The current study highlights a candidate genomic region on ECA7 as potentially important with regard to the manifestation of DLC. Further exploration of this region and the genes included within it will bring veterinarians and researchers closer to fully understanding the biological mechanisms underlying DLC in horses.status: publishe
清涼飮料税論
The production of J/\).psi\) and was measured with the ALICE detector in Pb-Pb collisions at the LHC. The measurement was performed at forward rapidity 2.5 < y < 4 \() down to zero transverse momentum \(p_{\rm T} in the dimuon decay channel. Inclusive J/\).psi\) yields were extracted in different centrality classes and the centrality dependence of the average is presented. The J/\).psi\) suppression, quantified with the nuclear modification factor , was studied as a function of centrality, transverse momentum and rapidity. Comparisons with similar measurements at lower collision energy and theoretical models indicate that the J/\).psi\) production is the result of an interplay between color screening and recombination mechanisms in a deconfined partonic medium, or at its hadronization. Results on the suppression are provided via the ratio of over J/\).psi\) measured in pp and Pb-Pb collisions