20 research outputs found
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Pyk2 activates the NLRP3 inflammasome by directly phosphorylating ASC and contributes to inflammasome-dependent peritonitis
The inflammasome adaptor protein, ASC, contributes to both innate immune responses and inflammatory diseases via self-oligomerization, which leads to the activation of the protease, caspase-1. Here, we report that the cytosolic tyrosine kinases, FAK and Pyk2, are differentially involved in NLRP3 and AIM2 inflammasome activation. The inhibition of FAK and Pyk2 with RNA interference or chemical inhibitors dramatically abolished ASC oligomerization, caspase-1 activation, and IL-1β secretion in response to NLRP3 or AIM2 stimulation. Pyk2 is phosphorylated by the kinase Syk and relocalizes to the ASC specks upon NLRP3 inflammasome activation. Pyk2, but not FAK, could directly phosphorylate ASC at Tyr146, and only the phosphorylated ASC could participate in speck formation and trigger IL-1β secretion. Moreover, the clinical-trial-tested Pyk2/FAK dual inhibitor PF-562271 reduced monosodium urate-mediated peritonitis, a disease model used for studying the consequences of NLRP3 activation. Our results suggest that although Pyk2 and FAK are involved in inflammasome activation, only Pyk2 directly phosphorylates ASC and brings ASC into an oligomerization-competent state by allowing Tyr146 phosphorylation to participate ASC speck formation and subsequent NLRP3 inflammation
Pulmonary Tuberculosis and Delay in Anti-Tuberculous Treatment Are Important Risk Factors for Chronic Obstructive Pulmonary Disease
OBJECTIVE: Tuberculosis (TB) remains the leading cause of death among infectious diseases worldwide. It has been suggested as an important risk factor of chronic obstructive pulmonary disease (COPD), which is also a major cause of morbidity and mortality. This study investigated the impact of pulmonary TB and anti-TB treatment on the risk of developing COPD. DESIGN, SETTING, AND PARTICIPANTS: This cohort study used the National Health Insurance Database of Taiwan, particularly the Longitudinal Health Insurance Database 2005 to obtain 3,176 pulmonary TB cases and 15,880 control subjects matched in age, sex, and timing of entering the database. MAIN OUTCOME MEASURES: Hazard ratios of potential risk factors of COPD, especially pulmonary TB and anti-TB treatment. RESULTS: The mean age of pulmonary TB cases was 51.9±19.2. The interval between the initial study date and commencement of anti-TB treatment (delay in anti-TB treatment) was 75.8±65.4 days. Independent risk factors for developing COPD were age, male, low income, and history of pulmonary TB (hazard ratio 2.054 [1.768-2.387]), while diabetes mellitus was protective. The impact of TB persisted for six years after TB diagnosis and was significant in women and subjects aged >70 years. Among TB patients, delay in anti-TB treatment had a dose-response relationship with the risk of developing COPD. CONCLUSIONS: Some cases of COPD may be preventable by controlling the TB epidemic, early TB diagnosis, and prompt initiation of appropriate anti-TB treatment. Follow-up care and early intervention for COPD may be necessary for treated TB patients
Pyk2 activates the NLRP3 inflammasome by directly phosphorylating ASC and contributes to inflammasome-dependent peritonitis
The inflammasome adaptor protein, ASC, contributes to both innate immune responses and inflammatory diseases via self-oligomerization, which leads to the activation of the protease, caspase-1. Here, we report that the cytosolic tyrosine kinases, FAK and Pyk2, are differentially involved in NLRP3 and AIM2 inflammasome activation. The inhibition of FAK and Pyk2 with RNA interference or chemical inhibitors dramatically abolished ASC oligomerization, caspase-1 activation, and IL-1β secretion in response to NLRP3 or AIM2 stimulation. Pyk2 is phosphorylated by the kinase Syk and relocalizes to the ASC specks upon NLRP3 inflammasome activation. Pyk2, but not FAK, could directly phosphorylate ASC at Tyr146, and only the phosphorylated ASC could participate in speck formation and trigger IL-1β secretion. Moreover, the clinical-trial-tested Pyk2/FAK dual inhibitor PF-562271 reduced monosodium urate-mediated peritonitis, a disease model used for studying the consequences of NLRP3 activation. Our results suggest that although Pyk2 and FAK are involved in inflammasome activation, only Pyk2 directly phosphorylates ASC and brings ASC into an oligomerization-competent state by allowing Tyr146 phosphorylation to participate ASC speck formation and subsequent NLRP3 inflammation
Thermoelectric Figure-of-Merit of Fully Dense Single-Crystalline SnSe
Single-crystalline
SnSe has attracted much attention because of its record high figure-of-merit <i>ZT</i> ≈ 2.6; however, this high <i>ZT</i> has
been associated with the low mass density of samples which leaves
the intrinsic <i>ZT</i> of fully dense pristine SnSe in
question. To this end, we prepared high-quality fully dense SnSe single
crystals and performed detailed structural, electrical, and thermal
transport measurements over a wide temperature range along the major
crystallographic directions. Our single crystals were fully dense
and of high purity as confirmed via high statistics <sup>119</sup>Sn Mössbauer spectroscopy that revealed <0.35 at. % Sn(IV)
in pristine SnSe. The temperature-dependent heat capacity (<i>C</i><sub>p</sub>) provided evidence for the displacive second-order
phase transition from <i>Pnma</i> to <i>Cmcm</i> phase at <i>T</i><sub>c</sub> ≈ 800 K and a small
but finite Sommerfeld coefficient γ<sub>0</sub> which implied
the presence of a finite Fermi surface. Interestingly, despite its
strongly temperature-dependent band gap inferred from density functional
theory calculations, SnSe behaves like a low-carrier-concentration
multiband metal below 600 K, above which it exhibits a semiconducting
behavior. Notably, our high-quality single-crystalline SnSe exhibits
a thermoelectric figure-of-merit <i>ZT</i> ∼1.0,
∼0.8, and ∼0.25 at 850 K along the <i>b</i>, <i>c</i>, and <i>a</i> directions, respectively