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"Christian, Sonal"
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C+ 133.5 nm Emission Mechanisms on Mars Revealed by the MAVEN Observations
C+ emission is generated by electron impact, dissociative ionization, photoionization, and resonant scattering with carbon-related atoms, molecules, and ions in the Martian ionosphere and thermosphere. The contribution of each mechanism to the emission, however, has not been elucidated due to the difficulty of observation and the fact that a part of the emission cross section is unclear. The current paper isolates the C+ emission mechanism using remote-sensing and in situ observations on board Mars Atmosphere and Volatile EvolutioN. Both electron impact and dissociative ionization/photoionization contribute to C+ emission below 150 km altitude when the CO density is high, but only dissociative ionization/photoionization contributes to the emission for the low CO density case, while only dissociative ionization/photoionization dominates the emission at altitudes between 150 and 165 km for both CO density cases. It is difficult to estimate the total flux of suprathermal electrons in the ionosphere from remote-sensing observations of C+ emission because the contribution of electron impact to C+ emission is small. In contrast, C-atom remote-sensing observations might provide a better understanding of the total flux of suprathermal electrons in the ionosphere than C+ emission, and global ultraviolet observations could be utilized as a tool for monitoring the ionosphere. The total flux of suprathermal electrons estimated from C-atom emission may be utilized to isolate the contribution of each C+ emission process to the brightness more accurately. This suggests that the C+ and C-atom emissions might be tracers of spatiotemporal variations in the Martian ionosphere and thermosphere.
Journal Article
The PYRIN domain-only protein POP2 inhibits inflammasome priming and activation
Inflammasomes are protein platforms linking recognition of microbe, pathogen-associated and damage-associated molecular patterns by cytosolic sensory proteins to caspase-1 activation. Caspase-1 promotes pyroptotic cell death and the maturation and secretion of interleukin (IL)-1β and IL-18, which trigger inflammatory responses to clear infections and initiate wound-healing; however, excessive responses cause inflammatory disease. Inflammasome assembly requires the PYRIN domain (PYD)-containing adaptor ASC, and depends on PYD–PYD interactions. Here we show that the PYD-only protein POP2 inhibits inflammasome assembly by binding to ASC and interfering with the recruitment of ASC to upstream sensors, which prevents caspase-1 activation and cytokine release. POP2 also impairs macrophage priming by inhibiting the activation of non-canonical IκB kinase ɛ and IκBα, and consequently protects from excessive inflammation and acute shock
in vivo
. Our findings advance our understanding of the complex regulatory mechanisms that maintain a balanced inflammatory response and highlight important differences between individual POP members.
Excessive inflammasome activation leads to inflammatory diseases, but how inflammasomes are regulated by PYD-only adaptors is unclear. Here the authors show that the PYD-only protein POP2 inhibits both inflammasome priming and assembly by interfering, respectively, with IκBα activation and NLRP3-ASC interaction.
Journal Article
The Cohesin Subunit Rad21 Is Required for Synaptonemal Complex Maintenance, but Not Sister Chromatid Cohesion, during Drosophila Female Meiosis
Replicated sister chromatids are held in close association from the time of their synthesis until their separation during the next mitosis. This association is mediated by the ring-shaped cohesin complex that appears to embrace the sister chromatids. Upon proteolytic cleavage of the α-kleisin cohesin subunit at the metaphase-to-anaphase transition by separase, sister chromatids are separated and segregated onto the daughter nuclei. The more complex segregation of chromosomes during meiosis is thought to depend on the replacement of the mitotic α-kleisin cohesin subunit Rad21/Scc1/Mcd1 by the meiotic paralog Rec8. In Drosophila, however, no clear Rec8 homolog has been identified so far. Therefore, we have analyzed the role of the mitotic Drosophila α-kleisin Rad21 during female meiosis. Inactivation of an engineered Rad21 variant by premature, ectopic cleavage during oogenesis results not only in loss of cohesin from meiotic chromatin, but also in precocious disassembly of the synaptonemal complex (SC). We demonstrate that the lateral SC component C(2)M can interact directly with Rad21, potentially explaining why Rad21 is required for SC maintenance. Intriguingly, the experimentally induced premature Rad21 elimination, as well as the expression of a Rad21 variant with destroyed separase consensus cleavage sites, do not interfere with chromosome segregation during meiosis, while successful mitotic divisions are completely prevented. Thus, chromatid cohesion during female meiosis does not depend on Rad21-containing cohesin.
Journal Article
Patient and Health Care Professional Perceptions of the Experience and Impact of Symptoms of Moderate-to-Severe Crohn’s Disease in US and Europe: Results from the Cross-Sectional CONFIDE Study
BackgroundCrohn’s disease (CD) significantly affects patients’ health-related quality of life and well-being.AimsCommunicating Needs and Features of IBD Experiences (CONFIDE) survey explores the experience and impact of moderate-to-severe CD symptoms on patients’ lives and identifies communication gaps between patients and health care professionals (HCPs).MethodsOnline, quantitative, cross-sectional surveys of patients, and HCPs were conducted in the United States (US), Europe (France, Germany, Italy, Spain, United Kingdom), and Japan. Criteria based on previous treatment, steroid use, and/or hospitalization defined moderate-to-severe CD. US and Europe data are presented as descriptive statistics.ResultsSurveys were completed by 215 US and 547 European patients and 200 US and 503 European HCPs. In both patient groups, top three symptoms currently (past month) experienced were diarrhea, bowel urgency, and increased stool frequency, with more than one-third patients wearing diaper/pad/protection at least once a week in past 3 months due to fear of bowel urgency-related accidents. HCPs ranked diarrhea, blood in stool, and increased stool frequency as the most common symptoms. Although 34.0% US and 27.2% European HCPs ranked bowel urgency among the top five symptoms affecting patient lives, only 12.0% US and 10.9% European HCPs ranked it among top three most impactful symptoms on treatment decisions.ConclusionBowel urgency is common and impactful among patients with CD in the US and Europe. Differences in patient and HCP perceptions of experiences and impacts of bowel urgency exist, with HCPs underestimating its burden. Proactive communication between HCPs and patients in clinical settings is crucial for improving health outcomes in patients with CD.
Journal Article
68Ga labelled Exendin for radioguided surgery of intrapancreatic insulin producing lesions in patients with congenital hyperinsulinism
Background
Congenital hyperinsulinism (CHI) is a life threatening disease. Localization of affected intrapancreatic beta cells responsible for focal forms during surgery can be challenging. In this study we investigated a new radioguided surgical (RGS) approach using [
68
Ga]Exendin to facilitate intraoperative focus detection. All patients were scanned initially with [
18
F]-DOPA-PET followed by [
68
Ga]Exendin PET to differentiate between focal and non-focal forms. Focal CHI patients were then operated. At the beginning of standard surgical dissection of the pancreas in CHI patients (
n
= 12), 46 MBq of [
68
Ga]Exendin were injected intravenously. Intrapancreatic localization of the foci was determined by using a hand-held positron- and gamma-radiation probe. RGS was carried out as enucleation of CHI foci. Duration of surgery (defined as the time lapse from first incision until final suture placement) for RGS was compared with historical data of patients operated on without RGS. Long term follow-up data on euglycemic control were retrieved from patient´s medical files.
Results
[
18
F]-DOPA- and [
68
Ga]Exendin PET findings were concordant in all patients. Overall, 12 CHI patients underwent RGS. In 11/12 children (92%) the CHI foci localized pre-operatively by [
68
Ga]Exendin PET could be detected intraoperatively using the hand-held positron probe. There was a high correlation between PET imaging results and positron probe findings in respect to the identification of the affected pancreatic region. One pancreatic lesion in close proximity to the left kidney could not be detected by the positron probe. Histopathology confirmed all resected lesions as CHI foci. Intraoperatively, the signal of the focus was > 10 times higher than the signal of normal adjacent pancreatic tissue. Median duration of surgery was 4.7 h (CI 3.5–6.7) in RGS patients compared to 5.5 h (CI 4-6.7) in patients undergoing surgery without radio guidance. All patients remained euglycemic after surgery (median follow-up 3 years, range 2 to 4.5).
Conclusions
In this study, we demonstrated the use of [
68
Ga]Exendin for intraoperative localization of intrapancreatic CHI foci. RGS facilitates localization of intrapancreatic CHI focus and thus potentially reduces duration of surgery and perioperative complications.
Journal Article
An rhs gene of Pseudomonas aeruginosa encodes a virulence protein that activates the inflammasome
The rhs genes are a family of enigmatic composite genes, widespread among Gram-negative bacteria. In this study, we characterized rhsT, a Pseudomonas aeruginosa rhs gene that encodes a toxic protein. Expression of rhsT was induced upon contact with phagocytic cells. The RhsT protein was exposed on the bacterial surface and translocated into phagocytic cells; these cells subsequently underwent inflammasome-mediated death. Moreover, RhsT enhanced host secretion of the potent proinflammatory cytokines IL-18and IL-18 in an inflammasome-dependent manner. In a mouse model of acute pneumonia, infection with a P. aeruginosa strain lacking rhsT was associated with less IL-18 production, fewer recruited leukocytes, reduced pulmonary bacterial load, and enhanced animal survival. Thus, rhsT encodes a virulence determinant that activates the inflammasome.
Journal Article
The PYRIN domain–only protein POP3 inhibits ALR inflammasomes and regulates responses to infection with DNA viruses
Much is known about the activation of inflammasomes, but less is known about their negative regulation. Stehlik and colleagues demonstrate that the pyrin domain–only protein POP3 negatively regulates inflammasomes involved in sensing DNA.
The innate immune system responds to infection and tissue damage by activating cytosolic sensory complexes called 'inflammasomes'. Cytosolic DNA is sensed by AIM2-like receptors (ALRs) during bacterial and viral infections and in autoimmune diseases. Subsequently, recruitment of the inflammasome adaptor ASC links ALRs to the activation of caspase-1. A controlled immune response is crucial for maintaining homeostasis, but the regulation of ALR inflammasomes is poorly understood. Here we identified the PYRIN domain (PYD)-only protein POP3, which competes with ASC for recruitment to ALRs, as an inhibitor of DNA virus–induced activation of ALR inflammasomes
in vivo
. Data obtained with a mouse model with macrophage-specific POP3 expression emphasize the importance of the regulation of ALR inflammasomes in monocytes and macrophages.
Journal Article
TRIM21 facilitates inflammasome assembly and contributes to autoinflammatory disease
Inflammasomes are cytosolic multiprotein complexes facilitating the maturation and release of the inflammatory cytokines interleukin (IL)−1β and IL-18 and pyroptosis. ASC (apoptosis-associated-speck-like protein containing a CARD) is the central inflammasome adaptor. ASC polymerization is crucial for inflammasome assembly, and ASC particle release propagates inflammasome responses to bystander cells. However, control of inflammasome and ASC particle assembly to limit chronic inflammation and the emergence of autoinflammatory diseases is still incompletely understood. Here, we show that the E3 ubiquitin ligase TRIM (tripartite-motif-containing protein) 21, a common autoantigen in autoimmune diseases, is involved in inflammasome assembly. Specifically, TRIM21 binds to and ubiquitinates ASC to facilitate ASC/NLRP3 interactions, ASC polymerization and the release of ASC/TRIM21-containing particles during pyroptosis in human and mouse macrophages. Furthermore, we detect systemic ASC/TRIM21 particles and autoantibodies in human and mouse autoinflammatory disease. Thus, our findings highlight a previously unrecognized role of TRIM21 as an inflammasome component and driver of autoinflammation.
Journal Article
