What is the impact of religious repression on forced migration? While current and historical cases highlight the significance of state-sponsored religions repression, existing quantitative studies on ...forced migration have not sufficiently addressed the role of religion as a determinant of flight. We argue that religious repression undermines the quality of life, quality of religious observance, and physical integrity of religious communities, and therefore increases incentives to leave. We test this through a quantitative analysis of forced migration data from 1990 to 2008 and several measures of religious repression, using a negative binomial regression. We find that state-driven religious repression, in particular religious bans, tends to increase forced migration. These findings contribute to the body of forced migration literature and the study of religion and politics by demonstrating the significant effects religious repression has on this aspect of world politics.
ATP-binding and hydrolysis of human NLRP3 Brinkschulte, Rebecca; Fußhöller, David M; Hoss, Florian ...
Communications biology,
11/2022, Volume:
5, Issue:
1
Journal Article
Peer reviewed
Open access
The innate immune system uses inflammasomal proteins to recognize danger signals and fight invading pathogens. NLRP3, a multidomain protein belonging to the family of STAND ATPases, is characterized ...by its central nucleotide-binding NACHT domain. The incorporation of ATP is thought to correlate with large conformational changes in NLRP3, leading to an active state of the sensory protein. Here we analyze the intrinsic ATP hydrolysis activity of recombinant NLRP3 by reverse phase HPLC. Wild-type NLRP3 appears in two different conformational states that exhibit an approximately fourteen-fold different hydrolysis activity in accordance with an inactive, autoinhibited state and an open, active state. The impact of canonical residues in the nucleotide binding site as the Walker A and B motifs and sensor 1 and 2 is analyzed by site directed mutagenesis. Cellular experiments show that reduced NLRP3 hydrolysis activity correlates with higher ASC specking after inflammation stimulation. Addition of the kinase NEK7 does not change the hydrolysis activity of NLRP3. Our data provide a comprehensive view on the function of conserved residues in the nucleotide-binding site of NLRP3 and the correlation of ATP hydrolysis with inflammasome activity.
Heritable factors play an important etiologic role in connective tissue disorders (CTD) with vascular involvement, and a genetic diagnosis is getting increasingly important for gene-tailored, ...personalized patient management.
We analyzed 32 disease-associated genes by using targeted next-generation sequencing and exome sequencing in a clinically relevant cohort of 199 individuals. We classified and refined sequence variants according to their likelihood for pathogenicity.
We identified 1 pathogenic variant (PV; in FBN1 or SMAD3) in 15 patients (7.5%) and ≥1 likely pathogenic variant (LPV; in COL3A1, FBN1, FBN2, LOX, MYH11, SMAD3, TGFBR1, or TGFBR2) in 19 individuals (9.6%), together resulting in 17.1% diagnostic yield. Thirteen PV/LPV were novel. Of PV/LPV-negative patients 47 (23.6%) showed ≥1 variant of uncertain significance (VUS). Twenty-five patients had concomitant variants. In-depth evaluation of reported/calculated variant classes resulted in reclassification of 19.8% of variants.
Variant classification and refinement are essential for shaping mutational spectra of disease genes, thereby improving clinical sensitivity. Obligate stringent multigene analysis is a powerful tool for identifying genetic causes of clinically related CTDs. Nonetheless, the relatively high rate of PV/LPV/VUS-negative patients underscores the existence of yet unknown disease loci and/or oligogenic/polygenic inheritance.
γδ T cells are unconventional T cells that have been demonstrated to be crucial for the pathogenesis and potentially for the cure of HIV-1 infection. The ectonucleotidase CD39 is part of the ...purinergic pathway that regulates immune responses by degradation of pro-inflammatory ATP in concert with CD73. Few studies on the expression of the ectoenzymes CD73 and CD39 on human γδ T cells in HIV have been performed to date.
PBMC of n=86 HIV-1-infected patients were compared to PBMC of n=26 healthy individuals using 16-color flow cytometry determining the surface expression of CD39 and CD73 on Vδ1 and Vδ2 T cells in association with differentiation (CD45RA, CD28, CD27), activation and exhaustion (TIGIT, PD-1, CD38, and HLA-DR), and assessing the intracellular production of pro- and anti-inflammatory cytokines (IL-2, TGF-ß, TNF-α, Granzyme B, IL-10, IFN-γ) after
stimulation with PMA/ionomycin.
CD39 and CD73 expression on γδ T cells were inversed in HIV infection which correlated with HIV disease progression and immune activation. CD39, but not CD73 expression on γδ T cells of ART-treated patients returned to levels comparable with those of healthy individuals. Only a small subset (<1%) of γδ T cells co-expressed CD39 and CD73 in healthy or HIV-infected individuals. There were significantly more exhausted and terminally differentiated CD39+ Vδ1 T cells regardless of the disease status. Functionally, IL-10 was only detectable in CD39+ γδ T cells after
stimulation in all groups studied. Viremic HIV-infected patients showed the highest levels of IL-10 production. The highest percentage of IL-10+ cells was found in the small CD39/CD73 co-expressing γδ T-cell population, both in healthy and HIV-infected individuals. Also, CD39+ Vδ2 T cells produced IL-10 more frequently than their CD39+ Vδ1 counterparts in all individuals regardless of the HIV status.
Our results point towards a potential immunomodulatory role of CD39+ and CD73+ γδ T cells in the pathogenesis of chronic HIV infection that needs further investigation.
HIF1A is a transcription factor that plays a central role for the adaptation to tissue hypoxia and for the inflammatory response of myeloid cells, including DCs. HIF1A is stabilized by hypoxia but ...also by TLR ligands under normoxic conditions. The underlying signaling events leading to the accumulation of HIF1A in the presence of oxygen are still poorly understood. Here, we show that in contrast to hypoxic stabilization of HIF1A, normoxic, TLR-mediated HIF1A accumulation in DCs follows a different pathway that predominantly requires MYD88-dependent NF-κB activity. The TLR-induced HIF1A controls a subset of proinflammatory genes that are insufficiently induced following hypoxia-mediated HIF1A induction. Thus, TLR activation and hypoxia stabilize HIF1A via distinct signaling pathways, resulting in differential HIF1A-dependent gene expression.
Nonanesthesiologist administered propofol (NAAP) sedation for flexible bronchoscopy is controversial, because there is no established airway management (AM) training for pulmonologists. The aim was ...to investigate the performance and acceptance of a proposed AM algorithm and training for pulmonologists performing NAAP sedation. The algorithm includes using 3 maneuvers including bag mask ventilation (BMV), laryngeal tube (LT), and needle cricothyrotomy (NCT). During training (consisting of 2 sessions with a break of 9 weeks in between), these maneuvers were demonstrated and exercised, followed by 4 consecutive attempts to succeed with each of these devices. The primary outcome was the improvement of completion time needed for a competent airway. Secondary outcomes were the trainees' overall reactions to the training and algorithm, and the perceptions of psychological safety (PS). The 23 staff members of the Department of Pulmonology performed a total of 552 attempts at AM procedures (4 attempts at each of the 3 maneuvers in 2 sessions), and returned a total of 42 questionnaires (4 questionnaires were not returned). Median completion times of LT and NCT improved significantly between Sessions 1 and 2 (P = 0.005 and P = 0.04, respectively), whereas BMV was only marginally improved (P = 0.05). Trainees perceived training to be useful and expressed satisfaction with this training and the algorithm. The perception of PS increased after training. An AM algorithm and training for pulmonologists leads to improved technical AM skills, and is considered useful by trainees and raised their perception of PS during training. It thus represents a promising program.
Pelvic radiographs are routinely obtained in adult trauma to optimise early management. In adults, pelvic fractures are associated with high early transfusion requirement, high injury severity scores ...and an increased incidence of other abdominal and thoracic injuries. It is unclear whether this holds true in children.
To determine whether the screening pelvic radiograph is necessary in paediatric trauma.
The notes of all patients who presented after trauma to the Starship Children's Hospital and were triaged to the resuscitation room during 1997 were reviewed. Results of initial radiography were obtained and correlated with later imaging.
Our review of 444 injured children seen over a period of 1 year revealed that of 347 children who had screening pelvic radiographs, only 1 had a pelvic fracture. The fracture in this child was clinically apparent and required no specific treatment.
The presence of a pelvic fracture is rare in injured children. By omitting screening pelvic radiographs there are potential benefits, including reduced radiation exposure to children and cost savings. Uninterpretable or abnormal clinical examination or haematuria requires further investigation, but routine screening for pelvic fracture is unnecessary.
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