Warping and F-term uplifting

We analyse the effective supergravity model of a warped compactification with matter on D3 and D7-branes. We find that the main effect of the warp factor is to modify the F-terms while leaving the D-terms invariant. Hence warped models with moduli stabilisation and a small positive cosmological constant resulting from a large warping can only be achieved with an almost vanishing D-term and a F-term uplifting. By studying string-motivated examples with gaugino condensation on magnetised D7-branes, we find that even with a vanishing D-term, it is difficult to achieve a Minkowski minimum for reasonable parameter choices. When coupled to an ISS sector the AdS vacua is uplifted, resulting in a small gravitino mass for a warp factor of order 10^-5.Comment: 24 pages, v3: typos, minor clarifications adde

Nursing home nurses’ and community-dwelling older adults’ reported knowledge, attitudes, and behavior toward antibiotic use

Abstract Background Antibiotic overuse causes antibiotic resistance, one of the most important threats to human health. Older adults, particularly those in nursing homes, often receive antibiotics when they are not indicated. Methods To understand knowledge, attitudes, and behaviors of nursing home (NH) nurses and community-dwelling older adults towards antibiotic use, especially in clinical situations consistent with antibiotic overuse, we conducted a mixed-method survey in two NHs and one Family Medicine clinic in North Carolina, among English-speaking nurses and community-dwelling, cognitively intact adults aged 65 years or older. Based on the Knowledge-Attitude-Practice model, the survey assessed knowledge, attitudes, and behavior towards antibiotic use, including three vignettes designed to elicit possible antibiotic overuse: asymptomatic bacteriuria (ASB), a viral upper respiratory illness (URI), and a wound from a fall. Results Of 31 NH nurses and 66 community-dwelling older adults, 70% reported knowledge of the dangers of taking antibiotics. Nurses more often reported evidence-based attitudes towards antibiotics than older adults, except 39% agreed with the statement “by the time I am sick enough to go to the doctor with a cold, I expect an antibiotic”, while only 28% of older adults agreed with it. A majority of nurses did not see the need for antibiotics in any of the three vignettes: 77% for the ASB vignette, 87% for the URI vignette, and 97% for the wound vignette. Among older adults, 50% did not perceive a need for antibiotics in the ASB vignette, 58% in the URI vignette, and 74% in the wound vignette. Conclusions While a substantial minority had no knowledge of the dangers of antibiotic use, non-evidence-based attitudes towards antibiotics, and behaviors indicating inappropriate management of suspected infections, most NH nurses and community-dwelling older adults know the harms of antibiotic use and demonstrate evidence-based attitudes and behaviors. However, more work is needed to improve the knowledge, attitudes and behaviors that may contribute to antibiotic overuse

The Density and Temperature of Molecular Clouds in M33

We have observed the $^{12}$CO J=2-1, J=3-2, and $^{13}$CO J=2-1 lines in a sample of seven giant molecular clouds in the Local Group spiral galaxy M33. The $^{12}$CO/$^{13}$CO J=2-1 line ratio is constant across the entire sample, while the observed $^{12}$CO J=3-2/J=2-1 line ratio has a weak dependence on the star formation environment of the cloud, with large changes in the line ratio seen only for clouds in the immediate vicinity of an extremely luminous HII region. A large velocity gradient analysis indicates that clouds without HII regions have temperatures of 10-20 K, clouds with HII regions have temperatures of 15-100 K, and the cloud in the giant HII region has a temperature of at least 100 K. Interestingly, the giant HII region appears capable of raising the kinetic temperature of the molecular gas only for clouds that are quite nearby ($< 100$ pc). The continuous change of physical conditions across the observed range of star formation environments suggests that the unusual physical conditions in the cloud in the giant HII region are due to post-star formation changes in the molecular gas, rather than intrinsic properties of the gas related to the formation of the giant HII region.Comment: 14 pages, aastex, 4 postscript figures; accepted for publication in ApJ; also available at http://www.physics.mcmaster.ca/Wilson_Preprint

Activation of caspase-1 by the NLRP3 inflammasome regulates the NADPH oxidase NOX2 to control phagosome function

Phagocytosis is a fundamental cellular process that is pivotal for immunity as it coordinates microbial killing, innate immune activation and antigen presentation. An essential step in this process is phagosome acidification, which regulates a number of functions of these organelles that allow them to participate in processes essential to both innate and adaptive immunity. Here we report that acidification of phagosomes containing Gram-positive bacteria is regulated by the NLRP3-inflammasome and caspase-1. Active caspase-1 accumulates on phagosomes and acts locally to control the pH by modulating buffering by the NADPH oxidase NOX2. These data provide insight into a mechanism by which innate immune signals can modify cellular defenses and establish a new function for the NLRP3-inflammasome and caspase-1 in host defense

CD36 coordinates NLRP3 inflammasome activation by facilitating the intracellular nucleation from soluble to particulate ligands in sterile inflammation

Particulate ligands including cholesterol crystals and amyloid fibrils induce NLRP3-dependent production of interleukin-1β (IL-1β) in atherosclerosis, Alzheimer's disease and diabetes. Soluble endogenous ligands including oxidized-LDL, amyloid-β and amylin peptides accumulate in these diseases. Here we identify a CD36-mediated endocytic pathway that coordinates the intracellular conversion of these soluble ligands to crystals or fibrils, resulting in lysosomal disruption and NLRP3-inflammasome activation. Consequently, macrophages lacking CD36 failed to elicit IL-1β production in response to these ligands and targeting CD36 in atherosclerotic mice reduced serum IL-1β and plaque cholesterol crystal accumulation. Collectively, these findings highlight the importance of CD36 in the accrual and nucleation of NLRP3 ligands from within the macrophage and position CD36 as a central regulator of inflammasome activation in sterile inflammation

Multifunctional proteins revealed by overlapping clustering in protein interaction network

Motivation: Multifunctional proteins perform several functions. They are expected to interact specifically with distinct sets of partners, simultaneously or not, depending on the function performed. Current graph clustering methods usually allow a protein to belong to only one cluster, therefore impeding a realistic assignment of multifunctional proteins to clusters

Excess BMI Accelerates Islet Autoimmunity in Older Children and Adolescents

Objective: Sustained excess BMI increases the risk of type 1 diabetes (T1D) in autoantibody-positive relatives without diabetes of patients. We tested whether elevated BMI also accelerates the progression of islet autoimmunity before T1D diagnosis. Research design and methods: We studied 706 single autoantibody-positive pediatric TrialNet participants (ages 1.6-18.6 years at baseline). Cumulative excess BMI (ceBMI) was calculated for each participant based on longitudinally accumulated BMI ≥85th age- and sex-adjusted percentile. Recursive partitioning analysis and multivariable modeling defined the age cut point differentiating the risk for progression to multiple positive autoantibodies. Results: At baseline, 175 children (25%) had a BMI ≥85th percentile. ceBMI range was -9.2 to 15.6 kg/m2 (median -1.91), with ceBMI ≥0 kg/m2 corresponding to persistently elevated BMI ≥85th percentile. Younger age increased the progression to multiple autoantibodies, with age cutoff of 9 years defined by recursive partitioning analysis. Although ceBMI was not significantly associated with progression from single to multiple autoantibodies overall, there was an interaction with ceBMI ≥0 kg/m2, age, and HLA (P = 0.009). Among children ≥9 years old without HLA DR3-DQ2 and DR4-DQ8, ceBMI ≥0 kg/m2 increased the rate of progression from single to multiple positive autoantibodies (hazard ratio 7.32, P = 0.004) and conferred a risk similar to that in those with T1D-associated HLA haplotypes. In participants <9 years old, the effect of ceBMI on progression to multiple autoantibodies was not significant regardless of HLA type. Conclusions: These data support that elevated BMI may exacerbate islet autoimmunity prior to clinical T1D, particularly in children with lower risk based on age and HLA. Interventions to maintain normal BMI may prevent or delay the progression of islet autoimmunity

Epidemiology, clinical features and management of autoimmune hepatitis in Switzerland: a retrospective and prospective cohort study

BACKGROUND AND AIMS: The Swiss Autoimmune Hepatitis Cohort Study is a nationwide registry, initiated in 2017, that collects retrospective and prospective clinical data and biological samples from patients of all ages with autoimmune hepatitis treated at Swiss hepatology centres. Here, we report the analysis of the first 5 years of registry data. RESULTS: A total of 291 patients with autoimmune hepatitis have been enrolled, 30 of whom were diagnosed before 18 years of age and composed the paediatric cohort. Paediatric cohort: median age at diagnosis 12.5 years (range 1–17, interquartile range (IQR) 8–15), 16 (53%) girls, 6 (32%) with type 2 autoimmune hepatitis, 8 (27%) with autoimmune sclerosing cholangitis, 1 with primary biliary cholangitis variant syndrome, 4 (15%) with inflammatory bowel disease and 10 (41%) with advanced liver fibrosis at diagnosis. Adult cohort: median age at diagnosis 54 years (range 42–64, IQR 18–81), 185 (71%) women, 51 (20%) with primary biliary cholangitis variant syndrome, 22 (8%) with primary sclerosing cholangitis variant syndrome, 9 (4%) with inflammatory bowel disease and 66 (32%) with advanced liver fibrosis at diagnosis. The median follow-up time for the entire cohort was 5.2 years (IQR 3–9.3 years). Treatment in children: 29 (97%) children were initially treated with corticosteroids, 28 of whom received combination treatment with azathioprine. Budesonide was used in four children, all in combination with azathioprine. Mycophenolate mofetil was used in five children, all of whom had previously received corticosteroids and thiopurine. Treatment in adults (data available for 228 patients): 219 (96%) were treated with corticosteroids, mostly in combination with azathioprine. Predniso(lo)ne was the corticosteroid used in three-quarters of patients; the other patients received budesonide. A total of 78 (33%) patients received mycophenolate mofetil, 62 of whom had previously been treated with azathioprine. Complete biochemical response was achieved in 13 of 19 (68%) children and 137 of 182 (75%) adults with available follow-up data. All children were alive at the last follow-up, and none had undergone liver transplantation. Five (2%) adults underwent liver transplantation, two of whom had a fulminant presentation. Four (2%) adults with autoimmune hepatitis died (two from liver-associated causes). CONCLUSION: Patients with autoimmune hepatitis in Switzerland had clinical features similar to those in other cohorts. The proportion of patients diagnosed with primary biliary cholangitis variant syndrome was higher than expected. Autoimmune hepatitis was managed according to guidelines, except for the use of budesonide in a small proportion of paediatric patients. The outcomes were excellent, but the findings must be confirmed over a longer follow-up period

In vitro neutrophil migration is associated with inhaled corticosteroid treatment and serum cytokines in pediatric asthma.

Background: Different asthma phenotypes are driven by molecular endotypes. A Th1-high phenotype is linked to severe, therapy-refractory asthma, subclinical infections and neutrophil inflammation. Previously, we found neutrophil granulocytes (NGs) from asthmatics exhibit decreased chemotaxis towards leukotriene B4 (LTB4), a chemoattractant involved in inflammation response. We hypothesized that this pattern is driven by asthma in general and aggravated in a Th1-high phenotype. Methods: NGs from asthmatic nd healthy children were stimulated with 10 nM LTB4/100 nM N-formylmethionine-leucyl-phenylalanine and neutrophil migration was documented following our prior SiMA (simplified migration assay) workflow, capturing morphologic and dynamic parameters from single-cell tracking in the images. Demographic, clinical and serum cytokine data were determined in the ALLIANCE cohort. Results: A reduced chemotactic response towards LTB4 was confirmed in asthmatic donors regardless of inhaled corticosteroid (ICS) treatment. By contrast, only NGs from ICS-treated asthmatic children migrate similarly to controls with the exception of Th1-high donors, whose NGs presented a reduced and less directed migration towards the chemokines. ICS-treated and Th1-high asthmatic donors present an altered surface receptor profile, which partly correlates with migration. Conclusions: Neutrophil migration in vitro may be affected by ICS-therapy or a Th1-high phenotype. This may be explained by alteration of receptor expression and could be used as a tool to monitor asthma treatment