The Catalogue for Astrophysical Turbulence Simulations (CATS)

Turbulence is a key process in many fields of astrophysics. Advances in numerical simulations of fluids over the last several decades have revolutionized our understanding of turbulence and related processes such as star formation and cosmic ray propagation. However, data from numerical simulations of astrophysical turbulence are often not made public. We introduce a new simulation-oriented database for the astronomical community: the Catalogue for Astrophysical Turbulence Simulations (CATS), located at www.mhdturbulence.com. CATS includes magnetohydrodynamic (MHD) turbulent box simulation data products generated by the public codes athena++, arepo, enzo, and flash. CATS also includes several synthetic observational data sets, such as turbulent HI data cubes. We also include measured power spectra and three-point correlation functions from some of these data. We discuss the importance of open-source statistical and visualization tools for the analysis of turbulence simulations such as those found in CATS.D.C. acknowledges compute resources provided by NSF TRAC allocations TG-AST090110, TG-MCA07S014, and TG-AST140008. C.F. acknowledges funding provided by the Australian Research Council (Discovery Project DP170100603 and Future Fellowship FT180100495), the Australia-Germany Joint Research Cooperation Scheme (UA-DAAD), and high-performance computing resources provided by the Leibniz Rechenzentrum, the Gauss Centre for Supercomputing (grants pr32lo), and the Australian National Computational Infrastructure (grant ek9) in the framework of the National Computational Merit Allocation Scheme and the ANU Merit Allocation Scheme.and from the National Computational Infrastructure (NCI), which is supported by the Australian Government (award jh2). A.L. acknowledges the support of the NSF AST 1816234, NASA TCAN 144AAG1967, NASA ATP AAH7546 and the Flatiron Institute. J.C.'s work is supported by the National R&D Program through the National Research Foundation of Korea Grants funded by the Korean Government (NRF2016R1A5A1013277 and NRF-2016R1D1A1B02015014). P.M. acknowledges support for this work provided by NASA through Einstein Postdoctoral Fellowship grant number PF7-180164 awarded by the Chandra X-ray Center, which is operated by the Smithsonian Astrophysical Observatory for NASA under contract NAS8-0306

Antigenicity and immunogenicity of sulphamethoxazole: demonstration of metabolism-dependent haptenation and T-cell proliferation in vivo

1. Sulphamethoxazole has been associated with the occurrence of hypersensitivity reactions. There is controversy as to whether the immune response is metabolism-dependent or -independent. We have therefore investigated the site of antigen formation and the nature of the drug signal presented to the immune system in vivo. 2. Male Wistar rats were dosed with sulphamethoxazole, sulphamethoxazole hydroxylamine or nitroso sulphamethoxazole. Antigen formation on cell surfaces was determined by flow cytometry using a specific anti-sulphamethoxazole antibody. Immunogenicity was determined by assessment of ex vivo T-cell proliferation. 3. Administration of nitroso sulphamethoxazole, but not sulphamethoxazole or sulphamethoxazole hydroxylamine, resulted in antigen formation on the surface of lymphocytes, splenocytes and epidermal keratinocytes, and a strong proliferative response of splenocytes on re-stimulation with nitroso sulphamethoxazole. Rats dosed with sulphamethoxazole or sulphamethoxazole hydroxylamine did not respond to any of the test compounds. 4. CD4(+) or CD8(+) depleted cells responded equally to nitroso sulphamethoxazole. The proliferative response to nitroso sulphamethoxazole was seen even after pulsing for only 5 min, and was not inhibited by glutathione. Responding cells produced IFN-γ, but not IL-4. 5. Haptenation of cells by sulphamethoxazole hydroxylamine was seen after depletion of glutathione by pre-treating the rats with diethyl maleate. Splenocytes from the glutathione-depleted sulphamethoxazole hydroxylamine-treated rats responded weakly to nitroso sulphamethoxazole, but not to sulphamethoxazole or sulphamethoxazole hydroxylamine. 6. Dosing of rats with sulphamethoxazole produced a cellular response to nitroso sulphamethoxazole (but not to sulphamethoxazole or its hydroxylamine) when the animals were primed with complete Freund's adjuvant. 7. These studies demonstrate the antigenicity of nitroso sulphamethoxazole in vivo and provide evidence for the role of drug metabolism and cell surface haptenation in the induction of a cellular immune response in the rat

Rivastigmine for the prevention of postoperative delirium in elderly patients undergoing elective cardiac surgery--a randomized controlled trial

OBJECTIVE: Cardiac surgery is frequently followed by postoperative delirium, which is associated with increased 1-year mortality, late cognitive deficits, and higher costs. Currently, there are no recommendations for pharmacologic prevention of postoperative delirium. Impaired cholinergic transmission is believed to play an important role in the development of delirium. We tested the hypothesis that prophylactic short-term administration of oral rivastigmine, a cholinesterase inhibitor, reduces the incidence of delirium in elderly patients during the first 6 days after elective cardiac surgery. DESIGN:: Double-blind, randomized, placebo-controlled trial. SETTING: One Swiss University Hospital. PATIENTS: One hundred twenty patients aged 65 or older undergoing elective cardiac surgery with cardiopulmonary bypass. INTERVENTION: Patients were randomly assigned to receive either placebo or 3 doses of 1.5 mg of oral rivastigmine per day starting the evening before surgery and continuing until the evening of the sixth postoperative day. MEASUREMENTS AND MAIN RESULTS: The primary predefined outcome was delirium diagnosed with the Confusion Assessment Method within 6 days postoperatively. Secondary outcome measures were the results of daily Mini-Mental State Examinations and clock drawing tests, and the use of a rescue treatment consisting of haloperidol and/or lorazepam in patients with delirium. Delirium developed in 17 of 57 (30%) and 18 of 56 (32%) patients in the placebo and rivastigmine groups, respectively (p = 0.8). There was no treatment effect on the time course of Mini-Mental State Examinations and clock drawing tests (p = 0.4 and p = 0.8, respectively). There was no significant difference in the number of patients receiving haloperidol (18 of 57 and 17 of 56, p = 0.9) or lorazepam (38 of 57 and 35 of 56, p = 0.6) in the placebo and rivastigmine groups, respectively. CONCLUSION: This negative or, because of methodologic issues, possibly failed trial does no support short-term prophylactic administration of oral rivastigmine to prevent postoperative delirium in elderly patients undergoing elective cardiac surgery with cardiopulmonary bypass

Monitoring of cerebral blood flow autoregulation in adults undergoing sevoflurane anesthesia: a prospective cohort study of two age groups.

Autoregulation of blood flow is a key feature of the human cerebral vascular system to assure adequate oxygenation and metabolism of the brain under changing physiological conditions. The impact of advanced age and anesthesia on cerebral autoregulation remains unclear. The primary objective of this study was to determine the effect of sevoflurane anesthesia on cerebral autoregulation in two different age groups. This is a follow-up analysis of data acquired in a prospective observational cohort study. One hundred thirty-three patients aged 18-40 and ≥65 years scheduled for major noncardiac surgery under general anesthesia were included. Cerebral autoregulation indices, limits, and ranges were compared in young and elderly patient groups. Forty-nine patients (37 %) aged 18-40 years and 84 patients (63 %) aged ≥65 years were included in the study. Age-adjusted minimum alveolar concentrations of sevoflurane were 0.89 ± 0.07 in young and 0.99 ± 0.14 in older subjects (P < 0.001). Effective autoregulation was found in a blood pressure range of 13.8 ± 9.8 mmHg in young and 10.2 ± 8.6 mmHg in older patients (P = 0.079). The lower limit of autoregulation was 66 ± 12 mmHg and 73 ± 14 mmHg in young and older patients, respectively (P = 0.075). The association between sevoflurane concentrations and autoregulatory capacity was similar in both age groups. Our data suggests that the autoregulatory plateau is shortened in both young and older patients under sevoflurane anesthesia with approximately 1 MAC. Lower and upper limits of cerebral blood flow autoregulation, as well as the autoregulatory range, are not influenced by the age of anesthetized patients. Trial registration ClinicalTrials.gov (NCT00512200)

Discovery of CDZ173 (Leniolisib), Representing a Structurally Novel Class of PI3K Delta-Selective Inhibitors

The predominant expression of phosphoinositide 3-kinase δ (PI3Kδ) in leukocytes and its critical role in B and T cell functions led to the hypothesis that selective inhibitors of this isoform would have potential as therapeutics for the treatment of allergic and inflammatory disease. Targeting specifically PI3Kδ should avoid potential side effects associated with the ubiquitously expressed PI3Kα and β isoforms. We disclose how morphing the heterocyclic core of previously discovered 4,6-diaryl quinazolines to a significantly less lipophilic 5,6,7,8-tetrahydropyrido­[4,3-<i>d</i>]­pyrimidine, followed by replacement of one of the phenyl groups with a pyrrolidine-3-amine, led to a compound series with an optimal on-target profile and good ADME properties. A final lipophilicity adjustment led to the discovery of CDZ173 (leniolisib), a potent PI3Kδ selective inhibitor with suitable properties and efficacy for clinical development as an anti-inflammatory therapeutic. <i>In vitro</i>, CDZ173 inhibits a large spectrum of immune cell functions, as demonstrated in B and T cells, neutrophils, monocytes, basophils, plasmocytoid dendritic cells, and mast cells. <i>In vivo</i>, CDZ173 inhibits B cell activation in rats and monkeys in a concentration- and time-dependent manner. After prophylactic or therapeutic dosing, CDZ173 potently inhibited antigen-specific antibody production and reduced disease symptoms in a rat collagen-induced arthritis model. Structurally, CDZ173 differs significantly from the first generation of PI3Kδ and PI3Kγδ-selective clinical compounds. Therefore, CDZ173 could differentiate by a more favorable safety profile. CDZ173 is currently in clinical studies in patients suffering from primary Sjögren’s syndrome and in APDS/PASLI, a disease caused by gain-of-function mutations of PI3Kδ

Deficiency of MALT1 paracaspase activity results in unbalanced regulatory and effector T and B cell responses leading to multiorgan inflammation

The paracaspase MALT1 plays an important role in immune receptor-driven signaling pathways leading to NF-κB activation. MALT1 promotes signaling by acting as a scaffold, recruiting downstream signaling proteins, as well as by proteolytic cleavage of multiple substrates. However, the relative contributions of these two different activities to T and B cell function are not well understood. To investigate how MALT1 proteolytic activity contributes to overall immune cell regulation, we generated MALT1 protease-deficient mice (Malt1(PD/PD)) and compared their phenotype with that of MALT1 knockout animals (Malt1(-/-)). Malt1(PD/PD) mice displayed defects in multiple cell types including marginal zone B cells, B1 B cells, IL-10-producing B cells, regulatory T cells, and mature T and B cells. In general, immune defects were more pronounced in Malt1(-/-) animals. Both mouse lines showed abrogated B cell responses upon immunization with T-dependent and T-independent Ags. In vitro, inactivation of MALT1 protease activity caused reduced stimulation-induced T cell proliferation, impaired IL-2 and TNF-α production, as well as defective Th17 differentiation. Consequently, Malt1(PD/PD) mice were protected in a Th17-dependent experimental autoimmune encephalomyelitis model. Surprisingly, Malt1(PD/PD) animals developed a multiorgan inflammatory pathology, characterized by Th1 and Th2/0 responses and enhanced IgG1 and IgE levels, which was delayed by wild-type regulatory T cell reconstitution. We therefore propose that the pathology characterizing Malt1(PD/PD) animals arises from an immune imbalance featuring pathogenic Th1- and Th2/0-skewed effector responses and reduced immunosuppressive compartments. These data uncover a previously unappreciated key function of MALT1 protease activity in immune homeostasis and underline its relevance in human health and disease

Deficiency in MALT1 paracaspase activity promotes multi-organ inflammation

The paracaspase MALT1 plays an important role in signaling pathways leading to NF-kB activation. To investigate the contribution of its proteolytic activity to overall pathway regulation we generated MALT1 protease-deficient mice (Malt1PD/PD) and compared them to MALT1 KO animals (Malt1-/-). Malt1PD/PD mice displayed defects in multiple cell types including Treg, IL10-producing B cells and mature T and B cells. Immune defects were more pronounced in Malt1-/- animals. Both mouse lines showed abrogated B cell responses upon immunization and were protected in a Th17-dependent EAE model. Surprisingly, Malt1PD/PD animals developed a multi-organ inflammation characterized by Th2-type responses and enhanced IgG1 and IgE levels which was prevented by reconstitution with WT Treg. These data uncover a previously unappreciated key function of MALT1 protease activity in immune homeostasis and its relevance in human health and disease