Therapeutic effects of pyrrolidine dithiocarbamate on acute lung injury in rabbits

<p>Abstract</p> <p>Background</p> <p>Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is an early characteristic of multiple organ dysfunction, responsible for high mortality and poor prognosis in patients. The present study aims to evaluate therapeutic effects and mechanisms of pyrrolidine dithiocarbamate (PDTC) on ALI.</p> <p>Methods</p> <p>Alveolar-arterial oxygen difference, lung tissue edema and compromise, NF-κB activation in polymorphonuclear neutrophil (PMN), and systemic levels of tumor necrosis factor-alpha (TNFa) and intercellular adhesion molecule-1 (ICAM-1) in rabbits induced by the intravenous administration of lipopolysaccharide (LPS) and treated with PDTC. Production of TNFa and IL-8, activation of Cathepsin G, and PMNs adhesion were also measured.</p> <p>Results</p> <p>The intravenous administration of PDTC had partial therapeutic effects on endotoxemia-induced lung tissue edema and damage, neutrophil influx to the lung, alveolar-capillary barrier dysfunction, and high systemic levels of TNFa and ICAM-1 as well as over-activation of NF-κB. PDTC could directly and partially inhibit LPS-induced TNFa hyper-production and over-activities of Cathepsin G. Such inhibitory effects of PDTC were related to the various stimuli and enhanced through combination with PI3K inhibitor.</p> <p>Conclusion</p> <p>NF-κB signal pathway could be one of targeting molecules and the combination with other signal pathway inhibitors may be an alternative of therapeutic strategies for ALI/ARDS.</p

Catalytic Cycle of Multicopper Oxidases Studied by Combined Quantum- and Molecular-Mechanical Free-Energy Perturbation Methods

We have used combined quantum mechanical and molecular mechanical free-energy perturbation methods in combination with explicit solvent simulations to study the reaction mechanism of the multicopper oxidases, in particular the regeneration of the reduced state from the native intermediate. For 52 putative states of the trinuclear copper cluster, differing in the oxidation states of the copper ions and the protonation states of water- and O2-derived ligands, we have studied redox potentials, acidity constants, isomerisation reactions, as well as water- and O2 binding reactions. Thereby, we can propose a full reaction mechanism of the multicopper oxidases with atomic detail. We also show that the two copper sites in the protein communicate so that redox potentials and acidity constants of one site are affected by up to 0.2 V or 3 pKa units by a change in the oxidation state of the other site

The psychology and policy of overcoming economic inequality

Data and materials’ availability: All data are publicly available for the survey data used (https://osf.io/njd62/) and from the UN Gender Inequality Index (https://hdr.undp.org/data-center/documentation-and-downloads). Financial transaction data were provided through an agreement with Columbia Business School.Recent arguments claim that behavioral science has focused – to its detriment – on the individual over the system when construing behavioral interventions. In this commentary, we argue that tackling economic inequality using both framings in tandem is invaluable. By studying individuals who have overcome inequality, “positive deviants,” and the system limitations they navigate, we offer potentially greater policy solutions.This research was supported in part by the National Science Foundation (no. 2218595) and by Undergraduate Global Engagement at Columbia University. Additional support was provided to individual researchers from the Columbia University Office of the Provost, Masaryk University Centre for International Cooperation, and the Benjamin A. Gilman International Fund from the United States Department of State

Reorganization Energy for Internal Electron Transfer in Multicopper Oxidases.

We have calculated the reorganization energy for the intramolecular electron transfer between the reduced type 1 copper site and the peroxy intermediate of the trinuclear cluster in the multicopper oxidase CueO. The calculations are performed at the combined quantum mechanics and molecular mechanics (QM/MM) level, based on molecular dynamics simulations with tailored potentials for the two copper sites. We obtain a reorganization energy of 91-133 kJ/mol, depending on the theoretical treatment. The two Cu sites contribute by 12 and 22 kJ/mol to this energy, whereas the solvent contribution is 34 kJ/mol. The rest comes from the protein, involving small contributions from many residues. We have also estimated the energy difference between the two electron-transfer states and show that the reduction of the peroxy intermediate is exergonic by 43-87 kJ/mol, depending on the theoretical method. Both the solvent and the protein contribute to this energy difference, especially charged residues close to the two Cu sites. We compare these estimates with energies obtained from QM/MM optimizations and QM calculations in a vacuum and discuss differences between the results obtained at various levels of theory

Factors associated with hospitalization in patients with H1N1 influenza in Afzalipour hospital, Kerman, Iran, 2015: A case-control study

Background and Objectives: Evidence suggests that underlying diseases increase the severity of influenza and lead to hospitalization or death. This study was conducted to determine the risk factors associated with hospitalization of patients in Afzalipour Hospital, Kerman, Iran during an outbreak of H1N1 influenza in December 2015.   Methods: In this case-control study, the case group comprised 85 patients who were hospitalized for influenza and the control group included 51 patients who had influenza symptoms and were discharged after required evaluations and check-up. The data were collected from both groups on a daily basis for two weeks. For data analysis, descriptive analysis, logistic regression analysis, Lasso Regression, and likelihood ratio were used. Analysis was performed using the Stata version 12 and R software.   Results: Among the variables examined, after removal of additional variables, 12 variables were introduced into the multivariate regression. The history of pulmonary disease and diabetes increased the odds of hospitalization following influenza by more than 11 (OR = 11.6, P. value = 0.003) and 9 times (OR = 9, P. value = 0.01), respectively.   Conclusion: Underlying disease and factors play a major role in exacerbating the disease. Therefore, the health system should take the necessary preventive measures when outbreaks occur