Protein disulfide bond generation in Escherichia coli DsbB–DsbA

The crystal structure of the DsbB–DsbA–ubiquinone ternary complex has revealed a mechanism of protein disulfide bond generation in Escherichia coli

Structure and mechanisms of the DsbB–DsbA disulfide bond generation machine

AbstractAll organisms possess specific cellular machinery that introduces disulfide bonds into proteins newly synthesized and transported out of the cytosol. In E. coli, the membrane-integrated DsbB protein cooperates with ubiquinone to generate a disulfide bond, which is transferred to DsbA, a periplasmic dithiol oxido-reductase that serves as the direct disulfide bond donor to proteins folding oxidatively in this compartment. Despite the extensive accumulation of knowledge on this oxidation system, molecular details of the DsbB reaction mechanisms had been controversial due partly to the lack of structural information until our recent determination of the crystal structure of a DsbA–DsbB–ubiquinone complex. In this review we discuss the structural and chemical nature of reaction intermediates in the DsbB catalysis and the illuminated molecular mechanisms that account for the de novo formation of a disulfide bond and its donation to DsbA. It is suggested that DsbB gains the ability to oxidize its specific substrate, DsbA, having very high redox potential, by undergoing a DsbA-induced rearrangement of cysteine residues. One of the DsbB cysteines that are now reduced then interacts with ubiquinone to form a charge transfer complex, leading to the regeneration of a disulfide at the DsbB active site, and the cycle can begin anew

PMR and RS3PE Syndrome

Polymyalgia rheumatica (PMR) and remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome are common inflammatory rheumatic diseases in the elderly. In this study, we investigated the difference of the therapeutic responses between patients with PMR and RS3PE syndrome. Twenty-four patients with PMR and 12 patients with RS3PE syndrome were treated with initial dosages of 10-20 mg per day oral prednisolone, and the dosages were then tapered. Percentages of patients with negative c-reactive protein (CRP) after 8-week treatment were significantly more in RS3PE syndrome than in PMR. Percentages of patients with relapse during one-year treatment were less likely to be in RS3PE syndrome than in PMR. These differences observed between the two disorders were not associated with the level of initial CRP. There was no significant difference in percentages of patients with prednisolone-free remission after two-year treatment between PMR and RS3PE syndrome. These results indicate that the early response to the treatment is greater in RS3PE syndrome than in PMR

Safety and Efficacy of Hospital Utilization of Tranexamic Acid in Civilian Adult Trauma Resuscitation

Introduction: Patients with trauma-induced coagulopathies may benefit from the use of antifibrinolytic agents, such as tranexamic acid (TXA). This study evaluated the safety and efficacy of TXA in civilian adults hospitalized with traumatic hemorrhagic shock.Methods: Patients who sustained blunt or penetrating trauma with signs of hemorrhagic shock from June 2014 through July 2018 were considered for TXA treatment. A retrospective control group was formed from patients seen in the same past five years who were not administered TXA and matched based on age, gender, Injury Severity Score (ISS), and mechanism of injury (blunt vs penetrating trauma). The primary outcome of this study was mortality measured at 24 hours, 48 hours, and 28 days. Secondary outcomes included total blood products transfused, hospital length of stay (LOS), intensive care unit LOS, and adverse events. We conducted three pre-specified subgroup analyses to assess outcomes of patients, including (1) those who were severely injured (ISS >15), (2) those who sustained significant blood loss (≥10 units of total blood products transfused), and (3) those who sustained blunt vs penetrating trauma.Results: Propensity matching yielded two cohorts: the hospital TXA group (n = 280) and a control group (n = 280). The hospital TXA group had statistically lower mortality at 28 days (1.1% vs 5%, odds ratio [OR] [0.21], (95% confidence interval [CI], 0.06, 0.72)) and used fewer units of blood products (median = 4 units, interquartile range (IQR) = [1, 10] vs median=7 units, IQR = [2, 12.5] for the hospital TXA and control groups, respectively, (95% CI for the difference in median, -3 to -1). There were no statistically significant differences between groups with regard to 24-hour mortality (1.1% vs 1.1%, OR = 1, 95% CI, 0.20, 5.00), 48-hour mortality (1.1% vs 1.4%, OR [0.74], 95% CI, 0.17, 3.37), hospital LOS (median= 9 days, IQR = (5, 16) vs median =12 days IQR = (6, 22.5) for the hospital TXA and control groups, respectively, 95% CI for the difference in median = (-5 to 0)), and incidence of thromboembolic events (eg, deep vein thrombosis, pulmonary embolism) during hospital stay (0.7% vs 0.7% for the hospital TXA and control group, respectively, OR [1], 95% CI, 0.14 to 7.15). We conducted subgroup analyses on patients with ISS>15, patients transfused with ≥10 units of blood products, and blunt vs penetrating trauma. The results indicated lower 28-day mortality for ISS>15 (1.8% vs 7.1%, OR [0.23], 95% CI, 0.06 to 0.81) and blunt trauma  (0.6% vs 6.3%, OR [0.09], 95% CI, 0.01 to 0.75); fewer units of blood products for penetrating trauma (median = 2 units, IQR = (1, 8) vs median = 8 units, IQR = (5, 15) for the hospital TXA and control groups, respectively, 95% CI for the difference in median = (-6 to -3)), and ISS>15 (median = 7 units, IQR = (2, 14) vs median = 8.5 units, IQR = (4, 16) for the hospital TXA and control groups, respectively, 95% CI for the difference in median, -3 to 0).Conclusion: The current study demonstrates a statistically significant reduction in mortality after TXA administration at 28 days, but not at 24 and 48 hours, in patients with traumatic hemorrhagic shock

Past infections and low ACPA in RA

Background : Rheumatoid arthritis (RA), an autoimmune disease of unknown etiology, is believed to occur as the result of actions of genetic and environmental factors. In this study, we examined the relation of past histories about infectious diseases with the levels anti-citrullinated protein autoantibodies (ACPA) in RA. Methods : Results of a questionnaire about histories of infectious diseases were obtained from 85 patients with RA, and were analyzed. Results : Significantly lower level of ACPA was detected in patients with the history of tonsillitis, otitis media or urinary cystitis than in those without it. There was no difference in the level of ACPA in RA patients between with and without cold / influenza, rubella, chickenpox, herpes labialis or herpes zoster. When RA patients were divided into two groups, high-level and low-level ACPA, multiple logistic regression analysis revealed that the history of otitis media was a significantly independent factor for the low level of ACPA. There was no significant relation between the level of rheumatoid factor and histories of infectious diseases. Conclusion : This study clarified that the past history of otitis media is associated with the low level of ACPA in RA

CRP in PMR and RS3PE syndrome

Polymyalgia rheumatica (PMR) and remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome are common inflammatory rheumatic diseases in the elderly. In this study, we investigate predictive factors which correspond to subsequent disease control of PMR and RS3PE syndrome. Twenty four patients, which contained 18 PMR and 6 RS3PE syndrome, were treated with initial dosages of 10-20 mg per day oral prednisolone, and the dosage of prednisolone was then tapered. Significantly higher initial CRP was observed in patients with poor disease control than in those with good disease control afterwards. The number of patients with negative CRP after 4 weeks was significantly more in patients with good disease control after 1 year than in those with poor disease control. Patients were shown to be in good disease control status after 1 year when CRP after 4 weeks became negative even if they had initial high CRP. Our study clarify that to make CRP negative after 4 weeks is associated with subsequent suppression of the disease activity and with decreased dosages of corticosteroids

Open Access

Cost-effective length and timing of school closure during an influenza pandemic depend on the severit

Immune Reactions Against Elongation Factor 2 Kinase: Specific Pathogenesis of Gastric Ulcer from Helicobacter pylori Infection

Helicobacter pylori (H. pylori) infection is a definite causative factor for gastric ulcers (GUs). In the present study we detected a specific antigen of gastric epithelial cells (HGC-27) using cell ELISA, which was recognized by the sera of GU patients (n = 20) but not in patients with chronic gastritis (CG; n = 20) or in healthy volunteers (HC; n = 10). This antigen was over-expressed by a stressful (heat-stressed) environment, and was identified as elongation factor 2 kinase (EF-2K) by western blotting. The GU patients' lymphocytes stimulated by H. pylori specifically disrupted heat-stressed HGC-27 cells in a cytotoxic assay. In flow cytometry, the effector cells (lymphocytes) from GU patients were significantly differentiated to T helper type 1 lymphocyte (Th1) and cytotoxic T lymphocyte (CTL) as opposed to those from CG patients. The target cells (HGC-27) expressed EF-2K and MHC-class I together with costimulatory molecules from heat stress. This antigen specific immune mechanism could have a prominent role in the pathogenesis of GU