Core architecture of a bacterial type II secretion system

Bacterial type II secretion systems (T2SSs) translocate virulence factors, toxins and enzymes across the cell outer membrane. Here we use negative stain and cryo-electron microscopy to reveal the core architecture of an assembled T2SS from the pathogen Klebsiella pneumoniae. We show that 7 proteins form a ~2.4 MDa complex that spans the cell envelope. The outer membrane complex includes the secretin PulD, with all domains modelled, and the pilotin PulS. The inner membrane assembly platform components PulC, PulE, PulL, PulM and PulN have a relative stoichiometric ratio of 2:1:1:1:1. The PulE ATPase, PulL and PulM combine to form a flexible hexameric hub. Symmetry mismatch between the outer membrane complex and assembly platform is overcome by PulC linkers spanning the periplasm, with PulC HR domains binding independently at the secretin base. Our results show that the T2SS has a highly dynamic modular architecture, with implication for pseudo-pilus assembly and substrate loading

Self-consistent field theory for the interactions between keratin intermediate filaments

Background: Keratins are important structural proteins found in skin, hair and nails. Keratin Intermediate Filaments are major components of corneocytes, nonviable horny cells of the Stratum Corneum, the outermost layer of skin. It is considered that interactions between unstructured domains of Keratin Intermediate Filaments are the key factor in maintaining the elasticity of the skin. Results: We have developed a model for the interactions between keratin intermediate filaments based on self-consistent field theory. The intermediate filaments are represented by charged surfaces, and the disordered terminal domains of the keratins are represented by charged heteropolymers grafted to these surfaces. We estimate the system is close to a charge compensation point where the heteropolymer grafting density is matched to the surface charge density. Using a protein model with amino acid resolution for the terminal domains, we find that the terminal chains can mediate a weak attraction between the keratin surfaces. The origin of the attraction is a combination of bridging and electrostatics. The attraction disappears when the system moves away from the charge compensation point, or when excess small ions and/or NMF-representing free amino acids are added. Conclusions: These results are in concordance with experimental observations, and support the idea that the interaction between keratin filaments, and ultimately in part the elastic properties of the keratin-containing tissue, is controlled by a combination of the physico-chemical properties of the disordered terminal domains and the composition of the medium in the inter-filament region. Keywords: Stratum corneum, Skin keratins, Intermediate filaments, Unstructured terminal domains, Bridging attractio

State stiffness parameters of the vascular wall in hypertensive patients complex therapy cytoprotector and sartans

A randomized study of the state of stiffness parameters arteries wall (CAVI — cardio-ankle vascular index), AI (augmentation index) PEP (duration of the voltage of the left ventricle) using «VaSera-1000» («Fukuda Denshi», Japan) in primary hypertension patients (80) not treated with systemic antihypertensive therapy. The effect of long-term (3 months) was be marketed. Losartan combined with Mexicor 300mg/day or mildronate 1000 mg/day for the specified parameters. It sets the initial reduction the properties of the arterial wall in patients with hypertension, in contrast to healthy individuals. Mexicor or mildronat accompanied by improvement east-cal properties of the arterial wall, reducing CAVI and AI in 3 months on 9.4% and 8.9%, 14.9% and 15.4%, respectively. In the control group-term change CAVI and AI no. Mexicor led to a more pronounced increase in PEP, than mildronate, respectively, on 23.7% and 18.9%. Losartan monotherapy results in a less pronounced decrease in the stiffness of the vessel wall

PARAMETERS OF ARACHYDONIC ACID CYCLE METABOLISM IN PATIENTS WITH ACUTE MYOCARDIAL INFARCTION ON THE BACKGROUND OF COMPLEX THERAPY OF OMEGA-3 POLYUNSATURATED FATTY ACIDS

The aim of the study was to evaluate the effect of omega-3 polyunsaturated fatty acids on the main metabolic rates of the arachydonic acid cycle in patients with acute myocardial infarction in the context of traditional complex therapy. Materials and methods of research. We conducted an open, randomized study of two groups of patients (n=59) with acute myocardial infarction (MI), which did not undergo angioplastic and thrombolysis: in the main group (n=26) traditional complex therapy (including double antiaggregant therapy) from the first day supplemented with Omega-3 triglycerides [EPA/DGA — 1.2/1-90%] 1g. per day. In the control group (n=33) only complex therapy was performed. The main components of the arachydonic acid cycle — thromboxane B2 (TxB2) and prostaglandin I2 (PgI2), as well as their analogues, thromboxane B3 (TxB3) and prostaglandin I3 (PgI3), resulting from the replacement of arachidonic acid by omega-3 PUFAs, were evaluated for all patients on the 1st, 7th, 14th days after the onset of MI in the blood plasma. Results of the study. On day 14, an increase in the level of prostaglandin I3 in the Omega-3 triglycerides [EPA/DGA — 1.2/1-90%] group was observed in 10 times, the level of thromboxane B3 was increased in 15.9 times, in the absence of significant differences between the groups in the thromboxane B2 and prostaglandin I2 level. A decrease in the ratios of PgI2 / PgI3 and TxB2 / TxB3 in the main group also was noted. Conclusion. Given the lower functional activity of thromboxane B3 and the decrease in the ratio of TxB2 / TxB3, against the background of Omega-3 triglycerides [EPA/DGA — 1.2/1-90%] therapy, one can judge the presence of an independent antiaggregant effect of omega-3-polyunsaturated fatty acids as a result of their use in patients with MI

Hypolidemic therapy today. New challenges and opportunities of statines

Prevention of fatal complications in patients with high cardiovascular risk means achieving target blood cholesterol and its fraction in low-density lipoprotein levels, which level depends on the cardiovascular risk (CVR) degree and is determined by the guidelines of the European Cardiology Society (2016) and the Russian National Atherosclerosis Society (2017). When choosing statins for lipid-lowering therapy, one should be guided by the hepatic metabolism nature, hypolipidemic activity, and the pleiotropic profiles of the drug

HYPOLIPIDEMIC AND PLEIOTROPIC EFFICACY OF ROSUVASTATIN IN ARTERIAL HYPERTENSION PATIENTS OF HIGH CARDIOVASCULAR RISK IN LONG-TERM OUTPATIENT FOLLOW-UP

Aim. To evaluate the pleiotropical and hypolipidepmic efficacy of generic rosuvastatin (Rosucard) comparing with atorvastatin in arterial hypertension patients (AH) with high and very high cardiovascular risk (CVR) during the long-term usage in outpatient circumstances. Material and methods. Totally, 114 patients studied (age 58,2±3,11 y. o.) with AH of II-III grades and with high or very high CVR by SCORE, taking antihypertension treatment with metoprolol, indapaminde, enalapril in effective dosages, who, during the previous 1 year of atorvastatin treatment (20 mg/day) did not reach the target level of cholesterol. Atorvastatin was replaced by rosuvastatin 10 mg/day for 1,5 year. If the mentioned dosage did not reach cholesterol and low-density lipoproteides (CLDL) to target levels by 6 weeks, dosage was increased to 20 mg/day, and then if again not achieved during next 6 weeks, to 40 mg/day.Results. Introduction of rosuvastatin to the complex treatment was followed by further decrease of atherogenic lipids: cholesterol by 24%, CLDL by 53% and was followed with the decrease of vessel wall stiffness — decreased CAVI by 12%, augmentation index by 17%, improvement of the vasodilation endothelium function by 24%.Conclusion. Rosucard has, together with hypolipidemic properties, the pleiotropic properties more prominent than in atorvastatin, that makes it to apply the drug in AH patients with high and very high CVR for prevention of cardiovascular complications in outpatient practice

Dabigatran for prevention of stroke after embolic stroke of undetermined source

BACKGROUND Cryptogenic strokes constitute 20 to 30% of ischemic strokes, and most cryptogenic strokes are considered to be embolic and of undetermined source. An earlier randomized trial showed that rivaroxaban is no more effective than aspirin in preventing recurrent stroke after a presumed embolic stroke from an undetermined source. Whether dabigatran would be effective in preventing recurrent strokes after this type of stroke was unclear. METHODS We conducted a multicenter, randomized, double-blind trial of dabigatran at a dose of 150 mg or 110 mg twice daily as compared with aspirin at a dose of 100 mg once daily in patients who had had an embolic stroke of undetermined source. The primary outcome was recurrent stroke. The primary safety outcome was major bleeding. RESULTS A total of 5390 patients were enrolled at 564 sites and were randomly assigned to receive dabigatran (2695 patients) or aspirin (2695 patients). During a median follow-up of 19 months, recurrent strokes occurred in 177 patients (6.6%) in the dabigatran group (4.1% per year) and in 207 patients (7.7%) in the aspirin group (4.8% per year) (hazard ratio, 0.85; 95% confidence interval [CI], 0.69 to 1.03; P=0.10). Ischemic strokes occurred in 172 patients (4.0% per year) and 203 patients (4.7% per year), respectively (hazard ratio, 0.84; 95% CI, 0.68 to 1.03). Major bleeding occurred in 77 patients (1.7% per year) in the dabigatran group and in 64 patients (1.4% per year) in the aspirin group (hazard ratio, 1.19; 95% CI, 0.85 to 1.66). Clinically relevant nonmajor bleeding occurred in 70 patients (1.6% per year) and 41 patients (0.9% per year), respectively. CONCLUSIONS In patients with a recent history of embolic stroke of undetermined source, dabigatran was not superior to aspirin in preventing recurrent stroke. The incidence of major bleeding was not greater in the dabigatran group than in the aspirin group, but there were more clinically relevant nonmajor bleeding events in the dabigatran group