Comparative analysis of rigidity across protein families

We present a comparative study in which 'pebble game' rigidity analysis is applied to multiple protein crystal structures, for each of six different protein families. We find that the main-chain rigidity of a protein structure at a given hydrogen bond energy cutoff is quite sensitive to small structural variations, and conclude that the hydrogen bond constraints in rigidity analysis should be chosen so as to form and test specific hypotheses about the rigidity of a particular protein. Our comparative approach highlights two different characteristic patterns ('sudden' or 'gradual') for protein rigidity loss as constraints are removed, in line with recent results on the rigidity transitions of glassy networks

Canonical and noncanonical sites determine NPT2A binding selectivity to NHERF1 PDZ1

Na+/H+ Exchanger Regulatory Factor-1 (NHERF1) is a scaffolding protein containing 2 PDZ domains that coordinates the assembly and trafficking of transmembrane receptors and ion channels. Most target proteins harboring a C-terminus recognition motif bind more-or-less equivalently to the either PDZ domain, which contain identical core-binding motifs. However some substrates such as the type II sodium-dependent phosphate co-transporter (NPT2A), uniquely bind only one PDZ domain. We sought to define the structural determinants responsible for the specificity of interaction between NHERF1 PDZ domains and NPT2A. By performing all-atom/explicit-solvent molecular dynamics (MD) simulations in combination with biological mutagenesis, fluorescent polarization (FP) binding assays, and isothermal titration calorimetry (ITC), we found that in addition to canonical interactions of residues at 0 and -2 positions, Arg at the -1 position of NPT2A plays a critical role in association with Glu43 and His27 of PDZ1 that are absent in PDZ2. Experimentally introduced mutation in PDZ1 (Glu43Asp and His27Asn) decreased binding to NPT2A. Conversely, introduction of Asp183Glu and Asn167His mutations in PDZ2 promoted the formation of favorable interactions yielding micromolar KDs. The results describe novel determinants within both the PDZ domain and outside the canonical PDZ-recognition motif that are responsible for discrimination of NPT2A between two PDZ domains. The results challenge general paradigms for PDZ recognition and suggest new targets for drug development

Clinical Practice Guidelines of the Russian Society for the Study of the Liver, the Russian Gastroenterological Association, the National Scientific Society of Infectious Disease Specialists for the Diagnosis and Treatment of Chronic Hepatitis C

Аim: diagnosis and treatment algorithms in the clinical recommendations intended for general practitioners, gastroenterologists, infectious disease specialists, hepatologists on the of chronic hepatitis C are presented.Summary. Chronic viral hepatitis C is a socially significant infection, the incidence of which in the Russian Federation remains significantly high. Over the past 10 years, great progress has been made in the treatment of hepatitis C — direct acting antiviral drugs have appeared. The spectrum of their effectiveness allows to achieve a sustained virological response in more than 90 % of cases, even in groups that were not previously considered even as candidates for therapy or were difficult to treat — patients receiving renal replacement therapy, after liver transplantation (or other organs), at the stage of decompensated liver cirrhosis, HIV co-infected, etc. Interferons are excluded from the recommendations due to their low effectiveness and a wide range of adverse events. The indications for the treatment have been expanded, namely, the fact of confirmation of viral replication. The terms of dispensary observation of patients without cirrhosis of the liver have been reduced (up to 12 weeks after the end of therapy). Also, these recommendations present approaches to active screening of hepatitis in risk groups, preventive and rehabilitation measures after the end of treatment.Conclusion. Great success has been achieved in the treatment of chronic hepatitis C. In most cases, eradication of viral HCV infection is a real task even in patients at the stage of cirrhosis of the liver, with impaired renal function, HIV co-infection, after solid organs transplantation

ДОСЛІДЖЕННЯ ПРОЦЕСІВ СТРУКТУРОУТВОРЕННЯ НАПОВНЕНИХ РОЗЧИНІВ НА ОСНОВІ АЛКИЛРЕЗОРЦИНОВ

The article presents the results of experimental and theoretical study of structure-forming peculiarities in alkylresorcin-based filled-in composites. A high efficiency of the mortars for construction of anti-filtration screens in facilities, operated in conditions of exposure to ground waters, has been demonstrated.В статье представлены результаты экспериментально-теоретических исследований особенностей структурообразования наполненных композиций на основе алкилрезорцинов. Показана высокая эффективность растворов для устройства противофильтрационных экранов на сооружениях, эксплуатирующихся в условиях воздействия грунтовых вод.У статті наведено результати експериментально-теоретичних досліджень особливостей структуроутворення наповнених композицій на основі алкілрезорцинів. Показано високу ефективність розчинів для улаштування протифільтраційних екранів на спорудах, що експлуатуються в умовах впливу ґрунтових вод

MULTISLICE COMPUTED TOMOGRAPHY IN THE DIAGNOSIS OF MIXED TRAUMATIC BRAIN INJURY

Objective: to study changes in the cross sectional optic nerve diameter (OND), by using multislice computed tomography (MSCT), in patients with mild traumatic brain injury  (TBI), as well as those with severe (including mixed) TBI before and  after craniotomy; to assess whether this technique can be integrated with a whole-body MSCT protocol in severe mixed TBI (MTBI).Material and methods. OND was retrospectively studied in two  selected groups of patients with injuries (a total of 51 patients):  Group 1 (n = 40) included 2 subgroups (n = 20 in each) with mild  TBI or severe MTBI; Group 2 (n = 11) comprised 2 subgroups with  severe TBI who had undergone decompressive (n = 6) or  osteoplastic (n = 5) craniotomy with subsequent OND measurement  after 12–18 hours. Results. Primary brain MSCT showed that the average OND was  6.12±1,01 mm in severe MTBI and 4.4±0.19 mm in mild TBI (Student’s t = 5.707). After decompressive craniotomy, there  was a decrease in OND from 6.26±0.27 to 5.38±0.22 mm (Student’s t = 2.486).Conclusion. Among the patients with severe MTBI, the OND at  primary MSCT is significantly greater than that in patients with mild  TBI, which may be due to elevated intracranial pressure, as shown  by the literature data. There is a statistically significant decrease in  OND after decompressive craniotomy and removal of the brain  compressive factor. Whole-body MSCT revealed no technical  obstacles to the application of an OND measurement technique

Epidemiology of healthcare-associated infections and mechanisms of antimicrobial resistance of responsible pathogens in Ukraine: a multicentre study

Background: Healthcare-associated infections (HAIs) caused by multidrug-resistant organisms (MDROs) have a high impact in terms of morbidity, mortality, and costs. Aim: To estimate the prevalence and incidence of HAIs, and to describe phenotypic and genotypic features of antimicrobial resistance in responsible pathogens in Ukraine. Methods: Prospective multicentre surveillance was conducted from January 2019 to December 2021 in 17 regional hospitals of Ukraine. Definitions of HAIs were adapted from the Centers for Disease Control and Prevention’s National Healthcare Safety Network. Findings: Among 37,968 patients, 6218 (16.4%) HAIs were observed. Of all HAI cases, 14.8% were detected after hospital discharge. The most frequently reported HAI types were pneumonia (24.4%), urinary tract infections (19.8%), surgical site infections (15.3%), and bloodstream infections (11.2%). Of all HAIs, 11.9% were defined as part of an outbreak. Death during hospitalization was reported in 12.6% of HAI cases. In total, 85.1% isolates from patients were found to be MDROs. Meticillin resistance was found in 41.2% of S. aureus (MRSA) isolates, and vancomycin resistance was found in 11.8% of enterococci. Antimicrobial resistance to third-generation cephalosporins was detected in 48.4% of all Enterobacterales. Antimicrobial resistance to carbapenems was detected in 71.3% of all non-fermentative Gram-negative bacteria. Of the all isolates tested, 25.1% were found to be multidrug-resistant (MDR)