Increasing Tetrahydrobiopterin in Cardiomyocytes Adversely Affects Cardiac Redox State and Mitochondrial Function Independently of Changes in NO Production

Tetrahydrobiopterin (BH4) represents a potential strategy for the treatment of cardiac remodeling, fibrosis and/or diastolic dysfunction. The effects of oral treatment with BH4 (Sapropterin™ or Kuvan™) are however dose-limiting with high dose negating functional improvements. Cardiomyocyte-specific overexpression of GTP cyclohydrolase I (mGCH) increases BH4 several-fold in the heart. Using this model, we aimed to establish the cardiomyocyte-specific responses to high levels of BH4. Quantification of BH4 and BH2 in mGCH transgenic hearts showed age-based variations in BH4:BH2 ratios. Hearts of mice (\u3c6 \u3emonths) have lower BH4:BH2 ratios than hearts of older mice while both GTPCH activity and tissue ascorbate levels were higher in hearts of young than older mice. No evident changes in nitric oxide (NO) production assessed by nitrite and endogenous iron–nitrosyl complexes were detected in any of the age groups. Increased BH4 production in cardiomyocytes resulted in a significant loss of mitochondrial function. Diminished oxygen consumption and reserve capacity was verified in mitochondria isolated from hearts of 12-month old compared to 3-month old mice, even though at 12 months an improved BH4:BH2 ratio is established. Accumulation of 4-hydroxynonenal (4-HNE) and decreased glutathione levels were found in the mGCH hearts and isolated mitochondria. Taken together, our results indicate that the ratio of BH4:BH2 does not predict changes in neither NO levels nor cellular redox state in the heart. The BH4 oxidation essentially limits the capacity of cardiomyocytes to reduce oxidant stress. Cardiomyocyte with chronically high levels of BH4 show a significant decline in redox state and mitochondrial function

Positive projections as generators of J-projections of type (B)

Let A be a von Neumann J-algebra of type (B) acting in an indefinite metric space. The aim of the paper is to study J-projections from A

Нефинансовые риски внедрения информационных систем в деятельность транспортно-логистических компаний

Today, digital transformation is a priority vector for development of all economic sectors of the Russian Federation; at the same time, special attention in this context is paid to the transport and logistics sector due to its great importance for the country’s economy. The implementation of information systems that meet modern requirements, as well as with added functionality, is one of the key components of work in the field of digital transformation of transport.Most often, in this regard the attention is paid to financial and technological risks, while the influence of the human factor is considered rather superficially. Hence, the need to examine the risks that are primarily associated with employees of transport and logistics companies, as well as the impact of those risks on digital transformation in general and on the process of implementing information systems in particular, to suggest ways to minimise those risks in the context of modern corporate culture. JSC Russian Railways, as well as PJSC Aeroflot Russian Airlines, are considered as examples of companies that have already implemented advancement within the digital transformation vector.На сегодняшний день цифровая трансформация является приоритетным вектором развития всех отраслей Российской Федерации; в то же время транспортно-логистическому сектору в этом плане уделяется особое внимание ввиду его большой значимости для экономики страны. Внедрение информационных систем, отвечающих современным требованиям, а также с дополненным функционалом – одна из ключевых частей работы в сфере цифровой трансформации транспорта.Чаще всего во внимание берутся финансовые и технологические риски, при этом влияние человеческого фактора рассматривается крайне поверхностно. В настоящей работе изучены те риски, которые в первую очередь связаны с сотрудниками транспортнологистических компаний, их влияние на цифровую трансформацию в целом и на процесс внедрения информационных систем в частности, а также предложены способы минимизации рисков в условиях современной корпоративной культуры. В качестве примеров компаний, которые уже начали работу в векторе цифровой трансформации рассмотрены в первую очередь ОАО «РЖД», а также ПАО «Аэрофлот»

Quality of life and health utility index in type 2 diabetes mellitus patients with various forms of hypoglycemia receiving basal-bolus insulin therapy

Analysis of the results of observational program «Quality of life, symptoms of hypoglycemia and treatment satisfaction in patients with type 2 diabetes receiving basal-bolus insulin therapy» are presented. One thousand patients with type 2 diabetes mellitus (DM2) from ten regions of Russia were included in the above program. The quality of life of DM2 patients with different forms of hypoglycemia on insulin therapy and their distribution according to the grades of quality of life impairment were studied; the health utility index ( Ut) for various forms of hypoglycemia was determined. Quality of life in DM2 patients with hypoglycemia was lower than in those without hypoglycemia. Patients with severe and nocturnal hypoglycemia episodes recorded the expressed disturbances in quality of life; the majority of patients in this group had critical or severe quality of life impairment. On the basis of real-world practice data, the values of health utility index for patients with and without hypoglycemia were determined. The obtained values of health utility index can be used to calculate QALY in pharmacoeconomic analysis

String Method for the Study of Rare Events

We present a new and efficient method for computing the transition pathways, free energy barriers, and transition rates in complex systems with relatively smooth energy landscapes. The method proceeds by evolving strings, i.e. smooth curves with intrinsic parametrization whose dynamics takes them to the most probable transition path between two metastable regions in the configuration space. Free energy barriers and transition rates can then be determined by standard umbrella sampling technique around the string. Applications to Lennard-Jones cluster rearrangement and thermally induced switching of a magnetic film are presented.Comment: 4 pages, 4 figure

A Doubly Nudged Elastic Band Method for Finding Transition States

A modification of the nudged elastic band (NEB) method is presented that enables stable optimisations to be run using both the limited-memory quasi-Newton (L-BFGS) and slow-response quenched velocity Verlet (SQVV) minimisers. The performance of this new `doubly nudged' DNEB method is analysed in conjunction with both minimisers and compared with previous NEB formulations. We find that the fastest DNEB approach (DNEB/L-BFGS) can be quicker by up to two orders of magnitude. Applications to permutational rearrangements of the seven-atom Lennard-Jones cluster (LJ7) and highly cooperative rearrangements of LJ38 and LJ75 are presented. We also outline an updated algorithm for constructing complicated multi-step pathways using successive DNEB runs.Comment: 13 pages, 8 figures, 2 table

Pharmacoeconomic analysis of use the oral hypoglycemic agents in patients with type 2 diabetes mellitus according to a real clinical practice

We aimed to conduct cost-utility analysis of two different regimens of the oral hypoglycemic therapy in 2 type diabetes mellitus (DM2). Methods. In the whole, 229 patients with DM2, receiving vildagliptin add-on to metformin (group 1) or sulphonylureas add-on to metformin (group 2) were enrolled in the study. Cost-utility ratio (CUR) was identified as a ratio of difference in total costs of treatment in the groups and difference in QALY in corresponding groups. The overall costs included direct costs of treatment as well as costs for treating of DM2 complications (severe hypoglycemia) and the costs related to the loss of GDP due to severe hypoglycemia events. Health utility value was evaluated for each patient on the basis of SF-6D questionnaire. Pharmacoeconomic expediency of treatment regimen was estimated by means of comparing the CUR and wiliness-to-pay ratio (WTP) for Russian Federation (RF). Results. The health utility value was higher in group 1 as compared to group 2: 0,757 vs 0,70 (p>0,05). The overall costs for treating one patient in group 1 during a year were 28 637,34 rubles, in group 2 - 10 231,55 rubles. CUR amounted 328 674,82 rubles and it was 4.4 times lower than upper border of WTP ratio in RF (1 457 400 rub.). Conclusion. The innovation treatment regimen with vildagliptin add-on to metformin is beneficial and may be considered as economically reasonable alternative to traditional treatment regimen with sulphonylureas add-on to metformin for DM2 patients in RF