Neoglycolipids Micelle-like Structures as a Basis for Drug Delivery Systems

Targeted drug delivery is one of the most promising tasks of nanomedicine, as this is a real way to increase the effectiveness of therapeutic effects against many diseases. In this regard, the development of new inexpensive highly effective stimulating and non-immunogenic drug delivery systems (DDS) is of great importance. In this work new molecular candidates were proposed and studied for the creation of such systems based on the use of new compounds, neoglycolipids. It is shown that these compounds are capable of self-association in aqueous solutions and can serve as potential carriers of drug compounds with targeted delivery determined by their terminal groups (in particular, glycans). The processes of their associates formation and features of their structure are investigated. The results show that these selforganizing nanoscale systems can be used as a basis for developing new drug delivery systems. Keywords: neoglycolipids, micelle-like structures, small-angle X-ray scattering, molecular dynamics simulatio

Hepatitis B virus and site-specific nucleases: effects of genetic modifications in CRISPR/Cas9 on antiviral activity

Chronic hepatitis B is a severe liver disease caused by persistent infection of hepatitis B virus in human hepatocytes. Chronic hepatitis B is one of the most common diseases in the world. According to recent estimations, more than 250 million people are chronically infected and more than 1 million of people die annually due to consequences of chronic hepatitis B: liver cirrhosis and hepatocellular carcinoma. The key factor of hepatitis B virus persistency is a special form of viral genome called circular covalently closed DNA. Current therapeutics suppress viral replication but have no effect on circular covalently closed DNA as it exists in the nuclei of hepatocytes as a minichromosome and is not accessible for therapeutics. Commonly, viral reactivation occurs after cessation of treatment. Therefore, duration of antiviral treatment is supposed to be indefinitely long. One of the most promising approaches to target circular covalently closed DNA is the technology of site-specific nucleases CRISPR/Cas9 from Streptococcus pyogenes. A short guide RNA recruits an SpCas9 protein to the viral genome and induces generation of DNA double strand breaks. However, there are several limitations of CRISPR/Cas9 hampering translation of this technology into the clinic. First, efficacy of CRISPR/Cas9 needs to be improved. Second, CRISPR/Cas9-mediated off-target mutagenesis represents a menacing problem which has to be addressed. To overcome these limitations, several approaches have been devised to improve CRISPR/Cas9 activity (modification of guide RNAs) and reduce off-target mutagenesis (a Cas9 protein with enhanced specificity, eSpCas9). In this study, we compared antiviral activity of a classic SpCas9 with an eSpCas9 system as well as analyzed effects of gRNAs modification on anti-HBV effects. Here, we demonstrated that SpCas9 has the highest antiviral potency, reducing transcription and replication of HBV over 90%. Hepatitis B virus covalently closed circular DNA declined over 90% post CRISPR/Cas9 transfection. Although it was previously shown that modified guide RNAs increase nucleolytic activity of CRISPR/Cas9, our results indicated that this modification impairs antiviral activity of CRISPR/Cas9. To conclude, CRISPR/Cas9 effectively suppress viral replication and transcription per se. Described modifications do not potentiate antiviral activity of CRISPR/Cas9 system and should not be used for development of future therapeutics. The best strategy to improve CRISPR/Cas9 efficacy is to design new highly effective guide RNAs

Состояние Шапшальского центра оледенения (Восточный Алтай) в 2015 году

Catalogues and maps of glaciers (for 2015) of Shapshal Glacier Center, located in the eastern part of the Russian Altai, have been created based on the first field glaciological observations and space images interpretation. In total 123 glaciers with the total area of 14.07 km2 have been allocated. In comparison with the data from the Glacier Inventory of the USSR (1955–1965), the total area of the glaciers has decreased by more than 2 times. The lower limit of glacier development is 2475 m, to the south-east of the region it rises by 1 km, the height of the firm line rises from 2860 m to 3460 m, respectively. Small glaciers prevail (70% of glaciers have an area less than 0.1 km2, the area of the largest glacier is 0.9 km2). In terms of quantity and area, cirque glaciers predominate, there are no valley glaciers. The largest numbers of glaciers have northern and northeastern exposure, with the largest areas of glaciers concentrated on the north-eastern slopes. The highest glaciation intensity has been detected on the eastern slope of the Skalistiy Ridge and the northeastern slope of the southern part of the Shapshalsky Ridge in the upper reaches of the Chon-Khem River, which are optimal for glaciers by a combination of mountain heights and position relative to moisture-bearing atmospheric flows. To the west of these areas, intensity of glacierization decreases due to lower mountain heights, to the east – due to lower precipitation. In general, with low (0.1 km−1 and less) intensity of glacierization, the Shapshal Centre is an area of dispersed glaciation, most glaciers of which are on the verge of disappearance.Получены новые карты и каталог ледников мало исследованного Шапшальского центра оледенения на Восточном Алтае. По состоянию на 2015 г. здесь насчитывалось 123 ледника суммарной площадью 14,07 км2. По сравнению с данными 1955–1965 гг. суммарная площадь ледников сократилась более чем вдвое. Преобладают малые каровые ледники северо-восточной и северной экспозиций. Площади ледников и интенсивность оледенения убывают с северо-запада на юго-восток

Сокращение ледников Восточного Алтая (Шапшальский центр) после максимума малого ледникового периода

Based on the analysis of remote data and field observations, we reconstructed the glaciation of the Shapshal Center (Eastern Altai) for the maximum of the Little Ice Age (LIA) and by the state of the glaciers as of 2001. At the maximum of the LIA, glaciation was represented by 358 glaciers with a total area of 84.43 km2. It was found 87% reduction of the total area of glaciers in the interval from the LIA maximum to 2015. During the reduction, valley glaciers disintegrated and glaciers in the Kargy River basin disappeared. The moraines of the LIA have low lake coverage (0.17% of area), therefore a probability of their breakthrough is low. We obtained data on the retreat of the Mushtuk Glacier (№ 78), the largest one of the Shapshal center, in five time slices from the LIA maximum. The highest retreat rates were reconstructed in the interval 1989–2001, but in the interval 2010–2016 the average rates decreased to 5 m/year. Changes in the mass balance index of the Mushtuk Glacier between from 1961 to 2018 were calculated. A sharp decrease in the mass balance in the 1990s and stabilization of values at a low level after 2001 were found. According to the calculations, the response time of the Mushtuk Glacier was about 9 years. If the current climatic conditions persist, there is reason to assume stabilization of glaciers in the coming years.Реконструированы ледники малоисследованного Шапшальского центра оледенения на Восточном Алтае в максимум малого ледникового периода, проанализирован характер их последующего сокращения. Детально рассмотрено сокращение крупнейшего ледника Шапшальского хребта по пяти временным срезам c 1955 по 2019 г. Проведены расчёты индекса баланса массы ледника и времени его климатического отклика

Possible Mechanisms of Fullerene C60 Antioxidant Action

Novel mechanism of antioxidant activity of buckminsterfullerene C60 based on protons absorbing and mild uncoupling of mitochondrial respiration and phosphorylation was postulated. In the present study we confirm this hypothesis using computer modeling based on Density Functional Theory. Fullerene's geroprotective activity is sufficiently higher than those of the most powerful reactive oxygen species scavengers. We propose here that C60 has an ability to acquire positive charge by absorbing inside several protons and this complex could penetrate into mitochondria. Such a process allows for mild uncoupling of respiration and phosphorylation. This, in turn, leads to the decrease in ROS production