Oxygen Content and Thermodynamic Stability of YBaCo2O6-delta Double Perovskite

The thermodynamic stability of the double perovskite YBaCo2O6−δ was studied using the coulometric titration technique and verified by measurements of the overall conductivity depending on oxygen partial pressure at a given temperature. As a result, the stability diagram of YBaCo2O6−δ was plotted. YBaCo2O6−δ was found to be thermodynamically stable in air at 850°C and higher temperatures, whereas its thermodynamic stability at 900°C is limited by the range of oxygen partial pressures −3.56 ≤ log(pO2/atm) ≤ −0.14. Oxygen content in YBaCo2O6−δ slightly decreases at 900°C from 5.035 at log(pO2/atm) = −0.14 to 4.989 in the atmosphere with log(pO2/atm) = −3.565 indicating a crucial role which variation of Co+3/Co+2 ratio plays in its stability. YBaCo2O6−δ decomposes into the mixture of YCoO3 and BaCoO3−z at the high pO2 stability limit, whereas YBaCo4O7, BaCo1−xYxO3−γ, and Y2O3 were identified as the products of its decomposition at the low pO2 one

7,8-Dihydro-8-oxo-1,N6-ethenoadenine: an exclusively Hoogsteen-paired thymine mimic in DNA that induces A→T transversions in Escherichia coli

14 pags., 9 figs.This work investigated the structural and biological properties of DNA containing 7,8-dihydro-8-oxo-1,N6-ethenoadenine (oxo-ϵA), a non-natural synthetic base that combines structural features of two naturally occurring DNA lesions (7,8-dihydro-8-oxoadenine and 1,N6-ethenoadenine). UV-, CD-, NMR spectroscopies and molecular modeling of DNA duplexes revealed that oxo-ϵA adopts the non-canonical syn conformation (χ = 65º) and fits very well among surrounding residues without inducing major distortions in local helical architecture. The adduct remarkably mimics the natural base thymine. When considered as an adenine-derived DNA lesion, oxo-ϵA was >99% mutagenic in living cells, causing predominantly A→T transversion mutations in Escherichia coli. The adduct in a single-stranded vector was not repaired by base excision repair enzymes (MutM and MutY glycosylases) or the AlkB dioxygenase and did not detectably affect the efficacy of DNA replication in vivo. When the biological and structural data are viewed together, it is likely that the nearly exclusive syn conformation and thymine mimicry of oxo-ϵA defines the selectivity of base pairing in vitro and in vivo, resulting in lesion pairing with A during replication. The base pairing properties of oxo-ϵA, its strong fluorescence and its invisibility to enzymatic repair systems in vivo are features that are sought in novel DNA-based probes and modulators of gene expression.MIT Skoltech Next Generation Program Pilot Grant (to J.M.E.); National Institutes of Health (NIH) [R01-CA080024 to J.M.E.]; NIEHS Center Grant [P30-ES002109 (to Center for Environmental Health Sciences, which provided access to NGS facilities)]; Skoltech (to T.S.Z.); MICINN [PID2020-116620GB-I00 to C.G.]; Ministry of Science and Higher Education Russian Federation [07515-2021-1049 to A.V.A. – synthesis and UV/CD studies]. Funding for open access charge: Skoltech.Peer reviewe

SPHK1/sphingosine kinase 1-mediated autophagy differs between neurons and SH-SY5Y neuroblastoma cells

Although implicated in neurodegeneration, autophagy has been characterized mostly in yeast and mammalian non-neuronal cells. In a recent study, we sought to determine if SPHK1 (sphingosine kinase 1), implicated previously in macroautophagy/autophagy in cancer cells, regulates autophagy in neurons. SPHK1 synthesizes sphingosine-1-phosphate (S1P), a bioactive lipid involved in cell survival. In our study, we discovered that, when neuronal autophagy is pharmacologically stimulated, SPHK1 relocalizes to the endocytic and autophagic organelles. Interestingly, in non-neuronal cells stimulated with growth factors, SPHK1 translocates to the plasma membrane, where it phosphorylates sphingosine to produce S1P. Whether SPHK1 also binds to the endocytic and autophagic organelles in non-neuronal cells upon induction of autophagy has not been demonstrated. Here, we determined if the effect in neurons is operant in the SH-SY5Y neuroblastoma cell line. In both non-differentiated and differentiated SH-SY5Y cells, a short incubation of cells in amino acid-free medium stimulated the formation of SPHK1-positive puncta, as in neurons. We also found that, unlike neurons in which these puncta represent endosomes, autophagosomes, and amphisomes, in SH-SY5Y cells SPHK1 is bound only to the endosomes. In addition, a dominant negative form of SPHK1 was very toxic to SH-SY5Y cells, but cultured primary cortical neurons tolerated it significantly better. These results suggest that autophagy in neurons is regulated by mechanisms that differ, at least in part, from those in SH-SY5Y cells

Опыт разработки и применения алгоритма клинико-организационного управления при туберкулезе на региональном уровне

Relevance. The high incidence, prevalence and mortality in tuberculosis determines the relevance of improving clinical and organizational processes in terms of algorithmization. The aim of the study was to develop and evaluate the effectiveness of the clinical and organizational management algorithm for tuberculosis medical care at the regional level. Materials and Methods. The object of the study (2007-2021) were the tuberculosis medical care system of the Sverdlovsk region, Russian Federation. The scientific and methodological bases were Department of Health Organization, Drug Supply, Medical Technologies and Hygiene of the Peoples’ Friendship University of Russia topic SRW № 214791-3-000. The development of the algorithm was carried out on the basis of a scientifically proven universal clinical management system. The epidemiological tuberculosis author data and of Rosstat in the Sverdlovsk region for 2007-2020 were used - general and structural morbidity, prevalence, mortality, as well as the number of 3, 4 and 6 groups of dispensary registration of patients. The efficiency of the algorithm was evaluated by the dynamics of the complex of epidemiological indicators of tuberculosis. Research methods were applied: content analysis, analytical, statistical, comparative, expert. Significance was assessed using the t-White test. Differences in the compared parameters were considered significant at p0.05. Results and Discussion. The effectiveness of the developed algorithm for managing regional tuberculosis medical care, including the components of needs analysis, systematization, automation and telecommunications, interdisciplinary integration, resource provision and performance evaluation, was confirmed by a significant decrease in the Sverdlovsk region for the period 2007-2020 general incidence by 2.05 times (from 119.9 to 51.7 per 100 thousand of the population), the incidence of children 0-14 years old by 1.48 times (from 18.7 to 12.6 per 100 thousand children of the corresponding age), prevalence in the population by 1.8 times (from 258.6 to 143 per 100 thousand of the population) and mortality from tuberculosis by 2.675 times (from 21.4 to 8.02 per 100 thousand of the population) (p0.001). The COVID-19 pandemic (2020-2021) did not worsen the epidemiological situation for tuberculosis in the region. In 2020, an active form of tuberculosis was detected in 2201 people, which is 16 % less than in 2019 (p0.05). The prevalence of epidemiologically dangerous bacillary forms of the disease for the period 2019-2020 decreased by 15.4 %, from 73.2 to 61.9 per 100 thousand population (p0.05). Conclusion. Clinical and organizational management of tuberculosis medical care based on the algorithmization of scientifically evidence processes increases the effectiveness of therapeutic and preventive measures and the social and epidemiological well-being of the population.Актуальность. Высокая заболеваемость, распространенность и смертность при туберкулезе определяет актуальность совершенствования клинико-организационных процессов управления методом алгоритмизации. Цель исследования - разработать, внедрить и оценить эффективность алгоритма клинико-организационного управления противотуберкулезной помощью на уровне региона. Материалы и методы. Объектом исследования (2007-2021 гг.) явилась система противотуберкулезной помощи Свердловской области, база и научно-методическое сопровождение осуществлялось кафедрой организации здравоохранения, лекарственного обеспечения, медицинских технологий и гигиены Российского университета дружбы народов в соответствии с темой НИР № 214791-3-000. Разработку алгоритма осуществляли на основании научно доказанной универсальной системы клинического управления. Использована авторская информация и данные по туберкулезу Росстата по Свердловской области 2007-2020 гг. - структура заболеваемости, распространенности, смертность, а также численность пациентов 3, 4 и 6 групп диспансерного учета. Оценку эффективности алгоритма проводили по динамике комплекса эпидемиологических показателей туберкулеза. Применены методы исследования: контент-анализ, аналитический, статистический, сравнительный, экспертный. Для оценки достоверности применялся критерий t-Уайта. Различия сравниваемых показателей считали достоверными при р < 0,05. Результаты и обсуждение. Эффективность разработанного алгоритма управления региональной противотуберкулезной помощью, включающего компоненты анализа потребности, систематизации, автоматизации и телекоммуникации, междисциплинарной интеграции, ресурсного обеспечения и оценки эффективности, подтверждена достоверным снижением в Свердловской области за период 2007-2020 гг. общей заболеваемости в 2,05 раза (с 119,9 до 51,7 на 100 тыс. населения), заболеваемости детей 0-14 лет в 1,48 раза (с 18,7 до 12,6 на 100 тыс. детей соответствующего возраста), распространенности в популяции в 1,8 раза (с 258,6 до 143 на 100 тыс. населения) и смертности от туберкулеза в 2,675 раза (с 21,4 до 8,02 на 100 тыс. населения) (p < 0,001). Пандемия COVID-19 (2020-2021 гг.) не ухудшила эпидемиологическую ситуацию по туберкулезу в регионе. В 2020 г. активная форма туберкулеза выявлена у 2201 человек, что на 16 % меньше, чем в 2019 г. (р < 0,05). Распространенность эпидемиологически опасных бациллярных форм заболевания за период 2019-2020 гг. снизилась на 15,4 %, с 73,2 до 61,9 на 100 тысяч населения (р < 0,05). Заключение. Клинико-организационное управление противотуберкулезной помощью на основе научно-доказанных процессов алгоритмизации повышает результативность лечебно-профилактических мероприятий и социально-эпидемиологическое благополучие населения

Levetiracetam mitigates doxorubicin-induced DNA and synaptic damage in neurons

Neurotoxicity may occur in cancer patients and survivors during or after chemotherapy. Cognitive deficits associated with neurotoxicity can be subtle or disabling and frequently include disturbances in memory, attention, executive function and processing speed. Searching for pathways altered by anti-cancer treatments in cultured primary neurons, we discovered that doxorubicin, a commonly used anti-neoplastic drug, significantly decreased neuronal survival. The drug promoted the formation of DNA double-strand breaks in primary neurons and reduced synaptic and neurite density. Pretreatment of neurons with levetiracetam, an FDA-approved anti-epileptic drug, enhanced survival of chemotherapy drug-treated neurons, reduced doxorubicin-induced formation of DNA double-strand breaks, and mitigated synaptic and neurite loss. Thus, levetiracetam might be part of a valuable new approach for mitigating synaptic damage and, perhaps, for treating cognitive disturbances in cancer patients and survivors