Репозиторий Университета

A comparative study performed in mice investigating the action of DF302, a novel fluoride-containing gamma-carboline derivative, in comparison to the structurally similar neuroprotective drug dimebon. Drug effects on learning and memory, emotionality, hippocampal neurogenesis and mitochondrial functions, as well as AMPA-mediated currents and the 5-HT6 receptor are reported. In the step-down avoidance and fear-conditioning paradigms, bolus administration of drugs at doses of 10 or 40 mg/kg showed that only the higher dose of DF302 improved long-term memory while dimebon was ineffective at either dosage. Short-term memory and fear extinction remained unaltered across treatment groups. During the 5-day predation stress paradigm, oral drug treatment over a period of 2 weeks at the higher dosage regimen decreased anxiety-like behaviour. Both compounds supressed inter-male aggression in CD1 mice, the most eminent being the effects of DF302 in its highest dose. DF302 at the higher dose decreased floating behaviour in a 2-day swim test and after 21-day ultrasound stress. The density of Ki67-positive cells, a marker of adult neurogenesis, was reduced in the dentate gyrus of stressed dimebon-treated and non-treated mice, but not in DF302-treated mice. Non-stressed mice that received DF302 had a higher density of Ki67-positive cells than controls unlike dimebon-treated mice. Similar to dimebon, DF302 effectively potentiated AMPA receptor-mediated currents, bound to the 5-HT6 receptor, inhibited mitochondrial permeability transition and displayed cytoprotective properties in cellular models of neurodegeneration. Thus, DF302 exerts multi-target effects on the key mechanisms of neurodegenerative pathologies and can be considered as an optimized novel analogue of the neuroprotective agent dimebon.

2 был модифицирован включением вектора (d-Arg) 8 для предотвращения действия эндопептидазы и увеличения продолжительности обезболивающего действия тетрапептида при пероральном введении , Целью данного исследования было оценить анальгетическую эффективность тетрапептида с (d-Arg) 8(тридекапептид, TDP) в экспериментальных моделях острой и хронической боли. Анальгезирующие эффекты TDP оценивали с использованием модели острой висцеральной боли у мышей (тест на корч) и модели хронической невропатической боли (хроническое сужающее повреждение (CCI) седалищного нерва) у крыс. Внутривенное введение морфина (0,32-1 мг / кг) и TDP (0,32-1,8 мг / кг) приводило к значительным антиноцицептивным эффектам, связанным с дозой, в тесте на корч. Активность TDP после введения ig была ниже, чем после внутривенного введения, но сравнима с таковой ig морфина. В модели CCI TDP (0,1, 1 и 10 мг / кг, мкг) вызывал выраженную анальгезию при повторном введении без каких-либо признаков толерантности. Однократное введение TDP после лечения морфином (7 дней) вызывало значительный обезболивающий эффект у морфин-толерантных крыс, что указывает на отсутствие перекрестной переносимости между этими двумя препаратами. Комбинированное введение TDP и морфина привело к снижению анальгетической толерантности к морфию. Отсутствие перекрестной толерантности к морфию и способность предотвращать морфиновую толерантность позволяет этому соединению быть потенциальным кандидатом для лечения хронической боли. Чтобы найти рецепторы-мишени для TDP, было проведено исследование стыковки. Было обнаружено, что молекула может связываться с рецептором NMDA с помощью электростатических, водородных связей и гидрофобных взаимодействий. Отсутствие перекрестной толерантности к морфию и способность предотвращать морфиновую толерантность позволяет этому соединению быть потенциальным кандидатом для лечения хронической боли. Чтобы найти рецепторы-мишени для TDP, было проведено исследование стыковки. Было обнаружено, что молекула может связываться с рецептором NMDA с помощью электростатических, водородных связей и гидрофобных взаимодействий. Отсутствие перекрестной толерантности к морфию и способность предотвращать морфиновую толерантность позволяет этому соединению быть потенциальным кандидатом для лечения хронической боли. Чтобы найти рецепторы-мишени для TDP, было проведено исследование стыковки. Было обнаружено, что молекула может связываться с рецептором NMDA с помощью электростатических, водородных связей и гидрофобных взаимодействий.

The Nicotiana tabacum 4/1 protein (Nt-4/1) of unknown function expressed in plant vasculature has been shown to localize to cytoplasmic bodies associated with endoplasmic reticulum. Here, we analyzed molecular interactions of an Nt-4/1 mutant with a deletion of 90 N-terminal amino acid residues (Nt-4/1d90) having a diffuse GFP-like localization. Upon transient co-expression with VAP27, a membrane protein known to localize to the ER, ER-plasma membrane contact sites and plasmodesmata, Nt-4/1d90 was concentrated around the cortical ER tubules, forming a network matching the shape of the cortical ER. Additionally, in response to mechanical stress, Nt-4/1d90 was re-localized to small spherical bodies, whereas the subcellular localization of VAP27 remained essentially unaffected. The Nt-4/1d90-containing bodies associated with microtubules, which underwent noticeable bundling under the conditions of mechanical stress. The Nt-4/1d90 re-localization to spherical bodies could also be induced by incubation at an elevated temperature, although under heat shock conditions the re-localization was less efficient and incomplete. An Nt-4/1d90 mutant, which had phosphorylation-mimicking mutations in a predicted cluster of four potentially phosphorylated residues, was found to both inefficiently re-localize to spherical bodies and tend to revert back to the initial diffuse localization. The presented data show that Nt-4/1 has a potential for response to stresses that is manifested by its deletion mutant Nt-4/1d90, and this response can be mediated by protein dephosphorylation.

Modeling tools provide a valuable support for DNA origami design. However, current solutions have limited application for conformational analysis of the designs. In this work we present a tool for a thorough study of DNA origami structure and dynamics. The tool is based on a novel coarse-grained model dedicated to geometry optimization and conformational analysis of DNA origami. We explored the ability of the model to predict dynamic behavior, global shapes, and fine details of two single-layer systems designed in hexagonal and square lattices using atomic force microscopy, Förster resonance energy transfer spectroscopy, and all-atom molecular dynamic simulations for validation of the results. We also examined the performance of the model for multilayer systems by simulation of DNA origami with published cryo-electron microscopy and atomic force microscopy structures. A good agreement between the simulated and experimental data makes the model suitable for conformational analysis of DNA origami objects. The tool is available at http://vsb.fbb.msu.ru/cosm as a web-service and as a standalone version.

Plant defense is achieved mainly through the induction of microbe-associated molecular patterns (MAMP)-triggered immunity (MTI), effector-triggered immunity (ETI), systemic acquired resistance (SAR), induced systemic resistance (ISR), and RNA silencing. Plant immunity is a highly complex phenomenon with its own unique features that have emerged as a result of the arms race between plants and pathogens. However, the regulation of these processes is the same for all living organisms, including plants, and is controlled by proteases. Different families of plant proteases are involved in every type of immunity: some of the proteases that are covered in this review participate in MTI, affecting stomatal closure and callose deposition. A large number of proteases act in the apoplast, contributing to ETI by managing extracellular defense. A vast majority of the endogenous proteases discussed in this review are associated with the programmed cell death (PCD) of the infected cells and exhibit caspase-like activities. The synthesis of signal molecules, such as salicylic acid, jasmonic acid, and ethylene, and their signaling pathways, are regulated by endogenous proteases that affect the induction of pathogenesis-related genes and SAR or ISR establishment. A number of proteases are associated with herbivore defense. In this review, we summarize the data concerning identified plant endogenous proteases, their effect on plant-pathogen interactions, their subcellular localization, and their functional properties, if available, and we attribute a role in the different types and stages of innate immunity for each of the proteases covered. View Full-Text

Гиперметилирование наблюдается в промоторных областях генов-супрессоров в раковых клетках опухоли. Реактивация этих генов путем деметилирования их промоторов является перспективной стратегией противоопухолевой терапии. Предыдущие эксперименты показали, что симметричные димерные бисбензимидазолы DBP (n) способны блокировать активность ДНК-метилтрансферазы. Также было обнаружено, что DBP (n) оказывает умеренное влияние на активацию общей экспрессии генов в популяции HeLa-TI, содержащей эпигенетически репрессированный геном саркомы птиц.

This review presents evidence that the skin mast cell, in particular the MCTC subtype, is the primary effector cell in urticaria. Mast cells are located in the upper dermis, the ideal situation for wheal formation and sensory nerve stimulation. Increased numbers of mast cells are found in both lesional and non‐lesional skin in CSU and inducible urticaria. Mast cell degranulation in the area of wheals has been demonstrated repeatedly by light and electron microscopy. Histamine, PGD2 and tryptase are found in the venous blood draining wheal formation. The last 2 are specific for mast cells rather than basophils. Mast cell reactivity is increased in active urticaria by local inflammatory cytokines and neuropeptides. Mast cell cytokines and neuropeptides, particularly nerve growth factor, induce a Th2 type inflammation that is particularly obvious at the sites of whealing. In conclusion, autoimmunity, either of Type 1 viz. IgE antibodies to local autoallergens, or Type 2b, viz. IgG autoantibodies to IgE or its receptor, are considered to be the most frequent causes of CSU. In both cases, the mast cell is likely to be the axial cell in producing the wheals.

Enteroviruses (EVs) belong to the family Picornaviridae and are responsible for mild to severe diseases in mammals including humans and non-human primates (NHP). Simian EVs were first discovered in the 1950s in the Old World Monkeys and recently in wild chimpanzee, gorilla and mandrill in Cameroon. In the present study, we screened by PCR EVs in 600 fecal samples of wild apes and monkeys that were collected at four sites in Gabon. A total of 32 samples were positive for EVs (25 from mandrills, 7 from chimpanzees, none from gorillas). The phylogenetic analysis of VP1 and VP2 genes showed that EVs identified in chimpanzees were members of two human EV species, EV-A and EV-B, and those identified in mandrills were members of the human species EV-B and the simian species EV-J. The identification of two novel enterovirus types, EV-B112 in a chimpanzee and EV-B113 in a mandrill, suggests these NHPs could be potential sources of new EV types. The identification of EV-B107 and EV90 that were previously found in humans indicates cross-species transfers. Also the identification of chimpanzee-derived EV110 in a mandrill demonstrated a wide host range of this EV. Further research of EVs in NHPs would help understanding emergence of new types or variants, and evaluating the real risk of cross-species transmission for humans as well for NHPs populations.

The review is summarizing for the first time the results of original research and literature data revealing the conditions of opportunistic microflora (OM) pathogenicity and virulence formation in the dynamics of the infectious process, as well as maintenance and formation of gene pools in host cells and microorganisms. It is established, that formation or loss of pathogenic and virulent properties of microorganisms in the body happens under the influence of its external environment, its overall physiological and immunological reactivity, mucosal immunity, as well as with the direct participation of horizontal gene transfer. Newly created microbial pathogens cause infectious-inflammatory diseases. However, acquired pathogenicity factors are lost after recovery. Plasticity of gene pools of the macroorganism and microorganisms allows owners of gene pools to respond adequately to changes in the external and internal body environment, improve and enhance overall and immunological reactivity of the macroorganism in ontogenesis, generate optimal for specific situations symbiotic or antagonistic relationships between them taking into account newly acquired or lost pathogenicity and virulence factors and form new phenotypic or genetic properties of microorganisms. Horizontal genetic transfer is the process of moving the genetic information which is possible between prokaryotic and eukaryotic cells both ways, as well as within a single cell.

Повышение эффективности и безопасности НПВП, незаменимого класса лекарственных средств, используемых для лечения острой и хронической боли, является важной и актуальной задачей. Для ее решения российскими экспертами в 2015 г. был представлен алгоритм выбора НПВП, основанный на оценке факторов риска (ФР) лекарственных осложнений и назначении препаратов с наименьшим негативным влиянием на желудочно- кишечный тракт (ЖКТ) и сердечно-сосудистую систему (ССС). Для проверки эффективности этого алгоритма был осуществлен проект «ПРИНЦИП».

Материал и методы. Исследуемую группу составили 439 больных с выраженной скелетно-мышечной болью (65% женщин и 35% мужчин; средний возраст – 51,3±14,4 года), которым назначались НПВП с использованием указанного выше алгоритма. У большинства отмечалось наличие ФР: у 62% – со стороны ЖКТ, у 88% – ССС. С учетом ФР были использованы 8 НПВП: ацеклофенак, диклофенак, ибупрофен, кетопрофен, мелоксикам, напроксен, нимесулид и целекоксиб, причем последний препарат назначался наиболее часто (57,4% случаев). У 30,2% больных НПВП были назначены в сочетании с ингибиторами протонной помпы. Период наблюдения составил 28 дней. Оценивались эффективность терапии (динамика боли по 10-балльной числовой рейтинговой шкале – ЧРШ) и развитие нежелательных реакций (НР).

Результаты и обсуждение. У подавляющего числа пациентов (94,9%) боль была полностью купирована. Значимых различий эффективности разных НПВП по динамике уменьшения боли (ЧРШ) отмечено не было. Число НР было минимальным и не различалось между разными НПВП, за исключением более высокой частоты диспепсии при использовании диклофенака (15,7%). Серьезных осложнений и отмен терапии из-за НР не было.

Заключение. Использование алгоритма выбора НПВП позволяет проводить эффективную и относительно безопасную терапию этими препаратами в реальной клинической практике.

There was an oversight in the Authorship of a recent Images in Urogynecology article titled: Rectocutaneous fistula with transmigration of the suture: a rare delayed complication of vault fixation with the sacrospinous ligament (DOI 10.1007/ s00192-015-2823-5). We would like to include Adj A/P Han How Chuan’s name in the list of authors. Adj A/P Han is a Senior Consultant and Department Head of Urogynaecology at the KK Hospital for Women and Children, Singapore.

BACKGROUND:

The 2013 International Classification of Headache Disorders-3 (ICHD-3) was published in a beta version to allow the clinicians to confirm the validity of the criteria or to suggest improvements based on field studies. The aim of this work was to review the Primary Headache Disorders Section of ICHD-3 beta data on children and adolescents (age 0-18 years), and to suggest changes, additions, and amendments.
METHODS:

Several experts in childhood headache across the world applied different aspects of ICHD-3 beta in their normal clinical practice. Based on their personal experience and the literature available on pediatric headache, they made observations and proposed suggestions for the primary headache disorders section of ICHD-3 beta data on children and adolescents.
RESULTS:

Some headache disorders in children have specific features which are different from those seen in adults and which should be acknowledged and considered. Some features in children were found to be age-dependent: clinical characteristics, risks factors and etiologies have a strong bio psycho-social basis in children and adolescents making primary headache disorders in children distinct from those in adults.
CONCLUSIONS:

Several recommendations are presented in order to make ICHD-3 more appropriate for use with children.

Exposure to benzene and its inevitable metabolites can result in deleterious effects on human health, including lymphocytopenia, hematotoxicity and cancer. However, the duration of exposure might alter the effects including immune consequences. The aim of this study was to determine whether benzene could modulate lymphocyte proliferation induced by the T cell mitogen concanavalin A, in rats, at different exposure durations. 386 Wistar rats were assigned into control and treatment groups which were subdivided into groups for 45, 90 and 135days for 0,6mL/kg of drinking water mixed benzene treatment. The percentage of CD3+, CD4+, CD8+ spleen lymphocytes was defined using the flow cytometer. Interleukin (IL)-4, IL-6, IL-10 and interferon-gamma, in supernatants of splenocyte cultures stimulated with Concanavalin A, were assessed by enzyme-linked immunosorbent assay (ELISA) technique. The decrease in the total lymphocyte and T cell counts were associated with increased benzene exposure duration. Th2-type cytokine, IL-4 significantly increased, whereas IL-6, CD4+T cells, CD4+/CD8+ ratio and CD3+ T cells decreased. Despite the positive correlation between benzene toxicity and indicated increased immune responses, 45-day exposure to benzene appeared to be the most sensitive time point for evaluating benzene cytotoxicity.