Enduring effects of conditional brain serotonin knockdown, followed by recovery, on adult rat neurogenesis and behavior

Serotonin (5-hydroxytryptamine, 5-HT) is a crucial signal in the neurogenic niche of the hippocampus, where it is involved in antidepressant action. Here, we utilized a new transgenic rat model (TetO-shTPH2), where brain 5-HT levels can be acutely altered based on doxycycline (Dox)-inducible shRNA-expression. On/off stimulations of 5-HT concentrations might uniquely mirror the clinical course of major depression (e.g., relapse after discontinuation of antidepressants) in humans. Specifically, we measured 5-HT levels, and 5-HT metabolite 5-HIAA, in various brain areas following acute tryptophan hydroxylase 2 (Tph2) knockdown, and replenishment, and examined behavior and proliferation and survival of newly generated cells in the dentate gyrus. We found that decreased 5-HT levels in the prefrontal cortex and raphe nuclei, but not in the hippocampus of TetO-shTPH2 rats, lead to an enduring anxious phenotype. Surprisingly, the reduction in 5-HT synthesis is associated with increased numbers of BrdU-labeled cells in the dentate gyrus. At 3 weeks of Tph2 replenishment, 5-HT levels return to baseline and survival of newly generated cells is unaffected. We speculate that the acutely induced decrease in 5-HT concentrations and increased neurogenesis might represent a compensatory mechanism

Изменчивость поверхностной абляции горных ледников Западного Шпицбергена

Measurements of surface ablation in 2016–2018 on the neighboring glaciers Aldegondabreen, Austre and Vestre Grønfjordbreen (West Spitsbergen) revealed significant differences in its magnitude both within the same altitude zones for one year, and on an interannual scale. Comparison of the region’s common variations in climatic conditions (air temperature, rainfall) and ablation data showed a significant contribution of the following additional factors of melting: aspect, size, altitude range, surface slope, the rocky bordering of glaciers. The maximum ablation were measured on the Aldegondabreen (with the smallest area and altitude range), which has a northeastern aspect; the average value over three years of observations was 1947 mm w.e. Austre Grønfjordbreen and Vestre Grønfjordbreen had in 2016–2018 average ablation values 1512 and 1385 mm w.e., respectively. The largest Vestre Grønfjordbreen has the lowest values of average ablation also because it lies higher then neighboring glaciers. Interannual variations of mean ablation in the same altitudinal zones show: the minimum scatter of values for the Aldegondabreen (130–370 mm w.e.); higher scatter of values for the Austre Grønfjordbreen (200–450 mm w.e.); the maximum scatter of values for the Vestre Grønfjordbreen (from 400–600 mm w.e. in most altitude zones to 1000 mm w.e. at altitudes of 250–350 m). Due to the influence of additional factors, the maximum average ablation was observed on the Aldegondabreen in 2016, on the Vestre Grønfjordbreen in 2017, and on the Austre Grønfjordbreen in 2017 and 2018. The results of the study indicate the need to take into account the contribution of these factors to the ablation parameters of the region’s glaciers in model calculations, as well as the relevance of a detailed study of the distribution of solar radiation on glaciers.Измерения значений абляции на соседних ледниках Альдегонда, Восточный и Западный Грёнфьорд (Западный Шпицберген) в 2016–2018 гг. показали наличие заметных вариаций в па­раметрах таяния, которые, помимо общих для района межгодовых изменений климатических условий (температура воздуха, осадки), обусловлены характеристиками экспозиции, размеров, высотных диапазонов, уклонов поверхности, скального обрамления ледников. Результаты ис­следования указывают на необходимость учета вклада этих характеристик в оценку абляции ледников района при модельных расчетах, а также на актуальность детального изучения рас­пределения солнечной радиации на рассматриваемых ледниках

Synchronous Closing and Flow Analysis for Model Checking Timed Systems

Abstract. Formal methods, in particular model checking, are increas-ingly accepted as integral part of system development. With large soft-ware systems beyond the range of fully automatic verification, however, a combination of decomposition and abstraction techniques is needed. To model check components of a system, a standard approach is to close the component with an abstraction of its environment, as standard model checkers often do not handle open reactive systems directly. To make it useful in practice, the closing of the component should be automatic, both for data and for control abstraction. Specifically for model checking asynchronous open systems, external input queues should be removed, as they are a potential source of a combinatorial state explosion. In this paper we investigate a class of environmental processes for which the asynchronous communication scheme can safely be replaced by a synchronous one. Such a replacement is possible only if the environment is constructed under rather a severe restriction on the behavior, which can be partially softened via the use of a discrete-time semantics. We employ data-flow analysis to detect instances of variables and timers influenced by the data passing between the system and the environment

Combined in Silico, Ex Vivo, and in Vivo Assessment of L-17, a Thiadiazine Derivative with Putative Neuro-and Cardioprotective and Antidepressant Effects

Depression associated with poor general medical condition, such as post-stroke (PSD) or post-myocardial infarction (PMID) depression, is characterized by resistance to classical antidepres-sants. Special treatment strategies should thus be developed for these conditions. Our study aims to investigate the mechanism of action of 2-morpholino-5-phenyl-6H-1,3,4-thiadiazine, hydrobro-mide (L-17), a recently designed thiadiazine derivative with putative neuro-and cardioprotective and antidepressant-like effects, using combined in silico (for prediction of the molecular binding mechanisms), ex vivo (for assessment of the neural excitability using c-Fos immunocytochemistry), and in vivo (for direct examination of the neuronal excitability) methodological approaches. We found that the predicted binding affinities of L-17 to serotonin (5-HT) transporter (SERT) and 5-HT3 and 5-HT1A receptors are compatible with selective 5-HT serotonin reuptake inhibitors (SSRIs) and antagonists of 5-HT3 and 5-HT1A receptors, respectively. L-17 robustly increased c-Fos immunoreac-tivity in the amygdala and decreased it in the hippocampus. L-17 dose-dependently inhibited 5-HT neurons of the dorsal raphe nucleus; this inhibition was partially reversed by the 5-HT1A antagonist WAY100135. We suggest that L-17 is a potent 5-HT reuptake inhibitor and partial antagonist of 5-HT3 and 5-HT1A receptors; the effects of L-17 on amygdaloid and hippocampal excitability might be mediated via 5-HT, and putatively mediate the antidepressant-like effects of this drug. Since L-17 also possesses neuro-and cardioprotective properties, it can be beneficial in PSD and PMID. Combined in silico predictions with ex vivo neurochemical and in vivo electrophysiological assessments might be a useful strategy for early assessment of the efficacy and neural mechanism of action of novel CNS drugs. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.Funding: The work of the authors of this study was supported by the Slovak Research and Development Agency (contract APVV-19-0435), Scientific Grant Agency of the Ministry of Education of the Slovak Republic, the Slovak Academy of Sciences (grant VEGA 2/0046/18), and a Government Contract of the Russian Federation with the Institute of Immunology and Physiology (AAAA-A18-118020690020-1)

Оценка баланса массы ледника Альдегонда (Западный Шпицберген) в 2015–2018 гг. на основе модели ArcticDEM, геодезических и гляциологических данных

The Aldegonda (Aldegondabreen) Glacier, located on the Nordenskjold Land, West Spitsbergen, covers the area of about 6  km2 (in 2018) and does constantly retreat since the very first observations of 1936. In August 2018, a topographic survey of the glacier was carried out. By comparing the results with the ArcticDEM model, built from space images of 2015, the difference in heights of the surface over three years had been calculated. Comparison of this difference with in situ data of glaciological measurements by the ablation stakes, made during the same period 2015–2018, demonstrated a high correlation between them. Considering the almost complete absence of snow cover on the glacier at the end of the summer season, the difference was recalculated into the spatial distribution of the specific mass balance by multiplying the ice density (0.88 g cm−3). Using the empirical dependence of the specific mass balance on the altitude above sea level, the obtained values were extrapolated to that part of the glacier which was not surveyed in 2018. The total loss of the Aldegonda Clacier mass for 2015–2018, calculated on the basis of topographic survey and the ArcticDEM, was estimated as 30.3 million tons (about 10.1 million tons per year). This magnitude gives the value of mean annual specific balance of approximately −1.76 m w.e, which is almost 2.5 times larger modulo than the previously published mean for the period 1936–1990, but close to the values of the early 2000s. Despite the small difference in the values obtained by geodetic and glaciological methods, the measurements does not show a systematic shift relative to each other and demonstrate approximately the same intervals of specific balance from the glacier tongue to its upper reaches (−1.08 ÷ −3.01 m w.e). This makes possible to conclude that the ArcticDEM model has the satisfactory vertical accuracy (both relative and absolute) to study on its basis changes in the surface height of an individual glacier.Путём сравнения результатов топографической съёмки с моделью местности ArcticDEM изучено снижение поверхности ледника Альдегонда за 2015–2018 гг. Потеря массы ледником за три года составила 30,3 млн т, или −1,76 м в.э. Исследование показало возможность применения ArcticDEM для масс-балансовых оценок отдельных ледников

Нарушение целостности эндотелиального монослоя биопротезов клапанов сердца как триггер развития первичной тканевой несостоятельности

Aim. To study the surface and cellular composition of non-calcified bioprosthetic heart valve (BHV) leaflets with varying degrees of structural deterioration to determine the possible mechanisms of primary tissue failure development.Materials and methods. An examination of six bioprosthetic heart valves (KemCor and PeriCor) extracted from mitral position due to the structural valve deterioration was performed. The structure of BHV leaflets was studied by hematoxylin – eosin staining and immunohistochemistry assay (with the following indicators – CD3, T lymphocytes; CD20, B lymphocytes; CD31, mature endothelial cells; CD34, endothelial progenitor cells; CD68, monocytes/macrophages; vimentin, mesenchymal cells; α-smooth muscle actin, vascular smooth muscle cells).Results. The degree of disruption of BHV leaflets in primary tissue failure differed significantly: relatively intact samples with the intact endothelial monolayer, areas with impairment of the surface layers (minimal and moderate damage) and areas with the spread of destruction into the extracellular matrix of the leaflet (expressed degeneration) were determined. Endothelial cells (monolayer with preserved or impaired integrity), macrophages, smooth muscle cells and other mesenchymal lineage cells were identified in BHV. T- and B-lymphocytes were not detected in the BHV leaflets. Conclusions. A characteristic feature of structurally deteriorated BHVs is impairment of endothelial monolayer integrity in areas of degraded extracellular matrix. In contrast to other types of bioprosthetic dysfunctions, structural valve deterioration was characterized by the absence of lymphocyte infiltration. Therefore, we suppose that endothelial mololayer injury is a trigger of structural BHV deterioration.Цель – морфологическое исследование поверхности и клеточного состава створок некальцинированных биопротезов клапанов сердца (БКС) с различной степенью их повреждения для  определения возможных механизмов развития первичной тканевой несостоятельности (ПТН).Материалы и методы. Исследовано шесть ксеноаортальных клапанов «КемКор» и «ПериКор», извлеченных из митральной позиции по причине развития ПТН. Структуру створок БКС и особенности ее изменения изучали гистологическим (окраска гематоксилин-эозином) и иммуногистохимическим методами. Иммуногистохимическое исследование БКС включало идентификацию маркеров: СD3 (Т-лимфоциты), СD20 (В- лимфоциты), СD31 и СD34 (эндотелиальные клетки), СD68 (моноциты/макрофаги), виментин (клетки мезенхимального ряда), α-гладкомышечный актин (гладкомышечные клетки).Результаты. Степень нарушения структуры створок БКС при ПТН существенно различалась: определялись  относительно сохранные образцы с интактным эндотелиальным монослоем на поверхности створки, образцы с минимальным или умеренным нарушением структуры эндотелиального слоя и образцы с выраженной деструкцией эндотелиального слоя створки БКС. В составе БКС были идентифицированы эндотелиальные клетки (монослой с сохраненной или нарушенной целостностью), макрофаги, гладкие миоциты и прочие клетки мезенхимального происхождения. Следует отметить, что нами не обнаружено Т- и B-лимфоцитов в створках БКС.Заключение. Характерным признаком структуры БКС, эксплантированных по причине ПТН, является нарушение целостности эндотелиального монослоя в участках дезинтеграции экстрацеллюлярного матрикса. Кроме того, в сравнении с другими типами протезных дисфункций ПТН отличается отсутствием лимфоцитарной инфильтрации. На основании полученных данных можно сделать вывод о триггерной роли дезинтеграции эндотелиального монослоя в развитии ПТН

Особенности послеоперационного периода при хирургии глаукомы у пациента с синдромом Стердж-Вебера (клинический случай)

   PURPOSE. To evaluate the effectiveness of surgical treatment of secondary glaucoma and to present the clinical features of the postoperative period in a patient with Sturge-Weber syndrome (SWS).   METHODS. A patient with SWS, choroidal hemangioma and secondary glaucoma was examined and treated (Ahmed valve implantation) at the S.N. Fedorov National Medical Research Center "MNTK "Eye Microsurgery" in Moscow.   RESULTS. Hypotension, a decrease in anterior chamber depth, serous choroidal detachment were observed on the first day after surgery on the left eye. Posterior scleral trepanation and injection of viscoelastic into the anterior chamber was performed. On the next day, IOP normalization and complete choroidal attachment were achieved, but macular detachment of neuroepithelium occurred and was successfully treated with injections of glucocorticosteroids. After one month, the retina and choroid were attached, IOP was 16 mm Hg in the left eye without hypotensive drops, visual acuity was 1.0 in both eyes.   CONCLUSION. Implantation of the Ahmed valve can be used in the treatment of secondary glaucoma in patients with SWS in order to reduce the IOP and minimize the risks of complications.   ЦЕЛЬ. Оценить эффективность хирургического лечения вторичной глаукомы и представить особенности клиники послеоперационного периода у пациента с синдромом Стердж-Вебера (ССВ).   МЕТОДЫ. В «МНТК «Микрохирургия глаза» им. акад. С. Н. Федорова» г. Москва проведено обследование пациента с ССВ, гемангиомой хориоидеи и декомпенсированной вторичной глаукомой и проведено хирургическое лечение глаукомы — имплантация клапана Ahmed.   РЕЗУЛЬТАТЫ. На первые сутки после операции на левом глазу выявлено: гипотония, измельчение передней камеры, серозная цилиохориоидальная отслойка. Проведена задняя трепанация склеры, восстановлен объем передней камеры вискоэластиком. На следующие сутки наблюдались нормализация ВГД и полное прилегание сосудистой оболочки, но обнаружена отслойка нейроэпителия в макулярной области, в связи с чем назначены инъекции глюкокортикостероидов с положительным эффектом. Через 1 месяц после операции жалобы отсутствуют, оболочки прилежат, на левом глазу ВГД 16 мм рт. ст. без гипотензивных капель, острота зрения на оба глаза 1,0.   ЗАКЛЮЧЕНИЕ. Имплантация дренажного клапана Ahmed может применяться в лечении вторичной глаукомы у пациентов с ССВ с целью снижения ВГД и минимизации рисков развития осложнений

Results of thrombectomy in lower-extremity ischemia in patients with COVID-19 and respiratory failure of different severity

Aim. To analyze the results of thrombectomy in lower-extremity ischemia in patients with coronavirus disease 2019 (COVID-19) and respiratory failure of different severity.Material and methods. This retrospective, cohort, comparative study for the period from May 1, 2020 to March 1, 2022 included 305 patients with acute lower-extremity ischemia and COVID-19. Depending on the type of oxygen support, three groups of patients were formed: group 1 (n=168) — nasal oxygen insufflation; group 2 (n=92) — non-invasive ventilation (NIV); group 3 (n=45) — artificial ventilation (AV). Thrombectomy was carried out according to the standard technique using Fogarty catheters (3F-6F — depending on the vessel size). After the diagnosis was established before and after the start of surgical treatment, all patients received the following therapy: Unfractionated IV heparin infusion at an initial rate of 1000 U/r, adjusted to maintain the activated partial thromboplastin time at 2-3 times the normal value; 2. Oral acetylsalicylic acid 125 mg; 3. Analgesics.Results. Myocardial infarction and ischemic stroke were not detected in the total sample. The highest number of deaths (group 1: 5,3%, n=9; group 2: 72,8%, n=67; group 3: 100%, n=45; p<0,0001), retrombosis (group 1 : 18,4%, n=31; group 2: 69,5%, n=64; group 3: 91,1%, n=41; p<0,0001) and limb amputations (group 1: 9,5%, n=16; group 2: 56,5%, n=52; group 3: 91,1%, n=41; p<0,0001) was recorded in group 3 patients.Conclusion. In patients receiving mechanical ventilation, COVID-19 have more aggressive course, which is expressed in an increase in laboratory para- meters (C-reactive protein, ferritin, interleukin-6, D-dimer), the severity of pneumonia and location of thrombosis in the tibial arteries. Among patients with COVID-19 receiving mechanical ventilation, the greatest number of rethromboses (91,1%), limb amputations (91,1%), and deaths (100%) are noted, which suggests the expediency of abandoning open thrombectomy in favor of anticoagulant/antiplatelet therapy in this cohort of patients. The development of arterial thrombosis in patients with COVID-19 receiving mechanical ventilation is an indicator of a high risk of death. Open thrombectomy in combination with anticoagulant/antiplatelet therapy is most effective in patients on nasal oxygen insufflation or NIV