Inhaled Interleukin-10 before and after induction of experimental endotoxemia in the rat : effects on the inflammatory response

To determine the effects of inhaled IL-10 at different doses and different time points on the pulmonary and systemic inflammatory response during endotoxemia, 48 ventilated, anaesthetized rats (mean body weight ± standard deviation, 500 ± 33g) were randomly assigned to six groups (n = 8, each). Interleukin-10 was nebulised either prior to or following the intravenous injection of LPS (5mg/kg) at two doses (5.0 mycro-g or 0.5 mycro-g) in our groups. Eight rats received the same insult with no further treatment (LPS-only group). Another eight rats served as controls without endotoxemia but with aerosolized phosphate-buffered saline, the solvent of IL-10 (Sham group). Concentrations of TNF-alpha, IL-1beta, IL-6, and IFN-gamma were analyzed in plasma and bronchoalveolar lavage fluid (BALF). In addition, the nitrite release from ex-vivo cultured alveolar macrophages was determined. As compared to the LPS-only group, the concentrations of the proinflammatory cytokines TNF-alpha, IL-1beta, IL-6, and IFN-gamma in plasma were significantly reduced in the group, which inhaled 5 mycro-g IL-10 before LPS injection (p< 0.0125). Spontaneous nitrite release from exvivo cultured alveolar macrophages was suppressed in this group (p< 0.0125). Inhalation of 0.5 mycro-g IL-10 before LPS injection and both dosages of IL-10 inhalation (5 mycro-g or 0.5 mycro-g) after LPS injection did not significantly influence either inflammatory cytokine concentrations in BALF, in plasma or the nitrite release from ex-vivo cultured alveolar macrophages. In this study, inhaled IL-10 only demonstrated anti-inflammatory effects when it was administered at 5 mycro-g prior to the induction of experimental endotoxemia. Interleukin-10 aerosol had no effect when it was given either following induction of endotoxemia or given at a lower dosage (which here was 0.5 mycro-g) either before or following injection of lipopolysaccharide.Das "Acute Respiratory Distress Syndrome" (ARDS) ist eine akut auftretende, überwiegend Sepsis-induzierte, inflammatorische Erkrankung der Lunge mit hoher Letalität. Ein komplexes Netzwerk aus Zytokinen und anderen proinflammatorischen Mediatoren unterhält die pulmonale Entzündungreaktion. Dem Zytokin Interleukin-10 (IL-10) könnte in diesem Zusammenhang aufgrund seines spezifisch antiinflammatorischen und immunmodulierenden Wirkspektrums eine therapeutische Bedeutung zukommen. In tierexperimentellen Untersuchungen konnten die protektiven Wirkungen von systemisch appliziertem Interleukin-10 bezüglich verringerter Wirkspiegel proinflammatorischer Mediatoren sowie des Überlebens der Versuchstiere bei Sepsis belegt werden. In einer Untersuchung an ARDS-Erkrankten wiesen Patienten, deren bronchoalveoläre Lavage (BAL) hohe Konzentrationen an Interleukin-10 enthielt, eine signifikant niedrigere Letalität auf als Patienten mit niedriger IL-10-Konzentration. Die Inhalation von IL-10 über den Luftweg könnte lokal in der Lunge die Freisetzung von Entzündungsmediatoren verringern und so den Verlauf eines ARDS positiv beeinflussen. Im Rahmen einer bereits durchgeführten Studie der eigenen Arbeitsgruppe konnte gezeigt werden, dass die Inhalation von IL-10 (0.19 mycro-g/Tier) vor Induktion einer experimentellen Endotoxinämie (Beobachtungszeitraum 6h) zur signifikanten Reduktion proinflammatorischer Zytokine im Plasma sowie der BAL führte. Daneben bewirkte IL-10 Aerosol eine signifikante Verringerung der Nitritproduktion aus ex vivo kultivierten Alveolarmakrophagen (AM). Mit der vorliegenden Studie sollte untersucht werden, ob vernebeltes IL-10 auch in einer geringeren Dosierung als in der ersten Studie angewandt antiinflammatorisch wirksam ist. Daneben sollte geklärt werden, ob der Zeitpunkt der Applikation des IL-10 Aerosol relevant ist. Konkret sollte untersucht werden, ob die Inhalation von IL-10 erst nach Induktion der experimentellen Endotoxinämie ebenfalls antinflammatorisches Potential besitzt. Die Generierung und Verneblung des IL-10 Aerosols erfolgte in der vorliegenden Untersuchung mittels eines speziell für diesen Einsatz von der eigenen Arbeitsgruppe entwickelten und charakterisierten Verneblersystems. Der Vernebler produziert stabil Aerosopartikel, deren Größenverteilung (rund 2 mycro-m) mit hoher Wahrscheinlichkeit in alvelären Bereichen deponiert. Die alveoläre Depositionsfraktion des Verneblers beträgt rund 4% und liegt damit in einem Bereich, der aus der Humanmedizin für die Verneblung bei intubierten Patienten bekannt ist. An 48 narkotisierten, kontrolliert beatmeten Ratten wurde die antiinflammatorische Wirkung eines IL-10-Aerosols untersucht. Die Induktion des experimentellen Lungenschadens erfolgte durch intravenöse Injektion von Endotoxin (Lipopolysaccharid; LPS, in einer Dosierung von 5mg/kg). Als löslicher Bestandteil der Membran gram-negativer Bakterien führt LPS über die Freisetzung proinflammatorischer Substanzen zu entzündlichen Reaktionen, die lokal beschränkt oder auch systemisch auftreten können. Bei Versuchstieren unterschiedlicher Spezies bewirkt die systemische Applikation von LPS pulmonale Veränderungen, die denen des septisch bedingten ARDS des Menschen qualitativ entsprechen. Die Tiere wurden zufällig in eine der sechs Versuchsgruppen eingeteilt (je n=8): Die LPS-Gruppe erhielt eine LPS-Injektion (5 mg/kg/KG) ohne anschließende therapeutische Intervention. Die mit IL-10 behandelten Tiere erhielten das IL-10-Aerosol entweder vor oder nach Induktion der experimentellen Endotoxinämie nach unten genanntem Protokoll. In einer Kontroll (Sham)-Gruppe wurde die Auswirkung von Narkose, chirurgischer Präparation, Beatmung und Aerosolapplikation (IL-10-Trägerlösung; phosphatgepufferte Kochsalzlösung) evaluiert. Neben der in vivo Beobachtung von Hämodynamik (Herzfrequenz, mittlerer arterieller Blutdruck), Lungenmechanik, arteriellen Blutgasen und Blutbild, untersuchten wir anhand von Blutproben und einer Bronchoalveolären Lavage (BAL) die systemische und pulmonale Inflammation (inflammatorische Zytokine TNFalpha, IL-1beta, IL-6 und IFNgamma in Plasma und BAL). Die Verneblung von IL-10 erfolgte in zwei Dosierungen und zu zwei Zeitpunkten: in einer Gruppe wurde IL-10 in einer Dosierung von 5.0 mycro-g (0.19 mycro-g/Tier) vor, und in einer weiteren Gruppe nach Induktion der experimentellen Endotoxinämie vernebelt. In zwei weiteren Versuchgruppen wurde IL-10 in einer Dosierung von 0.5 mycro-g (0.019 mycro-g/Tier) ebenfalls vor sowie nach Injektion von LPS vernebelt. Die Endotoxinämie führte nur zu geringen Verschlechterungen der klinischen Parameter, aber sowohl pulmonal (BAL) als auch systemisch (Plasma) zeigte sich ein Anstieg proinflammatorischer Mediatoren. Gegenüber den Tieren, deren Endotoxinämie unbehandelt blieb, bewirkte nur die Inhalation von IL-10 in der höheren Dosierung (5 mycro-g) das signifikante Abfallen der proinflammatorischen Zytokine TNFalpha, IL-1beta, IL-6 und IFNgamma im Plasma sowie der Freisetzung von Nitrit aus kultivierten AM. IL-10 Aerosol hatte in keiner Dosierung respektive zu keinem Applikationszeitpunkt antiinflammatorische Effekte auf die Zytokinkonzentrationen in der BAL. Die präemptive Vernebelung von IL-10 in einer Dosierung von 5 mycro-g (0.19 mycro-g/Tier) vor Induktion einer experimentellen Endotoxinämie zeigte sowohl auf die AM Kultur als auch systemisch (Plasma) antinflammatorisches Wirkprofil. Demgegenüber zeigte IL-10 keine antinflammatorische Effekte, wenn es erst nach Injektion von LPS oder aber in geringerer Dosierung vernebelt wurde. Zur antiinflammatorischen Therapie der experimentellen Endotoxinämie durch LPS Injektion in der Spezies Ratte erscheint IL-10 Aerosol nur wirksam, wenn es in ausreichender Dosierung (5 mycro-g) sowie vor Injektion von LPS appliziert wird

The variable elasticity of substitution function and endogenous growth : an empirical evidence from Vietnam

Purpose: To specify a Variable Elasticity of Substitution function (VES), in which the estimated Elasticity of Substitution (ES) can give some implications for the tendency of economic growth in the Vietnames manufacturing sector. Design/Methodology/Approach: The contribution and the relevant methodology is based on the Bayesian approach having some advantages over the frequentist method: (i) the simulation and prediction results are more reliable in Bayesian analysis due to combining prior knowledge about parameters with obverved data to compose a posterior model, whereas the frequentist approach is based only on available data; (ii) in probability sense, Bayesian credible intervals have a straightforward interpretation compared to frequentist confidence intervals. The Bayesian nonlinear regresion performed is suitable for fitting production functions and depicting economic growth. Findings: The specified VES function has the ES greater than one and this finding contradicts many previous empirical studies in the growth theory. This result points to the possibility of unbounded endogenous growth in the Vietnamese manufacturing sector. Practical implications: Based on the empirical results, in order to realize the possibility of endogenous growth for the studied Vietnamese manufacturing sector, policies of enforcing investment are needed. To raise the level of science and technique, as well as human capital of the Vietnamese enterprises, at the same time, there is great necessity to encourage R&D activities in both the private and public sectors. Originality/Value: Although this study organically builds upon recent studies about the link between the VES, the elasticity of factor subsitution and economic growth, its results proved that the VES is more appropriate than the Cobb-Douglas and the Constant Elasticity of Substitution (CES) to explain economic growth in the view of capital-labor relationship.peer-reviewe

Probabilistic models for protein conformational changes

Proteins are macromolecules that perform multiple functions. They are not rigid molecules, but instead proteins can change their conformation to perform critical tasks driven by binding small ligands, by assembling into large macromolecular complexes or by physiological factors. Characterization of protein conformational change and analyzing transitional pathways along protein conformational states are essentially tasks for computational biology. Here we propose probabilistic models to characterize protein conformational change. The first model disentangles protein structure into rigid bodies, whereas the second model proposes the probabilistic network model for the transitions between conformational states. Our first model is a generative process using Gaussian mixture models to represent rigid domains, which generated the input structures through spatial transformation. To estimate our model parameters, we use two approaches: using deterministic Expectation- Maximization algorithm and stochastic Gibbs sampler. The second model is an elastic way to expand the application spectrum of our model. The model uses anharmonic springs that involve the molecular distances that are allowed to break in a stochastic fashion. The function of the spring potential is inferred from a statistical analysis of a database of large-scale conformational changes in proteins. In addition we deploy our model in a webservice, as well as we deposit a precomputed dataset of rigid domains and a selective dataset of conformational pathway between conformational states. Finally, we employ graph-based algorithms to solve the problem of a model-free base solution. This work is not limited to biological applications, but can also be applied to robotics and computer vision. This thesis is based on the following publications and manuscripts, respectively: • Thach Nguyen, Michael Habeck, A probabilistic model for detecting rigid domains in protein structures, Bioinformatics, Volume 32, Issue 17, 1 September 2016, Pages i710–i717, https://doi.org/10.1093/bioinformatics/btw442 • Habeck M, Nguyen T. A probabilistic network model for structural transitions in biomolecules.Proteins. 2018;86:634–643.https://doi.org/10.1002/prot.25490 • Linh Dang, Thach Nguyen, Michael Habeck, and StephanWaack. A graph-based algorithm for detecting rigid domains in protein structures. Submitted • Thach Nguyen, Christian Böhm, Michael Habeck, A computational web server for segmenting protein structure into rigid bodies, in preparation

EFFECT OF EXTRACTION CONDITIONS ON POLYPHENOLS, FLAVONOIDS, S-ALLYL CYSTEINE CONTENT AND ANTIOXIDANT ACTIVITY OF BLACK GARLIC EXTRACTS

Black garlic is obtained from fresh garlic (Allium sativum L.) that has been aged for a long time at a high temperature under high humidity. Black garlic exerts metabolic and cardiovascular beneficial effects. In this study, (i) water and various concentrations of ethanol (50 % and 100 %) in water were used as solvent in the extraction of black garlic with different black garlic:solvent ratios (1:5, 1:10 and 1:15 w/v); (ii) the process was investigated in the temperatures ranging of 40 to 80 oC during 30 to 120 minutes, as well as determination of bioactive compounds content (total polyphenols, total flavonoids and S-allyl cysteine content) of all obtained extracts. The antioxidant activity was evaluated by DPPH (2,2-diphenyl-1-picrylhydrazyl) radical scavenging activity. The obtained results indicated that the aqueous ethanol (50 %) extracts presented the highest contents of polyphenols and flavonoids (7.94 mg GAE/g and 3.37 mg QE/g, respectively) and DPPH radical scavenging activity at black garlic: solvent ratio of 1:10 (w/v); while the water extract showed the highest S-allyl cysteine content (76.0 mg/kg) at the 1:10 ratio. The suitable condition for extracting of total polyphenols and flavonoids from black garlic was 60 oC for 90 minutes. With respect to SAC extraction, the suitable temperature and time of 80 oC and 90-120 minutes, respectively  were found.  

МЕТОД И СИСТЕМА ОЦЕНКИ ФИЗИОЛОГИЧЕСКИХ РЕЗЕРВОВ СПОРТСМЕНА ВО ВРЕМЯ ТРЕНИРОВОК

Introduction. An assessing of the sportsman's physiological reserve (PR) and its dynamics is important when planning and carrying out a training, forecasting sportsman's results. An importance of this problem increases in highperformance sports, and energy consumption sports. A complexity of solving of this problem is caused by the requirement of taking into account of the complex of the biomedical parameters and formation of an integral parameter. This parameter reflects functioning of various body systems which provide significant income to the sportsman’s result achievement. Objective. Development of the method and the system of PR assessing allowing complex investigation of the PR during the training process. Method and materials. For achievement of the aim the tasks were formulated and solved using methods of biomedical research and engineering, mathematical processing and analysis of the diagnostically valuable parameters. Results. The complex of the biomedical parameters reflecting sportsman’s body metabolism in condition of physical exercises is formed. They are the heart rate, the heart rate variability, the pulse frequency, the systolic and diastolic pressure, the respiratory rate, the blood saturation, and the stress index by Baevsky. It is important for PR assessing to assess parameters characterizing sportsman’s physiological reserves at the current moment and its dynamics. The circle diagram is proposed for taking into account of all mentioned parameters and its variation dynamics. The value of the integral PR parameter is an area of a polygon, which is obtained on the circle diagram using normalized values of the diagnostically significant parameters. The method of biomedical investigation of the sportsman and the method of PR assessing based on the complex of the body system parameters are developed. The scheme of assessing of sportsman's body physiological reserves before and after the training is proposed. The scheme allows to assess not only sportsman's body energy consumption during the training but also its recovery after the training. General structures of the biotechnical system and a structures of systems of picking up, registration, processing, and analysis of biomedical signals for assessing of sportsman's physiological reserves are developed. Special attention is given to the development of a wearable device for synchronous registration of the complex of biomedical parameters and algorithms of assessing of the diagnostically significant parameters of sportsman's body physiological reserves. Conclusion. The proposed method of sportsman's physiologic reserves investigation and the structure of the system with spatially distributed architecture allow sport medicine doctor and coach to assess an efficiency of sportsman's training process with respect to his potential capabilities, and efficiently control the training process.Введение. Оценка физиологического резерва (ФР) спортсмена и его динамики актуальна при планировании и проведении тренировок, прогнозировании результатов спортсмена. Актуальность данной проблемы усиливается в спорте высоких достижений, в частности в энергетически затратных видах спорта. Сложность решения этой проблемы обусловлена необходимостью учета комплекса медико-биологических показателей и формирования интегрального показателя, отражающего функционирование различных систем организма, которые обеспечивают значимый вклад в достижение результата спортсмена. Цель работы. Разработка метода и системы оценки ФР, позволяющих комплексно изучить ФР во время тренировочного процесса. Методы и материалы. Для достижения поставленной цели были сформулированы и решены задачи с использованием методов медико-биологических исследований, биомедицинской инженерии, математической обработки и анализа диагностически значимых показателей. Результаты. Сформирован комплекс медико-биологических показателей организма, отражающих метаболизм организма спортсмена в условиях физических нагрузок. Это частота сердечных сокращений, вариабельность сердечного ритма, частота пульса, систолическое и диастолическое давление, частота дыхания, сатурации крови, индекс напряженности Баевского. Для оценки ФР важно оценивать показатели, характеризующие физиологические резервы спортсмена в текущий момент времени и их динамику. Предложена круговая диаграмма для комплексного учета всех перечисленных показателей и динамики их изменения. Количественной мерой интегрального показателя ФР является площадь многогранника, полученного на круговой диаграмме по нормированным значениям диагностически значимых показателей. Разработан метод проведения медико-биологических исследований спортсмена и метод оценки ФР на основе комплекса показателей систем организма, предложена схема оценки физиологических резервов организма спортсмена до и после тренировок. Она позволяет оценить не только энергозатраты организма спортсмена во время тренировок, но и его восстановление после тренировок. Разработана обобщенная структура биотехнической системы и структуры системы съёма, регистрации, обработки и анализа биомедицинских сигналов для оценки физиологических резервов спортсмена. Особое внимание уделено разработке носимого устройства для синхронной регистрации комплекса биомедицинских сигналов и алгоритмам оценки диагностически значимых показателей физиологических резервов организма спортсмена. Заключение. Предложенный метод исследования физиологических резервов спортсмена и структура системы с пространственно-распределенной архитектурой позволяют тренеру и врачу спортивной медицины оценивать эффективность тренировочного процесса спортсмена с учетом его потенциальных возможностей, эффективно управлять тренировочным процессом

Quantitative analysis of TM lateral leakage in foundry fabricated silicon Rib waveguides

We show that thin, shallow ridge, silicon-on-insulator waveguides exhibiting a lateral leakage behavior can be designed and fabricated using a standard silicon photonic foundry platform. We analyze the propagation loss through the observation of the transmitted TM polarized guided mode and TE polarized radiation and experimentally demonstrate that propagation losses as low as 0.087 dB/mm can be achieved. This demonstration will open a new frontier for practical devices exploiting a lateral leakage behavior with potential applications in the fields of biosensing and quantum optics among others