Untersuchung des Zusammenspiels metabolischer und autoimmuner Oligodendrogliopathie im kombinatorischen Mausmodell der Multiplen Sklerose

Hintergrund: Oligodendrozyten-Degeneration und die daraus resultierende Demyelinisierung sind zentrale Merkmale der MS-Pathologie. Behandlungsansätze, welche die Oligodendrozyten und das Myelin schützen und die endogenen Regenerationsmechanismen fördern, stehen bisher noch nicht zur Verfügung. Oligodendrogliopathie und Demyelinisierung werden üblicherweise als direkte Folgen einer immun-vermittelten entzündlichen Reaktion gesehen. Intrinsische metabolische Störungen sind aber wahrscheinlich von ähnlicher Bedeutung. Obwohl wir über gute präklinische Modelle für die isolierte Untersuchung immun-vermittelter und metabolischer Oligodendrogliopathie verfügen, fehlen uns Modelle zur Untersuchung des Zusammenspiels zwischen beiden Prozessen. Fragestellung: Wir vermuten, dass die kontinuierliche Cuprizone-Intoxikation und die aktive Induktion der experimentellen autoimmunen Enzephalomyelitis (EAE) bei Mäusen uns erlauben würde, Interaktionen zwischen metabolischer und inflammatorischer Schädigung von Oligodendrozyten im ZNS zu untersuchen. Methoden: Weibliche C57BL/6 Mäuse wurden zur Induktion einer metabolischen Oligodendrozyten-Degeneration mit 0,25% Cuprizone für 18 Tage intoxikiert. Am 3. Tag der Cuprizone-Intoxikation wurden die Tiere mit MOG35-55 („myelin oligodendrocyte glycoprotein peptide“) immunisiert. Diese bewirkte die Formierung Myelin-autoreaktiver T-Zellen in den peripheren lymphatischen Organen. Die Mäuse wurden mithilfe eines strukturierten klinischen Score-Systems täglich beurteilt und am Höhepunkt der EAE finalisiert. Die ZNS-Präparate wurden (immun-) histochemisch hinsichtlich inflammatorischer Infiltrate, Demyelinisierung, Oligodendrozyten-Degeneration, Mikrogliose und Neurodegeneration untersucht. Ergebnisse: Trotz der immunsuppressiven Wirkung von Cuprizone kam es bei kontinuierlicher Intoxikation zur Formierung Myelin-autoreaktiver T-Zellen und zur Entwicklung motorischer Defizite. Obwohl die Cuprizone-Intoxikation zu einem milderen klinischen EAE-Verlauf und geringerem Ausmaß an Inflammation im Rückenmark führte, sorgte die Cuprizone-induzierte Oligodendrogliopathie im Vorderhirn zur verstärkten Lymphozyteninvasion am Ort der Läsion. Diese Vorderhirnläsionen ähnelten stark den Typ III MS-Läsionen und waren u.a. durch Oligodendrozyten-Apoptose, Demyelinisierung, Mikrogliose und Infiltration von Lymphozyten gekennzeichnet. Ausblick: Zusammenfassend haben wir im Rahmen dieser Studie ein präklinisches Mausmodell entwickelt, welches es uns erlaubt, das direkte Zusammenspiel zwischen immun-vermittelter und metabolischer Oligodendrogliopathie zu untersuchen. Das bessere Verständnis der genauen Mechanismen, die zur Demyelinisierung und folglich klinischen Progression führen, würde zur Entwicklung neuer Behandlungsansätze und Verbesserung der Prognose der Patienten mit MS führen

The multimodal Munich Clinical Deep Phenotyping study to bridge the translational gap in severe mental illness treatment research

Introduction: Treatment of severe mental illness (SMI) symptoms, especially negative symptoms and cognitive dysfunction in schizophrenia, remains a major unmet need. There is good evidence that SMIs have a strong genetic background and are characterized by multiple biological alterations, including disturbed brain circuits and connectivity, dysregulated neuronal excitation-inhibition, disturbed dopaminergic and glutamatergic pathways, and partially dysregulated inflammatory processes. The ways in which the dysregulated signaling pathways are interconnected remains largely unknown, in part because well-characterized clinical studies on comprehensive biomaterial are lacking. Furthermore, the development of drugs to treat SMIs such as schizophrenia is limited by the use of operationalized symptom-based clusters for diagnosis. Methods: In line with the Research Domain Criteria initiative, the Clinical Deep Phenotyping (CDP) study is using a multimodal approach to reveal the neurobiological underpinnings of clinically relevant schizophrenia subgroups by performing broad transdiagnostic clinical characterization with standardized neurocognitive assessments, multimodal neuroimaging, electrophysiological assessments, retinal investigations, and omics-based analyzes of blood and cerebrospinal fluid. Moreover, to bridge the translational gap in biological psychiatry the study includes in vitro investigations on human-induced pluripotent stem cells, which are available from a subset of participants. Results: Here, we report on the feasibility of this multimodal approach, which has been successfully initiated in the first participants in the CDP cohort; to date, the cohort comprises over 194 individuals with SMI and 187 age and gender matched healthy controls. In addition, we describe the applied research modalities and study objectives. Discussion: The identification of cross-diagnostic and diagnosis-specific biotype-informed subgroups of patients and the translational dissection of those subgroups may help to pave the way toward precision medicine with artificial intelligence-supported tailored interventions and treatment. This aim is particularly important in psychiatry, a field where innovation is urgently needed because specific symptom domains, such as negative symptoms and cognitive dysfunction, and treatment-resistant symptoms in general are still difficult to treat

Label-free characterization of white blood cells using fluorescence lifetime imaging and flow-cytometry: molecular heterogeneity and erythrophagocytosis [Invited]

Article reporting the results of blood cell characterization using label-free fluorescence imaging techniques and flow-cytometry. Autofluorescence parameters of different cell types – white blood cells, red blood cells, erythrophagocytic cells – are assessed and analyzed in terms of molecular heterogeneity and possibilities of differentiation between different cell types in vitro and in vivo

Target tracking with composite linear filters on noisy scenes

A tracking system using a bank of adaptive linear filters is proposed. Tracking is carried out by means of multiple target detections. The linear filters are designed from multiple views of a target using synthetic discriminant functions. For each view an optimum filter is derived from noisy reference image and disjoint background model. An iterative algorithm is used to improve the performance of the synthesized filters. The number of filters in the bank can be controlled to guarantee a prescribed tracking accuracy. Computer simulation results show that the proposed algorithm is able to precisely track a target.This work was supported the Russian Science Foundation grant №15-19-10010

Heat Flux Measurement in Shock Heated Combustible Gases and Clarification of Ignition Delay Time

Correct understanding of the ignition and combustion processes in the combustion chambers are critical for modeling advanced schemes of engines of high-speed aircraft and promising spacecraft. Moreover, experimental data on the ignition delay time are a universal basis for the development and testing of combustion kinetic models. Moreover, the higher the temperature of the fuel mixture, the smaller this time value and the more important its correct determination. The use of a thermoelectric detector allows to measure ignition delay times and record heat fluxes with a high time resolution (to tenths of μs) during ignition in propane–air mixtures. Due to the faster response time, the use of it allows refining the ignition delay time of the combustible mixture, and the detector itself can serve as a useful device that allows a more detailed study of the ignition processes

Geochemistry of authigenic pyrite mineralization of the Namkonson and Fuhan basins of the South China Sea according to the data of voyage 88 of the R/V «Akademik Lavrentev»

Актуальность. В наши дни особое внимание уделяется бассейнам, которые считаются потенциальными на наличие нефте- и газопроявлений. В этом отношении особый интерес проявляется к осадочным бассейнам Намкомсон и Фухань (Южно-Китайское море). В них установлены косвенные признаки глубинной дегазации по рифтовому разлому. Формирование нефти и газа тесно связано с образованием аутигенной сульфидной минерализации. Поэтому все больше вопросов возникает по поводу индикации проявлений нефтегазоностности провинций ассоциациями аутигенных минералов. В связи с этим изучение сульфидов от континентальных до океанических до сих пор является актуальной темой для исследований по всему миру. Цель: исследовать геохимические особенности пиритных образований из донных отложений осадочных бассейнов Намконсон и Фухань Южно-Китайского моря. Методы: масс-спектрометрия с индуктивно связанной плазмой; определение потерь после прокаливания и содержания SiO2 выполнено методом гравиметрии; атомно-эмиссионная спектрометрия с индуктивно связанной плазмой; оптическая и сканирующая электронная микроскопия; рентгеновская дифрактометрия; изотопная масс-спектрометрия. Результаты. Сульфидные образования из данного осадочного бассейна представляют собой агрегаты формы полой трубочки, размеры которых достигают максимум 5 см по длине и 5 мм по диаметру. Также обнаружены крупные сростки в виде ксеноморфных сгустков, сфероидальных образований. Сами агрегаты сложены преимущественно пиритом, присутствуют кварц и альбит. Пирит формирует глобулы и кристаллы формы октаэдра. В пиритных образованиях установлены высокие содержания кобальта (16,5...56,8 г/т), никеля (21,4...377 г/т) и молибдена (20,1...117 г/т). Цериевая аномалия составляет 0,90...0,93 г/т. Изотопные значения δ34S составляют от -32,9 до -47,0 ‰. Данные значения и построенные на их основе генетические диаграммы указывают на гидротермальное происхождение пиритных образований.The relevance. Nowadays, special attention is paid to basins that are considered potential for the presence of oil and gas occurrences. In this regard, the Namkomson and Fuhan sedimentary basins (South China Sea) are of interest. They established indirect signs of deep degassing along the rift fault. The formation of oil and gas is closely related to the formation of authigenic sulfide mineralization. Therefore, more and more questions arise about the indication of manifestations of oil and gas content of provinces by associations of authigenic minerals. In this regard, the study of sulfides from continental to oceanic is still a hot topic for research around the world. The aim of this work is to investigate the geochemical features of pyrite formations from bottom sediments of the Namсonson and Fuhan sedimentary basins of the South China Sea. Methods: inductively coupled plasma mass spectrometer; determination of losses after calcination and SiO2 content was performed by gravimetry; atomic emission spectrometer with inductively coupled plasma; optical and scanning electron microscopes; X-ray diffractometry; isotope mass spectrometry. Results. The sulfide formations from this sedimentary basin are hollow tube-shaped aggregates, up to a maximum of 5 cm in length and 5 mm in diameter. Large aggregates in the form of xenomorphic clots, spheroidal formations were also found. The aggregates themselves are composed mainly of pyrite, quartz and albite are also present. Pyrite forms globules and octahedral crystals. High contents of cobalt (16,5...56,8 g/t), nickel (21,4...377 g/t) and molybdenum (20,1...117 g/t) were established in pyrite formations. The Ce anomaly is 0,90...0,93. The isotopic values of δ34S range from -32,9 to -47,0 ‰. These values and the genetic diagrams derived from them indicate a hydrothermal/diagenetic origin for the pyrite formations