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Functionality of a bicistronic construction containing HEXA and HEXB genes encoding β-hexosaminidase A for cell-mediated therapy of Gm2 gangliosidoses

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Neural Regeneration Research 2022年第1期17卷 122-129页

作者： Alisa A.Shaimardanova Daria S.Chulpanova Valeriya V.Solovyeva Aleksandr m.aimaletdinov Albert A.Rizvanov Institute of Fundamental medicine and Biology Kazan Federal UniversityKazanRussia

Tay-Sachs disease and Sandhoff disease are severe hereditary neurodegenerative disorders caused by a deficiency ofβ-hexosaminidase A(HexA)enzyme,which results in the accumulation of Gm2 gangliosides in the nervous system *** this work,we analyzed the efficacy and safety of cell-mediated gene therapy for Sandhoff disease and Sandhoff disease using a bicistronic lentiviral vector encoding cDNA of HexAα-andβ-subunit genes separated by the nucleotide sequence of a P2A peptide(HEXA-HEXB).The functionality of the bicistronic construct containing the HEXA-HEXB genetic cassette was analyzed in a culture of HEK293T cells and human umbilical cord blood mononuclear cells(hUCBmCs).Our results showed that the enzymatic activity of HexA in the conditioned medium harvested from genetically modified HEK293T-HEXA-HEXB and hUCBmCs-HEXA-HEXB was increased by 23 and 8 times,respectively,compared with the conditioned medium of native *** blot analysis showed that hUCBmCs-HEXA-HEXB secreted both completely separated HEXA and HEXB proteins,and an uncleaved protein containing HEXA+HEXB linked by the P2A *** injection of genetically modified hUCBmCs-HEXA-HEXB to laboratory Wistar rats was carried out,and the HexA enzymatic activity in the blood plasma of experimental animals,as well as the number of live cells of immune system organs(spleen,thymus,bone marrow,lymph nodes)were determined.A significant increase in the enzymatic activity of HexA in the blood plasma of laboratory rats on days 6 and 9(by 2.5 and 3 times,respectively)after the administration of hUCBmCsHEXA-HEXB was *** the same time,the number of live cells in the studied organs remained ***,the functionality of the bicistronic genetic construct encoding cDNA of the HEXA and HEXB genes separated by the nucleotide sequence of the P2A peptide was shown in vitro and in *** hypothesize that due to the natural ability of hUCBmCs to overcome biological barriers,such a strategy can rest

关键词： bicistronic vector cell-mediated gene therapy Gm2 gangliosidosis P2A peptide Sandhoff disease Tay-Sachs disease umbilical cord blood mononuclear cells β-hexosaminidase

microglia:a promising therapeutic target in spinal cord injury

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Neural Regeneration Research 2025年第2期20卷 454-463页

作者： Xiaowei Zha Guoli Zheng Thomas Skutella Karl Kiening Andreas Unterberg alexander Younsi Department of Neurosurgery Heidelberg University HospitalHeidelbergGermany Department of Neuroanatomy Institute for Anatomy and Cell BiologyHeidelberg UniversityHeidelbergGermany

microglia are present throughout the central nervous system and are vital in neural repair,nutrition,phagocytosis,immunological regulation,and maintaining neuronal *** a healthy spinal cord,microglia are accountable for immune surveillance,however,when a spinal cord injury occurs,the microenvironment drastically changes,leading to glial scars and failed axonal *** this context,microglia vary their gene and protein expression during activation,and proliferation in reaction to the injury,influencing injury responses both favorably and unfavorably.A dynamic and multifaceted injury response is mediated by microglia,which interact directly with neurons,astrocytes,oligodendrocytes,and neural stem/progenitor *** a clear understanding of their essential nature and origin,the mechanisms of action and new functions of microglia in spinal cord injury require extensive *** review summarizes current studies on microglial genesis,physiological function,and pathological state,highlights their crucial roles in spinal cord injury,and proposes microglia as a therapeutic target.

关键词： astrocytes cytokines functional recovery immune regulation m1/m2 activation macrophages microglia neuroinflammation spinal cord injury therapy

Hepatoprotective actions of melatonin:Possible mediation by melatonin receptors

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World Journal of Gastroenterology 2010年第48期16卷 6087-6097页

作者： alexander m mathes Department of Anesthesiology Critical Care and Pain MedicineSaarland University Hospital

melatonin,the hormone of darkness and messenger of the photoperiod,is also well known to exhibit strong direct and indirect antioxidant properties. melatonin has previously been demonstrated to be a powerful organ protective substance in numerous models of injury; these beneficial effects have been attributed to the hormone's intense radical scavenging capacity. The present report reviews the hepatoprotective potential of the pineal hormone in various models of oxidative stress in vivo,and summarizes the extensive literature showing that melatonin may be a suitable experimental substance to reduce liver damage after sepsis,hemorrhagic shock,ischemia/reperfusion,and in numerous models of toxic liver injury. melatonin's influence on hepatic antioxidant enzymes and other potentially relevant pathways,such as nitric oxide signaling,hepatic cytokine and heat shock protein expression,are evaluated. Based on recent literature demonstrating the functional relevance of melatonin receptor activation for hepatic organ protection,this article finally suggests that melatonin receptors could mediate the hepatoprotective actions of melatonin therapy.

关键词： Antioxidant enzymes Hemorrhagic shock Hepatoprotection Ischemia Liver Liver function melatonin melatonin receptor Ramelteon Reperfusion Sepsis Toxic liver injury

Development of a Long-Term Operational Optimization model for a Building Energy System Supplied by a Geothermal Field

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Journal of Thermal Science 2022年第5期31卷 1293-1301页

作者： KÜmPEL alexander STOFFEL Phillip mÜLLER Dirk RWTH Aachen University E.ON Energy Research CenterInstitute for Energy Efficient Buildings and Indoor ClimateAachen 52074Germany

In order to reduce energy consumption and CO_(2) emissions in the building sector, more and more renewable energy sources are integrated into energy systems. Especially geothermal fields combined with heat pumps are able to supply buildings with heat and cold at low carbon emissions. However, using geothermal fields as heat and cold source influences the ground temperature. Consequently, the ground temperature can change dramatically over a building’s lifetime, leading to less efficient operation of the energy system. Therefore, a sustainable operation is required to ensure the long-term efficiency of geothermal fields. In this paper, we develop an optimization model to derive operating strategies for an efficient long-term operation of a building energy system coupled to a geothermal field. The investigated energy system is the main building of the *** Energy Research Center in Aachen, Germany, which includes a heat pump, two boilers, a combined heat, and power unit, a glycol cooler, and a geothermal field with 41 probes. For each component, we develop energy-based sub-models, which are connected to form the overall system. The geothermal field is modeled by using a g-functions approach as well as a simplified resistance-capacitance approach. To achieve short computing times and realize an optimization horizon of several years, the optimization problem is formulated as mixed-integer linear programming(mILP). The developed model is optimized regarding two different objectives: the minimization of energy costs and the minimization of long-term temperature changes in the ground. Conclusions for an efficient and sustainable operation of the field, especially for the cooling supply, can be derived from the optimization results. It is shown that a state of equilibrium should be aimed to achieve an energy-efficient operation, in which the temperature of the field is close to the initial ground temperature.

关键词： geothermal energy building energy systems operational optimization long-term operation

mtDNA mutations and aging--not a closed case after all?

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Signal Transduction and Targeted Therapy 2021年第3期6卷 555-556页

作者： alexander m.Wolf Laboratory for morphological and Biomolecular Imaging Faculty of MedicineNippon Medical SchoolTokyoJapan

In a recent paper in Nature Cancer,Smith et *** that mitochondrial DNA(mtDNA)mutations can confer a growth advantage to intestinal tumors by remodeling cell metabolism,particularly toward elevated de novo serine synthesis.1 For the reasons outlined below,in the past decade,the field of mtDNA biology has experienced a relative loss of *** findings of Smith et *** welcome new life into the complex field of mtDNA contributions to aging and cancer.

关键词： al. metabolism elevated

On the Analytical models of Protoplanetary Formation in Extrasolar Systems

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Space(Science & Technology) 2022年第1期2022卷 422-440页

作者： alexander m.Krot Laboratory of Self-Organization System modeling United Institute of Informatics ProblemsNational Academy of Sciences of Belarus6Surganov Str.220012 MinskBelarus

In this work,we consider a statistical theory for a cosmogonical body formation(so-called spheroidal body)to develop the analytical models of protoplanetary formation in extrasolar *** the framework of this theory,the models and evolution equations of the statistical mechanics have been proposed,while the well-known problem of gravitational condensation of infinite distributed cosmic substances has been *** paper derives the general equation of distribution of the specific angular momentum of forming protoplanets since the specific angular momentums(for particles or planetesimals)are averaged during a conglomeration process(under a planetary embryo formation).As a result,a new law for planetary distances(which generalizes Schmidt’s law)is derived *** paper develops also an alternative thermal emission of particles model of the formation of protoplanets in extrasolar *** the framework of this model,the equation for the thermal distribution function of the specific angular momentums of particles moving in elliptical orbits in the gravitational field is *** to this thermal escape model,only 0.8%of the total number of particles in the solar system composing the protoplanetary cloud has angular momentum 15.6 times higher than the angular momentum of the remaining 99%of *** conclusion agrees completely with the known fact of a nonuniform distribution of the angular momentums in our solar system noted by ter *** pointed out here,the exponential laws of planetary distances occur in some extrasolar systems.

关键词： momentum angular equation

Cloud-Based Optimal Control of Individual Borehole Heat Exchangers in a Geothermal Field

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Journal of Thermal Science 2022年第5期31卷 1253-1265页

作者： STOFFEL Phillip KÜmPEL alexander mÜLLER Dirk RWTH Aachen University E.ON Energy Research CenterInstitute for Energy Efficient Buildings and Indoor Climate52074 AachenGermany

Integrating renewable energy sources is a crucial component in reducing CO_(2) emissions in the building sector. In particular, shallow geothermal energy is expected to play a significant role in the regenerative energy supply of buildings. An effective control strategy for the geothermal field is crucial to reduce the overall energy consumption. This paper analyzes the benefits of controlling an existing field’s individual borehole heat exchangers(BHE) using nonlinear model predictive control(NmPC) and moving horizon estimation. The considered geothermal field consists of 41 BHEs and is used for heating and cooling. Each BHE is equipped with temperature sensors for in-and outflow and has individually controllable valves, while a central hydraulic pump feeds all BHEs. The sensor measurements are accessed through a cloud platform, enabling also set point writing for the pump speed and the valve positions. To control the BHEs individually, we propose a two-stage process. In the calibration stage, a moving horizon estimator estimates the actual borehole and ground temperatures for each BHE. In the second stage, first, a nonlinear model predictive controller optimizes the number of active BHEs necessary to meet the buildings’ energy demand. With the estimated ground temperatures as a basis, it is determined which BHEs shall be(de)-activated. The active BHEs are fed with a fixed volume flow of 24 L/min to ensure turbulent heat transfer. To reduce the power usage of the pumps, an optimal control problem based on a simple hydraulic model of the geothermal field is used. The methodology is analyzed through simulations first and then validated experimentally. The results show that half or more of the BHEs could be deactivated most of the time, leading to 67% savings in electricity consumption by the hydraulic pump. The experimental validation confirms the high energy saving potential of the proposed methodology, reducing the consumption of electrical energy by 71%. Additiona

关键词： geothermal energy moving horizon estimation model predictive control operation optimization optimal control

Recovery of Brachiopod and Ammonoid Faunas Following the End-Permian Crisis:Additional Evidence from the Lower Triassic of the Russian Far East and Kazakhstan

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Journal of Earth Science 2014年第1期25卷 1-44页

作者： Yuri D Zakharov alexander m Popov Far Eastern Geological Institute Far Eastern BranchRussian Academy of Sciences

After the End-Permian mass extinction, ammonoids reached levels of taxonomic diver- sity higher than in the Changhsingian by the Dienerian Substage of the Induan. However, brachiopods exhibit a prolonged delay in recovery, and their taxonomic diversity had not recovered to Late Permian levels even by the Olenekian. The differential patterns of recovery between these two clades may reflect fundamental differences in physiology and behavior. Brachiopods were benthic organisms that were dependent on specific trophic sources, and their general reduction in size during the Early Triassic may have been a response to a relative paucity of food resources. In contrast, ammonoids were sluggish- nektic organisms that utilized a wider range of trophic sources and that suffered no comparable size decrease during the Early Triassic. Brachiopods may have been at a disadvantage also due to vulner- abilities associated with their larval stage, during which they had to locate a suitable substrate for set- tlement. In contrast, ammonoids had no larval stage and juveniles may have been dispersed widely into favorable habitats. These factors may account for differences in the relative success of ammonoids and brachiopods at high-latitude regions following the End-Permian mass extinction： ammonoids success- fully reeolonized the Boreal region during the Early Triassic whereas brachiopods did not.

关键词： Lower Triassic South Primorye Kazakhstan brachiopod ammonoid biotic recovery.

Calculation of multi-layer plate damper under one-axial load

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Chinese Physics B 2016年第2期25卷 256-261页

作者：闫辉张露姜洪源 alexander m.Ulanov School of mechatronics Engineering Harbin Institute of Technology Harbin 150001 China Samara State Aerospace University Moskovskoe Shosse Samara 443086 Russia

A multi-layer damper with waved plates under one-axial load is considered. A method of theoretical calculation of its energy dissipation coefficient is proposed. An experimental research of own frequencies and vibration transfer ratios for different parameters of damper structure, harmonic vibration load and random load is performed. Results of this research are approximated by functions; it is possible to use these functions for the calculation of the damper too.

关键词： plate damper energy dissipation coefficient elastic-damping characteristics amplitude-frequencycharacteristics