What doesn't kill you makes you stranger: Dipeptidyl peptidase-4 (CD26) proteolysis differentially modulates the activity of many peptide hormones and cytokines generating novel cryptic bioactive ligands

Dipeptidyl peptidase 4 (DPP4) is an exopeptidase found either on cell surfaces where it is highly regulated in terms of its expression and surface availability (CD26) or in a free/circulating soluble constitutively available and intrinsically active form. It is responsible for proteolytic cleavage of many peptide substrates. In this review we discuss the idea that DPP4-cleaved peptides are not necessarily inactivated, but rather can possess either a modified receptor selectivity, modified bioactivity, new antagonistic activity, or even a novel activity relative to the intact parent ligand. We examine in detail five different major DPP4 substrates: glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), peptide tyrosine-tyrosine (PYY), and neuropeptide Y (NPY), and stromal derived factor 1 (SDF-1 aka CXCL12). We note that discussion of the cleaved forms of these five peptides are underrepresented in the research literature, and are both poorly investigated and poorly understood, representing a serious research literature gap. We believe they are understudied and misinterpreted as inactive due to several factors. This includes lack of accurate and specific quantification methods, sample collection techniques that are inherently inaccurate and inappropriate, and a general perception that DPP4 cleavage inactivates its ligand substrates. Increasing evidence points towards many DPP4-cleaved ligands having their own bioactivity. For example, GLP-1 can work through a different receptor than GLP-1R, DPP4-cleaved GIP can function as a GIP receptor antagonist at high doses, and DPP4-cleaved PYY, NPY, and CXCL12 can have different receptor selectivity, or can bind novel, previously unrecognized receptors to their intact ligands, resulting in altered signaling and functionality. We believe that more rigorous research in this area could lead to a better understanding of DPP4’s role and the biological importance of the generation of novel cryptic ligands. This will also significantly impact our understanding of the clinical effects and side effects of DPP4-inhibitors as a class of anti-diabetic drugs that potentially have an expanding clinical relevance. This will be specifically relevant in targeting DPP4 substrate ligands involved in a variety of other major clinical acute and chronic injury/disease areas including inflammation, immunology, cardiology, stroke, musculoskeletal disease and injury, as well as cancer biology and tissue maintenance in aging

МЕТАЛЛОКСИДНЫЕ ЭЛЕКТРОДЫ, ПОЛУЧЕННЫЕ ПЛАЗМЕННО-ЭЛЕКТРОЛИТИЧЕСКИМ ОКСИДИРОВАНИЕМ, ДЛЯ ПОТЕНЦИОМЕТРИЧЕСКОГО ОПРЕДЕЛЕНИЯ ЩЕЛОЧНОСТИ И ХЛОРИДОВ В ТЕХНОГЕННЫХ ВОДАХ

The behavior of metal-oxide electrodes formed using the method of plasma electrolytic oxidation in a tetraborate electrolyte and additionally modified by platinum at acid-base and precipitation potentiometric titration has been investigated. The possibility of application of the fabricated electrodes in analysis of man-made waste waters on the example of potentiometric determination of alkalinity and chlorides content has been demonstrated. The advantages of the fabricated metal-oxide systems related to their polyfunctional character and the possibility to determine two hydrochemistry parameters using a single electrode have been shown.Key words: metal-oxide electrodes, plasma electrolytic oxidation, potentiometry, hydrochemistry parameters(Russian)DOI: http://dx.doi.org/10.15826/analitika.2013.17.3.003G.I. Marinina, A.S. Lapina, M.S. Vasilyeva, O.D. Arefyeva, and N.B. KondrikovSchool of Natural Sciences, Far East Federal University,Vladivostok, RussiaИзучено поведение в кислотно-основном и осадительном потенциометрическом титровании металлоксидных электродов, сформированных методом плазменно-электролитического оксидирования в тетраборатном электролите, дополнительно модифицированных платиной. Показана возможность применения полученных электродов для анализа техногенных вод на примере потенциометрического определения щелочности и хлоридов. Отмечены преимущества полученных металлоксидных систем, вследствие их полифункциональности и возможности с помощью одного электрода определять два гидрохимических показателя. Ключевые слова: металлоксидные электроды, плазменно-электролитическое оксидирование, потенциометрия, гидрохимические показателиDOI: http://dx.doi.org/10.15826/analitika.2013.17.3.003  Литература1. Химические сенсоры и их системы / Ю.Г. Власов и [др.] // Ж. аналит. химии. 2010. Т. 65. № 9. С. 900-919.2. Бурахта В.А. Электрохимические сенсоры на основе полупроводниковых материалов в анализе объектов окружающей среды: Дис... докт хим. наук. Уральск, 2003. 311 с.3. Кимстач В.А. Металлические электроды с модифицированной поверхностью в осадительном и комплексометрическом потенциометрическом титровании: Дис... докт. хим. наук. Ростов-на-Дону, 1986. 428 с.4 Маринина Г.И., Тырин В.И. Поведение висмутового металлоксидного электрода при потенциометрической индикации реакции комплексообразования // Ж. аналит. химии. 1982. Т. 38, № 11. С. 1948-1953.5. Using of Ti/Co3O4/PbO2/(SnO2 + Sb2O3) modified electrode as indicator electrode in potentiometric and conductometric titration in aqueous solution / N.A. Ghalwa et [al.] // J. of Electroanalyt. Chem. 2012. V.664. P.7-13.6. Ludwig C., Schindler P.W. Surface Complexation on TiO2 // J. of Colloid and Interface Scien. 1995. V.169. P. 284-299. 7. Shin P.K. The pH-sensing and light-induced drift properties of titanium dioxide thin films deposited by MOCVD // App. Surf. Scien. 2003. V. 214. P. 214-221. 8. Fog A., Buck R.P. Electronic semiconducting oxides as pH sensors // Sens. Actuators. 1984. V.5 P.137-146.9. Molecularly imprinted TiO2 thin film using stable ground-state complex as template as applied to selective electrochemical determination of mercury / Z.H. Liu et [al.] // Talanta. 2006. V. 68. P. 1120-1125.10. Гордиенко П.С., Гнеденков С.В. Микродуговое оксидирование титана и его сплавов. Владивосток: Дальнаука, 1997. 185 с.11. Черненко В.И. Получение покрытий анодно-искровым электролизом. Л.: Химия, 1991. 128 с.12. Синтез пленок химических соединений на титане в условиях микроплазменных разрядов / О.А. Хрисанфова и [др.] // Ж. неорган. химии. 1995. Т. 40, № 4. С.558-562.13. Гордиенко П. С., Руднев В.С. Электрохимическое формирований покрытий на алюминии и его сплавах при потенциалах искрения и пробоя. Владивосток: Дальнаука, 1996. 233 с.14. Plasma electrolysis for surface engineering / A.L. Yerokhin et [al.] // Surf. Coat. Technol. 1999. V. 122 P. 73-93.15. Фазовый состав микродуговых покрытий на титане в боратном электролите / М.С. Васильева и [др.] // Ж. прикл. химии. 2002. Т. 75. № 4. С. 583-586.16. Элетроаналитические свойства некоторых пленочных оксидных электродов / Г.И. Маринина и [др.] // Ж. аналит. химии. 1996. Т. 51. № 9, С. 975-979.17. Влияние плазменно-электролитической обработки на состав и свойства оксидно-рутениево-титановых анодов / М.С. Васильева и [др.] // Ж. прикл. химии. 2004. Т. 77. № 12. С. 1968-1973.18. Коровин Н.В., Касаткин Э.В. Электрокатализаторы электрохимических устройств // Электрохимия. 1993. Т.29. № 4. С. 448-460.19. Влияние способа получения катализатора Pt мет/Ti на некоторые свойства активной фазы / Д.В. Малевич и [др.] // Ж. прикл. химии. 1997. Т.70, № 8. С. 1330- 1333.20. Об утверждении нормативов качества воды водных объектов рыбохозяйственного значения, в том числе нормативов предельно допустимых концентраций вредных веществ в водах водных объектов рыбохозяйственного значения: приказ Федерального агентства по рыболовству от 18.01.2010 г. № 20. Введ. 09.02.2010 г. 153 с.21. ГН 2.1.5.1315-03. Гигиенические нормативы: Предельно допустимые концентрации (ПДК) химических веществ в воде водных объектов хозяйственно-питьевого и культурно-бытового водопользования. Введ. 01.07.2003. 248 с. 

ВОЗМОЖНОСТИ ПРАКТИЧЕСКОГО ПРИМЕНЕНИЯ ОПТИКО-ЭЛЕКТРОННЫХ СИСТЕМ ВИЗУАЛИЗАЦИИ НА ВОЗДУШНЫХ СУДАХ

The article covers the following issues: the development and practical application of airborne electro-optic systems in the civil aviation aircraft. They provide flight visual information for the pilot day and night in visual and instrument weather conditions. The legal documents establishing the requirements for the application of this type of electro-optic systems in aircraft are presented. The classification of airborne electro-optic systems, commonly named as electronic visualization systems is analyzed. The ways of implementing the recommendations in their construction are considered. There have been analyzed the possibilities of systems of different classes: enhanced vision systems (EVS), synthetic vision systems (SVS), combine vision systems (CVS) and on-board vision systems with advanced visualization features, Enhanced Flight Vision Systems (EFVS). It is determined that nowadays EVS systems are considered to be the potential application systems. In order to analyze the possibilities of practical application of such systems in the issues of flight safety at low altitude and landing, flight experiments of the system installed on a light helicopter were conducted. The research introduces the results of flight experiments on the practical work of television and infrared (IR) viewing channels of a promising typical system in simple and complex observation conditions. Based on the results of flight experiments, a conclusion can be made about the relevance of practical application of electronic visualization systems on board the aircraft to ensure flight safety. It is determined that the systems can be used in flight both for land observation tasks and ensuring a safe flight. When flying the helicopter at low altitude and landing procedures the pilot should use visual information from the rear hemisphere of the lower tail unit by electro-optical visualization system. It was elicited that in the infrared (IR) channel and the fast rotation of visualization system camera located there is a corresponding delay of vision direction and the actual direction of flight. The vision is blurred. In the mode of the infrared spectrum information there appears a filtering problem of interference caused by helicopter engine exhaust gases and snow in the sector of observation. It makes it more difficult to obtain the benefits of visualization systems vision in adverse weather conditions. The conclusions indicated that perspective visualization systems for IR channels require additional use of methods and algorithms to ensure high-definition vision.Рассматриваются вопросы по развитию и практическому применению на воздушных судах гражданской авиации бортовых оптико-электронных систем, обеспечивающих получение информации видения пилоту в полете днем и ночью в простых и сложных метеоусловиях. Представлены нормативно-правовые документы, устанавливающие требования по применению подобного типа оптико-электронных систем на воздушных судах. Проанализирована классификация бортовых оптико-электронных систем, объединенных общим названием электронные системы визуализации. Рассмотрены пути реализации рекомендаций по их построению.Проанализированы возможности систем разных классов: систем улучшенного видения (Enhanced Vision Systems (EVS)), систем искусственного видения (Synthetic Vision Systems (SVS)), комбинированных систем искусственного видения (Combine Vision Systems (CVS)) и бортовых систем технического зрения с расширенными возможностями визуализации Enhanced Flight Vision Systems (EFVS)). Указано, что в настоящее время к системам перспективного применения относят системы класса EVS. С целью анализа возможностей практического применения таких систем в задачах обеспечения безопасности полета на малых высотах и посадки были проведены летные эксперименты системы, установленной на легком вертолете. Представлены результаты летных экспериментов по практической работе телевизионного и инфракрасного каналов видения типовой перспективной системы визуализации в простых и сложных условиях наблюдения. На основании результатов летных экспериментов сделаны выводы о целесообразности практического применения электронных систем визуализации на воздушных судах для обеспечения безопасности полета. Установлено, что системы можно применять при полете как для задач наблюдения, обследования местности, так и обеспечения безопасного полета. При полете вертолета на малых высотах и выполнении посадки пилоту целесообразно использовать от оптико-электронной системы визуализации информацию видения со стороны задней полусферы нижней хвостовой части. Выявлено, что в работе инфракрасного (ИК) канала и быстрых поворотах камеры системы визуализации проявляется запаздывание соответствия направлений видения и реального полета. Проявляется размытие изображения видения. В режиме регистрации информации ИК-спектра возникает проблема фильтрации помех, вызванных появлением в секторе наблюдения выхлопных газов двигателя вертолета, снега. Это затрудняет получение преимущества видения систем визуализации в сложных метеоусловиях. В выводах указано, что в перспективных системах визуализации для ИК каналов требуется дополнительное использование методов и алгоритмов обеспечения высокой четкости изображения видения

Age-related increase of kynurenine enhances miR29b-1-5p to decrease both CXCL12 signaling and the epigenetic enzyme Hdac3 in bone marrow stromal cells

Mechanisms leading to age-related reductions in bone formation and subsequent osteoporosis are still incompletely understood. We recently demonstrated that kynurenine (KYN), a tryptophan metabolite, accumulates in serum of aged mice and induces bone loss. Here, we report on novel mechanisms underlying KYN's detrimental effect on bone aging. We show that KYN is increased with aging in murine bone marrow mesenchymal stem cells (BMSCs). KYN reduces bone formation via modulating levels of CXCL12 and its receptors as well as histone deacetylase 3 (Hdac3). BMSCs responded to KYN by significantly decreasing mRNA expression levels of CXCL12 and its cognate receptors, CXCR4 and ACKR3, as well as downregulating osteogenic gene RUNX2 expression, resulting in a significant inhibition in BMSCs osteogenic differentiation. KYN's effects on these targets occur by increasing regulatory miRNAs that target osteogenesis, specifically miR29b-1-5p. Thus, KYN significantly upregulated the anti-osteogenic miRNA miR29b-1-5p in BMSCs, mimicking the up-regulation of miR-29b-1-5p in human and murine BMSCs with age. Direct inhibition of miR29b-1-5p by antagomirs rescued CXCL12 protein levels downregulated by KYN, while a miR29b-1-5p mimic further decreased CXCL12 levels. KYN also significantly downregulated mRNA levels of Hdac3, a target of miR-29b-1-5p, as well as its cofactor NCoR1. KYN is a ligand for the aryl hydrocarbon receptor (AhR). We hypothesized that AhR mediates KYN's effects in BMSCs. Indeed, AhR inhibitors (CH-223191 and 3',4'-dimethoxyflavone [DMF]) partially rescued secreted CXCL12 protein levels in BMSCs treated with KYN. Importantly, we found that treatment with CXCL12, or transfection with an miR29b-1-5p antagomir, downregulated the AhR mRNA level, while transfection with miR29b-1-5p mimic significantly upregulated its level. Further, CXCL12 treatment downregulated IDO, an enzyme responsible for generating KYN. Our findings reveal novel molecular pathways involved in KYN's age-associated effects in the bone microenvironment that may be useful translational targets for treating osteoporosis

Age-associated changes in microRNAs affect the differentiation potential of human mesenchymal stem cells: Novel role of miR-29b-1-5p expression

Age-associated osteoporosis is widely accepted as involving the disruption of osteogenic stem cell populations and their functioning. Maintenance of the local bone marrow (BM) microenvironment is critical for regulating proliferation and differentiation of the multipotent BM mesenchymal stromal/stem cell (BMSC) population with age. The potential role of microRNAs (miRNAs) in modulating BMSCs and the BM microenvironment has recently gained attention. However, miRNAs expressed in rapidly isolated BMSCs that are naïve to the non-physiologic standard tissue culture conditions and reflect a more accurate in vivo profile have not yet been reported. Here we directly isolated CD271 positive (+) BMSCs within hours from human surgical BM aspirates without culturing and performed microarray analysis to identify the age-associated changes in BMSC miRNA expression. One hundred and two miRNAs showed differential expression with aging. Target prediction and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that the up-regulated miRNAs targeting genes in bone development pathways were considerably enriched. Among the differentially up-regulated miRNAs the novel passenger strand miR-29b-1-5p was abundantly expressed as a mature functional miRNA with aging. This suggests a critical arm-switching mechanism regulates the expression of the miR-29b-1-5p/3p pair shifting the normally degraded arm, miR-29b-1-5p, to be the dominantly expressed miRNA of the pair in aging. The normal guide strand miR-29b-1-3p is known to act as a pro-osteogenic miRNA. On the other hand, overexpression of the passenger strand miR-29b-1-5p in culture-expanded CD271+ BMSCs significantly down-regulated the expression of stromal cell-derived factor 1 (CXCL12)/ C-X-C chemokine receptor type 4 (SDF-1(CXCL12)/CXCR4) axis and other osteogenic genes including bone morphogenetic protein-2 (BMP-2) and runt-related transcription factor 2 (RUNX2). In contrast, blocking of miR-29b-1-5p function using an antagomir inhibitor up-regulated expression of BMP-2 and RUNX2 genes. Functional assays confirmed that miR-29b-1-5p negatively regulates BMSC osteogenesis in vitro. These novel findings provide evidence of a pathogenic anti-osteogenic role for miR-29b-1-5p and other miRNAs in age-related defects in osteogenesis and bone regeneration

Electrooptical complex for terrain on-time survey

The article deals with a number of approaches to the use of electrooptical systems and unmanned aerial vehicles (UAV) to solve the tasks of live terrain surface screening, air incident spots and objects survey. The paper provides the grounds for the UAV airframe chosen structure and the design of the electrooptical complex. The light weight, high -wing monoplane airframe structure is suggested. Using the CNC production center, a UAV with high aerodynamic performance was developed. The UAV was fitted with the optoelectronic system. Structural design for the airborne and ground equipment of the survey complex was developed. The structural design comprises the forward-looking and side airborne surveillance cameras and also downward-looking cameras of visible and infrared bands to provide the day and night vision. The downward-looking cameras of visible and infrared bands, integrated into the UAV fuselage belly are used for the surface monitoring and survey. The flight test on the use of electrooptic system comprised the flight on the route and automatic return using the satellite system navigation. The test showed that navigation data correction was required. The positioning accumulative error elimination is suggested to be done via automated image registration with the contour extraction and landmark reference. The image processing results using Canny algorithm were presented. The recommendations on the algorithm practical application and speed of response are given. To solve the problem of terrain on-time surveillance and monitoring the flight routes were subjected to research. Based on the experiments performed, the recommendations were given on the electrooptic complex application and flight route plotting for the tasks of on-time search and rescue

Electrooptical complex for terrain on-time survey

The article deals with a number of approaches to the use of electrooptical systems and unmanned aerial vehicles (UAV) to solve the tasks of live terrain surface screening, air incident spots and objects survey. The paper provides the grounds for the UAV airframe chosen structure and the design of the electrooptical complex. The light weight, high -wing monoplane airframe structure is suggested. Using the CNC production center, a UAV with high aerodynamic performance was developed. The UAV was fitted with the optoelectronic system. Structural design for the airborne and ground equipment of the survey complex was developed. The structural design comprises the forward-looking and side airborne surveillance cameras and also downward-looking cameras of visible and infrared bands to provide the day and night vision. The downward-looking cameras of visible and infrared bands, integrated into the UAV fuselage belly are used for the surface monitoring and survey. The flight test on the use of electrooptic system comprised the flight on the route and automatic return using the satellite system navigation. The test showed that navigation data correction was required. The positioning accumulative error elimination is suggested to be done via automated image registration with the contour extraction and landmark reference. The image processing results using Canny algorithm were presented. The recommendations on the algorithm practical application and speed of response are given. To solve the problem of terrain on-time surveillance and monitoring the flight routes were subjected to research. Based on the experiments performed, the recommendations were given on the electrooptic complex application and flight route plotting for the tasks of on-time search and rescue.</jats:p