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В настоящее время число предприятий по добычи и переработки нефти и газа целью которых является не только достижение высоких производственных показателей, но и разработка подходов к уменьшению степени тяжести экологических и промышленных рисков, неуклонно растет. Эти задачи решаются путем создания корпоративных стандартов и регламентов. Оценка степени рисков служит важнейшим инструментом таких стандартов. Промышленные и экологические риски имеют высокую степень влияния на деятельность компании, и зачастую отечественные предприятия нефтегазовой отрасли делают акцент именно на эти риски. At present, the number of oil and gas production and processing enterprises whose goal is not only to achieve high production indicators, but also to develop approaches to reducing the severity of environmental and industrial risks is steadily growing. These tasks are solved by creating corporate standards and regulations. Risk assessment is an essential tool for such standards. Industrial and environmental risks have a high degree of influence on the company’s activities, and often domestic oil and gas companies focus on these risks.

Риски являются одной из природных составляющих жизни человека и сопровождают во всех отраслях его деятельности. Под риском подразумевается нанесение вреда здоровью или жизни людей, окружающему миру, имуществу отдельных лиц или государства. Risks are one of the natural components of human life and accompany in all areas of its activity. Risk means harm to human life or health, the environment, or the property of individuals or the state.

© 2016 Informa UK Limited, trading as Taylor & Francis Group.Objectives: The objective of this study was to study the association of polymorphisms MTHFR C677T (rs1801133) and MTR A2756G (rs1805087) with the risk of varicose veins in ethnical Russians. Methods: We genotyped 475 patients with varicose veins, 168 individual without chronic venous disease, and the population-based group of 896 subjects. Association was studied using logistic regression analysis adopting co-dominant, additive, recessive, and dominant models of inheritance. Results: None of the polymorphisms showed a statistically significant association with the risk of varicose veins. Conclusions: Our results provide evidence that the studied polymorphisms do not contribute to genetic susceptibility to varicose veins in ethnical Russians.

© The Author(s) 2015.Objective: To investigate the association of polymorphisms located near the FOXC2 gene with the risk of varicose veins in ethnic Russians. Methods: Allele, genotype, and haplotype frequencies were determined in the sample of 474 patients with primary varicose veins and in the control group of 478 individuals without a history of chronic venous disease. Results: Polymorphisms rs7189489, rs4633732, and rs1035550 showed the association with the increased risk of varicose veins, but none of the observed associations remained significant after correction for multiple testing. Haplotype analysis revealed the association of haplotype rs7189489 C–rs4633732 T–rs34221221 C–rs1035550 C–rs34152738 T–rs12711457 G with the increased risk of varicose veins (OR = 2.67, P = 0.01). Conclusions: Our results provide evidence that the studied polymorphisms do not play a major role in susceptibility to varicose veins development in the Russian population.

[Context]: Thanks to the large collecting area (3 × ∼1500 cm at 1.5 keV) and wide field of view (30′ across in full field mode) of the X-ray cameras on board the European Space Agency X-ray observatory XMM-Newton, each individual pointing can result in the detection of up to several hundred X-ray sources, most of which are newly discovered objects. Since XMM-Newton has now been in orbit for more than 15 yr, hundreds of thousands of sources have been detected. [Aims]: Recently, many improvements in the XMM-Newton data reduction algorithms have been made. These include enhanced source characterisation and reduced spurious source detections, refined astrometric precision of sources, greater net sensitivity for source detection, and the extraction of spectra and time series for fainter sources, both with better signal-to-noise. Thanks to these enhancements, the quality of the catalogue products has been much improved over earlier catalogues. Furthermore, almost 50% more observations are in the public domain compared to 2XMMi-DR3, allowing the XMM-Newton Survey Science Centre to produce a much larger and better quality X-ray source catalogue. [Methods]: The XMM-Newton Survey Science Centre has developed a pipeline to reduce the XMM-Newton data automatically. Using the latest version of this pipeline, along with better calibration, a new version of the catalogue has been produced, using XMM-Newton X-ray observations made public on or before 2013 December 31. Manual screening of all of the X-ray detections ensures the highest data quality. This catalogue is known as 3XMM. [Results]: In the latest release of the 3XMM catalogue, 3XMM-DR5, there are 565 962 X-ray detections comprising 396 910 unique X-ray sources. Spectra and lightcurves are provided for the 133 000 brightest sources. For all detections, the positions on the sky, a measure of the quality of the detection, and an evaluation of the X-ray variability is provided, along with the fluxes and count rates in 7 X-ray energy bands, the total 0.2-12 keV band counts, and four hardness ratios. With the aim of identifying the detections, a cross correlation with 228 catalogues of sources detected in all wavebands is also provided for each X-ray detection. [Conclusions]: 3XMM-DR5 is the largest X-ray source catalogue ever produced. Thanks to the large array of data products associated with each detection and each source, it is an excellent resource for finding new and extreme objects. F.J.C. acknowledges financial support by the Spanish Ministry of Economy and Competitiveness through grant AYA2012-31447, which is partly funded by the FEDER programme, and grant AYA2015-64346-C2-1-P. M.T.C. acknowledges financial support from the Spanish Ministry of Science and Innovation through grant AYA2010-21490-C02-1. The Italian team acknowledges financial support during the years from the Ministero dell’Istruzione, dell’Universita’ e della Ricerca (MIUR), from the Agenzia Spaziale Italiana (ASI) and from the Istituto Nazionale di Astrofisica (INAF).

[Context]: Thanks to the large collecting area (3 × ∼1500 cm at 1.5 keV) and wide field of view (30′ across in full field mode) of the X-ray cameras on board the European Space Agency X-ray observatory XMM-Newton, each individual pointing can result in the detection of up to several hundred X-ray sources, most of which are newly discovered objects. Since XMM-Newton has now been in orbit for more than 15 yr, hundreds of thousands of sources have been detected. [Aims]: Recently, many improvements in the XMM-Newton data reduction algorithms have been made. These include enhanced source characterisation and reduced spurious source detections, refined astrometric precision of sources, greater net sensitivity for source detection, and the extraction of spectra and time series for fainter sources, both with better signal-to-noise. Thanks to these enhancements, the quality of the catalogue products has been much improved over earlier catalogues. Furthermore, almost 50% more observations are in the public domain compared to 2XMMi-DR3, allowing the XMM-Newton Survey Science Centre to produce a much larger and better quality X-ray source catalogue. [Methods]: The XMM-Newton Survey Science Centre has developed a pipeline to reduce the XMM-Newton data automatically. Using the latest version of this pipeline, along with better calibration, a new version of the catalogue has been produced, using XMM-Newton X-ray observations made public on or before 2013 December 31. Manual screening of all of the X-ray detections ensures the highest data quality. This catalogue is known as 3XMM. [Results]: In the latest release of the 3XMM catalogue, 3XMM-DR5, there are 565 962 X-ray detections comprising 396 910 unique X-ray sources. Spectra and lightcurves are provided for the 133 000 brightest sources. For all detections, the positions on the sky, a measure of the quality of the detection, and an evaluation of the X-ray variability is provided, along with the fluxes and count rates in 7 X-ray energy bands, the total 0.2-12 keV band counts, and four hardness ratios. With the aim of identifying the detections, a cross correlation with 228 catalogues of sources detected in all wavebands is also provided for each X-ray detection. [Conclusions]: 3XMM-DR5 is the largest X-ray source catalogue ever produced. Thanks to the large array of data products associated with each detection and each source, it is an excellent resource for finding new and extreme objects., F.J.C. acknowledges financial support by the Spanish Ministry of Economy and Competitiveness through grant AYA2012-31447, which is partly funded by the FEDER programme, and grant AYA2015-64346-C2-1-P. M.T.C. acknowledges financial support from the Spanish Ministry of Science and Innovation through grant AYA2010-21490-C02-1. The Italian team acknowledges financial support during the years from the Ministero dell’Istruzione, dell’Universita’ e della Ricerca (MIUR), from the Agenzia Spaziale Italiana (ASI) and from the Istituto Nazionale di Astrofisica (INAF).

This tutorial is devoted to extending an existing catalogue with data taken elsewhere, either from CDS Vizier or Simbad database. As an example, we used the so-called 'Spectroscopic Survey of Stars in the Solar Neighborhood' (aka. S4N, Allende Prieto et al. 2004) in order to retrieve all objects with available data for the set of fundamental stellar parameters effective temperature, surface gravity and metallicity. Then for each object in this dataset we query Simbad database to retrieve the projected rotational velocity. This combines Vizier and Simbad queries made using Python astroquery module. The tutorial covers remote database access, filtering tables with arbitrary criteria, creating and writing your own tables, and basics of plotting in Python., 6 pages, 2 figures + python code (tutorial corrected in {\S}4 [remark in red]) - see also: http://goo.gl/mr9wZp

International audience

We study relations between the X-ray luminosity, orbital period and absolute near-infrared magnitude of persistent low-mass X-ray binaries (LMXBs). We show that often optical and near-infrared spectral energy distribution of LMXBs can be adequately described by a simple model of an accretion disc and a secondary star reprocessing X-ray emission of a central compact object. This gives us an evidence that using an X-ray luminosity and an absolute infrared magnitude of a persistent LMXB one can make reliable estimate of its orbital period. Using a sample of well-known LMXBs, we have constructed a correlation of L_X, P_orb and M_K values which can be approximated by a straight line with the RMS scatter at the level of ~0.3 mag. Such a correlation, being to some extent an analogous to the correlation, found by van Paradijs & McClintock 1994, might be helpful for future population studies especially in the light of forthcoming surveys of the Galaxy in X-ray and infrared spectral domains., 9 pages, 6 figures. Accepted for publication in MNRAS

International audience; VO-Paris Data Centre (VO-PDC) is a new data centre that gathers ten laboratories in Paris area (GEPI, IAP, IMCCE, LATMOS, LERMA, LESIA, LPMAA, LUTH, SYRTE, USN). It is specialized in the development of Virtual Observatory services. The objective of this federation is to build a sustainable infrastructure to offer high quality diffusion services to the community. It gives also the opportunity to promote exchanges and to share expertise on the development of VO services between scientists and computer engineers. VO-PDC is a multidisciplinary data center. Its main axes are atomic and molecular physics, VO-Theory, planetology and solar physics. It also develops several services concerning the diffusion of traditional astronomical data, catalogues, as well as geodesy services.

Nowadays, Virtual Observatory standards, resources, and services became powerful enough to help astronomers making real science on everyday basis. The key to the VO success is its entire transparency for a scientific user. This allows an astronomer to combine "online" VO-enabled parts with "offline" research stages including dedicated data processing and analysis, observations, numerical simulations; and helps to overpass one of the major issues that most present-day VO studies do not go further than data mining. Here we will present three VO-powered research projects combining VO and non-VO blocks, all of them resulted in peer-reviewed publications., Comment: Proceedings of the ADASS-XIX conference, 4 pages, 1 figure, to appear in ASP Conf. Series

An astronomical complex intended to detect optical transients (OTs) in a wide field and follow them up with high time resolution investigation is described., Comment: 4 pages, 3 figures. To be published in "Il Nuovo Cimento", Proceedings of the 4th Rome Workshop on Gamma-Ray Bursts in the Afterglow Era, eds. L. Piro, L. Amati, S. Covino, B. Gendre

International audience; The VO-Paris Data Centre (VO-PDC) is a new data centre that gathers ten laboratories in the Paris area (GEPI, IAP, IMCCE, LATMOS, LERMA, LESIA, LPMAA, LUTH, SYRTE, USN). It is specialized in the development of Virtual Observatory services. The objective of this federation is to build a sustainable infrastructure to offer high quality diffusion services to the community. It gives also the opportunity to promote exchanges and to share expertise on the development of VO services between scientists and computer engineers. VO-PDC is a multidisciplinary data center. Its main axes are atomic and molecular physics, VO-Theory, planetology and solar physics. It also develops several services concerning the diffusion of traditional astronomical data, catalogues, as well as geodesy services.

Galaxy clusters represent one of the largest-scale structures in the Universe, with their environments of varying density being ideal for inducing an increase in activity of the cluster galaxy members and the pervading Intracluster Medium (ICM) between them. However the precise drivers, thereby the inferred consequences, of differing states of galaxy cluster activity have not been adequately disentangled. If one can procure a sufficient dichotomic sample of cluster galaxies of differing sub-populations from relaxed and unrelaxed galaxy cluster dynamical states, one could analyse how these sub-populations `move' as a function of both radius and dynamical state. Specifically, using velocity dispersion profiles (VDPs) that weight against cluster galaxies across all radii with a Gaussian window function, one can determine how cluster galaxies of properties that pertain to galaxy evolutionary indicators respond to the cluster environment as a function of the clustocentric radius. In addition, analysing the rotational profiles of these sub-populations as a function of the clustocentric radius can help identify where the bulk of the kinetic energy lies. In view of these points, we have pooled data of galaxies from the Sloan Digital Sky Survey (SDSS) two composite galaxy clusters are assembled into unrelaxed and relaxed states, which are compared with one another through splitting their cluster galaxy populations by their evolutionary proxies (i.e. morphology, colour, mass and AGN), thus analysing their resultant VDPs and rotational profiles. It is therefore found that unrelaxed galaxy clusters possess increased interaction between cluster galaxies as the radius increases, driven by blue and red elliptical galaxies, suggesting an induction of activity by pre-processed groups. AGN-hosting cluster galaxy sub-populations within these unrelaxed environs however present increased activity as \(R\rightarrow0\), indicating these are recent infallers, potentially triggered due to interactions with the ICM. Rotational profiles of unrelaxed clusters build upon the VDPs, showing significant bulk rotation of cluster galaxies with prominent core rotation driven by redder sub-populations., 176 Pages, 45 Figures and 7 Tables, {"references": ["Abadi M. G., Moore B., Bower R. G., 1999, MNRAS, 308, 947", "Abazajian K. N., et al., 2009, ApJS, 182, 543", "Abdullah M. H., Ali G. B., Ismail H. A., Rassem M. A., 2011, MNRAS, 416, 2027", "Abell G. O., 1958, ApJS, 3, 211", "Abell G. O., 1959, Leaflet of the Astronomical Society of the Pacific, 8, 121", "Aghamousa A., et al., 2016, arXiv e-prints, p. arXiv:1611.00036", "Agulli I., Aguerri J. A. 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Weakening of the lower abdominal wall muscle via fibrosis causes visceral contents to bulge out, forming inguinal hernias. Humanized aromatase (Aromhum) transgenic male mice develop this weakness in the lower abdominal muscle (LAM) tissue, characterized by extensive fibrosis, muscle atrophy, and scrotal hernias. This mouse model incorporates the human version of the aromatase gene allowing for excessive estradiol (E2) production in skeletal muscle tissue. We have previously shown that the LAM fibroblasts are sensitive to local E2 production due to high levels of estrogen receptor alpha (ERα, Esr1)1. Here, we explore the origins of estrogen-driven muscle fibrosis in the LAM tissue of Aromhum mice at a single-cell level. Wild-type (WT) and Aromhum LAM tissues were processed via single-cell RNA sequencing (n = 3) and analyzed using Seurat. We observed a total of 22 UMAP clusters, including six fibroblast-like clusters. Five of these clusters express the fibro-adipogenic progenitor (FAP) marker Pdgfrα, and two of them are exclusively found in Aromhum LAM tissues. One Aromhum-enriched cluster highly expresses Esr1 and its downstream estrogen-responsive genes such as Pgr and Greb1. Pseudo-time analysis suggested that this cluster differentiates into a pathogenic fibroblast cluster characterized by high expression pro-inflammatory (Il33, Il6, Ccl8, C4b) and fibrosis-associated (Mmp3, Cthrc1, Saa3, Ptx3) genes. We further validated our findings via flow cytometry, immunocytochemistry, and western blots in LAM, upper abdominal muscle tissues, and quadriceps of both WT and Aromhum mice. We show that protein levels of Pdgfrα, ERα, Mmp3, C4b are greater in the fibroblasts freshly isolated from LAM tissues of Aromhum mice compared to WT mice. Moreover, Aromhum LAM tissue cell cycle analysis reveals that ∼15% of all ERα+ cells are in the G2-S phase compared with Inguinal hernias are found in ∼25% of the elderly male population2. Using an inguinal hernia mouse model that mimics the hernia pathophysiology of elderly men with estrogen excess and testosterone deficiency, we defined a specific population of estrogen-sensitive fibroblasts responsible for fibrosis and weakening of lower abdominal skeletal muscle tissue associated with hernias. We provide an insight into the specific disease-causing fibroblast populations and molecular targets that may be the basis for future therapeutics to prevent or treat inguinal hernias. References 1. Zhao H, Zhou L, Li L, et al. Shift from androgen to estrogen action causes abdominal muscle fibrosis, atrophy, and inguinal hernia in a transgenic male mouse model. Proceedings of the National Academy of Sciences. 2018;115(44): E10427-E10436. 2. Sazhin A, Zolotukhin I, Seliverstov E, et al. Prevalence and risk factors for abdominal wall hernia in the general Russian population. Hernia. 2019;23(6): 1237-1242. Presentation: Saturday, June 11, 2022 1:06 p.m. - 1:11 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Magnetic properties in amorphous multilayer nanostructures [(CoFeB)60C40/SiO2]200 and [(CoFeB)34(SiO2)66/C]46 with different content of the CoFeB magnetic alloy in metal-composite layers and inverse location of non-metallic phases C and SiO2 in composite layers or in interlayers, were investigated by magneto-optical methods in the transversal Kerr effect (TKE) geometry.Using the spectral and field dependences of the transversal Kerr effect TKE, it has been established that in the samples of both magnetic multilayer nanostructures (MLNS) the magneto-optical response and magnetic order are determined by the phase composition of the composite layers.In samples of MLNS [(CoFeB)60C40/SiO2]200 with a post-percolation content of metal clusters in metal-composite layers, the maximum of absolute TKE values decrease by about 2.5 times compared with the initial amorphous Co40Fe40B20 alloy, while the field dependences of TKE in samples of this MLNS has features that are characteristic of soft ferromagnets.In samples of MLNS [(CoFeB)34(SiO2)66/C]46 with a pre-percolation content of metal clusters in the oxide SiO2–x matrix of metal-composite layers, the TKE spectral dependences fundamentally differed from the TKE of the initial amorphous Co40Fe40B20 alloy both in shape and sign. 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Методом ионно-лучевого распыления двух мишеней (одна из сплава CoFeB, вторая из TiO2) на вращающуюся ситалловую подложку получена серия образцов с градиентом состава и толщины композита (CoFeB)x(TiO2)1–x. На дифрактограммах aморфных композитов обнаружено гало, соответствующее среднему межатомному расстоянию, близкому по величине к значениям межплоскостных расстояний самых интенсивных дифракционных линий в сплавах CoFe. Методом ИК-спектроскопии проведена идентификация мод, соответствующих межатомным связям в аморфных композитах (CoFeB)x(TiO2)1–x различного состава. Установлено наличие связей с кислородом всех элементов композита Fe–O, Co–O, Ti–O, B-O, а также образование промежуточных химических связей Ti–O–B, Ti–O–Co между атомами диэлектрической и металлической компонент композита. На основе полученных данных предложена модель аморфных композитов (Co45Fe45B10)x(TiO2)1–x, в которой металлические частицы представляются в виде ядра из металлических кластеров CoFe с оболочкой из оксидов и боридов/оксиборидов d-металлов, распределенных в диэлектрической матрице диоксида титана TiO2–х. ИСТОЧНИК ФИНАНСИРОВАНИЯРабота выполнена при поддержке Минобрнауки России в рамках государственного заданияВУЗам в сфере научной деятельности на 2017–2019 годы. Проект № 3.6263.2017/ВУ. REFERENCES Zolotukhin I. V., Kalinin Yu. E., Stognay O. V. New directions of physical materials science. Voronezh, Voronezh State University Publ., 2000, 456 p. (in Russ.) Gridnev S. A., Kalinin Yu. E., Sitnikov A. V., Stognay O.V. Nonlinear phenomena in nano- and microheterogeneous systems. Moscow, BINOM. Lab knowledge Publ., 2012, 352 p. (in Russ.) Stognay O. V. Electric transport and magnetic properties of amorphous nano-granulated metal-dielectric composites. Doc. Sci. diss, Voronezh, 2004, 280 p. 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XANES and USXES studies of interatomic interactions in (Co41Fe39B20)x(SiO2)1−x nanocomposites. Physics of the Solid State, 2008, v. 50(1), pp. 139–145. https://doi.org/10.1134/S1063783408010253 Shchekochikhin A. V., Domashevskaya E. P., Karpov S. I. Effect of elemental composition based on CoFeB-SiO2 on magnetic and magnetoresistive properties. Kondensirovannye sredy i mezhfaznye granitsy [Condensed Matter and Interphases], 2006, v. 8(1), pp. 64–66. URL: http://www.kcmf.vsu.ru/resources/t_08_1_2006_013.pdf (in Russ.) Domashevskaya E. P., Chan Van Tu, Chernyshev A. V., Lukin A. N. Investigation of the interato mic interaction in multilayer nanostructures (Co45Fe45Zr10/a-Si)40 and (Co45Fe45Zr10/SiO2) by method of IR-spectroscopy and small angle diffraction. Condensed Matter and Interphases, 2017, v. 19(2), pp. 195–204. https://doi.org/10.17308/kcmf.2017.19/192 (in Russ.) JCPDS − International Centrefor Diffraction Data. 2001, no. 51−0740. JCPDS − International Centre for Diffraction Data. 2001, no. 49−1588. JCPDS − International Centre for Diffraction Data. 2001, no. 48−1817. Kongfa Chen, Lihua Fang, Teng Zhang, San Ping Jiang. New zinc andbismuth doped glass sealants with substantially suppressed borondeposition and poisoning for solid oxide fuel cells. J. Mater. Chem. A, 2014, v. 2(43), pp. 18655–18665. https://doi.org/10.1039/c4ta02951h Wenjie Zhang, Bo Yang, Jinlei Chen. Effects of calcination temperature on preparation of borondoped TiO2 by sol-gel method. International Journal of Photoenergy, 2012, v. 2012, pp. 1–8. https://doi.org/10.1155/2012/528637 Rihcard A., Nyquistand R., Kagel O. Infrared Spectra of Inorganic Compounds. New York and London, Academic Press, 1971, 499 p. Milovanov Yu. S., Kuznetsov G. V., Skryshevsky V. A., Stupan S. M. Transport of Charge in Nanocomposite Structures of Silicon-SiO2, Silicon-TiO2. 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The second Gaia data release (Gaia DR2) contains high-precision positions, parallaxes and proper motions for 1.3 billion sources. The resulting Hertzsprung-Russel diagram reveals fine structures throughout the mass range. This paper aims to investigate the content of Gaia DR2 at the low-mass end and to characterize ultra-cool and brown dwarfs. We first retrieved the sample of spectroscopically confirmed ultra-cool stars and brown dwarfs (>M6) in Gaia DR2. We used their locus in the precise Hertzsprung-Russel diagram to select new candidates and to investigate their properties. About 70% of the bright enough objects from the known sample are recovered, filling the gap with Gaia DR1. Furthermore, Gaia DR2 contains ∼100 000 >M6 and ∼1000 L candidates (all are . L5). A tentative classification suggests that a few hundred of them are young or subdwarf candidates. Their distance distribution shows that the solar neighbourhood census is still not complete. Gaia DR2 offers a great wealth of information on low-mass objects. It provides a homogeneous and precise catalogue of candidates that is worthwhile to be further characterized with spectroscopic observations., {"references":["Allard, F., Homeier, D., & Freytag, B. 2013, MmSAI, 84,1053","Artigau, É., Lafrenière, D., Doyon, R., et al. 2009, in Ameri-can Institute of Physics Conference Series, Vol. 1094, 15thCambridge Workshop on Cool Stars, Stellar Systems, andthe Sun, ed. E. Stempels, 493–496","Baraffe, I., Homeier, D., Allard, F., & Chabrier, G. 2015,A&A, 577, A42","Best, W. M. J., Liu, M. C., Magnier, E., & Dupuy, T. 2018a,in American Astronomical Society Meeting Abstracts, Vol.231, American Astronomical Society Meeting Abstracts#231, 349.19","Best, W. M. J., Magnier, E. A., Liu, M. C., et al. 2018b, ApJS,234, 1","Burrows, A., Sudarsky, D., Sharp, C., et al. 1998, in Astro-nomical Society of the Pacific Conference Series, Vol. 134,Brown Dwarfs and Extrasolar Planets, ed. R. Rebolo, E. L.Martin, & M. R. Zapatero Osorio, 354","Capitanio, L., Lallement, R., Vergely, J. L., Elyajouri, M., &Monreal-Ibero, A. 2017, A&A, 606, A65","Cui, X.-Q., Zhao, Y.-H., Chu, Y.-Q., et al. 2012, Research inAstronomy and Astrophysics, 12, 1197","Dalton, G., Trager, S., Abrams, D. C., et al. 2014, in SPIE,Vol. 9147, Ground-based and Airborne Instrumentation forAstronomy V, 91470L","de Jong, R. S., Barden, S. C., Bellido-Tirado, O., et al. 2016,in SPIE, Vol. 9908, Ground-based and Airborne Instrumen-tation for Astronomy VI, 99081O","Eisenstein, D. J., Weinberg, D. H., Agol, E., et al. 2011, AJ,142, 72","Evans, D. W., Riello, M., De Angeli, F., et al. 2018, A&A,616, A4","Faherty, J. K., Gagne, J., Burgasser, A. J., et al. 2018, ArXive-prints","Faherty, J. K., Riedel, A. R., Cruz, K. L., et al. 2016, ApJS,225, 10","Folkes, S. L., Pinfield, D. J., Jones, H. R. A., et al. 2012,MNRAS, 427, 3280","Gaia Collaboration, Babusiaux, C., van Leeuwen, F., et al.2018a, A&A, 616, A10","Gaia Collaboration, Brown, A. G. A., Vallenari, A., et al.2018b, A&A, 616, A1","Gaia Collaboration, Brown, A. G. A., Vallenari, A., et al.2016a, A&A, 595, A2","Gaia Collaboration, Prusti, T., de Bruijne, J. H. J., et al.2016b, A&A, 595, A1","Majewski, S. R., Schiavon, R. P., Frinchaboy, P. M., et al.2017, AJ, 154, 94","Marocco, F., Jones, H. R. A., Day-Jones, A. C., et al. 2015,MNRAS, 449, 3651","Marrese, P. M., Marinoni, S., Fabrizio, M., & Giuffrida, G.2017, A&A, 607, A105","Paletou, F. & Zolotukhin, I. 2014, ArXiv e-prints 1408.7026","Rajpurohit, A. S., Reylé, C., Allard, F., et al. 2014, A&A, 564,A90","Robert, J., Gagné, J., Artigau, É., et al. 2016, ApJ, 830, 144","Schmidt, S. J., Hawley, S. L., West, A. A., et al. 2015, AJ,149, 158","Scholz, R.-D. & Bell, C. P. M. 2018, Research Notes of theAmerican Astronomical Society, 2, 33","Skrutskie, M. F., Cutri, R. M., Stiening, R., et al. 2006, AJ,131, 1163","Skrzypek, N., Warren, S. J., & Faherty, J. K. 2016, A&A, 589,A49","Smart, R. L., Marocco, F., Caballero, J. A., et al. 2017, MN-RAS, 469, 401","Smith, L., Lucas, P. W., Bunce, R., et al. 2014, MNRAS, 443,2327","Smith, L. C., Lucas, P. W., Kurtev, R., et al. 2018, MNRAS,474, 1826","Taylor, M. B. 2005, in Astronomical Society of the PacificConference Series, Vol. 347, Astronomical Data AnalysisSoftware and Systems XIV, ed. P. Shopbell, M. Britton, &R. Ebert, 29","Theissen, C. A., West, A. A., Shippee, G., Burgasser, A. J., &Schmidt, S. J. 2017, AJ, 153, 92","Wenger, M., Ochsenbein, F., Egret, D., et al. 2000, A&AS,143, 9","Zhang, Z. H., Gálvez-Ortiz, M. C., Pinfield, D. J., et al. 2018,MNRAS"]}

In the late 1990s, animal studies employing adeno-associated viral (AAV) gene transfer offered the promise that gene therapy could someday be used to treat patients with the bleeding disorder hemophilia. These studies in mice and dogs with hemophilia B (deficiency of coagulation factor IX, FIX) quickly led to a first trial in humans. However, two decades of cycling back and forth between the laboratory and the clinic, including multiple clinical trials, were needed to get it right in patients. At long last, the lead investigators of two clinical trials have reported spectacular successes with AAV gene transfer for both hemophilia A (deficiency of factor VIII, FVIII) and hemophilia B at the World Federation of Hemophilia (WFH) Congress (Orlando, Florida, July 2016).To treat hemophilia B, Lindsey George (The Children's Hospital of Philadelphia) and her collaborators from Spark Therapeutics (Philadelphia) delivered a version of FIX that has approximately eightfold higher biological activity than that of the wild-type molecule. They administered an engineered AAV capsid and a vector dose of merely 5 × 1011 vector genomes (vg)/kg, and achieved sustained circulating levels of 20–40% of normal coagulation activity in all four treated patients without toxicity. No subsequent bleeding episodes occurred in these patients, and a case of recurring joint bleeding was resolved. Although 1% of normal to change the disease phenotype from severe to moderate with the hope of reducing the frequency of bleeding episodes. Both current trials are based on targeting hepatocytes for therapeutic gene expression. An AAV vector with a hepatotropic capsid containing a single-stranded DNA genome was infused intravenously, and gene expression is controlled by a hepatocyte-specific promoter. As hemophilia is X-linked, the patients enrolled in these studies are all male. Hepatocytes are the natural site of FIX expression, whereas FVIII is normally expressed by liver endothelial cells. However, hepatocytes are generally a good target, because they are abundant and efficient in secreting proteins into the blood (which is essential for treatment of hemophilia). Furthermore, optimized transgene expression in hepatocytes tends to induce immune tolerance.Nonetheless, prior trials with AAV2 and AAV8 serotype vectors were hampered by vector dose–dependent CD8+ T-cell responses to the viral capsid, causing hepatotoxicity and loss of expression. Transient immune suppression was successfully applied to solve this problem in some but not all studies. It appears that this problem can be entirely circumvented by using low vector doses­—made possible here through optimization of the vector and incorporation of a more highly active version of FIX. For the hemophilia A trial, the researchers adapted a different strategy. They packaged a codon-optimized FVIII sequence into AAV5, a capsid that has reduced homology to those typically found in humans. Therefore, AAV5 may be less prone to activating memory lymphocyte responses. This may be further supported by a third clinical trial (sponsored by UniQure, Amsterdam, the Netherlands). Wolfgang Miesbach (University Hospital Frankfurt, Germany) reported average FIX levels of ~5% of normal in five hemophilia B patients who were treated with an AAV5 vector at 5 × 1012 vg/kg. Only one patient showed elevated liver enzyme levels and was treated with steroid drugs. However, even when these results are adjusted with the consideration that this study used the wild-type instead of the enhanced-activity version of FIX, an approximately 10-fold dose disadvantage is apparent compared to the trial at Penn.This outcome may be due to a lower transduction efficiency of AAV5 in human hepatocytes, as suggested by a recent article in Molecular Therapy.1xSuperior in vivo transduction of human hepatocytes using engineered AAV3 capsid. Vercauteren, K, Hoffman, BE, Zolotukhin, I, Keeler, GD, Xiao, JW, Basner-Tschakarjan, E et al. Mol Ther. 2016; 24: 1042–1049Abstract | Full Text | Full Text PDF | PubMed | Scopus (16)See all References Therefore, higher vector doses are required to achieve therapy. Given that FVIII is typically less efficiently expressed than FIX is, Pasi and colleagues used very high doses of 6 × 1013 vg/kg in the hemophilia A trial. Here, very mild elevations of liver enzyme levels were observed, and thus steroid drugs were administered. However, the reason for mild liver toxicity (which may not be immune mediated but still related to the high vector doses) is unclear. Only one patient had previously been treated at a threefold lower dose of 2 × 1013 vg/kg. He achieved substantially lower levels of 2–5% of normal. This discrepancy in the dose response remains to be resolved. An optimal vector dose would result in FVIII levels near normal but not superphysiological, with no or minimal/manageable toxicity. Thus far, the patients discussed here have been followed for up to 8 months. Long-term follow-up will establish whether this cure will last and whether factor levels will be stable. Encouragingly, hepatic AAV gene therapy in hemophilia A and B dogs directed stable levels for well over a decade.It has been estimated that a lifetime treatment of a patient with severe hemophilia amounts to a cost of US$25–50 million when using recombinant protein products. Gene therapy should be a much more cost-efficient alternative. Moreover, gene therapy may hold the key to treat hemophilia in the third world, where very few could afford these expensive protein drugs. Indeed, the majority of hemophilic patients worldwide currently are untreated. Hemophilia A is the more prevalent form of the disease and thus will require further improvements of the vector technology to be treatable at vector doses that are feasible to produce for large populations. At the same time, additional questions must be addressed for further development of this technology in the developed world as well. Currently utilized AAV capsids have low seroprevalence in the population, but patients with preexisting neutralizing antibodies nonetheless exist. Alternative capsids will need to be developed to enable giving gene therapy to these patients. Assuming that gene therapy in adult patients will be deemed safe, treatment of children may be considered so as to eliminate the disease earlier in life. Loss of episomal AAV vector genomes is a concern in a growing liver, and the risk of antibody (inhibitor) formation against the FVIII or FIX antigen is less clear in young patients with limited exposure. However, cautiously beginning by treating older pediatric patients may be a path to proceed initially. In any case, a cure for hemophilia by gene therapy is no longer merely a promise; it is a reality.

Automated search for star clusters in J,H,K_s data from 2MASS catalog has been performed using the method developed by Koposov et. al (2008). We have found and verified 153 new clusters in the interval of the galactic latitude -24 < b < 24 degrees. Color excesses E(B-V), distance moduli and ages were determined for 130 new and 14 yet-unstudied known clusters. In this paper, we publish a catalog of coordinates, diameters, and main parameters of all the clusters under study. A special web-site available at http://ocl.sai.msu.ru has been developed to facilitate dissemination and scientific usage of the results., 9 pages, 3 tables, 5 figures, accepted to Astronomy Letters