ОПРЕДЕЛЕНИЕ ФОКАЛЬНЫХ МЕХАНИЗМОВ СЛАБЫХ ЗЕМЛЕТРЯСЕНИЙ И СОВРЕМЕННАЯ ГЕОДИНАМИКА ЮГА ИРАНА

The Southern Iran territory, including the Zagros region and the margins of the Arabian and Eurasian plates, is a seismically active area with large industrial facilities of Iran. In this respect, studying modern geodynamics of this area is a top research task. This article presents a part of the studies conducted by the IPE RAS Seismological Expedition led by the Doctor of Physics and Mathematics S.S. Arefiev in 1999–2001. The research team studied the seismic setting on the construction site of the Bushehr Nuclear Power Plant. The main results discussed in the present article are the focal mechanism solutions based on the data of the IPE RAS seismic network. The network was deployed in the junction area of the Fars and Dezful tectonic provinces (north of the Bushehr NPP) and covered an area of 100´100 km. A specific feature of the seismic network was that it comprised local networks, and each local station was focused, first of all, on determining the precise locations of earthquake epicenters in a particular section of the crust. However, the scarcity of stations in such local networks and the technologies available at that time did not allow us to determine the mechanisms of earthquake foci. This problem was solved by integrating the seismological and tectonophysical methods. In the analysis, we used the tectonophysical approach that is usually applied to reconstruct stresses from the data on slickensides. This approach is based on a specific algorithm of the kinematic method developed by O.I. Gushchenko, which is used in the absence of sliding direction signs. It became possible, in addition to a few signs from the first P-wave arrivals (1–2 confident signs), to use the data on the S-wave polarization direction. By applying the Gushchenko algorithm to such data, the areas of P and T axes were quite reliably localized on a single hemisphere for determining the focal mechanisms. The focal mechanisms computed for 72 earthquakes correspond to the Kazerooni-Borazdzhan shearing zone and, at the same time, are indicative of the presence of crust incision me­chanisms in the Bushehr Peninsula. The focal mechanisms computed in our study, as well as the mechanisms reported in the Global CMT Project Catalogue, show that the Bushehr Peninsula is located near the western boundary of the zone of strike-slip faults, which extends from the north (Zagros) to the south (the Persian Gulf) and widens as a horsetail-shape structure. In the crust of the Persian Gulf coast, the intensity of the strike-slip component in the earthquake focal mechanism is minimal. The earthquake mechanisms in this region are mainly related to thrusting, reverse faulting and even the crust incision.Южный Иран в районе Загроса и границ Аравийской и Евразийской плит является сейсмически активной территорией, на которой находятся крупные промышленные объекты. В этой связи понятна актуальность изучения современной геодинамики региона. В работе представлена небольшая часть исследований, выполненных в процессе проведения изысканий сейсмологической экспедиции ИФЗ РАН под руководством д.ф.-м.н. С.С. Арефьева в 1999–2001 гг. Работы были связаны с изучением сейсмической обстановки в районе строительства АЭС Бушер. Главным результатом, обсуждаемым в статье, являются решения фокальных механизмов, полученных по данным сейсмической сети ИФЗ РАН. Сеть была развернута в области сопря­жения тектонических провинций Фарс и Дезфул (к северу от АЭС Бушер) и охватывала область 100´100 км. Особенностью сейсмических сетей локальных станций является ее нацеленность, прежде всего, на точность локации эпицентров землетрясений определенного участка коры. При этом немногочисленность станций таких локальных сетей и существовавшие в то время методы не позволяли определять механизмы очагов землетрясений. Эта задача была решена на основе комплексирования сейсмологических и тектонофизических методов. В ходе анализа был использован тектонофизический подход, который обычно применялся при реконструкции напряжений по данным о зеркалах скольжения. Он основан на специфическом алгоритме кинематического метода О.И. Гущенко, используемом в случае отсутствия знаков в направлении скольжения. Это дало возможность в дополнение к небольшому числу знаков по первым вступлениям P-волны (1–2 уверенных знака) использовать данные о направлении поляризации S-волны. Применение алгоритма метода О.И. Гущенко к таким данным позволило на единичной полусфере достаточно достоверно локализовать области выходов осей P и T при определении механизмов очагов. Полученные фокальные решения для 72 землетрясений соответствуют Казерун-Боразджанской зоне сдвигов и в то же время показывают наличие взрезовых механизмов для коры полуострова Бушер. Обобщение этих данных, а также данных о фокальных механизмах из базы «Global CMT Project» свидетельствует о том, что п-ов Бушер расположен вблизи западной границы зоны сдвигов, простирающейся с севера (Загрос) на юг (Персидский залив) и расширяющейся в виде конского хвоста. В коре побережья Персидского залива интенсивность компоненты сдвига в механизмах очагов землетрясений минимальна, здесь преимущественно возникают землетрясения с механизмами надвигового, взбросового и даже взрезового типа

Environmental Seismic Intensity scale - ESI 2007 La scala di Intensità Sismica basata sugli effetti ambientali - ESI 2007

ABSTRACT - The Environmental Seismic Intensity scale (ESI 2007) is2007) is a new earthquake intensity scale only based on the effects triggered by the earthquake in the natural environment. The coseismic effects considered more diagnostic for intensity evaluation are surface faulting and tectonic uplift/subsidence (primary effects), landslides, ground cracks, liquefactions, displaced boulders, tsunami and hydrological anomalies (secondary effects). The ESI 2007 scale follows the same basic structure as any other XII degree scale, such as the MCS, MM, MSK and EMS scales. This type of intensity scale was proposed to the scientific community since the beginning of '90s. The idea was definitely accepted in 1999, when a first version of the scale was developed by a Working Group of geologists, seismologists and engineers sponsored by the International Union for Quaternary Research (INQUA). In the following years, this version has been revised and updated. The ESI 2007 scale is the result of the revision of previous versions after its application to a large number of earthquakes worldwide. In the frame of INQUA SubCommission on Paleoseismicity, this activity was conducted by academic and research institutes coordinated by the Geological Survey of Italy - APAT (for further details, s e e h t t p : / / w w w. a p a t . g o v. i t / s i t e / e n - GB/Projects/INQUA_Scale/default.html). For intensity levels lower than IX, the main goal of this new scale is to bring the environmental effects in line with the damage indicators. In this range, the ESI 2007 scale should be used along with the other scales. In the range between X and XII, the distribution and size of environmental effects, specially primary tectonic features, becomes the most diagnostic tool to assess the intensity level. Documentary report and/or field observations on fault rupture length and surface displacement should be consistently implemented in the macroseismic study of past and future earthquakes. Therefore, the use of the ESI 2007 alone is recommended only when effects on humans and on manmade structures i) are absent, or too scarce (i.e. in sparsely populated or desert areas), and ii) saturate (i.e., for intensity X to XII) loosing their diagnostic value. After its official approval at the 17th INQUA Congress, the use of the ESI 2007 scale will be proposed to national institutions (geological surveys, academic and research institutes, departments for civil protection, environmental agencies, etc.), dealing in the field of earthquake intensity and seismic hazar

Anti-cancer effects and mechanism of actions of aspirin analogues in the treatment of glioma cancer

INTRODUCTION: In the past 25 years only modest advancements in glioma treatment have been made, with patient prognosis and median survival time following diagnosis only increasing from 3 to 7 months. A substantial body of clinical and preclinical evidence has suggested a role for aspirin in the treatment of cancer with multiple mechanisms of action proposed including COX 2 inhibition, down regulation of EGFR expression, and NF-κB signaling affecting Bcl-2 expression. However, with serious side effects such as stroke and gastrointestinal bleeding, aspirin analogues with improved potency and side effect profiles are being developed. METHOD: Effects on cell viability following 24 hr incubation of four aspirin derivatives (PN508, 517, 526 and 529) were compared to cisplatin, aspirin and di-aspirin in four glioma cell lines (U87 MG, SVG P12, GOS – 3, and 1321N1), using the PrestoBlue assay, establishing IC50 and examining the time course of drug effects. RESULTS: All compounds were found to decrease cell viability in a concentration and time dependant manner. Significantly, the analogue PN517 (IC50 2mM) showed approximately a twofold increase in potency when compared to aspirin (3.7mM) and cisplatin (4.3mM) in U87 cells, with similar increased potency in SVG P12 cells. Other analogues demonstrated similar potency to aspirin and cisplatin. CONCLUSION: These results support the further development and characterization of novel NSAID derivatives for the treatment of glioma

Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas

The most common pediatric brain tumors are low-grade gliomas (LGGs). We used whole-genome sequencing to identify multiple new genetic alterations involving BRAF, RAF1, FGFR1, MYB, MYBL1 and genes with histone-related functions, including H3F3A and ATRX, in 39 LGGs and low-grade glioneuronal tumors (LGGNTs). Only a single non-silent somatic alteration was detected in 24 of 39 (62%) tumors. Intragenic duplications of the portion of FGFR1 encoding the tyrosine kinase domain (TKD) and rearrangements of MYB were recurrent and mutually exclusive in 53% of grade II diffuse LGGs. Transplantation of Trp53-null neonatal astrocytes expressing FGFR1 with the duplication involving the TKD into the brains of nude mice generated high-grade astrocytomas with short latency and 100% penetrance. FGFR1 with the duplication induced FGFR1 autophosphorylation and upregulation of the MAPK/ERK and PI3K pathways, which could be blocked by specific inhibitors. Focusing on the therapeutically challenging diffuse LGGs, our study of 151 tumors has discovered genetic alterations and potential therapeutic targets across the entire range of pediatric LGGs and LGGNTs.Jinghui Zhang, Gang Wu, Claudia P Miller, Ruth G Tatevossian, James D Dalton, Bo Tang, Wilda Orisme, Chandanamali Punchihewa, Matthew Parker, Ibrahim Qaddoumi, Fredrick A Boop, Charles Lu, Cyriac Kandoth, Li Ding, Ryan Lee, Robert Huether, Xiang Chen, Erin Hedlund, Panduka Nagahawatte, Michael Rusch, Kristy Boggs, Jinjun Cheng, Jared Becksfort, Jing Ma, Guangchun Song, Yongjin Li, Lei Wei, Jianmin Wang, Sheila Shurtleff, John Easton, David Zhao, Robert S Fulton, Lucinda L Fulton, David J Dooling, Bhavin Vadodaria, Heather L Mulder, Chunlao Tang, Kerri Ochoa, Charles G Mullighan, Amar Gajjar, Richard Kriwacki, Denise Sheer, Richard J Gilbertson, Elaine R Mardis, Richard K Wilson, James R Downing, Suzanne J Baker and David W Elliso

Isomorphic diffuse glioma is a morphologically and molecularly distinct tumour entity with recurrent gene fusions of MYBL1 or MYB and a benign disease course

The “isomorphic subtype of diffuse astrocytoma” was identified histologically in 2004 as a supratentorial, highly differentiated glioma with low cellularity, low proliferation and focal diffuse brain infiltration. Patients typically had seizures since childhood and all were operated on as adults. To define the position of these lesions among brain tumours, we histologically, molecularly and clinically analysed 26 histologically prototypical isomorphic diffuse gliomas. Immunohistochemically, they were GFAP-positive, MAP2-, OLIG2- and CD34-negative, nuclear ATRX-expression was retained and proliferation was low. All 24 cases sequenced were IDH-wildtype. In cluster analyses of DNA methylation data, isomorphic diffuse gliomas formed a group clearly distinct from other glial/glio-neuronal brain tumours and normal hemispheric tissue, most closely related to paediatric MYB/MYBL1-altered diffuse astrocytomas and angiocentric gliomas. Half of the isomorphic diffuse gliomas had copy number alterations of MYBL1 or MYB (13/25, 52%). Gene fusions of MYBL1 or MYB with various gene partners were identified in 11/22 (50%) and were associated with an increased RNA-expression of the respective MYB-family gene. Integrating copy number alterations and available RNA sequencing data, 20/26 (77%) of isomorphic diffuse gliomas demonstrated MYBL1 (54%) or MYB (23%) alterations. Clinically, 89% of patients were seizure-free after surgery and all had a good outcome. In summary, we here define a distinct benign tumour class belonging to the family of MYB/MYBL1-altered gliomas. Isomorphic diffuse glioma occurs both in children and adults, has a concise morphology, frequent MYBL1 and MYB alterations and a specific DNA methylation profile. As an exclusively histological diagnosis may be very challenging and as paediatric MYB/MYBL1-altered diffuse astrocytomas may have the same gene fusions, we consider DNA methylation profiling very helpful for their identification

Therapeutic and Prognostic Implications of BRAF V600E in Pediatric Low-Grade Gliomas

Purpose BRAF V600E is a potentially highly targetable mutation detected in a subset of pediatric low-grade gliomas (PLGGs). Its biologic and clinical effect within this diverse group of tumors remains unknown. Patients and Methods A combined clinical and genetic institutional study of patients with PLGGs with long-term follow-up was performed (N = 510). Clinical and treatment data of patients with BRAF V600E mutated PLGG (n = 99) were compared with a large international independent cohort of patients with BRAF V600E mutated-PLGG (n = 180). Results BRAF V600E mutation was detected in 69 of 405 patients (17%) with PLGG across a broad spectrum of histologies and sites, including midline locations, which are not often routinely biopsied in clinical practice. Patients with BRAF V600E PLGG exhibited poor outcomes after chemotherapy and radiation therapies that resulted in a 10-year progression-free survival of 27% (95% CI, 12.1% to 41.9%) and 60.2% (95% CI, 53.3% to 67.1%) for BRAF V600E and wild-type PLGG, respectively (P < .001). Additional multivariable clinical and molecular stratification revealed that the extent of resection and CDKN2A deletion contributed independently to poor outcome in BRAF V600E PLGG. A similar independent role for CDKN2A and resection on outcome were observed in the independent cohort. Quantitative imaging analysis revealed progressive disease and a lack of response to conventional chemotherapy in most patients with BRAF V600E PLGG. Conclusion BRAF V600E PLGG constitutes a distinct entity with poor prognosis when treated with current adjuvant therapy. (C) 2017 by American Society of Clinical Oncolog

The Exopolysaccharide Matrix Modulates the Interaction between 3D Architecture and Virulence of a Mixed-Species Oral Biofilm

Virulent biofilms are responsible for a range of infections, including oral diseases. All biofilms harbor a microbial-derived extracellular-matrix. The exopolysaccharides (EPS) formed on tooth-pellicle and bacterial surfaces provide binding sites for microorganisms; eventually the accumulated EPS enmeshes microbial cells. The metabolic activity of the bacteria within this matrix leads to acidification of the milieu. We explored the mechanisms through which the Streptococcus mutans-produced EPS-matrix modulates the three-dimensional (3D) architecture and the population shifts during morphogenesis of biofilms on a saliva-coated-apatitic surface using a mixed-bacterial species system. Concomitantly, we examined whether the matrix influences the development of pH-microenvironments within intact-biofilms using a novel 3D in situ pH-mapping technique. Data reveal that the production of the EPS-matrix helps to create spatial heterogeneities by forming an intricate network of exopolysaccharide-enmeshed bacterial-islets (microcolonies) through localized cell-to-matrix interactions. This complex 3D architecture creates compartmentalized acidic and EPS-rich microenvironments throughout the biofilm, which triggers the dominance of pathogenic S. mutans within a mixed-species system. The establishment of a 3D-matrix and EPS-enmeshed microcolonies were largely mediated by the S. mutans gtfB/gtfC genes, expression of which was enhanced in the presence of Actinomyces naeslundii and Streptococcus oralis. Acidic pockets were found only in the interiors of bacterial-islets that are protected by EPS, which impedes rapid neutralization by buffer (pH 7.0). As a result, regions of low pH (<5.5) were detected at specific locations along the surface of attachment. Resistance to chlorhexidine was enhanced in cells within EPS-microcolony complexes compared to those outside such structures within the biofilm. Our results illustrate the critical interaction between matrix architecture and pH heterogeneity in the 3D environment. The formation of structured acidic-microenvironments in close proximity to the apatite-surface is an essential factor associated with virulence in cariogenic-biofilms. These observations may have relevance beyond the mouth, as matrix is inherent to all biofilms

Infant High-Grade Gliomas Comprise Multiple Subgroups Characterized by Novel Targetable Gene Fusions and Favorable Outcomes.

Infant high-grade gliomas appear clinically distinct from their counterparts in older children, indicating that histopathologic grading may not accurately reflect the biology of these tumors. We have collected 241 cases under 4 years of age, and carried out histologic review, methylation profiling, and custom panel, genome, or exome sequencing. After excluding tumors representing other established entities or subgroups, we identified 130 cases to be part of an "intrinsic" spectrum of disease specific to the infant population. These included those with targetable MAPK alterations, and a large proportion of remaining cases harboring gene fusions targeting ALK (n = 31), NTRK1/2/3 (n = 21), ROS1 (n = 9), and MET (n = 4) as their driving alterations, with evidence of efficacy of targeted agents in the clinic. These data strongly support the concept that infant gliomas require a change in diagnostic practice and management. SIGNIFICANCE: Infant high-grade gliomas in the cerebral hemispheres comprise novel subgroups, with a prevalence of ALK, NTRK1/2/3, ROS1, or MET gene fusions. Kinase fusion-positive tumors have better outcome and respond to targeted therapy clinically. Other subgroups have poor outcome, with fusion-negative cases possibly representing an epigenetically driven pluripotent stem cell phenotype.See related commentary by Szulzewsky and Cimino, p. 904.This article is highlighted in the In This Issue feature, p. 890

MAPK pathway activation in pilocytic astrocytoma

Pilocytic astrocytoma (PA) is the most common tumor of the pediatric central nervous system (CNS). A body of research over recent years has demonstrated a key role for mitogen-activated protein kinase (MAPK) pathway signaling in the development and behavior of PAs. Several mechanisms lead to activation of this pathway in PA, mostly in a mutually exclusive manner, with constitutive BRAF kinase activation subsequent to gene fusion being the most frequent. The high specificity of this fusion to PA when compared with other CNS tumors has diagnostic utility. In addition, the frequency of alteration of this key pathway provides an opportunity for molecularly targeted therapy in this tumor. Here, we review the current knowledge on mechanisms of MAPK activation in PA and some of the downstream consequences of this activation, which are now starting to be elucidated both in vitro and in vivo, as well as clinical considerations and possible future directions

Active Tectonics Around Almaty and along the Zailisky Alatau Rangefront

This is the author accepted manuscript. The final version is available from Wiley via http://onlinelibrary.wiley.com/doi/10.1002/2017TC004657/abstractThe Zailisky Alatau is a >250-km-long mountain range in Southern Kazakhstan. Its northern rangefront around the major city of Almaty has more than 4 km topographic relief, yet in contrast to other large mountain fronts in the Tien Shan, little is known about its Late Quaternary tectonic activity despite several destructive earthquakes in the historical record. We analyse the tectonic geomorphology of the rangefront fault using field observations, differential GPS measurements of fault scarps, historical and recent satellite imagery, metre-scale topography derived from stereo satellite images, and decimetre-scale elevation models from UAV surveys. Fault scarps ranging in height from ~2 m to >20 m in alluvial fans indicate surface rupturing earthquakes occurred along the rangefront fault since the Last Glacial Maximum (LGM). Minimum estimated magnitudes for those earthquakes are M6.8- 7. Radiocarbon dating results from charcoal layers in uplifted river terraces indicate a Holocene slip rate of ~1.2-2.2 mm/a. We find additional evidence for active tectonic deformation all along the Almaty rangefront, basinward in the Kazakh platform, and in the interior of the Zailisky mountain range. Our data indicate the seismic hazard faced by Almaty comes from a variety of sources, and we emphasize the problems related to urban growth into the loess-covered foothills and secondary earthquake effects. With our structural and geochronologic framework we present a schematic evolution of the Almaty rangefront that may be applicable to similar settings of tectonic shortening in the mountain ranges of Central Asia