HOXA10 controls osteoblastogenesis by directly activating bone regulatory and phenotypic genes

HOXA10 is necessary for embryonic patterning of skeletal elements, but its function in bone formation beyond this early developmental stage is unknown. Here we show that HOXA10 contributes to osteogenic lineage determination through activation of Runx2 and directly regulates osteoblastic phenotypic genes. In response to bone morphogenic protein BMP2, Hoxa10 is rapidly induced and functions to activate the Runx2 transcription factor essential for bone formation. A functional element with the Hox core motif was characterized for the bone-related Runx2 P1 promoter. HOXA10 also activates other osteogenic genes, including the alkaline phosphatase, osteocalcin, and bone sialoprotein genes, and temporally associates with these target gene promoters during stages of osteoblast differentiation prior to the recruitment of RUNX2. Exogenous expression and small interfering RNA knockdown studies establish that HOXA10 mediates chromatin hyperacetylation and trimethyl histone K4 (H3K4) methylation of these genes, correlating to active transcription. HOXA10 therefore contributes to early expression of osteogenic genes through chromatin remodeling. Importantly, HOXA10 can induce osteoblast genes in Runx2 null cells, providing evidence for a direct role in mediating osteoblast differentiation independent of RUNX2. We propose that HOXA10 activates RUNX2 in mesenchymal cells, contributing to the onset of osteogenesis, and that HOXA10 subsequently supports bone formation by direct regulation of osteoblast phenotypic genes. <br/

Визначення правового статусу садівницьких, городницьких та дачних товариств

Розкриваються особливості правового статусу садівницьких, городницьких та дач­них товариств, досліджується їх організаційно-правова форма та ті специфічні пра­вові ознаки, що знаходяться в її основі. У зв’язку з відсутністю правової бази діяль­ності цих товариств, робиться спроба сформувати основні теоретико-правові кон­цептуальні підходи до розуміння їх природи та змоделювати законодавчу схему регулювання їх діяльності.Раскрываются особенности правового статуса садоводческих, огороднических и дачных товариществ, исследуются их организационно-правовая форма и правовые особенности, составляющие ее основание. В связи с отсутствием правовых обоснований деятельности этих товариществ автор стремится сформировать основные теоре­тико-правовые концептуальные подходы к раскрытию их сущности и смоделировать законодательную схему регулирования деятельности рассматриваемых товариществ.In article features of legal status of garden, vegetable-garden and country companies reveal, their organizational legal form and those specific features that are in its basis are investigated. In connection with absence of legal base of activity of these communities is attempted to generate the basic theoretical-legal conceptual approaches to understanding of their nature and model legislative sphere of regulation of their activity becomes

High-order aberration compensation with Multi-frame Blind Deconvolution and Phase Diversity image restoration techniques

Context. For accurately measuring intensities and determining magnetic field strengths of small-scale solar (magnetic) structure, knowledge of and compensation for the point spread function is crucial. For images recorded with the Swedish 1-meter Solar Telescope, restoration with Multi-Frame Blind Deconvolution and Joint Phase Diverse Speckle methods lead to remarkable improvements in image quality but granulation contrasts that are too low, indicating additional stray light. Aims. We propose a method to compensate for stray light from high-order atmospheric aberrations not included in MFBD and JPDS processing. Methods. To compensate for uncorrected aberrations, a reformulation of the image restoration process is proposed that allows the average effect of hundreds of high-order modes to be compensated for by relying on Kolmogorov statistics for these modes. The applicability of the method requires simultaneous measurements of Fried's parameter r0. The method is tested with simulations as well as real data and extended to include compensation for conventional stray light. Results. We find that only part of the reduction of granulation contrast in SST images is due to uncompensated high-order aberrations. The remainder is still unaccounted for and attributed to stray light from the atmosphere, the telescope with its re-imaging system and to various high-altitude seeing effects. Conclusions. We conclude that statistical compensation of high-order modes is a viable method to reduce the loss of contrast occurring when a limited number of aberrations is explicitly compensated for with MFBD and JPDS processing. We show that good such compensation is possible with only 10 recorded frames. The main limitation of the method is that already MFBD and JPDS processing introduces high-order compensation that, if not taken into account, can lead to over-compensation.Comment: in press in Astronomy & Astrophysic

The KINDRA project – towards Open Science in Hydrogeology for higher impact

Groundwater knowledge and research in the European Union is often scattered and non-standardised. Therefore, KINDRA is conducting an EU-wide assessment of existing groundwater-related practical and scientific knowledge based on a new Hydrogeological Research Classification System (HRC-SYS). The classification is supported by a web service, the European Inventory of Groundwater Research (EIGR), which acts not only as a knowledge repository but also as a tool to help identify relevant research topics, existing research trends and critical research challenges. These results will be useful for producing synergies, implementing policies and optimising water management in Europe. This article presents the work of the project during the first two years in relation to a common classification system and an activity for data collection and training delivered by the EFG’s National Associations in 20 European countries

Antagonizing miR-218-5p attenuates Wnt signaling and reduces metastatic bone disease of triple negative breast cancer cells

Wnt signaling is implicated in bone formation and activated in breast cancer cells promoting primary and metastatic tumor growth. A compelling question is whether osteogenic miRNAs that increase Wnt activity for bone formation are aberrantly expressed in breast tumor cells to support metastatic bone disease. Here we report that miR-218-5p is highly expressed in bone metastases from breast cancer patients, but is not detected in normal mammary epithelial cells. Furthermore, inhibition of miR-218-5p impaired the growth of bone metastatic MDA-MB-231 cells in the bone microenvironment in vivo. These findings indicate a positive role for miR-218-5p in bone metastasis. Bioinformatic and biochemical analyses revealed a positive correlation between aberrant miR-218-5p expression and activation of Wnt signaling in breast cancer cells. Mechanistically, miR-218-5p targets the Wnt inhibitors Sclerostin (SOST) and sFRP-2, which highly enhances Wnt signaling. In contrast, delivery of antimiR-218-5p decreased Wnt activity and the expression of metastasis-related genes, including bone sialoprotein (BSP/IBSP), osteopontin (OPN/SPP1) and CXCR-4, implicating a Wnt/miR-218-5p regulatory network in bone metastatic breast cancer. Furthermore, miR-218-5p also mediates the Wnt-dependent up-regulation of PTHrP, a key cytokine promoting cancer-induced osteolysis. Antagonizing miR-218-5p reduced the expression of PTHrP and Rankl, inhibited osteoclast differentiation in vitro and in vivo, and prevented the development of osteolytic lesions in a preclinical metastasis model. We conclude that pathological elevation of miR-218-5p in breast cancer cells activates Wnt signaling to enhance metastatic properties of breast cancer cells and cancer-induced osteolytic disease, suggesting that miR-218-5p could be an attractive therapeutic target for preventing disease progression

Heat kernel estimates and spectral properties of a pseudorelativistic operator with magnetic field

Based on the Mehler heat kernel of the Schroedinger operator for a free electron in a constant magnetic field an estimate for the kernel of E_A is derived, where E_A represents the kinetic energy of a Dirac electron within the pseudorelativistic no-pair Brown-Ravenhall model. This estimate is used to provide the bottom of the essential spectrum for the two-particle Brown-Ravenhall operator, describing the motion of the electrons in a central Coulomb field and a constant magnetic field, if the central charge is restricted to Z below or equal 86

The Escape Problem for Irreversible Systems

The problem of noise-induced escape from a metastable state arises in physics, chemistry, biology, systems engineering, and other areas. The problem is well understood when the underlying dynamics of the system obey detailed balance. When this assumption fails many of the results of classical transition-rate theory no longer apply, and no general method exists for computing the weak-noise asymptotics of fundamental quantities such as the mean escape time. In this paper we present a general technique for analysing the weak-noise limit of a wide range of stochastically perturbed continuous-time nonlinear dynamical systems. We simplify the original problem, which involves solving a partial differential equation, into one in which only ordinary differential equations need be solved. This allows us to resolve some old issues for the case when detailed balance holds. When it does not hold, we show how the formula for the mean escape time asymptotics depends on the dynamics of the system along the most probable escape path. We also present new results on short-time behavior and discuss the possibility of focusing along the escape path.Comment: 24 pages, APS revtex macros (version 2.1) now available from PBB via `get oldrevtex.sty

Net neutrality discourses: comparing advocacy and regulatory arguments in the United States and the United Kingdom

Telecommunications policy issues rarely make news, much less mobilize thousands of people. Yet this has been occurring in the United States around efforts to introduce "Net neutrality" regulation. A similar grassroots mobilization has not developed in the United Kingdom or elsewhere in Europe. We develop a comparative analysis of U.S. and UK Net neutrality debates with an eye toward identifying the arguments for and against regulation, how those arguments differ between the countries, and what the implications of those differences are for the Internet. Drawing on mass media, advocacy, and regulatory discourses, we find that local regulatory precedents as well as cultural factors contribute to both agenda setting and framing of Net neutrality. The differences between national discourses provide a way to understand both the structural differences between regulatory cultures and the substantive differences between policy interpretations, both of which must be reconciled for the Internet to continue to thrive as a global medium