Tp53-dependent repression of cell cycle target genes: Global and mechanistic analysis

Most studies of p53 function have focused on genes transactivated by p53. It is less widely appreciated that p53 can repress target genes to affect a particular cellular response. There is evidence that repression is important for p53-induced apoptosis and cell cycle arrest. It is less clear if repression is important for other p53 functions. A comprehensive knowledge of the genes repressed by p53 and the cellular processes they affect is currently lacking. We used an expression profiling strategy to identify p53-responsive genes following adenoviral p53 gene transfer (Ad-p53) in PC3 prostate cancer cells. A total of 111 genes represented on the Affymetrix U133A microarray were repressed more than two fold (p ≤ 0.05) by p53. An objective assessment of array data quality was carried out using RT-PCR of 20 randomly selected genes. We estimate a confirmation rate of >95.5% for the complete data set. Functional over-representation analysis was used to identify cellular processes potentially affected by p53-mediated repression. Cell cycle regulatory genes exhibited significant enrichment (p ≤ 5E-28) within the repressed targets. Several of these genes are repressed in a p53-dependent manner following DNA damage, but preceding cell cycle arrest. These findings identify novel p53-repressed targets and indicate that p53-induced cell cycle arrest is a function of not only the transactivation of cell cycle inhibitors (e.g., p21), but also the repression of targets that act at each phase of the cell cycle. The mechanism of repression of this set of p53 targets was investigated. Most of the repressed genes identified here do not harbor consensus p53 DNA binding sites but do contain binding sites for E2F transcription factors. We demonstrate a role for E2F/RB repressor complexes in our system. Importantly, p53 is found at the promoter of CDC25A. CDC25A protein is rapidly degraded in response to DNA damage. Our group has demonstrated for the first time that CDC25A is also repressed at the transcript level by p53. This work has important implications for understanding the DNA damage cell cycle checkpoint response and the link between E2F/RB complexes and p53 in the repression of target genes. ^

A global perspective on intimate partner violence during pregnancy: An analysis of twelve developing countries

Violence against women has been recognized as a significant worldwide human rights issue and public health problem. Women of reproductive age may be particularly at risk, and pregnancy may trigger or escalate violence. Using data available from Demographic and Health Surveys on 271,103 women of reproductive age (15-49) from Bolivia, Cameroon, Colombia, Dominican Republic, Egypt, Haiti, India, Kenya, Nicaragua, Peru, South Africa, and Zambia, this study examined the nature of domestic violence during pregnancy in developing countries, including prevalence, demographic and risk factors, maternal and child health outcomes, perpetrators of violence, help-seeking behavior, and social support. In the majority of countries analyzed, violence during pregnancy consistently occurred at approximately one-third the rate at which domestic violence occurred overall. Younger women and women with more children were particularly at risk. Abuse during pregnancy was significantly associated with history of a terminated pregnancy and under-5 child mortality in most countries, and with neonatal and post-neonatal mortality in most Latin American countries. Women who were abused during pregnancy were most often abused by their current or former husband or boyfriend and most never attempted to seek help. In most countries that examined social support, women abused during pregnancy had significantly less contact with family and friends. Implications for practice and research are discussed. ^

Chemical analysis with regard to global and local climatic forcing measured on sediment core GeoB3711-1, GeoB3711-3 and GeoB4917-8

Global and local climatic forcing, e.g. concentration of atmospheric CO2 or insolation, influence the distribution of C3 and C4 plants in southwest Africa. C4 plants dominate in more arid and warmer areas and are favoured by lower pCO2 levels. Several studies have assessed past and present continental vegetation by the analysis of terrestrial n-alkanes in near-coastal deep sea sediments using single samples or a small number of samples from a given climatic stage. The objectives of this study were to evaluate vegetation changes in southwest Africa with regard to climatic changes during the Late Pleistocene and the Holocene and to elucidate the potential of single sample simplifications. We analysed two sediment cores at high resolution, altogether ca. 240 samples, from the Southeast Atlantic Ocean (20°S and 12°S) covering the time spans of 18 to 1 ka and 56 to 2 ka, respectively. Our results for 20°S showed marginally decreasing C4 plant domination (of ca. 5%) during deglaciation based on average chain length (ACL27-33 values) and carbon isotopic composition of the C31 and C33 n-alkanes. Values for single samples from 18 ka and the Holocene overlap and, thus, are not significantly representative of the climatic stages they derive from. In contrast, at 12°S the n-alkane parameters show a clear difference of plant type for the Late Pleistocene (C4 plant domination, 66% C4 on average) and the Holocene (C3 plant domination, 40% C4 on average). During deglaciation vegetation change highly correlates with the increase in pCO2 (r² = 0.91). Short-term climatic events such as Heinrich Stadials or Antarctic warming periods are not reflected by vegetation changes in the catchment area. Instead, smaller vegetation fluctuations during the Late Pleistocene occur in accordance with local variations of insolation.

A global seasonal surface ocean climatology of phytoplankton types based on CHEMTAX analysis of HPLC pigments

Much advancement has been made in recent years in field data assimilation, remote sensing and ecosystem modeling, yet our global view of phytoplankton biogeography beyond chlorophyll biomass is still a cursory taxonomic picture with vast areas of the open ocean requiring field validations. High performance liquid chromatography (HPLC) pigment data combined with inverse methods offer an advantage over many other phytoplankton quantification measures by way of providing an immediate perspective of the whole phytoplankton community in a sample as a function of chlorophyll biomass. Historically, such chemotaxonomic analysis has been conducted mainly at local spatial and temporal scales in the ocean. Here, we apply a widely tested inverse approach, CHEMTAX, to a global climatology of pigment observations from HPLC. This study marks the first systematic and objective global application of CHEMTAX, yielding a seasonal climatology comprised of ~1500 1°x1° global grid points of the major phytoplankton pigment types in the ocean characterizing cyanobacteria, haptophytes, chlorophytes, cryptophytes, dinoflagellates, and diatoms, with results validated against prior regional studies where possible. Key findings from this new global view of specific phytoplankton abundances from pigments are a) the large global proportion of marine haptophytes (comprising 32 ± 5% of total chlorophyll), whose biogeochemical functional roles are relatively unknown, and b) the contrasting spatial scales of complexity in global community structure that can be explained in part by regional oceanographic conditions. These publicly accessible results will guide future parameterizations of marine ecosystem models exploring the link between phytoplankton community structure and marine biogeochemical cycles.

Analysis of an ancient global warming event, the Paleocene-Eocene thermal maximum, under examination from ODP Holes 113-689B and 113-690B

Spatiotemporal patterns of carbonate dissolution provide a critical constraint on carbon input during an ancient (~55.5 Ma) global warming event known as the Paleocene-Eocene thermal maximum (PETM), yet the magnitude of lysocline shoaling in the Southern Ocean is poorly constrained due to limited spatial coverage in the circum-Antarctic region. This shortcoming is partially addressed by comparing patterns of carbonate sedimentation at the Site 690 PETM reference section to those herein reconstructed for nearby Site 689. Biochemostratigraphic correlation of the two records reveals that the first ~36 ka of the carbon isotope excursion (CIE) signaling PETM conditions is captured by the Site 689 section, while the remainder of the CIE interval and nearly all of the CIE recovery are missing due to a coring gap. A relatively expanded stratigraphy and higher carbonate content at mid-bathyal Site 689 indicate that dissolution was less severe than at Site 690. Thus, the bathymetric transect delimited by these two PETM records indicates that the lysocline shoaled above Site 689 (~1,100 m) while the calcite compensation depth remained below Site 690 (~1,900 m) in the Weddell Sea region. The ensuing recovery of carbonate sedimentation conforms to a bathymetric trend best explained by gradual lysocline deepening as negative feedback mechanisms neutralized ocean acidification. Further, biochemostratigraphic evidence indicates the tail end of the CIE recovery interval at both sites has been truncated by a hiatus most likely related to vigorous production and advection of intermediate waters.

Analysis of the upcoming Modernisation of the Trade Pillar of the European Union-Mexico Global Agreement

Study for the EU Parliament co-authored by Rodrigo Polanco: The 1997 Global Agreement between the EC and its Member States and Mexico, together with the set of decisions taken in its framework, has been effective, and thus modifications of the agreement are mainly motivated by changes in the global landscape since it was first enacted. Therefore, broad considerations on how the European Union (EU) trade policy is shaped are extremely relevant for the upcoming negotiations with Mexico. In this context, the needs and expectations, both from the EU and Mexico, regarding any further agreements are examined, focusing in particular on areas beyond trade in goods and services such as procurement, investment, and regulatory cooperation. It is argued that the 'old' Association Agreements should be taken as models for any modifications, given their emphasis on EU-specific issues and their ability to accommodate the needs of Mexico in any deepened agreement.

Empirical global value chain analysis in electronics and automobile industries :An application of Asian international input-output tables

This study aims to examine the international value distribution structure among major East Asian economies and the US. The mainstream trade theory explains the gains from trade; however, global value chain (GVC) approach emphasises uneven benefits of globalization among trading partners. The present study is mainly based on this view, examining which economy gains the most and which the least from the East Asian production networks. Two key industries, i.e., electronics and automobile, are our principle focus. Input-output method is employed to trace the creation and flows of value-added within the region. A striking fact is that some ASEAN economies increasingly reduce their shares of value-added, taken by developed countries, particularly by Japan. Policy implications are discussed in the final section.

Compilation of a regionally-extended inter-country input-output table and its application to global value chain analysis

Studies on the rise of global value chains (GVCs) have attracted a great deal of interest in the recent economics literature. However, due to statistical and methodological challenges, most existing research ignores domestic regional heterogeneity in assessing the impact of joining GVCs. GVCs are supported not only directly by domestic regions that export goods and services to the world market, but also indirectly by other domestic regions that provide parts, components, and intermediate services to final exporting regions. To better understand the nature of a country's position and degree of participation in GVCs, we need to fully examine the role of individual domestic regions. Understanding the domestic components of GVCs is especially important for larger economies such as China, the US, India and Japan, where there may be large variations in economic scale, geography of manufacturing, and development stages at the domestic regional level. This paper proposes a new framework for measuring domestic linkages to global value chains. This framework measures domestic linkages by endogenously embedding a target country's (e.g. China and Japan) domestic interregional input–output tables into the OECD inter-country input–output model. Using this framework, we can more clearly understand how global production is fragmented and extended internationally and domestically.

Effect of Aspect Ratio on the Three-Dimensional Global Instability Analysis of Incompressible Open Cavity Flows

The stability analysis of open cavity flows is a problem of great interest in the aeronautical industry. This type of flow can appear, for example, in landing gears or auxiliary power unit configurations. Open cavity flows is very sensitive to any change in the configuration, either physical (incoming boundary layer, Reynolds or Mach numbers) or geometrical (length to depth and length to width ratio). In this work, we have focused on the effect of geometry and of the Reynolds number on the stability properties of a threedimensional spanwise periodic cavity flow in the incompressible limit. To that end, BiGlobal analysis is used to investigate the instabilities in this configuration. The basic flow is obtained by the numerical integration of the Navier-Stokes equations with laminar boundary layers imposed upstream. The 3D perturbation, assumed to be periodic in the spanwise direction, is obtained as the solution of the global eigenvalue problem. A parametric study has been performed, analyzing the stability of the flow under variation of the Reynolds number, the L/D ratio of the cavity, and the spanwise wavenumber β. For consistency, multidomain high order numerical schemes have been used in all the computations, either basic flow or eigenvalue problems. The results allow to define the neutral curves in the range of L/D = 1 to L/D = 3. A scaling relating the frequency of the eigenmodes and the length to depth ratio is provided, based on the analysis results.

First steps in the discovery of patterns in the academic results of telecommunication engineering students in the subjects Analysis of Circuits and Mathematics

In this paper, the results of six years of research in engineering education, in the application of the European Higher Education Area (EHEA) to improve the performance of the students in the subject Analysis of Circuits of Telecommunication Engineering, are analysed taking into consideration the fact that there would be hidden variables that both separate students into subgroups and show the connection among several basic subjects such as Analysis of Circuits (AC) and Mathematics (Math). The discovery of these variables would help us to explain the characteristics of the students through the teaching and learning methodology, and would show that there are some characteristics that instructors do not take into account but that are of paramount importance

Global flow analysis as a practical compilation tool

This paper addresses the issue of the practicality of global flow analysis in logic program compilation, in terms of speed of the analysis, precisión, and usefulness of the information obtained. To this end, design and implementation aspects are discussed for two practical abstract interpretation-based flow analysis systems: MA , the MCC And-parallel Analyzer and Annotator; and Ms, an experimental mode inference system developed for SB-Prolog. The paper also provides performance data obtained (rom these implementations and, as an example of an application, a study of the usefulness of the mode information obtained in reducing run-time checks in independent and-parallelism.Based on the results obtained, it is concluded that the overhead of global flow analysis is not prohibitive, while the results of analysis can be quite precise and useful.

On the practicality of global flow analysis of logic programs

This paper addresses the issue of the practicality of global flow analysis in logic program compilation, in terms of both speed and precision of analysis. It discusses design and implementation aspects of two practical abstract interpretation-based flow analysis systems: MA3, the MOO Andparallel Analyzer and Annotator; and Ms, an experimental mode inference system developed for SB-Prolog. The paper also provides performance data obtained from these implementations. Based on these results, it is concluded that the overhead of global flow analysis is not prohibitive, while the results of analysis can be quite precise and useful.

Efficient numerical methods for global linear instability. Analysis and modeling of non-orthogonal swept attachment-line boundary layer flow

The aim of this thesis is to study the mechanisms of instability that occur in swept wings when the angle of attack increases. For this, a simplified model for the a simplified model for the non-orthogonal swept leading edge boundary layer has been used as well as different numerical techniques in order to solve the linear stability problem that describes the behavior of perturbations superposed upon this base flow. Two different approaches, matrix-free and matrix forming methods, have been validated using direct numerical simulations with spectral resolution. In this way, flow instability in the non-orthogonal swept attachment-line boundary layer is addressed in a linear analysis framework via the solution of the pertinent global (Bi-Global) PDE-based eigenvalue problem. Subsequently, a simple extension of the extended G¨ortler-H¨ammerlin ODEbased polynomial model proposed by Theofilis, Fedorov, Obrist & Dallmann (2003) for orthogonal flow, which includes previous models as particular cases and recovers global instability analysis results, is presented for non-orthogonal flow. Direct numerical simulations have been used to verify the stability results and unravel the limits of validity of the basic flow model analyzed. The effect of the angle of attack, AoA, on the critical conditions of the non-orthogonal problem has been documented; an increase of the angle of attack, from AoA = 0 (orthogonal flow) up to values close to _/2 which make the assumptions under which the basic flow is derived questionable, is found to systematically destabilize the flow. The critical conditions of non-orthogonal flows at 0 _ AoA _ _/2 are shown to be recoverable from those of orthogonal flow, via a simple analytical transformation involving AoA. These results can help to understand the mechanisms of destabilization that occurs in the attachment line of wings at finite angles of attack. Studies taking into account variations of the pressure field in the basic flow or the extension to compressible flows are issues that remain open. El objetivo de esta tesis es estudiar los mecanismos de la inestabilidad que se producen en ciertos dispositivos aerodinámicos cuando se aumenta el ángulo de ataque. Para ello se ha utilizado un modelo simplificado del flujo de base, así como diferentes técnicas numéricas, con el fin de resolver el problema de estabilidad lineal asociado que describe el comportamiento de las perturbaciones. Estos métodos; sin y con formación de matriz, se han validado utilizando simulaciones numéricas directas con resolución espectral. De esta manera, la inestabilidad del flujo de capa límite laminar oblicuo entorno a la línea de estancamiento se aborda en un marco de análisis lineal por medio del método Bi-Global de resolución del problema de valores propios en derivadas parciales. Posteriormente se propone una extensión simple para el flujo no-ortogonal del modelo polinomial de ecuaciones diferenciales ordinarias, G¨ortler-H¨ammerlin extendido, propuesto por Theofilis et al. (2003) para el flujo ortogonal, que incluye los modelos previos como casos particulares y recupera los resultados del analisis global de estabilidad lineal. Se han realizado simulaciones directas con el fin de verificar los resultados del análisis de estabilidad así como para investigar los límites de validez del modelo de flujo base utilizado. En este trabajo se ha documentado el efecto del ángulo de ataque AoA en las condiciones críticas del problema no ortogonal obteniendo que el incremento del ángulo de ataque, de AoA = 0 (flujo ortogonal) hasta valores próximos a _/2, en el cual las hipótesis sobre las que se basa el flujo base dejan de ser válidas, tiende sistemáticamente a desestabilizar el flujo. Las condiciones críticas del caso no ortogonal 0 _ AoA _ _/2 pueden recuperarse a partir del caso ortogonal mediante el uso de una transformación analítica simple que implica el ángulo de ataque AoA. Estos resultados pueden ayudar a comprender los mecanismos de desestabilización que se producen en el borde de ataque de las alas de los aviones a ángulos de ataque finitos. Como tareas pendientes quedaría realizar estudios que tengan en cuenta variaciones del campo de presión en el flujo base así como la extensión de éste al caso de flujos compresibles.

Order 10 4 speedup in global linear instability analysis using matrix formation

A unified solution framework is presented for one-, two- or three-dimensional complex non-symmetric eigenvalue problems, respectively governing linear modal instability of incompressible fluid flows in rectangular domains having two, one or no homogeneous spatial directions. The solution algorithm is based on subspace iteration in which the spatial discretization matrix is formed, stored and inverted serially. Results delivered by spectral collocation based on the Chebyshev-Gauss-Lobatto (CGL) points and a suite of high-order finite-difference methods comprising the previously employed for this type of work Dispersion-Relation-Preserving (DRP) and Padé finite-difference schemes, as well as the Summationby- parts (SBP) and the new high-order finite-difference scheme of order q (FD-q) have been compared from the point of view of accuracy and efficiency in standard validation cases of temporal local and BiGlobal linear instability. The FD-q method has been found to significantly outperform all other finite difference schemes in solving classic linear local, BiGlobal, and TriGlobal eigenvalue problems, as regards both memory and CPU time requirements. Results shown in the present study disprove the paradigm that spectral methods are superior to finite difference methods in terms of computational cost, at equal accuracy, FD-q spatial discretization delivering a speedup of ð (10 4). Consequently, accurate solutions of the three-dimensional (TriGlobal) eigenvalue problems may be solved on typical desktop computers with modest computational effort.

Spatial linear global instability analysis of the HIFiRE-5 elliptic cone model flow

The linear instability of the three-dimensional boundary-layer over the HIFiRE-5 flight test geometry, i.e. a rounded-tip 2:1 elliptic cone, at Mach 7, has been analyzed through spatial BiGlobal analysis, in a effort to understand transition and accurately predict local heat loads on next-generation ight vehicles. The results at an intermediate axial section of the cone, Re x = 8x10 5, show three different families of spatially amplied linear global modes, the attachment-line and cross- ow modes known from earlier analyses, and a new global mode, peaking in the vicinity of the minor axis of the cone, termed \center-line mode". We discover that a sequence of symmetric and anti-symmetric centerline modes exist and, for the basic ow at hand, are maximally amplied around F* = 130kHz. The wavenumbers and spatial distribution of amplitude functions of the centerline modes are documented