Regulation of chromatin structure, Smad binding and AFP expression by the Forkhead box transcription factor: Foxa1

Transcription factors must be able to access their DNA binding sites to either activate or repress transcription. However, DNA wrapping and compaction into chromatin occludes most binding sites from ready access by proteins. Pioneer transcription factors are capable of binding their DNA elements within a condensed chromatin context and then reducing the level of nucleosome occupancy so that the chromatin structure is more accessible. This altered accessibility increases the probability of other transcription factors binding to their own DNA binding elements. My hypothesis is that Foxa1, a ‘pioneer’ transcription factor, activates alpha-fetoprotein (AFP) expression by binding DNA in a chromatinized environment, reducing the nucleosome occupancy and facilitating binding of additional transcription factors.^ Using retinoic-acid differentiated mouse embryonic stem cells, we illustrate a mechanism for activation of the tumor marker AFP by the pioneer transcription factor Foxa1 and TGF-β downstream effector transcription factors Smad2 and Smad4. In differentiating embryonic stem cells, binding of the Foxa1 forkhead box transcription factor to chromatin reduces nucleosome occupancy and levels of linker histone H1 at the AFP distal promoter. The more accessible DNA is subsequently bound by the Smad2 and Smad4 transcription factors, concurrent with activation of transcription. Chromatin immunoprecipitation analyses combined with siRNA-mediated knockdown indicate that Smad protein binding and the reduction of nucleosome occupancy at the AFP distal promoter is dependent on Foxa1. In addition to facilitating transcription factor binding, Foxa1 is also associated with histone modifications related to active gene expression. Acetylation of lysine 9 on histone H3, a mark that is associated active transcription, is dependent on Foxa1, while methylation of H3K4, also associated with active transcription, is independent of Foxa1. I propose that Foxa1 potentiates a region of chromatin to respond to Smad proteins, leading to active expression of AFP.^ These studies demonstrate one mechanism whereby a transcription factor can alter the accessibility of additional transcription factors to chromatin, by altering nucleosome positions. Specifically, Foxa1 exposes DNA so that Smad4 can bind to its regulatory element and activate transcription of the tumor-marker gene AFP.^

Understanding treatment-related symptoms, symptom management techniques, and symptom management self-efficacy in a sample of non-muscle invasive bladder cancer patients

The current literature available on bladder cancer symptom management from the perspective of the patients themselves is limited. There is also limited psychosocial research specific to bladder cancer patients and no previous studies have developed and validated measures for bladder cancer patients’ symptom management self-efficacy. The purpose of this study was to investigate non-muscle invasive bladder cancer patients’ health related quality of life through two main study objectives: (1) to describe the treatment related symptoms, reported effectiveness of symptom-management techniques, and the advice a sample of non-muscle invasive bladder cancer patients would convey to physicians and future patients; and (2) to evaluate Lepore’s symptom management self-efficacy measure on a sample of non-muscle invasive bladder cancer patients. Methods. A total of twelve (n=12) non-muscle invasive bladder cancer patients participated in an in-depth interview and a sample of 46 (n=4) non-muscle invasive bladder cancer patients participated in the symptom-management self-efficacy survey. Results. A total of five symptom categories emerged for the participants’ 59 reported symptoms. Four symptom management categories emerged out of the 71 reported techniques. A total of 62% of the participants’ treatment related symptom-management techniques were reported as effective in managing their treatment-related symptoms. Five advice categories emerged out of the in-depth interviews: service delivery; medical advice; physician-patient communication; encouragement; and no advice. An exploratory factor analysis indicated a single-factor structure for the total population and a multiple factor structure for three subgroups: all males, married males, and all married participants. Conclusion. These findings can inform physicians and patients of effective symptom-management techniques thus improving patients’ health-related quality of life. The advice these patients’ impart can improve service-delivery and patient education.^

Structure-function analysis of human Integrator subunit-4

Structure-function analysis of human Integrator subunit 4 Anupama Sataluri Advisor: Eric. J. Wagner, Ph.D. Uridine-rich small nuclear RNAs (U snRNA) are RNA Polymerase-II (RNAPII) transcripts that are ubiquitously expressed and are known to be essential for gene expression. snRNAs play a key role in mRNA splicing and in histone mRNA expression. Inaccurate snRNA biosynthesis can lead to diseases related to defective splicing and histone mRNA expression. Although the 3′ end formation mechanism and processing machinery of other RNAPII transcripts such as mRNA has been well studied, the mechanism of snRNA 3′ end processing has remained a mystery until the recent discovery of the machinery that mediates this process. In 2005, a complex of 14 subunits (the Integrator complex) associated with RNA Polymerase-II was discovered. The 14subunits were annotated Integrator 1-14 based on their size. The subunits of this complex together were found to facilitate 3′ end processing of snRNA. Identification of the Integrator complex propelled research in the direction of understanding the events of snRNA 3’end processing. Recent studies from our lab confirmed that Integrator subunit (IntS) 9 and 11 together perform the endonucleolytic cleavage of the nascent snRNA 3′ end to generate mature snRNA. However, the role of other members of the Integrator complex remains elusive. Current research in our lab is focused on deciphering the role of each subunit within the Integrator complex This work specifically focuses on elucidating the role of human Integrator subunit 4 (IntS4) and understanding how it facilitates the overall function of the complex. IntS4 has structural similarity with a protein called “Symplekin”, which is part of the mRNA 3’end processing machinery. Symplekin has been thoroughly researched in recent years and structure-function correlation studies in the context of mRNA 3’end processing have reported a scaffold function for Symplekin due to the presence of HEAT repeat motifs in its N-terminus. Based upon the structural similarity between IntS4 and Symplekin, we hypothesized that Integrator subunit 4 may be behaving as a Symplekin-like scaffold molecule that facilitates the interaction between other members of the Integrator Complex. To answer this question, the two important goals of this study were to: 1) identify the region of IntS4, which is important for snRNA 3′ end processing and 2) determine binding partners of IntS4 which promote its function as a scaffold. IntS4 structurally consists of a highly conserved N-terminus with 8 HEAT repeats, followed by a nonconserved C- terminus. A series of siRNA resistant N and C-terminus deletion constructs as well as specific point mutants within its N-terminal HEAT repeats were generated for human IntS4 and, utilizing a snRNA transcriptional readthrough GFP-reporter assay, we tested their ability to rescue misprocessing. This assay revealed a possible scaffold like property of IntS4. To probe IntS4 for interaction partners, we performed co-immunoprecipitation on nuclear extracts of IntS4 expressing stable cell lines and identified IntS3 and IntS5 among other Integrator subunits to be binding partners which facilitate the scaffold like function of hIntS4. These findings have established a critical role for IntS4 in snRNA 3′ end processing, identified that both its N and C termini are essential for its function, and mapped putative interaction domains with other Integrator subunits.

Heregulin -beta 1 directly associates with RhoA via the immunoglobulin -like domain thereby modulating breast cancer metastasis-related properties

Heregulins constitute a family of growth factors belonging to the epidermal growth factor (EGF) family. Breast cancers that overexpress specific members of the EGF receptor family (EGFR, ErbB2, ErbB3, ErbB4) have increased metastatic potential, and Heregulin-β1 (HRGβ1), a ligand for ErbB3 and ErbB4, has also been shown to induce metastasis-related properties in breast cancer cells in vitro. The secreted form of the HRGβ1 is composed of five distinct structural domains, including the N-terminal domain, an immunoglobulin-like domain (IgG-like), a glycosylation domain, an EGF-like domain, and a β1-specific domain. Of these, the EGF-like domain is well characterized for its function in metastasis-related properties as well as its structure. However, the contributions of the other HRGβ1 domains in breast cancer metastasis remains unclear. ^ To investigate this, HRGβ1 proteins with targeted domain deletions were purified and subjected to assays for metastasis-related properties, including aggregation, invasion, activation of EGFR family members, and motility of breast cancer cells. These assays showed that retaining the EGF-like domain of HRGβ1 is important for activation of EGFRs. Interestingly, the HRGβ1 protein lacking the IgG-like domain (NGEB) led to a decrease in breast cancer cell motility, indicating the IgG-like domain modulates cell motility, an important step in cancer metastasis. ^ To understand the underlying mechanisms, I performed protein sequence and structural analysis of HRGβ1 and identified that the IgG-like domain of HRGβ1 shares sequence homology and three-dimensional structural similarity with the IgG-like domain of TRIO. TRIO is a cytoplasmic protein that directly associates with RhoA, a GTPase involved in cell reorganization and cell motility. Therefore, I hypothesized that HRGβ1 may translocate inside the breast cancer cells through receptor mediated endocytosis and bind to RhoA via its IgG-like domain. I show wild type HRGβ1 but not NGEB binds RhoA in vitro and in vivo, leading to RhoA activation. Inhibition of HRG-β1 internalization via endocytosis disrupted HRGβ1 binding to RhoA. Additionally, breast cancer cell motility induced by HRG-β1 is reduced after treatment with inhibitors to both endocytosis and RhoA function, similar to levels seen with NGEB treatment. ^ Thus, in addition to the well-known role of HRGβ1 as an extracellular stimulator of the EGFR family members, HRGβ1 also functions within the cell as a binding partner and activator of RhoA to modulate cancer cell motility. ^

Elevated CO2 levels do not affect the shell structure of the bivalve Arctica islandica from the western Baltic

Shells of the bivalve Arctica islandica are used to reconstruct paleo-environmental conditions (e.g. temperature) via biogeochemical proxies, i.e. biogenic components that are related closely to environmental parameters at the time of shell formation. Several studies have shown that proxies like element and isotope-ratios can be affected by shell growth and microstructure. Thus it is essential to evaluate the impact of changing environmental parameters such as high pCO2 and consequent changes in carbonate chemistry on shell properties to validate these biogeochemical proxies for a wider range of environmental conditions. Growth experiments with Arctica islandica from the Western Baltic Sea kept under different pCO2 levels (from 380 to 1120 µatm) indicate no affect of elevated pCO2 on shell growth or crystal microstructure, indicating that A. islandica shows an adaptation to a wider range of pCO2 levels than reported for other species. Accordingly, proxy information derived from A. islandica shells of this region contains no pCO2 related bias.

Changes in the foreign trade structure of the Russian Far East under the process of transition toward a market economy

Under the process of transition toward a market economy, the economic connections of the Russian Far East (RFE) with external regions changed from a division of labor among the regions of the USSR (Russia) to an international division of labor. This happened due to factors including the liberalization of the trade system away from a state monopoly, the presence of rich natural resources and of developed industries related to these resources, the advantage of geographically proximity to Asia-Pacific countries, and the political and economic division of the once unified national economic space during the process of transition. The economic connections of RFE with external economies changed radically under the transition toward the market economy. First, the value of foreign trade increased dramatically and the importance of foreign trade for the RFE economy increased enormously. Second, however, different territories of RFE traveled along different trajectories, due to factors involving their industrial structure and geographical conditions. Third, in recent years connections with China, in the areas of both exports and imports, have grown. Fourth, the share within exports of "fuel, mineral resources and metal" increased radically from the end of the 1990s, and the share of "machine, facilities and transportation means" increased from 2002 year within imports. Under this situation, especially since 2002, there has been a major change in the structure of foreign trade.

Related Lending and Bank Performance: Evidence from Indonesia

After the Asian financial crisis of 1997, it was confirmed that banks lend to their related parties in many countries. The question examined in this article is whether related lending functions to alleviate the problems of asymmetric information or transfers profits from depositors and minority shareholders to related parties. The effects of related lending on the profitability and risk of banks in Indonesia are examined using panel data from 1994 to 2007 comprising a total of 74 Indonesian banks. The effects on return on asset (ROA) varied at different periods. Before and right after the crisis, a higher credit allocation to related parties increased ROA. In middle of the crisis, it turned to negative; and this has also been the case in the most recent period as the Indonesian economy has normalized. Effects of related lending on bank risk measured by the Z-score and non-performing loan is not clear. After undergoing bank restructuring, related lending has decreased and the profit structure of banks has changed.

Impact of product-related environmental regulations in Asia : descriptive statistics from a survey of firms in Penang, Malaysia

This paper summarizes the main results of a unique firm survey conducted in Penang, Malaysia in 2012 on product-related environmental regulations. The results show that firms receiving foreign-direct investment have adapted well to regulations but faced more rejections. Several research questions are addressed and examined by using the survey data. Major findings are as follows. First, adaptation involves changes in input procurement and market diversification, which potentially changes the structure of supply chains. Second, belonging to global supply chains is a key factor in compliance, but this requires firms to meet tougher customer requirements. Third, there is much room for government policy to play a role in assisting firms.

Impact of product-related environmental regulations in Asia : descriptive statistics from a survey of firms in Vietnam

This paper summarizes the main results of a unique firm survey conducted in Vietnam in 2011 on product-related environmental regulations (PRERs). The results of this survey are compared with the results of a corresponding survey of firms in Penang, Malaysia (Michida, et al. 2014b). The major findings are as follows. First, adaptation to PRERs involves changes in input procurement and results in market diversification, which potentially alters the structure of supply chains. This finding is consistent with the Malaysian survey result. Second, connections to global supply chains are key to compliance, but this requires firms to meet more stringent customer requirements. Third, government policy can play an important role in assisting firms to comply with PRERs.

Competition may explain the fine-scale spatial patterns and genetic structure of two co-occurring plant congeners

1. The spatial distribution of individual plants within a population and the population’s genetic structure are determined by several factors, like dispersal, reproduction mode or biotic interactions. The role of interspecific interactions in shaping the spatial genetic structure of plant populations remains largely unknown. 2. Species with a common evolutionary history are known to interact more closely with each other than unrelated species due to the greater number of traits they share. We hypothesize that plant interactions may shape the fine genetic structure of closely related congeners. 3. We used spatial statistics (georeferenced design) and molecular techniques (ISSR markers) to understand how two closely related congeners, Thymus vulgaris (widespread species) and T. loscosii (narrow endemic) interact at the local scale. Specific cover, number of individuals of both study species and several community attributes were measured in a 10 × 10 m plot. 4. Both species showed similar levels of genetic variation, but differed in their spatial genetic structure. Thymus vulgaris showed spatial aggregation but no spatial genetic structure, while T. loscosii showed spatial genetic structure (positive genetic autocorrelation) at short distances. The spatial pattern of T. vulgaris’ cover showed significant dissociation with that of T. loscosii. The same was true between the spatial patterns of the cover of T. vulgaris and the abundance of T. loscosii and between the abundance of each species. Most importantly, we found a correlation between the genetic structure of T. loscosii and the abundance of T. vulgaris: T. loscosii plants were genetically more similar when they were surrounded by a similar number of T. vulgaris plants. 5. Synthesis. Our results reveal spatially complex genetic structures of both congeners at small spatial scales. The negative association among the spatial patterns of the two species and the genetic structure found for T. loscosii in relation to the abundance of T. vulgaris indicate that competition between the two species may account for the presence of adapted ecotypes of T. loscosii to the abundance of a competing congeneric species. This suggests that the presence and abundance of close congeners can influence the genetic spatial structure of plant species at fine scales.

Governance Structure Choices in Supply Chain Management Evidence from Spanish and Chinese Pork Chain Cases

The author participated in the 6 th EU Framework Project ―Q-pork Chains (FP6-036245-2)‖ from 2007 to 2009. With understanding of work reports from China and other countries, it is found that compared with other countries, China has great problems in pork quality and safety. By comparing the pork chain management between China and Spain, It is found that the difference in governance structure is one of the main differences in pork chain management between Spain and China. In China, spot-market relationship still dominates governance structure of pork chain, especially between the numerous house-hold pig holders and the great number of small slaughters. While in Spain, chain agents commonly apply cooperatives or integrations to cooperate. It also has been proven by recent studies, that in quality management at the chain level that supply chain integration has a direct effect on quality management practices (Han, 2010). Therefore, the author started to investigate the governance structure choices in supply chain management. And it has been set as the first research objective, which is to explain the governance structure choices process and the influencing factors in supply chain management, analyzing the pork chains cases in Spain and in China. During the further investigation, the author noticed the international trade of pork between Spain and China is not smooth since the signature of bi-lateral agreement on pork trade in 2007. Thus, another objective of the research is to find and solve the problems exist in the international pork chain between Spain and China. For the first objective, to explain the governance structure choices in supply chain management, the thesis conducts research in three main sections. 10 First of all, the thesis gives a literature overview in chapter two on Supply Chain Management (SCM), agri-food chain management and pork chain management. It concludes that SCM is a systems approach to view the supply chains as a whole, and to manage the total flow of goods inventory from the supplier to the ultimate customer. It includes the bi-directional flow of products (materials and services) and information, and the associated managerial and operational activities. And it also is a customer focus to create unique and individual source of customer value with an appropriate use of resources, leading to customer satisfaction and building competitive chain advantages. Agri-food chain management and pork chain management are applications of SCM in agri-food sector and pork sector respectively. Then, the research gives a comparative study in chapter three in the pork chain and pork chain management between Spain and China. Many differences are found, while the main difference is governance structure in pork chain management. Furthermore, the author gives an empirical study on governance structure choice in chapter five. It is concluded that governance structure of supply chain consists of a collection of rules/institutions/constraints structuring the transactions between the various stakeholders. Based on the overview on literatures closely related with governance structure, such as transaction cost economics, transaction value analysis and resource-based view theories, seven hypotheses are proposed, which are: Hypothesis 1: Transaction cost has positive relationship with governance structure choice Hypothesis 2: Uncertainty has positive relationship with transaction cost; higher uncertainty exerts high transaction cost Hypothesis 3: The relationship between asset specificity and transaction cost is positive Hypothesis 4: Collaboration advantages and governance structure choice have positive relationship11 Hypothesis 5: Willingness to collaborate has positive relationship with collaboration advantages Hypothesis 6: Capability to collaborate has positive relationship with collaboration advantages Hypothesis 7: Uncertainty has negative effect on collaboration advantages It is noted that as transaction cost value is negative, the transaction cost mentioned in the hypotheses is its absolute value. To test the seven hypotheses, Structural Equation Model (SEM) is applied and data collected from 350 pork slaughtering and processing companies in Jiangsu, Shandong and Henan Provinces in China is used. Based on the empirical SEM model and its results, the seven hypotheses are proved. The author generates several conclusions accordingly. It is found that the governance structure choice of the chain not only depends on transaction cost, it also depends on collaboration advantages. Exchange partners establish more stable and more intense relationship to reduce transaction cost and to maximize collaboration advantages. ―Collaboration advantages‖ in this thesis is defined as the joint value achieved through transaction (mutual activities) of agents in supply chains. This value forms as improvements, mainly in mutual logistics systems, cash response, information exchange, technological improvements and innovative improvements and quality management improvements, etc. Governance structure choice is jointly decided by transaction cost and collaboration advantages. Chain agents take different governance structures to coordinate in order to decrease their transaction cost and to increase their collaboration advantages. In China´s pork chain case, spot market relationship dominates the governance structure among the numerous backyard pig farmer and small family slaughterhouse 12 as they are connected by acquaintance relationship and the transaction cost in turn is low. Their relationship is reliable as they know each other in the neighborhood; as a result, spot market relationship is suitable for their exchange. However, the transaction between large-scale slaughtering and processing industries and small-scale pig producers is becoming difficult. The information hold back behavior and hold-up behavior of small-scale pig producers increase transaction cost between them and large-scale slaughtering and processing industries. Thus, through the more intense and stable relationship between processing industries and pig producers, processing industries reduce the transaction cost and improve the collaboration advantages with their chain partners, in which quality and safety collaboration advantages be increased, meaning that processing industries are able to provide consumers products with better quality and higher safety. It is also drawn that transaction cost is influenced mainly by uncertainty and asset specificity, which is in line with new institutional economics theories developed by Williamson O. E. In China´s pork chain case, behavioral uncertainty is created by the hold-up behaviors of great numbers of small pig producers, while big slaughtering and processing industries having strong asset specificity. On the other hand, ―collaboration advantages‖ is influenced by chain agents´ willingness to collaborate and chain agents´ capabilities to cooperate. With the fast growth of big scale slaughtering and processing industries, they are more willing to know and make effort to cooperate with their chain members, and they are more capable to create joint value together with other chain agents. Therefore, they are now the main chain agents who drive more intense and stable governance structure in China‘s pork chain. For the other objective, to find and solve the problems in the international pork chain between Spain and China, the research gives an analysis in chapter four on the 13 international pork chain. This study gives explanations why the international trade of pork between Spain and China is not sufficient from the chain perspective. It is found that the first obstacle is the high quality and safety requirement set by Chinese government. It makes the Spanish companies difficult to get authorities to export. Other aspects, such as Spanish pork is not competitive in price compared with other countries such as Denmark, United States, Canada, etc., Chinese consumers do not have sufficient information on Spanish pork products, are also important reasons that Spain does not export great quantity of pork products to China. It is concluded that China´s government has too much concern on the quality and safety requirements to Spanish pork products, which makes trade difficult to complete. The two countries need to establish a more stable and intense trade relationship. They also should make the information exchange sufficient and efficient and try to break trade barriers. Spanish companies should consider proper price strategies to win the Chinese pork market

Structure function and Multifractal spectrum applied to Digital Elevation Model

A Digital Elevation Model (DEM) provides the information basis used for many geographic applications such as topographic and geomorphologic studies, landscape through GIS (Geographic Information Systems) among others. The DEM capacity to represent Earth?s surface depends on the surface roughness and the resolution used. Each DEM pixel depends on the scale used characterized by two variables: resolution and extension of the area studied. DEMs can vary in resolution and accuracy by the production method, although there are statistical characteristics that keep constant or very similar in a wide range of scales. Based on this property, several techniques have been applied to characterize DEM through multiscale analysis directly related to fractal geometry: multifractal spectrum and the structure function. The comparison of the results by both methods is discussed. The study area is represented by a 1024 x 1024 data matrix obtained from a DEM with a resolution of 10 x 10 m each point, which correspond with a region known as ?Monte de El Pardo? a property of Spanish National Heritage (Patrimonio Nacional Español) of 15820 Ha located to a short distance from the center of Madrid. Manzanares River goes through this area from North to South. In the southern area a reservoir is found with a capacity of 43 hm3, with an altitude of 603.3 m till 632 m when it is at the highest capacity. In the middle of the reservoir the minimum altitude of this area is achieved.

Identification of logically related heap regions

This paper introduces a novel technique for identifying logically related sections of the heap such as recursive data structures, objects that are part of the same multi-component structure, and related groups of objects stored in the same collection/array. When combined withthe lifetime properties of these structures, this information can be used to drive a range of program optimizations including pool allocation, object co-location, static deallocation, and region-based garbage collection. The technique outlined in this paper also improves the efficiency of the static analysis by providing a normal form for the abstract models (speeding the convergence of the static analysis). We focus on two techniques for grouping parts of the heap. The first is a technique for precisely identifying recursive data structures in object-oriented programs based on the types declared in the program. The second technique is a novel method for grouping objects that make up the same composite structure and that allows us to partition the objects stored in a collection/array into groups based on a similarity relation. We provide a parametric component in the similarity relation in order to support specific analysis applications (such as a numeric analysis which would need to partition the objects based on numeric properties of the fields). Using the Barnes-Hut benchmark from the JOlden suite we show how these grouping methods can be used to identify various types of logical structures allowing the application of many region-based program optimizations.

Diversity and Genetic structure of the Spanish collection of durum wheat (Triticum turgidum L) landraces

The objectives of this study were to assess diversity and genetic structure of a collection of Spanish durum wheat (Triticum turgidum L) landraces, using SSRs, DArTs and gliadin-markers, and to correlate the distribution of diversity with geographic and climatic features, as well as agro-morphological traits. A high level of diversity was detected in the genotypes analyzed, which were separated into nine populations with a moderate to great genetic divergence among them. The three subspecies taxa, dicoccon, turgidum and durum, present in the collection, largely determined the clustering of the populations. Genotype variation was lower in dicoccon (one major population) and turgidum (two major populations) than in durum (five major populations). Genetic differentiation by the agro-ecological zone of origin was greater in dicoccon and turgidum than in durum. DArT markers revealed two geographic substructures, east-west for dicoccon and northeast-southwest for turgidum. The ssp. durum had a more complex structure, consisting of seven populations with high intra-population variation. DArT markers allowed the detection of subgroups within some populations, with agro-morphological and gliadin differences, and distinct agro-ecological zones of origin. Two different phylogenetic groups were detected; revealing that some durum populations were more related to ssp. turgidum from northern Spain, while others seem to be more related to durum wheats from North Africa