Langerhans cells (LCs), residing in the epidermis, are able to induce potent immunogenic responses and also to mediate immune tolerance. We propose that tolerogenic and immunogenic responses of LCs are directed by signaling from the epidermis and involve counter‐acting gene circuits that are coupled to a core maturation gene module. We base our analysis on recent genetic and genomic findings facilitating the understanding of the molecular mechanisms controlling these divergent immune functions. Comparing gene regulatory network (GRN) analyses of various (...) types of dendritic cells (DCs) including LCs we integrate signaling‐dependent (TGFβ, EpCAM, β‐Catenin) and transcription factor (IRF4, IRF1, NFκB) regulated gene circuits that appear to orchestrate the distinctive LC functional states. Our model proposes, that while epidermal signaling in the steady‐state promotes LC tolerogenic function, the disruption of cell‐cell contacts coupled with inflammatory signaling induces LC immunogenic programing. The conceptual framework emphasizes the sensing of discrete epidermal and inflammatory cues by resident LCs in dictating their genomic programing and cell state dynamics. (shrink)

This paper looks at the commodification of interferon, marketed by Hoffmann La Roche as Roferon A in 1986, as a case study that helps us understand the role of pharmaceutical industry in cancer research, the impact of molecular biology on cancer therapy, and the relationships between biotech start-ups and established pharmaceutical firms. Drawing extensively on materials from the Roche company archives, the paper traces interferon’s trajectory from observed phenomenon to product. Roche embraced molecular biology in the late 1960s (...) to prepare for the moment when the patents on some of its bestselling drugs were going to expire. The company funded two basic science institutes to gain direct access to talents and scientific leads. These investments, I argue, were crucial for Roche’s success with recombinant interferon, along with more mundane, technical and regulatory know-how held at Roche’s Nutley base. The paper analyses in some detail the development process following the initial success of cloning the interferon gene in collaboration with Genentech. It looks at the factors necessary to scale up the production sufficiently for clinical trials. Using Alfred Chandler’s concept of ‘organizational capabilities’, I argue that the process is better described as ‘mobilisation’ than as ‘translation’. (shrink)

Complementary DNA clones corresponding to most of the proteins of a major amplification and effector of immune host defenses, the complement system, have been isolated and characterized. Availability of these molecular probes has substantially increased our information about and understanding of the structure of the complement proteins and regulation of complement gene expression. Information about the proteins has led to the generation of potential pharmacological agents for the selective control of inflammation. Understanding of the regulatory mechanism has provided insights (...) into the mechanisms accounting for the response to several cytokines including interferon‐gamma, interleukin‐1 and tumor necrosis factor. Finally, complement molecular genetics has been stimulated so that the basis for several complement deficiency disorders has been elucidated. (shrink)

Metazoan genomes contain thousands of protein‐coding and non‐coding RNA genes, most of which are differentially expressed, i.e., at different locations, at different times during development, or in response to environmental signals. Differential gene expression is achieved through complex regulatory networks that are controlled in part by two types of trans‐regulators: transcription factors (TFs) and microRNAs (miRNAs). TFs bind to cis‐regulatory DNA elements that are often located in or near their target genes, while miRNAs hybridize to cis‐regulatory (...) RNA elements mostly located in the 3′ untranslated region of their target mRNAs. Here, we describe how these trans‐regulators interact with each other in the context of gene regulatory networks to coordinate gene expression at the genome‐scale level, and discuss future challenges of integrating these networks with other types of functional networks. (shrink)

Prior researchers have studied individual components of a theoretical decision-making model. This paper presents the results of a more complete study of the model components and presents limited support of theory. The study examines the relative importance of regulatory, organizational, and personal constructs on an individual''s ethical sensitivity. Auditors from the major international accounting firms, located in two southeastern cities, are surveyed. Structural equation modeling is used to allow for the simultaneous evaluation of the three constructs of interest. The (...) results indicate that the regulatory and organizational constructs are negatively correlated with the personal experience construct. The three constructs are not significant causal factors on ethical sensitivity. This result may be due to the manner in which ethical sensitivity is typically measured or may indicate that the complexity of the ethical decision-making process is not fully captured in the theoretical models. Thus, the models suggested in the prior literature and the results presented in prior studies of the individual components may need to be reconsidered. (shrink)

Regulatory agencies in the United States have relied increasingly on consensus-based decision processes to build public support for their policies. If they are well-designed and managed effectively, consensus-based processes may increase support for an agency’s policies and enhance its institutional legitimacy. But poorly-designed processes may lead to a consensus trap, in which an agency commits to making decisions based on a consensus the participants will never be able to achieve. Two recent initiatives of the U.S. Environmental Protection Agency - (...) negotiated rule making and the Common Sense Initiative - suggest factors that may be associated with more and less sucessful consensus-based processes. (shrink)

It has been suggested that metallothioneins, discovered about 45 years ago, play a central role in heavy metal metabolism and detoxification, and in the management of various forms of stress. The metal‐regulatory transcription factor‐1 (MTF‐1) was shown to be essential for basal and heavy metal‐induced transcription of the stress‐responsive metallothionein‐I and metallothionein‐II. Recently it has become obvious that MTF‐1 has further roles in the transcriptional regulation of genes induced by various stressors and might even contribute to some aspects of (...) malignant cell growth. Furthermore, MTF‐1 is an essential gene, as mice null‐mutant for MTF‐1 die in utero due to liver degeneration. We describe here the state of knowledge on the complex activation of MTF‐1, and propose a model with MTF‐1 as an interconnected cellular stress‐sensor protein involved in heavy metal metabolism, hepatocyte differentiation and detoxification of toxic agents. BioEssays 23:1010–1017, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Clp ATPase chaperone proteins are found in procaryotes and eucaryotes. Recently, ClpC of Bacillus subtilis was found to be part of a regulatory switch(1). ClpC, in combination with the MecA and ComS proteins, regulates the activity of a transcription factor, ComK, which is necessary for the development of genetic competence (the ability to bind and take up exogenous DNA). The complex of ClpC:MecA:ComK renders ComK inactive. Interaction between ComS and the ternary complex releases active ComK. This regulatory switch (...) controls ComK activity in response to cell density signals that affect production of ComS. Regulated interaction between Clp ATPases and target proteins might prove to be widespread. (shrink)

Although the type‐I interferon (IFN‐I) response is considered vertebrate‐specific, recent findings about the Intracellular Pathogen Response (IPR) in nematode Caenorhabditis elegans indicate that there are similarities between these two transcriptional immunological programs. The IPR is induced during infection with natural intracellular fungal and viral pathogens of the intestine and promotes resistance against these pathogens. Similarly, the IFN‐I response is induced by viruses and other intracellular pathogens and promotes resistance against infection. Whether the IPR and the IFN‐I response evolved in (...) a divergent or convergent manner is an unanswered and exciting question, which could be addressed by further studies of immunity against intracellular pathogens in C. elegans and other simple host organisms. Here we highlight similar roles played by RIG‐I‐like receptors, purine metabolism enzymes, proteotoxic stressors, and transcription factors to induce the IPR and IFN‐I response, as well as the similar consequences of these defense programs on organismal development. (shrink)

Biomedical research has a strong impact on a country’s scientific-technological and socioeconomic development. It can make a significant contribution at three different levels: promotion of public health; the exchange of knowledge within the scientific community; and economic/ financial profitability. Africa only attracts ~3.3% of the world’s clinical research. This small proportion is due to, among several factors, the absence of two fundamental aspects: specific robust legislation and capacity for regulatory and ethical evaluation. There are five Portuguese- speaking African (...) countries – Angola, Cabo Verde, Guinea-Bissau, Mozambique and São Tomé and Príncipe. Despite presenting different degrees of clinical research development, these countries show a common serious insufficiency in the minimum conditions necessary for hosting, collaborating or leading biomedical research projects. These countries are also excluded from the support of international organisations for capacity building because of the language barrier. The Biomedical Ethics and Regulatory Capacity Building Partnership for Portuguese-Speaking African Countries project has developed methods to build capacity and partnership through research on national law, comparisons with international standards and by issuing recommendations at a national level. Through collaborative intensive training, trainees are taught to become educators at a national level. This, in turn, creates a sustainable impact at country level. BERC-Luso is a pioneering project, owing to a combination of innovative features. The partnership project: was developed exclusively in Portuguese; involves a large number of African countries, and national and international institutions; has been further enhanced by the diversity and complementarity of its action plans; and has also benefited from a broad participatory methodology based on resolution of recipients’ problems by the recipients themselves. It thus stands out as a model for similar future projects. (shrink)

Advances in the understanding of Ras oncoprotein function suggest novel points for anti‐tumor intervention. First, upstream‐acting guanine nucleotide exchange factors and SH2/SH3 domain‐containing adaptor proteins that link Ras with growth factor receptor tyrosine kinases have recently been characterized. Second, work on downstream‐acting Ras effector functions including the Ras GTPase‐activating protein (p120GAP) and the Raf kinase has revealed direct biochemical interactions that are functionally required for oncogenic Ras signalling. We summarize progress in these areas and discuss the potential for novel (...) applications to anti‐cancer chemotherapy. (shrink)

The combination of student Self-Regulation (SR) and the context of Regulatory Teaching (RT), each in varying degree, has recently been demonstrated to have effects on achievement emotions, factors and symptoms of stress, and coping strategies. The aim of the present research study is to verify its possible further effects, on academic behavioral confidence and procrastination. A total of 1193 university students completed validated online questionnaires with regard to specific subjects in their degree program. Using an ex post facto (...) design, multivariate analyses and structural equation modeling (SEM) were carried out in order to test the relationships predicted by the model. SR and RT had a significant joint effect in determining the degree of academic behavioral confidence and of procrastination. Academic behavioral confidence also significantly predicted reasons for procrastinating, and these in turn predicted activities of procrastination. Conclusions are discussed, insisting on the combined weight of the two variables in determining academic behavioral confidence, reasons for procrastinating and activities subject to procrastination, in university students. Implications for guidance and educational support of university students and teachers are analyzed. (shrink)

The generation of patterns and the diversity of cell types in a multicellular organism require differential gene regulation. At the heart of this process are enhancers or cis‐regulatory modules (CRMs), genomic regions that are bound by transcription factors (TFs) that control spatio‐temporal gene expression in developmental networks. To date, only a few CRMs have been studied in detail and the underlying cis‐regulatory code is not well understood. Here, we review recent progress on the genome‐wide identification of CRMs (...) with chromatin immunoprecipitation of TF‐DNA complexes followed by microarrays (ChIP‐on‐chip). We focus on two computational approaches that have succeeded in predicting the expression pattern driven by a CRM either based on TF binding site preferences and their expression levels, or quantitative analysis of CRM occupancy by key TFs. We also discuss the current limits of these methods and highlight some of the key problems that have to be solved to gain a more complete understanding of the structure and function of CRMs. (shrink)

Regulatory impact assessment (RIA) is seen as a tool for increasing evidence-based policy making and as such it is being integrated into decision-making procedures on a wide range of issues. Based on systematic consultation, clear criteria for policy choice, and economic analysis of how costs and benefits impact on a wide range of affected parties, this tool operates by using scientific knowledge and technical analysis rather than political considerations. Scientific knowledge can be used to achieve instrumental learning (Radaelli, 2009, (...) OECD), policy change (Sabatier, 1999), to impact on decision making (Caplan, 1979; C.H.Weiss, 1999) but also to seek legitimacy from the policy environment (Edelman, 1985; Schrefler, 2010). This article suggests an analytical framework for analysing RIA documents with insight from knowledge utilization theories. We argue that in order to better understand the RIA itself, we need to look at institutional factors as well. The combination of institutional context variables and variables for RIA document content analysis which make up worldviews in this framework provide the basis for the document analysis and exploration of RIA in its context. (shrink)

The development of efficient and strategic anti-corruption measures can be better achieved if a deeper understanding and identification of the causes of corruption are established. Over the past years, many studies have been devoted to the research of corruption in construction management. This has resulted in a significant increase in the body of knowledge on the subject matter, including the causative factors triggering these corrupt practices. However, an apropos systematic assessment of both past and current studies on the subject (...) matter which is needful for the future endeavor is lacking. Moreover, there is an absence of unified view of the causative factors of corruption identified in construction project management. This paper, therefore, presents a comprehensive review of the causes of corruption from selected articles in recognized construction management journals to address the mentioned gaps. A total number of 44 causes of corruption were identified from 37 publications and analyzed in terms of existing causal factors of corruption, annual trend of publications and the thematic categorization of the identified variables. The most identifiable causes were over close relationships, poor professional ethical standards, negative industrial and working conditions, negative role models and inadequate sanctions. A conceptual framework of causes of corruption was established, after categorizing the 44 variables into five unique categories. In descending order, the five constructs are Psychosocial-Specific Causes, Organizational-Specific Causes, Regulatory-Specific Causes, Project-Specific Causes and Statutory-Specific Causes. This study extends the current literature of corruption research in construction management and contributes to a deepened understanding of the causal instigators of corruption identified in CPM. The findings from this study provide valuable information and extended knowledge to industry practitioners and policymakers as well as anti-corruption agencies in the formulation and direction of anti-corruption measures. To corruption researchers in CM, this study is vital for further research. (shrink)

Transcription factor binding sites (TFBSs) on the DNA are generally accepted as the key nodes of gene control. However, the multitudes of TFBSs identified in genome‐wide studies, some of them seemingly unconstrained in evolution, have prompted the view that in many cases TF binding may serve no biological function. Yet, insights from transcriptional biochemistry, population genetics and functional genomics suggest that rather than segregating into ‘functional’ or ‘non‐functional’, TFBS inputs to their target genes may be generally cumulative, with varying degrees (...) of potency and redundancy. As TFBS redundancy can be diminished by mutations and environmental stress, some of the apparently ‘spurious’ sites may turn out to be important for maintaining adequate transcriptional regulation under these conditions. This has significant implications for interpreting the phenotypic effects of TFBS mutations, particularly in the context of genome‐wide association studies for complex traits. (shrink)

In this reply, we wish to defend our original position and address several of the points raised by two excellent responses. The first response (De Miguel Beriain) questions the relevance of the notion of ‘serious’ within the context of human germline genome modification (HGGM). We argue that the ‘serious’ factor is relevant and that there is a need for medical and social lenses to delineate the limits of acceptability and initial permissible applications of HGGM. In this way, ‘serious’ acts as (...) a starting point for further discussions and debates on the acceptability of the potential clinical translation of HGGM. Therefore, there is a pressing need to clarify its scope, from a regulatory perspective, so as to prevent individuals from using HGGM for non-therapeutic or enhancement purposes. The second response (Kalsi) criticizes the narrow interpretation of the objectivist approach and the apparent bias towards material innovations when discussing the right to benefit from scientific advancements. As an in-depth discussion of the objectivist and constructivist approaches was beyond the scope of our original paper, we chose to focus on one specific objectivist account, one which focuses on biological and scientific facts. We agree, however, with the critique that material innovations should not be the sole focus of the right to benefit from scientific advancements, which also incorporates freedom of scientific research and access to scientific knowledge scientific freedom and knowledge, including the influence of these on ethical thinking and cultures. (shrink)

This article addresses issues of regulatory convergence and Europeanization as they have developed within the agrochemicals sector. Taking the United Kingdom as a case study, the article considers the continuing importance of local and national factors within systems that are ostensibly international and standardized. In particular, the article shows how the embedded social relations of regulatory science in the United Kingdom, including institutional practices, judgments of expertise, and established relationships of trust, result in a “nation centeredness” and (...) divergence of regulatory cultures despite the putative development of a harmonized European framework. It is argued that, as a consequence, the claimed universalism of scientific culture in this area is in tension with the local conditions of its practice and enactment. (shrink)

ANNOTATION Sardak S.E. Global Regulatory System of Human Resources Development. – Manuscript. Thesis for the Doctor of Economic Science academic degree with major in 08.00.02 – World Economy and international economic relations. – SHEE «Kyiv National Economic University named after Vadym Hetman», Kyiv, 2014. The preconditions and factors of the global economic system with the identified relevant subjects areas and mechanisms of regulation instruments have been investigated. The crucial role of humans in the global economic system as a (...) key factor of production, the main resource, the producer and the consumer of economic and social benefits that are exposed to global threats, problems, challenges, trends and subjects has been confirmed. There have been revealed the causes and consequences of the public institutions transformation under the influence of globalization, which formed a qualitatively new conditions for social and economic development that determine the need for further changes in the areas of conceptual guideline for the management of human resources development, optimization of tasks, state and international institutions activity forms, integration of efforts as for monitoring, planning and forecasting. The modern major instruments and spheres of international cooperation to ensure human development have been determined. The integrated characteristic of human resources and their role in social development both from the standpoint of their use in labour processes and as a medium of civilization and social utility with the help of the categorical classification system organizing and expanding which enables to design and apply the appropriate approaches at all managerial levels have been defined. The necessity and the concept of human resources development in the context of the content of managerial influence identifying (self-development, self-management and external control of development) at different administrative levels that ensures the growth of human capital to the limits of its potential have been analysed. The survey of human activity system aspects in the global world, taking into account the parametrization of the global environment, its structure, management and development have been realized. The formed methodology principles of managerial influence on the development of human resources with scientific schools, hardness degrees, available models, research and providing theoretical and practical implementation peculiarities for groups of countries and territories of the world taken into consideration have been examined. There have been noted civilization and national differences in the forms of managerial influence on the development of human resources, which lead to the formation of human resources development national control systems conditioned by different value public strategic guidelines, especially in relation to social security, education, national management and state migration policy. The current and future requirements for global human resources development which are proposed to be achieved by the development and formalization of global civilizational paradigm of social development due to social coordination interaction have been given. The influence of the institute of state on the human resources development has been evaluated and it has been proved that in the beginning of the XXI century in the global environment the institute of state is the ultimate guarantor of its citizens’ labour ability and vital activity renewal, that makes it the main instrument of managerial influence on human development. The methodology of countries and territories matrix positioning by human development qualitative criteria and population size quantitative parameters which allows to design unified managerial measures as for human resources for similar national economies in the context of global regulatory trends has been proposed. The strategic trends of improvement of human resources development in the national economy, taking into account the differences in the development of human resources in different countries and areas which vary and differ in their focus, content and ways of implementation for such groups. The varying criteria for evaluating the effectiveness of the global impact on human resources development, taking into account the natural, biological, technological, economic, social and management dimensions and the results of human resources development management in social and economic systems at various levels have been revealed. The periodization and the forecast of the global dynamics of human resources development by analyzing and modeling the values of the absolute and relative terms correlation character have been carried out, which enables to make their retrospective and prospective comparison and to find chronological boundaries of qualitatively different periods. The configuration of the human resource development global coordinate system as a set of interrelated principles, components, fields, tools, frameworks, management levels and forms of managerial influence that allows with the help of institutional means to adapt the state of human resources development to a globally varying environment. (shrink)

This study examined the factors that affect the attitude and behavioral intentions toward electronic sports among students of higher education institutions based on the technology acceptance model. The conditional impact of preventive regulatory focus was analyzed in various aspects developed on the regulatory focus theory. These aspects comprised of perceived usefulness, perceived ease of use, and perceived risk on the attitude toward eSports. Accordingly, data were collected from 293 students of higher education institutions in China's Henan Province, (...) presenting a 54.56% response rate. The PLS-SEM analysis was subsequently implemented to confirm the proposed hypotheses. The empirical findings confirmed the significant positive impact of perceived usefulness and perceived ease of use on the attitude toward eSports. However, perceived risk negatively affected the attitude toward eSports. Meanwhile, the findings on the moderating hypotheses found a negligible impact on preventive regulatory focus. This impact was found explicitly on the perceived usefulness-perceived ease of use link with attitude toward eSports. However, the preventive regulatory focus negatively moderated the perceived risk attitude toward eSports. Finally, the implication and limitations were illustrated at the end of the paper. (shrink)

Moving forward rapidly in the clinical research phase, uterus transplantation may be a future treatment option for women with uterine factor infertility, which accounts for three per cent of all infertility in women. This new method of treatment would allow women, who currently rely on gestational surrogacy or adoption, to gestate and birth their own genetic offspring. Since uterus transplantation carries significant risk when compared with surrogacy and adoption as well as when compared with other organ transplants, it requires greater (...) justification because its goals are quality of life, not life-saving, in their scope. It is important to address questions regarding the physical, psychosocial and ethical risks and benefits of uterus transplantation for all three parties involved—the patient, the donor and the potential child—as well as discuss the regulatory implications as research on uterus transplantations moves forward. (shrink)

American policymakers delegate the administration of many welfare programs to states, where officials implement them in increasingly diverse ways. Welfare state scholarship has little to say about this subnational policy divergence, and it portrays the complexity of delegated governance as a barrier to nonelite legislative influence. Drawing on an ethnographic study of one state’s Medicaid program, this article shows that delegated governance offers ample opportunity for nonelite influence and policy divergence, but through regulatory governance rather than legislative advocacy. Medicaid (...) is opaque to politicians, whose inability to monitor program details creates conditions of bureaucratic autonomy and even activism: health-care agency personnel sequence regulatory tweaks to protect and expand entitlements. But budget cuts, outsourcing, and fraught provider relations also deprive bureaucrats of street-level know-how, and bureaucrats depend on beneficiaries’ advocates who selectively illuminate a path to reform. A full rendering of subnational divergence in American federalism requires attention to underexamined factors such as bureaucratic activism, agency advocacy, and regulatory governance. (shrink)

Nucleosome positioning is proposed to have an essential role in facilitating the regulated transcription of eukaryotic genes. Some transcription factors can bind to DNA when it is appropriately wrapped around the histone core, others cannot bind due to the severe deformation of DNA structure. The staged assembly of nucleosomes and positioning of histone‐DNA contacts away from promoter elements can facilitate the access of transcription factors to DNA. Positioned nucleosomes can also facilitate transcription through providing the appropriate scaffolding to (...) bring regulatory factors bound at dispersed sites into juxtaposition. (shrink)

Plant‐specific NAC transcription factors (TFs) evolve during the transition from aquatic to terrestrial plant life and are amplified to become one of the biggest TF families. This is because they regulate genes involved in water conductance and cell support. They also control flower and fruit formation. The review presented here focuses on various properties, regulatory intricacies, and developmental roles of NAC family members. Processes controlled by NACs depend majorly on their transcriptional properties. NACs can function as both activators (...) and/or repressors. Additionally, their homo/hetero dimerization abilities can also affect DNA binding and activation properties. The active protein levels are dependent on the regulatory cascades. Because NACs regulate both development and stress responses in plants, in‐depth knowledge about them has the potential to help guide future crop improvement studies. (shrink)

Numerous accessory factors modulate RNA polymerase response to regulatory signals and cellular cues and establish communications with co‐transcriptional RNA processing. Transcription regulators are astonishingly diverse, with similar mechanisms arising via convergent evolution. NusG/Spt5 elongation factors comprise the only universally conserved and ancient family of regulators. They bind to the conserved clamp helices domain of RNA polymerase, which also interacts with non‐homologous initiation factors in all domains of life, and reach across the DNA channel to form processivity (...) clamps that enable uninterrupted RNA chain synthesis. In addition to this ubiquitous function, NusG homologs exert diverse, and sometimes opposite, effects on gene expression by competing with each other and other regulators for binding to the clamp helices and by recruiting auxiliary factors that facilitate termination, antitermination, splicing, translation, etc. This surprisingly diverse range of activities and the underlying unprecedented structural changes make studies of these “transformer” proteins both challenging and rewarding. (shrink)

Introduction. The fourth industrial revolution significantly changes the structure of economic relations and transforms the importance of factors in the development of territories. The purpose of the article is to identify the most significant factors in the regional development of the Ural macro region in the context of the fourth industrial revolution and to determine the directions of impacts to ensure the competitiveness and long-term growth of territories. Methods. The methodological basis of the study is based on a (...) set of scientific approaches to economic growth, concepts of regional and institutional economics. Research methods include regional, comparative and econometric factor analysis. Scientific novelty of the study. A method for identifying the significance of factors in the development of regions is proposed and the key factors for developing the subjects of the Ural macro region in the context of the fourth industrial revolution are established. The study contributes to the scientific debate on the meaning and management of institutional development factors. Results. The author presents the results of diagnosing the regulatory environment and geographic factors of the subjects of the Ural macro region. An econometric analysis of their impact on economic development has been carried out. The statistical significance for developing the volume of mining and the quality of the legal environment in the regions has been established. Informal institutions (the authors explain the phenomenon by weak differentiation of cultural characteristics and business practices of regions due to their historical connectivity) and transport and geographical location (due to a decrease in spatial influence and an increase in the role of digital technologies in production chains in Industry 4.0). Conclusions. In the Sverdlovsk and Chelyabinsk regions, it was possible to ensure higher values of GRP per capita due to a favorable regulatory environment. In general, in the Russian regions in the second decade of the 21st century, the raw material orientation remains (among the studied objects, the economies of the Orenburg region and Udmurtia are the most extractive). To ensure the country’s long-term development, it is necessary to create a favorable business climate: improving the legal environment in the areas outlined in the study, increasing the level of trust and reducing the level of corruption. (shrink)

Gene targeting has allowed the dissection of complex biological processes at the genetic level. Our understanding of the nuances of skeletal muscle development has been greatly increased by the analysis of mice carrying targeted null mutations in the Myf‐5, MyoD and myogenin genes, encoding members of the myogenic regulatory factor (MRF) family. These experiments have elucidated the hierarchical relationships existing between the MRFs, and established that functional redundancy is a feature of the MRF regulatory network. Either MyoD or (...) Myf‐5 is sufficient for the formation or survival of skeletal myoblasts. Myogenin acts later in development and plays an essential in vivo role in the terminal differentiation of myotubes. (shrink)

The proteins encoded by the ras proto‐oncogenes play critical roles in normal cellular growth, differentiation and development in addition to their potential for malignant transformation. Several proteins that are involved in the control of the activity of p21ras have now been characterised. p120GAP stimulates the GTPase activity of p21ras and hence acts as a negative regulator of ras proteins. It may be controlled by tyrosine phosphorylation or association with tyrosine phosphorylated proteins. The neurofibromatosis type 1 (NF 1) gene also encodes (...) a potential GTPase activating protein which is likely to be subject to a different control mechanism. Guanosine nucleotide exchange factors for p21ras have now been identified: these may be positive regulators of ras protein function. It appears that p21ras is subject to rapid regulation by several distinct mechanisms which are likely to vary in different cell types; the ras proteins are thereby able to act as very sensitive cellular monitors of the extracellular environment. (shrink)

On January 18, 2011, President Obama signed Executive Order 13563, Improving Regulation and Regulatory Review, which instructs federal regulators to do the following: coordinate their agencies activities to simplify and harmonize rules that may be overlapping, inconsistent, or redundant; determine whether the present and future benefits of a proposed regulation justify its potential costs (including taking into account both quantitative and qualitative factors); increase participation of industry, experts, and the public (“stakeholders”) in the formal rule‐making process; encourage the (...) use of warnings, default rules, disclosure requirements, and provisions of information to the public as an alternative to traditional “command‐and‐control” rule‐making restricting consumer choice; and mandate a government‐wide review of all existing administrative rules to remove outdated regulations. Executive Order 13563 includes a qualitative “values” provision to be considered in the required cost–benefit analysis, which can potentially counteract the alleged regulatory reform rationale of President Obama. Furthermore, in Executive Order 13563, President Obama established a deadline of May 18, 2011, for all executive branch agencies to submit their plans to streamline their rulemaking operations and repeal those “overlapping, inconsistent, or redundant” rules. These two issues, along with complementary regulatory review proposals being discussed in the U.S. Congress, are evaluated in this essay. (shrink)

This paper deals with the problem of reconstruction of the intergenic interaction graph from the raw data of genetic co-expression coming with new technologies of bio-arrays (DMA-arrays, protein-arrays, etc.). These new imaging devices in general only give information about the asymptotical part (fixed configurations of co-expression or limit cycles of such configurations) of the dynamical evolution of the regulatory networks (genetic and/or proteic) underlying the functioning of living systems. Extracting the casual structure and interaction coefficients of a gene interaction (...) network from the observed configurations is a complex problem. But if all the fixed configurations are supposedly observed and if they are factorizable into two or more subsets of values, then the interaction graph possesses as many connected components as the number of factors and the solution is obtained in polynomial time. This new result allows us for example to partly solve the topology of the genetic regulatory network ruling the flowering in Arabidopsis thaliana. (shrink)

Classic genetics studies found that genomic imbalance caused by changing the dosage of part of the genome (aneuploidy) has more detrimental effects than altering the dosage of the whole genome (ploidy). Previous analysis revealed global modulation of gene expression triggered by aneuploidy across various species, including maize (Zea mays), Arabidopsis, yeast, mammals, etc. Plant microRNAs (miRNAs) are a class of 20‐ to 24‐nt endogenous small noncoding RNAs that carry out post‐transcriptional gene expression regulation. That miRNAs and their putative targets are (...) preferentially retained as duplicates after whole‐genome duplication, as are many transcription factors and signaling components, indicates miRNAs are likely to be dosage‐sensitive and potentially involved in genomic balance networks. This review addresses the following questions regarding the role of miRNAs in genomic imbalance. (1) How do aneuploidy and polyploidy impact the expression of miRNAs? (2) Do miRNAs play a regulatory role in modulating the expression of their targets under genomic imbalance? (shrink)

Background: Besides regulatory learning skills, learning also requires students to relate to their social context and negotiate it as they transition and adjust to medical training. As such, there is a need to consider and explore the role of social and cultural aspects in student learning, particularly in problem-based learning, where the learning paradigm differs from what most students have previously experienced. In this article, we report on the findings of a study exploring first-year medical students’ experiences during the (...) first semester of an undergraduate problem-based learning medical program at an African medical school. Method: We employed a qualitative case study approach using in-depth interviews with 23 first-year medical students. Participants ranged in age from 18 to 25 years. All students were bi/multilingual (some spoke three to five languages), with English as the learning language. We conducted an inductive thematic analysis to systematically identify and analyze patterns in the data using the Braun and Clarke framework. Results: Before medical school, students worked hard to compete for admission to medical school, were primarily taught using a teacher-centered approach, and preferred working alone. At the beginning of medical school, students found it challenging to understand the problem-based learning process, the role of the case, speaking and working effectively in a group, managing a heavy workload, and taking increased responsibility for their learning. By the end of the first semester, most students were handling the workload better, were more comfortable with their peers and facilitators, and appreciated the value of the problem-based learning approach. Conclusions: Our study highlights the importance of interrogating contextual sociocultural factors that could cause tension when implementing problem-based learning in non-western medical schools. Adjustment to problem-based learning requires a conceptual and pedagogic shift towards learner-centered practice, particularly concerning self direction, the role of the case, and collaborative learning. As such, there is a need to develop and implement research informed learning development programs that enable students to reflect on their sociocultural beliefs and practices, and enhance their regulatory learning competence to optimize meaningful and early engagement with the problem based learning process. (shrink)

While acknowledging the potential benefits of pharmacogenomics as a methodology, a number of comprehensive reports in the past several years examine a multitude of ethical, legal, and social factors that may limit the extent to which these benefits are realized — and realized in ethically acceptable ways. This article aims to identify and explore the most basic ethical and regulatory issues that are likely to arise if pharmacogenomics becomes widely enough used to have a significant impact on research (...) and clinical practice. First, however, it addresses the question of whether pharmacogenomic tests are unique when compared to other genetic tests and thus deserving of more or less stringent ethical and regulatory requirements. (shrink)

International regulation of autonomous weapon systems (AWS) is increasingly conceived as an exercise in risk management. This requires a shared approach for assessing the risks of AWS. This paper presents a structured approach to risk assessment and regulation for AWS, adapting a qualitative framework inspired by the Intergovernmental Panel on Climate Change (IPCC). It examines the interactions among key risk factors—determinants, drivers, and types—to evaluate the risk magnitude of AWS and establish risk tolerance thresholds through a risk matrix informed (...) by background knowledge of event likelihood and severity. Further, it proposes a methodology to assess community risk appetite, emphasizing that such assessments and resulting tolerance levels should be determined through deliberation in a multistakeholder forum. The paper highlights the complexities of applying risk-based regulations to AWS internationally, particularly the challenge of defining a global community for risk assessment and regulatory legitimization. (shrink)

Cryptocurrency has revolutionized the economic system of the world. It provides a new and innovative means of exchange that has speedily invaded the financial market trends and changed the traditional cash world. However, consumers have low acceptability for blockchain-based cryptocurrency due to increasing online scams and the absence of a regulatory framework. There is also a misconception about its usage on many platforms, which has created a clear gap in the literature to address this issue. Therefore, the current study (...) intends to investigate the effect of technology awareness on the behavioral intention of crypto users through perceived factors. It also empirically examines the moderating role of government support on these indirect paths. The underlying framework is investigated by surveying 333 respondents from the Z generation. Results revealed that perceived factors mediate the relationship between technology awareness and behavioral intention. Furthermore, government support strengthens the indirect relationship of technology awareness on behavioral intention through technology acceptance determinants, such that the effect of technology awareness on behavioral intention through perceived factors is more assertive when government support is high. The findings will provide a new dimension to different financial bodies implementing monetary policy and highlight the need to adopt innovative digital technologies in Pakistan. (shrink)

The SRL vs. ERL theory has shown that the combination of levels of student self-regulation and regulation from the teaching context produces linear effects on achievement emotions and coping strategies. However, a similar effect on stress factors and symptoms of university students has not yet been demonstrated. The aim of this study was to test this prediction. It was hypothesized that the level of student self-regulation (low/medium/high), in interaction with the level of external regulation from teaching (low/medium/high), would also (...) produce a linear effect on stress factors and symptoms of university students. A total of 527 undergraduate students completed validated questionnaires about self-regulation, regulatory teaching, stress factors and symptoms. Using an ex post facto design by selection, ANOVAs and MANOVAs (3 x 3; 5 x 1; 5 x 2) were carried out. The results confirmed that the level of self-regulation and the level of regulatory teaching jointly determined the level of stress factors and symptoms of university students. Once again, a five-level heuristic of possible combinations was configured to jointly determined university students’ level of academic stress. We concluded that the combination of different levels of student regulation levels and regulation from teaching process jointly determines university students’ level of academic stress. The implications for university students’ emotional health, stress prevention and well-being are established. (shrink)

BackgroundInstitutional Review Boards (IRBs) play a vital role in safeguarding the rights and interests of both research participants and researchers. However, China initiated the establishment of its own IRB system relatively late in comparison to international standards. Despite commendable progress, there is a pressing need to strengthen the organizational capacity building of Chinese IRBs. Hence, this study aims to analyze the key factors driving the enhancement of organizational capacity within these committees.MethodThe cross-sectional survey for this research was conducted from (...) July 2020 to January 2022. Following the statistical grouping based on the "2020 China Health Statistical Yearbook", a systematic investigation of IRBs in various provinces of China was carried out. In-depth interviews and questionnaire surveys were conducted with the chairpersons and administrative executives (or secretaries) of highly cooperative IRBs. Subsequently, data were collected from 107 IRBs. Qualitative Comparative Analysis (QCA) was employed as the method to analyze the factors influencing the organizational capacity of medical ethics committees and explore the diverse combinations of these factors.ResultsThrough a singular necessary condition analysis, the variable "protection of rights and interests" emerges as a critical factor contributing to the robust construction of Institutional Review Boards Institutional Review Boards (IRBs). Conversely, the variables of "lack of member ability, absence of review process, and deficiency in the supervision mechanism" collectively constitute a sufficient condition leading to weaker IRB construction. The state analysis uncovers three interpretation modes: member ability-oriented (M1), system process-oriented mode (M2), and resource system-oriented mode (M3).ConclusionsThe results of this study are effectively explicable using the "Triangular Force" model proposed for the hypothesis of IRBs' organizational capacity, which provides a solid foundation for the development of organizational capabilities in IRBs. To enhance the organizational capacity of IRBs in China, it is imperative to elevate the competence of committee members and strengthen team development. This can be achieved by establishing a comprehensive regulatory framework and refining procedural protocols. Moreover, clarifying the organizational structure and optimizing resource allocation are essential steps in bolstering the overall organizational capabilities of these committees. (shrink)

Cascades of transcriptional regulation are the common source of the forward drive in all developmental systems. Increases in complexity and specificity of gene expression at successive stages are based on the collaboration of varied combinations of transcription factors already expressed in the cells to turn on new genes, and the logical relationships between the transcription factors acting and becoming newly expressed from stage to stage are best visualized as gene regulatory networks. However, gene regulatory networks used (...) in different developmental contexts underlie processes that actually operate through different sets of rules, which affect the kinetics, synchronicity, and logical properties of individual network nodes. Contrasting early embryonic development in flies and sea urchins with adult mammalian hematopoietic development from stem cells, major differences are seen in transcription factor dosage dependence, the silencing or damping impacts of repression, and the impact of cellular regulatory history on the parts of the genome that are accessible to transcription factor action in a given cell type. These different features not only affect the kinds of models that can illuminate developmental mechanisms in the respective biological systems, but also reflect the evolutionary needs of these biological systems to optimize different aspects of development. (shrink)

BACKGROUND: Alzheimer's disease is intimately tied to amyloid-beta peptide. Extraneuronal brain plaques consisting primarily of Abeta aggregates are a hallmark of AD. Intraneuronal Abeta subunits are strongly implicated in disease progression. Protein sequence mutations of the Abeta precursor protein account for a small proportion of AD cases, suggesting that regulation of the associated gene may play a more important role in AD etiology. The APP promoter possesses a novel 30 nucleotide sequence, or "proximal regulatory element" , at -76/-47, from (...) the +1 transcription start site that confers cell type specificity. This PRE contains sequences that make it vulnerable to epigenetic modification and may present a viable target for drug studies. We examined PRE-nuclear protein interaction by gel electrophoretic mobility shift assay and PRE mutant EMSA. This was followed by functional studies of PRE mutant/reporter gene fusion clones. RESULTS: EMSA probed with the PRE showed DNA-protein interaction in multiple nuclear extracts and in human brain tissue nuclear extract in a tissue-type specific manner. We identified transcription factors that are likely to bind the PRE, using competition gel shift and gel supershift: Activator protein 2 , nm23 nucleoside diphosphate kinase/metastatic inhibitory protein , and specificity protein 1 . These sites crossed a known single nucleotide polymorphism . EMSA with PRE mutants and promoter/reporter clone transfection analysis further implicated PuF in cells and extracts. Functional assays of mutant/reporter clone transfections were evaluated by ELISA of reporter protein levels. EMSA and ELISA results correlated by meta-analysis. CONCLUSIONS: We propose that PuF may regulate the APP gene promoter and that AD risk may be increased by interference with PuF regulation at the PRE. PuF is targeted by calcium/calmodulin-dependent protein kinase II inhibitor 1, which also interacts with the integrins. These proteins are connected to vital cellular and neurological functions. In addition, the transcription factor PuF is a known inhibitor of metastasis and regulates cell growth during development. Given that APP is a known cell adhesion protein and ferroxidase, this suggests biochemical links among cell signaling, the cell cycle, iron metabolism in cancer, and AD in the context of overall aging. (shrink)

Many kinds of multifunctional regulatory proteins have been identified that perform distinct biochemical functions in the nucleus, the cytoplasm, or both. Here we describe the recent discovery by Hall et al. (2004)1 of a new type of multifunctional protein: a metabolic enzyme that doubles as a transcription factor. This enzyme, Arg5,6, functions as a catalytic enzyme in ornithine biosynthesis and also binds and regulates the promoters of nuclear and mitochondrial genes. It may also regulate precursor mRNA metabolism. We discuss (...) how proteins that serve as both metabolic enzymes and transcription factors might have evolved. BioEssays 27:467–471, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

How can firms mitigate the impact of moral violations on consumer evaluations? This question has pervaded the business ethics literature. Though prior research has identified decoupling as a moral reasoning strategy where consumers separate moral judgments from evaluations, it is unclear what motivates individuals to decouple. It is the objective of this research to explore regulatory focus theory as a motivating factor for moral decoupling. Three experiments are undertaken. Study one demonstrates that with a prevention mindset as opposed to (...) promotion mindset, moral decoupling can be achieved. Specifically, those in a prevention mindset report more favorable evaluations when information about a violation explicitly lowers consequences of moral violations. However, when the violation is related to the business functionality of the brand, those in a prevention mindset report less favorable evaluations, except when consequences are lowered. This indicates an inability to decouple, and results in negative emotions. The research shows that inability to decouple for those in a prevention mindset leads to negative emotions, lowering evaluations. These results contribute to the moral reasoning literature by linking regulatory focus to decoupling strategies. Further, the research bridges literature on norm activation, moral foundation, regulatory focus, and moral decoupling to reconcile theoretical differences in judgment styles. Implications for businesses and brands are discussed. (shrink)

The aging process involves changes in immune regulation, i.e. adaptive immunity declines whereas innate immunity becomes activated. NF‐κB signaling is the master regulator of the both immune systems. Two recent articles highlight the role of the NF‐κB system in aging and immune responses. Adler et al1 showed that the NF‐κB binding domain is the genetic regulatory motif which is most strongly associated with the aging process. Kwon et al2 studying HIV‐1 infection and subsequent immune deficiency process demonstrated that HIV‐1 (...) Tat protein binds to SIRT1 protein, a well‐known longevity factor, and inhibits the SIRT1‐mediated deacetylation of the p65 component of the NF‐κB complex. As a consequence, the transactivation efficiency of the NF‐κB factor was greatly potentiated, leading to the activation of immune system and later to the decline of adaptive immunity. These observations support the scenario where immune responses and aging process can be enforced by the potentiation of NF‐κB transactivation efficiency. Longevity factors, such as SIRT1 and its activators, might regulate the efficiency of the NF‐κB signaling, the major outcome of which is inflamm‐aging via proinflammatory responses. BioEssays 30:939–942, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

The role of membrane receptors is regarded as being to transduce the signal represented by ligand binding from the external cell surface across the membrane into the cell. Signals are subsequently conveyed from the cytoplasm to the nucleus through a combination of second-messenger molecules, kinase/phosphorylation cascades, and transcription factor (TF) translocation to effect changes in gene expression. Mounting evidence suggests that through direct targeting to the nucleus, polypeptide ligands and their receptors may have an important additional signaling role. Ligands such (...) as those of the platelet-derived and fibroblast growth factor classes, as well as cytokines such as interferon-γ and interleukins-1 and -5, have been found to localize in the nucleus through the action of nuclear localization sequences (NLSs). Where tested, these NLSs appear to be essential for full signaling activity and may be responsible for cotranslocating receptors to the nucleus in complexes with their ligands. The implication is that, subsequent to endocytosis at the membrane, particular polypeptide ligands or their receptors, or both, may translocate to the nucleus to participate directly in gene regulation. BioEssays 20:400–411, 1998.© 1998 John Wiley & Sons Inc. (shrink)

In this post‐sequencing era, geneticists can focus on functional genomics on a much larger scale than ever before. One goal is the discovery and elucidation of the intricate genetic networks that co‐ordinate transcriptional activation in different regulatory circuitries. High‐throughput gene expression measurement using DNA arrays has thus become routine strategy. This approach, however, does not directly identify gene loci that belong to the same regulatory group; e.g., those that are bound by a common (set of) transcription factor(s). Working (...) in yeast, two groups have recently published an elegant method that could circumvent this problem, by combining chromatin immunoprecipitation and DNA microarrays.(1,2) The method is likely to provide a powerful tool for the dissection of global regulatory networks in eukaryotic cells. BioEssays 23:473–476, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

The role of membrane receptors is regarded as being to transduce the signal represented by ligand binding from the external cell surface across the membrane into the cell. Signals are subsequently conveyed from the cytoplasm to the nucleus through a combination of second-messenger molecules, kinase/phosphorylation cascades, and transcription factor (TF) translocation to effect changes in gene expression. Mounting evidence suggests that through direct targeting to the nucleus, polypeptide ligands and their receptors may have an important additional signaling role. Ligands such (...) as those of the platelet-derived and fibroblast growth factor classes, as well as cytokines such as interferon-γ and interleukins-1 and -5, have been found to localize in the nucleus through the action of nuclear localization sequences (NLSs). Where tested, these NLSs appear to be essential for full signaling activity and may be responsible for cotranslocating receptors to the nucleus in complexes with their ligands. The implication is that, subsequent to endocytosis at the membrane, particular polypeptide ligands or their receptors, or both, may translocate to the nucleus to participate directly in gene regulation. BioEssays 20:400–411, 1998.© 1998 John Wiley & Sons Inc. (shrink)

We investigate two under-explored factors in mitigating the risk of corporate fraud and regulatory enforcement against fraud, namely institutional investors and political connections. The role of institutional investors in the effective monitoring of a firm’s management is well established in the literature. We further observe that firms that have a large proportion of their shares held by institutional investors have a lower incidence of enforcement actions against corporate fraud. The importance of political connections for enterprises, whether in a (...) developed market such as the United States or an emerging market such as China, has been established by previous studies. However, we find evidence of another positive effect of political connections: they may reduce the incidence of enforcement action against corporate fraud. We also find that political connections play a more significant role in reducing regulatory enforcement incidents against non-state-owned enterprises and firms in weaker legal environments, whereas institutional ownership plays a more important role in reducing regulatory enforcement incidents against state-owned enterprises. (shrink)

Insulators play a central role in subdividing the chromosome into a series of discrete topologically independent domains and in ensuring that enhancers and silencers contact their appropriate target genes. In this review we first discuss the general characteristics of insulator elements and their associated protein factors. A growing collection of insulator proteins have been identified including a family of proteins whose expression is developmentally regulated. We next consider several unexpected discoveries that require us to completely rethink how insulators function (...) (and how they can best be assayed). These discoveries also require a reevaluation of how insulators might restrict or orchestrate (by preventing or promoting) interactions between regulatory elements and their target genes. We conclude by connecting these new insights into the mechanisms of insulator action to dynamic changes in the three‐dimensional topology of the chromatin fiber and the generation of specific patterns of gene activity during development and differentiation. (shrink)

This article examines the regulation of nonsteroidal anti-inflammatory drugs, with particular focus on products approved for marketing in the United Kingdom, while denied marketing approval in the United States on safety grounds, and then subsequently withdrawn from the UK market on those grounds. Using international comparison of regulatory data never before accessed outside government and companies, together with interviews with relevant industry scientists and regulators, the article demonstrates the importance of regulatory expectations, deficits and paradigms. It is argued (...) both that these sociological concepts can be enriched by their application to detailed comparative case study of regulatory science, and that they provide an important policy-relevant framework with which to understand discrepant drug regulatory processes in a sociohistorical context. It is found that regulatory expectations and paradigms may be regarded as mediating factors between political culture and structural interests, on the one hand, and the outcomes of regulatory science, on the other. (shrink)

Consolidation of long-term memory is a highly and precisely regulated multistep process. The transcription regulator cAMP response element-binding protein (CREB) plays a key role in initiating memory consolidation. With time processing, first the cofactors are changed and, secondly, CREB gets dispensable. This ultimately changes the expressed gene program to genes required to maintain the memory. Regulation of memory consolidation also requires epigenetic mechanisms and control at the RNA level. At the neuronal circuit level, oscillation in the activity of CREB and (...) downstream factor define engram cells. Together the combination of all regulation mechanisms allows correct memory processing while keeping the process dynamic and flexible to adjust to different contexts. Also see the video abstract here https://youtu.be/BhSCSmorpEc. (shrink)

Mouse pre‐implantation development appears to be under the control of paracrine and autocrine growth factors. The epithelium of the oviduct and the uterus together, with the population of macrophages and lymphocytes present in the reproductive tract from the onset of pregnancy, are thought to be the major sources of paracrine growth factors targeted to the developing embryos. Some of the growth factors are synthesized by both uterine epithelial cells and activated lympho‐hematopoietic cells, suggesting a partial overlap of (...) the regulatory signals used by the reproductive and lympho‐hematopoietic systems. Such growth factors may be the long sought‐after mediators of the synchrony between the pre‐implantation embryo and the sex‐steroid hormone‐induced changes in the uterus. (shrink)