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Sample records for developing retinocollicular pathway

  1. Cultural pathways through universal development.

    Science.gov (United States)

    Greenfield, Patricia M; Keller, Heidi; Fuligni, Andrew; Maynard, Ashley

    2003-01-01

    We focus our review on three universal tasks of human development: relationship formation, knowledge acquisition, and the balance between autonomy and relatedness at adolescence. We present evidence that each task can be addressed through two deeply different cultural pathways through development: the pathways of independence and interdependence. Whereas core theories in developmental psychology are universalistic in their intentions, they in fact presuppose the independent pathway of development. Because the independent pathway is therefore well-known in psychology, we focus a large part of our review on empirically documenting the alternative, interdependent pathway for each developmental task. We also present three theoretical approaches to culture and development: the ecocultural, the sociohistorical, and the cultural values approach. We argue that an understanding of cultural pathways through human development requires all three approaches. We review evidence linking values (cultural values approach), ecological conditions (ecocultural approach), and socialization practices (sociohistorical approach) to cultural pathways through universal developmental tasks.

  2. Signaling pathways regulating murine pancreatic development

    DEFF Research Database (Denmark)

    Serup, Palle

    2012-01-01

    The recent decades have seen a huge expansion in our knowledge about pancreatic development. Numerous lineage-restricted transcription factor genes have been identified and much has been learned about their function. Similarly, numerous signaling pathways important for pancreas development have...... been identified and the specific roles have been investigated by genetic and cell biological methods. The present review presents an overview of the principal signaling pathways involved in regulating murine pancreatic growth, morphogenesis, and cell differentiation....

  3. Identifying pathways of teachers’ PCK development

    NARCIS (Netherlands)

    Wongsopawiro, Dirk S.; Zwart, Rosanne C.; van Driel, Jan H.

    2017-01-01

    This paper describes a method of analysing teacher growth in the context of science education. It focuses on the identification of pathways in the development of secondary school teachers’ pedagogical content knowledge (PCK) by the use of the interconnected model of teachers’ professional growth

  4. Unsustainable development pathways caused by tropical deforestation.

    Science.gov (United States)

    Carrasco, Luis Roman; Nghiem, Thi Phuong Le; Chen, Zhirong; Barbier, Edward B

    2017-07-01

    Global sustainability strategies require assessing whether countries' development trajectories are sustainable over time. However, sustainability assessments are limited because losses of natural capital and its ecosystem services through deforestation have not been comprehensively incorporated into national accounts. We update the national accounts of 80 nations that underwent tropical deforestation from 2000 to 2012 and evaluate their development trajectories using weak and strong sustainability criteria. Weak sustainability requires that countries do not decrease their aggregate capital over time. We adopt a strong sustainability criterion that countries do not decrease the value of their forest ecosystem services with respect to the year 2000. We identify several groups of countries: countries, such as Sri Lanka, Bangladesh, and India, that present sustainable development trajectories under both weak and strong sustainability criteria; countries, such as Brazil, Peru, and Indonesia, that present weak sustainable development but fail the strong sustainability criterion as a result of rapid losses of ecosystem services; countries, such as Madagascar, Laos, and Papua New Guinea, that present unsustainable development pathways as a result of deforestation; and countries, such as Democratic Republic of Congo and Sierra Leone, in which deforestation aggravates already unsustainable pathways. Our results reveal a large number of countries where tropical deforestation is both damaging to nature and not compensated by development in other sectors, thus compromising the well-being of their future generations.

  5. Accelerating Adverse Outcome Pathway (AOP) development ...

    Science.gov (United States)

    The Adverse Outcome Pathway (AOP) framework is increasingly being adopted as a tool for organizing and summarizing the mechanistic information connecting molecular perturbations by environmental stressors with adverse outcomes relevant for ecological and human health outcomes. However, the conventional process for assembly of these AOPs is time and resource intensive, and has been a rate limiting step for AOP use and development. Therefore computational approaches to accelerate the process need to be developed. We previously developed a method for generating computationally predicted AOPs (cpAOPs) by association mining and integration of data from publicly available databases. In this work, a cpAOP network of ~21,000 associations was established between 105 phenotypes from TG-GATEs rat liver data from different time points (including microarray, pathological effects and clinical chemistry data), 994 REACTOME pathways, 688 High-throughput assays from ToxCast and 194 chemicals. A second network of 128,536 associations was generated by connecting 255 biological target genes from ToxCast to 4,980 diseases from CTD using either HT screening activity from ToxCast for 286 chemicals or CTD gene expression changes in response to 2,330 chemicals. Both networks were separately evaluated through manual extraction of disease-specific cpAOPs and comparison with expert curation of the relevant literature. By employing data integration strategies that involve the weighting of n

  6. Regulatory pathways for vaccines for developing countries.

    Science.gov (United States)

    Milstien, Julie; Belgharbi, Lahouari

    2004-01-01

    Vaccines that are designed for use only in developing countries face regulatory hurdles that may restrict their use. There are two primary reasons for this: most regulatory authorities are set up to address regulation of products for use only within their jurisdictions and regulatory authorities in developing countries traditionally have been considered weak. Some options for regulatory pathways for such products have been identified: licensing in the country of manufacture, file review by the European Medicines Evaluation Agency on behalf of WHO, export to a country with a competent national regulatory authority (NRA) that could handle all regulatory functions for the developing country market, shared manufacturing and licensing in a developing country with competent manufacturing and regulatory capacity, and use of a contracted independent entity for global regulatory approval. These options have been evaluated on the basis of five criteria: assurance of all regulatory functions for the life of the product, appropriateness of epidemiological assessment, applicability to products no longer used in the domestic market of the manufacturing country, reduction of regulatory risk for the manufacturer, and existing rules and regulations for implementation. No one option satisfies all criteria. For all options, national infrastructures (including the underlying regulatory legislative framework, particularly to formulate and implement local evidence-based vaccine policy) must be developed. WHO has led work to develop this capacity with some success. The paper outlines additional areas of action required by the international community to assure development and use of vaccines needed for the developing world. PMID:15042235

  7. Metabolic Pathways Visualization Skills Development by Undergraduate Students

    Science.gov (United States)

    dos Santos, Vanessa J. S. V.; Galembeck, Eduardo

    2015-01-01

    We have developed a metabolic pathways visualization skill test (MPVST) to gain greater insight into our students' abilities to comprehend the visual information presented in metabolic pathways diagrams. The test is able to discriminate students' visualization ability with respect to six specific visualization skills that we identified as key to…

  8. Pathways to Inclusive Development through Innovation, Technology ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Technology and innovation can drive economic growth, help solve social and ... capacities within developing countries to create inclusive growth and poverty ... science, population and public health, and health systems research relevant to the ...

  9. Winding through the WNT pathway during cellular development and demise.

    Science.gov (United States)

    Li, F; Chong, Z Z; Maiese, K

    2006-01-01

    In slightly over a period of twenty years, our comprehension of the cellular and molecular mechanisms that govern the Wnt signaling pathway continue to unfold. The Wnt proteins were initially implicated in viral carcinogenesis experiments associated with mammary tumors, but since this period investigations focusing on the Wnt pathways and their transmembrane receptors termed Frizzled have been advanced to demonstrate the critical nature of Wnt for the development of a variety of cell populations as well as the potential of the Wnt pathway to avert apoptotic injury. In particular, Wnt signaling plays a significant role in both the cardiovascular and nervous systems during embryonic cell patterning, proliferation, differentiation, and orientation. Furthermore, modulation of Wnt signaling under specific cellular influences can either promote or prevent the early and late stages of apoptotic cellular injury in neurons, endothelial cells, vascular smooth muscle cells, and cardiomyocytes. A number of downstream signal transduction pathways can mediate the biological response of the Wnt proteins that include Dishevelled, beta-catenin, intracellular calcium, protein kinase C, Akt, and glycogen synthase kinase-3beta. Interestingly, these cellular cascades of the Wnt-Frizzled pathways can participate in several neurodegenerative, vascular, and cardiac disorders and may be closely integrated with the function of trophic factors. Identification of the critical elements that modulate the Wnt-Frizzled signaling pathway should continue to unlock the potential of Wnt pathway for the development of new therapeutic options against neurodegenerative and vascular diseases.

  10. Development, Implementation and Compliance of Treatment Pathways in Radiation Medicine

    Directory of Open Access Journals (Sweden)

    Louis ePotters

    2013-05-01

    Full Text Available INTRODUCTION: While much emphasis on safety in the radiation oncology clinic is placed on process, there remains considerable opportunity to increase safety, enhance outcomes and avoid ad-hoc care by instituting detailed treatment pathways. The purpose of this study was to review the process of developing evidence and consensus-based, outcomes-oriented treatment pathways that standardize treatment and patient management in a large multicenter radiation oncology practice. Further, we reviewed our compliance in incorporating these directives into our day-to-day clinical practice. METHODS: Using the Institute of Medicine guideline for developing treatment pathways, 87 disease specific pathways were developed and incorporated into the electronic medical system in our multi-facility radiation oncology department. Compliance in incorporating treatment pathways was assessed by mining our EMR data from January 1, 2010 through February 2012 for patients with breast and prostate cancer. RESULTS: This retrospective analysis of data from electronic medical records found overall compliance to breast and prostate cancer treatment pathways to be 97% and 99%, respectively. The reason for non-compliance proved to be either a failure to complete the prescribed care based on grade II or III toxicity (n=1 breast, 3 prostate or patient elected discontinuance of care (n=1 prostate or the physician chose a higher dose for positive/close margins (n=3 breast. CONCLUSION: This study demonstrates that consensus and evidence-based treatment pathways can be developed and implemented in a multi-center department of radiation oncology. And that for prostate and breast cancer there was a high degree of compliance using these directives. The development and implementation of these pathways serve as a key component of our safety program, most notably in our effort to facilitate consistent decision-making and reducing variation between physicians.

  11. Nudges, Pulls, and Serendipity: Multiple Pathways to Faculty Development

    Science.gov (United States)

    Stockley, Denise; McDonald, Jeanette; Hoessler, Carolyn

    2015-01-01

    Building on the rich faculty development literature worldwide, recent scholarship on the advancement, professionalism, and career paths of individuals entering the field has received greater attention. Through focus group discussions, faculty developers from colleges and universities around the world shared their pathways into and through faculty…

  12. How Stuttering Develops: The Multifactorial Dynamic Pathways Theory

    Science.gov (United States)

    Smith, Anne; Weber, Christine

    2017-01-01

    Purpose: We advanced a multifactorial, dynamic account of the complex, nonlinear interactions of motor, linguistic, and emotional factors contributing to the development of stuttering. Our purpose here is to update our account as the multifactorial dynamic pathways theory. Method: We review evidence related to how stuttering develops, including…

  13. The hippo pathway in heart development, regeneration, and diseases.

    Science.gov (United States)

    Zhou, Qi; Li, Li; Zhao, Bin; Guan, Kun-Liang

    2015-04-10

    The heart is the first organ formed during mammalian development. A properly sized and functional heart is vital throughout the entire lifespan. Loss of cardiomyocytes because of injury or diseases leads to heart failure, which is a major cause of human morbidity and mortality. Unfortunately, regenerative potential of the adult heart is limited. The Hippo pathway is a recently identified signaling cascade that plays an evolutionarily conserved role in organ size control by inhibiting cell proliferation, promoting apoptosis, regulating fates of stem/progenitor cells, and in some circumstances, limiting cell size. Interestingly, research indicates a key role of this pathway in regulation of cardiomyocyte proliferation and heart size. Inactivation of the Hippo pathway or activation of its downstream effector, the Yes-associated protein transcription coactivator, improves cardiac regeneration. Several known upstream signals of the Hippo pathway such as mechanical stress, G-protein-coupled receptor signaling, and oxidative stress are known to play critical roles in cardiac physiology. In addition, Yes-associated protein has been shown to regulate cardiomyocyte fate through multiple transcriptional mechanisms. In this review, we summarize and discuss current findings on the roles and mechanisms of the Hippo pathway in heart development, injury, and regeneration. © 2015 American Heart Association, Inc.

  14. Ecosystem services for meeting sustainable development goals: Challenges and pathways

    Directory of Open Access Journals (Sweden)

    Huq Nazmul

    2015-01-01

    Full Text Available The paper summarizes four presentations of the session “Environment and Wellbeing: The Role of Ecosystems for Sustainable Development” at the international conference “Sustainability in the Water- Energy-Food Nexus” held on 19-20th May 2014 in Bonn, Germany. The aim of the session was to present current stresses on ecosystem services imposed by global development trajectory, potential impacts on Sustainable Development Goals (SDGs and pathways to achieve SDGs. All four presentations agreed that global ecosystem services are under increasing pressure from degradation and may not be able to meet the growing Water-Energy- Food (WEF demands especially for the developing world. Three examples from Tanzania, Cambodia and Niger made attempt to understand how governance policies attributed to natural resource depletion such as forestry and common grazing. The examples showed that governance policies favoring economic development are heavily contributing to clearing up natural resource bases. As a result, there were increasing conflicts among different resource user groups. Two other presentations introduce conceptual pathways to achieve the targets of Sustainable Development Goals (SDGs under current resource stressed regime. The pathways suggested global technologies, decentralized solutions and consumption changes as the major means of achieving global sustainability and poverty eradication without any major trade-offs.

  15. Ecosystem services for meeting sustainable development goals: Challenges and pathways

    Directory of Open Access Journals (Sweden)

    Huq Nazmul

    2015-01-01

    Full Text Available The paper summarizes four presentations of the session “Environment and Wellbeing: The Role of Ecosystems for Sustainable Development” at the international conference “Sustainability in the Water- Energy-Food Nexus” held on 19-20th May 2014 in Bonn, Germany. The aim of the session was to present current stresses on ecosystem services imposed by global development trajectory, potential impacts on future Sustainable Development Goals (SDGs and pathways to achieve SDGs. All four presentations agreed that global ecosystem services are under increasing pressure from degradation and may not be able to meet the growing Water-Energy-Food (WEF demands especially for the developing world. Three examples from Tanzania, Cambodia and Niger made attempt to understand how government policies attributed to natural resource depletion such as forestry and common grazing. The examples showed that institutional policies favoring economic development contributing heavily to clearing up natural resource bases. As a result, there were increasing conflicts among different resource user groups. Two other presentations introduce conceptual pathways to achieve the targets of Sustainable Development Goals (SDGs under current resource stressed regime. The pathways suggested global technologies, decentralized solutions and consumption changes as the major means of achieving global sustainability and poverty eradication without any major trade-offs.

  16. Development of an Ingestion Pathway Model for AXAIRQ

    Energy Technology Data Exchange (ETDEWEB)

    Simpkins, A.A.

    1999-01-13

    AXAIRQ is a dose mode code used for prospective accident assessment at the Savannah River Site and is primarily used to show regulatory compliance. For completeness of pathway analysis, an ingestion model, AXINGST, has been developed for use with, and incorporation in, AXAIRQ. Currently available ingestion models were referenced as a basis for AXINGST. AXINGST calculates a conservative ingestion dose following an atmospheric release of radionuclides and includes site specific variables where applicable.

  17. Pathways to URM Retention: IBP's Professional Development and Mentoring Activities

    Science.gov (United States)

    Johnson, A.; Williamson Whitney, V.; Ricciardi, L.; Detrick, L.; Siegfried, D.; Fauver, A.; Ithier-Guzman, W.; Thomas, S. H.; Valaitis, S.

    2013-05-01

    As a not for profit organization, the Institute for Broadening Participation (IBP) hosts a variety of initiatives designed to increase the retention of underrepresented minority (URM) students pursuing pathways in STEM. IBP also assists with formative program evaluation design and implementation to help strengthen URM recruitment and retention elements. Successful initiatives include virtual and face-to-face components that bring together URM students with established URM and other scientists in academia, government and industry. These connections provide URMs with mentoring, networking opportunities, and professional skill development contributing to an improved retention rate of URM students. IBP's initiatives include the NASA One Stop Shopping Initiative (NASA OSSI), Pathways to Ocean Science and Engineering, and the Minorities Striving and Pursuing Higher Degrees of Success (MS PHD'S) in Earth System Science (ESS) Professional Development Program. The NASA OSSI recruits and facilitates student engagement in NASA education and employment opportunities. Pathways to Ocean Science connects and supports URM students with Ocean Science REU programs and serves as a resource for REU program directors. Pathways to Engineering has synthesized mentoring resources into an online mentoring manual for URM students that has been extensively vetted by mentoring experts throughout the country. The mentoring manual, which is organized by roles, provides undergraduates, graduates, postdocs, faculty and project directors with valuable resources. MS PHD'S, one of IBP's longest running and most successful initiatives, focuses on increasing the retention rate of URM students receiving advanced degrees in ESS. The program addresses barriers to retention in ESS including isolation, lack of preparation and professional development, and lack of mentoring. Program activities center on peer-to-peer community building, professional development exercises, networking experiences, one

  18. Development of a renal transplant clinical pathway: one hospital's journey.

    Science.gov (United States)

    Darrikhuma, I M

    1999-05-01

    Mounting pressures to resolve multiple challenges related to quality, cost, and access in a resource-driven, customer-focused health care environment have compelled clinicians to develop innovative strategies to provide cost-effective, state-of-the-art care. Targeted patient groups include those associated with high cost, high volume, or high resource use. Patients undergoing renal transplantation fall into one or more of these categories. Recently, the management of patients with end-stage renal disease (ESRD) has come under national focus, as evidenced by the fact that Health Care Financing Administration (HCFA) has commissioned an ESRD managed care demonstration project. The purpose of this article is to describe how one case management tool--the clinical pathway--can be used to decrease costs and improve outcomes associated with renal transplantation. This discussion will include a review of the origins and components of clinical pathways and a description of how one institution developed, implemented, evaluated, and refined a renal transplantation clinical pathway.

  19. Adverse outcome pathway development from protein alkylation to liver fibrosis.

    Science.gov (United States)

    Horvat, Tomislav; Landesmann, Brigitte; Lostia, Alfonso; Vinken, Mathieu; Munn, Sharon; Whelan, Maurice

    2017-04-01

    In modern toxicology, substantial efforts are undertaken to develop alternative solutions for in vivo toxicity testing. The adverse outcome pathway (AOP) concept could facilitate knowledge-based safety assessment of chemicals that does not rely exclusively on in vivo toxicity testing. The construction of an AOP is based on understanding toxicological processes at different levels of biological organisation. Here, we present the developed AOP for liver fibrosis and demonstrate a linkage between hepatic injury caused by chemical protein alkylation and the formation of liver fibrosis, supported by coherent and consistent scientific data. This long-term process, in which inflammation, tissue destruction, and repair occur simultaneously, results from the complex interplay between various hepatic cell types, receptors, and signalling pathways. Due to the complexity of the process, an adequate liver fibrosis cell model for in vitro evaluation of a chemical's fibrogenic potential is not yet available. Liver fibrosis poses an important human health issue that is also relevant for regulatory purposes. An AOP described with enough mechanistic detail might support chemical risk assessment by indicating early markers for downstream events and thus facilitating the development of an in vitro testing strategy. With this work, we demonstrate how the AOP framework can support the assembly and coherent display of distributed mechanistic information from the literature to support the use of alternative approaches for prediction of toxicity. This AOP was developed according to the guidance document on developing and assessing AOPs and its supplement, the users' handbook, issued by the Organisation for Economic Co-operation and Development.

  20. Notch pathway signaling in the skin antagonizes Merkel cell development.

    Science.gov (United States)

    Logan, Gregory J; Wright, Margaret C; Kubicki, Adam C; Maricich, Stephen M

    2018-02-15

    Merkel cells are mechanosensitive skin cells derived from the epidermal lineage whose development requires expression of the basic helix-loop-helix transcription factor Atoh1. The genes and pathways involved in regulating Merkel cell development during embryogenesis are poorly understood. Notch pathway signaling antagonizes Atoh1 expression in many developing body regions, so we hypothesized that Notch signaling might inhibit Merkel cell development. We found that conditional, constitutive overexpression of the Notch intracellular domain (NICD) in mouse epidermis significantly decreased Merkel cell numbers in whisker follicles and touch domes of hairy skin. Conversely, conditional deletion of the obligate NICD binding partner RBPj in the epidermis significantly increased Merkel cell numbers in whisker follicles, led to the development of ectopic Merkel cells outside of touch domes in hairy skin epidermis, and altered the distribution of Merkel cells in touch domes. Deletion of the downstream Notch effector gene Hes1 also significantly increased Merkel cell numbers in whisker follicles. Together, these data demonstrate that Notch signaling regulates Merkel cell production and patterning. Copyright © 2018 Elsevier Inc. All rights reserved.

  1. Maternal smoking and the retinoid pathway in the developing lung

    Directory of Open Access Journals (Sweden)

    Manoli Sara E

    2012-06-01

    Full Text Available Abstract Background Maternal smoking is a risk factor for pediatric lung disease, including asthma. Animal models suggest that maternal smoking causes defective alveolarization in the offspring. Retinoic acid signaling modulates both lung development and postnatal immune function. Thus, abnormalities in this pathway could mediate maternal smoking effects. We tested whether maternal smoking disrupts retinoic acid pathway expression and functioning in a murine model. Methods Female C57Bl/6 mice with/without mainstream cigarette smoke exposure (3 research cigarettes a day, 5 days a week were mated to nonsmoking males. Cigarette smoke exposure continued throughout the pregnancy and after parturition. Lung tissue from the offspring was examined by mean linear intercept analysis and by quantitative PCR. Cell culture experiments using the type II cell-like cell line, A549, tested whether lipid-soluble cigarette smoke components affected binding and activation of retinoic acid response elements in vitro. Results Compared to tobacco-naïve mice, juvenile mice with tobacco toxin exposure had significantly (P  Conclusions A murine model of maternal cigarette smoking causes abnormal alveolarization in association with altered retinoic acid pathway element expression in the offspring. An in vitro cell culture model shows that lipid-soluble components of cigarette smoke decrease retinoic acid response element activation. It is feasible that disruption of retinoic acid signaling contributes to the pediatric lung dysfunction caused by maternal smoking.

  2. Pathways, Pitfalls and Opportunities in Partnerships for Development

    DEFF Research Database (Denmark)

    Christensen, David; Vanhill, Josefine; Wolf, Andreas

    The municipal solid waste management systems of many developing countries are commonly constrained by factors such as limited financial resources and poor governance, making it a difficult proposition to break with complex, entrenched and unsustainable technologies and systems. This paper...... some lessons in such partnership building: In Uganda and Denmark respectively, the World Wildlife Fund and the network-administrating organization access2innovation have attempted to mobilize stakeholders around improving the municipal solid waste system in the rural district capital of Kasese. Through...... a municipal solid waste system characterization and mapping exercise, some emergent lessons and guiding principles in partnership building point to both pitfalls and opportunities for designing sustainable pathways....

  3. Transitions in pathways of human development and carbon emissions

    International Nuclear Information System (INIS)

    Lamb, W F; Bows-Larkin, A; Wood, F R; Steinberger, J K; Peters, G P; Roberts, J T

    2014-01-01

    Countries are known to follow diverse pathways of life expectancy and carbon emissions, but little is known about factors driving these dynamics. In this letter we estimate the cross-sectional economic, demographic and geographic drivers of consumption-based carbon emissions. Using clustering techniques, countries are grouped according to their drivers, and analysed with respect to a criteria of one tonne of carbon emissions per capita and a life expectancy over 70 years (Goldemberg’s Corner). Five clusters of countries are identified with distinct drivers and highly differentiated outcomes of life expectancy and carbon emissions. Representatives from four clusters intersect within Goldemberg’s Corner, suggesting diverse combinations of drivers may still lead to sustainable outcomes, presenting many countries with an opportunity to follow a pathway towards low-carbon human development. By contrast, within Goldemberg’s Corner, there are no countries from the core, wealthy consuming nations. These results reaffirm the need to address economic inequalities within international agreements for climate mitigation, but acknowledge plausible and accessible examples of low-carbon human development for countries that share similar underlying drivers of carbon emissions. In addition, we note differences in drivers between models of territorial and consumption-based carbon emissions, and discuss interesting exceptions to the drivers-based cluster analysis. (paper)

  4. Development of an open platform system for environmental pathway analysis

    International Nuclear Information System (INIS)

    LePoire, D. J.; Arnish, J. J.; Gnanapragasam, E.; Chen, S. Y.

    2001-01-01

    Most existing computer codes for environmental pathway modeling have been developed to satisfy a specific objective (e.g., perform analyses to demonstrate regulatory compliance). These codes were written in various computer languages and software environments over time and often are not mutually compatible. In recent years, largely driven by advancements in industrial software development, a new concept based on ''modularization'' has emerged. This approach entails the development of common ''modules,'' or components, that can be shared by and used in different applications that have certain common needs. For instance, an air dispersion model can be written as a common component to be shared by several different applications, each with the need to model air dispersion of some material release. When this concept is fully developed, modeling applications would become an exercise of selecting, integrating, and applying a consistent combination of appropriate pre-existing modules for a specific problem. Although modularization holds promising advantages over the traditional approach, a number of issues do exist. These issues must be fully addressed and resolved before the approach can be accepted as a new paradigm for environmental modeling. This paper discusses these issues and provides recommendations and a course of actions for future development

  5. Pathways of human development and carbon emissions embodied in trade

    Science.gov (United States)

    Steinberger, Julia K.; Timmons Roberts, J.; Peters, Glen P.; Baiocchi, Giovanni

    2012-02-01

    It has long been assumed that human development depends on economic growth, that national economic expansion in turn requires greater energy use and, therefore, increased greenhouse-gas emissions. These interdependences are the topic of current research. Scarcely explored, however, is the impact of international trade: although some nations develop socio-economically and import high-embodied-carbon products, it is likely that carbon-exporting countries gain significantly fewer benefits. Here, we use new consumption-based measures of national carbon emissions to explore how the relationship between human development and carbon changes when we adjust national emission rates for trade. Without such adjustment of emissions, some nations seem to be getting far better development `bang' for the carbon `buck' than others, who are showing scant gains for disproportionate shares of global emissions. Adjusting for the transfer of emissions through trade explains many of these outliers, but shows that further socio-economic benefits are accruing to carbon-importing rather than carbon-exporting countries. We also find that high life expectancies are compatible with low carbon emissions but high incomes are not. Finally, we see that, despite strong international trends, there is no deterministic industrial development trajectory: there is great diversity in pathways, and national histories do not necessarily follow the global trends.

  6. Standardising school nursing practice: developing and implementing a care pathways package.

    Science.gov (United States)

    Turney, Nicy; Clarke, Maggie; Stevenson, Emily

    2012-11-01

    The NHS has a longstanding relationship with care pathways for managing clinical processes and patient outcomes. Care pathways are an effective mechanism to improve the delivery of services in managing children's health. However, few individual NHS trusts have successfully developed and implemented local pathways. This paper describes the development and implementation of a comprehensive care pathways package for school nursing in a community health services trust in the East Midlands.

  7. Traffic pathways of Plasmodium vivax antigens during intraerythrocytic parasite development.

    Science.gov (United States)

    Bracho, Carmen; Dunia, Irene; De, La Rosa Mercedes; Benedetti, Ennio-Lucio; Perez, Hilda A

    2002-03-01

    We investigated the secretory traffic of a Plasmodium vivax antigen (Pv-148) synthesised by the parasite during the blood cycle, exported into the host cell cytosol and then transported to the surface membrane of the infected erythrocyte. Studies of the ultrastructure of erythrocytes infected with P. vivax showed that intracellular schizogony is accompanied by the generation of parasite-induced membrane profiles in the erythrocyte cytoplasm. These structures are detectable soon after the parasite invades the erythrocyte and develop an elaborate organisation, leading to a tubovesicular membrane (TVM) network, in erythrocytes infected with mature trophozoites. Interestingly, the clefts formed stacked, flattened cisternae resembling a classical Golgi apparatus. The TVM network stained with the fluorescent Golgi marker Bodipy-ceramide. Specific immunolabelling showed that Pv-148 was transferred from the parasite to the erythrocyte surface membrane via the clefts and the TVM network. These findings suggest that the TVM network is part of the secretory pathways involved in parasite protein transport across the Plasmodium-infected erythrocyte and that Pv- 148 may represent a marker that links the parasite with the host cell cytoplasm and, in turn, with the extracellular milieu.

  8. Measures of Hindu Pathways: Development and Preliminary Evidence of Reliability and Validity.

    Science.gov (United States)

    Tarakeshwar, Nalini; Pargament, Kenneth I.; Mahoney, Annette

    2003-01-01

    Examines religious practices of Hindus in the United States and develops measures of their religious pathways. Four religious pathways were identified: devotion, ethical action, knowledge, and physical restraint/yoga. Results indicate that the measures of the religious pathways possessed adequate psychometric properties and were predictive of…

  9. Adverse Outcome Pathway (AOP) Network Development for Fatty Liver

    Science.gov (United States)

    Adverse outcome pathways (AOPs) are descriptive biological sequences that start from a molecular initiating event (MIE) and end with an adverse health outcome. AOPs provide biological context for high throughput chemical testing and further prioritize environmental health risk re...

  10. Bioenergy development pathways for Europe. Potentials, costs and environmental impacts

    Energy Technology Data Exchange (ETDEWEB)

    De Wit, M.P.

    2011-09-26

    Fossil resources dominate the global energy system today which cannot be sustained indefinitely. Bioenergy use can meet a large share of future energy supply sustainably. For example, it can substitute fossil fuels including petroleum, and when sustainably produced, bioenergy avoids greenhouse gas emissions. However, with the recent increase of modern bioenergy use several drawbacks have become apparent that may lead to negative ecological impacts. Europe plays an important role in the further sustainable development of bioenergy due to its ambitious renewable energy policies and its state-of-the-art agricultural sector. The main objective of this thesis is to evaluate development pathways for bioenergy in Europe by assessing preconditions for its development, an economic outlook for such development and an assessment of its environmental implications. The technical European biomass potential has a substantial potential to contribute to Europe's energy consumption. Energy crop production on European croplands and grasslands supplemented with agricultural and forestry residues offers an ultimate technical potential of 27.7 EJ y-1. These findings were based on the assumption that agricultural land needs for future domestic food production decrease as productivities per hectare increase. Central and Eastern Europe pose the more attractive region with relatively high potentials and low costs. In European agriculture, it is possible to combine large-scale biomass production with food production sustained at current levels, without direct or indirect land-use changes and while accomplishing significant net cumulative greenhouse gas emission reductions when both bioenergy and agricultural production are considered. To accomplish this situation two preconditions need to be met: a gradual intensification of food production and implementation of structural improvements to agricultural management. Based on the current economic performance and future prospects for

  11. Conceptualizing pathways linking women's empowerment and prematurity in developing countries.

    Science.gov (United States)

    Afulani, Patience A; Altman, Molly; Musana, Joseph; Sudhinaraset, May

    2017-11-08

    Globally, prematurity is the leading cause of death in children under the age of 5. Many efforts have focused on clinical approaches to improve the survival of premature babies. There is a need, however, to explore psychosocial, sociocultural, economic, and other factors as potential mechanisms to reduce the burden of prematurity. Women's empowerment may be a catalyst for moving the needle in this direction. The goal of this paper is to examine links between women's empowerment and prematurity in developing settings. We propose a conceptual model that shows pathways by which women's empowerment can affect prematurity and review and summarize the literature supporting the relationships we posit. We also suggest future directions for research on women's empowerment and prematurity. The key words we used for empowerment in the search were "empowerment," "women's status," "autonomy," and "decision-making," and for prematurity we used "preterm," "premature," and "prematurity." We did not use date, language, and regional restrictions. The search was done in PubMed, Population Information Online (POPLINE), and Web of Science. We selected intervening factors-factors that could potentially mediate the relationship between empowerment and prematurity-based on reviews of the risk factors and interventions to address prematurity and the determinants of those factors. There is limited evidence supporting a direct link between women's empowerment and prematurity. However, there is evidence linking several dimensions of empowerment to factors known to be associated with prematurity and outcomes for premature babies. Our review of the literature shows that women's empowerment may reduce prematurity by (1) preventing early marriage and promoting family planning, which will delay age at first pregnancy and increase interpregnancy intervals; (2) improving women's nutritional status; (3) reducing domestic violence and other stressors to improve psychological health; and (4) improving

  12. Development of net energy ratio for quad-generation pathways

    DEFF Research Database (Denmark)

    Rudra, Souman; Rosendahl, Lasse; Kumar, Amit

    2012-01-01

    The conversion of biomass to four different outputs via gasification and catalytic methanation is a renewable technology that could reduce the use of fossil fuels and GHG emissions. This study investigates the energy aspects of producing electricity, heat, methanol and methane. The Gas Technology...... Institute (GTI) gasifier and Circulating Fluidized Bed (CFB) technologies are used for this quad generation process. Three different biomass feedstocks are considered in this study. The net energy ratio for six different pathways having the range of between 1.3–9.3. The lowest limit corresponds to the straw......-based power, heat, methanol and methane production pathway using GTI technology. Since more efficient alternatives exist for the generation of heat and electricity from biomass, it is argued that syngas is best used for methanol production. The aim of this study was to evaluate the energy performance...

  13. Wnt and the Wnt signaling pathway in bone development and disease

    Science.gov (United States)

    Wang, Yiping; Li, Yi-Ping; Paulson, Christie; Shao, Jian-Zhong; Zhang, Xiaoling; Wu, Mengrui; Chen, Wei

    2014-01-01

    Wnt signaling affects both bone modeling, which occurs during development, and bone remodeling, which is a lifelong process involving tissue renewal. Wnt signals are especially known to affect the differentiation of osteoblasts. In this review, we summarize recent advances in understanding the mechanisms of Wnt signaling, which is divided into two major branches: the canonical pathway and the noncanonical pathway. The canonical pathway is also called the Wnt/β-catenin pathway. There are two major noncanonical pathways: the Wnt-planar cell polarity pathway (Wnt-PCP pathway) and the Wnt-calcium pathway (Wnt-Ca2+ pathway). This review also discusses how Wnt ligands, receptors, intracellular effectors, transcription factors, and antagonists affect both the bone modeling and bone remodeling processes. We also review the role of Wnt ligands, receptors, intracellular effectors, transcription factors, and antagonists in bone as demonstrated in mouse models. Disrupted Wnt signaling is linked to several bone diseases, including osteoporosis, van Buchem disease, and sclerosteosis. Studying the mechanism of Wnt signaling and its interactions with other signaling pathways in bone will provide potential therapeutic targets to treat these bone diseases. PMID:24389191

  14. Asymmetry of radial and symmetry of tangential neuronal migration pathways in developing human fetal brains

    Directory of Open Access Journals (Sweden)

    Yuta eMiyazaki

    2016-01-01

    Full Text Available AbstractThe radial and tangential neural migration pathways are two major neuronal migration streams in humans that are critical during corticogenesis. Corticogenesis is a complex process of neuronal proliferation that is followed by neuronal migration and the formation of axonal connections. Existing histological assessments of these two neuronal migration pathways have limitations inherent to microscopic studies and are confined to small anatomic regions of interest. Thus, little evidence is available about their three-dimensional fiber pathways and development throughout the entire brain. In this study, we imaged and analyzed radial and tangential migration pathways in the whole human brain using high-angular resolution diffusion MR imaging (HARDI tractography. We imaged ten fixed, postmortem fetal (17 gestational weeks (GW, 18 GW, 19 GW, three 20 GW, three 21 GW and 22 GW and eight in vivo newborn (two 30 GW, 34 GW, 35 GW and four 40 GW brains with no neurological/pathological conditions. We statistically compared the volume of the left and right radial and tangential migration pathways, and the volume of the radial migration pathways of the anterior and posterior regions of the brain. In specimens 22 GW or younger, the volume of radial migration pathways of the left hemisphere was significantly larger than that of the right hemisphere. The volume of posterior radial migration pathways was also larger when compared to the anterior pathways in specimens 22 GW or younger. In contrast, no significant differences were observed in the radial migration pathways of brains older than 22 GW. Moreover, our study did not identify any significant differences in volumetric laterality in the tangential migration pathways. These results suggest that these two neuronal migration pathways develop and regress differently, and radial neuronal migration varies regionally based on hemispheric and anterior-posterior laterality, potentially explaining regional

  15. Beyond Superheroes and Advocacy: The Pathway of Teacher Leadership Development

    Science.gov (United States)

    Smylie, Mark A.; Eckert, Jonathan

    2018-01-01

    This article introduces new perspectives, principles and recommendations for the successful development of teacher leadership. It draws from literature on teacher leadership, work redesign, and on-the-job leadership development to explore key insights and questions for teacher leadership development, and it presents a conceptual-theoretical model…

  16. Ecdysone receptor agonism leading to lethal molting disruption in arthropods: Review and adverse outcome pathway development

    Science.gov (United States)

    Molting is a key biological process in growth, development, reproduction and survival in arthropods. Complex neuroendocrine pathways are involved in the regulation of molting and may potentially become targets of environmental endocrine disrupting compounds (EDCs). For example, s...

  17. BAD-mediated apoptotic pathway is associated with human cancer development.

    Science.gov (United States)

    Stickles, Xiaomang B; Marchion, Douglas C; Bicaku, Elona; Al Sawah, Entidhar; Abbasi, Forough; Xiong, Yin; Bou Zgheib, Nadim; Boac, Bernadette M; Orr, Brian C; Judson, Patricia L; Berry, Amy; Hakam, Ardeshir; Wenham, Robert M; Apte, Sachin M; Berglund, Anders E; Lancaster, Johnathan M

    2015-04-01

    The malignant transformation of normal cells is caused in part by aberrant gene expression disrupting the regulation of cell proliferation, apoptosis, senescence and DNA repair. Evidence suggests that the Bcl-2 antagonist of cell death (BAD)-mediated apoptotic pathway influences cancer chemoresistance. In the present study, we explored the role of the BAD-mediated apoptotic pathway in the development and progression of cancer. Using principal component analysis to derive a numeric score representing pathway expression, we evaluated clinico-genomic datasets (n=427) from corresponding normal, pre-invasive and invasive cancers of different types, such as ovarian, endometrial, breast and colon cancers in order to determine the associations between the BAD-mediated apoptotic pathway and cancer development. Immunofluorescence was used to compare the expression levels of phosphorylated BAD [pBAD (serine-112, -136 and -155)] in immortalized normal and invasive ovarian, colon and breast cancer cells. The expression of the BAD-mediated apoptotic pathway phosphatase, PP2C, was evaluated by RT-qPCR in the normal and ovarian cancer tissue samples. The growth-promoting effects of pBAD protein levels in the immortalized normal and cancer cells were assessed using siRNA depletion experiments with MTS assays. The expression of the BAD-mediated apoptotic pathway was associated with the development and/or progression of ovarian (n=106, pBAD-mediated apoptotic pathway is thus associated with the development of human cancers likely influenced by the protein levels of pBAD.

  18. Game Development as a Pathway to Information Technology Literacy

    Science.gov (United States)

    Frydenberg, Mark

    2016-01-01

    Teaching game development has become an accepted methodology for introducing programming concepts and capturing the interest of beginning computer science and information technology (IT) students. This study, conducted over three consecutive semesters, explores game development using a gaming engine, rather than a traditional programming language,…

  19. Adverse outcome pathway networks I: Development and applications

    Science.gov (United States)

    The US EPA is developing more cost effective and efficient ways to evaluate chemical safety using high throughput and computationally based testing strategies. An important component of this approach is the ability to translate chemical effects on fundamental biological processes...

  20. Adverse outcome pathway networks: Development, analytics and applications

    Science.gov (United States)

    The US EPA is developing more cost effective and efficient ways to evaluate chemical safety using high throughput and computationally based testing strategies. An important component of this approach is the ability to translate chemical effects on fundamental biological processes...

  1. Different Pathways to Leadership Development of College Women and Men

    Science.gov (United States)

    Shim, Woo-jeong

    2013-01-01

    Analyzing data from the Wabash National Study of Liberal Arts Education, this study explored gender differences in the development and learning of college students' leadership capacities as framed with the Social Change Leadership Model (SCM). The results show that female students reported higher scores on six out of eight SCM values, and…

  2. Competition between meiotic and apomictic pathways during ovule and seed development results in clonality.

    Science.gov (United States)

    Hojsgaard, Diego H; Martínez, Eric J; Quarin, Camilo L

    2013-01-01

    Meiotic and apomictic reproductive pathways develop simultaneously in facultative aposporous species, and compete to form a seed as a final goal. This developmental competition was evaluated in tetraploid genotypes of Paspalum malacophyllum in order to understand the low level of sexuality in facultative apomictic populations. Cyto-embryology on ovules, flow cytometry on seeds and progeny tests by DNA fingerprinting were used to measure the relative incidence of each meiotic or apomictic pathway along four different stages of the plant's life cycle, namely the beginning and end of gametogenesis, seed formation and adult offspring. A high variation in the frequencies of sexual and apomictic pathways occurred at the first two stages. A trend of radical decline in realized sexuality was then observed. Sexual and apomictic seeds were produced, but the efficiency of the sexual pathway dropped drastically, and exclusively clonal offspring remained. Both reproductive pathways are unstable at the beginning of development, and only the apomictic one remains functional. Key factors reducing sexuality are the faster growth and parthenogenetic development in the aposporous pathway, and an (epi)genetically negative background related to the extensive gene de-regulation pattern responsible for apomixis. The effects of inbreeding depression during post-fertilization development may further decrease the frequency of effective sexuality. No claim to original US government works. New Phytologist © 2012 New Phytologist Trust.

  3. Nuclear hydrogen - cogeneration and the transitional pathway to sustainable development

    International Nuclear Information System (INIS)

    Gurbin, G.M.; Talbot, K.H.

    1994-01-01

    The development of the next phase of the Bruce Energy Centre, in cooperation with Ontario Hydro, will see the introduction of a series of integrated energy processes whose end products will have environmental value added. Cogenerated nuclear steam and electricity were selected on the basis of economics, sustainability and carbon emissions. The introduction of hydrogen to combine with CO 2 from alcohol fermentation provided synthetic methanol as a feedstock to refine into ether for the rapidly expanding gasoline fuel additive market, large volumes of O 2 will enhance combustion processes and improve closed-looping of the systems. In the implementation of the commercial development, the first stage will require simultaneous electrolysis, methanol synthesis and additional fermentation capacity. Electricity and steam pricing will be key to viability and an 80-MV 'backup' fossil-fuelled, back pressure turbine cogeneration facility could be introduced in a compatible matter. Successful demonstration of transitional and integrating elements necessary to achieve sustainable development can serve as a model for electric utilities throughout the world. 11 ref., 1 tab., 4 figs

  4. Development of a synthetic pathway for a sustainable plasticizer

    DEFF Research Database (Denmark)

    Søndergaard, Helle

    monooleate originating from sunflower oil. Sunflower oil is less expensive and more accessible compared to castor oil and the SNS-A has been tested to have the same plasticizing effect and non-toxic effects as SNS. However, a sustainable and cheap way of synthesizing SNS-A has not been developed. The aim...... and three different catalysts, known to be efficient in CTH reactions. However, no satisfying results were obtained using CTH as a hydrogenation method. Using molecular hydrogen gas for hydrogenation also resulted in problems. The hydrogenation of the epoxide obtained from epoxidation with peracetic acid...

  5. Opportunities to change development pathways toward lower greenhouse gas emissions through energy efficiency

    Energy Technology Data Exchange (ETDEWEB)

    Alterra, Swart; Masanet, Eric; Lecocq, Franck; Najam, Adil; Schaeffer, Robert; Winkler, Harald; Sathaye, Jayant

    2008-07-04

    There is a multiplicity of development pathways in which low energy sector emissions are not necessarily associated with low economic growth. However, changes in development pathways can rarely be imposed from the top. On this basis, examples of energy efficiency opportunities to change development pathways toward lower emissions are presented in this paper. We review opportunities at the sectoral and macro level. The potential for action on nonclimate policies that influence energy use and emissions are presented. Examples are drawn from policies already adopted and implemented in the energy sector. The paper discusses relationships between energy efficiency policies and their synergies and tradeoffs with sustainable development and greenhouse gas emissions. It points to ways that energy efficiency could be mainstreamed into devel?opment choices.

  6. Family processes as pathways from income to young children's development.

    Science.gov (United States)

    Linver, Miriam R; Brooks-Gunn, Jeanne; Kohen, Dafna E

    2002-09-01

    A variety of family processes have been hypothesized to mediate associations between income and young children's development. Maternal emotional distress, parental authoritative and authoritarian behavior (videotaped mother-child interactions), and provision of cognitively stimulating activities (Home Observation for Measurement of the Environment [HOME] scales) were examined as possible mediators in a sample of 493 White and African American low-birth-weight premature infants who were followed from birth through age 5. Cognitive ability was assessed by standardized test, and child behavior problems by maternal report, when the children were 3 and 5 years of age. As expected, family income was associated with child outcomes. The provision of stimulating experiences in the home mediated the relation between family income and both children's outcomes; maternal emotional distress and parenting practices mediated the relation between income and children's behavior problems.

  7. Amazonian Dark Earths: pathways to sustainable development in tropical rainforests?

    Directory of Open Access Journals (Sweden)

    Morgan Schmidt

    2013-04-01

    Full Text Available Fertile dark anthrosols associated with pre-Columbian settlement across the Amazon Basin have sparked wide interest for their potential contribution to sustainable use and management of tropical soils and ecosystems. In the Upper Xingu region of the southern Amazon, research on archaeological settlements and among contemporary descendant populations provides critical new data on the formation and use of anthrosols. These findings provide a basis for describing the variability of soil modifications that result from diverse human activities and a general model for the formation of Amazonian anthrosols. They underscore the potential for indigenous systems of knowledge and resource management to inform efforts for conservation and sustainable development of Amazonian ecosystems.

  8. Renal denervation therapy for hypertension: pathways for moving development forward.

    Science.gov (United States)

    White, William B; Galis, Zorina S; Henegar, Jeffrey; Kandzari, David E; Victor, Ronald; Sica, Domenic; Townsend, Raymond R; Turner, J Rick; Virmani, Renu; Mauri, Laura

    2015-05-01

    This scientific statement provides a summary of presentations and discussions at a cardiovascular Think Tank co-sponsored by the American Society of Hypertension (ASH), the United States Food and Drug Administration (FDA), and the National Heart, Lung, and Blood Institute (NHLBI) held in North Bethesda, Maryland, on June 26, 2014. Studies of device therapies for the treatment of hypertension are requested by regulators to evaluate their safety and efficacy during their development programs. Think Tank participants thought that important considerations in undertaking such studies were: (1) Preclinical assessment: how likely it is that both efficacy and safety data indicating benefit in humans will be obtained, and/or whether a plausible mechanism of action for efficacy can be identified; (2) Early human trial(s): the ability to determine that the device has an acceptable benefit-to-risk balance for its use in the intended patient population and without the influence of drug therapy during a short-term follow-up period; and (3) Pivotal Phase III trial(s): the ability to prove the effectiveness of the device in a broad population in which the trial can be made as non-confounded as possible while still allowing for the determination for benefits when added to antihypertensive therapies. Copyright © 2015 American Society of Hypertension. All rights reserved.

  9. Evolution of JAK-STAT pathway components: mechanisms and role in immune system development.

    Directory of Open Access Journals (Sweden)

    Clifford Liongue

    Full Text Available BACKGROUND: Lying downstream of a myriad of cytokine receptors, the Janus kinase (JAK-Signal transducer and activator of transcription (STAT pathway is pivotal for the development and function of the immune system, with additional important roles in other biological systems. To gain further insight into immune system evolution, we have performed a comprehensive bioinformatic analysis of the JAK-STAT pathway components, including the key negative regulators of this pathway, the SH2-domain containing tyrosine phosphatase (SHP, Protein inhibitors against Stats (PIAS, and Suppressor of cytokine signaling (SOCS proteins across a diverse range of organisms. RESULTS: Our analysis has demonstrated significant expansion of JAK-STAT pathway components co-incident with the emergence of adaptive immunity, with whole genome duplication being the principal mechanism for generating this additional diversity. In contrast, expansion of upstream cytokine receptors appears to be a pivotal driver for the differential diversification of specific pathway components. CONCLUSION: Diversification of JAK-STAT pathway components during early vertebrate development occurred concurrently with a major expansion of upstream cytokine receptors and two rounds of whole genome duplications. This produced an intricate cell-cell communication system that has made a significant contribution to the evolution of the immune system, particularly the emergence of adaptive immunity.

  10. Alternative Pathways to Talent Development in Music: The Narrative of an Eminent Filipino Singer-Songwriter

    Science.gov (United States)

    Garces-Bacsal, Rhoda Myra

    2014-01-01

    The narrative of an eminent Filipino singer-songwriter, Noel Cabangon, provides a description of an alternative pathway to musical talent development. Most theories on talent development assume that a young artist would have access to the resources required for one to advance in the domain. The results of multiple in-depth interviews suggested…

  11. Necrotrophic pathogens use the salicylic acid signaling pathway to promote disease development in tomato.

    Science.gov (United States)

    Rahman, Taha Abd El; Oirdi, Mohamed El; Gonzalez-Lamothe, Rocio; Bouarab, Kamal

    2012-12-01

    Plants use different immune pathways to combat pathogens. The activation of the jasmonic acid (JA)-signaling pathway is required for resistance against necrotrophic pathogens; however, to combat biotrophic pathogens, the plants activate mainly the salicylic acid (SA)-signaling pathway. SA can antagonize JA signaling and vice versa. NPR1 (noninducible pathogenesis-related 1) is considered a master regulator of SA signaling. NPR1 interacts with TGA transcription factors, ultimately leading to the activation of SA-dependent responses. SA has been shown to promote disease development caused by the necrotrophic pathogen Botrytis cinerea through NPR1, by suppressing the expression of two JA-dependent defense genes, proteinase inhibitors I and II. We show here that the transcription factor TGA1.a contributes to disease development caused by B. cinerea in tomato by suppressing the expression of proteinase inhibitors I and II. Finally, we present evidence that the SA-signaling pathway contributes to disease development caused by another necrotrophic pathogen, Alternaria solani, in tomato. Disease development promoted by SA through NPR1 requires the TGA1.a transcription factor. These data highlight how necrotrophs manipulate the SAsignaling pathway to promote their disease in tomato.

  12. [The function of transcription factor P63 and its signaling pathway during limb development].

    Science.gov (United States)

    Ma, Wei; Tian, Wen

    2014-08-01

    The development of human limb is controlled by several transcription factors and signaling pathways, which are organized in precise time- and space-restricted manners. Recent studies showed that P63 and its signaling pathway play important roles in this process. Transcription factor P63, one member of the P53 family, is characterized by a similar amino acid domain, plays a crucial role in the development of limb and ectoderm differentiation, especially with its DNA binding domain, and sterile alpha motif domains. Mutated P63 gene may produce abnormal transcription factor P63 which can affect the signaling pathway. Furthermore, defective signaling protein in structure and/or quantity is synthesized though the pathway. Eventually, members of the signaling protein family are involved in the regulation of differentiation and development of stem cell, which causes deformity of limbs. In brief, three signaling pathways are related to the digit formation along three axes, including SHH-ZPA, FGFs-AER and Lmx1B-Wnt7a-En1. Each contains numerous signaling molecules which are integrated in self-regulatory modules that assure the acquisition or the correct digit complements. These finding has brought new clues for deciphering the etiology of congenital limb malformation and may provide alternatives for both prevention and treatment.

  13. Emergence, development and diversification of the TGF-beta signalling pathway within the animal kingdom.

    Science.gov (United States)

    Huminiecki, Lukasz; Goldovsky, Leon; Freilich, Shiri; Moustakas, Aristidis; Ouzounis, Christos; Heldin, Carl-Henrik

    2009-02-03

    The question of how genomic processes, such as gene duplication, give rise to co-ordinated organismal properties, such as emergence of new body plans, organs and lifestyles, is of importance in developmental and evolutionary biology. Herein, we focus on the diversification of the transforming growth factor-beta (TGF-beta) pathway -- one of the fundamental and versatile metazoan signal transduction engines. After an investigation of 33 genomes, we show that the emergence of the TGF-beta pathway coincided with appearance of the first known animal species. The primordial pathway repertoire consisted of four Smads and four receptors, similar to those observed in the extant genome of the early diverging tablet animal (Trichoplax adhaerens). We subsequently retrace duplications in ancestral genomes on the lineage leading to humans, as well as lineage-specific duplications, such as those which gave rise to novel Smads and receptors in teleost fishes. We conclude that the diversification of the TGF-beta pathway can be parsimoniously explained according to the 2R model, with additional rounds of duplications in teleost fishes. Finally, we investigate duplications followed by accelerated evolution which gave rise to an atypical TGF-beta pathway in free-living bacterial feeding nematodes of the genus Rhabditis. Our results challenge the view of well-conserved developmental pathways. The TGF-beta signal transduction engine has expanded through gene duplication, continually adopting new functions, as animals grew in anatomical complexity, colonized new environments, and developed an active immune system.

  14. Transcriptomic analysis in the developing zebrafish embryo after compound exposure: Individual gene expression and pathway regulation

    Energy Technology Data Exchange (ETDEWEB)

    Hermsen, Sanne A.B., E-mail: Sanne.Hermsen@rivm.nl [Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), P.O. Box 1, 3720 BA Bilthoven (Netherlands); Department of Toxicogenomics, Maastricht University, P.O. Box 616, 6200 MD, Maastricht (Netherlands); Institute for Risk Assessment Sciences (IRAS), Utrecht University, P.O. Box 80.178, 3508 TD, Utrecht (Netherlands); Pronk, Tessa E. [Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), P.O. Box 1, 3720 BA Bilthoven (Netherlands); Department of Toxicogenomics, Maastricht University, P.O. Box 616, 6200 MD, Maastricht (Netherlands); Brandhof, Evert-Jan van den [Centre for Environmental Quality, National Institute for Public Health and the Environment (RIVM), P.O. Box 1, 3720 BA Bilthoven (Netherlands); Ven, Leo T.M. van der [Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), P.O. Box 1, 3720 BA Bilthoven (Netherlands); Piersma, Aldert H. [Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), P.O. Box 1, 3720 BA Bilthoven (Netherlands); Institute for Risk Assessment Sciences (IRAS), Utrecht University, P.O. Box 80.178, 3508 TD, Utrecht (Netherlands)

    2013-10-01

    The zebrafish embryotoxicity test is a promising alternative assay for developmental toxicity. Classically, morphological assessment of the embryos is applied to evaluate the effects of compound exposure. However, by applying differential gene expression analysis the sensitivity and predictability of the test may be increased. For defining gene expression signatures of developmental toxicity, we explored the possibility of using gene expression signatures of compound exposures based on commonly expressed individual genes as well as based on regulated gene pathways. Four developmental toxic compounds were tested in concentration-response design, caffeine, carbamazepine, retinoic acid and valproic acid, and two non-embryotoxic compounds, D-mannitol and saccharin, were included. With transcriptomic analyses we were able to identify commonly expressed genes, which were mostly development related, after exposure to the embryotoxicants. We also identified gene pathways regulated by the embryotoxicants, suggestive of their modes of action. Furthermore, whereas pathways may be regulated by all compounds, individual gene expression within these pathways can differ for each compound. Overall, the present study suggests that the use of individual gene expression signatures as well as pathway regulation may be useful starting points for defining gene biomarkers for predicting embryotoxicity. - Highlights: • The zebrafish embryotoxicity test in combination with transcriptomics was used. • We explored two approaches of defining gene biomarkers for developmental toxicity. • Four compounds in concentration-response design were tested. • We identified commonly expressed individual genes as well as regulated gene pathways. • Both approaches seem suitable starting points for defining gene biomarkers.

  15. Development of a pluripotent stem cell derived neuronal model to identify chemically induced pathway perturbations in relation to neurotoxicity: Effects of CREB pathway inhibition

    Energy Technology Data Exchange (ETDEWEB)

    Pistollato, Francesca; Louisse, Jochem; Scelfo, Bibiana; Mennecozzi, Milena [Institute for Health and Consumer Protection (IHCP), JRC, Ispra (Italy); Accordi, Benedetta; Basso, Giuseppe [Oncohematology Laboratory, Department of Woman and Child Health, University of Padova, Padova (Italy); Gaspar, John Antonydas [Center of Physiology and Pathophysiology, Institute of Neurophysiology, University of Cologne, Cologne (Germany); Zagoura, Dimitra; Barilari, Manuela; Palosaari, Taina [Institute for Health and Consumer Protection (IHCP), JRC, Ispra (Italy); Sachinidis, Agapios [Center of Physiology and Pathophysiology, Institute of Neurophysiology, University of Cologne, Cologne (Germany); Bremer-Hoffmann, Susanne, E-mail: susanne.bremer@jrc.ec.europa.eu [Institute for Health and Consumer Protection (IHCP), JRC, Ispra (Italy)

    2014-10-15

    According to the advocated paradigm shift in toxicology, acquisition of knowledge on the mechanisms underlying the toxicity of chemicals, such as perturbations of biological pathways, is of primary interest. Pluripotent stem cells (PSCs), such as human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs), offer a unique opportunity to derive physiologically relevant human cell types to measure molecular and cellular effects of such pathway modulations. Here we compared the neuronal differentiation propensity of hESCs and hiPSCs with the aim to develop novel hiPSC-based tools for measuring pathway perturbation in relation to molecular and cellular effects in vitro. Among other fundamental pathways, also, the cAMP responsive element binding protein (CREB) pathway was activated in our neuronal models and gave us the opportunity to study time-dependent effects elicited by chemical perturbations of the CREB pathway in relation to cellular effects. We show that the inhibition of the CREB pathway, using 2-naphthol-AS-E-phosphate (KG-501), induced an inhibition of neurite outgrowth and synaptogenesis, as well as a decrease of MAP2{sup +} neuronal cells. These data indicate that a CREB pathway inhibition can be related to molecular and cellular effects that may be relevant for neurotoxicity testing, and, thus, qualify the use of our hiPSC-derived neuronal model for studying chemical-induced neurotoxicity resulting from pathway perturbations. - Highlights: • HESCs derived neuronal cells serve as benchmark for iPSC based neuronal toxicity test development. • Comparisons between hESCs and hiPSCs demonstrated variability of the epigenetic state • CREB pathway modulation have been explored in relation to the neurotoxicant exposure KG-501 • hiPSC might be promising tools to translate theoretical AoPs into toxicological in vitro tests.

  16. Two Distinct Pathways to Development of Squamous Cell Carcinoma of the Vulva

    International Nuclear Information System (INIS)

    Ueda, Y.; Enomoto, T.; Kimura, T.; Yoshino, K.; Fujita, M.; Kimura, T.

    2011-01-01

    Squamous cell carcinoma (SCC) accounts for approximately 95% of the malignant tumors of the vaginal vulva and is mostly found in elderly women. The future numbers of patients with vulva r SCC is expected to rise, mainly because of the proportional increase in the average age of the general population. Two different pathways for vulva r SCC have been put forth. The first pathway is triggered by infection with a high-risk-type Human Papillomavirus (HPV). Integration of the HPV DNA into the host genome leads to the development of a typical vulva r intraepithelial neoplasia (VIN), accompanied with overexpression ofP14"ARF and P16"INK4A . This lesion subsequently forms a warty- or basaloid-type SCC. The HPV vaccine is a promising new tool for prevention of this HPV related SCC of the vulva. The second pathway is HPV-independent. Keratinizing SCC develops within a background of lichen sclerosus (LS) through a differentiated VIN. It has a different set of genetic alterations than those in the first pathway, including p53 mutations, allelic imbalances (AI), and microsatellite instability (MSI). Further clinical and basic research is still required to understand and prevent vulvar SCC. Capsule. Two pathway for pathogenesis of squamous cell carcinoma of the value are reviewed.

  17. Two Distinct Pathways to Development of Squamous Cell Carcinoma of the Vulva

    Directory of Open Access Journals (Sweden)

    Yutaka Ueda

    2011-01-01

    Full Text Available Squamous cell carcinoma (SCC accounts for approximately 95% of the malignant tumors of the vaginal vulva and is mostly found in elderly women. The future numbers of patients with vulvar SCC is expected to rise, mainly because of the proportional increase in the average age of the general population. Two different pathways for vulvar SCC have been put forth. The first pathway is triggered by infection with a high-risk-type Human Papillomavirus (HPV. Integration of the HPV DNA into the host genome leads to the development of a typical vulvar intraepithelial neoplasia (VIN, accompanied with overexpression of p14ARF and p16INK4A. This lesion subsequently forms a warty- or basaloid-type SCC. The HPV vaccine is a promising new tool for prevention of this HPV related SCC of the vulva. The second pathway is HPV-independent. Keratinizing SCC develops within a background of lichen sclerosus (LS through a differentiated VIN. It has a different set of genetic alterations than those in the first pathway, including p53 mutations, allelic imbalances (AI, and microsatellite instability (MSI. Further clinical and basic research is still required to understand and prevent vulvar SCC. Capsule. Two pathway for pathogenesis of squamous cell carcinoma of the value are reviewed.

  18. Can Cultural Behavior Have a Negative Impact on the Development of Visual Integration Pathways?

    Science.gov (United States)

    Pretorius, E.; Naude, H.; van Vuuren, C. J.

    2002-01-01

    Contends that cultural practices such as carrying the baby on the mother's back for prolonged periods can impact negatively on development of visual integration during the sensorimotor stage pathways by preventing adequate or enough crawling. Maintains that crawling is essential for cross- modality integration and that higher mental functions may…

  19. Linking Social Change and Developmental Change: Shifting Pathways of Human Development

    Science.gov (United States)

    Greenfield, Patricia M.

    2009-01-01

    P. M. Greenfield's new theory of social change and human development aims to show how changing sociodemographic ecologies alter cultural values and learning environments and thereby shift developmental pathways. Worldwide sociodemographic trends include movement from rural residence, informal education at home, subsistence economy, and…

  20. PDP-1 links the TGF-β and IIS pathways to regulate longevity, development, and metabolism.

    Directory of Open Access Journals (Sweden)

    Sri Devi Narasimhan

    2011-04-01

    Full Text Available The insulin/IGF-1 signaling (IIS pathway is a conserved regulator of longevity, development, and metabolism. In Caenorhabditis elegans IIS involves activation of DAF-2 (insulin/IGF-1 receptor tyrosine kinase, AGE-1 (PI 3-kinase, and additional downstream serine/threonine kinases that ultimately phosphorylate and negatively regulate the single FOXO transcription factor homolog DAF-16. Phosphatases help to maintain cellular signaling homeostasis by counterbalancing kinase activity. However, few phosphatases have been identified that negatively regulate the IIS pathway. Here we identify and characterize pdp-1 as a novel negative modulator of the IIS pathway. We show that PDP-1 regulates multiple outputs of IIS such as longevity, fat storage, and dauer diapause. In addition, PDP-1 promotes DAF-16 nuclear localization and transcriptional activity. Interestingly, genetic epistasis analyses place PDP-1 in the DAF-7/TGF-β signaling pathway, at the level of the R-SMAD proteins DAF-14 and DAF-8. Further investigation into how a component of TGF-β signaling affects multiple outputs of IIS/DAF-16, revealed extensive crosstalk between these two well-conserved signaling pathways. We find that PDP-1 modulates the expression of several insulin genes that are likely to feed into the IIS pathway to regulate DAF-16 activity. Importantly, dysregulation of IIS and TGF-β signaling has been implicated in diseases such as Type 2 Diabetes, obesity, and cancer. Our results may provide a new perspective in understanding of the regulation of these pathways under normal conditions and in the context of disease.

  1. The optic pathway: the development of an eLearning animation.

    Science.gov (United States)

    Cooper, Claire; Erolin, Caroline

    2018-04-01

    The optic pathway is responsible for sending visual information from the eyes to the brain via electrical impulses. It is essential that a sound understanding of this pathway is established in order to determine an accurate diagnosis concerning visual field defects. Although easy for trained neurologists to understand, it is an area which medical students repeatedly struggle to visualise. It is proposed that audio-visual teaching resources can improve students understanding of complex areas of importance. This article describes the development and evaluation of a short animation created for use in the undergraduate neurology curriculum at the University of Dundee School of Medicine.

  2. Emergence of differentially regulated pathways associated with the development of regional specificity in chicken skin.

    Science.gov (United States)

    Chang, Kai-Wei; Huang, Nancy A; Liu, I-Hsuan; Wang, Yi-Hui; Wu, Ping; Tseng, Yen-Tzu; Hughes, Michael W; Jiang, Ting Xin; Tsai, Mong-Hsun; Chen, Chien-Yu; Oyang, Yen-Jen; Lin, En-Chung; Chuong, Cheng-Ming; Lin, Shau-Ping

    2015-01-23

    Regional specificity allows different skin regions to exhibit different characteristics, enabling complementary functions to make effective use of the integumentary surface. Chickens exhibit a high degree of regional specificity in the skin and can serve as a good model for when and how these regional differences begin to emerge. We used developing feather and scale regions in embryonic chickens as a model to gauge the differences in their molecular pathways. We employed cosine similarity analysis to identify the differentially regulated and co-regulated genes. We applied low cell techniques for expression validation and chromatin immunoprecipitation (ChIP)-based enhancer identification to overcome limited cell availabilities from embryonic chicken skin. We identified a specific set of genes demonstrating a high correlation as being differentially expressed during feather and scale development and maturation. Some members of the WNT, TGF-beta/BMP, and Notch family known to be involved in feathering skin differentiation were found to be differentially regulated. Interestingly, we also found genes along calcium channel pathways that are differentially regulated. From the analysis of differentially regulated pathways, we used calcium signaling pathways as an example for further verification. Some voltage-gated calcium channel subunits, particularly CACNA1D, are expressed spatio-temporally in the skin epithelium. These calcium signaling pathway members may be involved in developmental decisions, morphogenesis, or epithelial maturation. We further characterized enhancers associated with histone modifications, including H3K4me1, H3K27ac, and H3K27me3, near calcium channel-related genes and identified signature intensive hotspots that may be correlated with certain voltage-gated calcium channel genes. We demonstrated the applicability of cosine similarity analysis for identifying novel regulatory pathways that are differentially regulated during development. Our study

  3. Neurotransmitter signaling pathways required for normal development in Xenopus laevis embryos: a pharmacological survey screen.

    Science.gov (United States)

    Sullivan, Kelly G; Levin, Michael

    2016-10-01

    Neurotransmitters are not only involved in brain function but are also important signaling molecules for many diverse cell types. Neurotransmitters are widely conserved, from evolutionarily ancient organisms lacking nervous systems through man. Here, results are reported from a loss- and gain-of-function survey, using pharmacological modulators of several neurotransmitter pathways to examine possible roles for these pathways in normal embryogenesis. Applying reagents targeting the glutamatergic, adrenergic and dopaminergic pathways to embryos of Xenopus laevis from gastrulation to organogenesis stages, we observed and quantified numerous malformations, including craniofacial defects, hyperpigmentation, muscle mispatterning and miscoiling of the gut. These data implicate several key neurotransmitters in new embryonic patterning roles, reveal novel earlier stages for processes involved in eye development, suggest new targets for subsequent molecular-genetic investigation, and highlight the necessity for in-depth toxicology studies of psychoactive compounds to which human embryos might be exposed during pregnancy. © 2016 Anatomical Society.

  4. Early development of the circumferential axonal pathway in mouse and chick spinal cord.

    Science.gov (United States)

    Holley, J A

    1982-03-10

    The early development of the circumferential axonal pathway in the brachial and lumbar spinal cord of mouse and chick embryos was studied by scanning and transmission electron microscopy. The cellular processes which comprise this pathway grow in the transverse plane and along the lateral margin of the marginal zone (i.e., circumferentially oriented), as typified by the early embryonic commissural axons. The first formative event observed was in the ventrolateral margin of the primitive spinal cord ventricular zone. Cellular processes were found near the external limiting membrane that appeared to grow a variable distance either dorsally or ventrally. Later in development, presumptive motor column neurons migrated into the ventrolateral region, distal to these early circumferentially oriented processes. Concurrently, other circumferentially oriented perikarya and processes appeared along the dorsolateral margin. Due to their aligned sites of origin and parallel growth, the circumferential processes formed a more or less continuous line or pathway, which in about 10% of the scanned specimens could be followed along the entire lateral margin of the embryonic spinal cord. Several specimens later in development had two sets of aligned circumferential processes in the ventral region. Large numbers of circumferential axons were then found to follow the preformed pathway by fasciculation, after the primitive motor column had become established. Since the earliest circumferential processes appeared to differentiate into axons and were found nearly 24 hours prior to growth of most circumferential axons, their role in guidance as pioneering axons was suggested.

  5. DISC1 pathway in brain development: exploring therapeutic targets for major psychiatric disorders

    Directory of Open Access Journals (Sweden)

    Atsushi eKamiya

    2012-03-01

    Full Text Available Genetic risk factors for major psychiatric disorders play key roles in neurodevelopment. Thus, exploring the molecular pathways of risk genes is important not only for understanding the molecular mechanisms underlying brain development, but also to decipher how genetic disturbances affect brain maturation and functioning relevant to major mental illnesses. During the last decade, there has been significant progress in determining the mechanisms whereby risk genes impact brain development. Nonetheless, given that the majority of psychiatric disorders have etiological complexities encompassing multiple risk genes and environmental factors, the biological mechanisms of these diseases remain poorly understood. How can we move forward in our research for discovery of the biological markers and novel therapeutic targets for major mental disorders? Here we review recent progress in the neurobiology of Disrupted in schizophrenia 1 (DISC1, a major risk gene for major mental disorders, with a particular focus on its roles in cerebral cortex development. Convergent findings implicate DISC1 as part of a large, multi-step pathway implicated in various cellular processes and signal transduction. We discuss links between the DISC1 pathway and environmental factors, such as immune/inflammatory responses, which may suggest novel therapeutic targets. Existing treatments for major mental disorders are hampered by a limited number of pharmacological targets. Consequently, elucidation of the DISC1 pathway, and its association with neuropsychiatric disorders, may offer hope for novel treatment interventions.

  6. Emergence, development and diversification of the TGF-β signalling pathway within the animal kingdom

    Directory of Open Access Journals (Sweden)

    Moustakas Aristidis

    2009-02-01

    Full Text Available Abstract Background The question of how genomic processes, such as gene duplication, give rise to co-ordinated organismal properties, such as emergence of new body plans, organs and lifestyles, is of importance in developmental and evolutionary biology. Herein, we focus on the diversification of the transforming growth factor-β (TGF-β pathway – one of the fundamental and versatile metazoan signal transduction engines. Results After an investigation of 33 genomes, we show that the emergence of the TGF-β pathway coincided with appearance of the first known animal species. The primordial pathway repertoire consisted of four Smads and four receptors, similar to those observed in the extant genome of the early diverging tablet animal (Trichoplax adhaerens. We subsequently retrace duplications in ancestral genomes on the lineage leading to humans, as well as lineage-specific duplications, such as those which gave rise to novel Smads and receptors in teleost fishes. We conclude that the diversification of the TGF-β pathway can be parsimoniously explained according to the 2R model, with additional rounds of duplications in teleost fishes. Finally, we investigate duplications followed by accelerated evolution which gave rise to an atypical TGF-β pathway in free-living bacterial feeding nematodes of the genus Rhabditis. Conclusion Our results challenge the view of well-conserved developmental pathways. The TGF-β signal transduction engine has expanded through gene duplication, continually adopting new functions, as animals grew in anatomical complexity, colonized new environments, and developed an active immune system.

  7. The Pathways fertility preservation decision aid website for women with cancer: development and field testing.

    Science.gov (United States)

    Woodard, Terri L; Hoffman, Aubri S; Covarrubias, Laura A; Holman, Deborah; Schover, Leslie; Bradford, Andrea; Hoffman, Derek B; Mathur, Aakrati; Thomas, Jerah; Volk, Robert J

    2018-02-01

    To improve survivors' awareness and knowledge of fertility preservation counseling and treatment options, this study engaged survivors and providers to design, develop, and field-test Pathways: a fertility preservation patient decision aid website for young women with cancer©. Using an adapted user-centered design process, our stakeholder advisory group and research team designed and optimized the Pathways patient decision aid website through four iterative cycles of review and revision with clinicians (n = 21) and survivors (n = 14). Field-testing (n = 20 survivors) assessed post-decision aid scores on the Fertility Preservation Knowledge Scale, feasibility of assessing women's decision-making values while using the website, and website usability/acceptability ratings. Iterative stakeholder engagement optimized the Pathways decision aid website to meet survivors' and providers' needs, including providing patient-friendly information and novel features such as interactive value clarification exercises, testimonials that model shared decision making, financial/referral resources, and a printable personal summary. Survivors scored an average of 8.2 out of 13 (SD 1.6) on the Fertility Preservation Knowledge Scale. They rated genetic screening and having a biological child as strong factors in their decision-making, and 71% indicated a preference for egg freezing. Most women (> 85%) rated Pathways favorably, and all women (100%) said they would recommend it to other women. The Pathways decision aid is a usable and acceptable tool to help women learn about fertility preservation. The Pathways decision aid may help women make well-informed values-based decisions and prevent future infertility-related distress.

  8. Transcriptomic profiling of bovine IVF embryos revealed candidate genes and pathways involved in early embryonic development

    Directory of Open Access Journals (Sweden)

    Yandell Brian S

    2010-01-01

    Full Text Available Abstract Background Early embryonic loss is a large contributor to infertility in cattle. Although genetic factors are known to affect early embryonic development, the discovery of such factors has been a serious challenge. The objective of this study was to identify genes differentially expressed between blastocysts and degenerative embryos at early stages of development. Results Using microarrays, genome-wide RNA expression was profiled and compared for in vitro fertilization (IVF - derived blastocysts and embryos undergoing degenerative development up to the same time point. Surprisingly similar transcriptomic profiles were found in degenerative embryos and blastocysts. Nonetheless, we identified 67 transcripts that significantly differed between these two groups of embryos at a 15% false discovery rate, including 33 transcripts showing at least a two-fold difference. Several signaling and metabolic pathways were found to be associated with the developmental status of embryos, among which were previously known important steroid biosynthesis and cell communication pathways in early embryonic development. Conclusions This study presents the first direct and comprehensive comparison of transcriptomes between IVF blastocysts and degenerative embryos, providing important information for potential genes and pathways associated with early embryonic development.

  9. Developing a pathway for high-value, patient-centered total joint arthroplasty.

    Science.gov (United States)

    Van Citters, Aricca D; Fahlman, Cheryl; Goldmann, Donald A; Lieberman, Jay R; Koenig, Karl M; DiGioia, Anthony M; O'Donnell, Beth; Martin, John; Federico, Frank A; Bankowitz, Richard A; Nelson, Eugene C; Bozic, Kevin J

    2014-05-01

    Total joint arthroplasty (TJA) is one of the most widely performed elective procedures; however, there are wide variations in cost and quality among facilities where the procedure is performed. The purposes of this study were to (1) develop a generalizable clinical care pathway for primary TJA using inputs from clinical, academic, and patient stakeholders; and (2) identify system- and patient-level processes to provide safe, effective, efficient, and patient-centered care for patients undergoing TJA. We used a combination of quantitative and qualitative methods to design a care pathway that spans 14 months beginning with the presurgical office visit and concluding 12 months after discharge. We derived care suggestions from interviews with 16 hospitals selected based on readmission rates, cost, and quality (n = 10) and author opinion (n = 6). A 32-member multistakeholder panel refined the pathway during a 1-day workshop. Participants were selected based on leadership in orthopaedic (n = 4) and anesthesia (n = 1) specialty societies; involvement in organizations specializing in safety and high reliability care (n = 3), lean production/consumption of care (n = 3), and patient experience of care (n = 3); membership in an interdisciplinary care team of a hospital selected for interviewing (n = 8); recent receipt of a TJA (n = 1); and participation in the pathway development team (n = 9). The care pathway includes 40 suggested processes to improve care, 37 techniques to reduce waste, and 55 techniques to improve communication. Central themes include standardization and process improvement, interdisciplinary communication and collaboration, and patient/family engagement and education. Selected recommendations include standardizing care protocols and staff roles; aligning information flow with patient and process flow; identifying a role accountable for care delivery and communication; managing patient expectations; and stratifying patients into the most appropriate care

  10. A development of computer code for evaluating internal radiation dose through ingestion and inhalation pathways

    International Nuclear Information System (INIS)

    Lee, Jeong Ho; Lee, Chang Woo; Choi, Yong Ho; Chun, Ki Jung; Kim, Kook Chan; Kim, Sang Bok; Kim, Jin Kyu

    1991-07-01

    The computer codes were developed to evaluate internal radiation dose when radioactive isotopes released from nuclear facilities are taken through ingestion and inhalation pathways. Food chain models and relevant data base representing the agricultural and social environment of Korea are set up. An equilibrium model-KFOOD, which can deal with routine releases from a nuclear facility and a dynamic model-ECOREA, which is suitable for the description of acute radioactivity release following nuclear accident. (Author)

  11. Concise Review: Wnt Signaling Pathways in Skin Development and Epidermal Stem Cells.

    Science.gov (United States)

    Veltri, Anthony; Lang, Christopher; Lien, Wen-Hui

    2018-01-01

    Mammalian skin and its appendages constitute the integumentary system forming a barrier between the organism and its environment. During development, skin epidermal cells divide rapidly and stratify into a multilayered epithelium, as well as invaginate downward in the underlying mesenchyme to form hair follicles (HFs). In postnatal skin, the interfollicular epidermal (IFE) cells continuously proliferate and differentiate while HFs undergo cycles of regeneration. Epidermal regeneration is fueled by epidermal stem cells (SCs) located in the basal layer of the IFE and the outer layer of the bulge in the HF. Epidermal development and SC behavior are mainly regulated by various extrinsic cues, among which Wnt-dependent signaling pathways play crucial roles. This review not only summarizes the current knowledge of Wnt signaling pathways in the regulation of skin development and governance of SCs during tissue homeostasis, but also discusses the potential crosstalk of Wnt signaling with other pathways involved in these processes. Stem Cells 2018;36:22-35. © 2017 AlphaMed Press.

  12. Aligning the talent pathway: exploring the role and mechanisms of coherence in development.

    Science.gov (United States)

    Webb, Vincent; Collins, Dave; Cruickshank, Andrew

    2016-10-01

    Although our understanding of psychological and social factors in talent development continues to expand, knowledge of the broader system that underpins the entire talent pathways is relatively limited. Indeed, little work has moved beyond the recognition that coherence in this system is important to consider how this may be achieved; particularly in relation to coherent coaching. As such, the aim of this article was to address gaps in talent development and coaching literature and explore principles and potential mechanisms of coherent coaching in sport organisations' talent pathways. After defining and contextualising coherence in whole talent pathways, including barriers to attainment, we discuss how an understanding of coach epistemology can provide a basis for integrating personal and collective coach coherence and therefore a coherent performer experience. With epistemology as our focal point, we then consider how coherent coaching may be supported through the strategic recruitment and placement of coaches, complimentary coach education and development and the use of change agents who can set and shape the coaching milieu, facilitate cross-level communication and enable epistemology-focused reflection and evaluation. Finally, we conclude with some brief recommendations for advancing practically-meaningful knowledge in this important area.

  13. Kenya's Climate Change Action Plan. Low Carbon Climate Resilient Development Pathway

    Energy Technology Data Exchange (ETDEWEB)

    Murphy, D.; Sawyer, D.; Stiebert, S.; McFatridge, S. [International Institute for Sustainable Development IISD, Winnipeg, Manitoba (Canada); Wuertenberger, L.; Van Tilburg, X.; Hekkenberg, M. [Energy research Centre of the Netherlands ECN, Policy Studies, Amsterdam (Netherlands); Owino, T.; Battye, W. [ClimateCare, Nairobi (Kenya); Mutia, T. [Regional Institute for Social Enterprise Kenya RISE, Nairobi (Kenya); Olum, P. [Climate Change Consultant (Kenya)

    2012-12-15

    Kenya Vision 2030 - the long-term development blueprint for the country - aims to transform Kenya into 'a newly industrialising, middle-income country providing a high quality of life to all its citizens in a clean and secure environment'. A low carbon climate resilient development pathway, as set out in this Climate Change Action Plan, can help meet Vision 2030 goals through actions that address both sustainable development and climate change. This pathway can also help the Government achieve the Millennium Development Goals and other internationally agreed development goals without compromising the environment and its natural resources. As Kenya realizes its development aspirations, there will be gains and risks. A growing population and economy with migration to cities will mean increases in greenhouse gas (GHG) emissions. Resulting environmental and social conditions, including increased competition over resources, could intensify vulnerability to climate risks. Transitioning to a low carbon climate resilient development pathway can address future risks thereby improving Kenya's ability to prosper under a changing climate while reducing the emissions intensity of a growing economy. Moving forward on the 2010 National Climate Change Response Strategy will help Kenya transition to a low carbon climate resilient development pathway that puts people and livelihoods at the forefront. The strategy recognized the importance of climate change and development, and this Climate Change Action Plan is the logical next step. A yearlong multistakeholder participatory process involving the public sector, private sector and civil society resulted in this Action Plan that identifies priority climate change actions for Kenya for the short, medium and long term. The Government of Kenya takes climate change and its impact on development seriously. Climate change is considered a crosscutting issue that will be mainstreamed in the planning process both at the national

  14. The Hedgehog-GLI pathway in embryonic development and cancer: implications for pulmonary oncology therapy

    Science.gov (United States)

    Armas-López, Leonel; Zúñiga, Joaquín; Arrieta, Oscar; Ávila-Moreno, Federico

    2017-01-01

    Transcriptional regulation and epigenetic mechanisms closely control gene expression through diverse physiological and pathophysiological processes. These include the development of germ layers and post-natal epithelial cell-tissue differentiation, as well as, involved with the induction, promotion and/or progression of human malignancies. Diverse studies have shed light on the molecular similarities and differences involved in the stages of embryological epithelial development and dedifferentiation processes in malignant tumors of epithelial origin, of which many focus on lung carcinomas. In lung cancer, several transcriptional, epigenetic and genetic aberrations have been described to partly arise from environmental risk factors, but ethnic genetic predisposition factors may also play a role. The classification of the molecular hallmarks of cancer has been essential to study and achieve a comprehensive view of the interaction networks between cell signaling pathways and functional roles of the transcriptional and epigenetic regulatory mechanisms. This has in turn increased understanding on how these molecular networks are involved in embryo-layers and malignant diseases development. Ultimately, a major biomedicine goal is to achieve a thorough understanding of their roles as diagnostic, prognostic and treatment response indicators in lung oncological patients. Recently, several notable cell-signaling pathways have been studied based on their contribution to promoting and/or regulating the engagement of different cancer hallmarks, among them genome instability, exacerbated proliferative signaling, replicative immortality, tumor invasion-metastasis, inflammation, and immune-surveillance evasion mechanisms. Of these, the Hedgehog-GLI (Hh) cell-signaling pathway has been identified as a main molecular contribution into several of the abovementioned functional embryo-malignancy processes. Nonetheless, the systematic study of the regulatory epigenetic and

  15. The TOR signaling pathway regulates vegetative development and virulence in Fusarium graminearum.

    Science.gov (United States)

    Yu, Fangwei; Gu, Qin; Yun, Yingzi; Yin, Yanni; Xu, Jin-Rong; Shim, Won-Bo; Ma, Zhonghua

    2014-07-01

    The target of rapamycin (TOR) signaling pathway plays critical roles in controlling cell growth in a variety of eukaryotes. However, the contribution of this pathway in regulating virulence of plant pathogenic fungi is unknown. We identified and characterized nine genes encoding components of the TOR pathway in Fusarium graminearum. Biological, genetic and biochemical functions of each component were investigated. The FgFkbp12-rapamycin complex binds to the FgTor kinase. The type 2A phosphatases FgPp2A, FgSit4 and FgPpg1 were found to interact with FgTap42, a downstream component of FgTor. Among these, we determined that FgPp2A is likely to be essential for F. graminearum survival, and FgSit4 and FgPpg1 play important roles in cell wall integrity by positively regulating the phosphorylation of FgMgv1, a key MAP kinase in the cell wall integrity pathway. In addition, the FgPpg1 interacting protein, FgTip41, is involved in regulating mycelial growth and virulence. Notably, FgTip41 does not interact with FgTap42 but with FgPpg1, suggesting the existence of FgTap42:FgPpg1:FgTip41 heterotrimer in F. graminearum, a complex not observed in the yeast model. Collectively, we defined a genetic regulatory framework that elucidates how the TOR pathway regulates virulence and vegetative development in F. graminearum. © 2014 The Authors. New Phytologist © 2014 New Phytologist Trust.

  16. Robust Water Supply Infrastructure Development Pathways: What, When and Where Matters the Most? (INVITED)

    Science.gov (United States)

    Reed, Patrick; Zeff, Harrison; Characklis, Gregory

    2017-04-01

    Water supply adaptation frameworks that seek robustness must adaptively trigger actions that are contextually appropriate to emerging system observations and avoid long term high regret lock-ins. As an example, emerging water scarcity concerns in southeastern United States are associated with several deeply uncertain factors, including rapid population growth, limited coordination across adjacent municipalities and the increasing risks for sustained regional droughts. Managing these uncertainties will require that regional water utilities identify regionally coordinated, scarcity-mitigating infrastructure development pathways that trigger time appropriate actions. Mistakes can lead to water shortages, overbuilt stranded assets and possibly financial failures. This presentation uses the Research Triangle area of North Carolina to illustrate the key concerns and challenges that emerged when helping Raleigh, Durham, Cary and Chapel Hill develop their long term water supply infrastructure pathways through 2060. This example shows how the region's water utilities' long term infrastructure pathways are strongly shaped by their short term conservation policies (i.e., reacting to evolving demands) and their ability to consider regional water transfers (i.e., reacting to supply imbalances). Cooperatively developed, shared investments across the four municipalities expand their capacity to use short term transfers to better manage severe droughts with fewer investments in irreversible infrastructure options. Cooperative pathways are also important for avoiding regional robustness conflicts, where one party benefits strongly at the expense of one or more the others. A significant innovation of this work is the exploitation of weekly and annual dynamic risk-of-failure action triggers that exploit evolving feedbacks between co-evolving human demands and regional supplies. These dynamic action triggers provide high levels of adaptivity, tailor actions to their specific context

  17. Conserved genetic pathways controlling the development of the diffuse endocrine system in vertebrates and Drosophila.

    Science.gov (United States)

    Hartenstein, Volker; Takashima, Shigeo; Adams, Katrina L

    2010-05-01

    The midgut epithelium is formed by absorptive enterocytes, secretory cells and endocrine cells. Each of these lineages is derived from the pluripotent progenitors that constitute the embryonic endoderm; the mature midgut retains pools of self-renewing stem cells that continue to produce all lineages. Recent findings in vertebrates and Drosophila shed light on the genetic mechanism that specifies the fate of the different lineages. A pivotal role is played by the Notch signaling pathway that, in a manner that appears to be very similar to the way in which Notch signaling selects neural progenitors within the neurectoderm, distinguishes the fate of secretory/endocrine cells and enterocytes. Proneural genes encoding bHLH transcription factors are expressed and required in prospective endocrine cells; activation of the Notch pathways restricts the number of these cells and promotes enterocyte development. In this review we compare the development of the intestinal endocrine cells in vertebrates and insects and summarize recent findings dealing with genetic pathways controlling this cell type. Copyright 2009. Published by Elsevier Inc.

  18. Avoiding, transforming, transitioning: pathways to sustainable low carbon passenger transport in developing countries

    DEFF Research Database (Denmark)

    Meza, Maria Josefina Figueroa; Fulton, Lewis; Tiwari, Geetam

    2013-01-01

    This review examines conditions affecting road passenger transport in developing countries that can be instrumental to building a pathway for reducing carbon emissions while concurrently meeting sustainable development goals. By contrasting present and future status of these conditions a vision...... in motorized travel are also necessary from OECD countries; the focus there is given to what level of pricing and regulatory interventions could change behavior. The articulation of detailed visions can help clarify and prioritize areas where policy efforts can have great impact. Strong actions are necessary...

  19. Development and Performance of Alternative Electricity Sector Pathways Subject to Multiple Climate and Water Projections

    Science.gov (United States)

    Newmark, R. L.; Vorosmarty, C. J.; Miara, A.; Cohen, S.; Macknick, J.; Sun, Y.; Corsi, F.; Fekete, B. M.; Tidwell, V. C.

    2017-12-01

    Climate change impacts on air temperatures and water availability have the potential to alter future electricity sector investment decisions as well as the reliability and performance of the power sector. Different electricity sector configurations are more or less vulnerable to climate-induced changes. For example, once-through cooled thermal facilities are the most cost-effective and efficient technologies under cooler and wetter conditions, but can be substantially affected by and vulnerable to warmer and drier conditions. Non-thermal renewable technologies, such as PV and wind, are essentially "drought-proof" but have other integration and reliability challenges. Prior efforts have explored the impacts of climate change on electric sector development for a limited set of climate and electricity scenarios. Here, we provide a comprehensive suite of scenarios that evaluate how different electricity sector pathways could be affected by a range of climate and water resource conditions. We use four representative concentration pathway (RCP) scenarios under five global circulation models (GCM) as climate drivers to a Water Balance Model (WBM), to provide twenty separate future climate-water conditions. These climate-water conditions influence electricity sector development from present day to 2050 as determined using the Regional Energy Deployment Systems (ReEDS) model. Four unique electricity sector pathways will be considered, including business-as-usual, carbon cap, high renewable energy technology costs, and coal reliance scenarios. The combination of climate-water and electricity sector pathway scenarios leads to 80 potential future cases resulting in different national and regional electricity infrastructure configurations. The vulnerability of these configurations in relation to climate change (including in-stream thermal pollution impacts and environmental regulations) is evaluated using the Thermoelectric Power and Thermal Pollution (TP2M) model, providing

  20. Functions of the nonsense-mediated mRNA decay pathway in Drosophila development.

    Directory of Open Access Journals (Sweden)

    Mark M Metzstein

    2006-12-01

    Full Text Available Nonsense-mediated mRNA decay (NMD is a cellular surveillance mechanism that degrades transcripts containing premature translation termination codons, and it also influences expression of certain wild-type transcripts. Although the biochemical mechanisms of NMD have been studied intensively, its developmental functions and importance are less clear. Here, we describe the isolation and characterization of Drosophila "photoshop" mutations, which increase expression of green fluorescent protein and other transgenes. Mapping and molecular analyses show that photoshop mutations are loss-of-function mutations in the Drosophila homologs of NMD genes Upf1, Upf2, and Smg1. We find that Upf1 and Upf2 are broadly active during development, and they are required for NMD as well as for proper expression of dozens of wild-type genes during development and for larval viability. Genetic mosaic analysis shows that Upf1 and Upf2 are required for growth and/or survival of imaginal cell clones, but this defect can be overcome if surrounding wild-type cells are eliminated. By contrast, we find that the PI3K-related kinase Smg1 potentiates but is not required for NMD or for viability, implying that the Upf1 phosphorylation cycle that is required for mammalian and Caenorhabditis elegans NMD has a more limited role during Drosophila development. Finally, we show that the SV40 3' UTR, present in many Drosophila transgenes, targets the transgenes for regulation by the NMD pathway. The results establish that the Drosophila NMD pathway is broadly active and essential for development, and one critical function of the pathway is to endow proliferating imaginal cells with a competitive growth advantage that prevents them from being overtaken by other proliferating cells.

  1. Leading High School Transformation for College and Career Success: A Guide for Developing a System of Linked Learning Pathways

    Science.gov (United States)

    Stearns, Roman

    2014-01-01

    This ConnectEd Guide for Developing a System of Linked Learning Pathways will introduce school district leaders and their community partners to Linked Learning and a system of quality pathways that can transform high schools, instructional practice, and the student experience. Not intended to be prescriptive, this document can and should be…

  2. Migration Pathways of Thalamic Neurons and Development of Thalamocortical Connections in Humans Revealed by Diffusion MR Tractography.

    Science.gov (United States)

    Wilkinson, Molly; Kane, Tara; Wang, Rongpin; Takahashi, Emi

    2017-12-01

    The thalamus plays an important role in signal relays in the brain, with thalamocortical (TC) neuronal pathways linked to various sensory/cognitive functions. In this study, we aimed to see fetal and postnatal development of the thalamus including neuronal migration to the thalamus and the emergence/maturation of the TC pathways. Pathways from/to the thalami of human postmortem fetuses and in vivo subjects ranging from newborns to adults with no neurological histories were studied using high angular resolution diffusion MR imaging (HARDI) tractography. Pathways likely linked to neuronal migration from the ventricular zone and ganglionic eminence (GE) to the thalami were both successfully detected. Between the ventricular zone and thalami, more tractography pathways were found in anterior compared with posterior regions, which was well in agreement with postnatal observations that the anterior TC segment had more tract count and volume than the posterior segment. Three different pathways likely linked to neuronal migration from the GE to the thalami were detected. No hemispheric asymmetry of the TC pathways was quantitatively observed during development. These results suggest that HARDI tractography is useful to identify multiple differential neuronal migration pathways in human brains, and regional differences in brain development in fetal ages persisted in postnatal development. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  3. Proteomics of the rat myocardium during development of type 2 diabetes mellitus reveals progressive alterations in major metabolic pathways

    DEFF Research Database (Denmark)

    Edhager, Anders Valdemar; Povlsen, Jonas Agerlund; Løfgren, Bo

    2018-01-01

    in intracellular metabolic pathways in the Zucker diabetic fatty rat heart as T2DM develops using MS based proteomics. The pre-diabetic state only induced minor pathway changes, whereas onset and late T2DM caused pronounced perturbations. Two actin-associated proteins, ARPC2 and TPM3, were up-regulated at the pre...

  4. TLR-related pathway analysis : novel gene-gene interactions in the development of asthma and atopy

    NARCIS (Netherlands)

    Reijmerink, N. E.; Bottema, R. W. B.; Kerkhof, M.; Gerritsen, J.; Stelma, F. F.; Thijs, C.; van Schayck, C. P.; Smit, H. A.; Brunekreef, B.; Koppelman, G. H.; Postma, D. S.

    P>Background: The toll-like receptor (TLR)-related pathway is important in host defence and may be crucial in the development of asthma and atopy. Numerous studies have shown associations of TLR-related pathway genes with asthma and atopy phenotypes. So far it has not been investigated whether

  5. Structural Pathways of Cytokines May Illuminate Their Roles in Regulation of Cancer Development and Immunotherapy

    International Nuclear Information System (INIS)

    Guven-Maiorov, Emine; Acuner-Ozbabacan, Saliha Ece; Keskin, Ozlem; Gursoy, Attila; Nussinov, Ruth

    2014-01-01

    Cytokines are messengers between tissues and the immune system. They play essential roles in cancer initiation, promotion, metastasis, and immunotherapy. Structural pathways of cytokine signaling which contain their interactions can help understand their action in the tumor microenvironment. Here, our aim is to provide an overview of the role of cytokines in tumor development from a structural perspective. Atomic details of protein-protein interactions can help in understanding how an upstream signal is transduced; how higher-order oligomerization modes of proteins can influence their function; how mutations, inhibitors or antagonists can change cellular consequences; why the same protein can lead to distinct outcomes, and which alternative parallel pathways can take over. They also help to design drugs/inhibitors against proteins de novo or by mimicking natural antagonists as in the case of interferon-γ. Since the structural database (PDB) is limited, structural pathways are largely built from a series of predicted binary protein-protein interactions. Below, to illustrate how protein-protein interactions can help illuminate roles played by cytokines, we model some cytokine interaction complexes exploiting a powerful algorithm (PRotein Interactions by Structural Matching—PRISM)

  6. Structural Pathways of Cytokines May Illuminate Their Roles in Regulation of Cancer Development and Immunotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Guven-Maiorov, Emine; Acuner-Ozbabacan, Saliha Ece; Keskin, Ozlem; Gursoy, Attila [Center for Computational Biology and Bioinformatics and College of Engineering, Koc University, Rumelifeneri Yolu, 34450 Sariyer Istanbul (Turkey); Nussinov, Ruth, E-mail: nussinor@helix.nih.gov [Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD 21702 (United States); Sackler Institute of Molecular Medicine, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978 (Israel)

    2014-03-25

    Cytokines are messengers between tissues and the immune system. They play essential roles in cancer initiation, promotion, metastasis, and immunotherapy. Structural pathways of cytokine signaling which contain their interactions can help understand their action in the tumor microenvironment. Here, our aim is to provide an overview of the role of cytokines in tumor development from a structural perspective. Atomic details of protein-protein interactions can help in understanding how an upstream signal is transduced; how higher-order oligomerization modes of proteins can influence their function; how mutations, inhibitors or antagonists can change cellular consequences; why the same protein can lead to distinct outcomes, and which alternative parallel pathways can take over. They also help to design drugs/inhibitors against proteins de novo or by mimicking natural antagonists as in the case of interferon-γ. Since the structural database (PDB) is limited, structural pathways are largely built from a series of predicted binary protein-protein interactions. Below, to illustrate how protein-protein interactions can help illuminate roles played by cytokines, we model some cytokine interaction complexes exploiting a powerful algorithm (PRotein Interactions by Structural Matching—PRISM)

  7. Structural Pathways of Cytokines May Illuminate Their Roles in Regulation of Cancer Development and Immunotherapy

    Directory of Open Access Journals (Sweden)

    Emine Guven-Maiorov

    2014-03-01

    Full Text Available Cytokines are messengers between tissues and the immune system. They play essential roles in cancer initiation, promotion, metastasis, and immunotherapy. Structural pathways of cytokine signaling which contain their interactions can help understand their action in the tumor microenvironment. Here, our aim is to provide an overview of the role of cytokines in tumor development from a structural perspective. Atomic details of protein-protein interactions can help in understanding how an upstream signal is transduced; how higher-order oligomerization modes of proteins can influence their function; how mutations, inhibitors or antagonists can change cellular consequences; why the same protein can lead to distinct outcomes, and which alternative parallel pathways can take over. They also help to design drugs/inhibitors against proteins de novo or by mimicking natural antagonists as in the case of interferon-γ. Since the structural database (PDB is limited, structural pathways are largely built from a series of predicted binary protein-protein interactions. Below, to illustrate how protein-protein interactions can help illuminate roles played by cytokines, we model some cytokine interaction complexes exploiting a powerful algorithm (PRotein Interactions by Structural Matching—PRISM.

  8. Developing pathways for energy storage in the UK using a coevolutionary framework

    International Nuclear Information System (INIS)

    Taylor, Peter G.; Bolton, Ronan; Stone, Dave; Upham, Paul

    2013-01-01

    A number of recent techno-economic studies have shown that energy storage could offer significant benefits to a low-carbon UK energy system as it faces increased challenges in matching supply and demand. However, the majority of this work has not investigated the real-world issues affecting the widespread deployment of storage. This paper is designed to address this gap by drawing on the systems innovation and socio-technical transitions literature to identify some of the most important contextual factors which are likely to influence storage deployment. Specifically it uses a coevolutionary framework to examine how changes in ecosystems, user practices, business strategies, institutions and technologies are creating a new selection environment and potentially opening up the energy system to new variations of storage for both electricity and heat. The analysis shows how these different dimensions of the energy regime can coevolve in mutually reinforcing ways to create alternative pathways for the energy system which in turn have different flexibility requirements and imply different roles for storage technologies. Using this framework three pathways are developed – user led, decentralised and centralised – which illustrate potential long-term trajectories for energy storage technologies in a low-carbon energy system. - highlights: • Energy storage can play a significant role in a low carbon UK energy system. • Changes in the selection environment will impact its deployment. • Several different deployment pathways are possible. • Its precise role is still subject to considerable uncertainty

  9. An interplay between 2 signaling pathways: Melatonin-cAMP and IP3–Ca2+ signaling pathways control intraerythrocytic development of the malaria parasite Plasmodium falciparum

    International Nuclear Information System (INIS)

    Furuyama, Wakako; Enomoto, Masahiro; Mossaad, Ehab; Kawai, Satoru; Mikoshiba, Katsuhiko; Kawazu, Shin-ichiro

    2014-01-01

    Highlights: • A melatonin receptor antagonist blocked Ca 2+ oscillation in P. falciparum and inhibited parasite growth. • P. falciparum development is controlled by Ca 2+ - and cAMP-signaling pathways. • The cAMP-signaling pathway at ring form and late trophozoite stages governs parasite growth of P. falciparum. - Abstract: Plasmodium falciparum spends most of its asexual life cycle within human erythrocytes, where proliferation and maturation occur. Development into the mature forms of P. falciparum causes severe symptoms due to its distinctive sequestration capability. However, the physiological roles and the molecular mechanisms of signaling pathways that govern development are poorly understood. Our previous study showed that P. falciparum exhibits stage-specific spontaneous Calcium (Ca 2+ ) oscillations in ring and early trophozoites, and the latter was essential for parasite development. In this study, we show that luzindole (LZ), a selective melatonin receptor antagonist, inhibits parasite growth. Analyses of development and morphology of LZ-treated P. falciparum revealed that LZ severely disrupted intraerythrocytic maturation, resulting in parasite death. When LZ was added at ring stage, the parasite could not undergo further development, whereas LZ added at the trophozoite stage inhibited development from early into late schizonts. Live-cell Ca 2+ imaging showed that LZ treatment completely abolished Ca 2+ oscillation in the ring forms while having little effect on early trophozoites. Further, the melatonin-induced cAMP increase observed at ring and late trophozoite stage was attenuated by LZ treatment. These suggest that a complex interplay between IP 3 –Ca 2+ and cAMP signaling pathways is involved in intraerythrocytic development of P. falciparum

  10. Systematic enrichment analysis of gene expression profiling studies identifies consensus pathways implicated in colorectal cancer development

    Directory of Open Access Journals (Sweden)

    Jesús Lascorz

    2011-01-01

    Full Text Available Background: A large number of gene expression profiling (GEP studies on colorectal carcinogenesis have been performed but no reliable gene signature has been identified so far due to the lack of reproducibility in the reported genes. There is growing evidence that functionally related genes, rather than individual genes, contribute to the etiology of complex traits. We used, as a novel approach, pathway enrichment tools to define functionally related genes that are consistently up- or down-regulated in colorectal carcinogenesis. Materials and Methods: We started the analysis with 242 unique annotated genes that had been reported by any of three recent meta-analyses covering GEP studies on genes differentially expressed in carcinoma vs normal mucosa. Most of these genes (218, 91.9% had been reported in at least three GEP studies. These 242 genes were submitted to bioinformatic analysis using a total of nine tools to detect enrichment of Gene Ontology (GO categories or Kyoto Encyclopedia of Genes and Genomes (KEGG pathways. As a final consistency criterion the pathway categories had to be enriched by several tools to be taken into consideration. Results: Our pathway-based enrichment analysis identified the categories of ribosomal protein constituents, extracellular matrix receptor interaction, carbonic anhydrase isozymes, and a general category related to inflammation and cellular response as significantly and consistently overrepresented entities. Conclusions: We triaged the genes covered by the published GEP literature on colorectal carcinogenesis and subjected them to multiple enrichment tools in order to identify the consistently enriched gene categories. These turned out to have known functional relationships to cancer development and thus deserve further investigation.

  11. Fine-tuning of the flavonoid and monolignol pathways during apple early fruit development.

    Science.gov (United States)

    Baldi, Paolo; Moser, Mirko; Brilli, Matteo; Vrhovsek, Urska; Pindo, Massimo; Si-Ammour, Azeddine

    2017-05-01

    A coordinated regulation of different branches of the flavonoid pathway was highlighted that may contribute to elucidate the role of this important class of compounds during the early stages of apple fruit development. Apple (Malus × domestica Borkh.) is an economically important fruit appreciated for its organoleptic characteristics and its benefits for human health. The first stages after fruit set represent a very important and still poorly characterized developmental process. To enable the profiling of genes involved in apple early fruit development, we combined the suppression subtractive hybridization (SSH) protocol to next-generation sequencing. We identified and characterized genes induced and repressed during fruit development in the apple cultivar 'Golden Delicious'. Our results showed an opposite regulation of genes coding for enzymes belonging to flavonoid and monolignol pathways, with a strong induction of the former and a simultaneous repression of the latter. Two isoforms of phenylalanine ammonia-lyase and 4-coumarate:CoA ligase, key enzymes located at the branching point between flavonoid and monolignol pathways, showed opposite expression patterns during the period in analysis, suggesting a possible regulation mechanism. A targeted metabolomic analysis supported the SSH results and revealed an accumulation of the monomers catechin and epicatechin as well as several forms of procyanidin oligomers in apple fruitlets starting early after anthesis, together with a decreased production of other classes of flavonoids such as some flavonols and the dihydrochalcone phlorizin. Moreover, gene expression and metabolites accumulation of 'Golden Delicious' were compared to a wild apple genotype of Manchurian crabapple (Malus mandshurica (Maxim.) Kom.). Significant differences in both gene expression and metabolites accumulation were found between the two genotypes.

  12. Primary cilia and coordination of signaling pathways in heart development and tissue Homeostasis

    DEFF Research Database (Denmark)

    Clement, Christian Alexandro

    of primary cilia in coordinating Hh signaling in human pancreatic development and postnatal tissue homeostasis. In cultures of human pancreatic duct adenocarcinoma cell lines PANC-1 and CFPAC-1, Ptc in addition to Gli2 and Smo localize to primary cilia. These findings are consistent with the idea...... that the primary cilium continues to coordinate Hh signaling in cells derived from the mature pancreas. The fact that the Hh signaling pathway is active in the CFPAC-1 and PANC-1 cell lines without Hh stimulation suggests that ciliary Hh signaling plays a potential role in tumorigenesis. In conclusion, this thesis...

  13. Autism as an adaptive common variant pathway for human brain development

    Directory of Open Access Journals (Sweden)

    Mark H. Johnson

    2017-06-01

    Full Text Available While research on focal perinatal lesions has provided evidence for recovery of function, much less is known about processes of brain adaptation resulting from mild but widespread disturbances to neural processing over the early years (such as alterations in synaptic efficiency. Rather than being viewed as a direct behavioral consequence of life-long neural dysfunction, I propose that autism is best viewed as the end result of engaging adaptive processes during a sensitive period. From this perspective, autism is not appropriately described as a disorder of neurodevelopment, but rather as an adaptive common variant pathway of human functional brain development.

  14. Autism as an adaptive common variant pathway for human brain development.

    Science.gov (United States)

    Johnson, Mark H

    2017-06-01

    While research on focal perinatal lesions has provided evidence for recovery of function, much less is known about processes of brain adaptation resulting from mild but widespread disturbances to neural processing over the early years (such as alterations in synaptic efficiency). Rather than being viewed as a direct behavioral consequence of life-long neural dysfunction, I propose that autism is best viewed as the end result of engaging adaptive processes during a sensitive period. From this perspective, autism is not appropriately described as a disorder of neurodevelopment, but rather as an adaptive common variant pathway of human functional brain development. Copyright © 2017 The Author. Published by Elsevier Ltd.. All rights reserved.

  15. METABOLIC ENGINEERING TO DEVELOP A PATHWAY FOR THE SELECTIVE CLEAVAGE OF CARBON-NITROGEN BONDS

    Energy Technology Data Exchange (ETDEWEB)

    John J. Kilbane III

    2003-12-01

    The objective of the project is to develop biochemical pathways for the selective cleavage of C-N bonds in molecules found in petroleum. The initial phase of the project will focus on the isolation or development of an enzyme capable of cleaving the C-N bond in aromatic amides, specifically 2-aminobiphenyl. The objective of the second phase of the research will be to construct a biochemical pathway for the selective removal of nitrogen from carbazole by combining the carA genes from Sphingomonas sp. GTIN11 with the gene(s) encoding an appropriate amidase. The objective of the final phase of the project will be to develop derivative CN bond cleaving enzymes that have broader substrate ranges and to demonstrate the use of such strains to selectively remove nitrogen from petroleum. The project is on schedule and no major difficulties have been encountered. During the first year of the project (October, 2002-September, 2003) enrichment culture experiments have resulted in the isolation of promising cultures that may be capable of cleaving C-N bonds in aromatic amides, several amidase genes have been cloned and are currently undergoing directed evolution to obtain derivatives that can cleave C-N bonds in aromatic amides, and the carA genes from Sphingomonas sp. GTIN11, and Pseudomonas resinovorans CA10 were cloned in vectors capable of replicating in Escherichia coli. Future research will address expression of these genes in Rhodococcus erythropolis. Enrichment culture experiments and directed evolution experiments continue to be a main focus of research activity and further work is required to obtain an appropriate amidase that will selectively cleave C-N bonds in aromatic substrates. Once an appropriate amidase gene is obtained it must be combined with genes encoding an enzyme capable of converting carbazole to 2'aminobiphenyl-2,3-diol: specifically carA genes. The carA genes from two sources have been cloned and are ready for construction of C-N bond cleavage

  16. Spatio-temporal expression patterns of Wnt signaling pathway during the development of temporomandibular condylar cartilage.

    Science.gov (United States)

    Chen, Kan; Quan, Huixin; Chen, Gang; Xiao, Di

    2017-11-01

    There is a growing body of evidence supporting the involvement of the Wnt signaling pathway in various aspects of skeletal and joint development; however, it is unclear whether it is involved in the process of temporomandibular joint development. In order to clarify this issue, we examined the spatio-temporal distribution of mRNAs and proteins of the Wnt family during the formation of the mandibular condylar cartilage at the prenatal and postnatal stages. An in situ hybridization test revealed no mRNAs of β-catenin and Axin2 during early mesenchymal condensation; the ligands surveyed in this study (including Wnt-4, 5a, and 9a) were clearly detected at various ranges of expression, mainly in the condylar blastema and later distinct cartilaginous layers. Apart from β-catenin and Axin2, the Wnt family members surveyed in this study, including Lef-1, were found to be immunopositive during early chondrogenesis in the condylar cartilage at E14.5. After distinct chondrocyte layers were identified within the cartilage at E16.5, the expression of the Wnt signaling members was different and mainly restricted to proliferating cells and mineralized hypertrophic chondrocytes. In the adult mandibular condylar cartilage, the Wnt-4 mRNA, as well as the Wnt-4 and Wnt-9a proteins, was not observed. Our findings demonstrated that the Wnt signaling pathway was associated with the development of mandibular condylar cartilage. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. The Development and Assesment of Adaptation Pathways for Urban Pluvial Flooding

    Science.gov (United States)

    Babovic, F.; Mijic, A.; Madani, K.

    2017-12-01

    Around the globe, urban areas are growing in both size and importance. However, due to the prevalence of impermeable surfaces within the urban fabric of cities these areas have a high risk of pluvial flooding. Due to the convergence of population growth and climate change the risk of pluvial flooding is growing. When designing solutions and adaptations to pluvial flood risk urban planners and engineers encounter a great deal of uncertainty due to model uncertainty, uncertainty within the data utilised, and uncertainty related to future climate and land use conditions. The interaction of these uncertainties leads to conditions of deep uncertainty. However, infrastructure systems must be designed and built in the face of this deep uncertainty. An Adaptation Tipping Points (ATP) methodology was used to develop a strategy to adapt an urban drainage system in the North East of London under conditions of deep uncertainty. The ATP approach was used to assess the current drainage system and potential drainage system adaptations. These adaptations were assessed against potential changes in rainfall depth and peakedness-defined as the ratio of mean to peak rainfall. These solutions encompassed both traditional and blue-green solutions that the Local Authority are known to be considering. This resulted in a set of Adaptation Pathways. However, theses pathways do not convey any information regarding the relative merits and demerits of the potential adaptation options presented. To address this a cost-benefit metric was developed that would reflect the solutions' costs and benefits under uncertainty. The resulting metric combines elements of the Benefits of SuDS Tool (BeST) with real options analysis in order to reflect the potential value of ecosystem services delivered by blue-green solutions under uncertainty. Lastly, it is discussed how a local body can utilise the adaptation pathways; their relative costs and benefits; and a system of local data collection to help guide

  18. Gene expression in the lignin biosynthesis pathway during soybean seed development.

    Science.gov (United States)

    Baldoni, A; Von Pinho, E V R; Fernandes, J S; Abreu, V M; Carvalho, M L M

    2013-02-28

    The study of gene expression in plants is fundamental, and understanding the molecular mechanisms involved in important biological processes, such as biochemical pathways or signaling that are used or manipulated in improvement programs, are key for the production of high-quality soybean seeds. Reports related to gene expression of lignin in seeds are scarce in the literature. We studied the expression of the phenylalanine ammonia-lyase (PAL), cinnamate 4-hydroxylase, 4-hydroxycinnamate 3-hydroxylase, and cinnamyl alcohol dehydrogenase genes involved in lignin biosynthesis during the development of soybean (Glycine max L. Merrill) seeds. As the endogenous control, the eukaryotic elongation factor 1-beta gene was used in two biological replicates performed in triplicate. Relative quantitative expression of these genes during the R4, R5, R6, and R7 development stages was analyzed. Real-time polymerase chain reaction was used for the gene expression study. The analyses were carried out in an ABI PRISM 7500 thermocycler using the comparative Ct method and SYBR Green to detect amplification. The seed samples at the R4 stage were chosen as calibrators. Increased expression of the cinnamate-4-hydroxylase and PAL genes occurred in soybean seeds at the R5 and R6 development stages. The cinnamyl alcohol dehydrogenase gene was expressed during the final development phases of soybean seeds. In low-lignin soybean cultivars, the higher expression of the PAL gene occurs at development stages R6 and R7. Activation of the genes involved in the lignin biosynthesis pathway occurs at the beginning of soybean seed development.

  19. Investing in the foundation of sustainable development: pathways to scale up for early childhood development.

    Science.gov (United States)

    Richter, Linda M; Daelmans, Bernadette; Lombardi, Joan; Heymann, Jody; Boo, Florencia Lopez; Behrman, Jere R; Lu, Chunling; Lucas, Jane E; Perez-Escamilla, Rafael; Dua, Tarun; Bhutta, Zulfiqar A; Stenberg, Karin; Gertler, Paul; Darmstadt, Gary L

    2017-01-07

    Building on long-term benefits of early intervention (Paper 2 of this Series) and increasing commitment to early childhood development (Paper 1 of this Series), scaled up support for the youngest children is essential to improving health, human capital, and wellbeing across the life course. In this third paper, new analyses show that the burden of poor development is higher than estimated, taking into account additional risk factors. National programmes are needed. Greater political prioritisation is core to scale-up, as are policies that afford families time and financial resources to provide nurturing care for young children. Effective and feasible programmes to support early child development are now available. All sectors, particularly education, and social and child protection, must play a role to meet the holistic needs of young children. However, health provides a critical starting point for scaling up, given its reach to pregnant women, families, and young children. Starting at conception, interventions to promote nurturing care can feasibly build on existing health and nutrition services at limited additional cost. Failure to scale up has severe personal and social consequences. Children at elevated risk for compromised development due to stunting and poverty are likely to forgo about a quarter of average adult income per year, and the cost of inaction to gross domestic product can be double what some countries currently spend on health. Services and interventions to support early childhood development are essential to realising the vision of the Sustainable Development Goals. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Investing in the foundation of sustainable development: pathways to scale up for early childhood development

    Science.gov (United States)

    Richter, Linda M; Daelmans, Bernadette; Lombardi, Joan; Heymann, Jody; Boo, Florencia Lopez; Behrman, Jere R; Lu, Chunling; Lucas, Jane E; Perez-Escamilla, Rafael; Dua, Tarun; Bhutta, Zulfiqar A; Stenberg, Karin; Gertler, Paul; Darmstadt, Gary L

    2018-01-01

    Building on long-term benefits of early intervention (Paper 2 of this Series) and increasing commitment to early childhood development (Paper 1 of this Series), scaled up support for the youngest children is essential to improving health, human capital, and wellbeing across the life course. In this third paper, new analyses show that the burden of poor development is higher than estimated, taking into account additional risk factors. National programmes are needed. Greater political prioritisation is core to scale-up, as are policies that afford families time and financial resources to provide nurturing care for young children. Effective and feasible programmes to support early child development are now available. All sectors, particularly education, and social and child protection, must play a role to meet the holistic needs of young children. However, health provides a critical starting point for scaling up, given its reach to pregnant women, families, and young children. Starting at conception, interventions to promote nurturing care can feasibly build on existing health and nutrition services at limited additional cost. Failure to scale up has severe personal and social consequences. Children at elevated risk for compromised development due to stunting and poverty are likely to forgo about a quarter of average adult income per year, and the cost of inaction to gross domestic product can be double what some countries currently spend on health. Services and interventions to support early childhood development are essential to realising the vision of the Sustainable Development Goals. PMID:27717610

  1. Development of an instrument to analyze organizational characteristics in multidisciplinary care pathways : the case of colorectal cancer

    NARCIS (Netherlands)

    Pluimers, Dorine; van Vliet, Ellen J.; Niezink, Anne G.H.; van Mourik, Martijn S.; Eddes, Eric H.; Wouters, Michel W.; Tollenaar, Rob A.E.M.; van Harten, Wim H.

    2015-01-01

    Background: To analyze the organization of multidisciplinary care pathways such as colorectal cancer care, an instrument was developed based on a recently published framework that was earlier used in analyzing (monodisciplinary) specialist cataract care from a lean perspective. Methods: The

  2. The usefulness of lean six sigma to the development of a clinical pathway for hip fractures.

    Science.gov (United States)

    Niemeijer, Gerard C; Flikweert, Elvira; Trip, Albert; Does, Ronald J M M; Ahaus, Kees T B; Boot, Anja F; Wendt, Klaus W

    2013-10-01

    The objective of this study was to show the usefulness of lean six sigma (LSS) for the development of a multidisciplinary clinical pathway. A single centre, both retrospective and prospective, non-randomized controlled study design was used to identify the variables of a prolonged length of stay (LOS) for hip fractures in the elderly and to measure the effect of the process improvements--with the aim of improving efficiency of care and reducing the LOS. The project identified several variables influencing LOS, and interventions were designed to improve the process of care. Significant results were achieved by reducing both the average LOS by 4.2 days (-31%) and the average duration of surgery by 57 minutes (-36%). The average LOS of patients discharged to a nursing home reduced by 4.4 days. The findings of this study show a successful application of LSS methodology within the development of a clinical pathway. Further research is needed to explore the effect of the use of LSS methodology at clinical outcome and quality of life. © 2012 John Wiley & Sons Ltd.

  3. Metabolic Engineering to Develop a Pathway for the Selective Cleavage of Carbon-Nitrogen Bonds

    Energy Technology Data Exchange (ETDEWEB)

    John J. Kilbane II

    2005-10-01

    The objective of the project is to develop a biochemical pathway for the selective cleavage of C-N bonds in molecules found in petroleum. Specifically a novel biochemical pathway will be developed for the selective cleavage of C-N bonds in carbazole. The cleavage of the first C-N bond in carbazole is accomplished by the enzyme carbazole dioxygenase, that catalyzes the conversion of carbazole to 2-aminobiphenyl-2,3-diol. The genes encoding carbazole dioxygenase were cloned from Sphingomonas sp. GTIN11 and from Pseudomonas resinovorans CA10. The selective cleavage of the second C-N bond has been challenging, and efforts to overcome that challenge have been the focus of recent research in this project. Enrichment culture experiments succeeded in isolating bacterial cultures that can metabolize 2-aminobiphenyl, but no enzyme capable of selectively cleaving the C-N bond in 2-aminobiphenyl has been identified. Aniline is very similar to the structure of 2-aminobiphenyl and aniline dioxygenase catalyzes the conversion of aniline to catechol and ammonia. For the remainder of the project the emphasis of research will be to simultaneously express the genes for carbazole dioxygenase and for aniline dioxygenase in the same bacterial host and then to select for derivative cultures capable of using carbazole as the sole source of nitrogen.

  4. Regulation of Schistosoma mansoni development and reproduction by the mitogen-activated protein kinase signaling pathway.

    Science.gov (United States)

    Andrade, Luiza Freire de; Mourão, Marina de Moraes; Geraldo, Juliana Assis; Coelho, Fernanda Sales; Silva, Larissa Lopes; Neves, Renata Heisler; Volpini, Angela; Machado-Silva, José Roberto; Araujo, Neusa; Nacif-Pimenta, Rafael; Caffrey, Conor R; Oliveira, Guilherme

    2014-06-01

    Protein kinases are proven targets for drug development with an increasing number of eukaryotic Protein Kinase (ePK) inhibitors now approved as drugs. Mitogen-activated protein kinase (MAPK) family members connect cell-surface receptors to regulatory targets within cells and influence a number of tissue-specific biological activities such as cell proliferation, differentiation and survival. However, the contributions of members of the MAPK pathway to schistosome development and survival are unclear. We employed RNA interference (RNAi) to elucidate the functional roles of five S. mansoni genes (SmCaMK2, SmJNK, SmERK1, SmERK2 and SmRas) involved in MAPK signaling pathway. Mice were injected with post-infective larvae (schistosomula) subsequent to RNAi and the development of adult worms observed. The data demonstrate that SmJNK participates in parasite maturation and survival of the parasites, whereas SmERK are involved in egg production as infected mice had significantly lower egg burdens with female worms presenting underdeveloped ovaries. Furthermore, it was shown that the c-fos transcription factor was overexpressed in parasites submitted to RNAi of SmERK1, SmJNK and SmCaMK2 indicating its putative involvement in gene regulation in this parasite's MAPK signaling cascade. We conclude that MAPKs proteins play important roles in the parasite in vivo survival, being essential for normal development and successful survival and reproduction of the schistosome parasite. Moreover SmERK and SmJNK are potential targets for drug development.

  5. Developing pathways to low carbon land-based passenger transport in Great Britain by 2050

    International Nuclear Information System (INIS)

    Bristow, Abigail L.; Tight, Miles; Pridmore, Alison; May, Anthony D.

    2008-01-01

    The key aim of this paper is to examine strategic pathways to low carbon personal transport in Britain and to compare these with the current trajectory of transport policy. A 2050 baseline was established using trend information, forecasts and best evidence from the literature on response to policy intervention. A range of strategies are tested including: technological development, pricing, public transport and soft measures. We conclude that even dramatic technological advance cannot meet the more stringent targets for carbon reduction in the absence of considerable behavioural change. The most promising combinations of measures involve clear price signals to encourage both a reduction in the use of motorised transport and the development and purchase of more efficient vehicles; decarbonisation of public transport and facilitating measures to enhance access whilst reducing the need for motorised travel

  6. METABOLIC ENGINEERING TO DEVELOP A PATHWAY FOR THE SELECTIVE CLEAVAGE OF CARBON-NITROGEN BONDS

    Energy Technology Data Exchange (ETDEWEB)

    John J. Kilbane II

    2004-10-01

    The objective of the project is to develop biochemical pathways for the selective cleavage of C-N bonds in molecules found in petroleum. The initial phase of the project was focused on the isolation or development of an enzyme capable of cleaving the C-N bond in aromatic amides, specifically 2-aminobiphenyl. The objective of the second phase of the research will be to construct a biochemical pathway for the selective removal of nitrogen from carbazole by combining the carA genes from Sphingomonas sp. GTIN11 with the gene(s) encoding an appropriate deaminase. The objective of the final phase of the project will be to develop derivative C-N bond cleaving enzymes that have broader substrate ranges and to demonstrate the use of such strains to selectively remove nitrogen from petroleum. During the first year of the project (October, 2002-September, 2003) enrichment culture experiments resulted in the isolation of microbial cultures that utilize aromatic amides as sole nitrogen sources, several amidase genes were cloned and were included in directed evolution experiments to obtain derivatives that can cleave C-N bonds in aromatic amides, and the carA genes from Sphingomonas sp. GTIN11, and Pseudomonas resinovorans CA10 were cloned in vectors capable of replicating in Escherichia coli. During the second year of the project (October, 2003-September, 2004) enrichment culture experiments succeeded in isolating a mixed bacterial culture that can utilize 2-aminobiphenyl as a sole nitrogen source, directed evolution experiments were focused on the aniline dioxygenase enzyme that is capable of deaminating aniline, and expression vectors were constructed to enable the expression of genes encoding C-N bond cleaving enzymes in Rhodococcus hosts. The construction of a new metabolic pathway to selectively remove nitrogen from carbazole and other molecules typically found in petroleum should lead to the development of a process to improve oil refinery efficiency by reducing the

  7. Identifying Barriers and Pathways to Success for Renewable Energy Development on American Indian Lands

    Energy Technology Data Exchange (ETDEWEB)

    Necefer, Len Edward [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Univ. of Arizona, Tucson, AZ (United States); Jones, Thomas Elisha [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Carnegie Mellon Univ., Pittsburgh, PA (United States)

    2016-11-01

    American Indian tribes possess lands rich with renewable energy (RE) resources. Tribes have great potential and need to develop these resources, yet face a host of barriers that continue to impede development. Understanding these challenges as well as the pathways that can be taken to overcome them may facilitate more economic development to meet community needs and better position tribes to play a role in securing a low-carbon energy future for the United States. This paper presents the results of an expert elicitation of 24 tribal energy experts from federal, tribal, academic, and private industry backgrounds to identify barriers and opportunities for federally recognized tribes in the lower 48 states. Experts identified a number of unique challenges facing tribes including financing and funding, infrastructure, tribal leadership and staff, state-level influence, and partnerships. Cultural factors were seen only to be of concern with large-scale development. Tribal sovereignty is a significant motivation for RE development and has yet to be fully realized. Cultural considerations are critical to the success of future projects; smaller residential and community-scale projects may be a better fit. Improving partnerships between tribes and the private sector can increase RE deployment and overcome historical distrust. States can have a double-ended influence on projects within tribal lands through taxation.

  8. Career Development and Learning Pathways of Paralympic Coaches With a Disability.

    Science.gov (United States)

    Douglas, Scott; Falcão, William R; Bloom, Gordon A

    2018-01-01

    The purpose of this study was to gain an understanding of the career development and learning pathways of Paralympic head coaches who previously competed as Paralympic athletes. Each coach participated in a semistructured interview. A thematic analysis of the data revealed three higher order themes, which were called becoming a coach, learning to coach, and lifelong learning and teaching. Across these themes, participants discussed interactions with other coaches and athletes with a disability, learning from mentors and coaching clinics, as well as limited formal educational opportunities they experienced transitioning from athlete to head coach. The findings revealed that they acquired most of their knowledge from a combination of knowledge gained as athletes and informal sources, including trial and error. They also stressed the need for enhanced recruiting of parasport coaches and parasport coach education opportunities that would enhance programs for athletes with physical disabilities, from grassroots to Paralympic levels.

  9. From migration to settlement: the pathways, migration modes and dynamics of neurons in the developing brain

    Science.gov (United States)

    HATANAKA, Yumiko; ZHU, Yan; TORIGOE, Makio; KITA, Yoshiaki; MURAKAMI, Fujio

    2016-01-01

    Neuronal migration is crucial for the construction of the nervous system. To reach their correct destination, migrating neurons choose pathways using physical substrates and chemical cues of either diffusible or non-diffusible nature. Migrating neurons extend a leading and a trailing process. The leading process, which extends in the direction of migration, determines navigation, in particular when a neuron changes its direction of migration. While most neurons simply migrate radially, certain neurons switch their mode of migration between radial and tangential, with the latter allowing migration to destinations far from the neurons’ site of generation. Consequently, neurons with distinct origins are intermingled, which results in intricate neuronal architectures and connectivities and provides an important basis for higher brain function. The trailing process, in contrast, contributes to the late stage of development by turning into the axon, thus contributing to the formation of neuronal circuits. PMID:26755396

  10. Botrytis cinerea Manipulates the Antagonistic Effects between Immune Pathways to Promote Disease Development in Tomato[C][W][OA

    Science.gov (United States)

    El Oirdi, Mohamed; El Rahman, Taha Abd; Rigano, Luciano; El Hadrami, Abdelbasset; Rodriguez, María Cecilia; Daayf, Fouad; Vojnov, Adrian; Bouarab, Kamal

    2011-01-01

    Plants have evolved sophisticated mechanisms to sense and respond to pathogen attacks. Resistance against necrotrophic pathogens generally requires the activation of the jasmonic acid (JA) signaling pathway, whereas the salicylic acid (SA) signaling pathway is mainly activated against biotrophic pathogens. SA can antagonize JA signaling and vice versa. Here, we report that the necrotrophic pathogen Botrytis cinerea exploits this antagonism as a strategy to cause disease development. We show that B. cinerea produces an exopolysaccharide, which acts as an elicitor of the SA pathway. In turn, the SA pathway antagonizes the JA signaling pathway, thereby allowing the fungus to develop its disease in tomato (Solanum lycopersicum). SA-promoted disease development occurs through Nonexpressed Pathogen Related1. We also show that the JA signaling pathway required for tomato resistance against B. cinerea is mediated by the systemin elicitor. These data highlight a new strategy used by B. cinerea to overcome the plant’s defense system and to spread within the host. PMID:21665999

  11. FLOWERING LOCUS C (FLC) regulates development pathways throughout the life cycle of Arabidopsis.

    Science.gov (United States)

    Deng, Weiwei; Ying, Hua; Helliwell, Chris A; Taylor, Jennifer M; Peacock, W James; Dennis, Elizabeth S

    2011-04-19

    FLOWERING LOCUS C (FLC) has a key role in the timing of the initiation of flowering in Arabidopsis. FLC binds and represses two genes that promote flowering, FT and SOC1. We show that FLC binds to many other genes, indicating that it has regulatory roles other than the repression of flowering. We identified 505 FLC binding sites, mostly located in the promoter regions of genes and containing at least one CArG box, the motif known to be associated with MADS-box proteins such as FLC. We examined 40 of the target genes, and 20 showed increased transcript levels in an flc mutant compared with the wild type. Five genes showed decreased expression in the mutant, indicating that FLC binding can result in either transcriptional repression or activation. The genes we identified as FLC targets are involved in developmental pathways throughout the life history of the plant, many of which are associated with reproductive development. FLC is also involved in vegetative development, as evidenced by its binding to SPL15, delaying the progression from juvenile to adult phase. Some of the FLC target genes are also bound by two other MADS-box proteins, AP1 and SEP3, suggesting that MADS-box genes may operate in a network of control at different stages of the life cycle, many ultimately contributing to the development of the reproductive phase of the plant.

  12. Proteome profiling of flax (Linum usitatissimum) seed: characterization of functional metabolic pathways operating during seed development.

    Science.gov (United States)

    Barvkar, Vitthal T; Pardeshi, Varsha C; Kale, Sandip M; Kadoo, Narendra Y; Giri, Ashok P; Gupta, Vidya S

    2012-12-07

    Flax (Linum usitatissimum L.) seeds are an important source of food and feed due to the presence of various health promoting compounds, making it a nutritionally and economically important plant. An in-depth analysis of the proteome of developing flax seed is expected to provide significant information with respect to the regulation and accumulation of such storage compounds. Therefore, a proteomic analysis of seven seed developmental stages (4, 8, 12, 16, 22, 30, and 48 days after anthesis) in a flax variety, NL-97 was carried out using a combination of 1D-SDS-PAGE and LC-MSE methods. A total 1716 proteins were identified and their functional annotation revealed that a majority of them were involved in primary metabolism, protein destination, storage and energy. Three carbon assimilatory pathways appeared to operate in flax seeds. Reverse transcription quantitative PCR of selected 19 genes was carried out to understand their roles during seed development. Besides storage proteins, methionine synthase, RuBisCO and S-adenosylmethionine synthetase were highly expressed transcripts, highlighting their importance in flax seed development. Further, the identified proteins were mapped onto developmental seed specific expressed sequence tag (EST) libraries of flax to obtain transcriptional evidence and 81% of them had detectable expression at the mRNA level. This study provides new insights into the complex seed developmental processes operating in flax.

  13. Common-Lymphoid-Progenitor-Independent Pathways of Innate and T Lymphocyte Development

    Directory of Open Access Journals (Sweden)

    Maryam Ghaedi

    2016-04-01

    Full Text Available All lymphocytes are thought to develop from common lymphoid progenitors (CLPs. However, lymphoid-primed multipotent progenitors (LMPPs are more efficient than CLPs in differentiating into T cells and group 2 innate lymphoid cells (ILC2s. Here, we have divided LMPPs into CD127− (LMPP−s and CD127+ (LMPP+s subsets and compared them with Ly6D− and Ly6D+ CLPs. Adult LMPP+s differentiated into T cells and ILCs more rapidly and efficiently than other progenitors in transplantation assays. The development of T cells and ILC2s is highly active in the neonatal period. Neonatal CLPs are rare and, unlike prominent neonatal LMPP+s, do not efficiently differentiate into T cells and ILC2s. ILC2s generated in the neonatal period are long lived and persist in adult tissues. These results suggest that some ILCs and T cells may develop from LMPP+s via CLP-independent pathways.

  14. Secretin Modulates the Postnatal Development of Mouse Cerebellar Cortex Via PKA- and ERK-dependent Pathways

    Directory of Open Access Journals (Sweden)

    Lei Wang

    2017-11-01

    Full Text Available Postnatal development of the cerebellum is critical for its intact function such as motor coordination and has been implicated in the pathogenesis of psychiatric disorders. We previously reported that deprivation of secretin (SCT from cerebellar Purkinje neurons impaired motor coordination and motor learning function, while leaving the potential role of SCT in cerebellar development to be determined. SCT and its receptor (SCTR were constitutively expressed in the postnatal cerebellum in a temporal and cell-specific manner. Using a SCT knockout mouse model, we provided direct evidence showing altered developmental patterns of Purkinje cells (PCs and granular cells (GCs. SCT deprivation reduced the PC density, impaired the PC dendritic formation, induced accelerated GC migration and potentiated cerebellar apoptosis. Furthermore, our results indicated the involvement of protein kinase A (PKA and extracellular signal regulated kinase (ERK signaling pathways in SCT-mediated protective effects against neuronal apoptosis. Results of this study illustrated a novel function of SCT in the postnatal development of cerebellum, emphasizing the necessary role of SCT in cerebellar-related functions.

  15. Functional studies of signaling pathways in peri-implantation development of the mouse embryo by RNAi

    Directory of Open Access Journals (Sweden)

    Bell Graham

    2005-12-01

    Full Text Available Abstract Background Studies of gene function in the mouse have relied mainly on gene targeting via homologous recombination. However, this approach is difficult to apply in specific windows of time, and to simultaneously knock-down multiple genes. Here we report an efficient method for dsRNA-mediated gene silencing in late cleavage-stage mouse embryos that permits examination of phenotypes at post-implantation stages. Results We show that introduction of Bmp4 dsRNA into intact blastocysts by electroporation recapitulates the genetic Bmp4 null phenotype at gastrulation. It also reveals a novel role for Bmp4 in the regulation the anterior visceral endoderm specific gene expression and its positioning. We also show that RNAi can be used to simultaneously target several genes. When applied to the three murine isoforms of Dishevelled, it leads to earlier defects than previously observed in double knock-outs. These include severe delays in post-implantation development and defects in the anterior midline and neural folds at headfold stages. Conclusion Our results indicate that the BMP4 signalling pathway contributes to the development of the anterior visceral endoderm, and reveal an early functional redundancy between the products of the murine Dishevelled genes. The proposed approach constitutes a powerful tool to screen the functions of genes that govern the development of the mouse embryo.

  16. Small leucine rich proteoglycan family regulates multiple signalling pathways in neural development and maintenance.

    Science.gov (United States)

    Dellett, Margaret; Hu, Wanzhou; Papadaki, Vasiliki; Ohnuma, Shin-ichi

    2012-04-01

    The small leucine-rich repeat proteoglycan (SLRPs) family of proteins currently consists of five classes, based on their structural composition and chromosomal location. As biologically active components of the extracellular matrix (ECM), SLRPs were known to bind to various collagens, having a role in regulating fibril assembly, organization and degradation. More recently, as a function of their diverse proteins cores and glycosaminoglycan side chains, SLRPs have been shown to be able to bind various cell surface receptors, growth factors, cytokines and other ECM components resulting in the ability to influence various cellular functions. Their involvement in several signaling pathways such as Wnt, transforming growth factor-β and epidermal growth factor receptor also highlights their role as matricellular proteins. SLRP family members are expressed during neural development and in adult neural tissues, including ocular tissues. This review focuses on describing SLRP family members involvement in neural development with a brief summary of their role in non-neural ocular tissues and in response to neural injury. © 2012 The Authors Development, Growth & Differentiation © 2012 Japanese Society of Developmental Biologists.

  17. LFTR: in search of the ideal pathway to thorium utilization-development program and current status

    International Nuclear Information System (INIS)

    Soon, Benjamin

    2015-01-01

    Thorium has gained substantial attention as a potential energy source that could rival and eventually replace fossil fuels as humanity's primary energy source. This could not have come at a more opportune time as concerns about global climate change from CO 2 emissions and the approaching spectre of finite fossil fuel resources create serious challenges for the continuation of our advanced industrial societies, which are reliant on readily available and affordable energy. Thorium also potentially represents the catalyst with which the nuclear industry could reinvent itself and finally gain widespread public acceptance. There are many opinions on how to utilize thorium as a fuel, but the question of what constitutes an 'ideal' pathway has mostly been under-emphasized. Many specific characteristics of the thorium fuel cycle can differ significantly depending on the conditions and methodologies of utilization; characteristics such as safety, efficiency, waste profile and volume, and fissile protection can vary greatly according to reactor design and utilization philosophy. With thorium, we have been given an opportunity to start over, a blank slate. Therefore, in imagining the 'Thorium Economy' to come, it behoves the scientific and engineering communities to consider the most 'elegant' solution physically possible-what constitutes the 'ideal' and is it possible to reconcile it with what is both economically and technically practical? The characteristics desired of an 'ideal' nuclear reactor, in the areas of safety, efficiency, economy, and sustainability, and the 5 key design choices that could enable such a reactor will be discussed. This will be followed by an overview of the Liquid Fluoride Thorium Reactor, a 2-fluid Molten Salt Reactor currently under development by Flibe Energy in the United States. LFTR is a direct descendant of the MSRE, which was developed at Oak Ridge National Laboratory (ORNL) in the

  18. Arabidopsis CPR5 independently regulates seed germination and postgermination arrest of development through LOX pathway and ABA signaling.

    Directory of Open Access Journals (Sweden)

    Guilan Gao

    Full Text Available The phytohormone abscisic acid (ABA and the lipoxygenases (LOXs pathway play important roles in seed germination and seedling growth and development. Here, we reported on the functional characterization of Arabidopsis CPR5 in the ABA signaling and LOX pathways. The cpr5 mutant was hypersensitive to ABA in the seed germination, cotyledon greening and root growth, whereas transgenic plants overexpressing CPR5 were insensitive. Genetic analysis demonstrated that CPR5 gene may be located downstream of the ABI1 in the ABA signaling pathway. However, the cpr5 mutant showed an ABA independent drought-resistant phenotype. It was also found that the cpr5 mutant was hypersensitive to NDGA and NDGA treatment aggravated the ABA-induced delay in the seed germination and cotyledon greening. Taken together, these results suggest that the CPR5 plays a regulatory role in the regulation of seed germination and early seedling growth through ABA and LOX pathways independently.

  19. Development and implementation of a decision pathway for general practitioners for the management or referral of suspected allergy

    Directory of Open Access Journals (Sweden)

    Ray B. Jones

    2014-07-01

    Full Text Available Many patients with suspected allergy are referred to specialist care inappropriately. We aimed to develop and implement an online decision pathway to aid General Practitioners’ (GPs management decisions in suspected allergy. Our study involved 1487 GPs, 3 referral management centres, 5 GP system suppliers, 4 primary care trusts, and 1 specialist allergy clinic. The pathway was implemented by 3/5 GP system suppliers, published to Map of Medicine and on a specialist clinic website. In the first year, the pathway ranked in the top 10/160 local care maps accessed via Map of Medicine and was viewed 900 times. Only 96 GPs registered to use the clinic website. Only 110 (7% GPs responded to the feedback request, of which 13/110 (12% had used the pathway; nearly all thought it useful. It was used by referral management centres as explanation of rejected referrals. Alternative approaches to embed its use are required.

  20. Socio-Emotional Development Following Very Preterm Birth: Pathways to Psychopathology.

    Science.gov (United States)

    Montagna, Anita; Nosarti, Chiara

    2016-01-01

    Very preterm birth (VPT; develop cognitive and socio-emotional problems, as well as with increased vulnerability to psychiatric disorder, both with childhood and adult onset. Socio-emotional impairments that have been described in VPT individuals include diminished social competence and self-esteem, emotional dysregulation, shyness and timidity. However, the etiology of socio-emotional problems in VPT samples and their underlying mechanisms are far from understood. To date, research has focused on the investigation of both biological and environmental risk factors associated with socio-emotional problems, including structural and functional alterations in brain areas involved in processing emotions and social stimuli, perinatal stress and pain and parenting strategies. Considering the complex interplay of the aforementioned variables, the review attempts to elucidate the mechanisms underlying the association between very preterm birth, socio-emotional vulnerability and psychopathology. After a comprehensive overview of the socio-emotional impairments associated with VPT birth, three main models of socio-emotional development are presented and discussed. These focus on biological vulnerability, early life adversities and parenting, respectively. To conclude, a developmental framework is used to consider different pathways linking VPT birth to psychopathology, taking into account the interaction between medical, biological, and psychosocial factors.

  1. Socio-emotional development following very preterm birth: pathways to psychopathology

    Directory of Open Access Journals (Sweden)

    Anita eMontagna

    2016-02-01

    Full Text Available Very preterm birth (VPT; <32 weeks of gestation has been associated with an increased risk to develop cognitive and socio-emotional problems, as well as with increased vulnerability to psychiatric disorder, both with childhood and adult onset.Socio-emotional impairments that have been described in VPT individuals include diminished social competence and self-esteem, emotional dysregulation, shyness and timidity.However, the aetiology of socio-emotional problems in VPT samples and their underlying mechanisms are far from understood. To date, research has focused on the investigation of both biological and environmental risk factors associated with socio-emotional problems, including structural and functional alterations in brain areas involved in processing emotions and social stimuli, perinatal stress and pain and parenting strategies.Considering the complex interplay of the aforementioned variables, the review attempts to elucidate the mechanisms underlying the association between very preterm birth, socio-emotional vulnerability and psychopathology. After a comprehensive overview of the socio-emotional impairments associated with VPT birth, three main models of socio-emotional development are presented and discussed. These focus on biological vulnerability, early life adversities and parenting, respectively. To conclude, a developmental framework is used to consider different pathways linking VPT birth to psychopathology, taking into account the interaction between medical, biological and psychosocial factors.

  2. [Review of the initiation and development of the conception of clinical pathway].

    Science.gov (United States)

    Wang, Zhen-E; Shangguan, Qing-Miao; Wu, Ping

    2010-11-01

    Dupont, an American company, used the concept of "pathway" in industry to improve the quality of their products in 1957. In the 1970s, under the pressure of a rise in medical costs, some people realized the concept of the "key pathway" could be used in medicine too. In 1985, the Boston New England Medical Center Hospital (NEMC) succeeded in using the concept of the clinical pathway in medical practice, and afterwards the concept gradually found worldwide application. In 1996, the Fourth Military Medical University in China reported the application of clinical pathway in America. The West China Hospital began to try out the clinical pathway in 1998 and the concept gradually found application in China.

  3. The rice YABBY4 gene regulates plant growth and development through modulating the gibberellin pathway.

    Science.gov (United States)

    Yang, Chao; Ma, Yamei; Li, Jianxiong

    2016-10-01

    YABBY genes encode seed plant-specific transcription factors that play pivotal roles in diverse aspects of leaf, shoot, and flower development. Members of the YABBY gene family are primarily expressed in lateral organs in a polar manner and function to specify abaxial cell fate in dicotyledons, but this polar expression is not conserved in monocotyledons. The function of YABBY genes is therefore not well understood in monocotyledons. Here we show that overexpression of the rice (Oryza sativa L.) YABBY4 gene (OsYABBY4) leads to a semi-dwarf phenotype, abnormal development in the uppermost internode, an increased number of floral organs, and insensitivity to gibberellin (GA) treatment. We report on an important role for OsYABBY4 in negative control of the expression of a GA biosynthetic gene by binding to the promoter region of the gibberellin 20-oxidase 2 gene (GA20ox2), which is a direct target of SLR1 (the sole DELLA protein negatively controlling GA responses in rice). OsYABBY4 also suppresses the expression level of SLR1 and interacts with SLR1 protein. The interaction inhibits GA-dependent degradation of SLR1 and therefore leads to GA insensitivity. These data together suggest that OsYABBY4 serves as a DNA-binding intermediate protein for SLR1 and is associated with the GA signaling pathway regulating gene expression during plant growth and development. © The Author 2016. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  4. Development of an evidence-based decision pathway for vestibular schwannoma treatment options.

    Science.gov (United States)

    Linkov, Faina; Valappil, Benita; McAfee, Jacob; Goughnour, Sharon L; Hildrew, Douglas M; McCall, Andrew A; Linkov, Igor; Hirsch, Barry; Snyderman, Carl

    To integrate multiple sources of clinical information with patient feedback to build evidence-based decision support model to facilitate treatment selection for patients suffering from vestibular schwannomas (VS). This was a mixed methods study utilizing focus group and survey methodology to solicit feedback on factors important for making treatment decisions among patients. Two 90-minute focus groups were conducted by an experienced facilitator. Previously diagnosed VS patients were recruited by clinical investigators at the University of Pittsburgh Medical Center (UPMC). Classical content analysis was used for focus group data analysis. Providers were recruited from practices within the UPMC system and were surveyed using Delphi methods. This information can provide a basis for multi-criteria decision analysis (MCDA) framework to develop a treatment decision support system for patients with VS. Eight themes were derived from these data (focus group + surveys): doctor/health care system, side effects, effectiveness of treatment, anxiety, mortality, family/other people, quality of life, and post-operative symptoms. These data, as well as feedback from physicians were utilized in building a multi-criteria decision model. The study illustrated steps involved in the development of a decision support model that integrates evidence-based data and patient values to select treatment alternatives. Studies focusing on the actual development of the decision support technology for this group of patients are needed, as decisions are highly multifactorial. Such tools have the potential to improve decision making for complex medical problems with alternate treatment pathways. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Which factors are important for the successful development and implementation of clinical pathways? A qualitative study.

    Science.gov (United States)

    De Allegri, Manuela; Schwarzbach, Matthias; Loerbroks, Adrian; Ronellenfitsch, Ulrich

    2011-03-01

    Clinical pathways (CPs) are detailed longitudinal care plans delineating measures to be conducted during a patient's treatment. Although positive effects on resource consumption and quality of care have been shown, CPs are still underutilised in many clinical settings because their development and implementation are difficult. Evidence underpinning successful development and implementation is sparse. The authors conducted semistructured face-to-face interviews with key staff members involved in the design and implementation of CPs in a large surgery department. Interviewees were asked to provide opinions on various issues, which were previously identified as potentially important in CP development and implementation. The transcribed text was read and coded independently by two researchers. Respondents highlighted the importance of a multidisciplinary participatory approach for CP design and implementation. There was a strong initial fear of losing individual freedom of treatment, which subsided after people worked with CPs in clinical everyday life. It was appreciated that the project originated from people at different levels of the department's hierarchy. Likewise, it was felt that CP implementation granted more autonomy to lower-level staff. The structured qualitative approach of this study provides information on what issues are considered important by staff members for CP design and implementation. Whereas some concepts such as the importance of a multidisciplinary approach or continuous feedback of results are known from theories, others such as strengthening the authority especially of lower-level health professionals through CPs have not been described so far. Many of the findings point towards strong interactions between factors important for CP implementation and a department's organisational structure.

  6. Late-stage development of the Bryant Canyon turbidite pathway on the Louisiana continental slope

    Science.gov (United States)

    Twichell, David C.; Nelson, Hans; Damuth, John E.

    2000-01-01

    GLORIA sidescan imagery, multibeam bathymetry, seismic profiles, and piston cores (3–5 m penetration) reveal the near-surface geology of the Bryant Canyon turbidite pathway on the continental margin of Louisiana. This pathway extends from the continental shelf edge, across the continental slope, to a deep-sea fan on the continental rise. The pathway is narrow (thalweg no longer has a continuous down-slope gradient. Some mini-basin floors along the pathway are now more than 500 m deeper than their basin’s spill point. We propose a 6-stage conceptual model to explain our observations for the evolution of a mini-basin along this turbidite pathway. In this model, an active channel feeds sand to a mini-basin (Stabe B). Once the mini-basin is filled, the sand deposit is entrenched by a bypass channel (Stage C). When the turbidite system shuts off, salt migration oversteepens the mini-basin walls (Stage D) which collapse and create a layer of mass-transport deposits on the mini-basin floor (Stage E). The depositional succession is capped by a layer of highstand hemipelagic drape (Stage F). The Bryant Canyon turbidite pathway provides a recent example of a large turbidite pathway in the Gulf of Mexico that crosses an area of active salt tectonics thus providing a conceptual model for older systems in similar settings. In Bryant Canyon, thick turbidite sands presumably are found in mini-basins however, they are sealed by thick, fine-grained, mass-transport deposits which terminate mini-basin turbidite deposition cycles. The importance of mass-transport deposits in basins along this turbidite pathway is in startling contrast to the Trinity-Brazos pathway whose shallow subsurface expression is virtually free of mass-transport deposits and has undergone minimal deformation by salt movement.

  7. Using adaptive processes and adverse outcome pathways to develop meaningful, robust, and actionable environmental monitoring programs.

    Science.gov (United States)

    Arciszewski, Tim J; Munkittrick, Kelly R; Scrimgeour, Garry J; Dubé, Monique G; Wrona, Fred J; Hazewinkel, Rod R

    2017-09-01

    The primary goals of environmental monitoring are to indicate whether unexpected changes related to development are occurring in the physical, chemical, and biological attributes of ecosystems and to inform meaningful management intervention. Although achieving these objectives is conceptually simple, varying scientific and social challenges often result in their breakdown. Conceptualizing, designing, and operating programs that better delineate monitoring, management, and risk assessment processes supported by hypothesis-driven approaches, strong inference, and adverse outcome pathways can overcome many of the challenges. Generally, a robust monitoring program is characterized by hypothesis-driven questions associated with potential adverse outcomes and feedback loops informed by data. Specifically, key and basic features are predictions of future observations (triggers) and mechanisms to respond to success or failure of those predictions (tiers). The adaptive processes accelerate or decelerate the effort to highlight and overcome ignorance while preventing the potentially unnecessary escalation of unguided monitoring and management. The deployment of the mutually reinforcing components can allow for more meaningful and actionable monitoring programs that better associate activities with consequences. Integr Environ Assess Manag 2017;13:877-891. © 2017 The Authors. Integrated Environmental Assessment and Management Published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC). © 2017 The Authors. Integrated Environmental Assessment and Management Published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

  8. A new pathway for developing in vitro nanostructured non-viral gene carriers

    Energy Technology Data Exchange (ETDEWEB)

    Chu, Benjamin [Chemistry Department, Stony Brook University, Stony Brook, NY 11794-3400 (United States); Liang Dehai [Chemistry Department, Stony Brook University, Stony Brook, NY 11794-3400 (United States); Hadjiargyrou, Michael [Biomedical Engineering Department, Stony Brook University, Stony Brook, NY 11794-3400 (United States); Hsiao, Benjamin S [Chemistry Department, Stony Brook University, Stony Brook, NY 11794-3400 (United States)

    2006-09-13

    Extracellular and intracellular barriers typically prevent the efficient transfection of non-viral gene vectors. The formulation of a gene delivery carrier that can overcome the barriers would be a key for successful gene therapy. We have developed a novel pathway for the preparation of core-shelled DNA nanoparticles by invoking solvent-induced condensation of plasmid DNA ({beta}-galactosidase) in a poor solvent mixture and subsequent encapsulation of the condensed DNA globule in a tri-block copolymer (e.g. polylactide-poly(ethylene glycol)-polylactide, L{sub 8}E{sub 78}L{sub 8}). The polylactide shell can protect the encapsulated DNA from degradation during electrospinning of a mixture of encapsulated DNA nanoparticles and biodegradable PLGA (a random copolymer of lactide and glycolide) to form a non-woven nanofibrous DNA-containing scaffold. The bioactive plasmid DNA can then be released in an intact form and in sufficient quantity from the scaffold with a controlled release rate and to transfect cells in vitro. Further consideration of the stability of the DNA in extracellular and intracellular environments is proposed. In particular, the use of block copolymers with a positively charged block and a hydrophilic block, as well as tri-arm block copolymers with an additional hydrophobic, biodegradable block to stabilize the DNA chain of interest, is discussed.

  9. Development of Tool Representations in the Dorsal and Ventral Visual Object Processing Pathways

    Science.gov (United States)

    Kersey, Alyssa J.; Clark, Tyia S.; Lussier, Courtney A.; Mahon, Bradford Z.; Cantlon, Jessica F.

    2016-01-01

    Tools represent a special class of objects, because they are processed across both the dorsal and ventral visual object processing pathways. Three core regions are known to be involved in tool processing: the left posterior middle temporal gyrus, the medial fusiform gyrus (bilaterally), and the left inferior parietal lobule. A critical and relatively unexplored issue concerns whether, in development, tool preferences emerge at the same time and to a similar degree across all regions of the tool-processing network. To test this issue, we used functional magnetic resonance imaging to measure the neural amplitude, peak location, and the dispersion of tool-related neural responses in the youngest sample of children tested to date in this domain (ages 4–8 years). We show that children recruit overlapping regions of the adult tool-processing network and also exhibit similar patterns of co-activation across the network to adults. The amplitude and co-activation data show that the core components of the tool-processing network are established by age 4. Our findings on the distributions of peak location and dispersion of activation indicate that the tool network undergoes refinement between ages 4 and 8 years. PMID:26108614

  10. Pleiotropy of the Drosophila JAK pathway cytokine Unpaired 3 in development and aging.

    Science.gov (United States)

    Wang, Liqun; Sexton, Travis R; Venard, Claire; Giedt, Michelle; Guo, Qian; Chen, Qian; Harrison, Douglas A

    2014-11-15

    The Janus kinase (JAK) pathway is an essential, highly re-utilized developmental signaling cascade found in most metazoans. In vertebrates, the JAK intracellular cascade mediates signaling by dozens of cytokines and growth factors. In Drosophila, the Unpaired (Upd) family, encoded by three tandemly duplicated genes, is the only class of ligands associated with JAK stimulation. Unpaired has a central role in activation of JAK for most pathway functions, while Unpaired 2 regulates body size through insulin signaling. We show here that the third member of the family, unpaired 3 (upd3), overlaps upd in expression in some tissues and is essential for a subset of JAK-mediated developmental functions. First, consistent with the known requirements of JAK signaling in gametogenesis, we find that mutants of upd3 show an age-dependent impairment of fertility in both sexes. In oogenesis, graded JAK activity stimulated by Upd specifies the fates of the somatic follicle cells. As upd3 mutant females age, defects arise that can be attributed to perturbations of the terminal follicle cells, which require the highest levels of JAK activation. Therefore, in oogenesis, the activities of Upd and Upd3 both appear to quantitatively contribute to specification of those follicle cell fates. Furthermore, the sensitization of upd3 mutants to age-related decline in fertility can be used to investigate reproductive senescence. Second, loss of Upd3 during imaginal development results in defects of adult structures, including reduced eye size and abnormal wing and haltere posture. The outstretched wing and small eye phenotypes resemble classical alleles referred to as outstretched (os) mutations that have been previously ascribed to upd. However, we show that os alleles affect expression of both upd and upd3 and map to untranscribed regions, suggesting that they disrupt regulatory elements shared by both genes. Thus the upd region serves as a genetically tractable model for coordinate

  11. Development of transgenic Brassica juncea lines for reduced seed sinapine content by perturbing phenylpropanoid pathway genes.

    Directory of Open Access Journals (Sweden)

    Sachin Kajla

    Full Text Available Sinapine is a major anti-nutritive compound that accumulates in the seeds of Brassica species. When ingested, sinapine imparts gritty flavuor in meat and milk of animals and fishy odor to eggs of brown egg layers, thereby compromising the potential use of the valuable protein rich seed meal. Sinapine content in Brassica juncea germplasm ranges from 6.7 to 15.1 mg/g of dry seed weight (DSW which is significantly higher than the prescribed permissible level of 3.0 mg/g of DSW. Due to limited natural genetic variability, conventional plant breeding approach for reducing the sinapine content has largely been unsuccessful. Hence, transgenic approach for gene silencing was adopted by targeting two genes-SGT and SCT, encoding enzymes UDP- glucose: sinapate glucosyltransferase and sinapoylglucose: choline sinapoyltransferase, respectively, involved in the final two steps of sinapine biosynthetic pathway. These two genes were isolated from B. juncea and eight silencing constructs were developed using three different RNA silencing approaches viz. antisense RNA, RNAi and artificial microRNA. Transgenics in B. juncea were developed following Agrobacterium-mediated transformation. From a total of 1232 independent T0 transgenic events obtained using eight silencing constructs, 25 homozygous lines showing single gene inheritance were identified in the T2 generation. Reduction of seed sinapine content in these lines ranged from 15.8% to 67.2%; the line with maximum reduction had sinapine content of 3.79 mg/g of DSW. The study also revealed that RNAi method was more efficient than the other two methods used in this study.

  12. Requirements and potential development pathways for fission energy supply infrastructures of the 21st century - a systems viewpoint

    International Nuclear Information System (INIS)

    Wade, D. C.

    1999-01-01

    Using an energy supply systems approach, we envision attributes and characteristic needs of a future global fission-based energy supply infrastructure, enumerate potential pathways for meeting those needs, and identify the underlying enabling science and technology developments for R and D efforts to meet the needs

  13. Practical approaches to adverse outcome pathway development and weight‐of‐evidence evaluation as illustrated by ecotoxicological case studies

    Science.gov (United States)

    Adverse Outcome Pathways (AOPs) describe toxicant effects as a sequential chain of causally linked events beginning with a molecular perturbation and culminating in an adverse outcome at an individual or population level. Strategies for developing AOPs are still evolving and dep...

  14. Development of an instrument to analyze organizational characteristics in multidisciplinary care pathways; the case of colorectal cancer

    NARCIS (Netherlands)

    Pluimers, Dorine; van Vliet, Ellen J.; Niezink, Anne G.H.; van Mourik, Martijn S.; Eddes, Eric H.; Wouters, Michel W.; Tollenaar, Rob A.E.M.; van Harten, Willem H.

    2015-01-01

    Background To analyze the organization of multidisciplinary care pathways such as colorectal cancer care, an instrument was developed based on a recently published framework that was earlier used in analyzing (monodisciplinary) specialist cataract care from a lean perspective. Methods The instrument

  15. Translating Evidence Based Violence and Drug Use Prevention to Obesity Prevention: Development and Construction of the Pathways Program

    Science.gov (United States)

    Sakuma, Kari-Lyn K.; Riggs, Nathaniel R.; Pentz, Mary Ann

    2012-01-01

    Effective school-based obesity prevention programs are needed to prevent and reduce the growing obesity risk among youth. Utilizing the evidence-rich areas of violence and substance use prevention, translation science may provide an efficient means for developing curricula across multiple health behaviors. This paper introduces Pathways to Health,…

  16. Chapter 10 the primary cilium coordinates signaling pathways in cell cycle control and migration during development and tissue repair

    DEFF Research Database (Denmark)

    Christensen, Søren T; Pedersen, Stine F; Satir, Peter

    2008-01-01

    Cell cycle control and migration are critical processes during development and maintenance of tissue functions. Recently, primary cilia were shown to take part in coordination of the signaling pathways that control these cellular processes in human health and disease. In this review, we present...... an overview of the function of primary cilia and the centrosome in the signaling pathways that regulate cell cycle control and migration with focus on ciliary signaling via platelet-derived growth factor receptor alpha (PDGFRalpha). We also consider how the primary cilium and the centrosome interact...... with the extracellular matrix, coordinate Wnt signaling, and modulate cytoskeletal changes that impinge on both cell cycle control and cell migration....

  17. Enabling pathways to health equity: developing a framework for implementing social capital in practice.

    Science.gov (United States)

    Putland, Christine; Baum, Fran; Ziersch, Anna; Arthurson, Kathy; Pomagalska, Dorota

    2013-05-29

    Mounting evidence linking aspects of social capital to health and wellbeing outcomes, in particular to reducing health inequities, has led to intense interest in social capital theory within public health in recent decades. As a result, governments internationally are designing interventions to improve health and wellbeing by addressing levels of social capital in communities. The application of theory to practice is uneven, however, reflecting differing views on the pathways between social capital and health, and divergent theories about social capital itself. Unreliable implementation may restrict the potential to contribute to health equity by this means, yet to date there has been limited investigation of how the theory is interpreted at the level of policy and then translated into practice. The paper outlines a collaborative research project designed to address this knowledge deficit in order to inform more effective implementation. Undertaken in partnership with government departments, the study explored the application of social capital theory in programs designed to promote health and wellbeing in Adelaide, South Australia. It comprised three case studies of community-based practice, employing qualitative interviews and focus groups with community participants, practitioners, program managers and policy makers, to examine the ways in which the concept was interpreted and operationalized and identify the factors influencing success. These key lessons informed the development of practical resources comprising a guide for practitioners and briefing for policy makers. Overall the study showed that effective community projects can contribute to population health and wellbeing and reducing health inequities. Of specific relevance to this paper, however, is the finding that community projects rely for their effectiveness on a broader commitment expressed through policies and frameworks at the highest level of government decision making. In particular this

  18. Molecular pathways undergoing dramatic transcriptomic changes during tumor development in the human colon

    Directory of Open Access Journals (Sweden)

    Maglietta Rosalia

    2012-12-01

    Full Text Available Abstract Background The malignant transformation of precancerous colorectal lesions involves progressive alterations at both the molecular and morphologic levels, the latter consisting of increases in size and in the degree of cellular atypia. Analyzing preinvasive tumors of different sizes can therefore shed light on the sequence of these alterations. Methods We used a molecular pathway-based approach to analyze transcriptomic profiles of 59 colorectal tumors representing early and late preinvasive stages and the invasive stage of tumorigenesis. Random set analysis was used to identify biological pathways enriched for genes differentially regulated in tumors (compared with 59 samples of normal mucosa. Results Of the 880 canonical pathways we investigated, 112 displayed significant tumor-related upregulation or downregulation at one or more stages of tumorigenesis. This allowed us to distinguish between pathways whose dysregulation is probably necessary throughout tumorigenesis and those whose involvement specifically drives progression from one stage to the next. We were also able to pinpoint specific changes within each gene set that seem to play key roles at each transition. The early preinvasive stage was characterized by cell-cycle checkpoint activation triggered by DNA replication stress and dramatic downregulation of basic transmembrane signaling processes that maintain epithelial/stromal homeostasis in the normal mucosa. In late preinvasive lesions, there was also downregulation of signal transduction pathways (e.g., those mediated by G proteins and nuclear hormone receptors involved in cell differentiation and upregulation of pathways governing nuclear envelope dynamics and the G2>M transition in the cell cycle. The main features of the invasive stage were activation of the G1>S transition in the cell cycle, upregulated expression of tumor-promoting microenvironmental factors, and profound dysregulation of metabolic pathways (e

  19. Integrating parts of the APhA Career Pathway Evaluation Program for pharmacy professionals into a career development lab.

    Science.gov (United States)

    Linn, Brooke A; Burton, Samantha J; Shepler, Brian M

    To use parts of the APhA Career Pathway Evaluation Program for Pharmacy Professionals in a career development laboratory designed to provide students with relevant information that will help them prepare for successful careers across the profession of pharmacy. Students enrolled in the second professional year of pharmacy school participated in an interactive three-hour career development laboratory. Students completed the APhA Career Pathway Evaluation Program for Pharmacy Professionals Online Assessment Tool prior to the laboratory. In class, the students were randomized into eight groups. Two career profiles were assigned to each group for discussion during a thirty-minute brainstorming session. The groups reported their knowledge for each career profile to the entire class, and the instructors supplemented the discussion with details and more specific information about each profile. Two years of data were collected (n=300 students). One hundred and twenty four (41.3%) students responded to the voluntary post-laboratory survey questions. Overall, students rated the career pathway activities favorably with an average score of 8.13 out of 10. After participation in the discussion, 74 (59.7%) respondents indicated their career interests had been impacted. This career development laboratory is one example of how the APhA Career Pathway Evaluation Program for Pharmacy Professionals can be effectively incorporated into the PharmD curriculum in order to help students explore the various career options they might not have otherwise discovered on their own. Published by Elsevier Inc.

  20. The effect of maternal diabetes on the Wnt-PCP pathway during embryogenesis as reflected in the developing mouse eye

    Directory of Open Access Journals (Sweden)

    Beatriz López-Escobar

    2015-02-01

    Full Text Available Embryopathies that develop as a consequence of maternal diabetes have been studied intensely in both experimental and clinical scenarios. Accordingly, hyperglycaemia has been shown to downregulate the expression of elements in the non-canonical Wnt-PCP pathway, such as the Dishevelled-associated activator of morphogenesis 1 (Daam1 and Vangl2. Daam1 is a formin that is essential for actin polymerization and for cytoskeletal reorganization, and it is expressed strongly in certain organs during mouse development, including the eye, neural tube and heart. Daam1gt/gt and Daam1gt/+ embryos develop ocular defects (anophthalmia or microphthalmia that are similar to those detected as a result of hyperglycaemia. Indeed, studying the effects of maternal diabetes on the Wnt-PCP pathway demonstrated that there was strong association with the Daam1 genotype, whereby the embryopathy observed in Daam1gt/+ mutant embryos of diabetic dams was more severe. There was evidence that embryonic exposure to glucose in vitro diminishes the expression of genes in the Wnt-PCP pathway, leading to altered cytoskeletal organization, cell shape and cell polarity in the optic vesicle. Hence, the Wnt-PCP pathway appears to influence cell morphology and cell polarity, events that drive the cellular movements required for optic vesicle formation and that, in turn, are required to maintain the fate determination. Here, we demonstrate that the Wnt-PCP pathway is involved in the early stages of mouse eye development and that it is altered by diabetes, provoking the ocular phenotype observed in the affected embryos.

  1. Informal E-waste recycling in developing countries: review of metal(loid)s pollution, environmental impacts and transport pathways.

    Science.gov (United States)

    Ackah, Michael

    2017-11-01

    Crude or primitive recycling practices are often adopted in material resource recovery from E-waste in developing nations. Significant human health and environmental impacts may occur because of such practices. Literature on metal(loid)s pollution during E-waste processing is fragmented. Here, I review the health and environmental impacts of E-waste recycling operations and transport pathways of metal(loid)s, dispersed during operations. This paper is organised into five sections. Section 1 relates to the background of global E-waste generation and legal/illegal trade, citing specific cases from Ghana and other developing nations. Section 2 provides a brief information on sources of metal(loid)s in E-waste. Section 3 describes characteristics of informal E-waste recycling operations in developing nations. Section 4 examines the health and environmental impacts in E-waste recycling while section 5 evaluates major transport pathways of metal(loid)s contaminants.

  2. The Sustainable Development Goals – Pathways to Eco-innovation and a Global Green Economy?

    DEFF Research Database (Denmark)

    Andersen, Maj Munch

    points to the need for policy learning, suggesting these countries could leapfrog the greening of their economies by targeting green economic change through adopting eco-innovation policies for the greening of their companies rather than pursuing a traditional regulatory approach. Such a pathway...

  3. Are Green Jobs Career Pathways a Path to a 21st-Century Workforce Development System?

    Science.gov (United States)

    Scully-Russ, Ellen

    2013-01-01

    This article examines policy reports that advocate for new green jobs career pathways to help grow the green economy and create new opportunity structures in the green labor market. The reports are based on a series of propositions about the nature of green jobs and the existence of the political will to invest in new green education programs to…

  4. Development of a Novel Quantitative Adverse Outcome Pathway Predictive Model for Lung Cancer

    Science.gov (United States)

    Traditional methods for carcinogenicity testing are resource-intensive, retrospective, and time consuming. An increasing testing burden has generated interest in the adverse outcome pathway (AOP) concept as a tool to evaluate chemical safety in a more efficient, rapid and effecti...

  5. NF-κB-IKKβ pathway as a target for drug development: realities, challenges and perspectives.

    Science.gov (United States)

    Freitas, Rosana H C N; Fraga, Carlos A M

    2018-02-19

    Nuclear factor κB (NF-κB) comprises a family of proteins that act as transcription factors promoting the expression of many genes. Activation of NF-κB biochemical cascades is associated with the regulation of innate and adaptive immune responses and inflammation, among other physiological responses. However, genetic abnormalities and continuous stimulation of the NF-κB-IKKβ pathway are directly related to many types of inflammatory and autoimmune diseases, as well as to the genesis and survival of tumor cells. Inhibition of the NF-κB-IKKβ cascade can be considered an attractive therapeutic method for the genesis of new prototypes to combat these chronic multifactorial diseases. This review describes some prototypes and drugs that act to inhibit the NF-κB-IKKβ pathway, highlighting the realities, challenges and perspectives for therapeutic use. Although only proteasome inhibitors, such as bortezomib and carfilzomib, are a reality as therapeutically useful drugs among the known modulators of possible targets in the NF-κB-IKKβ pathway, some other prototypes described as IKKβ inhibitors have entered clinical stages as drug candidates for the control of inflammatory diseases. It is important to note that some classical drugs available on the pharmaceutical market, such as acetylsalicylic acid, were also described more recently as NF-κB pathway modulators as IKKβ inhibitors. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  6. Differentiating pathway-specific from nonspecific effects in high-throughput toxicity data: A foundation for prioritizing adverse outcome pathway development

    Science.gov (United States)

    The U.S. Environmental Protection Agency’s ToxCast program has screened thousands of chemicals for biological activity, primarily using high-throughput in vitro bioassays. Adverse outcome pathways (AOPs) offer a means to link pathway-specific biological activities with potential ...

  7. Shared learning for chronic conditions: a methodology for developing the Royal College of Paediatrics and Child Health (RCPCH) care pathways for children with allergies.

    Science.gov (United States)

    Warner, John O; Lloyd, Kate

    2011-11-01

    The Royal College of Paediatrics and Child Health (RCPCH) Science and Research Department was commissioned by the Department of Health to develop national care pathways for children with allergies. The pathways focus on defining the competences to deliver the highest standard of care for such children. By defining competences rather than criteria for onward referral, the authors have sought to create flexibility in delivery of care which will be responsive to regional variations in knowledge, skills and service. All pathways were developed by multidisciplinary working groups, based on a comprehensive review of evidence. The pathways were reviewed by a broad group of stakeholders and approved by the Allergy Care Pathways Project Board and the RCPCH Clinical Standards Committee. The results for all pathways are presented in two sections: a pathway algorithm and the competences. The entry points for each pathway are defined at the point where symptoms first occur and the ideal management is described from self-care through complete diagnosis to monitoring of progress. From the evidence review the working groups were able to make research recommendations. The authors present eight national care pathways for allergic conditions based on evidence review, expert consensus and stakeholder input. They provide a guide for training and development of services to facilitate improvements in delivery as close to the patient's home as possible. The authors recommend that these pathways are implemented locally by a multidisciplinary team with a focus on creating networks between primary, secondary and tertiary care to improve services for children with allergic conditions.

  8. Development of steroid signaling pathways during primordial follicle formation in the human fetal ovary.

    Science.gov (United States)

    Fowler, Paul A; Anderson, Richard A; Saunders, Philippa T; Kinnell, Hazel; Mason, J Ian; Evans, Dean B; Bhattacharya, Siladitya; Flannigan, Samantha; Franks, Stephen; Monteiro, Ana; O'Shaughnessy, Peter J

    2011-06-01

    Ovarian primordial follicle formation is critical for subsequent human female fertility. It is likely that steroid, and especially estrogen, signaling is required for this process, but details of the pathways involved are currently lacking. The aim was to identify and characterize key members of the steroid-signaling pathway expressed in the second trimester human fetal ovary. We conducted an observational study of the female fetus, quantifying and localizing steroid-signaling pathway members. The study was conducted at the Universities of Aberdeen, Edinburgh, and Glasgow. Ovaries were collected from 43 morphologically normal human female fetuses from women undergoing elective termination of second trimester pregnancies. We measured mRNA transcript levels and immunolocalized key steroidogenic enzymes and steroid receptors, including those encoded by ESR2, AR, and CYP19A1. Levels of mRNA encoding the steroidogenic apparatus and steroid receptors increased across the second trimester. CYP19A1 transcript increased 4.7-fold during this period with intense immunostaining for CYP19A detected in pregranulosa cells around primordial follicles and somatic cells around oocyte nests. ESR2 was localized primarily to germ cells, but androgen receptor was exclusively expressed in somatic cells. CYP17A1 and HSD3B2 were also localized to oocytes, whereas CYP11A1 was detected in oocytes and some pregranulosa cells. The human fetal ovary expresses the machinery to produce and detect multiple steroid signaling pathways, including estrogenic signaling, with the oocyte acting as a key component. This study provides a step-change in our understanding of local dynamics of steroid hormone signaling during the key period of human primordial follicle formation.

  9. Global microRNA profiles and signaling pathways in the development of cardiac hypertrophy

    Energy Technology Data Exchange (ETDEWEB)

    Feng, H.J.; Ouyang, W.; Liu, J.H.; Sun, Y.G.; Hu, R.; Huang, L.H.; Xian, J.L. [Southern Medical University, Department of Nuclear Medicine, Zhujiang Hospital, Guangzhou, China, Department of Nuclear Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou (China); Jing, C.F.; Zhou, M.J. [Sun Yat-Sen University, South China Sea Marine Biotechnology, National Engineering Research Center, Guangzhou, China, National Engineering Research Center, South China Sea Marine Biotechnology, Sun Yat-Sen University, Guangzhou (China)

    2014-04-11

    Hypertrophy is a major predictor of progressive heart disease and has an adverse prognosis. MicroRNAs (miRNAs) that accumulate during the course of cardiac hypertrophy may participate in the process. However, the nature of any interaction between a hypertrophy-specific signaling pathway and aberrant expression of miRNAs remains unclear. In this study, Spague Dawley male rats were treated with transverse aortic constriction (TAC) surgery to mimic pathological hypertrophy. Hearts were isolated from TAC and sham operated rats (n=5 for each group at 5, 10, 15, and 20 days after surgery) for miRNA microarray assay. The miRNAs dysexpressed during hypertrophy were further analyzed using a combination of bioinformatics algorithms in order to predict possible targets. Increased expression of the target genes identified in diverse signaling pathways was also analyzed. Two sets of miRNAs were identified, showing different expression patterns during hypertrophy. Bioinformatics analysis suggested the miRNAs may regulate multiple hypertrophy-specific signaling pathways by targeting the member genes and the interaction of miRNA and mRNA might form a network that leads to cardiac hypertrophy. In addition, the multifold changes in several miRNAs suggested that upregulation of rno-miR-331*, rno-miR-3596b, rno-miR-3557-5p and downregulation of rno-miR-10a, miR-221, miR-190, miR-451 could be seen as biomarkers of prognosis in clinical therapy of heart failure. This study described, for the first time, a potential mechanism of cardiac hypertrophy involving multiple signaling pathways that control up- and downregulation of miRNAs. It represents a first step in the systematic discovery of miRNA function in cardiovascular hypertrophy.

  10. Development and implementation of a clinical pathway approach to simulation-based training for foregut surgery.

    Science.gov (United States)

    Miyasaka, Kiyoyuki W; Buchholz, Joseph; LaMarra, Denise; Karakousis, Giorgos C; Aggarwal, Rajesh

    2015-01-01

    Contemporary demands on resident education call for integration of simulation. We designed and implemented a simulation-based curriculum for Post Graduate Year 1 surgery residents to teach technical and nontechnical skills within a clinical pathway approach for a foregut surgery patient, from outpatient visit through surgery and postoperative follow-up. The 3-day curriculum for groups of 6 residents comprises a combination of standardized patient encounters, didactic sessions, and hands-on training. The curriculum is underpinned by a summative simulation "pathway" repeated on days 1 and 3. The "pathway" is a series of simulated preoperative, intraoperative, and postoperative encounters in following up a single patient through a disease process. The resident sees a standardized patient in the clinic presenting with distal gastric cancer and then enters an operating room to perform a gastrojejunostomy on a porcine tissue model. Finally, the resident engages in a simulated postoperative visit. All encounters are rated by faculty members and the residents themselves, using standardized assessment forms endorsed by the American Board of Surgery. A total of 18 first-year residents underwent this curriculum. Faculty ratings of overall operative performance significantly improved following the 3-day module. Ratings of preoperative and postoperative performance were not significantly changed in 3 days. Resident self-ratings significantly improved for all encounters assessed, as did reported confidence in meeting the defined learning objectives. Conventional surgical simulation training focuses on technical skills in isolation. Our novel "pathway" curriculum targets an important gap in training methodologies by placing both technical and nontechnical skills in their clinical context as part of managing a surgical patient. Results indicate consistent improvements in assessments of performance as well as confidence and support its continued usage to educate surgery residents

  11. The Heme Biosynthesis Pathway Is Essential for Plasmodium falciparum Development in Mosquito Stage but Not in Blood Stages*

    Science.gov (United States)

    Ke, Hangjun; Sigala, Paul A.; Miura, Kazutoyo; Morrisey, Joanne M.; Mather, Michael W.; Crowley, Jan R.; Henderson, Jeffrey P.; Goldberg, Daniel E.; Long, Carole A.; Vaidya, Akhil B.

    2014-01-01

    Heme is an essential cofactor for aerobic organisms. Its redox chemistry is central to a variety of biological functions mediated by hemoproteins. In blood stages, malaria parasites consume most of the hemoglobin inside the infected erythrocytes, forming nontoxic hemozoin crystals from large quantities of heme released during digestion. At the same time, the parasites possess a heme de novo biosynthetic pathway. This pathway in the human malaria parasite Plasmodium falciparum has been considered essential and is proposed as a potential drug target. However, we successfully disrupted the first and last genes of the pathway, individually and in combination. These knock-out parasite lines, lacking 5-aminolevulinic acid synthase and/or ferrochelatase (FC), grew normally in blood-stage culture and exhibited no changes in sensitivity to heme-related antimalarial drugs. We developed a sensitive LC-MS/MS assay to monitor stable isotope incorporation into heme from its precursor 5-[13C4]aminolevulinic acid, and this assay confirmed that de novo heme synthesis was ablated in FC knock-out parasites. Disrupting the FC gene also caused no defects in gametocyte generation or maturation but resulted in a greater than 70% reduction in male gamete formation and completely prevented oocyst formation in female Anopheles stephensi mosquitoes. Our data demonstrate that the heme biosynthesis pathway is not essential for asexual blood-stage growth of P. falciparum parasites but is required for mosquito transmission. Drug inhibition of pathway activity is therefore unlikely to provide successful antimalarial therapy. These data also suggest the existence of a parasite mechanism for scavenging host heme to meet metabolic needs. PMID:25352601

  12. Development of computationally predicted Adverse Outcome Pathway (AOP) networks through data mining and integration of publicly available in vivo, in vitro, phenotype, and biological pathway data

    Science.gov (United States)

    The Adverse Outcome Pathway (AOP) framework is increasingly being adopted as a tool for organizing and summarizing the mechanistic information connecting molecular perturbations by environmental stressors with adverse outcomes relevant for ecological and human health outcomes. Ho...

  13. The Gustatory Signaling Pathway and Bitter Taste Receptors Affect the Development of Obesity and Adipocyte Metabolism in Mice.

    Directory of Open Access Journals (Sweden)

    Bert Avau

    Full Text Available Intestinal chemosensory signaling pathways involving the gustatory G-protein, gustducin, and bitter taste receptors (TAS2R have been implicated in gut hormone release. Alterations in gut hormone profiles may contribute to the success of bariatric surgery. This study investigated the involvement of the gustatory signaling pathway in the development of diet-induced obesity and the therapeutic potential of targeting TAS2Rs to induce body weight loss. α-gustducin-deficient (α-gust-/- mice became less obese than wild type (WT mice when fed a high-fat diet (HFD. White adipose tissue (WAT mass was lower in α-gust-/- mice due to increased heat production as a result of increases in brown adipose tissue (BAT thermogenic activity, involving increased protein expression of uncoupling protein 1. Intra-gastric treatment of obese WT and α-gust-/- mice with the bitter agonists denatonium benzoate (DB or quinine (Q during 4 weeks resulted in an α-gustducin-dependent decrease in body weight gain associated with a decrease in food intake (DB, but not involving major changes in gut peptide release. Both WAT and 3T3-F442A pre-adipocytes express TAS2Rs. Treatment of pre-adipocytes with DB or Q decreased differentiation into mature adipocytes. In conclusion, interfering with the gustatory signaling pathway protects against the development of HFD-induced obesity presumably through promoting BAT activity. Intra-gastric bitter treatment inhibits weight gain, possibly by directly affecting adipocyte metabolism.

  14. Marginal Iodine Deficiency Affects Dendritic Spine Development by Disturbing the Function of Rac1 Signaling Pathway on Cytoskeleton.

    Science.gov (United States)

    Min, Hui; Dong, Jing; Wang, Yi; Wang, Yuan; Yu, Ye; Shan, Zhongyan; Xi, Qi; Teng, Weiping; Chen, Jie

    2017-01-01

    Iodine deficiency (ID)-induced thyroid hormone (TH) insufficient during development leads to impairments of brain function, such as learning and memory. Marginal ID has been defined as subtle insufficiency of TH, characterized as low thyroxine (T 4 ) levels, whether marginal ID potentially had adverse effects on the development of hippocampus and the underlying mechanisms remain unclear. Thus, in the present study, we established Wistar rat models with ID diet during pregnancy and lactation. The effects of marginal ID on long-term potentiation (LTP) were investigated in the hippocampal CA1 region. To study the development of dendritic spines in pyramidal cells, Golgi-Cox staining was conducted on postnatal day (PN) 7, PN14, PN21, and PN28. The activation of Rac1 signaling pathway, which is essential for dendritic spine development by regulating actin cytoskeleton, was also investigated. Our results showed that marginal ID slightly reduced the field-excitatory postsynaptic potential (f-EPSP) slope and the population spike (PS) amplitude. Besides, the density of dendritic spines during the critical period of rat postnatal development was mildly decreased, and we found no significant change of spine morphology in marginal ID group. We also observed decreased activation of the Rac1 signaling pathway in pups subjected to maternal marginal ID. Our study may support the hypothesis that decreased T 4 induced by marginal ID results in slight impairments of LTP and leads to mild damage of dendritic spine development, which may be due to abnormal regulation of Rac1 signaling pathway on cytoskeleton.

  15. Roles of TGF-β/Smad signaling pathway in pathogenesis and development of gluteal muscle contracture.

    Science.gov (United States)

    Zhang, Xintao; Ma, Yukun; You, Tian; Tian, Xiaopeng; Zhang, Honglei; Zhu, Qi; Zhang, Wentao

    2015-02-01

    Gluteal muscle contracture (GMC) is a chronic fibrotic disease of gluteal muscles which is characterized by excessive deposition of collagen in the extracellular matrix. Transforming growth factor (TGF)-βs have been shown to play an important role in the progression of GMC. However, the underlying mechanisms are not entirely clear. We sought to explore the expression of TGF-β/Smad pathway proteins and their downstream targets in gluteal muscle contracture disease. The expression levels of collagens type I/III, TGF-β1, Smad2/3/4/7 and PAI-1 (plasminogen activator inhibitor type 1) in gluteal muscle contraction (GMC) patients were measured using immunohistochemistry, reverse transcription and polymerase chain reaction (RT-PCR) and western blot assays. The expressions of collagens type I/III and TGF-β1 were significantly increased in the contraction band compared with unaffected muscle. In addition, R-Smad phosphorylation and Smad4 protein expression in the contraction band were also elevated, while the expression of Smad7 was significantly decreased in the fibrotic muscle of the GMC patients compared to the unaffected adjacent muscle. The protein and mRNA levels of PAI-1 were also remarkably increased in the contraction band compared with adjacent muscle. Immunohistochemical analysis also demonstrated that the expression levels of TGF-β1 and PAI-1 were higher in contraction band than those in the adjacent muscle. Our data confirm the stimulating effects of the TGF-β/Smad pathway in gluteal muscle contracture disease and reveal the internal changes of TGF-β/Smad pathway proteins and their corresponding targets in gluteal muscle contracture patients.

  16. Development of net energy ratio and emission factor for quad-generation pathways

    DEFF Research Database (Denmark)

    Rudra, Souman; Rosendahl, Lasse; Kumar, Amit

    2014-01-01

    of this study was to evaluate the energy performance, reduce GHG and acid rain precursor emission, and use of biomass for different outputs based on demand. Finally, a sensitivity analysis and a comparative study ar conducted for expected technological improvements and factors that could increase the energy......, methanol and methane. Circulating fluidized bed gasifier and the gas technology institute (GTI) gasifier technologies are used for this quad-generation process. Two different biomass feedstocks are considered in this study. The net energy ratio for six different pathways having the range of between 1...

  17. Global developmental gene expression and pathway analysis of normal brain development and mouse models of human neuronal migration defects.

    Directory of Open Access Journals (Sweden)

    Tiziano Pramparo

    2011-03-01

    Full Text Available Heterozygous LIS1 mutations are the most common cause of human lissencephaly, a human neuronal migration defect, and DCX mutations are the most common cause of X-linked lissencephaly. LIS1 is part of a protein complex including NDEL1 and 14-3-3ε that regulates dynein motor function and microtubule dynamics, while DCX stabilizes microtubules and cooperates with LIS1 during neuronal migration and neurogenesis. Targeted gene mutations of Lis1, Dcx, Ywhae (coding for 14-3-3ε, and Ndel1 lead to neuronal migration defects in mouse and provide models of human lissencephaly, as well as aid the study of related neuro-developmental diseases. Here we investigated the developing brain of these four mutants and wild-type mice using expression microarrays, bioinformatic analyses, and in vivo/in vitro experiments to address whether mutations in different members of the LIS1 neuronal migration complex lead to similar and/or distinct global gene expression alterations. Consistent with the overall successful development of the mutant brains, unsupervised clustering and co-expression analysis suggested that cell cycle and synaptogenesis genes are similarly expressed and co-regulated in WT and mutant brains in a time-dependent fashion. By contrast, focused co-expression analysis in the Lis1 and Ndel1 mutants uncovered substantial differences in the correlation among pathways. Differential expression analysis revealed that cell cycle, cell adhesion, and cytoskeleton organization pathways are commonly altered in all mutants, while synaptogenesis, cell morphology, and inflammation/immune response are specifically altered in one or more mutants. We found several commonly dysregulated genes located within pathogenic deletion/duplication regions, which represent novel candidates of human mental retardation and neurocognitive disabilities. Our analysis suggests that gene expression and pathway analysis in mouse models of a similar disorder or within a common pathway can

  18. A Fat-Facets-Dscam1-JNK Pathway Enhances Axonal Growth in Development and after Injury

    Directory of Open Access Journals (Sweden)

    Marta Koch

    2018-02-01

    Full Text Available Injury to the adult central nervous systems (CNS can result in severe long-term disability because damaged CNS connections fail to regenerate after trauma. Identification of regulators that enhance the intrinsic growth capacity of severed axons is a first step to restore function. Here, we conducted a gain-of-function genetic screen in Drosophila to identify strong inducers of axonal growth after injury. We focus on a novel axis the Down Syndrome Cell Adhesion Molecule (Dscam1, the de-ubiquitinating enzyme Fat Facets (Faf/Usp9x and the Jun N-Terminal Kinase (JNK pathway transcription factor Kayak (Kay/Fos. Genetic and biochemical analyses link these genes in a common signaling pathway whereby Faf stabilizes Dscam1 protein levels, by acting on the 3′-UTR of its mRNA, and Dscam1 acts upstream of the growth-promoting JNK signal. The mammalian homolog of Faf, Usp9x/FAM, shares both the regenerative and Dscam1 stabilizing activities, suggesting a conserved mechanism.

  19. Developmental fluoride exposure influenced rat's splenic development and cell cycle via disruption of the ERK signal pathway.

    Science.gov (United States)

    Ma, Yanqin; Zhang, Kankan; Ren, Fengjun; Wang, Jundong

    2017-11-01

    Excessive fluoride exposure has been reported to cause damage to spleen. Neonatal period is characterized by rapid proliferation and differentiation of lymphocyte in the spleen. Children may be more sensitive to the toxicity of fluoride compared to the adults. The aim of this study was to investigate the effects of postnatal exposure (from neonatal period to early adulthood) to fluoride on the development of spleen on a regular basis and the underlying signal pathway. Results showed a marked decrease in spleen weight index and altered morphology in the spleen of fluoride-treated group on PND-84, which reflected fluoride inhibition of the development of spleen. Fluoride exposure induced cell cycle arrest of splenocytes and decreased the mRNA expression of IL-2, which indicated compromised baseline lymphocyte proliferation in the spleen. Time course research from 3-wk-of-age until 12-wk-of-age showed an adverse and cumulative impact of fluoride on the development of spleen. In view of the key role of MAPK/ERK pathway in lymphocyte development, Raf-1/MEK-1/ERK-2/c-fos mRNA expression and ERK/p-ERK protein expression were detected. Results showed despite a transitory increase in mRNA expression from PND-42 to PND-63 in fluoride-treated group, the expression of these genes on PND-84 decreased significantly compared with PND-42 or PND-63. NaF significantly inhibited the phosphorylation of ERK protein on PND-84. Taken together, these results emphasized the vital role of ERK pathway in the interfered development of spleen induced by a high dose of fluoride exposure in rats. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Transactional Pathways of Transgender Identity Development in Transgender and Gender Nonconforming Youth and Caregivers from the Trans Youth Family Study

    Science.gov (United States)

    Katz-Wise, Sabra L.; Budge, Stephanie L.; Fugate, Ellen; Flanagan, Kaleigh; Touloumtzis, Currie; Rood, Brian; Perez-Brumer, Amaya; Leibowitz, Scott

    2017-01-01

    Background A growing body of research has examined transgender identity development, but no studies have investigated developmental pathways as a transactional process between youth and caregivers, incorporating perspectives from multiple family members. The aim of this study was to conceptualize pathways of transgender identity development using narratives from both transgender and gender nonconforming (TGN) youth and their cisgender (non-transgender) caregivers. Methods The sample included 16 families, with 16 TGN youth, ages 7–18 years, and 29 cisgender caregivers (N = 45 family members). TGN youth represented multiple gender identities, including trans boy (n = 9), trans girl (n = 5), gender fluid boy (n = 1), and girlish boy (n = 1). Caregivers included mothers (n = 17), fathers (n = 11), and one grandmother. Participants were recruited from LGBTQ community organizations and support networks for families with transgender youth in the Midwest, Northeast, and South regions of the United States. Each family member completed a one-time in-person semi-structured qualitative interview that included questions about transgender identity development. Results Analyses revealed seven overarching themes of transgender identity development, which were organized into a conceptual model: Trans identity development, sociocultural influences/societal discourse, biological influences, family adjustment/impact, stigma/cisnormativity, support/resources, and gender affirmation/actualization. Conclusions Findings underscore the importance of assessing developmental processes among TGN youth as transactional, impacting both youth and their caregivers. PMID:29527139

  1. Identification of mechanosensitive genes during skeletal development: alteration of genes associated with cytoskeletal rearrangement and cell signalling pathways.

    Science.gov (United States)

    Rolfe, Rebecca A; Nowlan, Niamh C; Kenny, Elaine M; Cormican, Paul; Morris, Derek W; Prendergast, Patrick J; Kelly, Daniel; Murphy, Paula

    2014-01-20

    Mechanical stimulation is necessary for regulating correct formation of the skeleton. Here we test the hypothesis that mechanical stimulation of the embryonic skeletal system impacts expression levels of genes implicated in developmentally important signalling pathways in a genome wide approach. We use a mutant mouse model with altered mechanical stimulation due to the absence of limb skeletal muscle (Splotch-delayed) where muscle-less embryos show specific defects in skeletal elements including delayed ossification, changes in the size and shape of cartilage rudiments and joint fusion. We used Microarray and RNA sequencing analysis tools to identify differentially expressed genes between muscle-less and control embryonic (TS23) humerus tissue. We found that 680 independent genes were down-regulated and 452 genes up-regulated in humeri from muscle-less Spd embryos compared to littermate controls (at least 2-fold; corrected p-value ≤0.05). We analysed the resulting differentially expressed gene sets using Gene Ontology annotations to identify significant enrichment of genes associated with particular biological processes, showing that removal of mechanical stimuli from muscle contractions affected genes associated with development and differentiation, cytoskeletal architecture and cell signalling. Among cell signalling pathways, the most strongly disturbed was Wnt signalling, with 34 genes including 19 pathway target genes affected. Spatial gene expression analysis showed that both a Wnt ligand encoding gene (Wnt4) and a pathway antagonist (Sfrp2) are up-regulated specifically in the developing joint line, while the expression of a Wnt target gene, Cd44, is no longer detectable in muscle-less embryos. The identification of 84 genes associated with the cytoskeleton that are down-regulated in the absence of muscle indicates a number of candidate genes that are both mechanoresponsive and potentially involved in mechanotransduction, converting a mechanical stimulus

  2. The role of reaction pathways and support interactions in the development of high activity hydrotreating catalysts

    DEFF Research Database (Denmark)

    Topsøe, Henrik; Hinnemann, Berit; Nørskov, Jens Kehlet

    2005-01-01

    structures may be present as single sulfide sheets. Thus, stacking is not an essential feature of Type II catalysts. The article illustrates how the new scientific insight has aided the introduction of the new high activity BRIM (TM) type catalysts for FCC pre-treatment and production of ultra low sulfur...... exhibiting a metallic character are observed to be involved in adsorption, hydrogenation and C-S bond cleavage. The insight is seen to provide a new framework for understanding the DDS and HYD pathways and the role of steric hindrance and poisons. Density functional theory (DFT) calculations have illustrated...... how support interactions may influence the activity of sulfided catalysts. The brim sites and the tendency to form vacancies are seen to differ in types I and II Co-Mo-S. High-angle annular dark-field scanning transmission electron microscopy (HAADF-STEM) studies show that the high activity Type II...

  3. Cryopreservation in fish: current status and pathways to quality assurance and quality control in repository development.

    Science.gov (United States)

    Torres, Leticia; Hu, E; Tiersch, Terrence R

    2016-01-07

    Cryopreservation in aquatic species in general has been constrained to research activities for more than 60 years. Although the need for application and commercialisation pathways has become clear, the lack of comprehensive quality assurance and quality control programs has impeded the progress of the field, delaying the establishment of germplasm repositories and commercial-scale applications. In this review we focus on the opportunities for standardisation in the practices involved in the four main stages of the cryopreservation process: (1) source, housing and conditioning of fish; (2) sample collection and preparation; (3) freezing and cryogenic storage of samples; and (4) egg collection and use of thawed sperm samples. In addition, we introduce some key factors that would assist the transition to commercial-scale, high-throughput application.

  4. The development of a methodology to assess population doses from multiple sources and exposure pathways of radioactivity

    International Nuclear Information System (INIS)

    Hancox, J.; Stansby, S.; Thorne, M.

    2002-01-01

    The Environment Agency (EA) has new duties in accordance with the Basic Safety Standards Directive under which it is required to ensure that doses to individuals received from exposure to anthropogenic sources of radioactivity are within defined limits. In order to assess compliance with these requirements, the EA needs to assess the doses to members of the most highly exposed population groups ('critical' groups) from all relevant potential sources of anthropogenic radioactivity and all relevant potential exposure pathways to such radioactivity. The EA has identified a need to develop a methodology for the retrospective assessment of effective doses from multiple sources of radioactive materials and exposure pathways associated with those sources. Under contract to the EA, AEA Technology has undertaken the development of a suitable methodology as part of EA R and D Project P3-070. The methodology developed under this research project has been designed to support the EA in meeting its obligations under the Euratom Basic Safety Standards Directive and is consistent with UK and international approaches to radiation dosimetry and radiological protection. The development and trial application of the methodology is described in this report

  5. The F-box-containing protein UFO and AGAMOUS participate in antagonistic pathways governing early petal development in Arabidopsis.

    Science.gov (United States)

    Durfee, Tim; Roe, Judith L; Sessions, R Allen; Inouye, Carla; Serikawa, Kyle; Feldmann, Kenneth A; Weigel, Detlef; Zambryski, Patricia C

    2003-07-08

    The UNUSUAL FLORAL ORGANS (UFO) gene is required for multiple processes in the developing Arabidopsis flower, including the proper patterning and identity of both petals and stamens. The gene encodes an F-box-containing protein, UFO, which interacts physically and genetically with the Skp1 homolog, ASK1. In this report, we describe four ufo alleles characterized by the absence of petals, which uncover another role for UFO in promoting second whorl development. This UFO-dependent pathway is required regardless of the second whorl organ to be formed, arguing that it affects a basic process acting in parallel with those establishing organ identity. However, the pathway is dispensable in the absence of AGAMOUS (AG), a known inhibitor of petal development. In situ hybridization results argue that AG is not transcribed in the petal region, suggesting that it acts non-cell-autonomously to inhibit second whorl development in ufo mutants. These results are combined into a genetic model explaining early second whorl initiation/proliferation, in which UFO functions to inhibit an AG-dependent activity.

  6. Fostering development of nursing practices to support integrated care when implementing integrated care pathways: what levers to use?

    Science.gov (United States)

    Longpré, Caroline; Dubois, Carl-Ardy

    2017-11-29

    Care integration has been the focus of recent health system reforms. Given their functions at all levels of the care continuum, nurses have a substantial and primordial role to play in such integration processes. The aim of this study was to identify levers and strategies that organizations can use to support the development of a nursing practice aligned with the requirements of care integration in a health and social services centre (HSSC) in Quebec. The research design was a cross-sectional descriptive qualitative study based on a single case study with nested levels of analysis. The case was a public, multi-disciplinary HSSC in a semi-urban region of Quebec. Semi-structured interviews with 37 persons (nurses, professionals, managers, administrators) allowed for data saturation and ensured theoretical representation by covering four care pathways constituting different care integration contexts. Analysis involved four steps: preparing a predetermined list of codes based on the reference framework developed by Minkman (2011); coding transcript content; developing general and summary matrices to group observations for each care pathway; and creating a general model showing the overall results for the four pathways. The organization's capacity for response with regard to developing an integrated system of services resulted in two types of complementary interventions. The first involved investing in key resources and renewing organizational structures; the second involved deploying a series of organizational and clinical-administrative processes. In resource terms, integration efforts resulted in setting up new strategic services, re-arranging physical infrastructures, and deploying new technological resources. Organizational and clinical-administrative processes to promote integration involved renewing governance, improving the flow of care pathways, fostering continuous quality improvement, developing new roles, promoting clinician collaboration, and strengthening

  7. Dietary-Induced Signals That Activate the Gonadal Longevity Pathway during Development Regulate a Proteostasis Switch in Caenorhabditis elegans Adulthood

    Directory of Open Access Journals (Sweden)

    Netta Shemesh

    2017-08-01

    Full Text Available Cell-non-autonomous signals dictate the functional state of cellular quality control systems, remodeling the ability of cells to cope with stress and maintain protein homeostasis (proteostasis. One highly regulated cell-non-autonomous switch controls proteostatic capacity in Caenorhabditis elegans adulthood. Signals from the reproductive system down-regulate cyto-protective pathways, unless countered by signals reporting on germline proliferation disruption. Here, we utilized dihomo-γ-linolenic acid (DGLA that depletes the C. elegans germline to ask when cell-non-autonomous signals from the reproductive system determine somatic proteostasis and whether such regulation is reversible. We found that diet supplementation of DGLA resulted in the maintenance of somatic proteostasis after the onset of reproduction. DGLA-dependent proteostasis remodeling was only effective if animals were exposed to DGLA during larval development. A short exposure of 16 h during the second to fourth larval stages was sufficient and required to maintain somatic proteostasis in adulthood but not to extend lifespan. The reproductive system was required for DGLA-dependent remodeling of proteostasis in adulthood, likely via DGLA-dependent disruption of germline stem cells. However, arachidonic acid (AA, a somatic regulator of this pathway that does not require the reproductive system, presented similar regulatory timing. Finally, we showed that DGLA- and AA-supplementation led to activation of the gonadal longevity pathway but presented differential regulatory timing. Proteostasis and stress response regulators, including hsf-1 and daf-16, were only activated if exposed to DGLA and AA during development, while other gonadal longevity factors did not show this regulatory timing. We propose that C. elegans determines its proteostatic fate during development and is committed to either reproduction, and thus present restricted proteostasis, or survival, and thus present robust

  8. The secret role of microRNAs in cancer stem cell development and potential therapy: A Notch-pathway approach.

    Directory of Open Access Journals (Sweden)

    Marianna eProkopi

    2015-02-01

    Full Text Available MicroRNAs (miRNAs have been implicated in the development of some if not all cancer types and have been identified as attractive targets for prognosis, diagnosis and therapy of the disease. MiRNAs are a class of small non-coding RNAs (20-22 nucleotides in length that bind imperfectly to the 3’-untranslated region of target mRNA regulating gene expression. Aberrantly expressed miRNAs in cancer, sometimes known as oncomiRNAs, have been shown to play a major role in oncogenesis, metastasis and drug resistance. Amplification of oncomiRNAs during cancer development correlates with the silencing of tumor suppressor genes; on the other hand, down-regulation of miRNAs has also been observed in cancer and cancer stem cells (CSCs. In both cases, miRNA regulation is inversely correlated with cancer progression. Growing evidence indicates that miRNAs are also involved in the metastatic process by either suppressing or promoting metastasis-related genes leading to the reduction or activation of cancer cell migration and invasion processes. In particular, circulating miRNAs (vesicle-encapsulated or non-encapsulated have significant effects on tumorigenesis: membrane-particles, apoptotic bodies and exosomes have been described as providers of a cell-to-cell communication system transporting oncogenic miRNAs from tumors to neighboring cells and distant metastatic sites. It is hypothesized that MiRNAs control cancer development in a traditional manner, by regulating signaling pathways and factors. In addition, recent developments indicate a non-conventional mechanism of cancer regulation by stem cell reprogramming via a regulatory network consisting of miRNAs and Wnt/β-catenin, Notch, and Hedgehog signaling pathways, all of which are involved in controlling stem cell functions of CSCs. In this review, we focus on the role of miRNAs in the Notch pathway and how they regulate CSC self-renewal, differentiation and tumorigenesis by direct/indirect targeting of

  9. Early development and orientation of the acoustic funnel provides insight into the evolution of sound reception pathways in cetaceans.

    Directory of Open Access Journals (Sweden)

    Maya Yamato

    Full Text Available Whales receive underwater sounds through a fundamentally different mechanism than their close terrestrial relatives. Instead of hearing through the ear canal, cetaceans hear through specialized fatty tissues leading to an evolutionarily novel feature: an acoustic funnel located anterior to the tympanic aperture. We traced the ontogenetic development of this feature in 56 fetal specimens from 10 different families of toothed (odontocete and baleen (mysticete whales, using X-ray computed tomography. We also charted ear ossification patterns through ontogeny to understand the impact of heterochronic developmental processes. We determined that the acoustic funnel arises from a prominent V-shaped structure established early in ontogeny, formed by the malleus and the goniale. In odontocetes, this V-formation develops into a cone-shaped funnel facing anteriorly, directly into intramandibular acoustic fats, which is likely functionally linked to the anterior orientation of sound reception in echolocation. In contrast, the acoustic funnel in balaenopterids rotates laterally, later in fetal development, consistent with a lateral sound reception pathway. Balaenids and several fossil mysticetes retain a somewhat anteriorly oriented acoustic funnel in the mature condition, indicating that a lateral sound reception pathway in balaenopterids may be a recent evolutionary innovation linked to specialized feeding modes, such as lunge-feeding.

  10. The researchers' role in knowledge translation: a realist evaluation of the development and implementation of diagnostic pathways for cancer in two United Kingdom localities.

    Science.gov (United States)

    Banks, Jon; Wye, Lesley; Hall, Nicola; Rooney, James; Walter, Fiona M; Hamilton, Willie; Gjini, Ardiana; Rubin, Greg

    2017-12-13

    In examining an initiative to develop and implement new cancer diagnostic pathways in two English localities, this paper evaluates 'what works' and examines the role of researchers in facilitating knowledge translation amongst teams of local clinicians and policy-makers. Using realist evaluation with a mixed methods case study approach, we conducted documentary analysis of meeting minutes and pathway iterations to map pathway development. We interviewed 14 participants to identify the contexts, mechanisms and outcomes (CMOs) that led to successful pathway development and implementation. Interviews were analysed thematically and four CMO configurations were developed. One site produced three fully implemented pathways, while the other produced two that were partly implemented. In explaining the differences, we found that a respected, independent, well-connected leader modelling partnership working and who facilitates a local, stable group that agree about the legitimacy of the data and project (context) can empower local teams to become sufficiently autonomous (mechanism) to develop and implement research-based pathways (outcome). Although both teams designed relevant, research-based cancer pathways, in the site where the pathways were successfully implemented the research team merely assisted, while, in the other, the research team drove the initiative. Based on our study findings, local stakeholders can apply local and research knowledge to develop and implement research-based pathways. However, success will depend on how academics empower local teams to create autonomy. Crucially, after re-packaging and translating research for local circumstances, identifying fertile environments with the right elements for implementation and developing collaborative relationships with local leaders, academics must step back.

  11. Mycorrhizal phosphate uptake pathway in maize: Vital for growth and cob development on nutrient poor agricultural and greenhouse soils

    Directory of Open Access Journals (Sweden)

    Martin eWillmann

    2013-12-01

    Full Text Available Arbuscular mycorrhizal fungi (AMF form a mutually beneficial symbiosis with plant roots providing predominantly phosphorus in the form of orthophosphate (Pi in exchange for plant carbohydrates on low P soils. The goal of this work was to generate molecular-genetic evidence in support of a major impact of the mycorrhizal Pi uptake (MPU pathway on the productivity of the major crop plant maize under field and controlled conditions. Here we show, that a loss-of-function mutation in the mycorrhiza-specific Pi transporter gene Pht1;6 correlates with a dramatic reduction of above-ground biomass and cob production in agro-ecosystems with low P soils. In parallel mutant pht1;6 plants exhibited an altered fingerprint of chemical elements in shoots dependent on soil P availability. In controlled environments mycorrhiza development was impaired in mutant plants when grown alone. The presence of neighbouring mycorrhizal nurse plants enhanced the reduced mycorrhiza formation in pht1;6 roots. Uptake of 33P-labelled orthophosphate via the MPU pathway was strongly impaired in colonized mutant plants. Moreover, repression of the MPU pathway resulted in a redirection of Pi to neighbouring plants. In line with previous results, our data highlight the relevance of the MPU pathway in Pi allocation within plant communities and in particular the role of Pht1;6 for the establishment of symbiotic Pi uptake and for maize productivity and nutritional value in low-input agricultural systems. In a first attempt to identify cellular pathways which are affected by Pht1;6 activity, gene expression profiling via RNA-Seq was performed and revealed a set of maize genes involved in cellular signalling which exhibited differential regulation in mycorrhizal pht1;6 and control plants. The RNA data provided support for the hypothesis that fungal supply of Pi and/or Pi transport across Pht1;6 affects cell wall biosynthesis and hormone metabolism in colonized root cells.

  12. Finnish WorldSkills Achievers’ Vocational Talent Development and School-to-Work Pathways

    Directory of Open Access Journals (Sweden)

    Laura Pylväs

    2017-08-01

    Full Text Available This paper examines the perceptions of vocational expertise and school-to-work pathways among WorldSkills Competition (WSC achievers and their co-workers and employers within the Finnish context. At the biennial international WSC, young people (aged 18-to-23 years from over 60 countries demonstrate their skills in more than 40 trades. Individualized training for this competition is provided through the cooperation of vocational institutions (e.g., expert coaches, team leaders and competition panellists and industry (e.g., mentors, sponsors, materials, equipment. Semi-structured thematic interviews (N=51 were conducted in 2013 and 2014 with former Finnish WSC medal or diploma winners (n=18 who had since begun their working lives (1-to-15 years of work experience. Their employers (n=16 and colleagues (n=17 were also interviewed. Results showed that in addition to vocation-specific knowledge and skills, problem-solving skills, creativity, social skills and self-regulatory skills were acknowledged as the most significant elements of vocational expertise. The findings also indicated that formal vocational education combined with deliberate practice and training based on expert mentoring improved the long-term career progress and vocational expertise of the WSC achievers.

  13. Distinct RNAi Pathways in the Regulation of Physiology and Development in the Fungus Mucor circinelloides.

    Science.gov (United States)

    Ruiz-Vázquez, Rosa M; Nicolás, Francisco E; Torres-Martínez, Santiago; Garre, Victoriano

    2015-01-01

    The basal fungus Mucor circinelloides has become, in recent years, a valuable model to study RNA-mediated gene silencing or RNA interference (RNAi). Serendipitously discovered in the late 1900s, the gene silencing in M. circinelloides is a landscape of consensus and dissents. Although similar to other classical fungal models in the basic design of the essential machinery that is responsible for silencing of gene expression, the existence of small RNA molecules of different sizes generated during this process and the presence of a mechanism that amplifies the silencing signal, give it a unique identity. In addition, M. circinelloides combines the components of RNAi machinery to carry out functions that not only limit themselves to the defense against foreign genetic material, but it uses some of these elements to regulate the expression of its own genes. Thus, different combinations of RNAi elements produce distinct classes of endogenous small RNAs (esRNAs) that regulate different physiological and developmental processes in response to environmental signals. The recent discovery of a new RNAi pathway involved in the specific degradation of endogenous mRNAs, using a novel RNase protein, adds one more element to the exciting puzzle of the gene silencing in M. circinelloides, in addition to providing hints about the evolutionary origin of the RNAi mechanism. Copyright © 2015 Elsevier Inc. All rights reserved.

  14. Turmeric (Curcuma longa): miRNAs and their regulating targets are involved in development and secondary metabolite pathways.

    Science.gov (United States)

    Singh, Noopur; Sharma, Ashok

    Turmeric has been used as a therapeutic herb over centuries in traditional medicinal systems due to the presence of several secondary metabolite compounds. microRNAs are known to regulate gene expression at the post-transcriptional level by transcriptional cleavage or translation repression. miRNAs have been demonstrated to play an active role in secondary metabolism regulation. The present work was focused on the identification of the miRNAs involved in the regulation of secondary metabolite and development process of turmeric. Eighteen miRNA families were identified for turmeric. Sixteen miRNA families were observed to regulate 238 target transcripts. LncRNAs targets of the putative miRNA candidates were also predicted. Our results indicated their role in binding, reproduction, stress, and other developmental processes. Gene annotation and pathway analysis illustrated the biological function of the targets regulated by the putative miRNAs. The miRNA-mediated gene regulatory network also revealed co-regulated targets that were regulated by two or more miRNA families. miR156 and miR5015 were observed to be involved in rhizome development. miR5021 showed regulation for terpenoid backbone biosynthesis and isoquinoline alkaloid biosynthesis pathways. The flavonoid biosynthesis pathway was observed to be regulated by miR2919. The analysis revealed the probable involvement of three miRNAs (miR1168.2, miR156b and miR1858) in curcumin biosynthesis. Other miRNAs were found to be involved in the growth and developmental process of turmeric. Phylogenetic analysis of selective miRNAs was also performed. Copyright © 2017 Académie des sciences. Published by Elsevier Masson SAS. All rights reserved.

  15. Neurospora crassa female development requires the PACC and other signal transduction pathways, transcription factors, chromatin remodeling, cell-to-cell fusion, and autophagy.

    Directory of Open Access Journals (Sweden)

    Jennifer L Chinnici

    Full Text Available Using a screening protocol we have identified 68 genes that are required for female development in the filamentous fungus Neurospora crassa. We find that we can divide these genes into five general groups: 1 Genes encoding components of the PACC signal transduction pathway, 2 Other signal transduction pathway genes, including genes from the three N. crassa MAP kinase pathways, 3 Transcriptional factor genes, 4 Autophagy genes, and 5 Other miscellaneous genes. Complementation and RIP studies verified that these genes are needed for the formation of the female mating structure, the protoperithecium, and for the maturation of a fertilized protoperithecium into a perithecium. Perithecia grafting experiments demonstrate that the autophagy genes and the cell-to-cell fusion genes (the MAK-1 and MAK-2 pathway genes are needed for the mobilization and movement of nutrients from an established vegetative hyphal network into the developing protoperithecium. Deletion mutants for the PACC pathway genes palA, palB, palC, palF, palH, and pacC were found to be defective in two aspects of female development. First, they were unable to initiate female development on synthetic crossing medium. However, they could form protoperithecia when grown on cellophane, on corn meal agar, or in response to the presence of nearby perithecia. Second, fertilized perithecia from PACC pathway mutants were unable to produce asci and complete female development. Protein localization experiments with a GFP-tagged PALA construct showed that PALA was localized in a peripheral punctate pattern, consistent with a signaling center associated with the ESCRT complex. The N. crassa PACC signal transduction pathway appears to be similar to the PacC/Rim101 pathway previously characterized in Aspergillus nidulans and Saccharomyces cerevisiae. In N. crassa the pathway plays a key role in regulating female development.

  16. Neurospora crassa female development requires the PACC and other signal transduction pathways, transcription factors, chromatin remodeling, cell-to-cell fusion, and autophagy.

    Science.gov (United States)

    Chinnici, Jennifer L; Fu, Ci; Caccamise, Lauren M; Arnold, Jason W; Free, Stephen J

    2014-01-01

    Using a screening protocol we have identified 68 genes that are required for female development in the filamentous fungus Neurospora crassa. We find that we can divide these genes into five general groups: 1) Genes encoding components of the PACC signal transduction pathway, 2) Other signal transduction pathway genes, including genes from the three N. crassa MAP kinase pathways, 3) Transcriptional factor genes, 4) Autophagy genes, and 5) Other miscellaneous genes. Complementation and RIP studies verified that these genes are needed for the formation of the female mating structure, the protoperithecium, and for the maturation of a fertilized protoperithecium into a perithecium. Perithecia grafting experiments demonstrate that the autophagy genes and the cell-to-cell fusion genes (the MAK-1 and MAK-2 pathway genes) are needed for the mobilization and movement of nutrients from an established vegetative hyphal network into the developing protoperithecium. Deletion mutants for the PACC pathway genes palA, palB, palC, palF, palH, and pacC were found to be defective in two aspects of female development. First, they were unable to initiate female development on synthetic crossing medium. However, they could form protoperithecia when grown on cellophane, on corn meal agar, or in response to the presence of nearby perithecia. Second, fertilized perithecia from PACC pathway mutants were unable to produce asci and complete female development. Protein localization experiments with a GFP-tagged PALA construct showed that PALA was localized in a peripheral punctate pattern, consistent with a signaling center associated with the ESCRT complex. The N. crassa PACC signal transduction pathway appears to be similar to the PacC/Rim101 pathway previously characterized in Aspergillus nidulans and Saccharomyces cerevisiae. In N. crassa the pathway plays a key role in regulating female development.

  17. Tyrosine pathway regulation is host-mediated in the pea aphid symbiosis during late embryonic and early larval development.

    Science.gov (United States)

    Rabatel, Andréane; Febvay, Gérard; Gaget, Karen; Duport, Gabrielle; Baa-Puyoulet, Patrice; Sapountzis, Panagiotis; Bendridi, Nadia; Rey, Marjolaine; Rahbé, Yvan; Charles, Hubert; Calevro, Federica; Colella, Stefano

    2013-04-10

    Nutritional symbioses play a central role in insects' adaptation to specialized diets and in their evolutionary success. The obligatory symbiosis between the pea aphid, Acyrthosiphon pisum, and the bacterium, Buchnera aphidicola, is no exception as it enables this important agricultural pest insect to develop on a diet exclusively based on plant phloem sap. The symbiotic bacteria provide the host with essential amino acids lacking in its diet but necessary for the rapid embryonic growth seen in the parthenogenetic viviparous reproduction of aphids. The aphid furnishes, in exchange, non-essential amino acids and other important metabolites. Understanding the regulations acting on this integrated metabolic system during the development of this insect is essential in elucidating aphid biology. We used a microarray-based approach to analyse gene expression in the late embryonic and the early larval stages of the pea aphid, characterizing, for the first time, the transcriptional profiles in these developmental phases. Our analyses allowed us to identify key genes in the phenylalanine, tyrosine and dopamine pathways and we identified ACYPI004243, one of the four genes encoding for the aspartate transaminase (E.C. 2.6.1.1), as specifically regulated during development. Indeed, the tyrosine biosynthetic pathway is crucial for the symbiotic metabolism as it is shared between the two partners, all the precursors being produced by B. aphidicola. Our microarray data are supported by HPLC amino acid analyses demonstrating an accumulation of tyrosine at the same developmental stages, with an up-regulation of the tyrosine biosynthetic genes. Tyrosine is also essential for the synthesis of cuticular proteins and it is an important precursor for cuticle maturation: together with the up-regulation of tyrosine biosynthesis, we observed an up-regulation of cuticular genes expression. We were also able to identify some amino acid transporter genes which are essential for the switch

  18. Long-term athletic development- part 1: a pathway for all youth.

    Science.gov (United States)

    Lloyd, Rhodri S; Oliver, Jon L; Faigenbaum, Avery D; Howard, Rick; De Ste Croix, Mark B A; Williams, Craig A; Best, Thomas M; Alvar, Brent A; Micheli, Lyle J; Thomas, D Phillip; Hatfield, Disa L; Cronin, John B; Myer, Gregory D

    2015-05-01

    The concept of developing talent and athleticism in youth is the goal of many coaches and sports systems. Consequently, an increasing number of sporting organizations have adopted long-term athletic development models in an attempt to provide a structured approach to the training of youth. It is clear that maximizing sporting talent is an important goal of long-term athletic development models. However, ensuring that youth of all ages and abilities are provided with a strategic plan for the development of their health and physical fitness is also important to maximize physical activity participation rates, reduce the risk of sport- and activity-related injury, and to ensure long-term health and well-being. Critical reviews of independent models of long-term athletic development are already present within the literature; however, to the best of our knowledge, a comprehensive examination and review of the most prominent models does not exist. Additionally, considerations of modern day issues that may impact on the success of any long-term athletic development model are lacking, as are proposed solutions to address such issues. Therefore, within this 2-part commentary, Part 1 provides a critical review of existing models of practice for long-term athletic development and introduces a composite youth development model that includes the integration of talent, psychosocial and physical development across maturation. Part 2 identifies limiting factors that may restrict the success of such models and offers potential solutions.

  19. Metabolic Disorder, Inflammation, and Deregulated Molecular Pathways Converging in Pancreatic Cancer Development: Implications for New Therapeutic Strategies

    International Nuclear Information System (INIS)

    Motoo, Yoshiharu; Shimasaki, Takeo; Ishigaki, Yasuhito; Nakajima, Hideo; Kawakami, Kazuyuki; Minamoto, Toshinari

    2011-01-01

    Pancreatic cancer develops and progresses through complex, cumulative biological processes involving metabolic disorder, local inflammation, and deregulated molecular pathways. The resulting tumor aggressiveness hampers surgical intervention and renders pancreatic cancer resistant to standard chemotherapy and radiation therapy. Based on these pathologic properties, several therapeutic strategies are being developed to reverse refractory pancreatic cancer. Here, we outline molecular targeting therapies, which are primarily directed against growth factor receptor-type tyrosine kinases deregulated in tumors, but have failed to improve the survival of pancreatic cancer patients. Glycogen synthase kinase-3β (GSK3β) is a member of a serine/threonine protein kinase family that plays a critical role in various cellular pathways. GSK3β has also emerged as a mediator of pathological states, including glucose intolerance, inflammation, and various cancers (e.g., pancreatic cancer). We review recent studies that demonstrate the anti-tumor effects of GSK3β inhibition alone or in combination with chemotherapy and radiation. GSK3β inhibition may exert indirect anti-tumor actions in pancreatic cancer by modulating metabolic disorder and inflammation

  20. Metabolic Disorder, Inflammation, and Deregulated Molecular Pathways Converging in Pancreatic Cancer Development: Implications for New Therapeutic Strategies

    Energy Technology Data Exchange (ETDEWEB)

    Motoo, Yoshiharu, E-mail: motoo@kanazawa-med.ac.jp [Department of Medical Oncology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa 920-0293 (Japan); Shimasaki, Takeo [Department of Medical Oncology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa 920-0293 (Japan); Division of Translational & Clinical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa (Japan); Ishigaki, Yasuhito [Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa 920-0293 (Japan); Nakajima, Hideo [Department of Medical Oncology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa 920-0293 (Japan); Kawakami, Kazuyuki; Minamoto, Toshinari [Division of Translational & Clinical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa (Japan)

    2011-01-24

    Pancreatic cancer develops and progresses through complex, cumulative biological processes involving metabolic disorder, local inflammation, and deregulated molecular pathways. The resulting tumor aggressiveness hampers surgical intervention and renders pancreatic cancer resistant to standard chemotherapy and radiation therapy. Based on these pathologic properties, several therapeutic strategies are being developed to reverse refractory pancreatic cancer. Here, we outline molecular targeting therapies, which are primarily directed against growth factor receptor-type tyrosine kinases deregulated in tumors, but have failed to improve the survival of pancreatic cancer patients. Glycogen synthase kinase-3β (GSK3β) is a member of a serine/threonine protein kinase family that plays a critical role in various cellular pathways. GSK3β has also emerged as a mediator of pathological states, including glucose intolerance, inflammation, and various cancers (e.g., pancreatic cancer). We review recent studies that demonstrate the anti-tumor effects of GSK3β inhibition alone or in combination with chemotherapy and radiation. GSK3β inhibition may exert indirect anti-tumor actions in pancreatic cancer by modulating metabolic disorder and inflammation.

  1. Metabolic Disorder, Inflammation, and Deregulated Molecular Pathways Converging in Pancreatic Cancer Development: Implications for New Therapeutic Strategies

    Directory of Open Access Journals (Sweden)

    Toshinari Minamoto

    2011-01-01

    Full Text Available Pancreatic cancer develops and progresses through complex, cumulative biological processes involving metabolic disorder, local inflammation, and deregulated molecular pathways. The resulting tumor aggressiveness hampers surgical intervention and renders pancreatic cancer resistant to standard chemotherapy and radiation therapy. Based on these pathologic properties, several therapeutic strategies are being developed to reverse refractory pancreatic cancer. Here, we outline molecular targeting therapies, which are primarily directed against growth factor receptor-type tyrosine kinases deregulated in tumors, but have failed to improve the survival of pancreatic cancer patients. Glycogen synthase kinase-3β (GSK3β is a member of a serine/threonine protein kinase family that plays a critical role in various cellular pathways. GSK3β has also emerged as a mediator of pathological states, including glucose intolerance, inflammation, and various cancers (e.g., pancreatic cancer. We review recent studies that demonstrate the anti-tumor effects of GSK3β inhibition alone or in combination with chemotherapy and radiation. GSK3β inhibition may exert indirect anti-tumor actions in pancreatic cancer by modulating metabolic disorder and inflammation.

  2. Hepatitis B virus X promotes hepatocellular carcinoma development via nuclear protein 1 pathway

    Energy Technology Data Exchange (ETDEWEB)

    Bak, Yesol; Shin, Hye-jun; Bak, In seon [Disease Model Research Laboratory, Aging Intervention Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon (Korea, Republic of); Yoon, Do-young [Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Seoul (Korea, Republic of); Yu, Dae-Yeul, E-mail: dyyu10@kribb.re.kr [Disease Model Research Laboratory, Aging Intervention Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon (Korea, Republic of)

    2015-10-30

    Hepatocellular carcinoma (HCC) is one of the most common malignancies and chronic hepatitis B virus (HBV) infection is a major risk factor for HCC. Hepatitis B virus X (HBx) protein relates to trigger oncogenesis. HBx has oncogenic properties with a hyperproliferative response to HCC. Nuclear protein 1 (NUPR1) is a stress-response protein, frequently upregulated in several cancers. Recent data revealed that NUPR1 is involved in tumor progression, but its function in HCC is not revealed yet. Here we report HBx can induce NUPR1 in patients, mice, and HCC cell lines. In an HBx transgenic mouse model, we found that HBx overexpression upregulates NUPR1 expression consistently with tumor progression. Further, in cultured HBV positive cells, HBx knockdown induces downregulation of NUPR1. Smad4 is a representative transcription factor, regulated by HBx, and we showed that HBx upregulates NUPR1 by Smad4 dependent way. We found that NUPR1 can inhibit cell death and induce vasculogenic mimicry in HCC cell lines. Moreover, NUPR1 silencing in HepG2-HBx showed reduced cell motility. These results suggest that HBx can modulate NUPR1 expression through the Smad4 pathway and NUPR1 has a role in hepatocellular carcinoma progression. - Highlights: • NUPR1 is overexpressed in HBx transgenic mouse and HCC patients. • NUPR1 inactivation hampers the HBx induced growth, VM formation, and migration of HepG2 cells in vitro. • NUPR1 has a role for survival of HCC and mechanistically NUPR1 is activated by HBx-Smad4 axis.

  3. Neurotrophin-3 Regulates Synapse Development by Modulating TrkC-PTPσ Synaptic Adhesion and Intracellular Signaling Pathways.

    Science.gov (United States)

    Han, Kyung Ah; Woo, Doyeon; Kim, Seungjoon; Choii, Gayoung; Jeon, Sangmin; Won, Seoung Youn; Kim, Ho Min; Heo, Won Do; Um, Ji Won; Ko, Jaewon

    2016-04-27

    Neurotrophin-3 (NT-3) is a secreted neurotrophic factor that binds neurotrophin receptor tyrosine kinase C (TrkC), which in turn binds to presynaptic protein tyrosine phosphatase σ (PTPσ) to govern excitatory synapse development. However, whether and how NT-3 cooperates with the TrkC-PTPσ synaptic adhesion pathway and TrkC-mediated intracellular signaling pathways in rat cultured neurons has remained unclear. Here, we report that NT-3 enhances TrkC binding affinity for PTPσ. Strikingly, NT-3 treatment bidirectionally regulates the synaptogenic activity of TrkC: at concentrations of 10-25 ng/ml, NT-3 further enhanced the increase in synapse density induced by TrkC overexpression, whereas at higher concentrations, NT-3 abrogated TrkC-induced increases in synapse density. Semiquantitative immunoblotting and optogenetics-based imaging showed that 25 ng/ml NT-3 or light stimulation at a power that produced a comparable level of NT-3 (6.25 μW) activated only extracellular signal-regulated kinase (ERK) and Akt, whereas 100 ng/ml NT-3 (light intensity, 25 μW) further triggered the activation of phospholipase C-γ1 and CREB independently of PTPσ. Notably, disruption of TrkC intracellular signaling pathways, extracellular ligand binding, or kinase activity by point mutations compromised TrkC-induced increases in synapse density. Furthermore, only sparse, but not global, TrkC knock-down in cultured rat neurons significantly decreased synapse density, suggesting that intercellular differences in TrkC expression level are critical for its synapse-promoting action. Together, our data demonstrate that NT-3 is a key factor in excitatory synapse development that may direct higher-order assembly of the TrkC/PTPσ complex and activate distinct intracellular signaling cascades in a concentration-dependent manner to promote competition-based synapse development processes. In this study, we present several lines of experimental evidences to support the conclusion that

  4. Pathways to Improved Development for Children Living in Poverty: A Randomized Effectiveness Trial in Rural Mexico

    Science.gov (United States)

    Knauer, Heather A.; Kagawa, Rose M. C.; García-Guerra, Armando; Schnaas, Lourdes; Neufeld, Lynnette M.; Fernald, Lia C. H.

    2016-01-01

    Conditional cash transfer programs (CCTs) have shown mixed effects on child development outcomes in the context of poverty. Direct parenting support integrated with CCTs may improve the effectiveness of CCTs for children's development, and benefits could occur via improvements in parenting practices or the home environment. Here, we use data from…

  5. Mediational pathways connecting secondary education and age at marriage to maternal mortality: A comparison between developing and developed countries.

    Science.gov (United States)

    Hagues, Rachel Joy; Bae, DaYoung; Wickrama, Kandauda K A S

    2017-02-01

    While studies have shown that maternal mortality rates have been improving worldwide, rates are still high across developing nations. In general, poor health of women is associated with higher maternal mortality rates in developing countries. Understanding country-level risk factors can inform intervention and prevention efforts that could bring high maternal mortality rates down. Specifically, the authors were interested in investigating whether: (1) secondary education participation (SEP) or age at marriage (AM) of women were related to maternal mortality rates, and (2) adolescent birth rate and contraceptive use (CU) acted as mediators of this association. The authors add to the literature with this current article by showing the relation of SEP and AM to maternal mortality rates globally (both directly and indirectly through mediators) and then by comparing differences between developed and developing/least developed countries. Path analysis was used to test the hypothesized model using country level longitudinal data from 2000 to 2010 obtained from United Nations publications, World Health Organization materials, and World Bank development reports. Findings include a significant correlation between SEP and AM for developing countries; for developed countries the relation was not significant. As well, SEP in developing countries was associated with increased CU. Women in developing countries who finish school before marriage may have important social capital gains.

  6. Family: critical pathway in the emotional development of the child in the first year of life

    Directory of Open Access Journals (Sweden)

    Nancy Amor Pérez

    2013-06-01

    Full Text Available In this article, some considerations are explicit about the role of the family in the most sensitive period of life, the first year. It highlights the changes that have occurred in this educational agency today and its impact on child development, with emphasis on socio - affective area. It is a lso emphasized the stimulatin g role that everyone in the household must meet with the child, indicating affection as the fundamental nutrient not only to the physical development but also the psychological development of the child, since the leadership activity of the age is the emoti onal communication with the adult.

  7. Interplay between FMRP and lncRNA TUG1 regulates axonal development through mediating SnoN-Ccd1 pathway.

    Science.gov (United States)

    Guo, Ye; Chen, Xu; Xing, Ruxiao; Wang, Min; Zhu, Xiaojuan; Guo, Weixiang

    2018-02-01

    LncRNAs have recently emerged to influence the pathogenesis of fragile X syndrome (FXS), which is caused by the functional loss of fragile X mental retardation protein (FMRP). However, the interaction between FMRP and lncRNAs on regulating neuronal development remains elusive. Here, we reported that FMRP directly interacted with lncRNA TUG1, and decreased its stability. Furthermore, TUG1 bond to transcriptional regulator, SnoN, and negatively modulated SnoN-Ccd1 pathway to specifically control axonal development. These observations suggested interplay between FMRP and lncRNAs might contribute to the pathogenesis of FXS. © The Author(s) 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  8. Development and implementation of a critical pathway for prevention of adverse reactions to contrast media for computed tomography

    Energy Technology Data Exchange (ETDEWEB)

    Jang, Keun Jo [Presbyterian Medical Center, Seoul (Korea, Republic of); Kweon, Dae Cheol; Kim, Myeong Goo [Seoul National University Hospital, Seoul (Korea, Republic of); Yoo, Beong Gyu [Wonkwang Health Science College, Iksan (Korea, Republic of)

    2007-03-15

    The purpose of this study is to develop a critical pathway (CP) for the prevention of adverse reactions to contrast media for computed tomography. The CP was developed and implemented by a multidisciplinary group is Seoul National University Hospital. The CP was applied to CT patients. Patients who underwent CT scanning were included in the CP group from March in 2004. The satisfaction of the patients with CP was compared with non-CP groups. We also investigated the degree of satisfaction among the radiological technologists and nurses. The degree of patient satisfaction with the care process increased patient information (24%), prevention of adverse reactions to contrast media (19%), pre-cognitive effect of adverse reactions to contrast media (39%) and information degree of adverse reactions to contrast media (19%). This CP program can be used as one of the patient care tools for reducing the adverse reactions to contrast media and increasing the efficiency of care process in CT examination settings.

  9. Development and implementation of a critical pathway for prevention of adverse reactions to contrast media for computed tomography

    International Nuclear Information System (INIS)

    Jang, Keun Jo; Kweon, Dae Cheol; Kim, Myeong Goo; Yoo, Beong Gyu

    2007-01-01

    The purpose of this study is to develop a critical pathway (CP) for the prevention of adverse reactions to contrast media for computed tomography. The CP was developed and implemented by a multidisciplinary group is Seoul National University Hospital. The CP was applied to CT patients. Patients who underwent CT scanning were included in the CP group from March in 2004. The satisfaction of the patients with CP was compared with non-CP groups. We also investigated the degree of satisfaction among the radiological technologists and nurses. The degree of patient satisfaction with the care process increased patient information (24%), prevention of adverse reactions to contrast media (19%), pre-cognitive effect of adverse reactions to contrast media (39%) and information degree of adverse reactions to contrast media (19%). This CP program can be used as one of the patient care tools for reducing the adverse reactions to contrast media and increasing the efficiency of care process in CT examination settings

  10. Influences of different dietary energy level on sheep testicular development associated with AMPK/ULK1/autophagy pathway.

    Science.gov (United States)

    Pang, Jing; Li, Fengzhe; Feng, Xu; Yang, Hua; Han, Le; Fan, Yixuan; Nie, Haitao; Wang, Zhen; Wang, Feng; Zhang, Yanli

    2018-03-01

    Energy balance is an important feature for spermatozoa production in the testis. The 5'-AMP-activated protein kinase (AMPK) is a sensor of cell energy, has been implicated as a mediator between gonadal function and energy balance. Herein, we intended to determine the physiological effects of AMPK on testicular development in feed energy restricted and compensated pre-pubertal rams. Lambs had restricted feeding for 2 months and then provided compensatory feeding for another 3 months. Feed levels were 100%(control), 15% and 30% of energy restriction (ER) diets, respectively. The results showed that lambs fed the 30% ER diet had significantly lower testicular weight (P energy requirement after restriction. Taken together, dietary energy levels influence testicular development through autophagy and apoptosis interplay mediated by AMPK-ULK1 signal pathway, which also indicates the important role of the actions of AMPK in the testis homeostasis. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. MORN5 expression during craniofacial development and its interaction with the BMP and TGFB pathways

    Directory of Open Access Journals (Sweden)

    Petra Cela

    2016-08-01

    Full Text Available MORN5 (MORN repeat containing 5 is encoded by a locus positioned on chromosome 17 in the chicken genome. The MORN motif is found in multiple copies in several proteins including junctophilins or phosphatidylinositol phosphate kinase family and the MORN proteins themselves are found across the animal and plant kingdoms. MORN5 protein has a characteristic punctate pattern in the cytoplasm in immunofluorescence imaging. Previously, MORN5 was found among differentially expressed genes in a microarray profiling experiment of the chicken embryo head. Here, we provided in situ hybridization to analyse, in detail, the MORN5 expression in chick craniofacial structures. The expression of MORN5 was first observed at stage HH17-18 (E2.5. MORN5 expression gradually appeared on either side of the primitive oral cavity, within the maxillary region. At stage HH20 (E3, prominent expression was localised in the mandibular prominences lateral to the midline. From stage HH20 up to HH29 (E6, there was strong expression in restricted regions of the maxillary and mandibular prominences. The frontonasal mass (in the midline of the face expresses MORN5, starting at HH27 (E5. The expression was concentrated in the corners or globular processes, which will ultimately fuse with the cranial edges of the maxillary prominences. MORN5 expression was maintained in the fusion zone up to stage HH29. In sections in situs, MORN5 expression was localised preferentially in the mesenchyme. We examined signals that regulate MORN5 expression in the face based on a previous microarray study. Here we validated the array results with in situ hybridization and QPCR. MORN5 was downregulated 24h after Noggin and/or RA treatment. We also determined that BMP pathway genes are downstream of MORN5 following siRNA knockdown. Based on these results, we conclude that MORN5 is both regulated by and required for BMP signalling. The restricted expression of MORN5 in the lip fusion zone shown here

  12. Pathways to lean software development: An analysis of effective methods of change

    Science.gov (United States)

    Hanson, Richard D.

    This qualitative Delphi study explored the challenges that exist in delivering software on time, within budget, and with the original scope identified. The literature review identified many attempts over the past several decades to reform the methods used to develop software. These attempts found that the classical waterfall method, which is firmly entrenched in American business today was to blame for this difficulty (Chatterjee, 2010). Each of these proponents of new methods sought to remove waste, lighten out the process, and implement lean principles in software development. Through this study, the experts evaluated the barriers to effective development principles and defined leadership qualities necessary to overcome these barriers. The barriers identified were issues of resistance to change, risk and reward issues, and management buy-in. Thirty experts in software development from several Fortune 500 companies across the United States explored each of these issues in detail. The conclusion reached by these experts was that visionary leadership is necessary to overcome these challenges.

  13. Mechanical activation of mammalian target of rapamycin pathway is required for cartilage development

    OpenAIRE

    Guan, Yingjie; Yang, Xu; Yang, Wentian; Charbonneau, Cherie; Chen, Qian

    2014-01-01

    Mechanical stress regulates development by modulating cell signaling and gene expression. However, the cytoplasmic components mediating mechanotransduction remain unclear. In this study, elimination of muscle contraction during chicken embryonic development resulted in a reduction in the activity of mammalian target of rapamycin (mTOR) in the cartilaginous growth plate. Inhibition of mTOR activity led to significant inhibition of chondrocyte proliferation, cartilage tissue growth, and express...

  14. Cripto-1 Ablation Disrupts Alveolar Development in the Mouse Mammary Gland through a Progesterone Receptor–Mediated Pathway

    Science.gov (United States)

    Klauzinska, Malgorzata; McCurdy, David; Rangel, Maria Cristina; Vaidyanath, Arun; Castro, Nadia P.; Shen, Michael M.; Gonzales, Monica; Bertolette, Daniel; Bianco, Caterina; Callahan, Robert; Salomon, David S.; Raafat, Ahmed

    2016-01-01

    Cripto-1, a member of the epidermal growth factor–Cripto-1/FRL-1/Cryptic family, is critical for early embryonic development. Together with its ligand Nodal, Cripto-1 has been found to be associated with the undifferentiated status of mouse and human embryonic stem cells. Several studies have clearly shown that Cripto-1 is involved in regulating branching morphogenesis and epithelial-mesenchymal transition of the mammary gland both in vitro and in vivo and together with the cofactor GRP78 is critical for the maintenance of mammary stem cells ex vivo. Our previous studies showed that mammary-specific overexpression of human Cripto-1 exhibited dramatic morphological alterations in nulliparous mice mammary glands. The present study shows a novel mechanism for Cripto-1 regulation of mammary gland development through direct effects on progesterone receptor expression and pathways regulated by progesterone in the mammary gland. We demonstrate a strict temporal regulation of mouse Cripto-1 (mCripto-1) expression that occurs during mammary gland development and a stage-specific function of mCripto-1 signaling during mammary gland development. Our data suggest that Cripto-1, like the progesterone receptor, is not required for the initial ductal growth but is essential for subsequent side branching and alveologenesis during the initial stages of pregnancy. Dissection of the mechanism by which this occurs indicates that mCripto-1 activates receptor activator NF-κB/receptor activator NF-κB ligand, and NF-κB signaling pathways. PMID:26429739

  15. Advancing clinical development pathways for new CFTR modulators in cystic fibrosis.

    Science.gov (United States)

    Mayer-Hamblett, Nicole; Boyle, Michael; VanDevanter, Donald

    2016-05-01

    Cystic fibrosis (CF) is a life-shortening genetic disease affecting approximately 70,000 individuals worldwide. Until recently, drug development efforts have emphasised therapies treating downstream signs and symptoms resulting from the underlying CF biological defect: reduced function of the CF transmembrane conductance regulator (CFTR) protein. The current CF drug development landscape has expanded to include therapies that enhance CFTR function by either restoring wild-type CFTR protein expression or increasing (modulating) the function of mutant CFTR proteins in cells. To date, two systemic small-molecule CFTR modulators have been evaluated in pivotal clinical trials in individuals with CF and specific mutant CFTR genotypes that have led to regulatory review and/or approval. Advances in the discovery of CFTR modulators as a promising new class of therapies have been impressive, yet work remains to develop highly effective, disease-modifying modulators for individuals of all CF genotypes. The objectives of this review are to outline the challenges and opportunities in drug development created by systemic genotype-specific CFTR modulators, highlight the advantages of sweat chloride as an established biomarker of CFTR activity to streamline early-phase development and summarise options for later phase clinical trial designs that respond to the adoption of approved genotype-specific modulators into standard of care. An optimal development framework will be needed to move the most promising therapies efficiently through the drug development pipeline and ultimately deliver efficacious and safe therapies to all individuals with CF. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  16. Initiating the Pathway to Increase the Region's Income by Developing Tourism Village of Panglipuran Bali

    Directory of Open Access Journals (Sweden)

    M. Bashori Imron

    2015-12-01

    Full Text Available The head of regencies and cities needs to develop their imagination and inspiration in order to present the goal of region development and deliver the positive economic growth for the public. Initiating the tourism village program for the potential area may serve as a creative alternative. The aim of this research is to develop the idea of tourism village to improve the income of the region. In depth participation in the community and intensive interview with the tourism stakeholders have been chosen as the method of this study. The result of the research shows that the tourism village of Penglipuran has seven potentials as the main attractions as represented by the traditional architecture, artistic spatial arrangement, the bamboo forest, heroes cemetery, the beauty of Pura Panataran, remarkable village landscape, and Karang Memadu. The participation of local government may contribute the positive impact for the economic growth and improve the income of local community.

  17. Pathway — Using a State-of-the-Art Digital Video Database for Research and Development in Teacher Education

    Science.gov (United States)

    Adrian, Brian; Zollman, Dean; Stevens, Scott

    2006-02-01

    To demonstrate how state-of-the-art video databases can address issues related to the lack of preparation of many physics teachers, we have created the prototype Physics Teaching Web Advisory (Pathway). Pathway's Synthetic Interviews and related video materials are beginning to provide pre-service and out-of-field in-service teachers with much-needed professional development and well-prepared teachers with new perspectives on teaching physics. The prototype was limited to a demonstration of the systems. Now, with an additional grant we will extend the system and conduct research and evaluation on its effectiveness. This project will provide virtual expert help on issues of pedagogy and content. In particular, the system will convey, by example and explanation, contemporary ideas about the teaching of physics and applications of physics education research. The research effort will focus on the value of contemporary technology to address the continuing education of teachers who are teaching in a field in which they have not been trained.

  18. The GRIP1/14-3-3 pathway coordinates cargo trafficking and dendrite development

    NARCIS (Netherlands)

    Geiger, J.C.; Lipka, Joanna; Hoyer, S.; Schlager, M.A.; Wulf, Phebe; Weinges, S.; Demmers, J.; Hoogenraad, Casper

    2014-01-01

    Regulation of cargo transport via adaptor molecules is essential for neuronal development. However, the role of PDZ scaffolding proteins as adaptors in neuronal cargo trafficking is still poorly understood. Here, we show by genetic deletion in mice that the multi-PDZ domain scaffolding protein

  19. Supporting Adaptive Learning Pathways through the Use of Learning Analytics: Developments, Challenges and Future Opportunities

    Science.gov (United States)

    Mavroudi, Anna; Giannakos, Michail; Krogstie, John

    2018-01-01

    Learning Analytics (LA) and adaptive learning are inextricably linked since they both foster technology-supported learner-centred education. This study identifies developments focusing on their interplay and emphasises insufficiently investigated directions which display a higher innovation potential. Twenty-one peer-reviewed studies are…

  20. Pathways to Lean Software Development: An Analysis of Effective Methods of Change

    Science.gov (United States)

    Hanson, Richard D.

    2014-01-01

    This qualitative Delphi study explored the challenges that exist in delivering software on time, within budget, and with the original scope identified. The literature review identified many attempts over the past several decades to reform the methods used to develop software. These attempts found that the classical waterfall method, which is…

  1. How Adverse Outcome Pathways Can Aid the Development and Use of Computational Prediction Models for Regulatory Toxicology

    Energy Technology Data Exchange (ETDEWEB)

    Wittwehr, Clemens; Aladjov, Hristo; Ankley, Gerald; Byrne, Hugh J.; de Knecht, Joop; Heinzle, Elmar; Klambauer, Günter; Landesmann, Brigitte; Luijten, Mirjam; MacKay, Cameron; Maxwell, Gavin; Meek, M. E. (Bette); Paini, Alicia; Perkins, Edward; Sobanski, Tomasz; Villeneuve, Dan; Waters, Katrina M.; Whelan, Maurice

    2016-12-19

    Efforts are underway to transform regulatory toxicology and chemical safety assessment from a largely empirical science based on direct observation of apical toxicity outcomes in whole organism toxicity tests to a predictive one in which outcomes and risk are inferred from accumulated mechanistic understanding. The adverse outcome pathway (AOP) framework has emerged as a systematic approach for organizing knowledge that supports such inference. We argue that this systematic organization of knowledge can inform and help direct the design and development of computational prediction models that can further enhance the utility of mechanistic and in silico data for chemical safety assessment. Examples of AOP-informed model development and its application to the assessment of chemicals for skin sensitization and multiple modes of endocrine disruption are provided. The role of problem formulation, not only as a critical phase of risk assessment, but also as guide for both AOP and complementary model development described. Finally, a proposal for actively engaging the modeling community in AOP-informed computational model development is made. The contents serve as a vision for how AOPs can be leveraged to facilitate development of computational prediction models needed to support the next generation of chemical safety assessment.

  2. Children, computer exposure and musculoskeletal outcomes: the development of pathway models for school and home computer-related musculoskeletal outcomes.

    Science.gov (United States)

    Harris, Courtenay; Straker, Leon; Pollock, Clare; Smith, Anne

    2015-01-01

    Children's computer use is rapidly growing, together with reports of related musculoskeletal outcomes. Models and theories of adult-related risk factors demonstrate multivariate risk factors associated with computer use. Children's use of computers is different from adult's computer use at work. This study developed and tested a child-specific model demonstrating multivariate relationships between musculoskeletal outcomes, computer exposure and child factors. Using pathway modelling, factors such as gender, age, television exposure, computer anxiety, sustained attention (flow), socio-economic status and somatic complaints (headache and stomach pain) were found to have effects on children's reports of musculoskeletal symptoms. The potential for children's computer exposure to follow a dose-response relationship was also evident. Developing a child-related model can assist in understanding risk factors for children's computer use and support the development of recommendations to encourage children to use this valuable resource in educational, recreational and communication environments in a safe and productive manner. Computer use is an important part of children's school and home life. Application of this developed model, that encapsulates related risk factors, enables practitioners, researchers, teachers and parents to develop strategies that assist young people to use information technology for school, home and leisure in a safe and productive manner.

  3. Designing and Developing the Pennsylvania Early Care and Education Career Pathway System

    OpenAIRE

    Friday, Ola J.

    2017-01-01

    The early care and education (ECE) workforce plays a vital role in supporting the development of our youngest learners, and putting them on track for a lifetime of success. These critical practitioners work hard for little status or compensation. The profession is grappling with advancing the skills and competencies of practitioners already in the field and lifting the barriers to entry for those new to the profession. This complex work requires innovative strategies, new policies, and compre...

  4. Ochratoxin A Inhibits Mouse Embryonic Development by Activating a Mitochondrion-Dependent Apoptotic Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Yan-Der Hsuuw

    2013-01-01

    Full Text Available Ochratoxin A (OTA, a mycotoxin found in many foods worldwide, causes nephrotoxicity, hepatotoxicity, and immunotoxicity, both in vitro and in vivo. In the present study, we explored the cytotoxic effects exerted by OTA on the blastocyst stage of mouse embryos, on subsequent embryonic attachment, on outgrowth in vitro, and following in vivo implantation via embryo transfer. Mouse blastocysts were incubated with or without OTA (1, 5, or 10 μM for 24 h. Cell proliferation and growth were investigated using dual differential staining; apoptosis was measured using the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL assay; and embryo implantation and post-implantation development were assessed by examination of in vitro growth and the outcome of in vivo embryo transfer, respectively. Blastocysts treated with 10 μM OTA displayed a significantly increased level of apoptosis and a reduction in total cell number. Interestingly, we observed no marked difference in implantation success rate between OTA-pretreated and control blastocysts either during in vitro embryonic development (following implantation in a fibronectin-coated culture dish or after in vivo embryo transfer. However, in vitro treatment with 10 μM OTA was associated with increased resorption of post-implantation embryos by the mouse uterus, and decreased fetal weight upon embryo transfer. Our results collectively indicate that in vitro exposure to OTA triggers apoptosis and retards early post-implantation development after transfer of embryos to host mice. In addition, OTA induces apoptosis-mediated injury of mouse blastocysts, via reactive oxygen species (ROS generation, and promotes mitochondrion-dependent apoptotic signaling processes that impair subsequent embryonic development.

  5. A possible role for the canonical Wnt pathway in endocrine cell development in chicks

    International Nuclear Information System (INIS)

    Pedersen, Anna Hauntoft; Heller, R. Scott

    2005-01-01

    Wnt signalling is involved in many developmental processes such as proliferation, differentiation, cell fate decisions, and morphogenesis. However, little is known about Wnt signalling during pancreas development. Multiple Wnt ligands and Frizzled receptors are expressed in the embryonic mouse pancreas, the surrounding mesenchyme, and have also been detected in the chicken endoderm during development. The aim of this study was to investigate the role of canonical Wnt signalling on endocrine cell development by use of the in ovo electroporation of the chicken endoderm. Overexpression with a constitutive active form of β-catenin in combination with Ngn3 resulted in reduced numbers of glucagon cells. dnLEF-1 or naked-1 did not alter endocrine cell differentiation when co-expressed with Ngn3, but dnLEF-1 appeared to have some potential for inhibiting delamination of Ngn3 cells. In addition, neuronal β-III-tubulin, which had previously been considered a specific marker for neuronal cells, was observed in the pancreas and was upregulated in the electroporated Ngn3 cells and thus may be a new endocrine marker in the chicken

  6. Mechanical activation of mammalian target of rapamycin pathway is required for cartilage development.

    Science.gov (United States)

    Guan, Yingjie; Yang, Xu; Yang, Wentian; Charbonneau, Cherie; Chen, Qian

    2014-10-01

    Mechanical stress regulates development by modulating cell signaling and gene expression. However, the cytoplasmic components mediating mechanotransduction remain unclear. In this study, elimination of muscle contraction during chicken embryonic development resulted in a reduction in the activity of mammalian target of rapamycin (mTOR) in the cartilaginous growth plate. Inhibition of mTOR activity led to significant inhibition of chondrocyte proliferation, cartilage tissue growth, and expression of chondrogenic genes, including Indian hedgehog (Ihh), a critical mediator of mechanotransduction. Conversely, cyclic loading (1 Hz, 5% matrix deformation) of embryonic chicken growth plate chondrocytes in 3-dimensional (3D) collagen scaffolding induced sustained activation of mTOR. Mechanical activation of mTOR occurred in serum-free medium, indicating that it is independent of growth factor or nutrients. Treatment of chondrocytes with Rapa abolished mechanical activation of cell proliferation and Ihh gene expression. Cyclic loading of chondroprogenitor cells deficient in SH2-containing protein tyrosine phosphatase 2 (Shp2) further enhanced mechanical activation of mTOR, cell proliferation, and chondrogenic gene expression. This result suggests that Shp2 is an antagonist of mechanotransduction through inhibition of mTOR activity. Our data demonstrate that mechanical activation of mTOR is necessary for cell proliferation, chondrogenesis, and cartilage growth during bone development, and that mTOR is an essential mechanotransduction component modulated by Shp2 in the cytoplasm. © FASEB.

  7. Regulators of the proteasome pathway, Uch37 and Rpn13, play distinct roles in mouse development.

    Directory of Open Access Journals (Sweden)

    Amin Al-Shami

    Full Text Available Rpn13 is a novel mammalian proteasomal receptor that has recently been identified as an amplification target in ovarian cancer. It can interact with ubiquitin and activate the deubiquitinating enzyme Uch37 at the 26S proteasome. Since neither Rpn13 nor Uch37 is an integral proteasomal subunit, we explored whether either protein is essential for mammalian development and survival. Deletion of Uch37 resulted in prenatal lethality in mice associated with severe defect in embryonic brain development. In contrast, the majority of Rpn13-deficient mice survived to adulthood, although they were smaller at birth and fewer in number than wild-type littermates. Absence of Rpn13 produced tissue-specific effects on proteasomal function: increased proteasome activity in adrenal gland and lymphoid organs, and decreased activity in testes and brain. Adult Rpn13(-/- mice reached normal body weight but had increased body fat content and were infertile due to defective gametogenesis. Additionally, Rpn13(-/- mice showed increased T-cell numbers, resembling growth hormone-mediated effects. Indeed, serum growth hormone and follicular stimulating hormone levels were significantly increased in Rpn13(-/- mice, while growth hormone receptor expression was reduced in the testes. In conclusion, this is the first report characterizing the physiological roles of Uch37 and Rpn13 in murine development and implicating a non-ATPase proteasomal protein, Rpn13, in the process of gametogenesis.

  8. An interplay between 2 signaling pathways: Melatonin-cAMP and IP{sub 3}–Ca{sup 2+} signaling pathways control intraerythrocytic development of the malaria parasite Plasmodium falciparum

    Energy Technology Data Exchange (ETDEWEB)

    Furuyama, Wakako [National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido 080-8555 (Japan); Enomoto, Masahiro [Princess Margaret Cancer Centre, Department of Medical Biophysics, University of Toronto, M5G1L7 Toronto, Ontario (Canada); Mossaad, Ehab [National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido 080-8555 (Japan); Kawai, Satoru [Laboratory of Tropical Medicine and Parasitology, Dokkyo Medical University, Mibu, Tochigi 321-0293 (Japan); Mikoshiba, Katsuhiko [Laboratory for Developmental Neurobiology, RIKEN Brain Science Institute, Wako, Saitama 351-0198 (Japan); Kawazu, Shin-ichiro, E-mail: skawazu@obihiro.ac.jp [National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido 080-8555 (Japan)

    2014-03-28

    Highlights: • A melatonin receptor antagonist blocked Ca{sup 2+} oscillation in P. falciparum and inhibited parasite growth. • P. falciparum development is controlled by Ca{sup 2+}- and cAMP-signaling pathways. • The cAMP-signaling pathway at ring form and late trophozoite stages governs parasite growth of P. falciparum. - Abstract: Plasmodium falciparum spends most of its asexual life cycle within human erythrocytes, where proliferation and maturation occur. Development into the mature forms of P. falciparum causes severe symptoms due to its distinctive sequestration capability. However, the physiological roles and the molecular mechanisms of signaling pathways that govern development are poorly understood. Our previous study showed that P. falciparum exhibits stage-specific spontaneous Calcium (Ca{sup 2+}) oscillations in ring and early trophozoites, and the latter was essential for parasite development. In this study, we show that luzindole (LZ), a selective melatonin receptor antagonist, inhibits parasite growth. Analyses of development and morphology of LZ-treated P. falciparum revealed that LZ severely disrupted intraerythrocytic maturation, resulting in parasite death. When LZ was added at ring stage, the parasite could not undergo further development, whereas LZ added at the trophozoite stage inhibited development from early into late schizonts. Live-cell Ca{sup 2+} imaging showed that LZ treatment completely abolished Ca{sup 2+} oscillation in the ring forms while having little effect on early trophozoites. Further, the melatonin-induced cAMP increase observed at ring and late trophozoite stage was attenuated by LZ treatment. These suggest that a complex interplay between IP{sub 3}–Ca{sup 2+} and cAMP signaling pathways is involved in intraerythrocytic development of P. falciparum.

  9. Caesium-137 and strontium-90 in the food chains: model development using fallout data. [Pasture-cow-milk pathway

    Energy Technology Data Exchange (ETDEWEB)

    Haywood, S M [National Radiological Protection Board, Harwell (UK)

    1980-11-01

    The development of the models for the movement of /sup 137/Cs and /sup 90/Sr in the pasture-cow-milk pathway is briefly discussed. Using recorded deposition rates of these radionuclides as input to the basic model, it was found that the models for /sup 137/Cs and /sup 90/Sr in their initial form were found to predict higher levels of activity in milk than those recorded. The predicted contributions of the processes of root uptake into pasture grass and the resuspension of deposited activity on to pasture surfaces were shown to be responsible for much of the overestimation. Following a re-evaluation of all transfer parameters, major improvements in the quality of fit between the model predictions and measured levels of /sup 137/Cs and /sup 90/Sr in milk were obtained.

  10. Towards a Green Economy. Pathways to Sustainable Development and Poverty Eradication. A Synthesis for Policy Makers

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2011-07-01

    Nearly 20 years after the Earth Summit, nations are again on the Road to Rio, but in a world very different and very changed from that of 1992. Then we were just glimpsing some of the challenges emerging across the planet from climate change and the loss of species to desertification and land degradation. Today many of those seemingly far off concerns are becoming a reality with sobering implications for not only achieving the UN's Millennium Development Goals, but challenging the very opportunity for close to seven billion people - rising to nine billion by 2050 - to be able to thrive, let alone survive. Rio 1992 did not fail the world - far from it. It provided the vision and important pieces of the multilateral machinery to achieve a sustainable future. But this will only be possible if the environmental and social pillars of sustainable development are given equal footing with the economic one: where the often invisible engines of sustainability, from forests to freshwaters, are also given equal if not greater weight in development and economic planning. Towards a Green Economy is among UNEP's key contributions to the Rio+20 process and the overall goal of addressing poverty and delivering a sustainable 21st century. The report makes a compelling economic and social case for investing two per cent of global GDP in greening ten central sectors of the economy in order to shift development and unleash public and private capital flows onto a low-carbon, resource-efficient path. Such a transition can catalyse economic activity of at least a comparable size to business as usual, but with a reduced risk of the crises and shocks increasingly inherent in the existing model. New ideas are by their very nature disruptive, but far less disruptive than a world running low on drinking water and productive land, set against the backdrop of climate change, extreme weather events and rising natural resource scarcities. A green economy does not favour one political

  11. Towards a Green Economy. Pathways to Sustainable Development and Poverty Eradication. A Synthesis for Policy Makers

    International Nuclear Information System (INIS)

    2011-01-01

    Nearly 20 years after the Earth Summit, nations are again on the Road to Rio, but in a world very different and very changed from that of 1992. Then we were just glimpsing some of the challenges emerging across the planet from climate change and the loss of species to desertification and land degradation. Today many of those seemingly far off concerns are becoming a reality with sobering implications for not only achieving the UN's Millennium Development Goals, but challenging the very opportunity for close to seven billion people - rising to nine billion by 2050 - to be able to thrive, let alone survive. Rio 1992 did not fail the world - far from it. It provided the vision and important pieces of the multilateral machinery to achieve a sustainable future. But this will only be possible if the environmental and social pillars of sustainable development are given equal footing with the economic one: where the often invisible engines of sustainability, from forests to freshwaters, are also given equal if not greater weight in development and economic planning. Towards a Green Economy is among UNEP's key contributions to the Rio+20 process and the overall goal of addressing poverty and delivering a sustainable 21st century. The report makes a compelling economic and social case for investing two per cent of global GDP in greening ten central sectors of the economy in order to shift development and unleash public and private capital flows onto a low-carbon, resource-efficient path. Such a transition can catalyse economic activity of at least a comparable size to business as usual, but with a reduced risk of the crises and shocks increasingly inherent in the existing model. New ideas are by their very nature disruptive, but far less disruptive than a world running low on drinking water and productive land, set against the backdrop of climate change, extreme weather events and rising natural resource scarcities. A green economy does not favour one political perspective

  12. The Development of Green Skills through the Local TAFE Institute as a Potential Pathway to Regional Development

    Science.gov (United States)

    Brown, Mike

    2013-01-01

    This study analyses how one Victorian regional TAFE Institute is working towards understanding and contributing to skill formation for the green economy. While we already know that the provision of vocational education and training in regional areas contributes to regional innovation and development (Kilpatrick, Johns and Rosenblatt, 2000; Gelade…

  13. Pathways for acceleration of development and commercialization of novel thermoelectric materials

    Energy Technology Data Exchange (ETDEWEB)

    Jovovic, Vladimir; Heian, Ellen M.; Harris, Fred R.; Sootsman, Joseph; Kossakovski, Dmitri [ZT Plus, Azusa, CA (United States)

    2011-07-01

    Efficient and robust thermoelectric (TE) materials are the cornerstone of any future TE generator system implementation. Today, efforts at commercialization of TE materials often lack the rigor and speed necessary for market readiness of any new material. Here we present the requirements for optimizing a thermoelectric material through a defined development process. We discuss the optimization process, tools that assist in rapid evaluation of thermoelectric performance, and the reproducibility of samples when these methods are employed. The results from our case study demonstrate the feasibility of this approach to prepare reproducible commercial quantities of advanced thermoelectric materials. (orig.)

  14. Wastewater treatment plants as a pathway for microplastics: Development of a new approach to sample wastewater-based microplastics.

    Science.gov (United States)

    Ziajahromi, Shima; Neale, Peta A; Rintoul, Llew; Leusch, Frederic D L

    2017-04-01

    Wastewater effluent is expected to be a pathway for microplastics to enter the aquatic environment, with microbeads from cosmetic products and polymer fibres from clothes likely to enter wastewater treatment plants (WWTP). To date, few studies have quantified microplastics in wastewater. Moreover, the lack of a standardized and applicable method to identify microplastics in complex samples, such as wastewater, has limited the accurate assessment of microplastics and may lead to an incorrect estimation. This study aimed to develop a validated method to sample and process microplastics from wastewater effluent and to apply the developed method to quantify and characterise wastewater-based microplastics in effluent from three WWTPs that use primary, secondary and tertiary treatment processes. We applied a high-volume sampling device that fractionated microplastics in situ and an efficient sample processing procedure to improve the sampling of microplastics in wastewater and to minimize the false detection of non-plastic particles. The sampling device captured between 92% and 99% of polystyrene microplastics using 25 μm-500 μm mesh screens in laboratory tests. Microplastic type, size and suspected origin in all studied WWTPs, along with the removal efficiency during the secondary and tertiary treatment stages, was investigated. Suspected microplastics were characterised using Fourier Transform Infrared spectroscopy, with between 22 and 90% of the suspected microplastics found to be non-plastic particles. An average of 0.28, 0.48 and 1.54 microplastics per litre of final effluent was found in tertiary, secondary and primary treated effluent, respectively. This study suggests that although low concentrations of microplastics are detected in wastewater effluent, WWTPs still have the potential to act as a pathway to release microplastics given the large volumes of effluent discharged to the aquatic environment. This study focused on a single sampling campaign, with

  15. JOURNAL CLUB: Plagiarism in Manuscripts Submitted to the AJR: Development of an Optimal Screening Algorithm and Management Pathways.

    Science.gov (United States)

    Taylor, Donna B

    2017-04-01

    The objective of this study was to investigate the incidence of plagiarism in a sample of manuscripts submitted to the AJR using CrossCheck, develop an algorithm to identify significant plagiarism, and formulate management pathways. A sample of 110 of 1610 (6.8%) manuscripts submitted to AJR in 2014 in the categories of Original Research or Review were analyzed using CrossCheck and manual assessment. The overall similarity index (OSI), highest similarity score from a single source, whether duplication was from single or multiple origins, journal section, and presence or absence of referencing the source were recorded. The criteria outlined by the International Committee of Medical Journal Editors were the reference standard for identifying manuscripts containing plagiarism. Statistical analysis was used to develop a screening algorithm to maximize sensitivity and specificity for the detection of plagiarism. Criteria for defining the severity of plagiarism and management pathways based on the severity of the plagiarism were determined. Twelve manuscripts (10.9%) contained plagiarism. Nine had an OSI excluding quotations and references of less than 20%. In seven, the highest similarity score from a single source was less than 10%. The highest similarity score from a single source was the work of the same author or authors in nine. Common sections for duplication were the Materials and Methods, Discussion, and abstract. Referencing the original source was lacking in 11. Plagiarism was undetected at submission in five of these 12 articles; two had been accepted for publication. The most effective screening algorithm was to average the OSI including quotations and references and the highest similarity score from a single source and to submit manuscripts with an average value of more than 12% for further review. The current methods for detecting plagiarism are suboptimal. A new screening algorithm is proposed.

  16. A novel mouse model of tuberous sclerosis complex (TSC): eye-specific Tsc1-ablation disrupts visual-pathway development.

    Science.gov (United States)

    Jones, Iwan; Hägglund, Anna-Carin; Törnqvist, Gunilla; Nord, Christoffer; Ahlgren, Ulf; Carlsson, Leif

    2015-12-01

    Tuberous sclerosis complex (TSC) is an autosomal dominant syndrome that is best characterised by neurodevelopmental deficits and the presence of benign tumours (called hamartomas) in affected organs. This multi-organ disorder results from inactivating point mutations in either the TSC1 or the TSC2 genes and consequent activation of the canonical mammalian target of rapamycin complex 1 signalling (mTORC1) pathway. Because lesions to the eye are central to TSC diagnosis, we report here the generation and characterisation of the first eye-specific TSC mouse model. We demonstrate that conditional ablation of Tsc1 in eye-committed progenitor cells leads to the accelerated differentiation and subsequent ectopic radial migration of retinal ganglion cells. This results in an increase in retinal ganglion cell apoptosis and consequent regionalised axonal loss within the optic nerve and topographical changes to the contra- and ipsilateral input within the dorsal lateral geniculate nucleus. Eyes from adult mice exhibit aberrant retinal architecture and display all the classic neuropathological hallmarks of TSC, including an increase in organ and cell size, ring heterotopias, hamartomas with retinal detachment, and lamination defects. Our results provide the first major insight into the molecular etiology of TSC within the developing eye and demonstrate a pivotal role for Tsc1 in regulating various aspects of visual-pathway development. Our novel mouse model therefore provides a valuable resource for future studies concerning the molecular mechanisms underlying TSC and also as a platform to evaluate new therapeutic approaches for the treatment of this multi-organ disorder. © 2015. Published by The Company of Biologists Ltd.

  17. Development of models for fast fluid pathways through unsaturated heterogeneous porous media

    International Nuclear Information System (INIS)

    Robey, T.H.

    1994-11-01

    The pre-waste-emplacement ground water travel time requirement is a regulatory criterion that specifies ground water travel time to the accessible environment shall be greater than 1,000 years. Satisfying the ground water travel time criterion for the potential repository at Yucca Mountain requires the study of fast travel path formation in the unsaturated zone and development of models that simulate the formation of fast paths. Conceptual models for unsaturated flow that have been used for total-systems performance assessment generally fall into the categories of composite-porosity or fracture models. The actual hydrologic conditions at Yucca Mountain are thought to lie somewhere between the extremes of these two types of models. The current study considers the effects of heterogeneities on composite-porosity models and seeks to develop numerical methods (and models) that can produce locally saturated zones where fracture flow can occur. The credibility of the model and numerical methods is investigated by using test data from the INTRAVAL project (Swedish Nuclear Inspectorate, 1992) to attempt to predict in-situ volumetric water content at specific locations in Yucca Mountain. Work based on the numerical methods presented in this study is eventually intended to allow the calculation of ground water travel times in heterogeneous media. 60 refs

  18. The Drosophila wings apart gene anchors a novel, evolutionarily conserved pathway of neuromuscular development.

    Science.gov (United States)

    Morriss, Ginny R; Jaramillo, Carmelita T; Mikolajczak, Crystal M; Duong, Sandy; Jaramillo, Maryann S; Cripps, Richard M

    2013-11-01

    wings apart (wap) is a recessive, semilethal gene located on the X chromosome in Drosophila melanogaster, which is required for normal wing-vein patterning. We show that the wap mutation also results in loss of the adult jump muscle. We use complementation mapping and gene-specific RNA interference to localize the wap locus to the proximal X chromosome. We identify the annotated gene CG14614 as the gene affected by the wap mutation, since one wap allele contains a non-sense mutation in CG14614, and a genomic fragment containing only CG14614 rescues the jump-muscle phenotypes of two wap mutant alleles. The wap gene lies centromere-proximal to touch-insensitive larva B and centromere-distal to CG14619, which is tentatively assigned as the gene affected in introverted mutants. In mutant wap animals, founder cell precursors for the jump muscle are specified early in development, but are later lost. Through tissue-specific knockdowns, we demonstrate that wap function is required in both the musculature and the nervous system for normal jump-muscle formation. wap/CG14614 is homologous to vertebrate wdr68, DDB1 and CUL4 associated factor 7, which also are expressed in neuromuscular tissues. Thus, our findings provide insight into mechanisms of neuromuscular development in higher animals and facilitate the understanding of neuromuscular diseases that may result from mis-expression of muscle-specific or neuron-specific genes.

  19. Why some children with externalising problems develop internalising symptoms: testing two pathways in a genetically sensitive cohort study.

    Science.gov (United States)

    Wertz, Jasmin; Zavos, Helena; Matthews, Timothy; Harvey, Kirsten; Hunt, Alice; Pariante, Carmine M; Arseneault, Louise

    2015-07-01

    Children with externalising problems are at risk of developing internalising problems as they grow older. The pathways underlying this developmental association remain to be elucidated. We tested two processes that could explain why some children with externalising problems develop internalising symptoms in preadolescence: a mediation model whereby the association between early externalising and later new internalising symptoms is explained by negative experiences; and a genetic model, whereby genes influence both problems. We used data from the Environmental Risk (E-Risk) Study, a 1994-1995 birth cohort of 2,232 twins born in England and Wales. We assessed externalising and internalising problems using combined mothers' and teachers' ratings at age 5 and 12. We measured bullying victimisation, maternal dissatisfaction and academic difficulties between age 7 and 10 and used linear regression analyses to test the effects of these negative experiences on the association between early externalising and later internalising problems. We employed a Cholesky decomposition to examine the genetic influences on the association. Children with externalising problems at age 5 showed increased rates of new internalising problems at age 12 (r = .24, p children with externalising problems develop internalising symptoms in preadolescence. Negative experiences also contribute to the association, possibly through gene-environment interplay. Mental health professionals should monitor the development of internalising symptoms in young children with externalising problems. © 2014 Association for Child and Adolescent Mental Health.

  20. Pathways to Higher Education for Native Hawaiian Individual Development Account Participants

    Directory of Open Access Journals (Sweden)

    David W. Rothwell

    2013-11-01

    Full Text Available As the cost of higher education rises, a growing body of theory and research suggests that asset holding in the form of savings and net worth positively influence education expectations and outcomes. Native Hawaiians, like other Indigenous peoples, have disproportionately low college enrollment and graduation rates tied to a history of colonization. Using data from an Individual Development Account (IDA program for Native Hawaiians, I examine the trajectories through the program and find: (a welfare receipt and unemployment reduces the chances of IDA enrollment; (b net worth increases the probability of IDA graduation; and (c IDA graduates were more likely to gain a college degree over time compared to non-graduates. The study provides empirical evidence to the debate on asset-based interventions for Indigenous peoples.

  1. iTRAQ-Based Quantitative Proteomics Analysis of Black Rice Grain Development Reveals Metabolic Pathways Associated with Anthocyanin Biosynthesis.

    Science.gov (United States)

    Chen, Linghua; Huang, Yining; Xu, Ming; Cheng, Zuxin; Zhang, Dasheng; Zheng, Jingui

    2016-01-01

    Black rice (Oryza sativa L.), whose pericarp is rich in anthocyanins (ACNs), is considered as a healthier alternative to white rice. Molecular species of ACNs in black rice have been well documented in previous studies; however, information about the metabolic mechanisms underlying ACN biosynthesis during black rice grain development is unclear. The aim of the present study was to determine changes in the metabolic pathways that are involved in the dynamic grain proteome during the development of black rice indica cultivar, (Oryza sativa L. indica var. SSP). Isobaric tags for relative and absolute quantification (iTRAQ) MS/MS were employed to identify statistically significant alterations in the grain proteome. Approximately 928 proteins were detected, of which 230 were differentially expressed throughout 5 successive developmental stages, starting from 3 to 20 days after flowering (DAF). The greatest number of differentially expressed proteins was observed on 7 and 10 DAF, including 76 proteins that were upregulated and 39 that were downregulated. The biological process analysis of gene ontology revealed that the 230 differentially expressed proteins could be sorted into 14 functional groups. Proteins in the largest group were related to metabolic process, which could be integrated into multiple biochemical pathways. Specifically, proteins with a role in ACN biosynthesis, sugar synthesis, and the regulation of gene expression were upregulated, particularly from the onset of black rice grain development and during development. In contrast, the expression of proteins related to signal transduction, redox homeostasis, photosynthesis and N-metabolism decreased during grain maturation. Finally, 8 representative genes encoding different metabolic proteins were verified via quantitative real-time polymerase chain reaction (qRT-PCR) analysis, these genes had differed in transcriptional and translational expression during grain development. Expression analyses of

  2. Signaling in Parasitic Nematodes: Physicochemical Communication Between Host and Parasite and Endogenous Molecular Transduction Pathways Governing Worm Development and Survival.

    Science.gov (United States)

    Lok, James B

    2016-12-01

    Signaling or communication between host and parasite may occur over relatively long ranges to enable host finding and acquisition by infective parasitic nematode larvae. Innate behaviors in infective larvae transmitted from the soil that enhance the likelihood of host contact, such as negative geotaxis and hypermotility, are likely mediated by mechanoreception and neuromuscular signaling. Host cues such as vibration of the substratum, elevated temperature, exhaled CO 2 , and other volatile odorants are perceived by mechanosensory and chemosensory neurons of the amphidial complex. Beyond this, the molecular systems that transduce these external cues within the worm are unknown at this time. Overall, the signal transduction mechanisms that regulate switching between dauer and continuous reproductive development in Caenorhabditis elegans , and doubtless other free-living nematodes, have provided a useful framework for testing hypotheses about how the morphogenesis and development of infective parasitic nematode larvae and the lifespan of adult parasites are regulated. In C. elegans , four major signal transduction pathways, G protein-coupled receptor signaling, insulin/insulin-like growth factor signaling, TGFβ-like signaling and steroid-nuclear hormone receptor signaling govern the switch between dauer and continuous development and regulate adult lifespan. Parasitic nematodes appear to have conserved the functions of G-protein-coupled signaling, insulin-like signaling and steroid-nuclear hormone receptor signaling to regulate larval development before and during the infective process. By contrast, TGFβ-like signaling appears to have been adapted for some other function, perhaps modulation of the host immune response. Of the three signal transduction pathways that appear to regulate development in parasitic nematodes, steroid-nuclear hormone signaling is the most straightforward to manipulate with administered small molecules and may form the basis of new

  3. Exploring triacylglycerol biosynthetic pathway in developing seeds of Chia (Salvia hispanica L.: a transcriptomic approach.

    Directory of Open Access Journals (Sweden)

    Sreedhar R V

    Full Text Available Chia (Salvia hispanica L., a member of the mint family (Lamiaceae, is a rediscovered crop with great importance in health and nutrition and is also the highest known terrestrial plant source of heart-healthy omega-3 fatty acid, alpha linolenic acid (ALA. At present, there is no public genomic information or database available for this crop, hindering research on its genetic improvement through genomics-assisted breeding programs. The first comprehensive analysis of the global transcriptome profile of developing Salvia hispanica L. seeds, with special reference to lipid biosynthesis is presented in this study. RNA from five different stages of seed development was extracted and sequenced separately using the Illumina GAIIx platform. De novo assembly of processed reads in the pooled transcriptome using Trinity yielded 76,014 transcripts. The total transcript length was 66,944,462 bases (66.9 Mb, with an average length of approximately 880 bases. In the molecular functions category of Gene Ontology (GO terms, ATP binding and nucleotide binding were found to be the most abundant and in the biological processes category, the metabolic process and the regulation of transcription-DNA-dependent and oxidation-reduction process were abundant. From the EuKaryotic Orthologous Groups of proteins (KOG classification, the major category was "Metabolism" (31.97%, of which the most prominent class was 'carbohydrate metabolism and transport' (5.81% of total KOG classifications followed by 'secondary metabolite biosynthesis transport and catabolism' (5.34% and 'lipid metabolism' (4.57%. A majority of the candidate genes involved in lipid biosynthesis and oil accumulation were identified. Furthermore, 5596 simple sequence repeats (SSRs were identified. The transcriptome data was further validated through confirmative PCR and qRT-PCR for select lipid genes. Our study provides insight into the complex transcriptome and will contribute to further genome-wide research

  4. Lean Belt Certification: Pathway for Student, Resident, and Faculty Development and Scholarship.

    Science.gov (United States)

    Elghouche, Alhasan N; Lobo, Brian C; Wannemuehler, Todd J; Johnson, Kimberly E; Matt, Bruce H; Woodward-Hagg, Heather K; Kokoska, Mimi S

    2016-05-01

    Since July 2013, 20 trainee participants have completed the quality improvement curriculum within the Indiana University Department of Otolaryngology-Head & Neck Surgery, including 7 otolaryngology residents, 6 otolaryngology-bound medical students, and 7 psychiatry residents. Nine faculty and staff attended. Participants were highly satisfied with the quality and effectiveness of the program. Following program implementation, 2 otolaryngology residents and 2 medical students initiated their own quality improvement projects. Lean training directly resulted in oral and poster presentations at national conferences, journal publications, and institutional research and quality awards. Students completing the program established a local affiliate group of an international health care quality organization. Quality improvement training can be successfully incorporated into residency training with overwhelming program satisfaction and results in greater scholarly and professional development for motivated participants. The skillset acquired by participants leads to projects that improve patient care, increase value, and justify equipment and personnel retention and expansion. © American Academy of Otolaryngology—Head and Neck Surgery Foundation 2016.

  5. The steroid catabolic pathway of the intracellular pathogen Rhodococcus equi is important for pathogenesis and a target for vaccine development.

    Directory of Open Access Journals (Sweden)

    R van der Geize

    2011-08-01

    Full Text Available Rhodococcus equi causes fatal pyogranulomatous pneumonia in foals and immunocompromised animals and humans. Despite its importance, there is currently no effective vaccine against the disease. The actinobacteria R. equi and the human pathogen Mycobacterium tuberculosis are related, and both cause pulmonary diseases. Recently, we have shown that essential steps in the cholesterol catabolic pathway are involved in the pathogenicity of M. tuberculosis. Bioinformatic analysis revealed the presence of a similar cholesterol catabolic gene cluster in R. equi. Orthologs of predicted M. tuberculosis virulence genes located within this cluster, i.e. ipdA (rv3551, ipdB (rv3552, fadA6 and fadE30, were identified in R. equi RE1 and inactivated. The ipdA and ipdB genes of R. equi RE1 appear to constitute the α-subunit and β-subunit, respectively, of a heterodimeric coenzyme A transferase. Mutant strains RE1ΔipdAB and RE1ΔfadE30, but not RE1ΔfadA6, were impaired in growth on the steroid catabolic pathway intermediates 4-androstene-3,17-dione (AD and 3aα-H-4α(3'-propionic acid-5α-hydroxy-7aβ-methylhexahydro-1-indanone (5α-hydroxy-methylhexahydro-1-indanone propionate; 5OH-HIP. Interestingly, RE1ΔipdAB and RE1ΔfadE30, but not RE1ΔfadA6, also displayed an attenuated phenotype in a macrophage infection assay. Gene products important for growth on 5OH-HIP, as part of the steroid catabolic pathway, thus appear to act as factors involved in the pathogenicity of R. equi. Challenge experiments showed that RE1ΔipdAB could be safely administered intratracheally to 2 to 5 week-old foals and oral immunization of foals even elicited a substantial protective immunity against a virulent R. equi strain. Our data show that genes involved in steroid catabolism are promising targets for the development of a live-attenuated vaccine against R. equi infections.

  6. Development of rubber-enriched dandelion varieties by metabolic engineering of the inulin pathway.

    Science.gov (United States)

    Stolze, Anna; Wanke, Alan; van Deenen, Nicole; Geyer, Roland; Prüfer, Dirk; Schulze Gronover, Christian

    2017-06-01

    Natural rubber (NR) is an important raw material for a large number of industrial products. The primary source of NR is the rubber tree Hevea brasiliensis, but increased worldwide demand means that alternative sustainable sources are urgently required. The Russian dandelion (Taraxacum koksaghyz Rodin) is such an alternative because large amounts of NR are produced in its root system. However, rubber biosynthesis must be improved to develop T. koksaghyz into a commercially feasible crop. In addition to NR, T. koksaghyz also produces large amounts of the reserve carbohydrate inulin, which is stored in parenchymal root cell vacuoles near the phloem, adjacent to apoplastically separated laticifers. In contrast to NR, which accumulates throughout the year even during dormancy, inulin is synthesized during the summer and is degraded from the autumn onwards when root tissues undergo a sink-to-source transition. We carried out a comprehensive analysis of inulin and NR metabolism in T. koksaghyz and its close relative T. brevicorniculatum and functionally characterized the key enzyme fructan 1-exohydrolase (1-FEH), which catalyses the degradation of inulin to fructose and sucrose. The constitutive overexpression of Tk1-FEH almost doubled the rubber content in the roots of two dandelion species without any trade-offs in terms of plant fitness. To our knowledge, this is the first study showing that energy supplied by the reserve carbohydrate inulin can be used to promote the synthesis of NR in dandelions, providing a basis for the breeding of rubber-enriched varieties for industrial rubber production. © 2016 The Authors. Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.

  7. A germ cell determinant reveals parallel pathways for germ line development in Caenorhabditis elegans.

    Science.gov (United States)

    Mainpal, Rana; Nance, Jeremy; Yanowitz, Judith L

    2015-10-15

    Despite the central importance of germ cells for transmission of genetic material, our understanding of the molecular programs that control primordial germ cell (PGC) specification and differentiation are limited. Here, we present findings that X chromosome NonDisjunction factor-1 (XND-1), known for its role in regulating meiotic crossover formation, is an early determinant of germ cell fates in Caenorhabditis elegans. xnd-1 mutant embryos display a novel 'one PGC' phenotype as a result of G2 cell cycle arrest of the P4 blastomere. Larvae and adults display smaller germ lines and reduced brood size consistent with a role for XND-1 in germ cell proliferation. Maternal XND-1 proteins are found in the P4 lineage and are exclusively localized to the nucleus in PGCs, Z2 and Z3. Zygotic XND-1 turns on shortly thereafter, at the ∼300-cell stage, making XND-1 the earliest zygotically expressed gene in worm PGCs. Strikingly, a subset of xnd-1 mutants lack germ cells, a phenotype shared with nos-2, a member of the conserved Nanos family of germline determinants. We generated a nos-2 null allele and show that nos-2; xnd-1 double mutants display synthetic sterility. Further removal of nos-1 leads to almost complete sterility, with the vast majority of animals without germ cells. Sterility in xnd-1 mutants is correlated with an increase in transcriptional activation-associated histone modification and aberrant expression of somatic transgenes. Together, these data strongly suggest that xnd-1 defines a new branch for PGC development that functions redundantly with nos-2 and nos-1 to promote germline fates by maintaining transcriptional quiescence and regulating germ cell proliferation. © 2015. Published by The Company of Biologists Ltd.

  8. LKB1 mediates the development of conventional and innate T cells via AMP-dependent kinase autonomous pathways.

    Directory of Open Access Journals (Sweden)

    Marouan Zarrouk

    Full Text Available The present study has examined the role of the serine/threonine kinase LKB1 in the survival and differentiation of CD4/8 double positive thymocytes. LKB1-null DPs can respond to signals from the mature α/β T-cell-antigen receptor and initiate positive selection. However, in the absence of LKB1, thymocytes fail to mature to conventional single positive cells causing severe lymphopenia in the peripheral lymphoid tissues. LKB1 thus appears to be dispensable for positive selection but important for the maturation of positively selected thymocytes. LKB1 also strikingly prevented the development of invariant Vα14 NKT cells and innate TCR αβ gut lymphocytes. Previous studies with gain of function mutants have suggested that the role of LKB1 in T cell development is mediated by its substrate the AMP-activated protein kinase (AMPK. The present study now analyses the impact of AMPK deletion in DP thymocytes and shows that the role of LKB1 during the development of both conventional and innate T cells is mediated by AMPK-independent pathways.

  9. ROCK and RHO Playlist for Preimplantation Development: Streaming to HIPPO Pathway and Apicobasal Polarity in the First Cell Differentiation.

    Science.gov (United States)

    Alarcon, Vernadeth B; Marikawa, Yusuke

    2018-01-01

    In placental mammalian development, the first cell differentiation produces two distinct lineages that emerge according to their position within the embryo: the trophectoderm (TE, placenta precursor) differentiates in the surface, while the inner cell mass (ICM, fetal body precursor) forms inside. Here, we discuss how such position-dependent lineage specifications are regulated by the RHOA subfamily of small GTPases and RHO-associated coiled-coil kinases (ROCK). Recent studies in mouse show that activities of RHO/ROCK are required to promote TE differentiation and to concomitantly suppress ICM formation. RHO/ROCK operate through the HIPPO signaling pathway, whose cell position-specific modulation is central to establishing unique gene expression profiles that confer cell fate. In particular, activities of RHO/ROCK are essential in outside cells to promote nuclear localization of transcriptional co-activators YAP/TAZ, the downstream effectors of HIPPO signaling. Nuclear localization of YAP/TAZ depends on the formation of apicobasal polarity in outside cells, which requires activities of RHO/ROCK. We propose models of how RHO/ROCK regulate lineage specification and lay out challenges for future investigations to deepen our understanding of the roles of RHO/ROCK in preimplantation development. Finally, as RHO/ROCK may be inhibited by certain pharmacological agents, we discuss their potential impact on human preimplantation development in relation to fertility preservation in women.

  10. Polycyclic aromatic hydrocarbons disrupt axial development in sea urchin embryos through a β-catenin dependent pathway

    International Nuclear Information System (INIS)

    Pillai, Murali C.; Vines, Carol A.; Wikramanayake, Athula H.; Cherr, Gary

    2003-01-01

    Sea urchin (Lytechinus anemesis) embryos were used as an experimental system to investigate the mechanisms of the developmental toxicity of creosote, one of the most widely used wood preserving chemicals, as well as some of its polycyclic aromatic hydrocarbon (PAH) constituents (phenanthrene, fluoranthene, fluorene, pyrene and quinoline). Data suggest that creosote and PAHs affect axial development and patterning in sea urchin embryos by disrupting the regulation of β-catenin, a crucial transcriptional co-activator of specific target genes in the Wnt/wg signaling pathway. When ciliated blastula stage embryos were exposed to these compounds, they developed into exogastrulae with completely evaginated archentera, demonstrating that these chemicals disrupt axial development and patterning. This response occurred in a dose-dependent fashion, with the EC 50 of creosote for complete exogastrulation being 1.57 ppm, while the EC 50 s of the PAHs ranged from 0.41 ppm (2.0 μM) to 4.33 ppm (33.5 μM). Morphologically, the exogastrulae that developed from embryos exposed to creosote and PAHs appeared to be identical to those that resulted from exposure to lithium chloride, a classical agent known to induce vegetalization and exogastrulation in sea urchin embryos. Immunological studies using antibodies against β-catenin, a multi-functional protein known to be involved in cell-cell adhesion and cell fate specification during embryonic development, revealed high levels of nuclear accumulation of β-catenin by cells of creosote- and PAH-exposed embryos, irrespective of their positions in the developing embryo. Dissociated embryonic cells cultured in the presence of these agents rapidly responded in a similar fashion. Since β-catenin accumulation occurs in nuclei of several types of cancer cells, it is possible this may be a general mechanism by which PAHs affect a variety of different cell types

  11. How Adverse Outcome Pathways Can Aid the Development and Use of Computational Prediction Models for Regulatory Toxicology.

    Science.gov (United States)

    Wittwehr, Clemens; Aladjov, Hristo; Ankley, Gerald; Byrne, Hugh J; de Knecht, Joop; Heinzle, Elmar; Klambauer, Günter; Landesmann, Brigitte; Luijten, Mirjam; MacKay, Cameron; Maxwell, Gavin; Meek, M E Bette; Paini, Alicia; Perkins, Edward; Sobanski, Tomasz; Villeneuve, Dan; Waters, Katrina M; Whelan, Maurice

    2017-02-01

    Efforts are underway to transform regulatory toxicology and chemical safety assessment from a largely empirical science based on direct observation of apical toxicity outcomes in whole organism toxicity tests to a predictive one in which outcomes and risk are inferred from accumulated mechanistic understanding. The adverse outcome pathway (AOP) framework provides a systematic approach for organizing knowledge that may support such inference. Likewise, computational models of biological systems at various scales provide another means and platform to integrate current biological understanding to facilitate inference and extrapolation. We argue that the systematic organization of knowledge into AOP frameworks can inform and help direct the design and development of computational prediction models that can further enhance the utility of mechanistic and in silico data for chemical safety assessment. This concept was explored as part of a workshop on AOP-Informed Predictive Modeling Approaches for Regulatory Toxicology held September 24-25, 2015. Examples of AOP-informed model development and its application to the assessment of chemicals for skin sensitization and multiple modes of endocrine disruption are provided. The role of problem formulation, not only as a critical phase of risk assessment, but also as guide for both AOP and complementary model development is described. Finally, a proposal for actively engaging the modeling community in AOP-informed computational model development is made. The contents serve as a vision for how AOPs can be leveraged to facilitate development of computational prediction models needed to support the next generation of chemical safety assessment. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology.

  12. Updates to the Corn Ethanol Pathway and Development of an Integrated Corn and Corn Stover Ethanol Pathway in the GREET™ Model

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Zhichao [Argonne National Lab. (ANL), Argonne, IL (United States). Energy Systems Division; Dunn, Jennifer B. [Argonne National Lab. (ANL), Argonne, IL (United States). Energy Systems Division; Wang, Michael Q. [Argonne National Lab. (ANL), Argonne, IL (United States). Energy Systems Division

    2014-09-01

    Corn ethanol, a first-generation biofuel, is the predominant biofuel in the United States. In 2013, the total U.S. ethanol fuel production was 13.3 billion gallons, over 95% of which was produced from corn (RFA, 2014). The 2013 total renewable fuel mandate was 16.6 billion gallons according to the Energy Independence and Security Act (EISA) (U.S. Congress, 2007). Furthermore, until 2020, corn ethanol will make up a large portion of the renewable fuel volume mandated by Renewable Fuels Standard (RFS2). For the GREET1_2014 release, the corn ethanol pathway was subject to updates reflecting changes in corn agriculture and at corn ethanol plants. In the latter case, we especially focused on the incorporation of corn oil as a corn ethanol plant co-product. Section 2 covers these updates. In addition, GREET now includes options to integrate corn grain and corn stover ethanol production on the field and at the biorefinery. These changes are the focus of Section 3.

  13. Differential phosphorylation of Smad1 integrates BMP and neurotrophin pathways through Erk/Dusp in axon development.

    Science.gov (United States)

    Finelli, Mattéa J; Murphy, Kevin J; Chen, Lei; Zou, Hongyan

    2013-05-30

    Sensory axon development requires concerted actions of growth factors for the precise control of axonal outgrowth and target innervation. How developing sensory neurons integrate different cues is poorly understood. We demonstrate here that Smad1 activation is required for neurotrophin-mediated sensory axon growth in vitro and in vivo. Through differential phosphorylation, Smad1 exerts transcriptional selectivity to regulate the expression and activity of Erk1 and Erk2-two key neurotrophin effectors. Specifically, bone morphogenetic proteins (BMPs) signal through carboxy-terminal phosphorylation of Smad1 (pSmad1C) to induce Erk1/2 transcription for enhanced neurotrophin responsiveness. Meanwhile, neurotrophin signaling results in linker phosphorylation of Smad1 (pSmad1L), which in turn upregulates an Erk-specific dual-specificity phosphatase, Dusp6, leading to reduced pErk1/2 and constituting a negative-feedback loop for the prevention of axon overgrowth. Together, the BMP and neurotrophin pathways form a tightly regulated signaling network with a balanced ratio of Erk1/2 and pErk1/2 to direct the precise connections between sensory neurons and peripheral targets. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

  14. Pathways from Poverty.

    Science.gov (United States)

    Baldwin, Barbara, Ed.

    1995-01-01

    Articles in this theme issue are based on presentations at the Pathways from Poverty Workshop held in Albuquerque, New Mexico, on May 18-25, 1995. The event aimed to foster development of a network to address rural poverty issues in the Western Rural Development Center (WRDC) region. Articles report on outcomes from the Pathways from Poverty…

  15. Involvement of COX2–thromboxane pathway in TCDD-induced precardiac edema in developing zebrafish

    International Nuclear Information System (INIS)

    Teraoka, Hiroki; Okuno, Yuki; Nijoukubo, Daisuke; Yamakoshi, Ayumi; Peterson, Richard E.; Stegeman, John J.; Kitazawa, Takio; Hiraga, Takeo; Kubota, Akira

    2014-01-01

    Highlights: • We establish a new indicator of pericardial edema in developing zebrafish (precardiac edema). • Property of precardiac edema by TCDD is similar to that for conventional pericardial edema. • COX2b (but not COX2a)–thromboxane pathway is involved in precardiac edema by TCDD. - Abstract: The cardiovascular system is one of the most characteristic and important targets for developmental toxicity by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in fish larvae. However, knowledge of the mechanism of TCDD-induced edema after heterodimerization of aryl hydrocarbon receptor type 2 (AHR2) and AHR nuclear translocator type 1 (ARNT1) is still limited. In the present study, microscopic analysis with a high-speed camera revealed that TCDD increased the size of a small cavity between the heart and body wall in early eleutheroembryos, a toxic effect that we designate as precardiac edema. A concentration–response curve for precardiac edema at 2 days post fertilization (dpf) showed close similarity to that for conventional pericardial edema at 3 dpf. Precardiac edema caused by TCDD was reduced by morpholino knockdown of AHR2 and ARNT1, as well as by an antioxidant (ascorbic acid). A selective inhibitor of cyclooxygenase type 2 (COX2), NS398, also markedly inhibited TCDD-induced precardiac edema. A thromboxane receptor (TP) antagonist, ICI-192,605 almost abolished TCDD-induced precardiac edema and this effect was canceled by U46619, a TP agonist, which was not influential in the action of TCDD by itself. Knockdown of COX2b and thromboxane A synthase 1 (TBXS), but not COX2a, strongly reduced TCDD-induced precardiac edema. Knockdown of COX2b was without effect on mesencephalic circulation failure caused by TCDD. The edema by TCDD was also inhibited by knockdown of c-mpl, a thrombopoietin receptor necessary for thromobocyte production. Finally, induction of COX2b, but not COX2a, by TCDD was seen in eleutheroembryos at 3 dpf. These results suggest a role of the COX2b

  16. Extending the Pathway: Building on a National Science Foundation Workforce Development Project for Underserved k-12 Students

    Science.gov (United States)

    Slattery, W.; Smith, T.

    2014-12-01

    With new career openings in the geosciences expected and a large number of presently employed geoscientists retiring in the next decade there is a critical need for a new cadre of geoscientists to fill these positions. A project funded by the National Science Foundation titled K-12 Students, Teachers, Parents, Administrators and Higher Education Faculty: Partners Helping Rural Disadvantaged Students Stay on the Pathway to a Geoscience Career involving Wright State University and the Ripley, Lewis, Union, Huntington k-12 school district in Appalachian Ohio took led to dozens of seventh and eighth grade students traveling to Sandy Hook, New Jersey for a one week field experience to study oceanography with staff of the New Jersey Sea Grant Consortium. Teachers, parent chaperones, administrators and university faculty accompanied the students in the field. Teachers worked alongside their students in targeted professional development during the weeklong field experience. During the two academic years of the project, both middle school and high school teachers received professional development in Earth system science so that all students, not just those that were on the summer field experience could receive enhanced science learning. All ninth grade high school students were given the opportunity to take a high school/college dual credit Earth system science course. Community outreach provided widespread knowledge of the project and interest among parents to have their children participate. In addition, ninth grade students raised money themselves to fund a trip to the International Field Studies Forfar Field Station on Andros Island, Bahamas to study a tropical aquatic system. Students who before this project had never traveled outside of Ohio are currently discussing ways that they can continue on the pathway to a geoscience career by applying for internships for the summer between their junior and senior years. These are positive steps towards taking charge of their

  17. Involvement of COX2–thromboxane pathway in TCDD-induced precardiac edema in developing zebrafish

    Energy Technology Data Exchange (ETDEWEB)

    Teraoka, Hiroki, E-mail: hteraoka@rakuno.ac.jp [School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu (Japan); Okuno, Yuki; Nijoukubo, Daisuke; Yamakoshi, Ayumi [School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu (Japan); Peterson, Richard E. [School of Pharmacy, University of Wisconsin, Madison, WI (United States); Stegeman, John J. [Biology Department, Woods Hole Oceanographic Institution, Woods Hole, MA (United States); Kitazawa, Takio; Hiraga, Takeo [School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu (Japan); Kubota, Akira [School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu (Japan); Biology Department, Woods Hole Oceanographic Institution, Woods Hole, MA (United States)

    2014-09-15

    Highlights: • We establish a new indicator of pericardial edema in developing zebrafish (precardiac edema). • Property of precardiac edema by TCDD is similar to that for conventional pericardial edema. • COX2b (but not COX2a)–thromboxane pathway is involved in precardiac edema by TCDD. - Abstract: The cardiovascular system is one of the most characteristic and important targets for developmental toxicity by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in fish larvae. However, knowledge of the mechanism of TCDD-induced edema after heterodimerization of aryl hydrocarbon receptor type 2 (AHR2) and AHR nuclear translocator type 1 (ARNT1) is still limited. In the present study, microscopic analysis with a high-speed camera revealed that TCDD increased the size of a small cavity between the heart and body wall in early eleutheroembryos, a toxic effect that we designate as precardiac edema. A concentration–response curve for precardiac edema at 2 days post fertilization (dpf) showed close similarity to that for conventional pericardial edema at 3 dpf. Precardiac edema caused by TCDD was reduced by morpholino knockdown of AHR2 and ARNT1, as well as by an antioxidant (ascorbic acid). A selective inhibitor of cyclooxygenase type 2 (COX2), NS398, also markedly inhibited TCDD-induced precardiac edema. A thromboxane receptor (TP) antagonist, ICI-192,605 almost abolished TCDD-induced precardiac edema and this effect was canceled by U46619, a TP agonist, which was not influential in the action of TCDD by itself. Knockdown of COX2b and thromboxane A synthase 1 (TBXS), but not COX2a, strongly reduced TCDD-induced precardiac edema. Knockdown of COX2b was without effect on mesencephalic circulation failure caused by TCDD. The edema by TCDD was also inhibited by knockdown of c-mpl, a thrombopoietin receptor necessary for thromobocyte production. Finally, induction of COX2b, but not COX2a, by TCDD was seen in eleutheroembryos at 3 dpf. These results suggest a role of the COX2b

  18. Targetome Analysis Revealed Involvement of MiR-126 in Neurotrophin Signaling Pathway: A Possible Role in Prevention of Glioma Development.

    Science.gov (United States)

    Rouigari, Maedeh; Dehbashi, Moein; Ghaedi, Kamran; Pourhossein, Meraj

    2018-07-01

    For the first time, we used molecular signaling pathway enrichment analysis to determine possible involvement of miR-126 and IRS-1 in neurotrophin pathway. In this prospective study, Validated and predicted targets (targetome) of miR-126 were collected following searching miRtarbase (http://mirtarbase.mbc.nctu.edu.tw/) and miRWalk 2.0 databases, respectively. Then, approximate expression of miR-126 targeting in Glioma tissue was examined using UniGene database (http://www.ncbi. nlm.nih.gov/unigene). In silico molecular pathway enrichment analysis was carried out by DAVID 6.7 database (http://david. abcc.ncifcrf.gov/) to explore which signaling pathway is related to miR-126 targeting and how miR-126 attributes to glioma development. MiR-126 exerts a variety of functions in cancer pathogenesis via suppression of expression of target gene including PI3K, KRAS, EGFL7, IRS-1 and VEGF. Our bioinformatic studies implementing DAVID database, showed the involvement of miR-126 target genes in several signaling pathways including cancer pathogenesis, neurotrophin functions, Glioma formation, insulin function, focal adhesion production, chemokine synthesis and secretion and regulation of the actin cytoskeleton. Taken together, we concluded that miR-126 enhances the formation of glioma cancer stem cell probably via down regulation of IRS-1 in neurotrophin signaling pathway. Copyright© by Royan Institute. All rights reserved.

  19. Development of upwelling on pathway and freshwater transport of Pearl River plume in northeastern South China Sea

    Science.gov (United States)

    Chen, Zhaoyun; Jiang, Yuwu; Liu, James T.; Gong, Wenping

    2017-08-01

    In situ observations, satellite images, and numerical modeling results have shown that the Pearl River plume axis extends alongshore and passes through two separate upwelling regions—one off the Guangdong and Fujian coasts (the Yuedong upwelling) and the other in the Taiwan Bank during the initial and medium stages of the Yuedong upwelling, while it is directed offshore when the Yuedong upwelling is strong. Model experiments are conducted to examine the effects of wind strength and baroclinicity on the upwelling and the corresponding pathway and freshwater transport of the Pearl River plume. The baroclinic effect is important to intensifying the horizontal velocity at the upwelling front and freshwater transport in the northeastern South China Sea. The freshwater transport flux is further decomposed into advection, vertical shear, and tidal pumping components, and advection is the dominant contributor. As the Yuedong upwelling develops, the zone with a relatively high-pressure gradient moves offshore due to offshore Ekman transport and the shift in the upwelling front, which is responsible for the offshore transport of the river plume. When the river plume is transported to the outer-shelf, sometimes it can be further entrained into eddies, allowing its export to the open sea.

  20. Development and implementation of a clinical pathway for cardiac surgery in the intensive care unit: Effects on protocol adherence.

    Science.gov (United States)

    van der Kolk, Marion; van den Boogaard, Mark; Ter Brugge-Speelman, Corine; Hol, Jeroen; Noyez, Luc; van Laarhoven, Kees; van der Hoeven, Hans; Pickkers, Peter

    2017-12-01

    Cardiac surgery (CS) is facilitated by multiple perioperative guidelines and protocols. Use of a clinical pathway (CP) may facilitate the care of these patients. This is a pre-post design study in the ICU of a tertiary referral centre. A CP for CS patients in the ICU was developed by ICU-nurses and enabled them to execute proactively predefined actions in accordance with and within the preset boundaries which were part of a variance report. A tailored implementation strategy was used. Primary outcome measure was protocol adherence above 80% on the domains of blood pressure control, action on chest tube blood loss and electrolyte control within the CP. In a 4-month period, 84 consecutive CP patients were included and compared with 162 matched control patients admitted in the year before implementation; 3 patients were excluded. Propensity score was used as matching parameter. CP patients were more likely to receive early adequate treatment for derangements in electrolytes (96% vs 47%, P blueprint for the implementation and use of a CP in low-volume high complex surgery. © 2017 John Wiley & Sons, Ltd.

  1. ENU mutagenesis reveals that Notchless homolog 1 (Drosophila affects Cdkn1a and several members of the Wnt pathway during murine pre-implantation development

    Directory of Open Access Journals (Sweden)

    Lossie Amy C

    2012-12-01

    Full Text Available Abstract Background Our interests lie in determining the genes and genetic pathways that are important for establishing and maintaining maternal-fetal interactions during pregnancy. Mutation analysis targeted to a 34 Mb domain flanked by Trp53 and Wnt3 demonstrates that this region of mouse chromosome 11 contains a large number of essential genes. Two mutant alleles (l11Jus1 and l11Jus4, which fall into the same complementation group, survive through implantation but fail prior to gastrulation. Results Through a positional cloning strategy, we discovered that these homozygous mutant alleles contain non-conservative missense mutations in the Notchless homolog 1 (Drosophila (Nle1 gene. NLE1 is a member of the large WD40-repeat protein family, and is thought to signal via the canonical NOTCH pathway in vertebrates. However, the phenotype of the Nle1 mutant mice is much more severe than single Notch receptor mutations or even in animals in which NOTCH signaling is blocked. To test the hypothesis that NLE1 functions in multiple signaling pathways during pre-implantation development, we examined expression of multiple Notch downstream target genes, as well as select members of the Wnt pathway in wild-type and mutant embryos. We did not detect altered expression of any primary members of the Notch pathway or in Notch downstream target genes. However, our data reveal that Cdkn1a, a NOTCH target, was upregulated in Nle1 mutants, while several members of the Wnt pathway are downregulated. In addition, we found that Nle1 mutant embryos undergo caspase-mediated apoptosis as hatched blastocysts, but not as morulae or blastocysts. Conclusions Taken together, these results uncover potential novel functions for NLE1 in the WNT and CDKN1A pathways during embryonic development in mammals.

  2. [Development of a clinical pathway for the attention of patients with amyotrophic lateral sclerosis in a regional network. ALS Assistance Network-Comunidad de Madrid].

    Science.gov (United States)

    Rodríguez de Rivera, F J; Grande, M; García-Caballero, J; Muñoz-Blanco, J; Mora, J; Esteban, J; Guerrero, A; Matias-Guiu, J; de Andrés-Colsa, R; Buey, C; Díez-Tejedor, E

    2007-01-01

    Amyotrophic lateral sclerosis (ALS) requires complex multidisciplinary attention. Clinical pathways are assistance plans for certain diseases with a predictable course. These plans are established in isolated centers, not in multicenter regions. The aim is to develop a clinical pathway capable of organizing and homogenizing assistance given in ALS Assistance Network-Comunidad de Madrid which is made up of five hospitals, from the beginning until the end of the disease. In successive meetings, neurologists of these hospitals and members of the Madrid Health Service evaluated published therapeutic guidelines and other documents used in ALS assistance. A clinical pathway was developed adapting this information to social-health care conditions in the Comunidad de Madrid following the FOCUS-PDCA model. A clinical pathway was created consisting of a scientist-technical framework which arranges the attention in relationship to the diagnosis and treatment, according to the degree of disease progression and a chronogram. This is accompanied by several patient information documents on the disease and the tests that are required, and a patient assistance evaluation form. The standards are established to reach and to promote 354 constant improvement in patient care. Clinical pathway for the ALS assistance in a regional network organizes the attention and cares that the patients must receive from the beginning to the end of the disease. This arrangement and homogenization of the attention improves the quality of patient care, diminishes variability and rationalizes the use of the health care resources.

  3. Identifying early pathways of risk and resilience: The co-development of internalizing and externalizing symptoms and the role of harsh parenting

    OpenAIRE

    Wiggins, Jillian Lee; Mitchell, Colter; Hyde, Luke W.; Monk, Christopher S.

    2015-01-01

    Psychological disorders co-occur often in children, but little has been done to document the types of conjoint pathways internalizing and externalizing symptoms may take from the crucial early period of toddlerhood or how harsh parenting may overlap with early symptom co-development. To examine symptom co-development trajectories, we identified latent classes of individuals based on internalizing and externalizing symptoms across ages 3–9 and found three symptom co-development classes: normat...

  4. A two-step transport pathway allows the mother cell to nurture the developing spore in Bacillus subtilis.

    Science.gov (United States)

    Ramírez-Guadiana, Fernando H; Meeske, Alexander J; Rodrigues, Christopher D A; Barajas-Ornelas, Rocío Del Carmen; Kruse, Andrew C; Rudner, David Z

    2017-09-01

    One of the hallmarks of bacterial endospore formation is the accumulation of high concentrations of pyridine-2,6-dicarboxylic acid (dipicolinic acid or DPA) in the developing spore. This small molecule comprises 5-15% of the dry weight of dormant spores and plays a central role in resistance to both wet heat and desiccation. DPA is synthesized in the mother cell at a late stage in sporulation and must be translocated across two membranes (the inner and outer forespore membranes) that separate the mother cell and forespore. The enzymes that synthesize DPA and the proteins required to translocate it across the inner forespore membrane were identified over two decades ago but the factors that transport DPA across the outer forespore membrane have remained mysterious. Here, we report that SpoVV (formerly YlbJ) is the missing DPA transporter. SpoVV is produced in the mother cell during the morphological process of engulfment and specifically localizes in the outer forespore membrane. Sporulating cells lacking SpoVV produce spores with low levels of DPA and cells engineered to express SpoVV and the DPA synthase during vegetative growth accumulate high levels of DPA in the culture medium. SpoVV resembles concentrative nucleoside transporters and mutagenesis of residues predicted to form the substrate-binding pocket supports the idea that SpoVV has a similar structure and could therefore function similarly. These findings provide a simple two-step transport mechanism by which the mother cell nurtures the developing spore. DPA produced in the mother cell is first translocated into the intermembrane space by SpoVV and is then imported into the forespore by the SpoVA complex. This pathway is likely to be broadly conserved as DPA synthase, SpoVV, and SpoVA proteins can be found in virtually all endospore forming bacteria.

  5. Developing Family Psychoeducational Treatments for Patients with Bipolar and Other Severe Psychiatric Disorders: A Pathway from Basic Research to Clinical Trials.

    Science.gov (United States)

    Miklowitz, David J.; Hooley, Jill M.

    1998-01-01

    Describes the development pathway of family treatments for patients with severe and persistent psychiatric disorders in a population for whom family attributes have prognostic importance. The methodological complexities of psychosocial treatment studies are many. Moreover, the results of these studies often reflect interactions between treatment,…

  6. Use of an activated beta-catenin to identify Wnt pathway target genes in caenorhabditis elegans, including a subset of collagen genes expressed in late larval development.

    Science.gov (United States)

    Jackson, Belinda M; Abete-Luzi, Patricia; Krause, Michael W; Eisenmann, David M

    2014-04-16

    The Wnt signaling pathway plays a fundamental role during metazoan development, where it regulates diverse processes, including cell fate specification, cell migration, and stem cell renewal. Activation of the beta-catenin-dependent/canonical Wnt pathway up-regulates expression of Wnt target genes to mediate a cellular response. In the nematode Caenorhabditis elegans, a canonical Wnt signaling pathway regulates several processes during larval development; however, few target genes of this pathway have been identified. To address this deficit, we used a novel approach of conditionally activated Wnt signaling during a defined stage of larval life by overexpressing an activated beta-catenin protein, then used microarray analysis to identify genes showing altered expression compared with control animals. We identified 166 differentially expressed genes, of which 104 were up-regulated. A subset of the up-regulated genes was shown to have altered expression in mutants with decreased or increased Wnt signaling; we consider these genes to be bona fide C. elegans Wnt pathway targets. Among these was a group of six genes, including the cuticular collagen genes, bli-1 col-38, col-49, and col-71. These genes show a peak of expression in the mid L4 stage during normal development, suggesting a role in adult cuticle formation. Consistent with this finding, reduction of function for several of the genes causes phenotypes suggestive of defects in cuticle function or integrity. Therefore, this work has identified a large number of putative Wnt pathway target genes during larval life, including a small subset of Wnt-regulated collagen genes that may function in synthesis of the adult cuticle.

  7. A comparison of the physical and anthropometric qualities explanatory of talent in the elite junior Australian football development pathway.

    Science.gov (United States)

    Woods, Carl T; Cripps, Ashley; Hopper, Luke; Joyce, Christopher

    2017-07-01

    To compare the physical and anthropometric qualities explanatory of talent at two developmental levels in junior Australian football (AF). Cross-sectional observational. From a total of 134 juniors, two developmental levels were categorised; U16 (n=50; 15.6±0.3 y), U18 (n=84; 17.4±0.5 y). Within these levels, two groups were a priori defined; talent identified (U16; n=25; 15.7±0.2 y; U18 n=42; 17.5±0.4 y), non-talent identified (U16; n=25; 15.6±0.4 y; U18; n=42; 17.3±0.6 y). Players completed seven physical and anthropometric assessments commonly utilised for talent identification in AF. Binary logistic regression models were built to identify the qualities most explanatory of talent at each level. A combination of standing height, dominant leg dynamic vertical jump height and 20m sprint time provided the most parsimonious explanation of talent at the U16 level (AICc=60.05). At the U18 level, it was a combination of body mass and 20m sprint time that provided the most parsimonious explanation of talent (AICc=111.27). Despite similarities, there appears to be distinctive differences in physical and anthropometric qualities explanatory of talent at the U16 and U18 level. Coaches may view physical and anthropometric qualities more (or less) favourably at different levels of the AF developmental pathway. Given these results, future work should implement a longitudinal design, as physical and/or anthropometric qualities may deteriorate (or emerge) as junior AF players develop. Copyright © 2016 Sports Medicine Australia. All rights reserved.

  8. The development and codesign of the PATHway intervention: a theory-driven eHealth platform for the self-management of cardiovascular disease.

    Science.gov (United States)

    Walsh, Deirdre M J; Moran, Kieran; Cornelissen, Veronique; Buys, Roselien; Claes, Jomme; Zampognaro, Paolo; Melillo, Fabio; Maglaveras, Nicos; Chouvarda, Ioanna; Triantafyllidis, Andreas; Filos, Dimitris; Woods, Catherine B

    2018-03-15

    Cardiovascular diseases (CVDs) are a leading cause of premature death worldwide. International guidelines recommend routine delivery of all phases of cardiac rehabilitation (CR). Uptake of traditional CR remains suboptimal, as attendance at formal hospital-based CR programs is low, with community-based CR rates and individual long-term exercise maintenance even lower. Home-based CR programs have been shown to be equally effective in clinical and health-related quality of life outcomes and yet are not readily available. The aim of the current study was to develop the PATHway intervention (physical activity toward health) for the self-management of CVD. Increasing physical activity in individuals with CVD was the primary behavior. The PATHway intervention was theoretically informed by the behavior change wheel and social cognitive theory. All relevant intervention functions, behavior change techniques, and policy categories were identified and translated into intervention content. Furthermore, a person-centered approach was adopted involving an iterative codesign process and extensive user testing. Education, enablement, modeling, persuasion, training, and social restructuring were selected as appropriate intervention functions. Twenty-two behavior change techniques, linked to the six intervention functions and three policy categories, were identified for inclusion and translated into PATHway intervention content. This paper details the use of the behavior change wheel and social cognitive theory to develop an eHealth intervention for the self-management of CVD. The systematic and transparent development of the PATHway intervention will facilitate the evaluation of intervention effectiveness and future replication.

  9. Aberrant DNA methylation of WNT pathway genes in the development and progression of CIMP-negative colorectal cancer.

    Science.gov (United States)

    Galamb, Orsolya; Kalmár, Alexandra; Péterfia, Bálint; Csabai, István; Bodor, András; Ribli, Dezső; Krenács, Tibor; Patai, Árpád V; Wichmann, Barnabás; Barták, Barbara Kinga; Tóth, Kinga; Valcz, Gábor; Spisák, Sándor; Tulassay, Zsolt; Molnár, Béla

    2016-08-02

    The WNT signaling pathway has an essential role in colorectal carcinogenesis and progression, which involves a cascade of genetic and epigenetic changes. We aimed to analyze DNA methylation affecting the WNT pathway genes in colorectal carcinogenesis in promoter and gene body regions using whole methylome analysis in 9 colorectal cancer, 15 adenoma, and 6 normal tumor adjacent tissue (NAT) samples by methyl capture sequencing. Functional methylation was confirmed on 5-aza-2'-deoxycytidine-treated colorectal cancer cell line datasets. In parallel with the DNA methylation analysis, mutations of WNT pathway genes (APC, β-catenin/CTNNB1) were analyzed by 454 sequencing on GS Junior platform. Most differentially methylated CpG sites were localized in gene body regions (95% of WNT pathway genes). In the promoter regions, 33 of the 160 analyzed WNT pathway genes were differentially methylated in colorectal cancer vs. normal, including hypermethylated AXIN2, CHP1, PRICKLE1, SFRP1, SFRP2, SOX17, and hypomethylated CACYBP, CTNNB1, MYC; 44 genes in adenoma vs. NAT; and 41 genes in colorectal cancer vs. adenoma comparisons. Hypermethylation of AXIN2, DKK1, VANGL1, and WNT5A gene promoters was higher, while those of SOX17, PRICKLE1, DAAM2, and MYC was lower in colon carcinoma compared to adenoma. Inverse correlation between expression and methylation was confirmed in 23 genes, including APC, CHP1, PRICKLE1, PSEN1, and SFRP1. Differential methylation affected both canonical and noncanonical WNT pathway genes in colorectal normal-adenoma-carcinoma sequence. Aberrant DNA methylation appears already in adenomas as an early event of colorectal carcinogenesis.

  10. Inventory of geochemical sensors available for monitoring an underground site of nuclear waste repository research pathways for new developments

    International Nuclear Information System (INIS)

    Ignatiadis, I.; Gaucher, E.; Buschaert, S.

    2010-01-01

    methodologies and tools for these parameters indicate that today there are not suitable geochemical sensors for monitoring nuclear waste storing systems. On the basis of this report, we are led to propose some realistic pathways of research and development to be initiated or continue to mitigate the lack of geochemical sensors dedicated to the underground storage of nuclear waste. For that purpose, R and D pathways will be (i) the development of geophysical-electrochemical sensors and (ii) the development and manufacture of geochemical sensors made of robust and unalterable material (gold, platinum, glassy carbon). They must possess active principles everlasting, or protected or restored easily. Moreover, solid-state sensors fabricated with a few component of the argillaceous formations (pyrite, raw or purified argillite K119) or silicon semiconductor technology (such as ion sensitive field effect transistors, ISFETs) for measuring pH and interdigitated structures (IDS) for measuring conductivity and redox potential can be designed for use. Response characteristics of these sensors must be tested in aqueous samples with compositions similar to those present inside an underground repository and results were compared with those obtained with commercial electrodes obtaining a good agreement between commercial and the sensors. Electrochemical methods will be in the base of the sensors assessments. These approaches will be consisted in the continuous or semi-continuous analysis of large surface electrodes (pyrite, argillite, ) immersed in solutions with or without oxidant (nitrate, selenate and selenite) or reducer (sulfide, Fe 2+ ). The electrochemical behavior of these electrodes was compared to those of known inert and unattackable electrodes (Pt, Au, glassy carbon) positioned in the same operating conditions. Measurements realized by voltammetry (at open circuit potential and cyclic voltammetry), by Tafel polarization analysis and by electrochemical impedance spectroscopy (EIS

  11. Continuing Development of Alternative High-Throughput Screens to Determine Endocrine Disruption, Focusing on Androgen Receptor, Steroidogenesis, and Thyroid Pathways

    Science.gov (United States)

    The focus of this meeting is the SAP's review and comment on the Agency's proposed high-throughput computational model of androgen receptor pathway activity as an alternative to the current Tier 1 androgen receptor assay (OCSPP 890.1150: Androgen Receptor Binding Rat Prostate Cyt...

  12. Developing confidence in adverse outcome pathway-based toxicity predictions effects of the fungicide imazalil on fathead minnow reproduction (Poster)

    Science.gov (United States)

    An adverse outcome pathway (AOP) description linking inhibition of aromatase (cytochrome P450 [cyp] 19) to reproductive dysfunction was reviewed for scientific and technical quality and endorsed by the OECD. An intended application of the AOP framework is to support the use of me...

  13. Leucine Modulation of the mTOR Pathway for Cognition Modulation: Kinetic and In Vitro Studies and Model Development

    Science.gov (United States)

    2015-09-30

    ultimately at regional levels. In other words , the arrival of free leucine at a tissue site and taken up by the cells would impart a signal for...immunohistochemical techniques and immortalized rat hippocampal cells. Figure 2. Schematic of the Impact of Leucine on the mTOR Protein Synthesis Pathway

  14. Developing confidence in adverse outcome pathway-based toxicity predictions effects of the fungicide imazalil on fathead minnow reproduction

    Science.gov (United States)

    An adverse outcome pathway (AOP) description linking inhibition of aromatase (cytochrome P450 [cyp] 19) to reproductive dysfunction was reviewed for scientific and technical quality and endorsed by the OECD (https://aopwiki.org/wiki/index.php/Aop:25). An intended application of t...

  15. Development of an image-based screening system for inhibitors of the plastidial MEP pathway and of protein geranylgeranylation

    Science.gov (United States)

    Hartmann, Michael; Gas-Pascual, Elisabet; Hemmerlin, Andrea; Rohmer, Michel; Bach, Thomas J.

    2015-01-01

    In a preceding study we have recently established an in vivo visualization system for the geranylgeranylation of proteins in a stably transformed tobacco BY-2 cell line, which involves expressing a dexamethasone-inducible GFP fused to the prenylable, carboxy-terminal basic domain of the rice calmodulin CaM61, which naturally bears a CaaL geranylgeranylation motif (GFP-BD-CVIL). By using pathway-specific inhibitors it was there demonstrated that inhibition of the methylerythritol phosphate (MEP) pathway with oxoclomazone and fosmidomycin, as well as inhibition of protein geranylgeranyl transferase type 1 (PGGT-1), shifted the localization of the GFP-BD-CVIL protein from the membrane to the nucleus. In contrast, the inhibition of the mevalonate (MVA) pathway with mevinolin did not affect this localization. Furthermore, in this initial study complementation assays with pathway-specific intermediates confirmed that the precursors for the cytosolic isoprenylation of this fusion protein are predominantly provided by the MEP pathway. In order to optimize this visualization system from a more qualitative assay to a statistically trustable medium or a high-throughput screening system, we established now new conditions that permit culture and analysis in 96-well microtiter plates, followed by fluorescence microscopy. For further refinement, the existing GFP-BD-CVIL cell line was transformed with an estradiol-inducible vector driving the expression of a RFP protein, C-terminally fused to a nuclear localization signal (NLS-RFP). We are thus able to quantify the total number of viable cells versus the number of inhibited cells after various treatments. This approach also includes a semi-automatic counting system, based on the freely available image processing software. As a result, the time of image analysis as well as the risk of user-generated bias is reduced to a minimum. Moreover, there is no cross-induction of gene expression by dexamethasone and estradiol, which is an

  16. Clinical development of galunisertib (LY2157299 monohydrate, a small molecule inhibitor of transforming growth factor-beta signaling pathway

    Directory of Open Access Journals (Sweden)

    Herbertz S

    2015-08-01

    Full Text Available Stephan Herbertz,1 J Scott Sawyer,2 Anja J Stauber,2 Ivelina Gueorguieva,3 Kyla E Driscoll,4 Shawn T Estrem,2 Ann L Cleverly,3 Durisala Desaiah,2 Susan C Guba,2 Karim A Benhadji,2 Christopher A Slapak,2 Michael M Lahn21Lilly Deutschland GmbH, Bad Homburg, Germany; 2Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA; 3Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, UK; 4Lilly Research Laboratories, Eli Lilly and Company, New York, NY, USA Abstract: Transforming growth factor-beta (TGF-β signaling regulates a wide range of biological processes. TGF-β plays an important role in tumorigenesis and contributes to the hallmarks of cancer, including tumor proliferation, invasion and metastasis, inflammation, angiogenesis, and escape of immune surveillance. There are several pharmacological approaches to block TGF-β signaling, such as monoclonal antibodies, vaccines, antisense oligonucleotides, and small molecule inhibitors. Galunisertib (LY2157299 monohydrate is an oral small molecule inhibitor of the TGF-β receptor I kinase that specifically downregulates the phosphorylation of SMAD2, abrogating activation of the canonical pathway. Furthermore, galunisertib has antitumor activity in tumor-bearing animal models such as breast, colon, lung cancers, and hepatocellular carcinoma. Continuous long-term exposure to galunisertib caused cardiac toxicities in animals requiring adoption of a pharmacokinetic/pharmacodynamic-based dosing strategy to allow further development. The use of such a pharmacokinetic/pharmacodynamic model defined a therapeutic window with an appropriate safety profile that enabled the clinical investigation of galunisertib. These efforts resulted in an intermittent dosing regimen (14 days on/14 days off, on a 28-day cycle of galunisertib for all ongoing trials. Galunisertib is being investigated either as monotherapy or in combination with standard antitumor regimens (including nivolumab

  17. Development of a model of dementia support and pathway for culturally and linguistically diverse communities using co-creation and participatory action research.

    Science.gov (United States)

    Goeman, Dianne; King, Jordan; Koch, Susan

    2016-12-07

    To develop an inclusive model of culturally sensitive support, using a specialist dementia nurse (SDN), to assist people with dementia from culturally and linguistically diverse (CALD) communities and their carers to overcome barriers to accessing health and social care services. Co-creation and participatory action research, based on reflection, data collection, interaction and feedback from participants and stakeholders. An SDN support model embedded within a home nursing service in Melbourne, Australia was implemented between October 2013 and October 2015. People experiencing memory loss or with a diagnosis of dementia from CALD backgrounds and their carers and family living in the community setting and expert stakeholders. Reflections from the SDN on interactions with participants and expert stakeholder opinion informed the CALD dementia support model and pathway. Interaction with 62 people living with memory loss or dementia from CALD backgrounds, carers or family members receiving support from the SDN and feedback from 13 expert stakeholders from community aged-care services, consumer advocacy organisations and ethnic community group representatives informed the development and refinement of the CALD dementia model of care and pathway. We delineate the three components of the 'SDN' model: the organisational support; a description of the role; and the competencies needed. Additionally, we provide an accompanying pathway for use by health professionals delivering care to consumers with dementia from CALD backgrounds. Our culturally sensitive model of dementia care and accompanying pathway allows for the tailoring of health and social support to assist people from CALD backgrounds, their carers and families to adjust to living with memory loss and remain living in the community as long as possible. The model and accompanying pathway also have the potential to be rolled out nationally for use by health professionals across a variety of health services. Published

  18. Developmental pathways of change in health-related fitness and motor competence are related to obesity development in childhood

    OpenAIRE

    Rodrigues, Luis Paulo; Lopes, Vítor P.

    2013-01-01

    The epidemic obesity in chi1dhood is well acknowledged worldwide. Althongh researchers agree that explaining models for childhood obesity can include several risk factors, the question remains as to which speci fic predictors can be the touchstone to solving the probIem. In recent years, a modeI of developmental mechanisms influencing the physical activity and weight pathways of children has been presented by Stodden and colleagnes (2008). In this model it is predicted that children ...

  19. Development and Evaluation of an Educational E-Tool to Help Patients With Non-Hodgkin's Lymphoma Manage Their Personal Care Pathway.

    Science.gov (United States)

    Stienen, Jozette Jc; Ottevanger, Petronella B; Wennekes, Lianne; Dekker, Helena M; van der Maazen, Richard Wm; Mandigers, Caroline Mpw; van Krieken, Johan Hjm; Blijlevens, Nicole Ma; Hermens, Rosella Pmg

    2015-01-09

    An overload of health-related information is available for patients on numerous websites, guidelines, and information leaflets. However, the increasing need for personalized health-related information is currently unmet. This study evaluates an educational e-tool for patients with non-Hodgkin's lymphoma (NHL) designed to meet patient needs with respect to personalized and complete health-related information provision. The e-tool aims to help NHL patients manage and understand their personal care pathway, by providing them with insight into their own care pathway, the possibility to keep a diary, and structured health-related information. Together with a multidisciplinary NHL expert panel, we developed an e-tool consisting of two sections: (1) a personal section for patients' own care pathway and their experiences, and (2) an informative section including information on NHL. We developed an ideal NHL care pathway based on the available (inter)national guidelines. The ideal care pathway, including date of first consultation, diagnosis, and therapy start, was used to set up the personal care pathway. The informative section was developed in collaboration with the patient association, Hematon. Regarding participants, 14 patients and 6 laymen were asked to evaluate the e-tool. The 24-item questionnaire used discussed issues concerning layout (6 questions), user convenience (3 questions), menu clarity (3 questions), information clarity (5 questions), and general impression (7 questions). In addition, the panel members were asked to give their feedback by email. A comprehensive overview of diagnostics, treatments, and aftercare can be established by patients completing the questions from the personal section. The informative section consisted of NHL information regarding NHL in general, diagnostics, therapy, aftercare, and waiting times. Regarding participants, 6 patients and 6 laymen completed the questionnaire. Overall, the feedback was positive, with at least 75

  20. The development of a comprehensive multidisciplinary care pathway for patients with a hip fracture: design and results of a clinical trial.

    Science.gov (United States)

    Flikweert, Elvira R; Izaks, Gerbrand J; Knobben, Bas A S; Stevens, Martin; Wendt, Klaus

    2014-05-30

    Hip fractures frequently occur in older persons and severely decrease life expectancy and independence. Several care pathways have been developed to lower the risk of negative outcomes but most pathways are limited to only one aspect of care. The aim of this study was therefore to develop a comprehensive care pathway for older persons with a hip fracture and to conduct a preliminary analysis of its effect. A comprehensive multidisciplinary care pathway for patients aged 60 years or older with a hip fracture was developed by a multidisciplinary team. The new care pathway was evaluated in a clinical trial with historical controls. The data of the intervention group were collected prospectively. The intervention group included all patients with a hip fracture who were admitted to University Medical Center Groningen between 1 July 2009 and 1 July 2011. The data of the control group were collected retrospectively. The control group comprised all patients with a hip fracture who were admitted between 1 January 2006 and 1 January 2008. The groups were compared with the independent sample t-test, the Mann-Whitney U-test or the Chi-squared test (Phi test). The effect of the intervention on fasting time and length of stay was adjusted by linear regression analysis for differences between the intervention and control group. The intervention group included 256 persons (women, 68%; mean age (SD), 78 (9) years) and the control group 145 persons (women, 72%; mean age (SD), 80 (10) years). Median preoperative fasting time and median length of hospital stay were significantly lower in the intervention group: 9 vs. 17 hours (p < 0.001), and 7 vs. 11 days (p < 0.001), respectively. A similar result was found after adjustment for age, gender, living condition and American Society of Anesthesiologists (ASA) classification. In-hospital mortality was also lower in the intervention group: 2% vs. 6% (p < 0.05). There were no statistically significant differences in other

  1. Dact gene expression profiles suggest a role for this gene family in integrating Wnt and TGF-β signaling pathways during chicken limb development.

    Science.gov (United States)

    Sensiate, Lucimara Aparecida; Sobreira, Débora R; Da Veiga, Fernanda Cristina; Peterlini, Denner Jefferson; Pedrosa, Angelica Vasconcelos; Rirsch, Thaís; Joazeiro, Paulo Pinto; Schubert, Frank R; Collares-Buzato, Carla Beatriz; Xavier-Neto, José; Dietrich, Susanne; Alvares, Lúcia Elvira

    2014-03-01

    Dact gene family encodes multifunctional proteins that are important modulators of Wnt and TGF-β signaling pathways. Given that these pathways coordinate multiple steps of limb development, we investigated the expression pattern of the two chicken Dact genes (Dact1 and Dact2) from early limb bud up to stages when several tissues are differentiating. During early limb development (HH24-HH30) Dact1 and Dact2 were mainly expressed in the cartilaginous rudiments of the appendicular skeleton and perichondrium, presenting expression profiles related, but distinct. At later stages of development (HH31-HH35), the main sites of Dact1 and Dact2 expression were the developing synovial joints. In this context, Dact1 expression was shown to co-localize with regions enriched in the nuclear β-catenin protein, such as developing joint capsule and interzone. In contrast, Dact2 expression was restricted to the interzone surrounding the domains of bmpR-1b expression, a TGF-β receptor with crucial roles during digit morphogenesis. Additional sites of Dact expression were the developing tendons and digit blastemas. Our data indicate that Dact genes are good candidates to modulate and, possibly, integrate Wnt and TGF-β signaling during limb development, bringing new and interesting perspectives about the roles of Dact molecules in limb birth defects and human diseases. Copyright © 2013 Wiley Periodicals, Inc.

  2. Curcumin inhibits urothelial tumor development by suppressing IGF2 and IGF2-mediated PI3K/AKT/mTOR signaling pathway.

    Science.gov (United States)

    Tian, Binqiang; Zhao, Yingmei; Liang, Tao; Ye, Xuxiao; Li, Zuowei; Yan, Dongliang; Fu, Qiang; Li, Yonghui

    2017-08-01

    We have previously reported that curcumin inhibits urothelial tumor development in a rat bladder carcinogenesis model. In this study, we report that curcumin inhibits urothelial tumor development by suppressing IGF2 and IGF2-mediated PI3K/AKT/mTOR signaling pathway. Curcumin inhibits IGF2 expression at the transcriptional level and decreases the phosphorylation levels of IGF1R and IRS-1 in bladder cancer cells and N-methyl-N-nitrosourea (MNU)-induced urothelial tumor tissue. Ectopic expression of IGF2 and IGF1R, but not IGF1, in bladder cancer cells restored this process, suggesting that IGF2 is a target of curcumin. Moreover, introduction of constitutively active AKT1 abolished the inhibitory effect of curcumin on cell proliferation, migration, and restored the phosphorylation levels of 4E-BP1 and S6K1, suggesting that curcumin functions via suppressing IGF2-mediated AKT/mTOR signaling pathway. In summary, our results reveal that suppressing IGF2 and IGF2-mediated PI3K/AKT/mTOR signaling pathway is one of the mechanisms of action of curcumin. Our findings suggest a new therapeutic strategy against human bladder cancer caused by aberrant activation of IGF2, which are useful for translational application of curcumin.

  3. Consistent genomic alterations in carcinoma in situ of the urinary bladder confirm the presence of two major pathways in bladder cancer development

    DEFF Research Database (Denmark)

    Zieger, Karsten; Marcussen, Niels; Borre, Michael

    2009-01-01

    Bladder cancer develops through different pathways, provisionally entitled "papillary" and "invasive." Carcinoma in situ (CIS) is thought to be the precursor of invasive bladder cancer. However, little is known about chromosomal alterations of these clinically important lesions......, and the relationship between chromosomal alterations and the different pathways. We laser-microdissected 12 CIS and 4 dysplasia samples concomitant to invasive bladder cancer. We determined genome-wide chromosome copy number changes and loss of heterozygosity (LOH) using Mapping 10K SNP microarrays. We further...... examined 48 high-risk non-muscle-invasive bladder cancers using SNP microarrays to reveal characteristic changes correlated with the CIS-phenotype. DNA copy-number changes were further validated using QPCR in 77 independent tumor samples. CIS was found to be chromosomal unstable in 8 of 12 cases...

  4. Growth of the Developing Cerebral Cortex Is Controlled by MicroRNA-7 through the p53 Pathway

    Directory of Open Access Journals (Sweden)

    Andrew Pollock

    2014-05-01

    Full Text Available Proper growth of the mammalian cerebral cortex is crucial for normal brain functions and is controlled by precise gene-expression regulation. Here, we show that microRNA-7 (miR-7 is highly expressed in cortical neural progenitors and describe miR-7 sponge transgenic mice in which miR-7-silencing activity is specifically knocked down in the embryonic cortex. Blocking miR-7 function causes microcephaly-like brain defects due to reduced intermediate progenitor (IP production and apoptosis. Upregulation of miR-7 target genes, including those implicated in the p53 pathway, such as Ak1 and Cdkn1a (p21, is responsible for abnormalities in neural progenitors. Furthermore, ectopic expression of Ak1 or p21 and specific blockade of miR-7 binding sites in target genes using protectors in vivo induce similarly reduced IP production. Using conditional miRNA sponge transgenic approaches, we uncovered an unexpected role for miR-7 in cortical growth through its interactions with genes in the p53 pathway.

  5. Murine dishevelled 3 functions in redundant pathways with dishevelled 1 and 2 in normal cardiac outflow tract, cochlea, and neural tube development.

    Science.gov (United States)

    Etheridge, S Leah; Ray, Saugata; Li, Shuangding; Hamblet, Natasha S; Lijam, Nardos; Tsang, Michael; Greer, Joy; Kardos, Natalie; Wang, Jianbo; Sussman, Daniel J; Chen, Ping; Wynshaw-Boris, Anthony

    2008-11-01

    Dishevelled (Dvl) proteins are important signaling components of both the canonical beta-catenin/Wnt pathway, which controls cell proliferation and patterning, and the planar cell polarity (PCP) pathway, which coordinates cell polarity within a sheet of cells and also directs convergent extension cell (CE) movements that produce narrowing and elongation of the tissue. Three mammalian Dvl genes have been identified and the developmental roles of Dvl1 and Dvl2 were previously determined. Here, we identify the functions of Dvl3 in development and provide evidence of functional redundancy among the three murine Dvls. Dvl3(-/-) mice died perinatally with cardiac outflow tract abnormalities, including double outlet right ventricle and persistent truncus arteriosis. These mutants also displayed a misorientated stereocilia in the organ of Corti, a phenotype that was enhanced with the additional loss of a single allele of the PCP component Vangl2/Ltap (LtapLp/+). Although neurulation appeared normal in both Dvl3(-/-) and LtapLp/+ mutants, Dvl3(+/-);LtapLp/+ combined mutants displayed incomplete neural tube closure. Importantly, we show that many of the roles of Dvl3 are also shared by Dvl1 and Dvl2. More severe phenotypes were observed in Dvl3 mutants with the deficiency of another Dvl, and increasing Dvl dosage genetically with Dvl transgenes demonstrated the ability of Dvls to compensate for each other to enable normal development. Interestingly, global canonical Wnt signaling appeared largely unaffected in the double Dvl mutants, suggesting that low Dvl levels are sufficient for functional canonical Wnt signals. In summary, we demonstrate that Dvl3 is required for cardiac outflow tract development and describe its importance in the PCP pathway during neurulation and cochlea development. Finally, we establish several developmental processes in which the three Dvls are functionally redundant.

  6. Murine dishevelled 3 functions in redundant pathways with dishevelled 1 and 2 in normal cardiac outflow tract, cochlea, and neural tube development.

    Directory of Open Access Journals (Sweden)

    S Leah Etheridge

    2008-11-01

    Full Text Available Dishevelled (Dvl proteins are important signaling components of both the canonical beta-catenin/Wnt pathway, which controls cell proliferation and patterning, and the planar cell polarity (PCP pathway, which coordinates cell polarity within a sheet of cells and also directs convergent extension cell (CE movements that produce narrowing and elongation of the tissue. Three mammalian Dvl genes have been identified and the developmental roles of Dvl1 and Dvl2 were previously determined. Here, we identify the functions of Dvl3 in development and provide evidence of functional redundancy among the three murine Dvls. Dvl3(-/- mice died perinatally with cardiac outflow tract abnormalities, including double outlet right ventricle and persistent truncus arteriosis. These mutants also displayed a misorientated stereocilia in the organ of Corti, a phenotype that was enhanced with the additional loss of a single allele of the PCP component Vangl2/Ltap (LtapLp/+. Although neurulation appeared normal in both Dvl3(-/- and LtapLp/+ mutants, Dvl3(+/-;LtapLp/+ combined mutants displayed incomplete neural tube closure. Importantly, we show that many of the roles of Dvl3 are also shared by Dvl1 and Dvl2. More severe phenotypes were observed in Dvl3 mutants with the deficiency of another Dvl, and increasing Dvl dosage genetically with Dvl transgenes demonstrated the ability of Dvls to compensate for each other to enable normal development. Interestingly, global canonical Wnt signaling appeared largely unaffected in the double Dvl mutants, suggesting that low Dvl levels are sufficient for functional canonical Wnt signals. In summary, we demonstrate that Dvl3 is required for cardiac outflow tract development and describe its importance in the PCP pathway during neurulation and cochlea development. Finally, we establish several developmental processes in which the three Dvls are functionally redundant.

  7. Lauric Acid Stimulates Mammary Gland Development of Pubertal Mice through Activation of GPR84 and PI3K/Akt Signaling Pathway.

    Science.gov (United States)

    Meng, Yingying; Zhang, Jing; Zhang, Fenglin; Ai, Wei; Zhu, Xiaotong; Shu, Gang; Wang, Lina; Gao, Ping; Xi, Qianyun; Zhang, Yongliang; Liang, Xingwei; Jiang, Qingyan; Wang, Songbo

    2017-01-11

    It has been demonstrated that dietary fat affects pubertal mammary gland development. However, the role of lauric acid (LA) in this process remains unclear. Thus, this study aimed to investigate the effects of LA on mammary gland development in pubertal mice and to explore the underlying mechanism. In vitro, 100 μM LA significantly promoted proliferation of mouse mammary epithelial cell line HC11 by regulating expression of proliferative markers (cyclin D1/3, p21, PCNA). Meanwhile, LA activated the G protein-coupled receptor 84 (GPR84) and PI3K/Akt signaling pathway. In agreement, dietary 1% LA enhanced mammary duct development, increased the expression of GPR84 and cyclin D1, and activated PI3K/Akt in mammary gland of pubertal mice. Furthermore, knockdown of GPR84 or inhibition of PI3K/Akt totally abolished the promotion of HC11 proliferation induced by LA. These results showed that LA stimulated mammary gland development of pubertal mice through activation of GPR84 and PI3K/Akt signaling pathway.

  8. Gene expression profile analysis of Ligon lintless-1 (Li1) mutant reveals important genes and pathways in cotton leaf and fiber development.

    Science.gov (United States)

    Ding, Mingquan; Jiang, Yurong; Cao, Yuefen; Lin, Lifeng; He, Shae; Zhou, Wei; Rong, Junkang

    2014-02-10

    Ligon lintless-1 (Li1) is a monogenic dominant mutant of Gossypium hirsutum (upland cotton) with a phenotype of impaired vegetative growth and short lint fibers. Despite years of research involving genetic mapping and gene expression profile analysis of Li1 mutant ovule tissues, the gene remains uncloned and the underlying pathway of cotton fiber elongation is still unclear. In this study, we report the whole genome-level deep-sequencing analysis of leaf tissues of the Li1 mutant. Differentially expressed genes in leaf tissues of mutant versus wild-type (WT) plants are identified, and the underlying pathways and potential genes that control leaf and fiber development are inferred. The results show that transcription factors AS2, YABBY5, and KANDI-like are significantly differentially expressed in mutant tissues compared with WT ones. Interestingly, several fiber development-related genes are found in the downregulated gene list of the mutant leaf transcriptome. These genes include heat shock protein family, cytoskeleton arrangement, cell wall synthesis, energy, H2O2 metabolism-related genes, and WRKY transcription factors. This finding suggests that the genes are involved in leaf morphology determination and fiber elongation. The expression data are also compared with the previously published microarray data of Li1 ovule tissues. Comparative analysis of the ovule transcriptomes of Li1 and WT reveals that a number of pathways important for fiber elongation are enriched in the downregulated gene list at different fiber development stages (0, 6, 9, 12, 15, 18dpa). Differentially expressed genes identified in both leaf and fiber samples are aligned with cotton whole genome sequences and combined with the genetic fine mapping results to identify a list of candidate genes for Li1. Copyright © 2013 Elsevier B.V. All rights reserved.

  9. Molecular Pathways

    Science.gov (United States)

    Lok, Benjamin H.; Powell, Simon N.

    2012-01-01

    The Rad52 protein was largely ignored in humans and other mammals when the mouse knockout revealed a largely “no-effect” phenotype. However, using synthetic lethal approaches to investigate context dependent function, new studies have shown that Rad52 plays a key survival role in cells lacking the function of the BRCA1-BRCA2 pathway of homologous recombination. Biochemical studies also showed significant differences between yeast and human Rad52, in which yeast Rad52 can promote strand invasion of RPA-coated single-stranded DNA in the presence of Rad51, but human Rad52 cannot. This results in the paradox of how is human Rad52 providing Rad51 function: presumably there is something missing in the biochemical assays that exists in-vivo, but the nature of this missing factor is currently unknown. Recent studies have suggested that Rad52 provides back-up Rad51 function for all members of the BRCA1-BRCA2 pathway, suggesting that Rad52 may be a target for therapy in BRCA pathway deficient cancers. Screening for ways to inhibit Rad52 would potentially provide a complementary strategy for targeting BRCA-deficient cancers in addition to PARP inhibitors. PMID:23071261

  10. Development of the adverse outcome pathway "alkylation of DNA in male premeiotic germ cells leading to heritable mutations" using the OECD's users' handbook supplement.

    Science.gov (United States)

    Yauk, Carole L; Lambert, Iain B; Meek, M E Bette; Douglas, George R; Marchetti, Francesco

    2015-12-01

    The Organisation for Economic Cooperation and Development's (OECD) Adverse Outcome Pathway (AOP) programme aims to develop a knowledgebase of all known pathways of toxicity that lead to adverse effects in humans and ecosystems. A Users' Handbook was recently released to provide supplementary guidance on AOP development. This article describes one AOP-alkylation of DNA in male premeiotic germ cells leading to heritable mutations. This outcome is an important regulatory endpoint. The AOP describes the biological plausibility and empirical evidence supporting that compounds capable of alkylating DNA cause germ cell mutations and subsequent mutations in the offspring of exposed males. Alkyl adducts are subject to DNA repair; however, at high doses the repair machinery becomes saturated. Lack of repair leads to replication of alkylated DNA and ensuing mutations in male premeiotic germ cells. Mutations that do not impair spermatogenesis persist and eventually are present in mature sperm. Thus, the mutations are transmitted to the offspring. Although there are some gaps in empirical support and evidence for essentiality of the key events for certain aspects of this AOP, the overall AOP is generally accepted as dogma and applies broadly to any species that produces sperm. The AOP was developed and used in an iterative process to test and refine the Users' Handbook, and is one of the first publicly available AOPs. It is our hope that this AOP will be leveraged to develop other AOPs in this field to advance method development, computational models to predict germ cell effects, and integrated testing strategies. © 2015 Her Majesty the Queen in Right of Canada.

  11. Endogenous sulfur dioxide regulates hippocampal neuron apoptosis in developing epileptic rats and is associated with the PERK signaling pathway.

    Science.gov (United States)

    Niu, Manman; Han, Ying; Li, Qinrui; Zhang, Jing

    2018-02-05

    Epilepsy is among the most common neurological diseases in children. Recurrent seizures can result in hippocampal damage and seriously impair learning and memory functions in children. However, the mechanisms underlying epilepsy-related brain injury are unclear. Neuronal apoptosis is among the most common neuropathological manifestations of brain injury. Endogenous sulfur dioxide (SO 2 ) has been shown to be involved in seizures and related neuron apoptosis. However, the role of endogenous SO 2 in epilepsy remains unclear. This study assessed whether endogenous SO 2 is involved in epilepsy and its underlying mechanisms. Using a rat epilepsy model induced by an intraperitoneal injection of kainic acid (KA), we found that hippocampal neuron apoptosis was induced in epileptic rats, and the SO 2 content and aspartate aminotransferase (AAT) activity in the plasma were increased compared to those in the control group. However, the inhibition of SO 2 production by l-aspartate-β-hydroxamate (HDX) can subvert this response 72h after an epileptic seizure. No difference in apoptosis was observed 7 d after the epileptic seizure in the KA and KA+HDX groups. The protein expression levels of AAT2, glucose-regulated protein 78 (GRP78), pancreatic eIF2 kinase-like ER kinase (PERK) and phospho-PERK (p-PERK) were remarkably elevated in the hippocampi of the epileptic rats, while the HDX treatment was capable of reversing this process 7 d after the epileptic seizure. These results indicate that the inhibition of endogenous SO 2 production can alleviate neuronal apoptosis and is associated with the PERK signaling pathway during the initial stages after epileptic seizure, but inhibiting SO 2 production only delayed the occurrence of apoptosis and did not prevent neuronal apoptosis in the epileptic rats. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Smad4-dependent pathways control basement membrane deposition and endodermal cell migration at early stages of mouse development

    Directory of Open Access Journals (Sweden)

    Taylor Jennifer M

    2009-10-01

    Full Text Available Abstract Background Smad4 mutant embryos arrest shortly after implantation and display a characteristic shortened proximodistal axis, a significantly reduced epiblast, as well as a thickened visceral endoderm layer. Conditional rescue experiments demonstrate that bypassing the primary requirement for Smad4 in the extra-embryonic endoderm allows the epiblast to gastrulate. Smad4-independent TGF-β signals are thus sufficient to promote mesoderm formation and patterning. To further analyse essential Smad4 activities contributed by the extra-embryonic tissues, and characterise Smad4 dependent pathways in the early embryo, here we performed transcriptional profiling of Smad4 null embryonic stem (ES cells and day 4 embryoid bodies (EBs. Results Transcripts from wild-type versus Smad4 null ES cells and day 4 EBs were analysed using Illumina arrays. In addition to several known TGF-β/BMP target genes, we identified numerous Smad4-dependent transcripts that are mis-expressed in the mutants. As expected, mesodermal cell markers were dramatically down-regulated. We also observed an increase in non-canonical potency markers (Pramel7, Tbx3, Zscan4, germ cell markers (Aire, Tuba3a, Dnmt3l as well as early endoderm markers (Dpp4, H19, Dcn. Additionally, expression of the extracellular matrix (ECM remodelling enzymes Mmp14 and Mmp9 was decreased in Smad4 mutant ES and EB populations. These changes, in combination with increased levels of laminin alpha1, cause excessive basement membrane deposition. Similarly, in the context of the Smad4 null E6.5 embryos we observed an expanded basement membrane (BM associated with the thickened endoderm layer. Conclusion Smad4 functional loss results in a dramatic shift in gene expression patterns and in the endodermal cell lineage causes an excess deposition of, or an inability to breakdown and remodel, the underlying BM layer. These structural abnormalities probably disrupt reciprocal signalling between the epiblast and

  13. Cis-Natural Antisense Transcripts Are Mainly Co-expressed with Their Sense Transcripts and Primarily Related to Energy Metabolic Pathways during Muscle Development.

    Science.gov (United States)

    Zhao, Yunxia; Hou, Ye; Zhao, Changzhi; Liu, Fei; Luan, Yu; Jing, Lu; Li, Xinyun; Zhu, Mengjin; Zhao, Shuhong

    2016-01-01

    Cis-natural antisense transcripts (cis-NATs) are a new class of RNAs identified in various species. However, the biological functions of cis-NATs are largely unknown. In this study, we investigated the transcriptional characteristics and functions of cis-NATs in the muscle tissue of lean Landrace and indigenous fatty Lantang pigs. In total, 3,306 cis-NATs of 2,469 annotated genes were identified in the muscle tissue of pigs. More than 1,300 cis-NATs correlated with their sense genes at the transcriptional level, and approximately 80% of them were co-expressed in the two breeds. Furthermore, over 1,200 differentially expressed cis-NATs were identified during muscle development. Function annotation showed that the cis-NATs participated in muscle development mainly by co-expressing with genes involved in energy metabolic pathways, including citrate cycle (TCA cycle), glycolysis or gluconeogenesis, mitochondrial activation and so on. Moreover, these cis-NATs and their sense genes abruptly increased at the transition from the late fetal stages to the early postnatal stages and then decreased along with muscle development. In conclusion, the cis-NATs in the muscle tissue of pigs were identified and determined to be mainly co-expressed with their sense genes. The co-expressed cis-NATs and their sense gene were primarily related to energy metabolic pathways during muscle development in pigs. Our results offered novel evidence on the roles of cis-NATs during the muscle development of pigs.

  14. BIG1, a brefeldin A-inhibited guanine nucleotide-exchange protein regulates neurite development via PI3K-AKT and ERK signaling pathways.

    Science.gov (United States)

    Zhou, C; Li, C; Li, D; Wang, Y; Shao, W; You, Y; Peng, J; Zhang, X; Lu, L; Shen, X

    2013-12-19

    The elongation of neuron is highly dependent on membrane trafficking. Brefeldin A (BFA)-inhibited guanine nucleotide-exchange protein 1 (BIG1) functions in the membrane trafficking between the Golgi apparatus and the plasma membrane. BFA, an uncompetitive inhibitor of BIG1 can inhibit neurite outgrowth and polarity development. In this study, we aimed to define the possible role of BIG1 in neurite development and to further investigate the potential mechanism. By immunostaining, we found that BIG1 was extensively colocalized with synaptophysin, a marker for synaptic vesicles in soma and partly in neurites. The amount of both protein and mRNA of BIG1 were up-regulated during rat brain development. BIG1 depletion significantly decreased the neurite length and inhibited the phosphorylation of phosphatidylinositide 3-kinase (PI3K) and protein kinase B (AKT). Inhibition of BIG1 guanine nucleotide-exchange factor (GEF) activity by BFA or overexpression of the dominant-negative BIG1 reduced PI3K and AKT phosphorylation, indicating regulatory effects of BIG1 on PI3K-AKT signaling pathway is dependent on its GEF activity. BIG1 siRNA or BFA treatment also significantly reduced extracellular signal-regulated kinase (ERK) phosphorylation. Overexpression of wild-type BIG1 significantly increased ERK phosphorylation, but the dominant-negative BIG1 had no effect on ERK phosphorylation, indicating the involvement of BIG1 in ERK signaling regulation may not be dependent on its GEF activity. Our result identified a novel function of BIG1 in neurite development. The newly recognized function integrates the function of BIG1 in membrane trafficking with the activation of PI3K-AKT and ERK signaling pathways which are critical in neurite development. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

  15. Mediating Pathways in the Socio-Economic Gradient of Child Development: Evidence from Children 6-42 Months in Bogota

    Science.gov (United States)

    Rubio-Codina, Marta; Attanasio, Orazio; Grantham-McGregor, Sally

    2016-01-01

    Research has previously shown a gap of near 0.5 of a standard deviation (SD) in cognition and language development between the top and bottom household wealth quartile in children aged 6-42 months in a large representative sample of low- and middle-income families in Bogota, using the Bayley Scales of Infant and Toddler Development. The gaps in…

  16. Acceleration of bone development and regeneration through the Wnt/β-catenin signaling pathway in mice heterozygously deficient for GSK-3β

    International Nuclear Information System (INIS)

    Arioka, Masaki; Takahashi-Yanaga, Fumi; Sasaki, Masanori; Yoshihara, Tatsuya; Morimoto, Sachio; Takashima, Akihiko; Mori, Yoshihide; Sasaguri, Toshiyuki

    2013-01-01

    Highlights: •The Wnt/β-catenin signaling pathway was activated in GSK-3β +/− mice. •The cortical and trabecular bone volumes were increased in GSK-3β +/− mice. •Regeneration of a partial bone defect was accelerated in GSK-3β +/− mice. -- Abstract: Glycogen synthase kinase (GSK)-3β plays an important role in osteoblastogenesis by regulating the Wnt/β-catenin signaling pathway. Therefore, we investigated whether GSK-3β deficiency affects bone development and regeneration using mice heterozygously deficient for GSK-3β (GSK-3β +/− ). The amounts of β-catenin, c-Myc, cyclin D1, and runt-related transcription factor-2 (Runx2) in the bone marrow cells of GSK-3β +/− mice were significantly increased compared with those of wild-type mice, indicating that Wnt/β-catenin signals were enhanced in GSK-3β +/− mice. Microcomputed tomography of the distal femoral metaphyses demonstrated that the volumes of both the cortical and trabecular bones were increased in GSK-3β +/− mice compared with those in wild-type mice. Subsequently, to investigate the effect of GSK-3β deficiency on bone regeneration, we established a partial bone defect in the femur and observed new bone at 14 days after surgery. The volume and mineral density of the new bone were significantly higher in GSK-3β +/− mice than those in wild-type mice. These results suggest that bone formation and regeneration in vivo are accelerated by inhibition of GSK-3β, probably through activation of the Wnt/β-catenin signaling pathway

  17. A signaling pathway contributing to platelet storage lesion development: targeting PI3-kinase–dependent Rap1 activation slows storage-induced platelet deterioration

    Science.gov (United States)

    Schubert, Peter; Thon, Jonathan N.; Walsh, Geraldine M.; Chen, Cindy H.I.; Moore, Edwin D.; Devine, Dana V.; Kast, Juergen

    2015-01-01

    BACKGROUND The term platelet storage lesion (PSL) describes the structural and biochemical changes in platelets (PLTs) during storage. These are typified by alterations of morphologic features and PLT metabolism leading to reduced functionality and hence reduced viability for transfusion. While the manifestations of the storage lesion are well characterized, the biochemical pathways involved in the initiation of this process are unknown. STUDY DESIGN AND METHODS A complementary proteomic approach has recently been applied to analyze changes in the PLT proteome during storage. By employing stringent proteomic criteria, 12 proteins were identified as significantly and consistently changing in relative concentration over a 7-day storage period. Microscopy, Western blot analysis, flow cytometry, and PLT functionality analyses were used to unravel the involvement of a subset of these 12 proteins, which are connected through integrin signaling in one potential signaling pathway underlying storage lesion development. RESULTS Microscopic analysis revealed changes in localization of glycoprotein IIIa, Rap1, and talin during storage. Rap1 activation was observed to correlate with expression of the PLT activation marker CD62P. PLTs incubated for 7 days with the PI3-kinase inhibitor LY294002 showed diminished Rap1 activation as well as a moderate reduction in integrin αIIbβ3 activation and release of α-granules. Furthermore, this inhibitor seemed to improve PLT integrity and quality during storage as several in vitro probes showed a deceleration of PLT activation. CONCLUSION These results provide the first evidence for a signaling pathway mediating PSL in which PI3-kinase–dependent Rap1 activation leads to integrin αIIbβ3 activation and PLT degranulation. PMID:19497060

  18. Acceleration of bone development and regeneration through the Wnt/β-catenin signaling pathway in mice heterozygously deficient for GSK-3β

    Energy Technology Data Exchange (ETDEWEB)

    Arioka, Masaki [Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka (Japan); Department of Oral and Maxillofacial Surgery, Faculty of Dental Science, Kyushu University, Fukuoka (Japan); Takahashi-Yanaga, Fumi, E-mail: yanaga@clipharm.med.kyushu-u.ac.jp [Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka (Japan); Global Medical Science Education Unit, Faculty of Medical Sciences, Kyushu University, Fukuoka (Japan); Sasaki, Masanori [Department of Oral and Maxillofacial Surgery, Faculty of Dental Science, Kyushu University, Fukuoka (Japan); Yoshihara, Tatsuya; Morimoto, Sachio [Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka (Japan); Takashima, Akihiko [Department of Aging Neurobiology, National Center for Geriatrics and Gerontology, Oobu (Japan); Mori, Yoshihide [Department of Oral and Maxillofacial Surgery, Faculty of Dental Science, Kyushu University, Fukuoka (Japan); Sasaguri, Toshiyuki [Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka (Japan)

    2013-11-01

    Highlights: •The Wnt/β-catenin signaling pathway was activated in GSK-3β{sup +/−} mice. •The cortical and trabecular bone volumes were increased in GSK-3β{sup +/−} mice. •Regeneration of a partial bone defect was accelerated in GSK-3β{sup +/−} mice. -- Abstract: Glycogen synthase kinase (GSK)-3β plays an important role in osteoblastogenesis by regulating the Wnt/β-catenin signaling pathway. Therefore, we investigated whether GSK-3β deficiency affects bone development and regeneration using mice heterozygously deficient for GSK-3β (GSK-3β{sup +/−}). The amounts of β-catenin, c-Myc, cyclin D1, and runt-related transcription factor-2 (Runx2) in the bone marrow cells of GSK-3β{sup +/−} mice were significantly increased compared with those of wild-type mice, indicating that Wnt/β-catenin signals were enhanced in GSK-3β{sup +/−} mice. Microcomputed tomography of the distal femoral metaphyses demonstrated that the volumes of both the cortical and trabecular bones were increased in GSK-3β{sup +/−} mice compared with those in wild-type mice. Subsequently, to investigate the effect of GSK-3β deficiency on bone regeneration, we established a partial bone defect in the femur and observed new bone at 14 days after surgery. The volume and mineral density of the new bone were significantly higher in GSK-3β{sup +/−} mice than those in wild-type mice. These results suggest that bone formation and regeneration in vivo are accelerated by inhibition of GSK-3β, probably through activation of the Wnt/β-catenin signaling pathway.

  19. Pharma Opportunities and Risks Multiply as Regulatory Reform Remakes APAC: Expanded Accelerated Pathways Challenge Developer Value Story, Evidence Collection, and Market Access Strategies.

    Science.gov (United States)

    Grignolo, Alberto; Mingping, Zhang

    2018-01-01

    Sweeping reforms in the largest markets of the Asia-Pacific region are transforming the regulatory and commercial landscape for foreign pharmaceutical companies. Japan, South Korea, and China are leading the charge, establishing mechanisms and infrastructure that both reflect and help drive international regulatory convergence and accelerate delivery of needed, innovative products to patients. In this rapidly evolving regulatory and commercial environment, drug developers can benefit from reforms and proliferating accelerated pathway (AP) frameworks, but only with regulatory and evidence-generation strategies tailored to the region. Otherwise, they will confront significant pricing and reimbursement headwinds. Although APAC economies are at different stages of development, they share a common imperative: to balance pharmaceutical innovation with affordability. Despite the complexity of meeting these sometimes conflicting demands, companies that focus on demonstrating and delivering value for money, and that price new treatments reasonably and sustainably, can succeed both for their shareholders and the region's patient population.

  20. Alternative pathway for the development of Vα14+ NKT cells directly from CD4-CD8- thymocytes that bypasses the CD4+CD8+ stage.

    Science.gov (United States)

    Dashtsoodol, Nyambayar; Shigeura, Tomokuni; Aihara, Minako; Ozawa, Ritsuko; Kojo, Satoshi; Harada, Michishige; Endo, Takaho A; Watanabe, Takashi; Ohara, Osamu; Taniguchi, Masaru

    2017-03-01

    Although invariant V α 14 + natural killer T cells (NKT cells) are thought to be generated from CD4 + CD8 + double-positive (DP) thymocytes, the developmental origin of CD4 - CD8 - double-negative (DN) NKT cells still remains unresolved. Here we provide definitive genetic evidence obtained, through studies of mice with DP-stage-specific ablation of expression of the gene encoding the recombinase component RAG-2 (Rag2) and by a fate-mapping approach, that supports the proposal of the existence of an alternative developmental pathway through which a fraction of DN NKT cells with strong T-helper-type-1 (T H 1)-biased and cytotoxic characteristics develop from late DN-stage thymocytes, bypassing the DP stage. These findings provide new insight into understanding of the development of NKT cells and propose a role for timing of expression of the invariant T cell antigen receptor in determining the functional properties of NKT cells.

  1. Associations of Genetic Polymorphisms Relevant to Metabolic Pathway of Vitamin D3 with Development and Prognosis of Childhood Bronchial Asthma.

    Science.gov (United States)

    Zhang, Ying; Wang, Zhansheng; Ma, Tongshuai

    2017-08-01

    This study was aimed at investigating the correlation between genetic polymorphisms relevant to metabolic pathway of vitamin D3 (VD 3 ) and susceptibility to childhood bronchial asthma. Altogether 143 childhood patients with bronchial asthma and 143 healthy children of Chinese Han ethnicity were enrolled in this study. The key single-nucleotide polymorphisms (SNPs) were identified by HaploView 4.2 software and selected from previous investigations. Genomic DNAs were isolated from peripheral blood samples by using TaqMan Blood DNA kits. The genotyping of SNPs was performed by TaqMan SNPs genotyping assay. Odds ratios and corresponding 95% confidence intervals were calculated to evaluate the association between SNPs and susceptibility to bronchial asthma. Statistical analyses were conducted by using SPSS 13.0 software. Rs10766197 of CYP2R1, rs7041 and rs4588 of CG, rs4646536 of CYP27B1, rs2228570, rs7975232, and rs1544410 of VDR, as well as rs1805192 and rs10865710 of PPAR were shown to be significantly associated with increased risk of bronchial asthma. Besides, prognosis of childhood bronchial asthma, which was represented as Saint George Respiratory Questionnaire (SGRQ) scoring, was closely linked with CYP2R1 rs10766197, CYP27B1 rs4646536, VDR rs7975232, VDR rs1544410, PPAR rs1805192, and PPAR rs10865710. The haplotype analysis suggested that TA and CG of CG rs7041/rs4588, CA and AG of VDR rs7975232/rs1544410, and CC of PPAR rs1805192/rs10865710 were, respectively, correlated with levels of VD, IL-4, and IL-5. And only haplotypes of VDR showed associations with risk of bronchial asthma during childhood, whereas hardly any significance could be observed between the haplotypes and behavior of quality-of-life (SGRQ) scoring. Significant associations were found between rs10766197 of CYP2R1, rs7041 and rs4588 of CG, rs4646536 of CYP27B1, rs2228570, rs7975232, and rs1544410 of VDR, as well as rs1805192 and rs10865710 of PPAR and susceptibility to and prognosis of

  2. Parabolic-trough technology roadmap: A pathway for sustained commercial development and deployment of parabolic-trough technology

    International Nuclear Information System (INIS)

    David Kearney; Hank Price

    1999-01-01

    Technology roadmapping is a needs-driven technology planning process to help identify, select, and develop technology alternatives to satisfy a set of market needs. The DOE's Office of Power Technologies' Concentrating Solar Power (CSP) Program recently sponsored a technology roadmapping workshop for parabolic trough technology. The workshop was attended by an impressive cross section of industry and research experts. The goals of the workshop were to evaluate the market potential for trough power projects, develop a better understanding of the current state of the technology, and to develop a conceptual plan for advancing the state of parabolic trough technology. This report documents and extends the roadmap that was conceptually developed during the workshop

  3. Diverse and uneven pathways towards transition to low carbon development: The case of diffusion of solar PV technology in China

    NARCIS (Netherlands)

    Iizuka, M.

    2014-01-01

    Transition towards low carbon development (LCD) is an urgent challenge for the global community. As increased economic activities usually result in more carbon emissions, this challenge is particularly crucial for rapidly growing emerging countries. For these countries, reducing carbon emissions

  4. The EGF receptor and notch signaling pathways control the initiation of the morphogenetic furrow during Drosophila eye development.

    Science.gov (United States)

    Kumar, J P; Moses, K

    2001-07-01

    The onset of pattern formation in the developing Drosophila retina begins with the initiation of the morphogenetic furrow, the leading edge of a wave of retinal development that transforms a uniform epithelium, the eye imaginal disc into a near crystalline array of ommatidial elements. The initiation of this wave of morphogenesis is under the control of the secreted morphogens Hedgehog (Hh), Decapentaplegic (Dpp) and Wingless (Wg). We show that the Epidermal Growth Factor Receptor and Notch signaling cascades are crucial components that are also required to initiate retinal development. We also show that the initiation of the morphogenetic furrow is the sum of two genetically separable processes: (1) the 'birth' of pattern formation at the posterior margin of the eye imaginal disc; and (2) the subsequent 'reincarnation' of retinal development across the epithelium.

  5. Expression and clinical significance of the HIF-1a/ET-2 signaling pathway during the development and treatment of polycystic ovary syndrome.

    Science.gov (United States)

    Wang, Fan; Zhang, Zhenghong; Wang, Zhaokai; Xiao, Kaizhuan; Wang, Qing; Su, Jingqian; Wang, Zhengchao

    2015-04-01

    Polycystic ovary syndrome (PCOS) is a major health problem in reproductive-aged women worldwide, but the precise pathogenesis of PCOS remains unclear. Our previous study revealed that hypoxia-inducible factor (HIF)-1a mediated endothelin (ET)-2 signaling plays an important role in ovulation in rats. Therefore, the present study used a PCOS rat model to test the hypotheses that HIF-1a signaling is expressed and inhibited in ovaries during PCOS formation and that the HIF-1a/ET-2 signaling pathway is a target of dimethyldiguanide (DMBG) in the clinical treatment of PCOS. First, the development of a PCOS model and the effect of DMBG treatment were examined through ovarian histology and serum hormone levels, which were consistent with previous reports. Second, HIF-1a and ET-2 expression were detected by immunohistochemistry and western blot. The results showed decreased HIF-1a/ET-2 expression in the ovaries of PCOS rats, whereas DMBG treatment reversed the protein decreases and improved the PCOS symptoms. Third, to understand the molecular mechanism, HIF-1a/ET-2 mRNA expression was also examined. Interestingly, HIF-1a mRNA increased in the ovaries of PCOS rats, while ET-2 mRNA decreased, indicating that HIF-1a protein degradation may be involved in POCS development and treatment. Finally, HIF prolyl hydroxylase (PHD) activity was examined to further clarify the contribution of HIF-1a signaling to the development and treatment of PCOS. The results suggested that the inhibition of HIF-1a/ET-2 signaling may be caused by increased PHD activity in PCOS. DMBG-treated PCOS may further activate HIF-1a signaling at least partly through inhibiting PHD activity. Taken together, these results indicate that HIF-1a signaling is inhibited in a PCOS rat model through increasing PHD activity. DMBG treatment improved PCOS by rescuing this pathway, suggesting that HIF-1a signaling plays an important role in the development and treatment of PCOS. This HIF-1a-mediated ET-2 signaling pathway

  6. Policies built upon pathways

    NARCIS (Netherlands)

    Musterd, S.; Kovács, Z.; Musterd, S.; Kovács, Z.

    2013-01-01

    After the general introductions, the first substantive part of this volume (Part II) provides concise research-based discussions of policies developed in recognition of the important role played by the pathways along which city-regions have travelled. Our research has shown that it is highly

  7. Maternal “junk-food” feeding of rat dams alters food choices and development of the mesolimbic reward pathway in the offspring

    Science.gov (United States)

    Ong, Z. Y.; Muhlhausler, B. S.

    2011-01-01

    Individuals exposed to high-fat, high-sugar diets before birth have an increased risk of obesity in later life. Recent studies have shown that these offspring exhibit increased preference for fat, leading to suggestions that perinatal exposure to high-fat, high-sugar foods results in permanent changes within the central reward system that increase the subsequent drive to overconsume palatable foods. The present study has determined the effect of a maternal “junk-food” diet on the expression of key components of the mesolimbic reward pathway in the offspring of rat dams at 6 wk and 3 mo of age. We show that offspring of junk-food-fed (JF) dams exhibit higher fat intake from weaning until at least 3 mo of age (males: 16±0.6 vs. 11±0.8 g/kg/d; females: 19±1.3 vs. 13±0.4 g/kg/d; Pjunk-food intake in postnatal life.—Ong, Z. Y., Muhlhausler, B. S. Maternal “junk-food” feeding of rat dams alters food choices and development of the mesolimbic reward pathway in the offspring. PMID:21427213

  8. Reconstruction of the gene regulatory network involved in the sonic hedgehog pathway with a potential role in early development of the mouse brain.

    Directory of Open Access Journals (Sweden)

    Jinhua Liu

    2014-10-01

    Full Text Available The Sonic hedgehog (Shh signaling pathway is crucial for pattern formation in early central nervous system development. By systematically analyzing high-throughput in situ hybridization data of E11.5 mouse brain, we found that Shh and its receptor Ptch1 define two adjacent mutually exclusive gene expression domains: Shh+Ptch1- and Shh-Ptch1+. These two domains are associated respectively with Foxa2 and Gata3, two transcription factors that play key roles in specifying them. Gata3 ChIP-seq experiments and RNA-seq assays on Gata3-knockdown cells revealed that Gata3 up-regulates the genes that are enriched in the Shh-Ptch1+ domain. Important Gata3 targets include Slit2 and Slit3, which are involved in the process of axon guidance, as well as Slc18a1, Th and Qdpr, which are associated with neurotransmitter synthesis and release. By contrast, Foxa2 both up-regulates the genes expressed in the Shh+Ptch1- domain and down-regulates the genes characteristic of the Shh-Ptch1+ domain. From these and other data, we were able to reconstruct a gene regulatory network governing both domains. Our work provides the first genome-wide characterization of the gene regulatory network involved in the Shh pathway that underlies pattern formation in the early mouse brain.

  9. Regulation of melanin biosynthesis via the dihydroxynaphthalene pathway is dependent on sexual development in the ascomycete Sordaria macrospora.

    Science.gov (United States)

    Engh, Ines; Nowrousian, Minou; Kück, Ulrich

    2007-10-01

    The filamentous ascomycete Sordaria macrospora accumulates melanin during sexual development. The four melanin biosynthesis genes pks, teh, sdh and tih were isolated and their homology to genes involved in 1,8 dihydroxynaphthalene (DHN) melanin biosynthesis was shown. The presence of DHN melanin in S. macrospora was further confirmed by disrupting the pks gene encoding a putative polyketide synthase and by RNA interference-mediated silencing of the sdh gene encoding a putative scytalone dehydratase. Because melanin occurs in fruiting bodies that develop through several intermediate stages within 7 days of growth, a Northern analysis of a developmental time-course was conducted. These data revealed a time-dependent regulation of teh and sdh transcript levels. Comparing the transcriptional expression by real-time PCR of melanin biosynthesis genes in the wild type under conditions allowing or repressing sexual development, a significant downregulation during vegetative growth was detected. Quantitative real-time PCR and Northern blot analysis of melanin biosynthesis gene expression in different developmental mutants confirmed that melanin biosynthesis is linked to fruiting body development and is under the control of specific regulatory genes that participate in sexual differentiation.

  10. Development of a decision model for the techno-economic assessment of municipal solid waste utilization pathways.

    Science.gov (United States)

    Khan, Md Mohib-Ul-Haque; Jain, Siddharth; Vaezi, Mahdi; Kumar, Amit

    2016-02-01

    Economic competitiveness is one of the key factors in making decisions towards the development of waste conversion facilities and devising a sustainable waste management strategy. The goal of this study is to develop a framework, as well as to develop and demonstrate a comprehensive techno-economic model to help county and municipal decision makers in establishing waste conversion facilities. The user-friendly data-intensive model, called the FUNdamental ENgineering PrinciplEs-based ModeL for Estimation of Cost of Energy and Fuels from MSW (FUNNEL-Cost-MSW), compares nine different waste management scenarios, including landfilling and composting, in terms of economic parameters such as gate fees and return on investment. In addition, a geographic information system (GIS) model was developed to determine suitable locations for waste conversion facilities and landfill sites based on integration of environmental, social, and economic factors. Finally, a case study on Parkland County and its surrounding counties in the province of Alberta, Canada, was conducted and a sensitivity analysis was performed to assess the influence of the key technical and economic parameters on the calculated results. Copyright © 2015 Elsevier Ltd. All rights reserved.

  11. Pathways for sustainable development of mixed crop livestock systems: Taking a livestock and pro-poor approach

    NARCIS (Netherlands)

    Tarawali, S.A.; Herrero, M.; Descheemaeker, K.K.E.; Grings, E.; Blmmel, M.

    2011-01-01

    Mixed crop livestock systems provide the majority of the cereal and livestock domestic products for households in developing countries. We explore the question of whether such systems can respond to increasing demands for livestock products without compromising future livelihoods of the poor or the

  12. Pathways from Mothers' Early Social Support to Children's Language Development at Age 3

    Science.gov (United States)

    Chang, Young Eun

    2017-01-01

    The relationships between early maternal social support, maternal psychological well-being, the home learning environment, and children's language skills at age 3 in Korean families were examined. We hypothesized that maternal social support would predict children's language development through its effect on maternal psychological well-being and…

  13. Development highlights of micro-nano technologies in the MENA region and pathways for initiatives to support and network

    NARCIS (Netherlands)

    Al-Rawashdeh, M.I.M.; Alfeeli, B.; Rawashdeh, A.M.; Hessel, V.

    2013-01-01

    Current developments in the field of micro-nano technologies in the Middle East and North Africa (MENA) region are highlighted. Firstly, the scientific outcome of micro-nano technologies from the MENA region is analyzed. Egypt and Saudi Arabia are the leading countries, with >50% of the total MENA

  14. Identification of new members of Fertilisation Independent Seed Polycomb Group pathway involved in the control of seed development in Arabidopsis thaliana.

    Science.gov (United States)

    Guitton, Anne-Elisabeth; Page, Damian R; Chambrier, Pierre; Lionnet, Claire; Faure, Jean-Emmanuel; Grossniklaus, Ueli; Berger, Frédéric

    2004-06-01

    In higher plants, double fertilisation initiates seed development. One sperm cell fuses with the egg cell and gives rise to the embryo, the second sperm cell fuses with the central cell and gives rise to the endosperm. The endosperm develops as a syncytium with the gradual organisation of domains along an anteroposterior axis defined by the position of the embryo at the anterior pole and by the attachment to the placenta at the posterior pole. We report that ontogenesis of the posterior pole in Arabidopsis thaliana involves oriented migration of nuclei in the syncytium. We show that this migration is impaired in mutants of the three founding members of the FERTILIZATION INDEPENDENT SEED (FIS) class, MEDEA (MEA), FIS2 and FERTILIZATION INDEPENDENT ENDOSPERM (FIE). A screen based on a green fluorescent protein (GFP) reporter line allowed us to identify two new loci in the FIS pathway, medicis and borgia. We have cloned the MEDICIS gene and show that it encodes the Arabidopsis homologue of the yeast WD40 domain protein MULTICOPY SUPRESSOR OF IRA (MSI1). The mutations at the new fis loci cause the same cellular defects in endosperm development as other fis mutations, including parthenogenetic development, absence of cellularisation, ectopic development of posterior structures and overexpression of the GFP marker.

  15. Pathways to youth homelessness.

    Science.gov (United States)

    Martijn, Claudine; Sharpe, Louise

    2006-01-01

    Research documents high levels of psychopathology among homeless youth. Most research, however, has not distinguished between disorders that are present prior to homelessness and those that develop following homelessness. Hence whether psychological disorders are the cause or consequence of homelessness has not been established. The aim of this study is to investigate causal pathways to homelessness amongst currently homeless youth in Australia. The study uses a quasi-qualitative methodology to generate hypotheses for larger-scale research. High rates of psychological disorders were confirmed in the sample 35 homeless youth aged 14-25. The rates of psychological disorders at the point of homelessness were greater than in normative samples, but the rates of clinical disorder increased further once homeless. Further in-depth analyses were conducted to identify the temporal sequence for each individual with a view to establishing a set of causal pathways to homelessness and trajectories following homelessness that characterised the people in the sample. Five pathways to homelessness and five trajectories following homelessness were identified that accounted for the entire sample. Each pathway constituted a series of interactions between different factors similar to that described by Craig and Hodson (1998. Psychological Medicine, 28, 1379-1388) as "complex subsidiary pathways". The major findings were that (1) trauma is a common experience amongst homeless youth prior to homelessness and figured in the causal pathways to homelessness for over half of the sample; (2) once homeless, for the majority of youth there is an increase in the number of psychological diagnoses including drug and alcohol diagnoses; and (3) crime did not precede homelessness for all but one youth; however, following homelessness, involvement in criminal activity was common and became a distinguishing factor amongst youth. The implications of these findings for future research and service

  16. Developing Inhibitors of Ovarian Cancer Progression by Targeted Disruption of the Gamma-Synuclein Activated Migratory and Survival Signaling Pathways

    Science.gov (United States)

    2007-04-01

    Golub TR. A molecular signature of metastasis in primary solid tumors. Nat Gene 2003;33:49–54. 2. van’t Verr LJ, Dai H, van de Vijver MJ, et al. Gene...Philadelphia, Pennsylvania 19111 REPORT DATE: April 2007 TYPE OF REPORT: Final PREPARED FOR: U.S. Army Medical Research and... TYPE Final 3. DATES COVERED (From - To) 1 Apr 2003 – 31 Mar 2007 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Developing Inhibitors of Ovarian

  17. The development of models for the transfer of 137Cs and 90Sr in the pasture-cow-milk pathway using fallout data

    International Nuclear Information System (INIS)

    Haywood, S.M.; Simmonds, J.R.; Linsley, G.S.

    1980-11-01

    Records of the measurements of fallout in the UK between the years 1958-77 have been used to develop versions of a general model for transfer in the pasture-cow-milk pathway for the radionuclides 137 Cs and 90 Sr. The revised models take account of the experimentally observed processes of fixation of caesium in soils and the plant base absorption of strontium. They predict, with reasonable accuracy, the variation of activity levels in milk over the period for which records exist. The form of the models permits examination of the relative contributions of the most important transfer mechanisms and their time dependence in the soil-plant system. The study has indicated an upper limit for the resuspension factor in UK rural environments. (author)

  18. Metabolic and transcriptional elucidation of the carotenoid biosynthesis pathway in peel and flesh tissue of loquat fruit during on-tree development.

    Science.gov (United States)

    Hadjipieri, Margarita; Georgiadou, Egli C; Marin, Alicia; Diaz-Mula, Huertas M; Goulas, Vlasios; Fotopoulos, Vasileios; Tomás-Barberán, Francisco A; Manganaris, George A

    2017-06-14

    Carotenoids are the main colouring substances found in orange-fleshed loquat fruits. The aim of this study was to unravel the carotenoid biosynthetic pathway of loquat fruit (cv. 'Obusa') in peel and flesh tissue during distinct on-tree developmental stages through a targeted analytical and molecular approach. Substantial changes regarding colour parameters, both between peel and flesh and among the different developmental stages, were monitored, concomitant with a significant increment in carotenoid content. Key genes and individual compounds that are implicated in the carotenoid biosynthetic pathway were further dissected with the employment of molecular (RT-qPCR) and advanced analytical techniques (LC-MS). Results revealed significant differences in carotenoid composition between peel and flesh. Thirty-two carotenoids were found in the peel, while only eighteen carotenoids were identified in the flesh. Trans-lutein and trans-β-carotene were the major carotenoids in the peel; the content of the former decreased with the progress of ripening, while the latter registered a 7.2-fold increase. However, carotenoid profiling of loquat flesh indicated trans-β-cryptoxanthin, followed by trans-β-carotene and 5,8-epoxy-β-carotene to be the most predominant carotenoids. High amounts of trans-β-carotene in both tissues were supported by significant induction in a chromoplast-specific lycopene β-cyclase (CYCB) transcript levels. PSY1, ZDS, CYCB and BCH were up-regulated and CRTISO, LCYE, ECH and VDE were down-regulated in most of the developmental stages compared with the immature stage in both peel and flesh tissue. Overall, differential regulation of expression levels with the progress of on-tree fruit development was more evident in the middle and downstream genes of carotenoid biosynthetic pathway. Carotenoid composition is greatly affected during on-tree loquat development with striking differences between peel and flesh tissue. A link between gene up- or down

  19. On a Pathway Towards Thriving: Evaluating the Effectiveness of Tools to Promote Positive Development and Intentional Self Regulation in Youth

    Directory of Open Access Journals (Sweden)

    Edmond P. Bowers

    2013-12-01

    Full Text Available This article provides initial data about the reliability and validity of tools aimed at promoting youth intentional self regulation (ISR within mentoring programs. Based on the translation of the theory-based research about ISR and youth thriving conducted within the 4-H Study of Positive Youth Development (PYD, the GPS to Success tools use the metaphor of a car’s GPS navigational system to enhance goal-directed behaviors among youth. The core GPS tools are “growth grids,” designed to help mentors appraise ISR skill development and to link these skills to other grids assessing the Five Cs of PYD and Contribution. Data from 152 mentor and youth pairs from 4-H program sites in Oregon and North Carolina indicated that the growth grids were generally reliable. Although validity evidence was mixed, rubrics for “G” and “P” and for a global GPS score were related to a well-validated measure of ISR.

  20. Identifying early pathways of risk and resilience: The co-development of internalizing and externalizing symptoms and the role of harsh parenting

    Science.gov (United States)

    Wiggins, Jillian Lee; Mitchell, Colter; Hyde, Luke W.; Monk, Christopher S.

    2016-01-01

    Psychological disorders co-occur often in children, but little has been done to document the types of conjoint pathways internalizing and externalizing symptoms may take from the crucial early period of toddlerhood or how harsh parenting may overlap with early symptom co-development. To examine symptom co-development trajectories, we identified latent classes of individuals based on internalizing and externalizing symptoms across ages 3–9 and found three symptom co-development classes: normative symptoms (low), severe-decreasing symptoms (initially high but rapidly declining) and severe symptoms (high) trajectories. Next, joint models examined how parenting trajectories overlapped with internalizing and externalizing symptom trajectories. These trajectory classes demonstrated that, normatively, harsh parenting increased after toddlerhood, but the severe symptoms class was characterized by a higher level and steeper increase in harsh parenting and the severe-decreasing class by high, stable harsh parenting. Additionally, a transactional model examined the bi-directional relationships among internalizing and externalizing symptoms and harsh parenting as they may cascade over time in this early period. Harsh parenting uniquely contributed to externalizing symptoms, controlling for internalizing symptoms, but not vice versa. Also, internalizing symptoms appeared to be a mechanism by which externalizing symptoms increase. Results highlight the importance accounting for both internalizing and externalizing symptoms from an early age to understand risk for developing psychopathology and the role harsh parenting plays in influencing these trajectories. PMID:26439075

  1. Development of Pathways to Achieve the SE4ALL Energy Efficiency Objective: Global and Regional Potential for Energy Efficiency Improvements

    DEFF Research Database (Denmark)

    Gregg, Jay Sterling; Balyk, Olexandr; Pérez, Cristian Hernán Cabrera

    This study examines the three objectives of the UN Sustainable Energy for All (SE4ALL) initiative: 1. Ensure universal access to modern energy services by 2030. 2. Double the global rate of improvement in energy efficiency (from 1.3% to 2.6% annual reduction in energy intensity of GDP) by 2030. 3....... Double the share of renewable energy in global final energy from 18% to 36% by 2030. The integrated assessment model, ETSAP-TIAM, was used in this study to compare, from an economic optimization point of view, different scenarios for the development of the energy system between 2010 and 2030....... This analysis is conducted on a global and regional scale. The scenarios were constructed to analyze the effect of achieving the SE4ALL energy efficiency objective, the SE4ALL renewable energy objective, both together, and all three SE4ALL objectives. Synergies exist between renewable energy and energy...

  2. Four pathways in the analysis of adult development and aging: comparing analyses of reasoning about personal-life dilemmas.

    Science.gov (United States)

    Pratt, M W; Diessner, R; Hunsberger, B; Pancer, S M; Savoy, K

    1991-12-01

    Four systems for analyzing thinking about 2 personal-life dilemmas, as discussed by 29 men and 35 women (ages 35-85), were compared. Kohlberg's (1976) moral judgment stages, Kegan's (1982) ego-development stages, Gilligan's (1982) moral orientation system, and Suedfeld and Tetlock's (1977) integrative complexity scoring were used. Subjects completed Kohlberg's (Colby & Kohlberg, 1987) standard moral judgment measure, a self-concept description, and several questionnaires. The Kohlberg, Kegan, and integrative complexity codings of the dilemmas were positively related to each other and to the standard Kohlberg moral stage scores. There were no age-group differences and few gender differences on the measures. However, education, role-taking skills, and greater sensitivity to age changes in the self positively predicted higher stage scores across maturity.

  3. Co-controlling CO2 and NOx emission in China's cement industry: An optimal development pathway study

    Directory of Open Access Journals (Sweden)

    Xiang-Zhao Feng

    2018-03-01

    Full Text Available It is of important practical significance to reduce NOx emission and CO2 emission in China's cement industry. This paper firstly identifies key factors that influence China's future cement demand, and then uses the Gompertz model to project China's future cement demand and production. Furthermore, the multi-pollutant abatement planning model (MAP was developed based on the TIMES model to analyze the co-benefits of CO2 and NOx control in China's cement industry. During modeling analysis, three scenarios such as basic as usual scenario (BAU, moderately low carbon scenario (MLC, and radically low carbon scenario (RLC, were built according to different policy constraints and emission control goals. Moreover, the benefits of co-controlling NOx and CO2 emission in China's cement industry have been estimated. Finally, this paper proposes a cost-efficient, green, and low carbon development roadmap for the Chinese cement sector, and puts forwards countermeasures as follows: first, different ministries should enhance communication and coordination about how to promote the co-control of NOx and CO2 in cement industry. Second, co-control technology list should be issued timely for cement industry, and the R&D investment on new technologies and demonstration projects should be increased. Third, the phase-out of old cement capacity needs to be continued at policy level. Fourth, it is important to scientifically evaluate the relevant environmental impact and adverse motivation of ammonia production by NOx removal requirement in cement industry. Keywords: Cement industry, CO2 abatement, NOx reduction, Co-benefit analysis

  4. Xenopus Zic3 controls notochord and organizer development through suppression of the Wnt/β-catenin signaling pathway.

    Science.gov (United States)

    Fujimi, Takahiko J; Hatayama, Minoru; Aruga, Jun

    2012-01-15

    Zic3 controls neuroectodermal differentiation and left-right patterning in Xenopus laevis embryos. Here we demonstrate that Zic3 can suppress Wnt/β-catenin signaling and control development of the notochord and Spemann's organizer. When we overexpressed Zic3 by injecting its RNA into the dorsal marginal zone of 2-cell-stage embryos, the embryos lost mesodermal dorsal midline structures and showed reduced expression of organizer markers (Siamois and Goosecoid) and a notochord marker (Xnot). Co-injection of Siamois RNA partially rescued the reduction of Xnot expression caused by Zic3 overexpression. Because the expression of Siamois in the organizer region is controlled by Wnt/β-catenin signaling, we subsequently examined the functional interaction between Zic3 and Wnt signaling. Co-injection of Xenopus Zic RNAs and β-catenin RNA with a reporter responsive to the Wnt/β-catenin cascade indicated that Zic1, Zic2, Zic3, Zic4, and Zic5 can all suppress β-catenin-mediated transcriptional activation. In addition, co-injection of Zic3 RNA inhibited the secondary axis formation caused by ventral-side injection of β-catenin RNA in Xenopus embryos. Zic3-mediated Wnt/β-catenin signal suppression required the nuclear localization of Zic3, and involved the reduction of β-catenin nuclear transport and enhancement of β-catenin degradation. Furthermore, Zic3 co-precipitated with Tcf1 (a β-catenin co-factor) and XIC (I-mfa domain containing factor required for dorsoanterior development). The findings in this report produce a novel system for fine-tuning of Wnt/β-catenin signaling. Copyright © 2011. Published by Elsevier Inc.

  5. Development of a pathway model to assess the exposure of European pine trees to pine wood nematode via the trade of wood.

    Science.gov (United States)

    Douma, J C; van der Werf, W; Hemerik, L; Magnusson, C; Robinet, C

    2017-04-01

    Pine wood nematode (PWN), Bursaphelenchus xylophilus, is a threat for pine species (Pinus spp.) throughout the world. The nematode is native to North America, and invaded Japan, China, Korea, and Taiwan, and more recently Portugal and Spain. PWN enters new areas through trade in wood products. Once established, eradication is not practically feasible. Therefore, preventing entry of PWN into new areas is crucial. Entry risk analysis can assist in targeting management to reduce the probability of entry. Assessing the entry of PWN is challenging due to the complexity of the wood trade and the wood processing chain. In this paper, we develop a pathway model that describes the wood trade and wood processing chain to determine the structure of the entry process. We consider entry of PWN through imported coniferous wood from China, a possible origin of Portuguese populations, to Europe. We show that exposure increased over years due to an increase in imports of sawn wood. From 2000 to 2012, Europe received an estimated 84 PWN propagules from China, 88% of which arose from imported sawn wood and 12% from round wood. The region in Portugal where the PWN was first reported is among those with the highest PWN transfer per unit of imported wood due to a high host cover and vector activity. An estimated 62% of PWN is expected to enter in countries where PWN is not expected to cause the wilt of pine trees because of low summer temperatures (e.g., Belgium, Sweden, Norway). In these countries, PWN is not easily detected, and such countries can thus serve as potential reservoirs of PWN. The model identifies ports and regions with high exposure, which helps targeting monitoring and surveillance, even in areas where wilt disease is not expected to occur. In addition, we show that exposure is most efficiently reduced by additional treatments in the country of origin, and/or import wood from PWN-free zones. Pathway modelling assists plant health managers in analyzing risks along the

  6. Oxcarbazepine causes neurocyte apoptosis and developing brain damage by triggering Bax/Bcl-2 signaling pathway mediated caspase 3 activation in neonatal rats.

    Science.gov (United States)

    Song, Y; Zhong, M; Cai, F-C

    2018-01-01

    Anti-epileptic drugs (AEDs) are the main methods for treatment of neonatal seizures; however, a few AEDs may cause developing brain damage of neonate. This study aims to investigate effects of oxcarbazepine (OXC) on developing brain damage of neonatal rats. Both of neonatal and adult rats were divided into 6 groups, including Control, OXC 187.5 mg/kg, OXC 281.25 mg/kg, OXC 375 mg/kg group, LEV and PHT group. Body weight and brain weight were evaluated. Hematoxylin and eosin (HE) and Nissl staining were used to observe neurocyte morphology and Nissl bodies, respectively. Apoptosis was examined using TUNEL assay, and caspase 8 activity was evaluated using spectrophotometer method. Cytochrome C-release was evaluated using flow cytometry. Western blot was used to examine Bax and Bcl-2 expression. OXC 375 mg/kg treatment significantly decreased brain weight compared to Control group in neonatal rats (P5 rats) (pOxcarbazepine at a concentration of 281.25 mg/kg or more causes neurocyte apoptosis and developing brain damage by triggering Bax/Bcl-2 signaling pathway mediated caspase 3 activation in neonatal rats.

  7. After the Liverpool Care Pathway--development of heuristics to guide end of life care for people with dementia: protocol of the ALCP study.

    Science.gov (United States)

    Davies, N; Manthorpe, J; Sampson, E L; Iliffe, S

    2015-09-02

    End of life care guidance for people with dementia is lacking and this has been made more problematic in England with the removal of one of the main end of life care guidelines which offered some structure, the Liverpool Care Pathway. This guidance gap may be eased with the development of heuristics (rules of thumb) which offer a fast and frugal form of decision-making. To develop a toolkit of heuristics (rules of thumb) for practitioners to use when caring for people with dementia at the end of life. A mixed-method study using a co-design approach to develop heuristics in three phases. In phase 1, we will conduct at least six focus groups with family carers, health and social care practitioners from both hospital and community care services, using the 'think-aloud' method to understand decision-making processes and to develop a set of heuristics. The focus group topic guide will be developed from the findings of a previous study of 46 interviews of family carers about quality end-of-life care for people with dementia and a review of the literature. A multidisciplinary development team of health and social care practitioners will synthesise the findings from the focus groups to devise and refine a toolkit of heuristics. Phase 2 will test the use of heuristics in practice in five sites: one general practice, one community nursing team, one hospital ward and two palliative care teams working in the community. Phase 3 will evaluate and further refine the toolkit of heuristics through group interviews, online questionnaires and semistructured interviews. This study has received ethical approval from a local NHS research ethics committee (Rec ref: 15/LO/0156). The findings of this study will be presented in peer-reviewed publications and national and international conferences. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  8. Investigating alternatives to the fish early-life stage test: a strategy for discovering and annotating adverse outcome pathways for early fish development.

    Science.gov (United States)

    Villeneuve, Daniel; Volz, David C; Embry, Michelle R; Ankley, Gerald T; Belanger, Scott E; Léonard, Marc; Schirmer, Kristin; Tanguay, Robert; Truong, Lisa; Wehmas, Leah

    2014-01-01

    The fish early-life stage (FELS) test (Organisation for Economic Co-operation and Development [OECD] test guideline 210) is the primary test used internationally to estimate chronic fish toxicity in support of ecological risk assessments and chemical management programs. As part of an ongoing effort to develop efficient and cost-effective alternatives to the FELS test, there is a need to identify and describe potential adverse outcome pathways (AOPs) relevant to FELS toxicity. To support this endeavor, the authors outline and illustrate an overall strategy for the discovery and annotation of FELS AOPs. Key events represented by major developmental landmarks were organized into a preliminary conceptual model of fish development. Using swim bladder inflation as an example, a weight-of-evidence-based approach was used to support linkage of key molecular initiating events to adverse phenotypic outcomes and reduced young-of-year survival. Based on an iterative approach, the feasibility of using key events as the foundation for expanding a network of plausible linkages and AOP knowledge was explored and, in the process, important knowledge gaps were identified. Given the scope and scale of the task, prioritization of AOP development was recommended and key research objectives were defined relative to factors such as current animal-use restrictions in the European Union and increased demands for fish toxicity data in chemical management programs globally. The example and strategy described are intended to guide collective efforts to define FELS-related AOPs and develop resource-efficient predictive assays that address the toxicological domain of the OECD 210 test. © 2013 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

  9. Dexter energy transfer pathways.

    Science.gov (United States)

    Skourtis, Spiros S; Liu, Chaoren; Antoniou, Panayiotis; Virshup, Aaron M; Beratan, David N

    2016-07-19

    Energy transfer with an associated spin change of the donor and acceptor, Dexter energy transfer, is critically important in solar energy harvesting assemblies, damage protection schemes of photobiology, and organometallic opto-electronic materials. Dexter transfer between chemically linked donors and acceptors is bridge mediated, presenting an enticing analogy with bridge-mediated electron and hole transfer. However, Dexter coupling pathways must convey both an electron and a hole from donor to acceptor, and this adds considerable richness to the mediation process. We dissect the bridge-mediated Dexter coupling mechanisms and formulate a theory for triplet energy transfer coupling pathways. Virtual donor-acceptor charge-transfer exciton intermediates dominate at shorter distances or higher tunneling energy gaps, whereas virtual intermediates with an electron and a hole both on the bridge (virtual bridge excitons) dominate for longer distances or lower energy gaps. The effects of virtual bridge excitons were neglected in earlier treatments. The two-particle pathway framework developed here shows how Dexter energy-transfer rates depend on donor, bridge, and acceptor energetics, as well as on orbital symmetry and quantum interference among pathways.

  10. Modeling Pathways of Character Development across the First Three Decades of Life: An Application of Integrative Data Analysis Techniques to Understanding the Development of Hopeful Future Expectations.

    Science.gov (United States)

    Callina, Kristina Schmid; Johnson, Sara K; Tirrell, Jonathan M; Batanova, Milena; Weiner, Michelle B; Lerner, Richard M

    2017-06-01

    There were two purposes of the present research: first, to add to scholarship about a key character virtue, hopeful future expectations; and second, to demonstrate a recent innovation in longitudinal methodology that may be especially useful in enhancing the understanding of the developmental course of hopeful future expectations and other character virtues that have been the focus of recent scholarship in youth development. Burgeoning interest in character development has led to a proliferation of short-term, longitudinal studies on character. These data sets are sometimes limited in their ability to model character development trajectories due to low power or relatively brief time spans assessed. However, the integrative data analysis approach allows researchers to pool raw data across studies in order to fit one model to an aggregated data set. The purpose of this article is to demonstrate the promises and challenges of this new tool for modeling character development. We used data from four studies evaluating youth character strengths in different settings to fit latent growth curve models of hopeful future expectations from participants aged 7 through 26 years. We describe the analytic strategy for pooling the data and modeling the growth curves. Implications for future research are discussed in regard to the advantages of integrative data analysis. Finally, we discuss issues researchers should consider when applying these techniques in their own work.

  11. Oocyte exposure to ZnO nanoparticles inhibits early embryonic development through the γ-H2AX and NF-κB signaling pathways.

    Science.gov (United States)

    Liu, Jing; Zhao, Yong; Ge, Wei; Zhang, Pengfei; Liu, Xinqi; Zhang, Weidong; Hao, Yanan; Yu, Shuai; Li, Lan; Chu, Meiqiang; Min, Lingjiang; Zhang, Hongfu; Shen, Wei

    2017-06-27

    The impacts of zinc oxide nanoparticles on embryonic development following oocyte stage exposure are unknown and the underlying mechanisms are sparsely understood. In the current investigation, intact nanoparticles were detected in ovarian tissue in vivo and cultured cells in vitro under zinc oxide nanoparticles treatment. Zinc oxide nanoparticles exposure during the oocyte stage inhibited embryonic development. Notably, in vitro culture data closely matched in vivo embryonic data, in that the impairments caused by Zinc oxide nanoparticles treatment passed through cell generations; and both gamma-H2AX and NF-kappaB pathways were involved in zinc oxide nanoparticles caused embryo-toxicity. Copper oxide and silicon dioxide nanoparticles have been used to confirm that particles are important for the toxicity of zinc oxide nanoparticles. The toxic effects of zinc oxide nanoparticles emanate from both intact nanoparticles and Zn2+. Our investigation along with others suggests that zinc oxide nanoparticles are toxic to the female reproductive system [ovaries (oocytes)] and subsequently embryo-toxic and that precaution should be taken regarding human exposure to their everyday use.

  12. Early drug development of inhibitors of the insulin-like growth factor-I receptor pathway: lessons from the first clinical trials.

    Science.gov (United States)

    Rodon, Jordi; DeSantos, Victoria; Ferry, Robert Jean; Kurzrock, Razelle

    2008-09-01

    The insulin-like growth factor-I receptor (IGF-IR) was first cloned in 1986. Since then, intense work has defined classic phosphorelays activated via the IGF-IR, which regulate cell proliferation, apoptosis, motility, and fate. The understanding of the roles of hormones in cancer and the growth hormone-IGF-IGF-binding protein axis specifically has yield to a second wave of development: the design of specific inhibitors that interrupt the signaling associated with this axis. The ability to manipulate these pathways holds not only significant therapeutic implications but also increase the chance of deeper insight about the role of the axis in carcinogenesis and metastasis. Nowadays, >25 molecules with the same goal are at different stages of development. Here, we review the clinical and preclinical experience with the two most-investigated strategies, tyrosine kinase inhibitors and monoclonal antibodies, and the advantages and disadvantages of each strategy, as well as other alternatives and possible drug combinations. We also review the biomarkers explored in the first clinical trials, the strategies that have been explored thus far, and the clinical trials that are going to explore their role in cancer treatment.

  13. The Ca2+/H+ antiporter TMEM165 expression, localization in the developing, lactating and involuting mammary gland parallels the secretory pathway Ca2+ATPase (SPCA1)

    Science.gov (United States)

    Plasma membrane Ca2+-ATPase 2 (PMCA2) knockout mice showed that ~ 60 % of calcium in milk is transported across the mammary cells apical membrane by PMCA2. The remaining milk calcium is thought to arrive via the secretory pathway through the actions of secretory pathway Ca2+-ATPase’s 1 and/or 2 (SP...

  14. Pathways to diversification

    OpenAIRE

    Al Hashemi, Hamed

    2016-01-01

    A fundamental research question in regional economic development, is why some regions are able to diversify into new products and industries, while others continue to face challenges in diversification? This doctorate research explores the different pathways to diversification. It follows the three-stage modular structure of DBA for Cranfield School of Management. This thesis consists of a systematic literature review, a single qualitative case study on UAE, and a research synthesis of publis...

  15. Liver-Enriched Gene 1, a Glycosylated Secretory Protein, Binds to FGFR and Mediates an Anti-stress Pathway to Protect Liver Development in Zebrafish.

    Directory of Open Access Journals (Sweden)

    Minjie Hu

    2016-02-01

    Full Text Available Unlike mammals and birds, teleost fish undergo external embryogenesis, and therefore their embryos are constantly challenged by stresses from their living environment. These stresses, when becoming too harsh, will cause arrest of cell proliferation, abnormal cell death or senescence. Such organisms have to evolve a sophisticated anti-stress mechanism to protect the process of embryogenesis/organogenesis. However, very few signaling molecule(s mediating such activity have been identified. liver-enriched gene 1 (leg1 is an uncharacterized gene that encodes a novel secretory protein containing a single domain DUF781 (domain of unknown function 781 that is well conserved in vertebrates. In the zebrafish genome, there are two copies of leg1, namely leg1a and leg1b. leg1a and leg1b are closely linked on chromosome 20 and share high homology, but are differentially expressed. In this report, we generated two leg1a mutant alleles using the TALEN technique, then characterized liver development in the mutants. We show that a leg1a mutant exhibits a stress-dependent small liver phenotype that can be prevented by chemicals blocking the production of reactive oxygen species. Further studies reveal that Leg1a binds to FGFR3 and mediates a novel anti-stress pathway to protect liver development through enhancing Erk activity. More importantly, we show that the binding of Leg1a to FGFR relies on the glycosylation at the 70th asparagine (Asn(70 or N(70, and mutating the Asn(70 to Ala(70 compromised Leg1's function in liver development. Therefore, Leg1 plays a unique role in protecting liver development under different stress conditions by serving as a secreted signaling molecule/modulator.

  16. Development and initial cohort validation of the Arthritis Research UK Musculoskeletal Health Questionnaire (MSK-HQ) for use across musculoskeletal care pathways.

    Science.gov (United States)

    Hill, Jonathan C; Kang, Sujin; Benedetto, Elena; Myers, Helen; Blackburn, Steven; Smith, Stephanie; Dunn, Kate M; Hay, Elaine; Rees, Jonathan; Beard, David; Glyn-Jones, Sion; Barker, Karen; Ellis, Benjamin; Fitzpatrick, Ray; Price, Andrew

    2016-08-05

    Current musculoskeletal outcome tools are fragmented across different healthcare settings and conditions. Our objectives were to develop and validate a single musculoskeletal outcome measure for use throughout the pathway and patients with different musculoskeletal conditions: the Arthritis Research UK Musculoskeletal Health Questionnaire (MSK-HQ). A consensus workshop with stakeholders from across the musculoskeletal community, workshops and individual interviews with a broad mix of musculoskeletal patients identified and prioritised outcomes for MSK-HQ inclusion. Initial psychometric validation was conducted in four cohorts from community physiotherapy, and secondary care orthopaedic hip, knee and shoulder clinics. Stakeholders (n=29) included primary care, physiotherapy, orthopaedic and rheumatology patients (n=8); general practitioners, physiotherapists, orthopaedists, rheumatologists and pain specialists (n=7), patient and professional national body representatives (n=10), and researchers (n=4). The four validation cohorts included 570 participants (n=210 physiotherapy, n=150 hip, n=150 knee, n=60 shoulder patients). Outcomes included the MSK-HQ's acceptability, feasibility, comprehension, readability and responder burden. The validation cohort outcomes were the MSK-HQ's completion rate, test-retest reliability and convergent validity with reference standards (EQ-5D-5L, Oxford Hip, Knee, Shoulder Scores, and the Keele MSK-PROM). Musculoskeletal domains prioritised were pain severity, physical function, work interference, social interference, sleep, fatigue, emotional health, physical activity, independence, understanding, confidence to self-manage and overall impact. Patients reported MSK-HQ items to be 'highly relevant' and 'easy to understand'. Completion rates were high (94.2%), with scores normally distributed, and no floor/ceiling effects. Test-retest reliability was excellent, and convergent validity was strong (correlations 0.81-0.88). A new

  17. Metabolite and transcript profiling of berry skin during fruit development elucidates differential regulation between Cabernet Sauvignon and Shiraz cultivars at branching points in the polyphenol pathway.

    Science.gov (United States)

    Degu, Asfaw; Hochberg, Uri; Sikron, Noga; Venturini, Luca; Buson, Genny; Ghan, Ryan; Plaschkes, Inbar; Batushansky, Albert; Chalifa-Caspi, Vered; Mattivi, Fulvio; Delledonne, Massimo; Pezzotti, Mario; Rachmilevitch, Shimon; Cramer, Grant R; Fait, Aaron

    2014-07-26

    Grapevine berries undergo complex biochemical changes during fruit maturation, many of which are dependent upon the variety and its environment. In order to elucidate the varietal dependent developmental regulation of primary and specialized metabolism, berry skins of Cabernet Sauvignon and Shiraz were subjected to gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS) based metabolite profiling from pre-veraison to harvest. The generated dataset was augmented with transcript profiling using RNAseq. The analysis of the metabolite data revealed similar developmental patterns of change in primary metabolites between the two cultivars. Nevertheless, towards maturity the extent of change in the major organic acid and sugars (i.e. sucrose, trehalose, malate) and precursors of aromatic and phenolic compounds such as quinate and shikimate was greater in Shiraz compared to Cabernet Sauvignon. In contrast, distinct directional projections on the PCA plot of the two cultivars samples towards maturation when using the specialized metabolite profiles were apparent, suggesting a cultivar-dependent regulation of the specialized metabolism. Generally, Shiraz displayed greater upregulation of the entire polyphenol pathway and specifically higher accumulation of piceid and coumaroyl anthocyanin forms than Cabernet Sauvignon from veraison onwards. Transcript profiling revealed coordinated increased transcript abundance for genes encoding enzymes of committing steps in the phenylpropanoid pathway. The anthocyanin metabolite profile showed F3'5'H-mediated delphinidin-type anthocyanin enrichment in both varieties towards maturation, consistent with the transcript data, indicating that the F3'5'H-governed branching step dominates the anthocyanin profile at late berry development. Correlation analysis confirmed the tightly coordinated metabolic changes during development, and suggested a source-sink relation between the central and specialized

  18. KeyPathwayMinerWeb

    DEFF Research Database (Denmark)

    List, Markus; Alcaraz, Nicolas; Dissing-Hansen, Martin

    2016-01-01

    , for instance), KeyPathwayMiner extracts connected sub-networks containing a high number of active or differentially regulated genes (proteins, metabolites) in the molecular profiles. The web interface at (http://keypathwayminer.compbio.sdu.dk) implements all core functionalities of the KeyPathwayMiner tool set......We present KeyPathwayMinerWeb, the first online platform for de novo pathway enrichment analysis directly in the browser. Given a biological interaction network (e.g. protein-protein interactions) and a series of molecular profiles derived from one or multiple OMICS studies (gene expression...... such as data integration, input of background knowledge, batch runs for parameter optimization and visualization of extracted pathways. In addition to an intuitive web interface, we also implemented a RESTful API that now enables other online developers to integrate network enrichment as a web service...

  19. Certification Criteria for Linked Learning Pathways

    Science.gov (United States)

    ConnectEd: The California Center for College and Career, 2010

    2010-01-01

    Pathways offer a promising strategy for transforming high schools and improving student outcomes. However, to achieve these desired results, pathways must be of high quality. To guide sites in planning and implementing such pathways, a design team of experts developed the criteria outlined in this document. Sites can choose to go through a…

  20. A3 adenosine receptor agonist prevents the development of paclitaxel-induced neuropathic pain by modulating spinal glial-restricted redox-dependent signaling pathways.

    Science.gov (United States)

    Janes, Kali; Esposito, Emanuela; Doyle, Timothy; Cuzzocrea, Salvatore; Tosh, Dillip K; Jacobson, Kenneth A; Salvemini, Daniela

    2014-12-01

    Chemotherapy-induced peripheral neuropathy accompanied by chronic neuropathic pain is the major dose-limiting toxicity of several anticancer agents including the taxane paclitaxel (Taxol). A critical mechanism underlying paclitaxel-induced neuropathic pain is the increased production of peroxynitrite in spinal cord generated in response to activation of the superoxide-generating enzyme, NADPH oxidase. Peroxynitrite in turn contributes to the development of neuropathic pain by modulating several redox-dependent events in spinal cord. We recently reported that activation of the Gi/Gq-coupled A3 adenosine receptor (A3AR) with selective A3AR agonists (ie, IB-MECA) blocked the development of chemotherapy induced-neuropathic pain evoked by distinct agents, including paclitaxel, without interfering with anticancer effects. The mechanism or mechanisms of action underlying these beneficial effects has yet to be explored. We now demonstrate that IB-MECA attenuates the development of paclitaxel-induced neuropathic pain by inhibiting the activation of spinal NADPH oxidase and two downstream redox-dependent systems. The first relies on inhibition of the redox-sensitive transcription factor (NFκB) and mitogen activated protein kinases (ERK and p38) resulting in decreased production of neuroexcitatory/proinflammatory cytokines (TNF-α, IL-1β) and increased formation of the neuroprotective/anti-inflammatory IL-10. The second involves inhibition of redox-mediated posttranslational tyrosine nitration and modification (inactivation) of glia-restricted proteins known to play key roles in regulating synaptic glutamate homeostasis: the glutamate transporter GLT-1 and glutamine synthetase. Our results unravel a mechanistic link into biomolecular signaling pathways employed by A3AR activation in neuropathic pain while providing the foundation to consider use of A3AR agonists as therapeutic agents in patients with chemotherapy-induced peripheral neuropathy. Copyright © 2014

  1. Pathway Distiller - multisource biological pathway consolidation.

    Science.gov (United States)

    Doderer, Mark S; Anguiano, Zachry; Suresh, Uthra; Dashnamoorthy, Ravi; Bishop, Alexander J R; Chen, Yidong

    2012-01-01

    One method to understand and evaluate an experiment that produces a large set of genes, such as a gene expression microarray analysis, is to identify overrepresentation or enrichment for biological pathways. Because pathways are able to functionally describe the set of genes, much effort has been made to collect curated biological pathways into publicly accessible databases. When combining disparate databases, highly related or redundant pathways exist, making their consolidation into pathway concepts essential. This will facilitate unbiased, comprehensive yet streamlined analysis of experiments that result in large gene sets. After gene set enrichment finds representative pathways for large gene sets, pathways are consolidated into representative pathway concepts. Three complementary, but different methods of pathway consolidation are explored. Enrichment Consolidation combines the set of the pathways enriched for the signature gene list through iterative combining of enriched pathways with other pathways with similar signature gene sets; Weighted Consolidation utilizes a Protein-Protein Interaction network based gene-weighting approach that finds clusters of both enriched and non-enriched pathways limited to the experiments' resultant gene list; and finally the de novo Consolidation method uses several measurements of pathway similarity, that finds static pathway clusters independent of any given experiment. We demonstrate that the three consolidation methods provide unified yet different functional insights of a resultant gene set derived from a genome-wide profiling experiment. Results from the methods are presented, demonstrating their applications in biological studies and comparing with a pathway web-based framework that also combines several pathway databases. Additionally a web-based consolidation framework that encompasses all three methods discussed in this paper, Pathway Distiller (http://cbbiweb.uthscsa.edu/PathwayDistiller), is established to allow

  2. Development of integrated care pathways: toward a care management system to meet the needs of frail and disabled community-dwelling older people

    Directory of Open Access Journals (Sweden)

    Nicole Dubuc

    2013-05-01

    Full Text Available Introduction: The home care and services provided to older adults with the same needs are often inadequate and highly varied. Integrated care pathways (ICPs can resolve these issues. The aim of this study was to develop the content of ICPs to follow up frail and disabled community-dwelling older people. Theory and method: A rigorous process was applied according to a series of steps: identification of desirable characteristics and a theoretical framework; review of evidence-based practices and current practices; and determination of ICPs by an interdisciplinary task team. Results: ICPs are intended to prevent specific problems, maximize independence, and promote successful aging. They are organized according to a dynamic process: (1 needs assessment and assessment of risk/protection factors; (2 data-collection summary and goals identification; (3 planning of interventions from a client-centered view; (4 coordination, delivery, and follow-up; and (5 identification of variances, as well as review and adjustment of plans. Conclusion: Once computerized, these ICPs will facilitate the exchange of information as well as the clinical decision-making process with a perspective to adequately matching the needs of an individual person with resources that delay or slow the progression of frailty and disability. Once aggregated, the data will also support managers in organizing teamwork and follow-up for clients.

  3. Development of integrated care pathways: toward a care management system to meet the needs of frail and disabled community-dwelling older people

    Directory of Open Access Journals (Sweden)

    Nicole Dubuc

    2013-05-01

    Full Text Available Introduction: The home care and services provided to older adults with the same needs are often inadequate and highly varied. Integrated care pathways (ICPs can resolve these issues. The aim of this study was to develop the content of ICPs to follow up frail and disabled community-dwelling older people.Theory and method: A rigorous process was applied according to a series of steps: identification of desirable characteristics and a theoretical framework; review of evidence-based practices and current practices; and determination of ICPs by an interdisciplinary task team.Results: ICPs are intended to prevent specific problems, maximize independence, and promote successful aging. They are organized according to a dynamic process: (1 needs assessment and assessment of risk/protection factors; (2 data-collection summary and goals identification; (3 planning of interventions from a client-centered view; (4 coordination, delivery, and follow-up; and (5 identification of variances, as well as review and adjustment of plans.Conclusion: Once computerized, these ICPs will facilitate the exchange of information as well as the clinical decision-making process with a perspective to adequately matching the needs of an individual person with resources that delay or slow the progression of frailty and disability. Once aggregated, the data will also support managers in organizing teamwork and follow-up for clients.

  4. The zinc transporter SLC39A13/ZIP13 is required for connective tissue development; its involvement in BMP/TGF-beta signaling pathways.

    Directory of Open Access Journals (Sweden)

    Toshiyuki Fukada

    Full Text Available BACKGROUND: Zinc (Zn is an essential trace element and it is abundant in connective tissues, however biological roles of Zn and its transporters in those tissues and cells remain unknown. METHODOLOGY/PRINCIPAL FINDINGS: Here we report that mice deficient in Zn transporter Slc39a13/Zip13 show changes in bone, teeth and connective tissue reminiscent of the clinical spectrum of human Ehlers-Danlos syndrome (EDS. The Slc39a13 knockout (Slc39a13-KO mice show defects in the maturation of osteoblasts, chondrocytes, odontoblasts, and fibroblasts. In the corresponding tissues and cells, impairment in bone morphogenic protein (BMP and TGF-beta signaling were observed. Homozygosity for a SLC39A13 loss of function mutation was detected in sibs affected by a unique variant of EDS that recapitulates the phenotype observed in Slc39a13-KO mice. CONCLUSIONS/SIGNIFICANCE: Hence, our results reveal a crucial role of SLC39A13/ZIP13 in connective tissue development at least in part due to its involvement in the BMP/TGF-beta signaling pathways. The Slc39a13-KO mouse represents a novel animal model linking zinc metabolism, BMP/TGF-beta signaling and connective tissue dysfunction.

  5. Application of benchmark dose modeling to protein expression data in the development and analysis of mode of action/adverse outcome pathways for testicular toxicity.

    Science.gov (United States)

    Chepelev, Nikolai L; Meek, M E Bette; Yauk, Carole Lyn

    2014-11-01

    Reliable quantification of gene and protein expression has potential to contribute significantly to the characterization of hypothesized modes of action (MOA) or adverse outcome pathways for critical effects of toxicants. Quantitative analysis of gene expression by benchmark dose (BMD) modeling has been facilitated by the development of effective software tools. In contrast, protein expression is still generally quantified by a less robust effect level (no or lowest [adverse] effect levels) approach, which minimizes its potential utility in the consideration of dose-response and temporal concordance for key events in hypothesized MOAs. BMD modeling is applied here to toxicological data on testicular toxicity to investigate its potential utility in analyzing protein expression relevant to the proposed MOA to inform human health risk assessment. The results illustrate how the BMD analysis of protein expression in animal tissues in response to toxicant exposure: (1) complements other toxicity data, and (2) contributes to consideration of the empirical concordance of dose-response relationships, as part of the weight of evidence for hypothesized MOAs to facilitate consideration and application in regulatory risk assessment. Lack of BMD analysis in proteomics has likely limited its use for these purposes. This paper illustrates the added value of BMD modeling to support and strengthen hypothetical MOAs as a basis to facilitate the translation and uptake of the results of proteomic research into risk assessment. Copyright © 2014 Her Majesty the Queen in Right of Canada. Journal of Applied Toxicology © 2014 John Wiley & Sons, Ltd.

  6. Mainstreaming Low-Carbon Climate-Resilient growth pathways into investment decision-making - lessons from development financial institutions on approaches and tools

    International Nuclear Information System (INIS)

    Cochran, Ian; Eschalier, Claire; Deheza, Mariana

    2015-01-01

    The integration or 'mainstreaming' of the transition to a low-carbon climate-resilient future as a prism through which to make financial decisions poses a broad number of operational challenges. This background paper for the March 31 event is drawn from the report currently underway by CDC Climat Research supported by the Group Agence Francaise de Developpement and the Group Caisse des depots entitled 'Mainstreaming Low-Carbon Climate-Resilient Growth Pathways into International Finance Institutions' Activities: Identifying standards and tools and a typology for integration into operational decision-making'. Drawing from existing studies of current practice among mainly public development finance institutions (DFIs), this paper presents three families of tools and metrics used by DFIs to integrate climate change into investment decision-making. It presents a number of examples of how institutions have mainstreamed these issues into upstream strategic and downstream assessment processes. This paper also identifies the further challenge of moving from a system of tools and indicators that focus principally on climate finance tracking - important to foster trust and progress on international cooperation - to a means of aligning activities across financial institutions and the entire economy with the transition to a low-carbon climate-resilient economic model necessary to achieve the 2 deg. C commitment. (authors)

  7. Predictors and pathways of language and motor development in four prospective cohorts of young children in Ghana, Malawi, and Burkina Faso.

    Science.gov (United States)

    Prado, Elizabeth L; Abbeddou, Souheila; Adu-Afarwuah, Seth; Arimond, Mary; Ashorn, Per; Ashorn, Ulla; Bendabenda, Jaden; Brown, Kenneth H; Hess, Sonja Y; Kortekangas, Emma; Lartey, Anna; Maleta, Kenneth; Oaks, Brietta M; Ocansey, Eugenia; Okronipa, Harriet; Ouédraogo, Jean Bosco; Pulakka, Anna; Somé, Jérôme W; Stewart, Christine P; Stewart, Robert C; Vosti, Stephen A; Yakes Jimenez, Elizabeth; Dewey, Kathryn G

    2017-11-01

    Previous reviews have identified 44 risk factors for poor early child development (ECD) in low- and middle-income countries. Further understanding of their relative influence and pathways is needed to inform the design of interventions targeting ECD. We conducted path analyses of factors associated with 18-month language and motor development in four prospective cohorts of children who participated in trials conducted as part of the International Lipid-Based Nutrient Supplements (iLiNS) Project in Ghana (n = 1,023), Malawi (n = 675 and 1,385), and Burkina Faso (n = 1,122). In two cohorts, women were enrolled during pregnancy. In two cohorts, infants were enrolled at 6 or 9 months. In multiple linear regression and structural equation models (SEM), we examined 22 out of 44 factors identified in previous reviews, plus 12 additional factors expected to be associated with ECD. Out of 42 indicators of the 34 factors examined, 6 were associated with 18-month language and/or motor development in 3 or 4 cohorts: child linear and ponderal growth, variety of play materials, activities with caregivers, dietary diversity, and child hemoglobin/iron status. Factors that were not associated with child development were indicators of maternal Hb/iron status, maternal illness and inflammation during pregnancy, maternal perceived stress and depression, exclusive breastfeeding during 6 months postpartum, and child diarrhea, fever, malaria, and acute respiratory infections. Associations between socioeconomic status and language development were consistently mediated to a greater extent by caregiving practices than by maternal or child biomedical conditions, while this pattern for motor development was not consistent across cohorts. Key elements of interventions to ensure quality ECD are likely to be promotion of caregiver activities with children, a variety of play materials, and a diverse diet, and prevention of faltering in linear and ponderal growth and improvement in child

  8. The TRPM1 Channel Is Required for Development of the Rod ON Bipolar Cell-AII Amacrine Cell Pathway in the Retinal Circuit.

    Science.gov (United States)

    Kozuka, Takashi; Chaya, Taro; Tamalu, Fuminobu; Shimada, Mariko; Fujimaki-Aoba, Kayo; Kuwahara, Ryusuke; Watanabe, Shu-Ichi; Furukawa, Takahisa

    2017-10-11

    Neurotransmission plays an essential role in neural circuit formation in the central nervous system (CNS). Although neurotransmission has been recently clarified as a key modulator of retinal circuit development, the roles of individual synaptic transmissions are not yet fully understood. In the current study, we investigated the role of neurotransmission from photoreceptor cells to ON bipolar cells in development using mutant mouse lines of both sexes in which this transmission is abrogated. We found that deletion of the ON bipolar cation channel TRPM1 results in the abnormal contraction of rod bipolar terminals and a decreased number of their synaptic connections with amacrine cells. In contrast, these histological alterations were not caused by a disruption of total glutamate transmission due to loss of the ON bipolar glutamate receptor mGluR6 or the photoreceptor glutamate transporter VGluT1. In addition, TRPM1 deficiency led to the reduction of total dendritic length, branch numbers, and cell body size in AII amacrine cells. Activated Goα, known to close the TRPM1 channel, interacted with TRPM1 and induced the contraction of rod bipolar terminals. Furthermore, overexpression of Channelrhodopsin-2 partially rescued rod bipolar cell development in the TRPM1 -/- retina, whereas the rescue effect by a constitutively closed form of TRPM1 was lower than that by the native form. Our results suggest that TRPM1 channel opening is essential for rod bipolar pathway establishment in development. SIGNIFICANCE STATEMENT Neurotransmission has been recognized recently as a key modulator of retinal circuit development in the CNS. However, the roles of individual synaptic transmissions are not yet fully understood. In the current study, we focused on neurotransmission between rod photoreceptor cells and rod bipolar cells in the retina. We used genetically modified mouse models which abrogate each step of neurotransmission: presynaptic glutamate release, postsynaptic glutamate

  9. Telemedicine utilization to support the management of the burns treatment involving patient pathways in both developed and developing countries: a case study.

    Science.gov (United States)

    Syed-Abdul, Shabbir; Scholl, Jeremiah; Chen, Chiehfeng Cliff; Santos, Martinho D P S; Jian, Wen-Shan; Liou, Der-Ming; Li, Yu-Chuan

    2012-01-01

    This case study reports on the utilization of telemedicine to support the management of the burns treatment in the islands of Sao Tome and Principe by Taipei Medical University-affiliated hospital in Taiwan. The authors share experiences about usage of telemedicine to support treatment of the burn victims in a low-income country that receive reconstructive surgery in a developed country. Throughout the entire care process, telemedicine has been used not only to provide an expert advice from distance but also to help establish and maintain the doctor-patient relationship, to keep patients in contact with their families, and to help educate and consult the medical personal physically present in Sao Tome and Principe. This case study presents the details of how this process has been conducted to date, on what were learned from this process, and on issues that should be considered to improve this process in the future. The authors plan to create instructional videos and post them on YouTube to aid clinical workers providing similar treatment during the acute care and rehabilitation process and also to support eLearning in many situations where it otherwise is not possible to use videoconferencing to establish real-time contact between doctors at the local site and remote specialists.

  10. Thyroid hormone-dependent development of early cortical networks: Temporal specificity and the contribution of trkB and mTOR pathways

    Directory of Open Access Journals (Sweden)

    Sören eWesterholz

    2013-08-01

    Full Text Available Early in neocortical network development, triiodothyronine (T3 promotes GABAergic neurons’ population increase, their somatic growth and the formation of GABAergic synapses. In the presence of T3, GABAergic interneurons form longer axons and conspicuous axonal arborizations, with an increased number of putative synaptic boutons. Here we show that the increased GABAergic axonal growth is positively correlated with the proximity to non-GABAergic neurons. A differential innervation emerges from a T3-dependent decrease of axonal length in fields with low density of neuronal cell bodies, combined with an increased bouton formation in fields with high density of neuronal somata. T3 addition to deprived networks after the first two weeks of development did not rescue deficits in the GABAergic synaptic bouton distribution, or in the frequency and duration of spontaneous bursts. During the critical two-week-period, GABAergic signaling is depolarizing as revealed by calcium imaging experiments. Interestingly, T3 enhanced the expression of the potassium-chloride cotransporter 2 (KCC2, and accelerated the developmental shift from depolarizing to hyperpolarizing GABAergic signaling in non-GABAergic neurons.The T3-related increase of spontaneous network activity was remarkably reduced after blockade of either tropomyosin-receptor kinase B (trkB or mammalian target of rapamycin (mTOR pathways. T3-dependent increase in GABAergic neurons’ soma size was mediated mainly by mTOR signaling. Conversely, the T3-dependent selective increase of GABAergic boutons near non-GABAergic cell bodies is mediated by trkB signaling only. Both trkB and mTOR signaling mediate T3-dependent reduction of the GABAergic axon extension. The circuitry context is relevant for the interaction between T3 and trkB signaling, but not for the interactions between T3 and mTOR signaling.

  11. Murine dishevelled 3 functions in redundant pathways with dishevelled 1 and 2 in normal cardiac outflow tract, cochlea, and neural tube development.

    OpenAIRE

    S Leah Etheridge; Saugata Ray; Shuangding Li; Natasha S Hamblet; Nardos Lijam; Michael Tsang; Michael Tsang; Joy Greer; Natalie Kardos; Jianbo Wang; Daniel J Sussman; Ping Chen; Anthony Wynshaw-Boris

    2008-01-01

    Dishevelled (Dvl) proteins are important signaling components of both the canonical beta-catenin/Wnt pathway, which controls cell proliferation and patterning, and the planar cell polarity (PCP) pathway, which coordinates cell polarity within a sheet of cells and also directs convergent extension cell (CE) movements that produce narrowing and elongation of the tissue. Three mammalian Dvl genes have been identified and the developmental roles of Dvl1 and Dvl2 were previously determined. Here, ...

  12. Protein design for pathway engineering.

    Science.gov (United States)

    Eriksen, Dawn T; Lian, Jiazhang; Zhao, Huimin

    2014-02-01

    Design and construction of biochemical pathways has increased the complexity of biosynthetically-produced compounds when compared to single enzyme biocatalysis. However, the coordination of multiple enzymes can introduce a complicated set of obstacles to overcome in order to achieve a high titer and yield of the desired compound. Metabolic engineering has made great strides in developing tools to optimize the flux through a target pathway, but the inherent characteristics of a particular enzyme within the pathway can still limit the productivity. Thus, judicious protein design is critical for metabolic and pathway engineering. This review will describe various strategies and examples of applying protein design to pathway engineering to optimize the flux through the pathway. The proteins can be engineered for altered substrate specificity/selectivity, increased catalytic activity, reduced mass transfer limitations through specific protein localization, and reduced substrate/product inhibition. Protein engineering can also be expanded to design biosensors to enable high through-put screening and to customize cell signaling networks. These strategies have successfully engineered pathways for significantly increased productivity of the desired product or in the production of novel compounds. Copyright © 2013 Elsevier Inc. All rights reserved.

  13. BF*F allotype of the alternative pathway of complement: A marker of protection against the development of antiphospholipid antibodies in patients with systemic lupus erythematosus.

    Science.gov (United States)

    Picceli, V F; Skare, T L; Nisihara, R M; Nass, F R; Messias-Reason, I T; Utiyama, S R R

    2016-04-01

    B factor (BF) from the alternative complement pathway seems to participate in the pathophysiology of systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). To study the allotypic variability of BF in SLE and their associations with clinical and autoantibodies profile. BF allotypes were determined by high-voltage agarose gel electrophoresis, under constant cooling, followed by immunofixation with anti-human BF antibody, in 188 SLE patients and 103 controls. Clinical and serological data were obtained from medical examination and records. No significant differences of BF variants between patients and controls were found, neither in relation to epidemiologic or clinical manifestations. Associations of phenotype BF SS07 and allotype BF*S07 were found with anticardiolipin IgM (aCl-IgM) antibodies (p = 0.014 and p = 0.009 respectively), but not with aCl-IgG, lupus anticoagulant (LA), anti β2GPI or clinical APS. A significant decrease in BF*F allotype (p = 0.043) and BF SF phenotype (p = 0.018) was detected in patients with anti-phospholipid antibodies as a whole (aCl-IgG, aCl-IgM, LA and anti β2GPI). There is a link between phenotype BF SS07 and allotype BF*S07 with aCl-IgM in SLE patients; BF*F allotype could be considered a marker of protection against the development of antiphospholipid antibodies in these patients. © The Author(s) 2015.

  14. Integration of the tricarboxylic acid (TCA cycle with cAMP signaling and Sfl2 pathways in the regulation of CO2 sensing and hyphal development in Candida albicans.

    Directory of Open Access Journals (Sweden)

    Li Tao

    2017-08-01

    Full Text Available Morphological transitions and metabolic regulation are critical for the human fungal pathogen Candida albicans to adapt to the changing host environment. In this study, we generated a library of central metabolic pathway mutants in the tricarboxylic acid (TCA cycle, and investigated the functional consequences of these gene deletions on C. albicans biology. Inactivation of the TCA cycle impairs the ability of C. albicans to utilize non-fermentable carbon sources and dramatically attenuates cell growth rates under several culture conditions. By integrating the Ras1-cAMP signaling pathway and the heat shock factor-type transcription regulator Sfl2, we found that the TCA cycle plays fundamental roles in the regulation of CO2 sensing and hyphal development. The TCA cycle and cAMP signaling pathways coordinately regulate hyphal growth through the molecular linkers ATP and CO2. Inactivation of the TCA cycle leads to lowered intracellular ATP and cAMP levels and thus affects the activation of the Ras1-regulated cAMP signaling pathway. In turn, the Ras1-cAMP signaling pathway controls the TCA cycle through both Efg1- and Sfl2-mediated transcriptional regulation in response to elevated CO2 levels. The protein kinase A (PKA catalytic subunit Tpk1, but not Tpk2, may play a major role in this regulation. Sfl2 specifically binds to several TCA cycle and hypha-associated genes under high CO2 conditions. Global transcriptional profiling experiments indicate that Sfl2 is indeed required for the gene expression changes occurring in response to these elevated CO2 levels. Our study reveals the regulatory role of the TCA cycle in CO2 sensing and hyphal development and establishes a novel link between the TCA cycle and Ras1-cAMP signaling pathways.

  15. Integration of the tricarboxylic acid (TCA) cycle with cAMP signaling and Sfl2 pathways in the regulation of CO2 sensing and hyphal development in Candida albicans.

    Science.gov (United States)

    Tao, Li; Zhang, Yulong; Fan, Shuru; Nobile, Clarissa J; Guan, Guobo; Huang, Guanghua

    2017-08-01

    Morphological transitions and metabolic regulation are critical for the human fungal pathogen Candida albicans to adapt to the changing host environment. In this study, we generated a library of central metabolic pathway mutants in the tricarboxylic acid (TCA) cycle, and investigated the functional consequences of these gene deletions on C. albicans biology. Inactivation of the TCA cycle impairs the ability of C. albicans to utilize non-fermentable carbon sources and dramatically attenuates cell growth rates under several culture conditions. By integrating the Ras1-cAMP signaling pathway and the heat shock factor-type transcription regulator Sfl2, we found that the TCA cycle plays fundamental roles in the regulation of CO2 sensing and hyphal development. The TCA cycle and cAMP signaling pathways coordinately regulate hyphal growth through the molecular linkers ATP and CO2. Inactivation of the TCA cycle leads to lowered intracellular ATP and cAMP levels and thus affects the activation of the Ras1-regulated cAMP signaling pathway. In turn, the Ras1-cAMP signaling pathway controls the TCA cycle through both Efg1- and Sfl2-mediated transcriptional regulation in response to elevated CO2 levels. The protein kinase A (PKA) catalytic subunit Tpk1, but not Tpk2, may play a major role in this regulation. Sfl2 specifically binds to several TCA cycle and hypha-associated genes under high CO2 conditions. Global transcriptional profiling experiments indicate that Sfl2 is indeed required for the gene expression changes occurring in response to these elevated CO2 levels. Our study reveals the regulatory role of the TCA cycle in CO2 sensing and hyphal development and establishes a novel link between the TCA cycle and Ras1-cAMP signaling pathways.

  16. Pathway Design, Engineering, and Optimization.

    Science.gov (United States)

    Garcia-Ruiz, Eva; HamediRad, Mohammad; Zhao, Huimin

    The microbial metabolic versatility found in nature has inspired scientists to create microorganisms capable of producing value-added compounds. Many endeavors have been made to transfer and/or combine pathways, existing or even engineered enzymes with new function to tractable microorganisms to generate new metabolic routes for drug, biofuel, and specialty chemical production. However, the success of these pathways can be impeded by different complications from an inherent failure of the pathway to cell perturbations. Pursuing ways to overcome these shortcomings, a wide variety of strategies have been developed. This chapter will review the computational algorithms and experimental tools used to design efficient metabolic routes, and construct and optimize biochemical pathways to produce chemicals of high interest.

  17. The development, implementation and evaluation of clinical pathways for chronic obstructive pulmonary disease (COPD) in Saskatchewan: protocol for an interrupted times series evaluation.

    Science.gov (United States)

    Rotter, Thomas; Plishka, Christopher; Hansia, Mohammed Rashaad; Goodridge, Donna; Penz, Erika; Kinsman, Leigh; Lawal, Adegboyega; O'Quinn, Sheryl; Buchan, Nancy; Comfort, Patricia; Patel, Prakesh; Anderson, Sheila; Winkel, Tanya; Lang, Rae Lynn; Marciniuk, Darcy D

    2017-11-28

    Chronic obstructive pulmonary disease (COPD) has substantial economic and human costs; it is expected to be the third leading cause of death worldwide by 2030. To minimize these costs high quality guidelines have been developed. However, guidelines alone rarely result in meaningful change. One method of integrating guidelines into practice is the use of clinical pathways (CPWs). CPWs bring available evidence to a range of healthcare professionals by detailing the essential steps in care and adapting guidelines to the local context. We are working with local stakeholders to develop CPWs for COPD with the aims of improving care while reducing utilization. The CPWs will employ several steps including: standardizing diagnostic training, unifying components of chronic disease care, coordinating education and reconditioning programs, and ensuring care uses best practices. Further, we have worked to identify evidence-informed implementation strategies which will be tailored to the local context. We will conduct a three-year research project using an interrupted time series (ITS) design in the form of a multiple baseline approach with control groups. The CPW will be implemented in two health regions (experimental groups) and two health regions will act as controls (control groups). The experimental and control groups will each contain an urban and rural health region. Primary outcomes for the study will be quality of care operationalized using hospital readmission rates and emergency department (ED) presentation rates. Secondary outcomes will be healthcare utilization and guideline adherence, operationalized using hospital admission rates, hospital length of stay and general practitioner (GP) visits. Results will be analyzed using segmented regression analysis. Funding has been procured from multiple stakeholders. The project has been deemed exempt from ethics review as it is a quality improvement project. Intervention implementation is expected to begin in summer of 2017

  18. Role of the Varroa mite in honeybee (Apis mellifera) colony loss: A case study for adverse outcome pathway development with a nonchemical stressor

    Science.gov (United States)

    Significant honeybee colony losses have been reported across North America and Europe in recent years. A number of factors, both chemical and nonchemical, have been associated with such losses. Adverse outcome pathways (AOPs) provide a conceptual framework to describe and evalu...

  19. Adapting biomarker technologies to adverse outcome pathways (AOPs) research: current thoughts on using in vivo discovery for developing in vitro target methods

    Science.gov (United States)

    Adverse outcome pathways (AOP) research is a relatively new concept in human systems biology for assessing the molecular level linkage from an initiating (chemical) event that could lead to a disease state. Although most implementations of AOPs are based on liquids analyses, the...

  20. Development and application of the adverse outcome pathway framework for understanding and predicting chronic toxicity: II. A focus on growth impairment in fish

    NARCIS (Netherlands)

    Groh, K.J.; Carvalho, R.N.; Chipman, J.K.; Denslow, N.D.; Halder, M.; Murphy, C.A.; Roelofs, D.; Rolaki, A.; Schirmer, K.; Watanabe, K.H.

    2015-01-01

    Adverse outcome pathways (AOPs) organize knowledge on the progression of toxicity through levels of biological organization. By determining the linkages between toxicity events at different levels, AOPs lay the foundation for mechanism-based alternative testing approaches to hazard assessment. Here,

  1. Development of inhibitors of the 2C-methyl-D-erythritol 4-phosphate (MEP) pathway enzymes as potential anti-infective agents

    NARCIS (Netherlands)

    Masini, Tiziana; Hirsch, Anna K H

    2014-01-01

    Important pathogens such as Mycobacterium tuberculosis and Plasmodium falciparum, the causative agents of tuberculosis and malaria, respectively, and plants, utilize the 2C-methyl-D-erythritol 4-phosphate (MEP, 5) pathway for the biosynthesis of isopentenyl diphosphate (1) and dimethylallyl

  2. Mapping Nursing Pathways

    Directory of Open Access Journals (Sweden)

    Melanie Birks

    2015-09-01

    Full Text Available Articulated education pathways between the vocational education training sector and universities provide opportunities for students wishing to progress to higher qualifications. Enrolled nurses seeking to advance their career in nursing can choose to enter baccalaureate degree programs through such alternative entry routes. Awarding of credit for prior studies is dependent on accurate assessment of the existing qualification against that which is sought. This study employed a modified Delphi method to inform the development of an evidence-based, structured approach to mapping the pathway from the nationally consistent training package of the Diploma of Nursing to the diversity of baccalaureate nursing programs across Australia. The findings of this study reflect the practical nature of the role of the enrolled nurse, particularly the greater emphasis placed on direct care activities as opposed to those related to professional development and the generation and use of evidence. These findings provide a valuable summative overview of the relationship between the Diploma of Nursing and the expectations of the registered nurse role.

  3. Epigenetic regulation of the Hedgehog and Wnt pathways in cancer

    NARCIS (Netherlands)

    Wils, Leon J.; Bijlsma, Maarten F.

    2018-01-01

    The Hedgehog (Hh) and wingless-Int1 (Wnt) pathways are important for tissue patterning in the developing embryo. In adult tissue, both pathways are typically dormant but are activated under certain conditions such as tissue damage. Aberrant activation of these pathways by mutations in key pathway

  4. Survival pathways under stress

    Indian Academy of Sciences (India)

    First page Back Continue Last page Graphics. Survival pathways under stress. Bacteria survive by changing gene expression. pattern. Three important pathways will be discussed: Stringent response. Quorum sensing. Proteins performing function to control oxidative damage.

  5. New Pathways for Alimentary Mucositis

    Directory of Open Access Journals (Sweden)

    Joanne M. Bowen

    2008-01-01

    Full Text Available Alimentary mucositis is a major dose-limiting toxicity associated with anticancer treatment. It is responsible for reducing patient quality of life and represents a significant economic burden in oncology. The pathobiology of alimentary mucositis is extremely complex, and an increased understanding of mechanisms and pathway interactions is required to rationally design improved therapies. This review describes the latest advances in defining mechanisms of alimentary mucositis pathobiology in the context of pathway activation. It focuses particularly on the recent genome-wide analyses of regimen-related mucosal injury and the identification of specific regulatory pathways implicated in mucositis development. This review also discusses the currently known alimentary mucositis risk factors and the development of novel treatments. Suggestions for future research directions have been raised.

  6. Developing Breast Cancer Program at Xavier; Genomic and Proteomic Analysis of Signaling Pathways Involved in Xenohormone and MEK5 Regulation of Breast Cancer

    Science.gov (United States)

    2010-05-01

    Tagatose are rare. In this study we have determined the effect of these rare ketohexoses on breast cancer cell proliferation and estrogen signalling...Cancer Center (TCC) will build a core of human talent that will address scientific problems such as drug resistance and the effect of environmental agents...pathways for ER(+) (MCF-7) and ER(-) (MCF-7-MEK5) as potentially more effective therapeutic targets. 11 Abstract of RCMI proposal submitted to

  7. Pathways Intern Report

    Science.gov (United States)

    Huggett, Daniel James

    2017-01-01

    The National Aeronautics and Space Administration (NASA) provides a formal training program for prospective employees titled, Pathways Intern Employment. The Pathways program targets graduate and undergraduate students who strive to become an active contributor to NASA's goal of space exploration. The report herein provides an account of Daniel Huggett's Pathways experience for the Spring and Summer 2017 semesters.

  8. Neurophysiology and itch pathways.

    Science.gov (United States)

    Schmelz, Martin

    2015-01-01

    As we all can easily differentiate the sensations of itch and pain, the most straightforward neurophysiologic concept would consist of two specific pathways that independently encode itch and pain. Indeed, a neuronal pathway for histamine-induced itch in the peripheral and central nervous system has been described in animals and humans, and recently several non-histaminergic pathways for itch have been discovered in rodents that support a dichotomous concept differentiated into a pain and an itch pathway, with both pathways being composed of different "flavors." Numerous markers and mediators have been found that are linked to itch processing pathways. Thus, the delineation of neuronal pathways for itch from pain pathways seemingly proves that all sensory aspects of itch are based on an itch-specific neuronal pathway. However, such a concept is incomplete as itch can also be induced by the activation of the pain pathway in particular when the stimulus is applied in a highly localized spatial pattern. These opposite views reflect the old dispute between specificity and pattern theories of itch. Rather than only being of theoretic interest, this conceptual problem has key implication for the strategy to treat chronic itch as key therapeutic targets would be either itch-specific pathways or unspecific nociceptive pathways.

  9. Diverse Pathways in Children's Learning.

    Science.gov (United States)

    Lambert, Beverley

    1996-01-01

    Used a Partially Ordered Scaling of Items method to analyze block construction play in a replication of Innes and King-Shaw's 1985 study. Found several developmental pathways for block play, illustrating the web-like nature of conceptual development. Results suggest a contextual developmental approach to better acknowledge individual diversity in…

  10. Targeting the GPI biosynthetic pathway.

    Science.gov (United States)

    Yadav, Usha; Khan, Mohd Ashraf

    2018-02-27

    The GPI (Glycosylphosphatidylinositol) biosynthetic pathway is a multistep conserved pathway in eukaryotes that culminates in the generation of GPI glycolipid which in turn anchors many proteins (GPI-APs) to the cell surface. In spite of the overall conservation of the pathway, there still exist subtle differences in the GPI pathway of mammals and other eukaryotes which holds a great promise so far as the development of drugs/inhibitors against specific targets in the GPI pathway of pathogens is concerned. Many of the GPI structures and their anchored proteins in pathogenic protozoans and fungi act as pathogenicity factors. Notable examples include GPI-anchored variant surface glycoprotein (VSG) in Trypanosoma brucei, GPI-anchored merozoite surface protein 1 (MSP1) and MSP2 in Plasmodium falciparum, protein-free GPI related molecules like lipophosphoglycans (LPGs) and glycoinositolphospholipids (GIPLs) in Leishmania spp., GPI-anchored Gal/GalNAc lectin and proteophosphoglycans in Entamoeba histolytica or the GPI-anchored mannoproteins in pathogenic fungi like Candida albicans. Research in this active area has already yielded encouraging results in Trypanosoma brucei by the development of parasite-specific inhibitors of GlcNCONH 2 -β-PI, GlcNCONH 2 -(2-O-octyl)-PI and salicylic hydroxamic acid (SHAM) targeting trypanosomal GlcNAc-PI de-N-acetylase as well as the development of antifungal inhibitors like BIQ/E1210/gepinacin/G365/G884 and YW3548/M743/M720 targeting the GPI specific fungal inositol acyltransferase (Gwt1) and the phosphoethanolamine transferase-I (Mcd4), respectively. These confirm the fact that the GPI pathway continues to be the focus of researchers, given its implications for the betterment of human life.

  11. MicroRNA-129-5p inhibits the development of autoimmune encephalomyelitis-related epilepsy by targeting HMGB1 through the TLR4/NF-kB signaling pathway.

    Science.gov (United States)

    Liu, Ai-Hua; Wu, Ya-Ting; Wang, Yu-Ping

    2017-06-01

    The study aimed to explore the effects of microRNA-129-5p (miR-129-5p) on the development of autoimmune encephalomyelitis (AE)-related epilepsy by targeting HMGB1 through the TLR4/NF-kB signaling pathway in a rat model. AE-related epilepsy models were established. Sprague-Dawley (SD) rats were randomly divided into control, model, miR-129-5p mimics, miR-129-5p inhibitor, HMGB1 shRNA, TLR4/NF-kB (TLR4/NF-kB signaling pathway was inhibited) and miR-129-5p mimics+HMGB1 shRNA groups respectively. Latency to a first epilepsy seizure attack was recorded. Neuronal injuries in the hippocampus regions were detected using HE, Nissl and FJB staining methods 24h following model establishment. Microglial cells were detected by OX-42 immunohistochemistry. Expressions of miR-129-5p, HMGB1 and TLR4/NF-kB signaling pathway-related proteins were detected by qRT-PCR. Protein expressions of HMGB1 and TLR4/NF-kB signaling pathway-related proteins were detected by Western blotting. Dual luciferase reporter gene assay showed that miR-129-5p was negatively targeting HMGB1. Neurons of hippocampal tissues in rats were heavily injured by an injection of lithium chloride. Compared with the model and control groups, neuronal injury of the hippocampus and AE-related epilepsy decreased and microglial cells increased in the miR-129-5p mimics, HMGB1 shRNA and TLR4/NF-kB groups; however, in the miR-129-5p inhibitor group, miR-129-5p expression decreased, HMGB1 expression increased, TLR4/NF-kB signaling pathway was activated, latency to a first epilepsy seizure attack was shortened, and neuronal injury increased. This study provides evidence that miR-129-5p inhibits the development of AE-related epilepsy by suppressing HMGB1 expression and inhibiting TLR4/NF-kB signaling pathway. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Developing a clinical pathway for the identification and management of anxiety and depression in adult cancer patients: an online Delphi consensus process.

    Science.gov (United States)

    Shaw, Joanne M; Price, Melanie A; Clayton, Josephine M; Grimison, Peter; Shaw, Tim; Rankin, Nicole; Butow, Phyllis N

    2016-01-01

    People with cancer and their families experience high levels of psychological morbidity. However, many cancer services do not routinely screen patients for anxiety and depression, and there are no standardized clinical referral pathways. This study aimed to establish consensus on elements of a draft clinical pathway tailored to the Australian context. A two-round Delphi study was conducted to gain consensus among Australian oncology and psycho-oncology clinicians about the validity of 39 items that form the basis of a clinical pathway that includes screening, assessment, referral and stepped care management of anxiety and depression in the context of cancer. The expert panel comprised 87 multidisciplinary clinician members of the Australian Psycho-oncology Co-operative Research Group (PoCoG). Respondents rated their level of agreement with each statement on a 5-point Likert scale. Consensus was defined as >80% of respondents scoring within 2 points on the Likert scale. Consensus was reached for 21 of 39 items, and a further 15 items approached consensus except for specific contextual factors, after two Delphi rounds. Formal screening for anxiety and depression, a stepped care model of management and recommendations for inclusion of length of treatment and time to review were endorsed. Consensus was not reached on items related to roles and responsibilities, particularly those not applicable across cancer settings. This study identified a core set of evidence- and consensus-based principles considered essential to a stepped care model of care incorporating identification, referral and management of anxiety and depression in adult cancer patients.

  13. Targeting Wnt Pathways in Disease

    Science.gov (United States)

    Zimmerman, Zachary F.; Moon, Randall T.

    2012-01-01

    Wnt-mediated signal transduction pathways have long been recognized for their roles in regulating embryonic development, and have more recently been linked to cancer, neurologic diseases, inflammatory diseases, and disorders of endocrine function and bone metabolism in adults. Although therapies targeting Wnt signaling are attractive in theory, in practice it has been difficult to obtain specific therapeutics because many components of Wnt signaling pathways are also involved in other cellular processes, thereby reducing the specificity of candidate therapeutics. New technologies, and advances in understanding the mechanisms of Wnt signaling, have improved our understanding of the nuances of Wnt signaling and are leading to promising new strategies to target Wnt signaling pathways. PMID:23001988

  14. Targeting Apoptosis Signaling Pathways for Anticancer Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Fulda, Simone, E-mail: simone.fulda@kgu.de [Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt (Germany)

    2011-08-29

    Treatment approaches for cancer, for example chemotherapy, radiotherapy, or immunotherapy, primarily act by inducing cell death in cancer cells. Consequently, the inability to trigger cell death pathways or alternatively, evasion of cancer cells to the induction of cell death pathways can result in resistance of cancers to current treatment protocols. Therefore, in order to overcome treatment resistance a better understanding of the underlying mechanisms that regulate cell death and survival pathways in cancers and in response to cancer therapy is necessary to develop molecular-targeted therapies. This strategy should lead to more effective and individualized treatment strategies that selectively target deregulated signaling pathways in a tumor type- and patient-specific manner.

  15. Targeting Apoptosis Signaling Pathways for Anticancer Therapy

    International Nuclear Information System (INIS)

    Fulda, Simone

    2011-01-01

    Treatment approaches for cancer, for example chemotherapy, radiotherapy, or immunotherapy, primarily act by inducing cell death in cancer cells. Consequently, the inability to trigger cell death pathways or alternatively, evasion of cancer cells to the induction of cell death pathways can result in resistance of cancers to current treatment protocols. Therefore, in order to overcome treatment resistance a better understanding of the underlying mechanisms that regulate cell death and survival pathways in cancers and in response to cancer therapy is necessary to develop molecular-targeted therapies. This strategy should lead to more effective and individualized treatment strategies that selectively target deregulated signaling pathways in a tumor type- and patient-specific manner.

  16. Method for determining heterologous biosynthesis pathways

    KAUST Repository

    Gao, Xin

    2017-08-10

    The present invention relates to a method and system for dynamically analyzing, determining, predicting and displaying ranked suitable heterologous biosynthesis pathways for a specified host. The present invention addresses the problem of finding suitable pathways for the endogenous metabolism of a host organism because the efficacy of heterologous biosynthesis is affected by competing endogenous pathways. The present invention is called MRE (Metabolic Route Explorer), and it was conceived and developed to systematically and dynamically search for, determine, analyze, and display promising heterologous pathways while considering competing endogenous reactions in a given host organism.

  17. Dysregulated Pathway Identification of Alzheimer's Disease Based on Internal Correlation Analysis of Genes and Pathways.

    Science.gov (United States)

    Kong, Wei; Mou, Xiaoyang; Di, Benteng; Deng, Jin; Zhong, Ruxing; Wang, Shuaiqun

    2017-11-20

    Dysregulated pathway identification is an important task which can gain insight into the underlying biological processes of disease. Current pathway-identification methods focus on a set of co-expression genes and single pathways and ignore the correlation between genes and pathways. The method proposed in this study, takes into account the internal correlations not only between genes but also pathways to identifying dysregulated pathways related to Alzheimer's disease (AD), the most common form of dementia. In order to find the significantly differential genes for AD, mutual information (MI) is used to measure interdependencies between genes other than expression valves. Then, by integrating the topology information from KEGG, the significant pathways involved in the feature genes are identified. Next, the distance correlation (DC) is applied to measure the pairwise pathway crosstalks since DC has the advantage of detecting nonlinear correlations when compared to Pearson correlation. Finally, the pathway pairs with significantly different correlations between normal and AD samples are known as dysregulated pathways. The molecular biology analysis demonstrated that many dysregulated pathways related to AD pathogenesis have been discovered successfully by the internal correlation detection. Furthermore, the insights of the dysregulated pathways in the development and deterioration of AD will help to find new effective target genes and provide important theoretical guidance for drug design. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  18. Pathway enrichment analysis approach based on topological structure and updated annotation of pathway.

    Science.gov (United States)

    Yang, Qian; Wang, Shuyuan; Dai, Enyu; Zhou, Shunheng; Liu, Dianming; Liu, Haizhou; Meng, Qianqian; Jiang, Bin; Jiang, Wei

    2017-08-16

    Pathway enrichment analysis has been widely used to identify cancer risk pathways, and contributes to elucidating the mechanism of tumorigenesis. However, most of the existing approaches use the outdated pathway information and neglect the complex gene interactions in pathway. Here, we first reviewed the existing widely used pathway enrichment analysis approaches briefly, and then, we proposed a novel topology-based pathway enrichment analysis (TPEA) method, which integrated topological properties and global upstream/downstream positions of genes in pathways. We compared TPEA with four widely used pathway enrichment analysis tools, including database for annotation, visualization and integrated discovery (DAVID), gene set enrichment analysis (GSEA), centrality-based pathway enrichment (CePa) and signaling pathway impact analysis (SPIA), through analyzing six gene expression profiles of three tumor types (colorectal cancer, thyroid cancer and endometrial cancer). As a result, we identified several well-known cancer risk pathways that could not be obtained by the existing tools, and the results of TPEA were more stable than that of the other tools in analyzing different data sets of the same cancer. Ultimately, we developed an R package to implement TPEA, which could online update KEGG pathway information and is available at the Comprehensive R Archive Network (CRAN): https://cran.r-project.org/web/packages/TPEA/. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  19. Learning from the Cardiologists and Developing Eluting Stents Targeting the Mtor Pathway for Pulmonary Application; A Future Concept for Tracheal Stenosis

    Science.gov (United States)

    Zarogoulidis, Paul; Darwiche, Kaid; Tsakiridis, Kosmas; Teschler, Helmut; Yarmus, Lonny; Zarogoulidis, Konstantinos; Freitag, Lutz

    2014-01-01

    Tracheal stenosis due to either benign or malignant disease is a situation that the pulmonary physicians and thoracic surgeons have to cope in their everyday clinical practice. In the case where tracheal stenosis is caused due to malignancy mini-interventional interventions with laser, apc, cryoprobe, balloon dilation or with combination of more than one equipment and technique can be used. On the other hand, in the case of a benign disease such as; tracheomalacia the clinician can immediately upon diagnosis proceed to the stent placement. In both situations however; it has been observed that the stents induce formation of granuloma tissue in both or one end of the stent. Therefore a frequent evaluation of the patient is necessary, taking also into account the nature of the primary disease. Evaluation methodologies identifying different types and extent of the trachea stenosis have been previously published. However; we still do not have an effective adjuvant therapy to prevent granuloma tissue formation or prolong already treated granuloma lesions. There have been proposed many mechanisms which induce the abnormal growth of the local tissue, such as; local pressure, local stress, inflammation and vascular endothelial growth factor overexpression. Immunomodulatory agents inhibiting the mTOR pathway are capable of inhibiting the inflammatory cascade locally. In the current mini-review we will try to present the current knowledge of drug eluting stents inhibiting the mTOR pathway and propose a future application of these stents as a local anti-proliferative treatment. PMID:24454525

  20. Learning from the Cardiologists and Developing Eluting Stents Targeting the Mtor Pathway for Pulmonary Application; A Future Concept for Tracheal Stenosis.

    Science.gov (United States)

    Zarogoulidis, Paul; Darwiche, Kaid; Tsakiridis, Kosmas; Teschler, Helmut; Yarmus, Lonny; Zarogoulidis, Konstantinos; Freitag, Lutz

    2013-08-26

    Tracheal stenosis due to either benign or malignant disease is a situation that the pulmonary physicians and thoracic surgeons have to cope in their everyday clinical practice. In the case where tracheal stenosis is caused due to malignancy mini-interventional interventions with laser, apc, cryoprobe, balloon dilation or with combination of more than one equipment and technique can be used. On the other hand, in the case of a benign disease such as; tracheomalacia the clinician can immediately upon diagnosis proceed to the stent placement. In both situations however; it has been observed that the stents induce formation of granuloma tissue in both or one end of the stent. Therefore a frequent evaluation of the patient is necessary, taking also into account the nature of the primary disease. Evaluation methodologies identifying different types and extent of the trachea stenosis have been previously published. However; we still do not have an effective adjuvant therapy to prevent granuloma tissue formation or prolong already treated granuloma lesions. There have been proposed many mechanisms which induce the abnormal growth of the local tissue, such as; local pressure, local stress, inflammation and vascular endothelial growth factor overexpression. Immunomodulatory agents inhibiting the mTOR pathway are capable of inhibiting the inflammatory cascade locally. In the current mini-review we will try to present the current knowledge of drug eluting stents inhibiting the mTOR pathway and propose a future application of these stents as a local anti-proliferative treatment.

  1. The photovoltaic pathway

    International Nuclear Information System (INIS)

    Jourde, P.; Guerin de Montgareuil, A.; Mattera, F.; Jaussaud, C.; Boulanger, P.; Veriat, G.; Firon, M.

    2004-01-01

    Photovoltaic conversion, the direct transformation of light into electricity, is, of the three pathways for solar energy, the one experiencing most rapid growth, and for which scientific and technological advances are most promising, as regards significant improvements in its economic balance. While the long-term trend, in Europe, is favorable, with annual growth set at 30%, the cost per photovoltaic kilowatt-hour remains some ten times higher than that achieved with natural gas or nuclear energy (after connection to the grid), this being a handicap, at first blush, for high power ratings. For remote locations, where its advantage is unquestionable, in spite of the added cost of storage between insolation periods (this more than compensating for savings in terms of connection costs), this pathway sets its future prospects on marked module cost reductions. Such reduction may only be achieved by way of technological breakthroughs, to which CEA, active as it has been, in this area, for some thirty years, intends making a contribution, as linchpin of French research and technology, and a key protagonist on the European scene. One of the avenues being pursued concerns fabrication of high-efficiency cells from mineral or organic thin films, with particularly strong expectations with respect to the all-polymer path, complementary of the silicon pathway. Concurrently, device reliability needs must be improved, this being another factor making for an improved overall balance. To achieve easier transfer to industry of laboratory outcomes, CEA is relying, in particular, on the new cell fabrication platform set up in Grenoble, this complementing its other R and D resources, including those installed at Cadarache, allowing testing of cells and entire photovoltaic systems in actual operating conditions. Another path for cost reductions being explored by CEA research workers consists in construction of systems integrated into the built environment: this affords new prospects

  2. Developmental Pathways in Juvenile Externalizing and Internalizing Problems

    Science.gov (United States)

    Loeber, Rolf; Burke, Jeffrey D.

    2011-01-01

    This article summarizes the empirical studies showing pathways in the development of externalizing and delinquent behaviors. Pathways are defined as the orderly temporal development between more than two problem behaviors. The paper addresses the following questions: (1) What are the developmental pathways between different diagnoses of Disruptive…

  3. Exposures from aquatic pathways

    International Nuclear Information System (INIS)

    Berkovski, V.; Voitsekhovitch, O.; Nasvit, O.; Zhelezniak, M.; Sansone, U.

    1996-01-01

    Methods for estimation aquatic pathways contribution to the total population exposure are discussed. Aquatic pathways are the major factor for radionuclides spreading from the Chernobyl Exclusion zone. An annual outflow of 90 Sr and 137 Cs comprised 10-20 TBq and 2-4 TBq respectively and the population exposed by this effluence constitutes almost 30 million people. The dynamic of doses from 90 Sr and ' C s, which Dnieper water have to delivered, is calculated. The special software has been developed to simulate the process of dose formation in the of diverse Dnieper regions. Regional peculiarities of municipal tap, fishing and irrigation are considered. Seventy-year prediction of dose structure and function of dose forming is performed. The exposure is estimated for 12 regions of the Dnieper basin and the Crimea. The maximal individual annual committed effective doses due to the use of water by ordinary members of the population in Kiev region from 90 Sr and 137 Cs in 1986 are 1.7*10 -5 Sv and 2.7*10 -5 Sv respectively. A commercial fisherman on Kiev reservoir in 1986 received 4.7*10 -4 Sv and 5*10 -3 Sv from 90 Sr and 137 Cs, respectively. The contributions to the collective cumulative (over 70 years) committed effective dose (CCCED 70 ) of irrigation, municipal tap water and fish consumption for members of the population respectively are 18%, 43%, 39% in Kiev region, 8%, 25%, 67% in Poltava region, and 50%, 50%, 0% (consumption of Dnieper fish is absent) in the Crimea. The predicted contribution of the Strontium-90 to CCCED 70 resulting from the use of water is 80%. The CCCED 70 to the population of the Dnieper regions (32.5 million people) is 3000 person-Sv due to the use the Dnieper water

  4. The oxylipin pathway in Arabidopsis.

    Science.gov (United States)

    Creelman, Robert A; Mulpuri, Rao

    2002-01-01

    Oxylipins are acyclic or cyclic oxidation products derived from the catabolism of fatty acids which regulate many defense and developmental pathways in plants. The dramatic increase in the volume of publications and reviews on these compounds since 1997 documents the increasing interest in this compound and its role in plants. Research on this topic has solidified our understanding of the chemistry and biosynthetic pathways for oxylipin production. However, more information is still needed on how free fatty acids are produced and the role of beta-oxidation in the biosynthetic pathway for oxylipins. It is also becoming apparent that oxylipin content and composition changes during growth and development and during pathogen or insect attack. Oxylipins such as jasmonic acid (JA) or 12-oxo-phytodienoic acid modulate the expression of numerous genes and influence specific aspects of plant growth, development and responses to abiotic and biotic stresses. Although oxylipins are believed to act alone, several examples were presented to illustrate that JA-induced responses are modulated by the type and the nature of crosstalk with other signaling molecules such as ethylene and salicylic acid. How oxylipins cause changes in gene expression and instigate a physiological response is becoming understood with the isolation of mutations in both positive and negative regulators in the jasmonate signaling pathway and the use of cDNA microarrays.

  5. Inhibition of primary roots and stimulation of lateral root development in Arabidopsis thaliana by the rhizobacterium Serratia marcescens 90-166 is through both auxin-dependent and -independent signaling pathways.

    Science.gov (United States)

    Shi, Chun-Lin; Park, Hyo-Bee; Lee, Jong Suk; Ryu, Sangryeol; Ryu, Choong-Min

    2010-03-01

    The rhizobacterium Serratia marcescens strain 90-166 was previously reported to promote plant growth and induce resistance in Arabidopsis thaliana. In this study, the influence of strain 90-166 on root development was studied in vitro. We observed inhibition of primary root elongation, enhanced lateral root emergence, and early emergence of second order lateral roots after inoculation with strain 90-166 at a certain distance from the root. Using the DR5::GUS transgenic A. thaliana plant and an auxin transport inhibitor, N-1-naphthylphthalamic acid, the altered root development was still elicited by strain 90-166, indicating that this was not a result of changes in plant auxin levels. Intriguingly, indole-3-acetic acid, a major auxin chemical, was only identified just above the detection limit in liquid culture of strain 90-166 using liquid chromatography-mass spectrometry. Focusing on bacterial determinants of the root alterations, we found that primary root elongation was inhibited in seedlings treated with cell supernatant (secreted compounds), while lateral root formation was induced in seedlings treated with lysate supernatant (intracellular compounds). Further study revealed that the alteration of root development elicited by strain 90-166 involved the jasmonate, ethylene, and salicylic acid signaling pathways. Collectively, our results suggest that strain 90-166 can contribute to plant root development via multiple signaling pathways.

  6. Quantitative Assays for RAS Pathway Proteins and Phosphorylation States

    Science.gov (United States)

    The NCI CPTAC program is applying its expertise in quantitative proteomics to develop assays for RAS pathway proteins. Targets include key phosphopeptides that should increase our understanding of how the RAS pathway is regulated.

  7. Two-Electron Transfer Pathways.

    Science.gov (United States)

    Lin, Jiaxing; Balamurugan, D; Zhang, Peng; Skourtis, Spiros S; Beratan, David N

    2015-06-18

    The frontiers of electron-transfer chemistry demand that we develop theoretical frameworks to describe the delivery of multiple electrons, atoms, and ions in molecular systems. When electrons move over long distances through high barriers, where the probability for thermal population of oxidized or reduced bridge-localized states is very small, the electrons will tunnel from the donor (D) to acceptor (A), facilitated by bridge-mediated superexchange interactions. If the stable donor and acceptor redox states on D and A differ by two electrons, it is possible that the electrons will propagate coherently from D to A. While structure-function relations for single-electron superexchange in molecules are well established, strategies to manipulate the coherent flow of multiple electrons are largely unknown. In contrast to one-electron superexchange, two-electron superexchange involves both one- and two-electron virtual intermediate states, the number of virtual intermediates increases very rapidly with system size, and multiple classes of pathways interfere with one another. In the study described here, we developed simple superexchange models for two-electron transfer. We explored how the bridge structure and energetics influence multielectron superexchange, and we compared two-electron superexchange interactions to single-electron superexchange. Multielectron superexchange introduces interference between singly and doubly oxidized (or reduced) bridge virtual states, so that even simple linear donor-bridge-acceptor systems have pathway topologies that resemble those seen for one-electron superexchange through bridges with multiple parallel pathways. The simple model systems studied here exhibit a richness that is amenable to experimental exploration by manipulating the multiple pathways, pathway crosstalk, and changes in the number of donor and acceptor species. The features that emerge from these studies may assist in developing new strategies to deliver multiple

  8. Wood ethanol and synthetic natural gas pathways

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2006-11-30

    This report provided details of updates to the wood ethanol pathway recently added to the GHGenius model, an analytical tool used to analyze emissions from conventional and alternative fuel combustion processes. The pathway contains data developed by the United States Department of Energy. A number of co-products were added to the wood and agricultural residue pathways, including furfural, xylitol, lignin, and glycerol. New chemical inputs included nitrogen gas, ammonia, enzymes and yeast. Biological ethanol pathways were reviewed, and separate inputs for wood, agricultural residues, corn ethanol, and wheat ethanol were added. The model was updated to reflect current research conducted on the gasification of wood and the upgrading of the gas to produce pipeline quality natural gas. New process developments in producing pipeline quality gas from coal were also added. The ability to model enzyme consumption was added to all ethanol pathways. 25 refs., 41 tabs., 8 figs.

  9. Wood ethanol and synthetic natural gas pathways

    International Nuclear Information System (INIS)

    2006-01-01

    This report provided details of updates to the wood ethanol pathway recently added to the GHGenius model, an analytical tool used to analyze emissions from conventional and alternative fuel combustion processes. The pathway contains data developed by the United States Department of Energy. A number of co-products were added to the wood and agricultural residue pathways, including furfural, xylitol, lignin, and glycerol. New chemical inputs included nitrogen gas, ammonia, enzymes and yeast. Biological ethanol pathways were reviewed, and separate inputs for wood, agricultural residues, corn ethanol, and wheat ethanol were added. The model was updated to reflect current research conducted on the gasification of wood and the upgrading of the gas to produce pipeline quality natural gas. New process developments in producing pipeline quality gas from coal were also added. The ability to model enzyme consumption was added to all ethanol pathways. 25 refs., 41 tabs., 8 figs

  10. Quercetin, ascorbic acid, caffeine and ellagic acid are more efficient than rosiglitazone, metformin and glimepiride in interfering with pathways leading to the development of neurological complications associated with diabetes: A comparative in-vitro study

    Directory of Open Access Journals (Sweden)

    Vineet Mehta

    2017-06-01

    Full Text Available Neuropathy is the least understood and most devastating complication associated with diabetes. Diabetic neuropathy develops in patients despite of regular therapy, indicating that marketed drugs has minimal effect on pathways leading to the development and progression of these complications. Present study was aimed to evaluate natural compounds for their ability to interfere with pathways leading to the development of diabetes mediated neurological complications and compare their efficacy with marketed anti-diabetic drugs. Anti-diabetic potential of ascorbic acid, gallic acid, quercetin, ellagic acid, cinnamic acid, caffeine and piperine was predicted by evaluating in-silico interaction energy (kcal/mol of these compounds with insulin receptor, peroxisome proliferator-activated receptor gamma-γ and dipeptidyl peptidase-4 proteins. Ascorbic acid, gallic acid, quercetin and ellagic acid showed excellent in-vitro antioxidant activity in DPPH radical scavenging and inhibition of lipid peroxidation assay, which was 1.5–3 folds better than the marketed drugs. Quercetin, gallic acid, cinnamic acid, piperine and caffeine efficiently prevented H2O2 induced genotoxicity, which commercial drugs failed to prevent. Further, quercetin, ellagic acid, caffeine and ascorbic acid were 3–4.7 folds better than marketed drugs in inhibiting α-amylase activity. Herbal molecules and rosiglitazone showed comparable results for glucose uptake, which may be attributed to enhanced GLUT4 translocation into primary neuronal culture under hyperglycemic conditions. In conclusion, currently available marketed anti-diabetic drugs have minimal effect on the pathways leading to diabetic neuropathy and supplementing diabetic therapeutics with quercetin, ascorbic acid, caffeine and ellagic acid may be better suited to counter diabetic neuropathy through inhibiting oxidative stress, genotoxicity and improving neuronal glucose utilization.

  11. Crystallization Pathways in Biomineralization

    Science.gov (United States)

    Weiner, Steve; Addadi, Lia

    2011-08-01

    A crystallization pathway describes the movement of ions from their source to the final product. Cells are intimately involved in biological crystallization pathways. In many pathways the cells utilize a unique strategy: They temporarily concentrate ions in intracellular membrane-bound vesicles in the form of a highly disordered solid phase. This phase is then transported to the final mineralization site, where it is destabilized and crystallizes. We present four case studies, each of which demonstrates specific aspects of biological crystallization pathways: seawater uptake by foraminifera, calcite spicule formation by sea urchin larvae, goethite formation in the teeth of limpets, and guanine crystal formation in fish skin and spider cuticles. Three representative crystallization pathways are described, and aspects of the different stages of crystallization are discussed. An in-depth understanding of these complex processes can lead to new ideas for synthetic crystallization processes of interest to materials science.

  12. Maternal "junk-food" feeding of rat dams alters food choices and development of the mesolimbic reward pathway in the offspring.

    Science.gov (United States)

    Ong, Z Y; Muhlhausler, B S

    2011-07-01

    Individuals exposed to high-fat, high-sugar diets before birth have an increased risk of obesity in later life. Recent studies have shown that these offspring exhibit increased preference for fat, leading to suggestions that perinatal exposure to high-fat, high-sugar foods results in permanent changes within the central reward system that increase the subsequent drive to overconsume palatable foods. The present study has determined the effect of a maternal "junk-food" diet on the expression of key components of the mesolimbic reward pathway in the offspring of rat dams at 6 wk and 3 mo of age. We show that offspring of junk-food-fed (JF) dams exhibit higher fat intake from weaning until at least 3 mo of age (males: 16 ± 0.6 vs. 11 ± 0.8 g/kg/d; females: 19 ± 1.3 vs. 13 ± 0.4 g/kg/d; Pjunk-food intake in postnatal life.

  13. Hierarchically organized layout for visualization of biochemical pathways.

    Science.gov (United States)

    Tsay, Jyh-Jong; Wu, Bo-Liang; Jeng, Yu-Sen

    2010-01-01

    Many complex pathways are described as hierarchical structures in which a pathway is recursively partitioned into several sub-pathways, and organized hierarchically as a tree. The hierarchical structure provides a natural way to visualize the global structure of a complex pathway. However, none of the previous research on pathway visualization explores the hierarchical structures provided by many complex pathways. In this paper, we aim to develop algorithms that can take advantages of hierarchical structures, and give layouts that explore the global structures as well as local structures of pathways. We present a new hierarchically organized layout algorithm to produce layouts for hierarchically organized pathways. Our algorithm first decomposes a complex pathway into sub-pathway groups along the hierarchical organization, and then partition each sub-pathway group into basic components. It then applies conventional layout algorithms, such as hierarchical layout and force-directed layout, to compute the layout of each basic component. Finally, component layouts are joined to form a final layout of the pathway. Our main contribution is the development of algorithms for decomposing pathways and joining layouts. Experiment shows that our algorithm is able to give comprehensible visualization for pathways with hierarchies, cycles as well as complex structures. It clearly renders the global component structures as well as the local structure in each component. In addition, it runs very fast, and gives better visualization for many examples from previous related research. 2009 Elsevier B.V. All rights reserved.

  14. Migration pathways in soils

    International Nuclear Information System (INIS)

    Gronow, J.R.

    1986-01-01

    This study looked at diffusive migration through three types of deformation; the projectile pathways, hydraulic fractures of the sediments and faults, and was divided into three experimental areas: autoradiography, the determination of diffusion coefficients and electron microscopy of model projectile pathways in clay. For the autoradiography, unstressed samples were exposed to two separate isotopes, Pm-147 (a possible model for Am behaviour) and the poorly sorbed iodide-125. The results indicated that there was no enhanced migration through deformed kaolin samples nor through fractured Great Meteor East (GME) sediment, although some was evident through the projectile pathways in GME and possibly through the GME sheared samples. The scanning electron microscopy of projectile pathways in clay showed that emplacement of a projectile appeared to have no effect on the orientation of particles at distances greater than two projectile radii from the centre of a projectile pathway. It showed that the particles were not simply aligned with the direction of motion of the projectile but that, the closer to the surface of a particular pathway, the closer the particles lay to their original orientation. This finding was of interest from two points of view: i) the ease of migration of a pollutant along the pathway, and ii) possible mechanisms of hole closure. It was concluded that, provided that there is no advective migration, the transport of radionuclides through sediments containing these defects would not be significantly more rapid than in undeformed sediments. (author)

  15. Targeting the Fanconi Anemia Pathway to Identify Tailored Anticancer Therapeutics

    Directory of Open Access Journals (Sweden)

    Chelsea Jenkins

    2012-01-01

    Full Text Available The Fanconi Anemia (FA pathway consists of proteins involved in repairing DNA damage, including interstrand cross-links (ICLs. The pathway contains an upstream multiprotein core complex that mediates the monoubiquitylation of the FANCD2 and FANCI heterodimer, and a downstream pathway that converges with a larger network of proteins with roles in homologous recombination and other DNA repair pathways. Selective killing of cancer cells with an intact FA pathway but deficient in certain other DNA repair pathways is an emerging approach to tailored cancer therapy. Inhibiting the FA pathway becomes selectively lethal when certain repair genes are defective, such as the checkpoint kinase ATM. Inhibiting the FA pathway in ATM deficient cells can be achieved with small molecule inhibitors, suggesting that new cancer therapeutics could be developed by identifying FA pathway inhibitors to treat cancers that contain defects that are synthetic lethal with FA.

  16. Evaluation and development of soil values for the pathway 'soil to plant'. Significance of mercury evaporation for the burden of plants

    International Nuclear Information System (INIS)

    Gaeth, S.; Schlueter, K.

    1998-05-01

    In cooperation with the Ad-hoc working group 'Transfer of heavy metals from soil to plant' of the Laenderarbeitsgemeinschaft Bodenschutz (LABO) the significance of mercury evaporation for the deduction of threshold values in respect of the impact via the pathway soil to plant was investigated. Mercury contamination of food- and feeding stuff plants was examined with special emphasis. For these purposes a lab experiment including three different soils with varying initial mercury load (background level, geogenic and anthropogenic contamination) and two different plant species (parsely and spinach) was carried out under defined conditions in closed lysimeters. Mercury uptake via the roots was minimised since the plants grew in isolated customary substrate which showed a low concentration of mercury. Thus, only the surrounding soil evaporated mercury. The concentrations of mercury in the plants in the background level treatment (0.1 mg Hg/kg dry soil) were 0.15 mg/kg dry matter (spinach) and 0.44 mg/kg dry matter (parsely). The treatment with anthropogenic contaminated soil (111 mg Hg/kg dry soil) resulted in concentrations in the two plants of 2.0 and 2.6 mg/kg dry matter, respectively. A comparable order of magnitude was achieved in the geogenic contaminated treatment (34 mg Hg/kg dry soil) with 2.1 mg/kg dry matter. Experiments conducted with radioactive 203 Hg showed in each case recoveries of 20 to 34% in the leaves regarding the evaporated Hg-tracer. Also in the stem and in the roots Hg-tracer could be detected, indicating a translocation within the plant from leaf to root. By means of a comprehensive literature study the state of the art for Hg-evaporation and Hg-uptake of plants was compiled. Comparing the experimental results with data derived from literature, the Hg-concentrations found are confirmed by results of other authors. (orig.) [de

  17. Highly efficient visible-light driven photochromism: developments towards a solid-state molecular switch operating through a triplet-sensitised pathway.

    Science.gov (United States)

    Brayshaw, Simon K; Schiffers, Stephanie; Stevenson, Anna J; Teat, Simon J; Warren, Mark R; Bennett, Robert D; Sazanovich, Igor V; Buckley, Alastair R; Weinstein, Julia A; Raithby, Paul R

    2011-04-11

    We introduce a new highly efficient photochromic organometallic dithienylethene (DTE) complex, the first instance of a DTE core symmetrically modified by two Pt(II) chromophores [Pt(PEt(3))(2)(C≡C)(DTE)(C≡C)Pt(PEt(3))(2)Ph] (1), which undergoes ring-closure when activated by visible light in solvents of different polarity, in thin films and even in the solid state. Complex 1 has been synthesised and fully photophysically characterised by (resonance) Raman and transient absorption spectroscopy complemented by calculations. The ring-closing photoconversion in a single crystal of 1 has been followed by X-ray crystallography. This process occurs with the extremely high yield of 80%--considerably outperforming the other DTE derivatives. Remarkably, the photocyclisation of 1 occurs even under visible light (>400 nm), which is not absorbed by the non-metallated DTE core HC≡C(DTE)C≡CH (2) itself. This unusual behaviour and the high photocyclisation yields in solution are attributed to the presence of a heavy atom in 1 that enables a triplet-sensitised photocyclisation pathway, elucidated by transient absorption spectroscopy and DFT calculations. The results of resonance Raman investigation confirm the involvement of the alkynyl unit in the frontier orbitals of both closed and open forms of 1 in the photocyclisation process. The changes in the Raman spectra upon cyclisation have permitted the identification of Raman marker bands, which include the acetylide stretching vibration. Importantly, these bands occur in the spectral region unobstructed by other vibrations and can be used for non-destructive monitoring of photocyclisation/photoreversion processes and for optical readout in this type of efficiently photochromic thermally stable systems. This study indicates a strategy for generating efficient solid-state photoswitches in which modification of the Pt(II) units has the potential to tune absorption properties and hence operational wavelength across the visible

  18. Pathways to man

    International Nuclear Information System (INIS)

    Harley, J.H.

    1980-01-01

    The study of radionuclide pathways leading to man generally has the goal of allowing us to predict human exposure from measurements of the radionuclide concentration in some segment of the environment. This modelling process provides a valuable tool in both the regulatory and health protection fields. However, most of the models in the regulatory field and in the health physics profession were designed to maximize exposure estimates. It is preferable to have scientifically defensible estimates and to add suitable safety factors at the end. Thus we are still faced with the development and validation of suitable models for many of the radionuclides of interest. The most useful models will include means of assessing variability and uncertainty. In this case variability might be considered as the differences in behavior due to age, sex or other factors in animals or man and those differences among plant species or animal species that determine their uptake factors. The uncertainty, on the other hand, would be the estimate of possible error in the experimental measurements. Model parameters would always have some variability even for site-specific cases and broad averages for population groups would have to include a factor expressing the possible variabilty and uncertainity. Thus any exposure calculation would have to be expressed with some range and valid assessments of this range are required

  19. DMPD: Regulatory pathways in inflammation. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17967718 Regulatory pathways in inflammation. Mantovani A, Garlanda C, Locati M, Ro....html) (.csml) Show Regulatory pathways in inflammation. PubmedID 17967718 Title Regulatory pathways in infl

  20. Machine learning methods for metabolic pathway prediction

    Directory of Open Access Journals (Sweden)

    Karp Peter D

    2010-01-01

    Full Text Available Abstract Background A key challenge in systems biology is the reconstruction of an organism's metabolic network from its genome sequence. One strategy for addressing this problem is to predict which metabolic pathways, from a reference database of known pathways, are present in the organism, based on the annotated genome of the organism. Results To quantitatively validate methods for pathway prediction, we developed a large "gold standard" dataset of 5,610 pathway instances known to be present or absent in curated metabolic pathway databases for six organisms. We defined a collection of 123 pathway features, whose information content we evaluated with respect to the gold standard. Feature data were used as input to an extensive collection of machine learning (ML methods, including naïve Bayes, decision trees, and logistic regression, together with feature selection and ensemble methods. We compared the ML methods to the previous PathoLogic algorithm for pathway prediction using the gold standard dataset. We found that ML-based prediction methods can match the performance of the PathoLogic algorithm. PathoLogic achieved an accuracy of 91% and an F-measure of 0.786. The ML-based prediction methods achieved accuracy as high as 91.2% and F-measure as high as 0.787. The ML-based methods output a probability for each predicted pathway, whereas PathoLogic does not, which provides more information to the user and facilitates filtering of predicted pathways. Conclusions ML methods for pathway prediction perform as well as existing methods, and have qualitative advantages in terms of extensibility, tunability, and explainability. More advanced prediction methods and/or more sophisticated input features may improve the performance of ML methods. However, pathway prediction performance appears to be limited largely by the ability to correctly match enzymes to the reactions they catalyze based on genome annotations.

  1. Machine learning methods for metabolic pathway prediction

    Science.gov (United States)

    2010-01-01

    Background A key challenge in systems biology is the reconstruction of an organism's metabolic network from its genome sequence. One strategy for addressing this problem is to predict which metabolic pathways, from a reference database of known pathways, are present in the organism, based on the annotated genome of the organism. Results To quantitatively validate methods for pathway prediction, we developed a large "gold standard" dataset of 5,610 pathway instances known to be present or absent in curated metabolic pathway databases for six organisms. We defined a collection of 123 pathway features, whose information content we evaluated with respect to the gold standard. Feature data were used as input to an extensive collection of machine learning (ML) methods, including naïve Bayes, decision trees, and logistic regression, together with feature selection and ensemble methods. We compared the ML methods to the previous PathoLogic algorithm for pathway prediction using the gold standard dataset. We found that ML-based prediction methods can match the performance of the PathoLogic algorithm. PathoLogic achieved an accuracy of 91% and an F-measure of 0.786. The ML-based prediction methods achieved accuracy as high as 91.2% and F-measure as high as 0.787. The ML-based methods output a probability for each predicted pathway, whereas PathoLogic does not, which provides more information to the user and facilitates filtering of predicted pathways. Conclusions ML methods for pathway prediction perform as well as existing methods, and have qualitative advantages in terms of extensibility, tunability, and explainability. More advanced prediction methods and/or more sophisticated input features may improve the performance of ML methods. However, pathway prediction performance appears to be limited largely by the ability to correctly match enzymes to the reactions they catalyze based on genome annotations. PMID:20064214

  2. Community College Pathways: 2012-2013 Descriptive Report

    Science.gov (United States)

    Van Campen, James; Sowers, Nicole; Strother, Scott

    2013-01-01

    The Community College Pathways (CCP) program had an outstanding second year. In 2012-2013, the program reproduced the positive outcomes realized in the first year of implementation, including successful course completion rates of over 50 percent for both Pathways. Simultaneously, the administration of the Pathways has continued to develop and…

  3. Quadrupolar transfer pathways

    Science.gov (United States)

    Antonijevic, Sasa; Bodenhausen, Geoffrey

    2006-06-01

    A set of graphical conventions called quadrupolar transfer pathways is proposed to describe a wide range of experiments designed for the study of quadrupolar nuclei with spin quantum numbers I = 1, 3/2, 2, 5/2, etc. These pathways, which inter alea allow one to appreciate the distinction between quadrupolar and Zeeman echoes, represent a generalization of the well-known coherence transfer pathways. Quadrupolar transfer pathways not merely distinguish coherences with different orders -2 I ⩽ p ⩽ +2 I, but allow one to follow the fate of coherences associated with single transitions that have the same coherence orderp=mIr-mIs but can be distinguished by a satellite orderq=(mIr)2-(mIs)2.

  4. HDR-Pathways

    Data.gov (United States)

    Department of Veterans Affairs — Pathways is a SOAP/REST web service interface accessed via HTTPS that provides administrative data (Appointments, Exam Requests and Exams information) from VistA in...

  5. Updating the Wnt pathways

    Science.gov (United States)

    Yu, Jia; Virshup, David M.

    2014-01-01

    In the three decades since the discovery of the Wnt1 proto-oncogene in virus-induced mouse mammary tumours, our understanding of the signalling pathways that are regulated by the Wnt proteins has progressively expanded. Wnts are involved in an complex signalling network that governs multiple biological processes and cross-talk with multiple additional signalling cascades, including the Notch, FGF (fibroblast growth factor), SHH (Sonic hedgehog), EGF (epidermal growth factor) and Hippo pathways. The Wnt signalling pathway also illustrates the link between abnormal regulation of the developmental processes and disease manifestation. Here we provide an overview of Wnt-regulated signalling cascades and highlight recent advances. We focus on new findings regarding the dedicated Wnt production and secretion pathway with potential therapeutic targets that might be beneficial for patients with Wnt-related diseases. PMID:25208913

  6. The Cdk4-E2f1 pathway regulates early pancreas development by targeting Pdx1+ progenitors and Ngn3+ endocrine precursors

    Science.gov (United States)

    Kim, So Yoon; Rane, Sushil G.

    2011-01-01

    Cell division and cell differentiation are intricately regulated processes vital to organ development. Cyclin-dependent kinases (Cdks) are master regulators of the cell cycle that orchestrate the cell division and differentiation programs. Cdk1 is essential to drive cell division and is required for the first embryonic divisions, whereas Cdks 2, 4 and 6 are dispensable for organogenesis but vital for tissue-specific cell development. Here, we illustrate an important role for Cdk4 in regulating early pancreas development. Pancreatic development involves extensive morphogenesis, proliferation and differentiation of the epithelium to give rise to the distinct cell lineages of the adult pancreas. The cell cycle molecules that specify lineage commitment within the early pancreas are unknown. We show that Cdk4 and its downstream transcription factor E2f1 regulate mouse pancreas development prior to and during the secondary transition. Cdk4 deficiency reduces embryonic pancreas size owing to impaired mesenchyme development and fewer Pdx1+ pancreatic progenitor cells. Expression of activated Cdk4R24C kinase leads to increased Nkx2.2+ and Nkx6.1+ cells and a rise in the number and proliferation of Ngn3+ endocrine precursors, resulting in expansion of the β cell lineage. We show that E2f1 binds and activates the Ngn3 promoter to modulate Ngn3 expression levels in the embryonic pancreas in a Cdk4-dependent manner. These results suggest that Cdk4 promotes β cell development by directing E2f1-mediated activation of Ngn3 and increasing the pool of endocrine precursors, and identify Cdk4 as an important regulator of early pancreas development that modulates the proliferation potential of pancreatic progenitors and endocrine precursors. PMID:21490060

  7. Molecular pathways towards psychiatric disorders

    International Nuclear Information System (INIS)

    Chela-Flores, J.

    1987-07-01

    The observed fibrillar-neuronal organization of the cerebral cortex suggests that in the aetiology of certain psychiatric disorders the genomic response of the neuron to the challenge presented by stress or insults at various stages of development, is to set off a programmed chain of molecular events (or ''pathways''), as demonstrated in previous genetic studies. The understanding of these pathways is important in order to enhance our ability to influence these illnesses, and are hypothesized to be initiated by a nucleolar mechanism for inducing abnormal synthesis of the nerve growth factor (NGF). The hypothesis is used to approach tentatively the still open question regarding the pathogenesis of mental retardation (MR) and senile dementia (SD). (author). 25 refs

  8. Sugar - hormone crosstalk in seed development: Two redundant pathways of IAA biosynthesis are regulated differentially in the invertase-deficient miniature1 (mn1) seed mutant in maize

    Science.gov (United States)

    The miniature1 (mn1) seed phenotype is a loss-of-function mutation at the Mn1 locus that encodes a cell wall invertase; its deficiency leads to pleiotropic changes including altered sugar levels and decreased levels of IAA throughout seed development. To understand the molecular details of such suga...

  9. Questioning the Pace and Pathway of E-Government Development in Africa: A Case Study of South Africa's Cape Gateway Project

    Science.gov (United States)

    Maumbe, Blessing Mukabeta; Owei, Vesper; Alexander, Helen

    2008-01-01

    The paper examines e-government development in Africa. This study is based on the Cape Gateway project in South Africa, a leading e-government initiative on the continent. We observe that African countries have jumped on the e-government band wagon by looking mostly at the benefits without a clear risk assessment. We argue that African countries…

  10. DMPD: Mechanisms of selection mediated by interleukin-7, the preBCR, and hemokinin-1during B-cell development. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 14962188 Mechanisms of selection mediated by interleukin-7, the preBCR, and hemokin...ng) (.svg) (.html) (.csml) Show Mechanisms of selection mediated by interleukin-7, the preBCR, and hemokinin...-1during B-cell development. PubmedID 14962188 Title Mechanisms of selection medi

  11. Girls' Access to Education in China: Actors, Cultures and the Windmill of Development Management. CREATE Pathways to Access. Research Monograph No. 39

    Science.gov (United States)

    Wang, Xiaojun Grace

    2010-01-01

    The world has a mixed record towards achieving EFA [Education for All] and the MDGs [Millennium Development Goals] in relation to the targets on gender equity in basic education. For researchers and practitioners, this raises the question of which factors influence the processes leading to the improvement of access and quality of girls' education…

  12. Breast cancer cells can switch between estrogen receptor alpha and ErbB signaling and combined treatment against both signaling pathways postpones development of resistance

    DEFF Research Database (Denmark)

    Sonne-Hansen, Katrine; Norrie, Ida C; Emdal, Kristina Bennet

    2010-01-01

    circumvent development of resistance. Limited effects were observed when targeting EGFR and ErbB2 with the monoclonal antibodies cetuximab, trastuzumab, and pertuzumab, whereas the pan-ErbB inhibitor CI-1033 selectively inhibited growth of fulvestrant resistant cell lines. CI-1033 inhibited Erk but not Akt...

  13. Assessing the Molecular Genetics of the Development of Executive Attention in Children: Focus on Genetic Pathways Related to the Anterior Cingulate Cortex and Dopamine

    Science.gov (United States)

    Brocki, Karin; Clerkin, Suzanne M.; Guise, Kevin G.; Fan, Jin; Fossella, John A.

    2009-01-01

    It is well-known that children show gradual and protracted improvement in an array of behaviors involved in the conscious control of thought and emotion. Non-invasive neuroimaging in developing populations has revealed many neural correlates of behavior, particularly in the developing cingulate cortex and fronto-striatal circuits. These brain regions, themselves, undergo protracted molecular and cellular change in the first two decades of human development and, as such, are ideal regions of interest for cognitive- and imaging-genetic studies that seek to link processes at the biochemical and synaptic levels to brain activity and behavior. We review our research to-date that employs both adult and child-friendly versions of the Attention Network Task (ANT) in an effort to begin to describe the role of specific genes in the assembly of a functional attention system. Presently, we constrain our predictions for genetic association studies by focusing on the role of the anterior cingulate cortex (ACC) and of dopamine in the development of executive attention. PMID:19344637

  14. A pathway-specific microarray analysis highlights the complex and co-ordinated transcriptional networks of the developing grain of field-grown barley

    DEFF Research Database (Denmark)

    Hansen, Michael; Friis, Carsten; Bowra, Steve

    2009-01-01

    The aim of the study was to describe the molecular and biochemical interactions associated with amino acid biosynthesis and storage protein accumulation in the developing grains of field-grown barley. Our strategy was to analyse the transcription of genes associated with the biosynthesis of stora...

  15. Mechanism of right thoracic adolescent idiopathic scoliosis at risk for progression; a unifying pathway of development by normal growth and imbalance

    DEFF Research Database (Denmark)

    Wong, Christian

    2015-01-01

    Adolescent idiopathic scoliosis is regarded as a multifactorial disease and none of the many suggested causal etiologies have yet prevailed. I will suggest that adolescent idiopathic scoliosis has one common denominator, namely that initial curve development is mediated through one common normal...

  16. Alternatives to the Fish Early Life-Stage Test: A Research Strategy for Discovering and Annotating Adverse Outcome Pathways During Fish Development

    Science.gov (United States)

    The OECD 210 fish early life]stage (FELS) test is the primary guideline test used to estimate chronic fish toxicity, as well as support ecological risk assessments and chemical management programs around the world. As a step toward developing alternatives to the FELS test, a HES...

  17. Investigating Alternatives to the Fish Early Life-Stage Test: A Strategy for Discovering and Annotating Adverse Outcome Pathways for Early Fish Development

    Science.gov (United States)

    The fish early life-stage (FELS) test (OECD Test Guideline 210) is the primary test used internationally to estimate chronic fish toxicity in support of ecological risk assessments and chemical management programs. As part of an on-going effort to develop efficient and cost-effec...

  18. The Co-Occurring Development of Executive Function Skills and Receptive Vocabulary in Preschool-Aged Children: A Look at the Direction of the Developmental Pathways

    Science.gov (United States)

    Weiland, Christina; Barata, M. Clara; Yoshikawa, Hirokazu

    2014-01-01

    Despite consensus in the developmental literature regarding the role of executive function (EF) skills in supporting the development of language skills during the preschool years, we know relatively little about the associations between EF skills, including all EF components, and vocabulary skills among preschool-aged children. In this paper, we…

  19. The Hippo Pathway: Immunity and Cancer.

    Science.gov (United States)

    Taha, Zaid; J Janse van Rensburg, Helena; Yang, Xiaolong

    2018-03-28

    Since its discovery, the Hippo pathway has emerged as a central signaling network in mammalian cells. Canonical signaling through the Hippo pathway core components (MST1/2, LATS1/2, YAP and TAZ) is important for development and tissue homeostasis while aberrant signaling through the Hippo pathway has been implicated in multiple pathologies, including cancer. Recent studies have uncovered new roles for the Hippo pathway in immunology. In this review, we summarize the mechanisms by which Hippo signaling in pathogen-infected or neoplastic cells affects the activities of immune cells that respond to these threats. We further discuss how Hippo signaling functions as part of an immune response. Finally, we review how immune cell-intrinsic Hippo signaling modulates the development/function of leukocytes and propose directions for future work.

  20. YAP and the Hippo pathway in pediatric cancer.

    Science.gov (United States)

    Ahmed, Atif A; Mohamed, Abdalla D; Gener, Melissa; Li, Weijie; Taboada, Eugenio

    2017-01-01

    The Hippo pathway is an important signaling pathway that controls cell proliferation and apoptosis. It is evolutionarily conserved in mammals and is stimulated by cell-cell contact, inhibiting cell proliferation in response to increased cell density. During early embryonic development, the Hippo signaling pathway regulates organ development and size, and its functions result in the coordinated balance between proliferation, apoptosis, and differentiation. Its principal effectors, YAP and TAZ, regulate signaling by the embryonic stem cells and determine cell fate and histogenesis. Dysfunction of this pathway contributes to cancer development in adults and children. Emerging studies have shed light on the upregulation of Hippo pathway members in several pediatric cancers and may offer prognostic information on rhabdomyosarcoma, osteosarcoma, Wilms tumor, neuroblastoma, medulloblastoma, and other brain gliomas. We review the results of such published studies and highlight the potential clinical application of this pathway in pediatric oncologic and pathologic studies. These studies support targeting this pathway as a novel treatment strategy.

  1. Pathways to deep decarbonization - Interim 2014 Report

    International Nuclear Information System (INIS)

    2014-01-01

    The interim 2014 report by the Deep Decarbonization Pathways Project (DDPP), coordinated and published by IDDRI and the Sustainable Development Solutions Network (SDSN), presents preliminary findings of the pathways developed by the DDPP Country Research Teams with the objective of achieving emission reductions consistent with limiting global warming to less than 2 deg. C. The DDPP is a knowledge network comprising 15 Country Research Teams and several Partner Organizations who develop and share methods, assumptions, and findings related to deep decarbonization. Each DDPP Country Research Team has developed an illustrative road-map for the transition to a low-carbon economy, with the intent of taking into account national socio-economic conditions, development aspirations, infrastructure stocks, resource endowments, and other relevant factors. The interim 2014 report focuses on technically feasible pathways to deep decarbonization

  2. AtbZIP34 is required for Arabidopsis pollen wall patterning and the control of several metabolic pathways in developing pollen

    Czech Academy of Sciences Publication Activity Database

    Gibalová, Antónia; Reňák, David; Matczuk, Katarzyna; Dupľáková, Nikoleta; Cháb, David; Twell, D.; Honys, David

    2009-01-01

    Roč. 70, č. 5 (2009), s. 581-601 ISSN 0167-4412 R&D Projects: GA ČR GA522/06/0896; GA ČR GA522/09/0858; GA MŠk(CZ) LC06004 Institutional research plan: CEZ:AV0Z50380511 Keywords : bZIP transcription factor * AtbZIP34 * Male gametophyte development Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.978, year: 2009

  3. The Competitiveness of SMK and Diploma 3 Graduates of Hospitality at the Entry Level and Employability Skills in Developing Career Pathways

    OpenAIRE

    Dalimunthe, Femmy Indriany; Sutadji, Eddy; Setianingsih, Rita Margaretha

    2016-01-01

    Along with the development of the ASEAN Economic Community in 2015, Indonesia is required to generate professional human resources in order to compete with other countries, particularly subject to competition in the services sector. Hotel is a product in the hospitality industry that have an important role in the tourism business.Intense competition in the hospitality industry demand the hotels to provide the best service to the customers. Vocational education has a function to prepare a prof...

  4. Probabilistic pathway construction.

    Science.gov (United States)

    Yousofshahi, Mona; Lee, Kyongbum; Hassoun, Soha

    2011-07-01

    Expression of novel synthesis pathways in host organisms amenable to genetic manipulations has emerged as an attractive metabolic engineering strategy to overproduce natural products, biofuels, biopolymers and other commercially useful metabolites. We present a pathway construction algorithm for identifying viable synthesis pathways compatible with balanced cell growth. Rather than exhaustive exploration, we investigate probabilistic selection of reactions to construct the pathways. Three different selection schemes are investigated for the selection of reactions: high metabolite connectivity, low connectivity and uniformly random. For all case studies, which involved a diverse set of target metabolites, the uniformly random selection scheme resulted in the highest average maximum yield. When compared to an exhaustive search enumerating all possible reaction routes, our probabilistic algorithm returned nearly identical distributions of yields, while requiring far less computing time (minutes vs. years). The pathways identified by our algorithm have previously been confirmed in the literature as viable, high-yield synthesis routes. Prospectively, our algorithm could facilitate the design of novel, non-native synthesis routes by efficiently exploring the diversity of biochemical transformations in nature. Copyright © 2011 Elsevier Inc. All rights reserved.

  5. The core regulatory network of the abscisic acid pathway in banana: genome-wide identification and expression analyses during development, ripening, and abiotic stress.

    Science.gov (United States)

    Hu, Wei; Yan, Yan; Shi, Haitao; Liu, Juhua; Miao, Hongxia; Tie, Weiwei; Ding, Zehong; Ding, XuPo; Wu, Chunlai; Liu, Yang; Wang, Jiashui; Xu, Biyu; Jin, Zhiqiang

    2017-08-29

    Abscisic acid (ABA) signaling plays a crucial role in developmental and environmental adaptation processes of plants. However, the PYL-PP2C-SnRK2 families that function as the core components of ABA signaling are not well understood in banana. In the present study, 24 PYL, 87 PP2C, and 11 SnRK2 genes were identified from banana, which was further supported by evolutionary relationships, conserved motif and gene structure analyses. The comprehensive transcriptomic analyses showed that banana PYL-PP2C-SnRK2 genes are involved in tissue development, fruit development and ripening, and response to abiotic stress in two cultivated varieties. Moreover, comparative expression analyses of PYL-PP2C-SnRK2 genes between BaXi Jiao (BX) and Fen Jiao (FJ) revealed that PYL-PP2C-SnRK2-mediated ABA signaling might positively regulate banana fruit ripening and tolerance to cold, salt, and osmotic stresses. Finally, interaction networks and co-expression assays demonstrated that the core components of ABA signaling were more active in FJ than in BX in response to abiotic stress, further supporting the crucial role of the genes in tolerance to abiotic stress in banana. This study provides new insights into the complicated transcriptional control of PYL-PP2C-SnRK2 genes, improves the understanding of PYL-PP2C-SnRK2-mediated ABA signaling in the regulation of fruit development, ripening, and response to abiotic stress, and identifies some candidate genes for genetic improvement of banana.

  6. Pathway-based analyses.

    Science.gov (United States)

    Kent, Jack W

    2016-02-03

    New technologies for acquisition of genomic data, while offering unprecedented opportunities for genetic discovery, also impose severe burdens of interpretation and penalties for multiple testing. The Pathway-based Analyses Group of the Genetic Analysis Workshop 19 (GAW19) sought reduction of multiple-testing burden through various approaches to aggregation of highdimensional data in pathways informed by prior biological knowledge. Experimental methods testedincluded the use of "synthetic pathways" (random sets of genes) to estimate power and false-positive error rate of methods applied to simulated data; data reduction via independent components analysis, single-nucleotide polymorphism (SNP)-SNP interaction, and use of gene sets to estimate genetic similarity; and general assessment of the efficacy of prior biological knowledge to reduce the dimensionality of complex genomic data. The work of this group explored several promising approaches to managing high-dimensional data, with the caveat that these methods are necessarily constrained by the quality of external bioinformatic annotation.

  7. Wound care clinical pathway: a conceptual model.

    Science.gov (United States)

    Barr, J E; Cuzzell, J

    1996-08-01

    A clinical pathway is a written sequence of clinical processes or events that guides a patient with a defined problem toward an expected outcome. Clinical pathways are tools to assist with the cost-effective management of clinical outcomes related to specific problems or disease processes. The primary obstacles to developing clinical pathways for wound care are the chronic natures of some wounds and the many variables that can delay healing. The pathway introduced in this article was modeled upon the three phases of tissue repair: inflammatory, proliferative, and maturation. This physiology-based model allows clinicians to identify and monitor outcomes based on observable and measurable clinical parameters. The pathway design, which also includes educational and behavioral outcomes, allows the clinician to individualize the expected timeframe for outcome achievement based on individual patient criteria and expert judgement. Integral to the pathway are the "4P's" which help standardize the clinical processes by wound type: Protocols, Policies, Procedures, and Patient education tools. Four categories into which variances are categorized based on the cause of the deviation from the norm are patient, process/system, practitioner, and planning/discharge. Additional research is warranted to support the value of this clinical pathway in the clinical arena.

  8. A Spatial-Economic Cost-Reduction Pathway Analysis for U.S. Offshore Wind Energy Development from 2015–2030

    Energy Technology Data Exchange (ETDEWEB)

    Beiter, Philipp [National Renewable Energy Lab. (NREL), Golden, CO (United States); Musial, Walter [National Renewable Energy Lab. (NREL), Golden, CO (United States); Smith, Aaron [National Renewable Energy Lab. (NREL), Golden, CO (United States); Kilcher, Levi [National Renewable Energy Lab. (NREL), Golden, CO (United States); Damiani, Rick [National Renewable Energy Lab. (NREL), Golden, CO (United States); Maness, Michael [National Renewable Energy Lab. (NREL), Golden, CO (United States); Sirnivas, Senu [National Renewable Energy Lab. (NREL), Golden, CO (United States); Stehly, Tyler [National Renewable Energy Lab. (NREL), Golden, CO (United States); Gevorgian, Vahan [National Renewable Energy Lab. (NREL), Golden, CO (United States); Mooney, Meghan [National Renewable Energy Lab. (NREL), Golden, CO (United States); Scott, George [National Renewable Energy Lab. (NREL), Golden, CO (United States)

    2016-09-01

    This report describes a comprehensive effort undertaken by the National Renewable Energy Laboratory (NREL) to understand the cost of offshore wind energy for markets in the United States. The study models the cost impacts of a range of offshore wind locational cost variables for more than 7,000 potential coastal sites in U.S. offshore wind resource areas. It also assesses the impact of more than 50 technology innovations on potential future costs for both fixed-bottom and floating wind systems. Comparing these costs to an initial site-specific assessment of local avoided generating costs, the analysis provides a framework for estimating the economic potential for offshore wind. The analysis is intended to inform a broad set of stakeholders and enable an assessment of offshore wind as part of energy development and energy portfolio planning. It provides information that federal and state agencies and planning commissions could use to inform initial strategic decisions about offshore wind developments in the United States.

  9. Comparison of pathways associated with hepatitis B- and C-infected hepatocellular carcinoma using pathway-based class discrimination method.

    Science.gov (United States)

    Lee, Sun Young; Song, Kwang Hoon; Koo, Imhoi; Lee, Kee-Ho; Suh, Kyung-Suk; Kim, Bu-Yeo

    2012-06-01

    Molecular signatures causing hepatocellular carcinoma (HCC) from chronic infection of hepatitis B virus (HBV) or hepatitis C virus (HCV) are not clearly known. Using microarray datasets composed of HCV-positive HCC or HBV-positive HCC, pathways that could discriminate tumor tissue from adjacent non-tumor liver tissue were selected by implementing nearest shrunken centroid algorithm. Cancer-related signaling pathways and lipid metabolism-related pathways were predominantly enriched in HCV-positive HCC, whereas functionally diverse pathways including immune-related pathways, cell cycle pathways, and RNA metabolism pathways were mainly enriched in HBV-positive HCC. In addition to differentially involved pathways, signaling pathways such as TGF-β, MAPK, and p53 pathways were commonly significant in both HCCs, suggesting the presence of common hepatocarcinogenesis process. The pathway clustering also verified segregation of pathways into the functional subgroups in both HCCs. This study indicates the functional distinction and similarity on the pathways implicated in the development of HCV- and/or HBV-positive HCC. Copyright © 2012 Elsevier Inc. All rights reserved.

  10. Curation and Computational Design of Bioenergy-Related Metabolic Pathways

    Energy Technology Data Exchange (ETDEWEB)

    Karp, Peter D. [SRI International, Menlo Park, CA (United States)

    2014-09-12

    Pathway Tools is a systems-biology software package written by SRI International (SRI) that produces Pathway/Genome Databases (PGDBs) for organisms with a sequenced genome. Pathway Tools also provides a wide range of capabilities for analyzing predicted metabolic networks and user-generated omics data. More than 5,000 academic, industrial, and government groups have licensed Pathway Tools. This user community includes researchers at all three DOE bioenergy centers, as well as academic and industrial metabolic engineering (ME) groups. An integral part of the Pathway Tools software is MetaCyc, a large, multiorganism database of metabolic pathways and enzymes that SRI and its academic collaborators manually curate. This project included two main goals: I. Enhance the MetaCyc content of bioenergy-related enzymes and pathways. II. Develop computational tools for engineering metabolic pathways that satisfy specified design goals, in particular for bioenergy-related pathways. In part I, SRI proposed to significantly expand the coverage of bioenergy-related metabolic information in MetaCyc, followed by the generation of organism-specific PGDBs for all energy-relevant organisms sequenced at the DOE Joint Genome Institute (JGI). Part I objectives included: 1: Expand the content of MetaCyc to include bioenergy-related enzymes and pathways. 2: Enhance the Pathway Tools software to enable display of complex polymer degradation processes. 3: Create new PGDBs for the energy-related organisms sequenced by JGI, update existing PGDBs with new MetaCyc content, and make these data available to JBEI via the BioCyc website. In part II, SRI proposed to develop an efficient computational tool for the engineering of metabolic pathways. Part II objectives included: 4: Develop computational tools for generating metabolic pathways that satisfy specified design goals, enabling users to specify parameters such as starting and ending compounds, and preferred or disallowed intermediate compounds

  11. Using Cognitive Testing to Develop Items for Surveying Asian American Cancer Patients and Their Caregivers as a Pathway to Culturally Competent Care.

    Science.gov (United States)

    Bolcic-Jankovic, Dragana; Lu, Fengxin; Colten, Mary Ellen; McCarthy, Ellen P

    2016-02-01

    We report the results from cognitive interviews with Asian American patients and their caregivers. We interviewed seven caregivers and six patients who were all bilingual Asian Americans. The main goal of the cognitive interviews was to test a survey instrument developed for a study about perspectives of Asian American patients with advanced cancer who are facing decisions around end-of-life care. We were particularly interested to see whether items commonly used in White and Black populations are culturally meaningful and equivalent in Asian populations, primarily those of Chinese and Vietnamese ethnicity. Our exploration shows that understanding respondents' language proficiency, degree of acculturation, and cultural context of receiving, processing, and communicating information about medical care can help design questions that are appropriate for Asian American patients and caregivers, and therefore can help researchers obtain quality data about the care Asian American cancer patients receive. © The Author(s) 2016.

  12. Epigenetic Pathways in Human Disease: The Impact of DNA Methylation on Stress-Related Pathogenesis and Current Challenges in Biomarker Development

    Directory of Open Access Journals (Sweden)

    M. Austin Argentieri

    2017-04-01

    Full Text Available HPA axis genes implicated in glucocorticoid regulation play an important role in regulating the physiological impact of social and environmental stress, and have become a focal point for investigating the role of glucocorticoid regulation in the etiology of disease. We conducted a systematic review to critically assess the full range of clinical associations that have been reported in relation to DNA methylation of CRH, CRH-R1/2, CRH-BP, AVP, POMC, ACTH, ACTH-R, NR3C1, FKBP5, and HSD11β1/2 genes in adults. A total of 32 studies were identified. There is prospective evidence for an association between HSD11β2 methylation and hypertension, and functional evidence of an association between NR3C1 methylation and both small cell lung cancer (SCLC and breast cancer. Strong associations have been reported between FKBP5 and NR3C1 methylation and PTSD, and biologically-plausible associations have been reported between FKBP5 methylation and Alzheimer's Disease. Mixed associations between NR3C1 methylation and mental health outcomes have been reported according to different social and environmental exposures, and according to varying gene regions investigated. We conclude by highlighting key challenges and future research directions that will need to be addressed in order to develop both clinically meaningful prognostic biomarkers and an evidence base that can inform public policy practice.

  13. A Spatial-Economic Cost-Reduction Pathway Analysis for U.S. Offshore Wind Energy Development from 2015-2030

    Energy Technology Data Exchange (ETDEWEB)

    Beiter, Philipp; Stehly, Tyler

    2016-10-05

    The potential for cost reduction and economic viability for offshore wind varies considerably within the United States. This analysis models the cost impact of a range of offshore wind locational cost variables across more than 7,000 potential coastal sites in the United States' offshore wind resource area. It also assesses the impact of over 50 technology innovations on potential future costs between 2015 and 2027 (Commercial Operation Date) for both fixed-bottom and floating wind systems. Comparing these costs to an initial assessment of local avoided generating costs, this analysis provides a framework for estimating the economic potential for offshore wind. Analyzing economic potential within this framework can help establish a refined understanding across industries of the technology and site-specific risks and opportunities associated with future offshore wind development. The findings from the original report indicate that under the modeled scenario, offshore wind can be expected to achieve significant cost reductions and may approach economic viability in some parts of the United States within the next 15 years.

  14. The creative pathways of everyday life

    DEFF Research Database (Denmark)

    Tanggaard, Lene

    2015-01-01

    interested in the simultaneous development of persons and social practices. Pathways are created in ordinary life; their formation may involve creativity and the improvisational co-creation of opportunities for action. Studying pathways may therefore direct creativity researchers toward the potentials...... in the mundane processes of everyday life is, however, seldom highlighted by researchers working explicitly on creativity. The premise of the present paper is that a focus on everyday life can help us understand creative processes in broader terms. I “creative pathways” may serve as a useful term for researchers...... of creativity in daily life and shed light of the processes of creativity. Creative pathways are present in existing ways of moving and doing things; they are also created in the here-and-now by persons acting in correspondence with the affordances in social practices. A focus on creative pathways is consistent...

  15. Synthetic Metabolic Pathways

    DEFF Research Database (Denmark)

    topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls. Authoritative and practical, Synthetic Metabolic Pathways: Methods and Protocols aims to ensure successful results in the further study...

  16. Profiling and functional data on the developing olfactory/GnRH system reveal cellular and molecular pathways essential for this process and potentially relevant for the Kallmann syndrome

    Directory of Open Access Journals (Sweden)

    Giulia eGaraffo

    2013-12-01

    Full Text Available During embryonic development, immature neurons in the olfactory epithelium (OE extend axons through the nasal mesenchyme, to contact projection neurons in the olfactory bulb. Axon navigation is accompanied by migration of the GnRH+ neurons, which enter the anterior forebrain and home in the septo-hypothalamic area. This process can be interrupted at various points and lead to the onset of the Kallmann syndrome (KS, a disorder characterized by anosmia and central hypogonadotropic hypogonadism. Several genes has been identified in human and mice that cause KS or a KS-like phenotype. In mice a set of transcription factors appears to be required for olfactory connectivity and GnRH neuron migration; thus we explored the transcriptional network underlying this developmental process by profiling the OE and the adjacent mesenchyme at three embryonic ages. We also profiled the OE from embryos null for Dlx5, a homeogene that causes a KS-like phenotype when deleted. We identified 20 interesting genes belonging to the following categories: 1 transmembrane adhesion/receptor, 2 axon-glia interaction, 3 scaffold/adapter for signalling, 4 synaptic proteins. We tested some of them in zebrafish embryos: the depletion of five (of six Dlx5 targets affected axonal extension and targeting, while three (of three affected GnRH neuron position and neurite organization. Thus, we confirmed the importance of cell-cell and cell-matrix interactions and identified new molecules needed for olfactory connection and GnRH neuron migration. Using available and newly generated data, we predicted/prioritized putative KS-disease genes, by building conserved co-expression networks with all known disease genes in human and mouse. The results show the overall validity of approaches based on high-throughput data and predictive bioinformatics to identify genes potentially relevant for the molecular pathogenesis of KS. A number of candidate will be discussed, that should be tested in

  17. Novel personalized pathway-based metabolomics models reveal key metabolic pathways for breast cancer diagnosis

    DEFF Research Database (Denmark)

    Huang, Sijia; Chong, Nicole; Lewis, Nathan

    2016-01-01

    diagnosis. We applied this method to predict breast cancer occurrence, in combination with correlation feature selection (CFS) and classification methods. Results: The resulting all-stage and early-stage diagnosis models are highly accurate in two sets of testing blood samples, with average AUCs (Area Under.......993. Moreover, important metabolic pathways, such as taurine and hypotaurine metabolism and the alanine, aspartate, and glutamate pathway, are revealed as critical biological pathways for early diagnosis of breast cancer. Conclusions: We have successfully developed a new type of pathway-based model to study...... metabolomics data for disease diagnosis. Applying this method to blood-based breast cancer metabolomics data, we have discovered crucial metabolic pathway signatures for breast cancer diagnosis, especially early diagnosis. Further, this modeling approach may be generalized to other omics data types for disease...

  18. Clinical pathways for inborn errors of metabolism: warranted and feasible

    Directory of Open Access Journals (Sweden)

    Demirdas Serwet

    2013-02-01

    Full Text Available Abstract Inborn errors of metabolism (IEMs are known for their low prevalence and multidisciplinary care mostly founded on expert opinion. Clinical pathways are multidisciplinary tools to organise care which provide a clear route to the best care and improve communication. In 2010 the Dutch Society for Children and Adults with an Inborn Error of Metabolism (VKS initiated development of clinical pathways for inborn errors of metabolism. In this letter to the editor we describe why it is warranted to develop clinical pathways for IEMs and shortly discuss the process of development for these pathways in the Netherlands.

  19. PathwayAccess: CellDesigner plugins for pathway databases.

    Science.gov (United States)

    Van Hemert, John L; Dickerson, Julie A

    2010-09-15

    CellDesigner provides a user-friendly interface for graphical biochemical pathway description. Many pathway databases are not directly exportable to CellDesigner models. PathwayAccess is an extensible suite of CellDesigner plugins, which connect CellDesigner directly to pathway databases using respective Java application programming interfaces. The process is streamlined for creating new PathwayAccess plugins for specific pathway databases. Three PathwayAccess plugins, MetNetAccess, BioCycAccess and ReactomeAccess, directly connect CellDesigner to the pathway databases MetNetDB, BioCyc and Reactome. PathwayAccess plugins enable CellDesigner users to expose pathway data to analytical CellDesigner functions, curate their pathway databases and visually integrate pathway data from different databases using standard Systems Biology Markup Language and Systems Biology Graphical Notation. Implemented in Java, PathwayAccess plugins run with CellDesigner version 4.0.1 and were tested on Ubuntu Linux, Windows XP and 7, and MacOSX. Source code, binaries, documentation and video walkthroughs are freely available at http://vrac.iastate.edu/~jlv.

  20. A gene expression signature of RAS pathway dependence predicts response to PI3K and RAS pathway inhibitors and expands the population of RAS pathway activated tumors.

    Science.gov (United States)

    Loboda, Andrey; Nebozhyn, Michael; Klinghoffer, Rich; Frazier, Jason; Chastain, Michael; Arthur, William; Roberts, Brian; Zhang, Theresa; Chenard, Melissa; Haines, Brian; Andersen, Jannik; Nagashima, Kumiko; Paweletz, Cloud; Lynch, Bethany; Feldman, Igor; Dai, Hongyue; Huang, Pearl; Watters, James

    2010-06-30

    Hyperactivation of the Ras signaling pathway is a driver of many cancers, and RAS pathway activation can predict response to targeted therapies. Therefore, optimal methods for measuring Ras pathway activation are critical. The main focus of our work was to develop a gene expression signature that is predictive of RAS pathway dependence. We used the coherent expression of RAS pathway-related genes across multiple datasets to derive a RAS pathway gene expression signature and generate RAS pathway activation scores in pre-clinical cancer models and human tumors. We then related this signature to KRAS mutation status and drug response data in pre-clinical and clinical datasets. The RAS signature score is predictive of KRAS mutation status in lung tumors and cell lines with high (> 90%) sensitivity but relatively low (50%) specificity due to samples that have apparent RAS pathway activation in the absence of a KRAS mutation. In lung and breast cancer cell line panels, the RAS pathway signature score correlates with pMEK and pERK expression, and predicts resistance to AKT inhibition and sensitivity to MEK inhibition within both KRAS mutant and KRAS wild-type groups. The RAS pathway signature is upregulated in breast cancer cell lines that have acquired resistance to AKT inhibition, and is downregulated by inhibition of MEK. In lung cancer cell lines knockdown of KRAS using siRNA demonstrates that the RAS pathway signature is a better measure of dependence on RAS compared to KRAS mutation status. In human tumors, the RAS pathway signature is elevated in ER negative breast tumors and lung adenocarcinomas, and predicts resistance to cetuximab in metastatic colorectal cancer. These data demonstrate that the RAS pathway signature is superior to KRAS mutation status for the prediction of dependence on RAS signaling, can predict response to PI3K and RAS pathway inhibitors, and is likely to have the most clinical utility in lung and breast tumors.

  1. A gene expression signature of RAS pathway dependence predicts response to PI3K and RAS pathway inhibitors and expands the population of RAS pathway activated tumors

    Directory of Open Access Journals (Sweden)

    Paweletz Cloud

    2010-06-01

    Full Text Available Abstract Background Hyperactivation of the Ras signaling pathway is a driver of many cancers, and RAS pathway activation can predict response to targeted therapies. Therefore, optimal methods for measuring Ras pathway activation are critical. The main focus of our work was to develop a gene expression signature that is predictive of RAS pathway dependence. Methods We used the coherent expression of RAS pathway-related genes across multiple datasets to derive a RAS pathway gene expression signature and generate RAS pathway activation scores in pre-clinical cancer models and human tumors. We then related this signature to KRAS mutation status and drug response data in pre-clinical and clinical datasets. Results The RAS signature score is predictive of KRAS mutation status in lung tumors and cell lines with high (> 90% sensitivity but relatively low (50% specificity due to samples that have apparent RAS pathway activation in the absence of a KRAS mutation. In lung and breast cancer cell line panels, the RAS pathway signature score correlates with pMEK and pERK expression, and predicts resistance to AKT inhibition and sensitivity to MEK inhibition within both KRAS mutant and KRAS wild-type groups. The RAS pathway signature is upregulated in breast cancer cell lines that have acquired resistance to AKT inhibition, and is downregulated by inhibition of MEK. In lung cancer cell lines knockdown of KRAS using siRNA demonstrates that the RAS pathway signature is a better measure of dependence on RAS compared to KRAS mutation status. In human tumors, the RAS pathway signature is elevated in ER negative breast tumors and lung adenocarcinomas, and predicts resistance to cetuximab in metastatic colorectal cancer. Conclusions These data demonstrate that the RAS pathway signature is superior to KRAS mutation status for the prediction of dependence on RAS signaling, can predict response to PI3K and RAS pathway inhibitors, and is likely to have the most clinical

  2. HPV: Molecular pathways and targets.

    Science.gov (United States)

    Gupta, Shilpi; Kumar, Prabhat; Das, Bhudev C

    2018-04-05

    Infection of high-risk human papillomaviruses (HPVs) is a prerequisite for the development of cervical carcinoma. HPV infections are also implicated in the development of other types of carcinomas. Chronic or persistent infection of HPV is essential but HPV alone is inadequate, additional endogenous or exogenous cues are needed along with HPV to induce cervical carcinogenesis. The strategies that high-risk HPVs have developed in differentiating epithelial cells to reach a DNA-synthesis competent state leading to tumorigenic transformation are basically due to overexpression of the E6 and E7 oncoproteins and the activation of diverse cellular regulatory or signaling pathways that are targeted by them. Moreover, the Wnt/β-catenin/Notch and phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathways are deregulated in various cancers, and have also been implicated in HPV-induced cancers. These are basically related to the "cancer hallmarks," and include sustaining proliferative signals, the evasion of growth suppression and immune destruction, replicative immortality, inflammation, invasion, metastasis and angiogenesis, as well as genome instability, resisting cell death, and deregulation of cellular energetics. These information could eventually aid in identifying or developing new diagnostic, prognostic biomarkers, and may contribute to design more effective targeted therapeutics and treatment strategies. Although surgery, chemotherapy and radiotherapy can cure more than 90% of women with early stage cervical cancer, the recurrent and metastatic disease remains a major cause of cancer mortality. Numerous efforts have been made to design new drugs and develop gene therapies to treat cervical cancer. In recent years, research on treatment strategies has proposed several options, including the role of HPV E5, E6, and E7 oncogenes, which are retained and overexpressed in most of the cervical cancers and whose respective oncoproteins are critical to the induction

  3. Pathway analysis of IMC

    DEFF Research Database (Denmark)

    Skrypnyuk, Nataliya; Nielson, Flemming; Pilegaard, Henrik

    2009-01-01

    We present the ongoing work on the pathway analysis of a stochastic calculus. Firstly we present a particular stochastic calculus that we have chosen for our modeling - the Interactive Markov Chains calculus, IMC for short. After that we specify a few restrictions that we have introduced into the...... into the syntax of IMC in order to make our analysis feasible. Finally we describe the analysis itself together with several theoretical results that we have proved for it.......We present the ongoing work on the pathway analysis of a stochastic calculus. Firstly we present a particular stochastic calculus that we have chosen for our modeling - the Interactive Markov Chains calculus, IMC for short. After that we specify a few restrictions that we have introduced...

  4. Aquatic pathway 2

    International Nuclear Information System (INIS)

    1977-01-01

    This third part of the investigation discusses the preliminary results of sub-investigations concerning problems of the release of radioactive substances into the environment via the water pathway. On the basis of papers on the emission into the draining ditch and the exchange processes there, investigations of a possible incorporation via different exposure pathways are reported. Special regard is paid to drinking water supply aquatic foodstuffs, the river sediment, the utilisation of the agricultural surfaces and the draining ditch including its pre-pollution. The dynamics of contamination processes is reported on with regard to the problem of accidents. The colloquium will give an outline of the progress made so far and admit participants' suggestions for further work on the sub-investigations. The following colloquia will report further findings, in particular effects on aquatic ecosystems. (orig.) [de

  5. Genes and (Common) Pathways Underlying Drug Addiction

    Science.gov (United States)

    Li, Chuan-Yun; Mao, Xizeng; Wei, Liping

    2008-01-01

    Drug addiction is a serious worldwide problem with strong genetic and environmental influences. Different technologies have revealed a variety of genes and pathways underlying addiction; however, each individual technology can be biased and incomplete. We integrated 2,343 items of evidence from peer-reviewed publications between 1976 and 2006 linking genes and chromosome regions to addiction by single-gene strategies, microrray, proteomics, or genetic studies. We identified 1,500 human addiction-related genes and developed KARG (http://karg.cbi.pku.edu.cn), the first molecular database for addiction-related genes with extensive annotations and a friendly Web interface. We then performed a meta-analysis of 396 genes that were supported by two or more independent items of evidence to identify 18 molecular pathways that were statistically significantly enriched, covering both upstream signaling events and downstream effects. Five molecular pathways significantly enriched for all four different types of addictive drugs were identified as common pathways which may underlie shared rewarding and addictive actions, including two new ones, GnRH signaling pathway and gap junction. We connected the common pathways into a hypothetical common molecular network for addiction. We observed that fast and slow positive feedback loops were interlinked through CAMKII, which may provide clues to explain some of the irreversible features of addiction. PMID:18179280

  6. Genes and (common pathways underlying drug addiction.

    Directory of Open Access Journals (Sweden)

    Chuan-Yun Li

    2008-01-01

    Full Text Available Drug addiction is a serious worldwide problem with strong genetic and environmental influences. Different technologies have revealed a variety of genes and pathways underlying addiction; however, each individual technology can be biased and incomplete. We integrated 2,343 items of evidence from peer-reviewed publications between 1976 and 2006 linking genes and chromosome regions to addiction by single-gene strategies, microrray, proteomics, or genetic studies. We identified 1,500 human addiction-related genes and developed KARG (http://karg.cbi.pku.edu.cn, the first molecular database for addiction-related genes with extensive annotations and a friendly Web interface. We then performed a meta-analysis of 396 genes that were supported by two or more independent items of evidence to identify 18 molecular pathways that were statistically significantly enriched, covering both upstream signaling events and downstream effects. Five molecular pathways significantly enriched for all four different types of addictive drugs were identified as common pathways which may underlie shared rewarding and addictive actions, including two new ones, GnRH signaling pathway and gap junction. We connected the common pathways into a hypothetical common molecular network for addiction. We observed that fast and slow positive feedback loops were interlinked through CAMKII, which may provide clues to explain some of the irreversible features of addiction.

  7. The Glymphatic Pathway.

    Science.gov (United States)

    Benveniste, Helene; Lee, Hedok; Volkow, Nora D

    2017-01-01

    The overall premise of this review is that cerebrospinal fluid (CSF) is transported within a dedicated peri-vascular network facilitating metabolic waste clearance from the central nervous system while we sleep. The anatomical profile of the network is complex and has been defined as a peri-arterial CSF influx pathway and peri-venous clearance routes, which are functionally coupled by interstitial bulk flow supported by astrocytic aquaporin 4 water channels. The role of the newly discovered system in the brain is equivalent to the lymphatic system present in other body organs and has been termed the "glymphatic pathway" or "(g)lymphatics" because of its dependence on glial cells. We will discuss and review the general anatomy and physiology of CSF from the perspective of the glymphatic pathway, a discovery which has greatly improved our understanding of key factors that control removal of metabolic waste products from the central nervous system in health and disease and identifies an additional purpose for sleep. A brief historical and factual description of CSF production and transport will precede the ensuing discussion of the glymphatic system along with a discussion of its clinical implications.

  8. A strategy for evaluating pathway analysis methods.

    Science.gov (United States)

    Yu, Chenggang; Woo, Hyung Jun; Yu, Xueping; Oyama, Tatsuya; Wallqvist, Anders; Reifman, Jaques

    2017-10-13

    Researchers have previously developed a multitude of methods designed to identify biological pathways associated with specific clinical or experimental conditions of interest, with the aim of facilitating biological interpretation of high-throughput data. Before practically applying such pathway analysis (PA) methods, we must first evaluate their performance and reliability, using datasets where the pathways perturbed by the conditions of interest have been well characterized in advance. However, such 'ground truths' (or gold standards) are often unavailable. Furthermore, previous evaluation strategies that have focused on defining 'true answers' are unable to systematically and objectively assess PA methods under a wide range of conditions. In this work, we propose a novel strategy for evaluating PA methods independently of any gold standard, either established or assumed. The strategy involves the use of two mutually complementary metrics, recall and discrimination. Recall measures the consistency of the perturbed pathways identified by applying a particular analysis method to an original large dataset and those identified by the same method to a sub-dataset of the original dataset. In contrast, discrimination measures specificity-the degree to which the perturbed pathways identified by a particular method to a dataset from one experiment differ from those identifying by the same method to a dataset from a different experiment. We used these metrics and 24 datasets to evaluate six widely used PA methods. The results highlighted the common challenge in reliably identifying significant pathways from small datasets. Importantly, we confirmed the effectiveness of our proposed dual-metric strategy by showing that previous comparative studies corroborate the performance evaluations of the six methods obtained by our strategy. Unlike any previously proposed strategy for evaluating the performance of PA methods, our dual-metric strategy does not rely on any ground truth

  9. Low Carbon Development Pathways in Indian Agriculture

    Directory of Open Access Journals (Sweden)

    Wang Sonam Wangyel

    2017-01-01

    Full Text Available Indian agriculture sector is a significant emitter of Green House Gas (GHG, which is projected to increase by 47% between 2011 and 2020. In response to this, India has committed itself to voluntarily reduce its emissions intensity (emissions per unit GDP between 20 to 25 percent below 2005 levels by 2020. This would require rapid and significant scaling up of mitigation efforts including the agriculture sector, which remains a challenge, as mitigation is not a priority in Indian agriculture. The study found out that in-spite of numerous mitigation technologies that are readily available for takeoff, the scale of adoption and deployment is far from sufficient to meet the emission targets set by the Government of India, mainly due to lack of financial incentives, capacity building of farmers, and an enabling policy at different levels. This study identified a suite of feasible interventions for promoting low carbon agriculture such as: low tillage systems as it has negative costs due to savings on tillage and fuel; introduction of superior livestock breeds to reduce numbers (especially unproductive cattle and increase yield; use of livestock wastes to produce energy for cooking and heating through bio-gas technology can not only reduce methane emission but also save electricity costs for the households and; introduction of carbon credits and exploration of domestic carbon markets. An enabling policy environment must be created for these interventions to take off.

  10. Deciphering chemotaxis pathways using cross species comparisons

    Directory of Open Access Journals (Sweden)

    Armitage Judith P

    2010-01-01

    Full Text Available Abstract Background Chemotaxis is the process by which motile bacteria sense their chemical environment and move towards more favourable conditions. Escherichia coli utilises a single sensory pathway, but little is known about signalling pathways in species with more complex systems. Results To investigate whether chemotaxis pathways in other bacteria follow the E. coli paradigm, we analysed 206 species encoding at least 1 homologue of each of the 5 core chemotaxis proteins (CheA, CheB, CheR, CheW and CheY. 61 species encode more than one of all of these 5 proteins, suggesting they have multiple chemotaxis pathways. Operon information is not available for most bacteria, so we developed a novel statistical approach to cluster che genes into putative operons. Using operon-based models, we reconstructed putative chemotaxis pathways for all 206 species. We show that cheA-cheW and cheR-cheB have strong preferences to occur in the same operon as two-gene blocks, which may reflect a functional requirement for co-transcription. However, other che genes, most notably cheY, are more dispersed on the genome. Comparison of our operons with shuffled equivalents demonstrates that specific patterns of genomic location may be a determining factor for the observed in vivo chemotaxis pathways. We then examined the chemotaxis pathways of Rhodobacter sphaeroides. Here, the PpfA protein is known to be critical for correct partitioning of proteins in the cytoplasmically-localised pathway. We found ppfA in che operons of many species, suggesting that partitioning of cytoplasmic Che protein clusters is common. We also examined the apparently non-typical chemotaxis components, CheA3, CheA4 and CheY6. We found that though variants of CheA proteins are rare, the CheY6 variant may be a common type of CheY, with a significantly disordered C-terminal region which may be functionally significant. Conclusions We find that many bacterial species potentially have multiple

  11. Policy Pathways: Energy Management Programmes for Industry

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2012-09-06

    The IEA Policy Pathway publications provide details on how to implement specific recommendations drawn from the IEA 25 Energy Efficiency Policy Recommendations. This Policy Pathway, jointly produced by the International Energy Agency and the Institute for Industrial Productivity, develops the critical steps for policy makers implementing energy management programmes for industry. Optimising energy use in industry is essential to improve industrial competitiveness and achieve wider societal goals such as energy security, economic recovery and development, climate change mitigation and environmental protection.While there is significant potential to decrease energy consumption in this sector, opportunities to improve energy efficiency are still under-exploited. Energy management programmes have shown to be instrumental in addressing many of the barriers that inhibit wide-scale uptake of energy management in industry. The Policy Pathway builds on lessons learned from country experiences and provides actionable guidance on how to plan and design, implement, evaluate and monitor energy management programmes for industry.

  12. Allorecognition pathways in transplant rejection and tolerance.

    Science.gov (United States)

    Ali, Jason M; Bolton, Eleanor M; Bradley, J Andrew; Pettigrew, Gavin J

    2013-10-27

    With the advent of cellular therapies, it has become clear that the success of future therapies in prolonging allograft survival will require an intimate understanding of the allorecognition pathways and effector mechanisms that are responsible for chronic rejection and late graft loss.Here, we consider current understanding of T-cell allorecognition pathways and discuss the most likely mechanisms by which these pathways collaborate with other effector mechanisms to cause allograft rejection. We also consider how this knowledge may inform development of future strategies to prevent allograft rejection.Although both direct and indirect pathway CD4 T cells appear active immediately after transplantation, it has emerged that indirect pathway CD4 T cells are likely to be the dominant alloreactive T-cell population late after transplantation. Their ability to provide help for generating long-lived alloantibody is likely one of the main mechanisms responsible for the progression of allograft vasculopathy and chronic rejection.Recent work has suggested that regulatory T cells may be an effective cellular therapy in transplantation. Given the above, adoptive therapy with CD4 regulatory T cells with indirect allospecificity is a rational first choice in attempting to attenuate the development and progression of chronic rejection; those with additional properties that enable inhibition of germinal center alloantibody responses hold particular appeal.

  13. Altered Leukocyte Sphingolipid Pathway in Breast Cancer

    Directory of Open Access Journals (Sweden)

    Larissa P. Maia

    2017-11-01

    Full Text Available Sphingolipid metabolism pathway is essential in membrane homeostasis, and its dysfunction has been associated with favorable tumor microenvironment, disease progression, and chemotherapy resistance. Its major components have key functions on survival and proliferation, with opposing effects. We have profiled the components of the sphingolipid pathway on leukocytes of breast cancer (BC patients undergoing chemotherapy treatment and without, including the five sphingosine 1-phosphate (S1P receptors, the major functional genes, and cytokines, in order to better understand the S1P signaling in the immune cells of these patients. To the best of our knowledge, this is the first characterization of the sphingolipid pathway in whole blood of BC patients. Skewed gene profiles favoring high SPHK1 expression toward S1P production during BC development was observed, which was reversed by chemotherapy treatment, and reached similar levels to those found in healthy donors. Such levels were also correlated with high levels of TNF-α. Our data revealed an important role of the sphingolipid pathway in immune cells in BC with skewed signaling of S1P receptors, which favored cancer development even under chemotherapy, and may probably be a trigger of cancer resistance. Thus, these molecules must be considered as a target pathway for combined BC therapeutics.

  14. The future use of pathway analysis in IAEA safeguards

    International Nuclear Information System (INIS)

    Budlong Sylvester, Kory; Pilat, J.; Murphy, Chantell

    2013-01-01

    Pathway analysis has the potential to play an important role in the development of a safeguards system that is more information driven, leveraging all the information available to the International Atomic Energy Agency (IAEA). Pathway analysis should be seen as an extension of traditional hypothesis testing used by the Agency in the past. The most attractive pathways based on the assessed capabilities of a given state can be identified and used in the development of state-level safeguards approaches. This ranking of pathways can be revised based on evidence of pathway use, or preparations for use, allowing limited safeguards resources to flow to the areas of highest concern. The possible uses of pathway analysis in the implementation of the IAEA's state-level concept are described along with implementation issues that will likely arise. The paper is followed by the slides of the presentation. (authors)

  15. A career path in clinical pathways.

    Science.gov (United States)

    Bower, K A

    1998-03-01

    Much like the development of a clinical path, the creation of a career path requires knowledge of patterns of behavior, needs for standardized education and skill development, along with variance analysis and individualized care. This nationally known nursing entrepreneur tells the story of her involvement in the development of case management and clinical pathways and how she turned that into a successful business that has changed how patient care is managed nationally and internationally.

  16. Th17 response and autophagy - main pathways implicated in the development of inflammatory bowel disease by genome-wide association studies: new factors involved in inflammatory bowel disease susceptibility

    Directory of Open Access Journals (Sweden)

    Roberto Díaz-Peña

    2015-09-01

    Full Text Available Inflammatory bowel disease (IBD is an entity that mainly includes ulcerative colitis (UC and Crohn's disease (CD. Improved health care, diet changes, and higher industrialization are associated with an increase in IBD prevalence. This supports the central role of environmental factors in the pathology of this disease. However, IBD also shows a relevant genetic component as shown by high heritability. Classic genetic studies showed relevant associations between IBD susceptibility and genes involved in the immune response. This is consistent with prior theories about IBD development. According to these, contact of the immune system with a high number of harmless antigens from the diet and the bacterial flora should originate tolerance while preserving response against pathogens. Failure to achieve this balance may originate the typical inflammatory response associated with IBD. Recently, genome-wide association studies (GWASs have confirmed the implication of the immune system, particularly the Th17 immune response, previously associated to other autoimmune diseases, and of autophagy. In this paper, the mechanisms involved in these two relevant pathways and their potential role in the pathogenesis of IBD are reviewed.

  17. Aquatic pathway 1

    International Nuclear Information System (INIS)

    1976-01-01

    This first part of the study discusses problems of exposure due to the emission of radioactive substances into the environment via the water pathway. Discussion is started with a paper on the fundamentals of calculation and another paper on the results of preliminary radiological model calculations. The colloquium will assess the present state of knowledge, helps to find an agreement between divergent opinions and determine open questions and possible solutions. Ten main problems have been raised, most of which pertain to site conditions. They are trated as sub-investigations by individual participants or working groups. The findings will be discussed in further colloquia. (orig.) [de

  18. The Reactome pathway knowledgebase.

    Science.gov (United States)

    Croft, David; Mundo, Antonio Fabregat; Haw, Robin; Milacic, Marija; Weiser, Joel; Wu, Guanming; Caudy, Michael; Garapati, Phani; Gillespie, Marc; Kamdar, Maulik R; Jassal, Bijay; Jupe, Steven; Matthews, Lisa; May, Bruce; Palatnik, Stanislav; Rothfels, Karen; Shamovsky, Veronica; Song, Heeyeon; Williams, Mark; Birney, Ewan; Hermjakob, Henning; Stein, Lincoln; D'Eustachio, Peter

    2014-01-01

    Reactome (http://www.reactome.org) is a manually curated open-source open-data resource of human pathways and reactions. The current version 46 describes 7088 human proteins (34% of the predicted human proteome), participating in 6744 reactions based on data extracted from 15 107 research publications with PubMed links. The Reactome Web site and analysis tool set have been completely redesigned to increase speed, flexibility and user friendliness. The data model has been extended to support annotation of disease processes due to infectious agents and to mutation.

  19. Seychelles Fisheries Connectivity and Transport Pathways

    Science.gov (United States)

    2015-09-30

    1 DISTRIBUTION STATEMENT A. Approved for public release; distribution is unlimited. Seychelles Fisheries Connectivity and Transport Pathways...overarching goal for the proposed work is to develop predictive capabilities for physical oceanography for the Seychelles region in support of locally...for ocean observations in the Seychelles region that will lead to long-term data collection efforts. In collaboration with local partnerships, we

  20. Pathways to deep decarbonization in India

    DEFF Research Database (Denmark)

    Shukla, P.; Dhar, Subash; Pathak, Minal

    This report is a part of the global Deep Decarbonisation Pathways (DDP) Project. The analysis consider two development scenarios for India and assess alternate roadmaps for transiting to a low carbon economy consistent with the globally agreed 2°C stabilization target. The report does not conside...

  1. Instructional Partnerships: A Pathway to Leadership

    Science.gov (United States)

    Moreillon, Judi, Ed.; Ballard, Susan, Ed.

    2013-01-01

    In this Best of "Knowledge Quest" monograph, the editors have collected seminal articles to support pre-service and in-service school librarians in developing and strengthening the instructional partner role. "Instructional Partnerships: A Pathway to Leadership" provides readers with background knowledge, research-based…

  2. Columbia River pathway report

    International Nuclear Information System (INIS)

    1991-07-01

    This report summarizes the river-pathway portion of the first phase of the Hanford Environmental Dose Reconstruction (HEDR) Project. The HEDR Project is estimating radiation doses that could have been received by the public from the Department of Energy's Hanford Site, in southeastern Washington State. Phase 1 of the river-pathway dose reconstruction effort sought to determine whether dose estimates could be calculated for populations in the area from above the Hanford Site at Priest Rapids Dam to below the site at McNary Dam from January 1964 to December 1966. Of the potential sources of radionuclides from the river, fish consumption was the most important. Doses from drinking water were lower at Pasco than at Richland and lower at Kennewick than at Pasco. The median values of preliminary dose estimates calculated by HEDR are similar to independent, previously published estimates of average doses to Richland residents. Later phases of the HEDR Project will address dose estimates for periods other than 1964--1966 and for populations downstream of McNary Dam. 17 refs., 19 figs., 1 tab

  3. An Automated Pipeline for Engineering Many-Enzyme Pathways: Computational Sequence Design, Pathway Expression-Flux Mapping, and Scalable Pathway Optimization.

    Science.gov (United States)

    Halper, Sean M; Cetnar, Daniel P; Salis, Howard M

    2018-01-01

    Engineering many-enzyme metabolic pathways suffers from the design curse of dimensionality. There are an astronomical number of synonymous DNA sequence choices, though relatively few will express an evolutionary robust, maximally productive pathway without metabolic bottlenecks. To solve this challenge, we have developed an integrated, automated computational-experimental pipeline that identifies a pathway's optimal DNA sequence without high-throughput screening or many cycles of design-build-test. The first step applies our Operon Calculator algorithm to design a host-specific evolutionary robust bacterial operon sequence with maximally tunable enzyme expression levels. The second step applies our RBS Library Calculator algorithm to systematically vary enzyme expression levels with the smallest-sized library. After characterizing a small number of constructed pathway variants, measurements are supplied to our Pathway Map Calculator algorithm, which then parameterizes a kinetic metabolic model that ultimately predicts the pathway's optimal enzyme expression levels and DNA sequences. Altogether, our algorithms provide the ability to efficiently map the pathway's sequence-expression-activity space and predict DNA sequences with desired metabolic fluxes. Here, we provide a step-by-step guide to applying the Pathway Optimization Pipeline on a desired multi-enzyme pathway in a bacterial host.

  4. Storylines and Pathways for Adaptation in Europe,

    DEFF Research Database (Denmark)

    Hilden, Mikael; Jeuken, Ad; Zandersen, Marianne

    2018-01-01

    as a central concept that helps to understand the range of available actions and the sequence of actions that can be taken under different scenarios of climate change and societal development. The chapter stresses the need to broadly understand the factors that affect adaptation challenges and that determine......This chapter focuses on how one can place climate change and adaptation actions in a wider context of societal change. It examines ways of conceptualizing the societal context for adaptation actions and illustrates how it plays out in different regions and substance areas in Europe and how...... this information can be used in reflecting on possibilities for adaptation at different levels. It places adaptation to climate change in the frame of Representative Concentration Pathways and Shared Socioeconomic Pathways, taking into account regional differences within Europe. The adaptation pathways are used...

  5. Decoding resistant hypertension signalling pathways.

    Science.gov (United States)

    Parreira, Ricardo Cambraia; Lacerda, Leandro Heleno Guimarães; Vasconcellos, Rebecca; Lima, Swiany Silveira; Santos, Anderson Kenedy; Fontana, Vanessa; Sandrim, Valéria Cristina; Resende, Rodrigo Ribeiro

    2017-12-01

    Resistant hypertension (RH) is a clinical condition in which the hypertensive patient has become resistant to drug therapy and is often associated with increased cardiovascular morbidity and mortality. Several signalling pathways have been studied and related to the development and progression of RH: modulation of sympathetic activity by leptin and aldosterone, primary aldosteronism, arterial stiffness, endothelial dysfunction and variations in the renin-angiotensin-aldosterone system (RAAS). miRNAs comprise a family of small non-coding RNAs that participate in the regulation of gene expression at post-transcriptional level. miRNAs are involved in the development of both cardiovascular damage and hypertension. Little is known of the molecular mechanisms that lead to development and progression of this condition. This review aims to cover the potential roles of miRNAs in the mechanisms associated with the development and consequences of RH, and explore the current state of the art of diagnostic and therapeutic tools based on miRNA approaches. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

  6. Cleanup standards and pathways analysis methods

    International Nuclear Information System (INIS)

    Devgun, J.S.

    1993-01-01

    Remediation of a radioactively contaminated site requires that certain regulatory criteria be met before the site can be released for unrestricted future use. Since the ultimate objective of remediation is to protect the public health and safety, residual radioactivity levels remaining at a site after cleanup must be below certain preset limits or meet acceptable dose or risk criteria. Release of a decontaminated site requires proof that the radiological data obtained from the site meet the regulatory criteria for such a release. Typically release criteria consist of a composite of acceptance limits that depend on the radionuclides, the media in which they are present, and federal and local regulations. In recent years, the US Department of Energy (DOE) has developed a pathways analysis model to determine site-specific soil activity concentration guidelines for radionuclides that do not have established generic acceptance limits. The DOE pathways analysis computer code (developed by Argonne National Laboratory for the DOE) is called RESRAD (Gilbert et al. 1989). Similar efforts have been initiated by the US Nuclear Regulatory Commission (NRC) to develop and use dose-related criteria based on genetic pathways analyses rather than simplistic numerical limits on residual radioactivity. The focus of this paper is radionuclide contaminated soil. Cleanup standards are reviewed, pathways analysis methods are described, and an example is presented in which RESRAD was used to derive cleanup guidelines

  7. Hedgehog signaling pathway in neuroblastoma differentiation.

    Science.gov (United States)

    Souzaki, Ryota; Tajiri, Tatsuro; Souzaki, Masae; Kinoshita, Yoshiaki; Tanaka, Sakura; Kohashi, Kenichi; Oda, Yoshinao; Katano, Mitsuo; Taguchi, Tomoaki

    2010-12-01

    The hedgehog (Hh) signaling pathway is activated in some adult cancers. On the other hand, the Hh signaling pathway plays an important role in the development of the neural crest in embryos. The aim of this study is to show the activation of Hh signaling pathway in neuroblastoma (NB), a pediatric malignancy arising from neural crest cells, and to reveal the meaning of the Hh signaling pathway in NB development. This study analyzed the expression of Sonic hedgehog (Shh), GLI1, and Patched 1 (Ptch1), transactivators of Hh signaling pathway, by immunohistochemistry in 82 NB and 10 ganglioneuroblastoma cases. All 92 cases were evaluated for the status of MYCN amplification. Of the 92 cases, 67 (73%) were positive for Shh, 62 cases (67%) were positive for GLI1, and 73 cases (79%) were positive for Ptch1. Only 2 (10%) of the 20 cases with MYCN amplification were positive for Shh and GLI1, and 4 cases (20%) were positive for Ptch1 (MYCN amplification vs no MYCN amplification, P ≦ .01). The percentage of GLI1-positive cells in the cases with INSS stage 1 without MYCN amplification was significantly higher than that with INSS stage 4. Of 72 cases without MYCN amplification, 60 were GLI1-positive. Twelve cases were GLI1-negative, and the prognosis of the GLI1-positive cases was significantly better than that of the GLI1-negative cases (P = .015). Most of NBs without MYCN amplification were positive for Shh, GLI1, and Ptch1. In the cases without MYCN amplification, the high expression of GLI1 was significantly associated with early clinical stage and a good prognosis of the patients. In contrast to adult cancers, the activation of the Hh signaling pathway in NB may be associated with the differentiation of the NB. Copyright © 2010 Elsevier Inc. All rights reserved.

  8. Summer 2014 Pathways Report

    Science.gov (United States)

    Hand, Zachary

    2014-01-01

    Over the summer I had the exciting opportunity to work for NASA at the Kennedy Space Center as a Mission Assurance Engineering intern. When I was offered a position in mission assurance for the Safety and Mission Assurance directorate's Launch Services Division, I didn't really know what I would be doing, but I knew it would be an excellent opportunity to learn and grow professionally. In this report I will provide some background information on the Launch Services Division, as well as detail my duties and accomplishments during my time as an intern. Additionally, I will relate the significance of my work experience to my current academic work and future career goals. This report contains background information on Mission Assurance Engineering, a description of my duties and accomplishments over the summer of 2014, and relates the significance of my work experience to my school work and future career goals. It is a required document for the Pathways program.

  9. Representing Development

    DEFF Research Database (Denmark)

    Representing Development presents the different social representations that have formed the idea of development in Western thinking over the past three centuries. Offering an acute perspective on the current state of developmental science and providing constructive insights into future pathways, ...

  10. Integrated care pathways for airway diseases (AIRWAYS-ICPs)

    NARCIS (Netherlands)

    Bousquet, J.; Addis, A.; Adcock, I.; Agache, I.; Agusti, A.; Alonso, A.; Annesi-Maesano, I.; Anto, J. M.; Bachert, C.; Baena-Cagnani, C. E.; Bai, C.; Baigenzhin, A.; Barbara, C.; Barnes, P. J.; Bateman, E. D.; Beck, L.; Bedbrook, A.; Bel, E. H.; Benezet, O.; Bennoor, K. S.; Benson, M.; Bernabeu-Wittel, M.; Bewick, M.; Bindslev-Jensen, C.; Blain, H.; Blasi, F.; Bonini, M.; Bonini, S.; Boulet, L. P.; Bourdin, A.; Bourret, R.; Bousquet, P. J.; Brightling, C. E.; Briggs, A.; Brozek, J.; Buhl, R.; Bush, A.; Caimmi, D.; Calderon, M.; Calverley, P.; Camargos, P. A.; Camuzat, T.; Canonica, G. W.; Carlsen, K. H.; Casale, T. B.; Cazzola, M.; Cepeda Sarabia, A. M.; Cesario, A.; Chen, Y. Z.; Chkhartishvili, E.; Chavannes, N. H.; Chiron, R.; Chuchalin, A.; Chung, K. F.; Cox, L.; Crooks, G.; Crooks, M. G.; Cruz, A. A.; Custovic, A.; Dahl, R.; Dahlen, S. E.; de Blay, F.; Dedeu, T.; Deleanu, D.; Demoly, P.; Devillier, P.; Didier, A.; Dinh-Xuan, A. T.; Djukanovic, R.; Dokic, D.; Douagui, H.; Dubakiene, R.; Eglin, S.; Elliot, F.; Emuzyte, R.; Fabbri, L.; Fink Wagner, A.; Fletcher, M.; Fokkens, W. J.; Fonseca, J.; Franco, A.; Frith, P.; Furber, A.; Gaga, M.; Garcés, J.; Garcia-Aymerich, J.; Gamkrelidze, A.; Gonzales-Diaz, S.; Gouzi, F.; Guzmán, M. A.; Haahtela, T.; Harrison, D.; Hayot, M.; Heaney, L. G.; Heinrich, J.; Hellings, P. W.; Hooper, J.; Humbert, M.; Hyland, M.; Iaccarino, G.; Jakovenko, D.; Jardim, J. R.; Jeandel, C.; Jenkins, C.; Johnston, S. L.; Jonquet, O.; Joos, G.; Jung, K. S.; Kalayci, O.; Karunanithi, S.; Keil, T.; Khaltaev, N.; Kolek, V.; Kowalski, M. L.; Kull, I.; Kuna, P.; Kvedariene, V.; Le, L. T.; Lodrup Carlsen, K. C.; Louis, R.; MacNee, W.; Mair, A.; Majer, I.; Manning, P.; de Manuel Keenoy, E.; Masjedi, M. R.; Melen, E.; Melo-Gomes, E.; Menzies-Gow, A.; Mercier, G.; Mercier, J.; Michel, J. P.; Miculinic, N.; Mihaltan, F.; Milenkovic, B.; Molimard, M.; Momas, I.; Montilla-Santana, A.; Morais-Almeida, M.; Morgan, M.; N'Diaye, M.; Nafti, S.; Nekam, K.; Neou, A.; Nicod, L.; O'Hehir, R.; Ohta, K.; Paggiaro, P.; Palkonen, S.; Palmer, S.; Papadopoulos, N. G.; Papi, A.; Passalacqua, G.; Pavord, I.; Pigearias, B.; Plavec, D.; Postma, D. S.; Price, D.; Rabe, K. F.; Radier Pontal, F.; Redon, J.; Rennard, S.; Roberts, J.; Robine, J. M.; Roca, J.; Roche, N.; Rodenas, F.; Roggeri, A.; Rolland, C.; Rosado-Pinto, J.; Ryan, D.; Samolinski, B.; Sanchez-Borges, M.; Schünemann, H. J.; Sheikh, A.; Shields, M.; Siafakas, N.; Sibille, Y.; Similowski, T.; Small, I.; Sola-Morales, O.; Sooronbaev, T.; Stelmach, R.; Sterk, P. J.; Stiris, T.; Sud, P.; Tellier, V.; To, T.; Todo-Bom, A.; Triggiani, M.; Valenta, R.; Valero, A. L.; Valiulis, A.; Valovirta, E.; van Ganse, E.; Vandenplas, O.; Vasankari, T.; Vestbo, J.; Vezzani, G.; Viegi, G.; Visier, L.; Vogelmeier, C.; Vontetsianos, T.; Wagstaff, R.; Wahn, U.; Wallaert, B.; Whalley, B.; Wickman, M.; Williams, D. M.; Wilson, N.; Yawn, B. P.; Yiallouros, P. K.; Yorgancioglu, A.; Yusuf, O. M.; Zar, H. J.; Zhong, N.; Zidarn, M.; Zuberbier, T.

    2014-01-01

    The objective of Integrated Care Pathways for Airway Diseases (AIRWAYS-ICPs) is to launch a collaboration to develop multi-sectoral care pathways for chronic respiratory diseases in European countries and regions. AIRWAYS-ICPs has strategic relevance to the European Union Health Strategy and will

  11. Integrated care pathways for airway diseases (AIRWAYS-ICPs)

    NARCIS (Netherlands)

    Bousquet, J.; Addis, A.; Adcock, I.; Agache, I.; Agusti, A.; Alonso, A.; Annesi-Maesano, I.; Anto, J. M.; Bachert, C.; Baena-Cagnani, C. E.; Bai, C.; Baigenzhin, A.; Barbara, C.; Barnes, P. J.; Bateman, E. D.; Beck, L.; Bedbrook, A.; Bel, E. H.; Benezet, O.; Bennoor, K. S.; Benson, M.; Bernabeu-Wittel, M.; Bewick, M.; Bindslev-Jensen, C.; Blain, H.; Blasi, F.; Bonini, M.; Bonini, S.; Boulet, L. P.; Bourdin, A.; Bourret, R.; Bousquet, P. J.; Brightling, C. E.; Briggs, A.; Brozek, J.; Buh, R.; Bush, A.; Caimmi, D.; Calderon, M.; Calverley, P.; Camargos, P. A.; Camuzat, T.; Canonica, G. W.; Carlsen, K. H.; Casale, T. B.; Cazzola, M.; Sarabia, A. M. Cepeda; Cesario, A.; Chen, Y. Z.; Chkhartishvili, E.; Chavannes, N. H.; Chiron, R.; Chuchalin, A.; Chung, K. F.; Cox, L.; Crooks, G.; Crooks, M. G.; Cruz, A. A.; Custovic, A.; Dahl, R.; Dahlen, S. E.; De Blay, F.; Dedeu, T.; Deleanu, D.; Demoly, P.; Devillier, P.; Didier, A.; Dinh-Xuan, A. T.; Djukanovic, R.; Dokic, D.; Douagui, H.; Dubakiene, R.; Eglin, S.; Elliot, F.; Emuzyte, R.; Fabbri, L.; Wagner, A. Fink; Fletcher, M.; Fokkens, W. J.; Fonseca, J.; Franco, A.; Frith, P.; Furber, A.; Gaga, M.; Garces, J.; Garcia-Aymerich, J.; Gamkrelidze, A.; Gonzales-Diaz, S.; Gouzi, F.; Guzman, M. A.; Haahtela, T.; Harrison, D.; Hayot, M.; Heaney, L. G.; Heinrich, J.; Hellings, P. W.; Hooper, J.; Humbert, M.; Hyland, M.; Iaccarino, G.; Jakovenko, D.; Jardim, J. R.; Jeandel, C.; Jenkins, C.; Johnston, S. L.; Jonquet, O.; Joos, G.; Jung, K. S.; Kalayci, O.; Karunanithi, S.; Keil, T.; Khaltaev, N.; Kolek, V.; Kowalski, M. L.; Kull, I.; Kuna, P.; Kvedariene, V.; Le, L. T.; Carlsen, K. C. Lodrup; Louis, R.; MacNee, W.; Mair, A.; Majer, I.; Manning, P.; Keenoy, E. de Manuel; Masjedi, M. R.; Meten, E.; Melo-Gomes, E.; Menzies-Gow, A.; Mercier, G.; Mercier, J.; Michel, J. P.; Miculinic, N.; Mihaltan, F.; Milenkovic, B.; Molimard, M.; Mamas, I.; Montilla-Santana, A.; Morais-Almeida, M.; Morgan, M.; N'Diaye, M.; Nafti, S.; Nekam, K.; Neou, A.; Nicod, L.; O'Hehir, R.; Ohta, K.; Paggiaro, P.; Palkonen, S.; Palmer, S.; Papadopoulos, N. G.; Papi, A.; Passalacqua, G.; Pavord, I.; Pigearias, B.; Plavec, D.; Postma, D. S.; Price, D.; Rabe, K. F.; Pontal, F. Radier; Redon, J.; Rennard, S.; Roberts, J.; Robine, J. M.; Roca, J.; Roche, N.; Rodenas, F.; Roggeri, A.; Rolland, C.; Rosado-Pinto, J.; Ryan, D.; Samolinski, B.; Sanchez-Borges, M.; Schunemann, H. J.; Sheikh, A.; Shields, M.; Siafakas, N.; Sibille, Y.; Similowski, T.; Small, I.; Sola-Morales, O.; Sooronbaev, T.; Stelmach, R.; Sterk, P. J.; Stiris, T.; Sud, P.; Tellier, V.; To, T.; Todo-Bom, A.; Triggiani, M.; Valenta, R.; Valero, A. L.; Valiulis, A.; Valovirta, E.; Van Ganse, E.; Vandenplas, O.; Vasankari, T.; Vestbo, J.; Vezzani, G.; Viegi, G.; Visier, L.; Vogelmeier, C.; Vontetsianos, T.; Wagstaff, R.; Wahn, U.; Wallaert, B.; Whalley, B.; Wickman, M.; Williams, D. M.; Wilson, N.; Yawn, B. P.; Yiallouros, P. K.; Yorgancioglu, A.; Yusuf, O. M.; Zar, H. J.; Zhong, N.; Zidarn, M.; Zuberbier, T.

    The objective of Integrated Care Pathways for Airway Diseases (AIRWAYS-ICPs) is to launch a collaboration to develop multi-sectoral care pathways for chronic respiratory diseases in European countries and regions. AIRWAYS-ICPs has strategic relevance to the European Union Health Strategy and will

  12. Pathways to Aggression in Urban Elementary School Youth

    Science.gov (United States)

    Ozkol, Hivren; Zucker, Marla; Spinazzola, Joseph

    2011-01-01

    This study examined the pathways from violence exposure to aggressive behaviors in urban, elementary school youth. We utilized structural equation modeling to examine putative causal pathways between children's exposure to violence, development of posttraumatic stress symptoms, permissive attitudes towards violence, and engagement in aggressive…

  13. Protein-Trap Insertional Mutagenesis Uncovers New Genes Involved in Zebrafish Skin Development, Including a Neuregulin 2a-Based ErbB Signaling Pathway Required during Median Fin Fold Morphogenesis.

    Directory of Open Access Journals (Sweden)

    Stephanie E Westcot

    Full Text Available Skin disorders are widespread, but available treatments are limited. A more comprehensive understanding of skin development mechanisms will drive identification of new treatment targets and modalities. Here we report the Zebrafish Integument Project (ZIP, an expression-driven platform for identifying new skin genes and phenotypes in the vertebrate model Danio rerio (zebrafish. In vivo selection for skin-specific expression of gene-break transposon (GBT mutant lines identified eleven new, revertible GBT alleles of genes involved in skin development. Eight genes--fras1, grip1, hmcn1, msxc, col4a4, ahnak, capn12, and nrg2a--had been described in an integumentary context to varying degrees, while arhgef25b, fkbp10b, and megf6a emerged as novel skin genes. Embryos homozygous for a GBT insertion within neuregulin 2a (nrg2a revealed a novel requirement for a Neuregulin 2a (Nrg2a-ErbB2/3-AKT signaling pathway governing the apicobasal organization of a subset of epidermal cells during median fin fold (MFF morphogenesis. In nrg2a mutant larvae, the basal keratinocytes within the apical MFF, known as ridge cells, displayed reduced pAKT levels as well as reduced apical domains and exaggerated basolateral domains. Those defects compromised proper ridge cell elongation into a flattened epithelial morphology, resulting in thickened MFF edges. Pharmacological inhibition verified that Nrg2a signals through the ErbB receptor tyrosine kinase network. Moreover, knockdown of the epithelial polarity regulator and tumor suppressor lgl2 ameliorated the nrg2a mutant phenotype. Identifying Lgl2 as an antagonist of Nrg2a-ErbB signaling revealed a significantly earlier role for Lgl2 during epidermal morphogenesis than has been described to date. Furthermore, our findings demonstrated that successive, coordinated ridge cell shape changes drive apical MFF development, making MFF ridge cells a valuable model for investigating how the coordinated regulation of cell polarity

  14. Protein-Trap Insertional Mutagenesis Uncovers New Genes Involved in Zebrafish Skin Development, Including a Neuregulin 2a-Based ErbB Signaling Pathway Required during Median Fin Fold Morphogenesis.

    Science.gov (United States)

    Westcot, Stephanie E; Hatzold, Julia; Urban, Mark D; Richetti, Stefânia K; Skuster, Kimberly J; Harm, Rhianna M; Lopez Cervera, Roberto; Umemoto, Noriko; McNulty, Melissa S; Clark, Karl J; Hammerschmidt, Matthias; Ekker, Stephen C

    2015-01-01

    Skin disorders are widespread, but available treatments are limited. A more comprehensive understanding of skin development mechanisms will drive identification of new treatment targets and modalities. Here we report the Zebrafish Integument Project (ZIP), an expression-driven platform for identifying new skin genes and phenotypes in the vertebrate model Danio rerio (zebrafish). In vivo selection for skin-specific expression of gene-break transposon (GBT) mutant lines identified eleven new, revertible GBT alleles of genes involved in skin development. Eight genes--fras1, grip1, hmcn1, msxc, col4a4, ahnak, capn12, and nrg2a--had been described in an integumentary context to varying degrees, while arhgef25b, fkbp10b, and megf6a emerged as novel skin genes. Embryos homozygous for a GBT insertion within neuregulin 2a (nrg2a) revealed a novel requirement for a Neuregulin 2a (Nrg2a)-ErbB2/3-AKT signaling pathway governing the apicobasal organization of a subset of epidermal cells during median fin fold (MFF) morphogenesis. In nrg2a mutant larvae, the basal keratinocytes within the apical MFF, known as ridge cells, displayed reduced pAKT levels as well as reduced apical domains and exaggerated basolateral domains. Those defects compromised proper ridge cell elongation into a flattened epithelial morphology, resulting in thickened MFF edges. Pharmacological inhibition verified that Nrg2a signals through the ErbB receptor tyrosine kinase network. Moreover, knockdown of the epithelial polarity regulator and tumor suppressor lgl2 ameliorated the nrg2a mutant phenotype. Identifying Lgl2 as an antagonist of Nrg2a-ErbB signaling revealed a significantly earlier role for Lgl2 during epidermal morphogenesis than has been described to date. Furthermore, our findings demonstrated that successive, coordinated ridge cell shape changes drive apical MFF development, making MFF ridge cells a valuable model for investigating how the coordinated regulation of cell polarity and cell shape

  15. Developing an Integrated Treatment Pathway for a Post-Coronary Artery Bypass Grating (CABG) Geriatric Patient with Comorbid Hypertension and Type 1 Diabetes Mellitus for Treating Acute Hypoglycemia and Electrolyte Imbalance.

    Science.gov (United States)

    Naqvi, Atta Abbas; Shah, Amna; Ahmad, Rizwan; Ahmad, Niyaz

    2017-01-01

    The ailments afflicting the elderly population is a well-defined specialty of medicine. It calls for an immaculately designed health-care plan to treat diseases in geriatrics. For chronic illnesses such as diabetes mellitus (DM), coronary heart disease, and hypertension (HTN), they require proper management throughout the rest of patient's life. An integrated treatment pathway helps in treatment decision-making and improving standards of health care for the patient. This case describes an exclusive clinical pharmacist-driven designing of an integrated treatment pathway for a post-coronary artery bypass grafting (CABG) geriatric male patient with DM type I and HTN for the treatment of hypoglycemia and electrolyte imbalance. The treatment begins addressing the chief complaints which were vomiting and unconsciousness. Biochemical screening is essential to establish a diagnosis of electrolyte imbalance along with blood glucose level after which the integrated pathway defines the treatment course. This individualized treatment pathway provides an outline of the course of treatment of acute hypoglycemia, electrolyte imbalance as well as some unconfirmed diagnosis, namely, acute coronary syndrome and respiratory tract infection for a post-CABG geriatric patient with HTN and type 1 DM. The eligibility criterion for patients to be treated according to treatment pathway is to fall in the defined category.

  16. Exploring Student and Advisor Experiences in a College-University Pathway Program: A Study of the Bachelor of Commerce Pathway

    Science.gov (United States)

    Percival, Jennifer; DiGiuseppe, Maurice; Goodman, Bill; LeSage, Ann; Hinch, Ron; Samis, John; Sanchez, Otto; Rodrigues, Anna; Raby, Phil; Longo, Fabiola; De La Rocha, Arlene

    2015-01-01

    Currently, there is great interest across Ontario in the expansion of pathway programs between colleges and universities. Through strategic partnerships, two Ontario-based postsecondary institutions (a college and a university) have developed innovative and effective pathway programs that facilitate the transition of students between institutions…

  17. Connectome imaging for mapping human brain pathways.

    Science.gov (United States)

    Shi, Y; Toga, A W

    2017-09-01

    With the fast advance of connectome imaging techniques, we have the opportunity of mapping the human brain pathways in vivo at unprecedented resolution. In this article we review the current developments of diffusion magnetic resonance imaging (MRI) for the reconstruction of anatomical pathways in connectome studies. We first introduce the background of diffusion MRI with an emphasis on the technical advances and challenges in state-of-the-art multi-shell acquisition schemes used in the Human Connectome Project. Characterization of the microstructural environment in the human brain is discussed from the tensor model to the general fiber orientation distribution (FOD) models that can resolve crossing fibers in each voxel of the image. Using FOD-based tractography, we describe novel methods for fiber bundle reconstruction and graph-based connectivity analysis. Building upon these novel developments, there have already been successful applications of connectome imaging techniques in reconstructing challenging brain pathways. Examples including retinofugal and brainstem pathways will be reviewed. Finally, we discuss future directions in connectome imaging and its interaction with other aspects of brain imaging research.

  18. Role of Notch signalling pathway in cancer and its association with ...

    Indian Academy of Sciences (India)

    The Notch signalling pathway is an evolutionarily conserved cell signalling pathway involved in the development of organ- ... Abnormal Notch signalling is seen in many cancers like T-cell acute ...... Morgan T. H. 1917 The theory of the gene.

  19. Understanding trade pathways to target biosecurity surveillance

    Directory of Open Access Journals (Sweden)

    Manuel Colunga-Garcia

    2013-09-01

    Full Text Available Increasing trends in global trade make it extremely difficult to prevent the entry of all potential invasive species (IS. Establishing early detection strategies thus becomes an important part of the continuum used to reduce the introduction of invasive species. One part necessary to ensure the success of these strategies is the determination of priority survey areas based on invasion pressure. We used a pathway-centred conceptual model of pest invasion to address these questions: what role does global trade play in invasion pressure of plant ecosystems and how could an understanding of this role be used to enhance early detection strategies? We concluded that the relative level of invasion pressure for destination ecosystems can be influenced by the intensity of pathway usage (import volume and frequency, the number and type of pathways with a similar destination, and the number of different ecological regions that serve as the source for imports to the same destination. As these factors increase, pressure typically intensifies because of increasing a propagule pressure, b likelihood of transporting pests with higher intrinsic invasion potential, and c likelihood of transporting pests into ecosystems with higher invasibility. We used maritime containerized imports of live plants into the contiguous U.S. as a case study to illustrate the practical implications of the model to determine hotspot areas of relative invasion pressure for agricultural and forest ecosystems (two ecosystems with high potential invasibility. Our results illustrated the importance of how a pathway-centred model could be used to highlight potential target areas for early detection strategies for IS. Many of the hotspots in agricultural and forest ecosystems were within major U.S. metropolitan areas. Invasion ecologists can utilize pathway-centred conceptual models to a better understand the role of human-mediated pathways in pest establishment, b enhance current

  20. TRWG developmental pathway for biospecimen-based assessment modalities

    Energy Technology Data Exchange (ETDEWEB)

    Translational Research Working Group; Srivastava, Sudhir; Gray, Joe W.; Reid, Brian J.; Grad, Oren; Greenwood, Addison; Hawk, Ernest T.

    2008-09-03

    The Translational Research Working Group (TRWG) was created as a national initiative to evaluate the current status of NCI's investment in translational research and envision its future. The TRWG conceptualized translational research as a set of six developmental processes or pathways focused on various clinical goals. One of those pathways describes the development of biospecimen-based assays that utilize biomarkers for the detection, diagnosis, prognosis, and assessment of response to cancer treatment. The biospecimen-based assessment modality (BM) pathway was conceived not as comprehensive description of the corresponding real-world processes, but rather as a tool designed to facilitate movement of a candidate assay through the translational process to the point where it can be handed off for definitive clinical testing. This paper introduces the pathway in the context of prior work and discusses key challenges associated with the biomarker development process in light of the pathway.

  1. Escher: A Web Application for Building, Sharing, and Embedding Data-Rich Visualizations of Biological Pathways

    DEFF Research Database (Denmark)

    King, Zachary A.; Draeger, Andreas; Ebrahim, Ali

    2015-01-01

    Escher is a web application for visualizing data on biological pathways. Three key features make Escher a uniquely effective tool for pathway visualization. First, users can rapidly design new pathway maps. Escher provides pathway suggestions based on user data and genome-scale models, so users c...... of these features and explains how the development approach used for Escher can be used to guide the development of future visualization tools....

  2. Novel metabolic pathways in Archaea.

    Science.gov (United States)

    Sato, Takaaki; Atomi, Haruyuki

    2011-06-01

    The Archaea harbor many metabolic pathways that differ to previously recognized classical pathways. Glycolysis is carried out by modified versions of the Embden-Meyerhof and Entner-Doudoroff pathways. Thermophilic archaea have recently been found to harbor a bi-functional fructose-1,6-bisphosphate aldolase/phosphatase for gluconeogenesis. A number of novel pentose-degrading pathways have also been recently identified. In terms of anabolic metabolism, a pathway for acetate assimilation, the methylaspartate cycle, and two CO2-fixing pathways, the 3-hydroxypropionate/4-hydroxybutyrate cycle and the dicarboxylate/4-hydroxybutyrate cycle, have been elucidated. As for biosynthetic pathways, recent studies have clarified the enzymes responsible for several steps involved in the biosynthesis of inositol phospholipids, polyamine, coenzyme A, flavin adeninedinucleotide and heme. By examining the presence/absence of homologs of these enzymes on genome sequences, we have found that the majority of these enzymes and pathways are specific to the Archaea. Copyright © 2011 Elsevier Ltd. All rights reserved.

  3. Evolution of the TOR Pathway.

    NARCIS (Netherlands)

    Dam, T.J.P. van; Zwartkruis, F.J.; Bos, J.L.; Snel, B.

    2011-01-01

    The TOR kinase is a major regulator of growth in eukaryotes. Many components of the TOR pathway are implicated in cancer and metabolic diseases in humans. Analysis of the evolution of TOR and its pathway may provide fundamental insight into the evolution of growth regulation in eukaryotes and

  4. Pathways Intern Report

    Science.gov (United States)

    Bell, Evan A.

    2015-01-01

    During my time at NASA, I worked with the Granular Mechanics and Regolith Organization (GMRO), better known as Swamp Works. The goal of the lab is to find ways to utilize resources found after the astronaut or robot has landed on another planet or asteroid. This concept is known as in-situ resource utilization and it is critical to long term missions such as those to Mars. During my time here I worked on the Asteroid and Lava Tube Free Flyer project (ALTFF). A lava tube, such as the one shown in figure 1, is a long tear drop shaped cavern that is produced when molten lava tunnels through the surrounding rock creating large unground pathways. Before mining for resources on Mars or on asteroids, a sampling mission must be done to scout out useful resource deposits. ALTFF's goal is to provide a low cost, autonomous scout robot that can sample the surface and return to the mother ship or lander for further processing of the samples. The vehicle will be looking for water ice in the regolith that can be processed into either potable water, hydrogen and oxygen fuel, or a binder material for 3D printing. By using a low cost craft to sample, there is much less risk to the more expensive mother ship or lander. While my main task was the construction of a simulation environment to test control code in and the construction of the asteroid free flyer prototype, there were other tasks that I performed relating to the ALTFF project.

  5. pathways in myogenesis

    Directory of Open Access Journals (Sweden)

    Marta Milewska

    2014-05-01

    Full Text Available The commitment of myogenic cells in skeletal muscle differentiation requires earlier irreversible interruption of the cell cycle. At the molecular level, several key regulators of the cell cycle have been identified: cyclin-dependent kinases and their cyclins stimulate the cell cycle progress and its arrest is determined by the activity of cdk inhibitors (Cip/Kip and INK protein families and pocket protein family: Rb, p107 and p130. The biological activity of cyclin/cdk complexes allows the successive phases of the cell cycle to occur. Myoblast specialization, differentiation and fusion require the activity of myogenic regulatory factors, which include MyoD, myogenin, Myf5 and MRF4. MyoD and Myf5 play a role in muscle cell specialization, myogenin controls the differentiation process, whereas MRF4 is involved in myotube maturation. The deregulation of the cell cycle leads to uncontrolled proliferation, which antagonizes the functions of myogenic factors and it explains the lack of differentiation-specific gene expression in dividing cells. Conversely, the myogenic factor MyoD seems to cooperate with cell cycle inhibitors leading to inhibition of cell cycle progress and commitment to the differentiation process. The hypophosphorylated form of Rb and cdk inhibitors play an important role in permanent arrest of the cell cycle in differentiated myotubes. Furthermore, cyclin/cdk complexes not only regulate cell division by phosphorylation of several substrates, but may also control other cellular processes such as signal transduction, differentiation and apoptosis. Beyond regulating the cell cycle, Cip/Kip proteins play an important role in cell death, transcription regulation, cell fate determination, cell migration and cytoskeletal dynamics. The article summarizes current knowledge concerning the interactions of intracellular signaling pathways controlling crucial stages of fetal and regenerative myogenesis.

  6. Overlapping riboflavin supply pathways in bacteria.

    Science.gov (United States)

    García-Angulo, Víctor Antonio

    2017-03-01

    Riboflavin derivatives are essential cofactors for a myriad of flavoproteins. In bacteria, flavins importance extends beyond their role as intracellular protein cofactors, as secreted flavins are a key metabolite in a variety of physiological processes. Bacteria obtain riboflavin through the endogenous riboflavin biosynthetic pathway (RBP) or by the use of importer proteins. Bacteria frequently encode multiple paralogs of the RBP enzymes and as for other micronutrient supply pathways, biosynthesis and uptake functions largely coexist. It is proposed that bacteria shut down biosynthesis and would rather uptake riboflavin when the vitamin is environmentally available. Recently, the overlap of riboflavin provisioning elements has gained attention and the functions of duplicated paralogs of RBP enzymes started to be addressed. Results point towards the existence of a modular structure in the bacterial riboflavin supply pathways. Such structure uses subsets of RBP genes to supply riboflavin for specific functions. Given the importance of riboflavin in intra and extracellular bacterial physiology, this complex array of riboflavin provision pathways may have developed to contend with the various riboflavin requirements. In riboflavin-prototrophic bacteria, riboflavin transporters could represent a module for riboflavin provision for particular, yet unidentified processes, rather than substituting for the RBP as usually assumed.

  7. Research advances in Hedgehog signaling pathway in hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    LIU Jia

    2015-02-01

    Full Text Available Hedgehog (Hh signaling pathway is present in many animals and plays an important role in regulating embryonic development and differentiation. Aberrant activation of Hh signaling contributes to the pathogenesis of many malignancies. Recent studies have shown that dysregulated Hh signaling pathway participates in the tumorigenesis, tumor invasion, and metastasis of hepatocellular carcinoma (HCC. Investigation of the relationship between Hh signaling pathway and HCC will help elucidate the molecular mechanism of pathogenesis of HCC and provide a new insight into the development of novel anticancer therapy and therapeutic target.

  8. Whole Algae Hydrothermal Liquefaction Technology Pathway

    Energy Technology Data Exchange (ETDEWEB)

    Biddy, Mary J.; Davis, Ryan; Jones, Susanne B.; Zhu, Yunhua

    2013-03-31

    In support of the Bioenergy Technologies Office, the National Renewable Energy Laboratory (NREL) and the Pacific Northwest National Laboratory (PNNL) are undertaking studies of biomass conversion technologies to hydrocarbon fuels to identify barriers and target research toward reducing conversion costs. Process designs and preliminary economic estimates for each of these pathway cases were developed using rigorous modeling tools (Aspen Plus and Chemcad). These analyses incorporated the best information available at the time of development, including data from recent pilot and bench-scale demonstrations, collaborative industrial and academic partners, and published literature and patents. This pathway case investigates the feasibility of using whole wet microalgae as a feedstock for conversion via hydrothermal liquefaction. Technical barriers and key research needs have been assessed in order for the hydrothermal liquefaction of microalgae to be competitive with petroleum-derived gasoline, diesel and jet range blendstocks.

  9. Transition pathways for a UK low carbon electricity future

    International Nuclear Information System (INIS)

    Foxon, Timothy J.

    2013-01-01

    Achieving long-term targets for greenhouse gas emissions reductions, such as the UK's legally-binding target of reducing its emissions by 80% by 2050, will require a transition in systems for meeting and shaping energy service demands, involving radical substitution to low-carbon supply technologies and improvements in end-use energy efficiency. This paper describes the development and high-level analysis of a set of transition pathways to a UK low carbon electricity system, explaining key features of the core pathways developed and the distinctiveness and value of the approach. The pathways use an ‘action space’ concept to explore the dynamic interactions between choices made by actors, which are influenced by the competing governance ‘framings’ or ‘logics’ that different actors pursue. The paper sets out three core transition pathways – Market Rules, Central Co-ordination and Thousand Flowers, in which market, government and civil society logics respectively dominate. It summarises the key technological and institutional changes in these pathways, and the roles of actors in bringing these about. This leads to an identification of the key risks to the realisation of each of the pathways, and of the challenges for individuals, businesses, social movements and policy-makers in taking action to bring them about and sustain them. - Highlights: ► Development of a set of transition pathways to a UK low carbon electricity system. ► Action space to explore the dynamic interactions between choices made by actors. ► Three core pathways in which market, government and civil society logics dominate. ► Key technological and institutional changes, and the roles of actors in pathways. ► Challenges for different actors in realising pathways.

  10. Career pathways in research: support and management.

    Science.gov (United States)

    Kenkre, J E; Foxcroft, D R

    This article, the third in the series on career pathways, highlights support and management careers open to nurses working in the NHS and research and development, or people working for funding bodies or charitable organisations. These roles involve ensuring that the right infrastructure is in place to support research projects, and the correct decisions are made about which research projects should be supported and commissioned.

  11. Non-Smad signaling pathways.

    Science.gov (United States)

    Mu, Yabing; Gudey, Shyam Kumar; Landström, Maréne

    2012-01-01

    Transforming growth factor-beta (TGFβ) is a key regulator of cell fate during embryogenesis and has also emerged as a potent driver of the epithelial-mesenchymal transition during tumor progression. TGFβ signals are transduced by transmembrane type I and type II serine/threonine kinase receptors (TβRI and TβRII, respectively). The activated TβR complex phosphorylates Smad2 and Smad3, converting them into transcriptional regulators that complex with Smad4. TGFβ also uses non-Smad signaling pathways such as the p38 and Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) pathways to convey its signals. Ubiquitin ligase tumor necrosis factor (TNF)-receptor-associated factor 6 (TRAF6) and TGFβ-associated kinase 1 (TAK1) have recently been shown to be crucial for the activation of the p38 and JNK MAPK pathways. Other TGFβ-induced non-Smad signaling pathways include the phosphoinositide 3-kinase-Akt-mTOR pathway, the small GTPases Rho, Rac, and Cdc42, and the Ras-Erk-MAPK pathway. Signals induced by TGFβ are tightly regulated and specified by post-translational modifications of the signaling components, since they dictate the subcellular localization, activity, and duration of the signal. In this review, we discuss recent findings in the field of TGFβ-induced responses by non-Smad signaling pathways.

  12. Functional assay of the alternative complement pathway of rat serum

    International Nuclear Information System (INIS)

    Coonrod, J.D.; Jenkins, S.D.

    1979-01-01

    Two functional assays of the alternative pathway of complement activation in rat serum were developed. In the first assay, conditions were established for titration of alternative pathway activity by use of the 50% hemolytic end-point of rabbit red blood cells (RaRBC) in serum treated with ethyleneglycol-bis-(beta-aminoethyl ether)-N, N'-tetraacetic acid (EGTA). The second assay of alternative pathway activity was based on the opsonization of heat-killed radiolabeled pneumococci of serotype 25 (Pn25). Opsonization of Pn25 was shown to proceed entirely via the alternative pathway in rat serum. There was excellent correlation between the results obtained with the RaRBC lysis test and those obtained with the opsonization test. Because of its technical simplicity, the RaRBC lysis test appeared to be the single most useful test of alternative pathway activity in rat serum. (Auth.)

  13. Stress responses during ageing: molecular pathways regulating protein homeostasis.

    Science.gov (United States)

    Kyriakakis, Emmanouil; Princz, Andrea; Tavernarakis, Nektarios

    2015-01-01

    The ageing process is characterized by deterioration of physiological function accompanied by frailty and ageing-associated diseases. The most broadly and well-studied pathways influencing ageing are the insulin/insulin-like growth factor 1 signaling pathway and the dietary restriction pathway. Recent studies in diverse organisms have also delineated emerging pathways, which collectively or independently contribute to ageing. Among them the proteostatic-stress-response networks, inextricably affect normal ageing by maintaining or restoring protein homeostasis to preserve proper cellular and organismal function. In this chapter, we survey the involvement of heat stress and endoplasmic reticulum stress responses in the regulation of longevity, placing emphasis on the cross talk between different response mechanisms and their systemic effects. We further discuss novel insights relevant to the molecular pathways mediating these stress responses that may facilitate the development of innovative interventions targeting age-related pathologies such as diabetes, cancer, cardiovascular and neurodegenerative diseases.

  14. Integrated Genomic Analysis of the Ubiquitin Pathway across Cancer Types

    Direc