Sample records for yap state micronesia

  1. Vegetation survey of Yap, Federated States of Micronesia

    Treesearch

    Marjorie C. Falanruw; Craig D. Whitesell; Thomas G. Cole; Colin D. MacLean; Alan H. Ambacher

    1987-01-01

    Yap is one of the four States in the Federated States of Micronesia. Knowledge of the extent and composition of its vegetation, including forest land, is needed for land-use planning. To fill this need, a formal agreement was drawn up between the High Commissioner of the U.S. Trust Territory of the Pacific Islands and two agencies of the U.S. Department of Agriculture-...

  2. Retention and Attrition of Pacific School Teachers and Administrators (RAPSTA) Study: Yap State, Federated States of Micronesia. Research Series.

    ERIC Educational Resources Information Center

    Research and Development Cadre, Honolulu, HI.

    Pacific Resources for Education and Learning (PREL) works closely with 10 American-affiliated Pacific entities: (1) American Samoa; (2) the Commonwealth of Northern Mariana Islands; (3) the Federated States of Micronesia (Chuuk, Kosrae, Pohnpei, Yap); (4) Guam; (5) Hawaii; (6) the Republic of the Marshall Islands; and (7) the Republic of Palau.…

  3. Provisional keys to the genera of seaweeds of Micronesia, with new records for Guam and Yap

    PubMed Central

    LOBBAN, CHRISTOPHER S.; N'YEURT, ANTOINE D.R.

    2008-01-01

    Artificial keys to the genera of blue-green, red, brown, and green marine benthic algae of Micronesia are given, including virtually all the genera reported from Palau, Guam, Commonwealth of the Northern Marianas, Federated States of Micronesia and the Marshall Islands. Twenty-two new species or genera are reported here for Guam and 7 for Yap; 11 of these are also new for Micronesia. Note is made of several recent published records for Guam and 2 species recently raised from varietal status. Finally, a list is given of nomenclatural changes that affect the 2003 revised checklist. An interactive version of the keys is included in the algal biodiversity website at http://university.uog.edu/botany/474. PMID:18958300

  4. Federated States of Micronesia's forest resources, 2006

    Treesearch

    Joseph A. Donnegan; Sarah L. Butler; Olaf Kuegler; Bruce A. Hiserote

    2011-01-01

    The Forest Inventory and Analysis program collected, analyzed, and summarized field data on 73 forested field plots on the islands of Kosrae, Chuuk, Pohnpei, and Yap in the Federated States of Micronesia (FSM). Estimates of forest area, tree stem volume and biomass, the numbers of trees, tree damages, and the distribution of tree sizes were summarized for this...

  5. We Navigate Together into the Future. Selected Papers from the PIALA Conference 2016, Pacific Islands Association of Libraries, Archives, and Museums Annual Conference (26th, Colonia, Yap State, Federated States of Micronesia, November 21-26, 2016)

    ERIC Educational Resources Information Center

    Drake, Paul Burton, Ed.

    2017-01-01

    This publication follows the tradition of publishing selected papers from the Pacific Islands Association of Libraries, Archives and Museums (PIALA) annual conferences. This 26th annual conference was held in Colonia, Yap State, Federated States of Micronesia, November 21-26, 2016 and celebrated the Association's Twenty-Fifth anniversary. This…

  6. Telemedicine in the Federated States of Micronesia.

    PubMed

    Rutstein, D

    2000-09-01

    Telemedicine (other than costly long distance telephone and facsimile messages) in the Federated States of Micronesia (FSM) started approximately 4 years ago with the establishment of Internet access in the State of Yap. A local access, for medical use only, via already established trunk lines maintained by Continental Airlines was established. It provided a connection to CompuServe at a baud rate of 300 bps. FSM TeleCom provided this free service. While this connection was slow, it allowed medical staff at Yap State Hospital to send and receive text based e-mail regarding patient management. By its use interest was generated in both medical and non-medical individuals to develop a commercial full scale Internet service. In March 1996, TeleCom became a full scale commercial Internet Service Provider in Yap. Rates were reasonable and the CompuServe access was phased out. The full scale internet allowed medical personnel to engage in telemedicine activities, including email; email attachments; the search and retrieval of medical literature; transmission to medical specialists of X-rays, ECG's and other images; and real-time teleconferencing over the Internet with both audio and video. In addition, to the improvement of medical care, this allowed for greater efficiency in arranging referral of patients for medical treatment outside of the FSM.

  7. Trees of Yap: a field guide

    Treesearch

    Marjorie V. Cushing Falanruw

    2015-01-01

    Descriptions, drawings, and photographs are presented for trees found on the Yap Islands in the Federated States of Micronesia. Included are all recorded native trees and most introduced trees as well as new records of native and introduced trees. Additional information is provided on tree distribution, status, vernacular names in Micronesia, and English names when...

  8. Retention and Attrition of Pacific School Teachers and Administrators (RAPSTA) Study: Kosrae State, Federated States of Micronesia. Research Series.

    ERIC Educational Resources Information Center

    Research and Development Cadre, Honolulu, HI.

    Pacific Resources for Education and Learning (PREL) works with 10 American-affiliated Pacific entities: American Samoa, the Commonwealth of Northern Mariana Islands, the Federated States of Micronesia (Chuuk, Kosrae, Pohnpei, Yap), Guam, Hawaii, the Republic of the Marshall Islands, and the Republic of Palau. The survey raises awareness of the…

  9. Retention and Attrition of Pacific School Teachers and Administrators (RAPSTA) Study: Pohnpei State, Federated States of Micronesia. Research Series.

    ERIC Educational Resources Information Center

    Research and Development Cadre, Honolulu, HI.

    Pacific Resources for Education and Learning (PREL) works with 10 American-affiliated Pacific entities: American Samoa, the Commonwealth of Northern Mariana Islands, the Federated States of Micronesia (Chuuk, Kosrae, Pohnpei, Yap), Guam, Hawaii, the Republic of the Marshall Islands, and the Republic of Palau. The main purpose of this survey was to…

  10. Retention and Attrition of Pacific School Teachers and Administrators (RAPSTA) Study: Chuuk State, Federated States of Micronesia. Research Series.

    ERIC Educational Resources Information Center

    Research and Development Cadre, Honolulu, HI.

    Pacific Resources for Education and Learning (PREL) works with 10 American-affiliated Pacific entities: (1) American Samoa; (2) the Commonwealth of Northern Mariana Islands; (3) the Federated States of Micronesia (Chuuk, Kosrae, Pohnpei, Yap); (4) Guam; (5) Hawaii; (6) the Republic of the Marshall Islands; and (7) the Republic of Palau. This…

  11. Vegetation types on acid soils of Micronesia

    Treesearch

    Marjorie C. Falanruw; Thomas G.. Cole; Craig D. Whitesell

    1987-01-01

    The soils and vegetation of the Caroline high islands, Federated States of Micronesia, are being mapped by the U.S. Department of Agriculture's Forest Service and Soil Conservation Service. By the end of 1987, vegetation maps and reports on Kosrae, Pohnpei, Yap, four Truk Islands, and Palau are expected to be available. To compare soil types with vegetation types...

  12. Correlates of Academic Performance of Freshman Students at the College of Micronesia--Federated States of Micronesia, Pohnpei Campus

    ERIC Educational Resources Information Center

    Lamsis, Pablo H., Jr.

    2010-01-01

    The study aimed to correlate the performance of Pohnpei Campus freshman students in the College of Micronesia-Federated States of Micronesia during the fall semester 2009 to students' socio-demographic characteristics, parents'/guardians' socio-demographic characteristics, and school characteristics. The Student Survey Questionnaire gathered data…

  13. Vitamin A deficiency among children--Federated States of Micronesia, 2000.

    PubMed

    2001-06-22

    Vitamin A, a fat-soluble, heat-stable nutrient (retinol) derived from animal sources and certain fruits and vegetables, forms the basic component of retinal pigments and plays a vital role in optimal health, growth, and development. Vitamin A deficiency (VAD) (serum retinol < or = 20 microg/dL [< or = 0.7 micromol/L] for subclinical VAD) can substantially increase the risk for childhood mortality from infectious and noninfectious causes. VAD impairs the mobilization and transport of iron and is usually associated with anemia and reduced growth. VAD is a major public health problem in parts of Africa, Asia, Latin America, and the Western Pacific. In Chuuk and Pohnpei, two of the four Federated States of Micronesia (FSM) (2000 population: 107,008), nutrition surveys during the early 1990s documented VAD prevalences among the highest in the world (CDC, unpublished data, 1991; U.S. Public Health Service, unpublished data, 1994). In response to these findings, FSM health authorities, with support of the United Nations Children's Fund (UNICEF), began distributing vitamin A supplements in 1993 and 1998 in Chuuk and Pohnpei, respectively. In November 1999, FSM requested assistance from CDC in VAD assessment surveys of children in Kosrae and Yap, the other two FSM states. This report summarizes levels of serum retinol and prevalence of VAD and other indicators of nutritional status among children aged 24-59 months in Kosrae and Yap. The findings indicated low serum retinol levels and high VAD prevalences but no substantial stunting or wasting. A comprehensive, long-term national strategy is needed in FSM to promote sustained improvement in vitamin A status.

  14. Forest pathology in Yap, Palau, Pohnpei, Kosrae, Guam and Saipan, Sept. 2013

    Treesearch

    Phil Cannon

    2014-01-01

    In September of 2013, an opportunity was seized by the Regional Forest Pathologist to do some work on the following islands in Micronesia and the Marianas: Yap, Palau, Guam, Saipan, Pohnpei, and Kosrae. The principle justification for doing the work at this time was that satellite images showed large areas of dead mangroves on Yap (Liu, pers. com). Many...

  15. On the status, reproductive biology and management of fruit bats of Yap, Micronesia

    Treesearch

    Marjorie V. C. Falanruw

    1988-01-01

    Traditional exploitation of fruit bats of Yap is limited, however commercial exploitation greatly reduced populations until they were protected indefinitely. There will be continued need to manage this resource. This paper is based on field work conducted while Yap's bats were intensively hunted. Data from field work is augmented with information from...

  16. Commercial coral-reef fisheries across Micronesia: A need for improving management

    NASA Astrophysics Data System (ADS)

    Houk, P.; Rhodes, K.; Cuetos-Bueno, J.; Lindfield, S.; Fread, V.; McIlwain, J. L.

    2012-03-01

    A dearth of scientific data surrounding Micronesia's coral-reef fisheries has limited their formal assessment and continues to hinder local and regional management efforts. We approach this problem by comparing catch-based datasets from market landings across Micronesia to evaluate fishery status in the Commonwealth of the Northern Mariana Islands (CNMI), Guam, Yap, and Pohnpei. Initial examinations found that calm weather and low lunar illumination predicted between 6% (Yap) and 30% (CNMI) of the variances in daily commercial landings. Both environmentally driven catch success and daily catch variability increased in accordance with reef-fish demand indices. Subsequent insight from species composition and size-at-capture data supported these findings, highlighting reduced trophic levels and capture sizes where higher human-population-per-reef-area existed. Among the 12-15 target species and/or species complexes that accounted for 70% of the harvest biomass, capture sizes were consistently smallest for CNMI and Guam, often below the reported mean reproductive sizes. Comparatively, Pohnpei has the greatest potential for reef fisheries, with a large reef area (303 km2) and a moderate human population (34,000 people). However, the estimated harvest volume of 476 mt year-1 was 8-9 times higher than other jurisdictions. Even on Yap where the reef-fish demand index was lowest (67.7 people km-2 reef habitat), many target fish were harvested below their mean reproductive sizes, including the iconic green bumphead parrotfish and humphead wrasse, as well as several other herbivores. We discuss our results with respect to the contemporary doctrine surrounding size-spectra, catch composition, and catch frequencies that afford insight into fishery pressure and status. We posit that regional catch-based policies (initially) instituted at the market level, combined with area and gear-based restrictions, represent plausible vectors for improving Micronesian fisheries.

  17. Carnivorous plants in Micronesia

    Treesearch

    Robert R. Ziemer

    1988-01-01

    Micronesia encompasses about 2,100 islands scattered over some 12 million sq km of the central Pacific between Hawaii and the Philippines. Only about 125 of these small islands are inhabited. The total land area of Micronesia is less than 3,200 sq km, about the size of the state of Rhode Island. The largest island is Guam, with an area of about 540 sq km. There are...

  18. Population decline induced by gonorrhoea and tuberculosis transmission: Micronesia during the Japanese occupation, 1919–45

    PubMed Central

    Singer, Burton H.

    2011-01-01

    The islands of Yap in Micronesia survived a period of severe depopulation during the Japanese occupation from 1919 to 1945. Using data from historical documents, supplemented by ethnographic evidence, we calibrate a simulation model that accounts for this phenomenon. Our model tracks the reproduction histories of a synthetic cohort of women in Yap, including effects of infertility due to gonorrhoea as well as tuberculosis mortality, and predicts the net reproduction rate (NRR). In this particular case and throughout history, human migrations and associated social and cultural interactions have frequently been accompanied by dramatic changes in patterns of disease transmission and substantial demographic consequences. Despite the broad emphasis on mortality as a measure of demographic consequences in the historical and contemporary literature, there are important instances where life expectancy at birth, fertility rates, and total population size are important demographic consequences. We find that gonorrhoea may have significantly contributed to depopulation during the Japanese occupation of Micronesia, due to repeated infections and high risk of sterility. Results of our model suggest that gonorrhoea alone could have reduced the net reproduction rate by 82%, whereas deaths from tuberculosis may have contributed to a 17% decline. PMID:21666856

  19. Use classification of mangrove areas, Pohnpei, Federated States of Micronesia

    Treesearch

    Nora N. Devoe

    1992-01-01

    An integrated biotic inventory of mangrove areas of Pohnpei, Federated States of Micronesia, was undertaken to determine priority areas for preservation and sustained-yield management. Criteria for the designation of reserve areas included: the presence of threatened or endangered species; rare species or particularly rich biota; undisturbed old-growth communities; the...

  20. Vegetation survey of Moen, Dublon, Fefan, and Eten, State of Truk, Federated States of Micronesia

    Treesearch

    Marjorie Falanruw; Thomas G. Cole; Alan H Ambacher; Katherine E. McDuffie; John. Hom

    1987-01-01

    Truk is one of the four States of the Federated States of Micronesia (FSM). Knowledge of the extent and composition of its vegetation, including forest land, is needed for land-use planning. To fill this need, a formal agreement was drawn up between the High Commissioner of the Trust Territory of the Pacific Islands and two agencies of the U.S. Department of...

  1. Use of monitoring data to support conservation management and policy decisions in Micronesia.

    PubMed

    Montambault, Jensen Reitz; Wongbusarakum, Supin; Leberer, Trina; Joseph, Eugene; Andrew, Wayne; Castro, Fran; Nevitt, Brooke; Golbuu, Yimnang; Oldiais, Noelle W; Groves, Craig R; Kostka, Willy; Houk, Peter

    2015-10-01

    Adaptive management implies a continuous knowledge-based decision-making process in conservation. Yet, the coupling of scientific monitoring and management frameworks remains rare in practice because formal and informal communication pathways are lacking. We examined 4 cases in Micronesia where conservation practitioners are using new knowledge in the form of monitoring data to advance marine conservation. These cases were drawn from projects in Micronesia Challenge jurisdictions that received funding for coupled monitoring-to-management frameworks and encompassed all segments of adaptive management. Monitoring in Helen Reef, Republic of Palau, was catalyzed by coral bleaching and revealed evidence of overfishing that led to increased enforcement and outreach. In Nimpal Channel, Yap, Federated States of Micronesia (FSM), monitoring the recovery of marine food resources after customary restrictions were put in place led to new, more effective enforcement approaches. Monitoring in Laolao Bay, Saipan, Commonwealth of the Northern Mariana Islands, was catalyzed by observable sediment loads from poor land-use practices and resulted in actions that reduced land-based threats, particularly littering and illegal burning, and revealed additional threats from overfishing. Pohnpei (FSM) began monitoring after observed declines in grouper spawning aggregations. This data led to adjusting marine conservation area boundaries and implementing market-based size class restrictions. Two themes emerged from these cases. First, in each case monitoring was conducted in a manner relevant to the social and ecological systems and integrated into the decision-making process. Second, conservation practitioners and scientists in these cases integrated culturally appropriate stakeholder engagement throughout all phases of the adaptive management cycle. More broadly, our study suggests, when describing adaptive management, providing more details on how monitoring and management activities are

  2. The Palau AHEC--academizing the public health work plan: capacity development and innovation in Micronesia.

    PubMed

    Dever, Greg; Finau, Sitaleki; Kuartei, Stevenson; Durand, A Mark; Rykken, David; Yano, Victor; Untalan, Pedro; Withy, Kelley; Tellei, Patrick; Baravilala, Wame; Pierantozzi, Sandra; Tellei, Jullie

    2005-03-01

    The Palau Area Health Education Center (AHEC)--a program of the University of Hawaii's John A. Burns School of Medicine (JABSOM) and based at Palau Community College--was established in 2001 in response to the recommendations of the 1998 Institute of Medicine (IOM) report--Pacific Partnerships for Health--Charting a New Course for the 21st Century1. One of IOM's core recommendations was to promote the training of the primary health care workforce among the U.S.-Associated Pacific Islands. Since its inception in 2001, the Palau AHEC has coordinated overall 37 postgraduate and undergraduate courses in General Practice and Public Health taught by the University of Auckland Faculty of Medicine and Health Sciences and the Fiji School of Medicine's School of Public Health and Primary Care (SPH&PC) in Palau, Yap State, and the Republic of the Marshall Islands. Currently 139 physicians, nurses, health administrators, and environmental health workers are registered as active students in Palau (58), Yap State (22), and the RMI (59). Notably, the Palau AHEC and the SPH&PC have worked in an innovative partnership with the Palau Ministry of Health to operationalize the MOH's public health work plan to implement a comprehensive community health survey of all 4,376 households in Palau, interviewing 79% of the total population, to determine Palau's health indicators. To accomplish this, the SPH&PC developed and taught a curriculum for Palau physicians and public health nurses on how to design the survey, gather, and analyze data in order to develop and implement appropriately responsive intervention and treatment programs to address Palau's old and newer morbidities. In early FY2005, two other Micronesian AHECs--the Yap State and Commonwealth of the Northern Mariana Islands AHECs--were funded through JABSOM administered grants which will also address the primary care training needs of Micronesia's remote and isolated health workforce.

  3. Benchmarking the State of Yap's Education Management Information System. REL 2016-117

    ERIC Educational Resources Information Center

    Cicchinelli, Louis F.; Kendall, John S.; Dandapani, Nitara

    2016-01-01

    A quality data management system, such as an education management information system (EMIS), a state longitudinal data system, or a data warehouse, is key to ensuring that education policy, planning, and strategy decisions are grounded in accurate information. The chief state school officers of the Federated States of Micronesia have recognized…

  4. Micronesian Art Historical Research and Library Collection Resources in Micronesia.

    ERIC Educational Resources Information Center

    Haynes, Douglas

    This paper briefly describes the geographic region and some indigenous artifacts of Micronesia. The state of art historical research in the area and currently available library resources are discussed. Micronesia is comprised of seven island nations peopled by distinctly unique cultural groups. Study of Micronesian art and architecture is…

  5. Mosquitoes of Guam and the Northern Marianas: Distribution, Checklists, and Notes on Mosquito-Borne Pathogens

    DTIC Science & Technology

    2011-09-01

    2011). Also, a recent outbreak of Zika virus on Yap Island, Micronesia31 raised concern over its spread to Guam and other islands of the Marianas...1991 ;(suppl 3):33-39. 31. Duffy MR, Chen TH, Hancock WT, et al. Zika virus outbreak on Yap Island, Federated States of Micronesia. N Eng/ J Med... virus or malaria by the US Army Public Health Command Region- Pacific and no positive samples were detected (W.K.R., written communication, March

  6. Microphthalmia and anophthalmia in Chuuk State, Federated States of Micronesia.

    PubMed

    Yomai, A A; Pavlin, B I

    2010-04-01

    Microphthalmia ('small eye') and anophthalmia ('no eye') are rare congenital defects of eye development. Previous studies utilizing a variety of methodologies have estimated their combined incidence at anywhere from 4 to 30 cases per 100,000 live births. In Chuuk, Federated States of Micronesia, there have been 42 cases detected since 1988, yielding an estimated incidence of 140 cases per 100,000. A number of putative genetic and environmental causes have previously been associated with microphthalmia and anophthalmia, including vitamin A deficiency. To date, it is unclear which of these factors may play a role in the alarmingly high rates observed in Chuuk. The Chuuk Division of Public Health has proposed a study to explore these potential causes, which will hopefully shed light on the prevention of these rare but debilitating conditions.

  7. Micronesia: Understanding Our Government.

    ERIC Educational Resources Information Center

    Laue, John Paul; Tuck, Betty H.

    Part of an adult education curriculum development project, the document describes the islands of Micronesia, emphasizing governmental structure and how it operates. The document was developed with Micronesians for Micronesians and is in two main sections. Section I tells stories about the interests and needs of each of the districts in Micronesia,…

  8. Educational Technology and the World Wide Web in the Pacific Islands

    ERIC Educational Resources Information Center

    Iding, Marie; Skouge, James

    2005-01-01

    This paper describes technology issues that educators, teacher educators and students in the Pacific Islands confront, specifically in American Samoa (a U.S. territory) and Chuuk (one of the Federated States of Micronesia). It will also briefly mention issues relevant to Yap and Kosrae (two other states in Micronesia), and the Marshall Islands.…

  9. Areca (betel) nut chewing practices of adults and health behaviors of their children in the Freely Associated States, Micronesia: Findings from the Children's Healthy Living (CHL) Program.

    PubMed

    Paulino, Yvette C; Ettienne, Reynolette; Novotny, Rachel; Wilkens, Lynne R; Shomour, Moria; Sigrah, Cecilia; Remengesau, Shelley D; Johnson, Emihner L; Alfred, Julia M; Gilmatam, Daisy F

    2017-10-01

    Chewing areca (betel) nut has been deemed carcinogenic. The practice has become a public health concern in Micronesia. The Children's Healthy Living (CHL) Program included an areca (betel) nut questionnaire in a survey of household characteristics in the Freely Associated States (FAS). This paper describes areca (betel) nut chewing practices of adults and the health behaviors of their children. A cross-section of 1200 children (2-8 year-olds) and their caregivers in Chuuk, Kosrae, Pohnpei, Republic of Palau, Republic of the Marshall Islands (RMI), and Yap were recruited. Socio-demographics, adult areca (betel) nut chewing practices, and other health behaviors of children and adults were assessed. Child anthropometric measurements were collected to estimate weight status. The FAS areca (betel) nut chewing prevalence was 42%, ranging from 3% (RMI) to 94% (Yap). Among chewers, 84% added tobacco, 97% added slaked lime, 85% added betel leaf, and 24% mixed the components with alcohol. Among FAS children, 95% practiced daily teeth-brushing and 53% visited the dentist annually. Compared to non-chewing households, areca (betel) nut chewing households were more likely to have very young children enrolled, more highly educated adults, and members that used tobacco and alcohol. The FAS areca (betel) nut chewing prevalence (42%) is above the world prevalence of 10-20%, with wide variability across the islands. The oral health findings in this study may inform future oral cancer prevention programs or policies. Regular monitoring of areca (betel) nut use is needed to measure the impact of such programs or policies. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Erosion and sedimentation control on roads and construction sites in the Federated States of Micronesia

    Treesearch

    Robert R. Ziemer; Walter F. Megahan

    1991-01-01

    Enclosed is the report that Walt Megahan and I prepared following our trip to States of Micronesia. As we discussed earlier, we felt that it was redundant to produce a set of guidelines for road construction since the FAO Conservation Guide 13/5 that was issued in 1989 (ISBN 92-5-102789-X) covers the subject extensively. We felt that we could best tailor this report to...

  11. PIALA '95. Preservation of Culture through Archives and Libraries. Papers from the Annual Pacific Islands Association of Libraries and Archives Conference (5th, Colonia, Yap, Federated States of Micronesia, November 6-10, 1995).

    ERIC Educational Resources Information Center

    Cohen, Arlene, Ed.

    The annual conference of the Pacific Islands Association of Libraries and Archives addressed various topics of interest to librarians, archivists, and educators in the Pacific Islands. The proceedings include welcoming remarks by 2 Yap state government officials and PIALA President Herbert Del Rosario; a keynote address by Dr. Marcia J.…

  12. MAPPING IN MICRONESIA.

    USGS Publications Warehouse

    Olsen, Randle W.; Swinnerton, J.R.

    1984-01-01

    The U. S. Geological Survey has recently completed a series of new topographic maps of Micronesia in cooperation with the Trust Territory of the Pacific Islands, the Federal agency administering the islands. Monocolor 1:10,000-scale manuscripts were compiled, from which 1:25,000-scale metric quadrangles were derived with symbology consistent with USGS quadrangle mapping. The publication of these new maps coincides with the impending political changes resulting from self-determination referendums held in Micronesia. Local sources have helped considerably with field logistics and resolution of geographic name controversies. Technical aspects of this project included development of tropical feature symbology, location of cadastral subdivisions and associated boundaries and mapping of many outlying coral reefs.

  13. Climate change in the federated states of Micronesia: Food and water security, climate risk management, and adaptive strategies

    USGS Publications Warehouse

    Fletcher, Charles H.; Richmond, Bruce M.

    2010-01-01

    This is a report of findings following research and a three-week field assessment (April 2009) of the Federated States of Micronesia (FSM) in response to nation-wide marine inundation by extreme tides (December 2007, September 2008, December 2008).3 The study was conducted at the request of the US Department of Agriculture Forest Service and the state and federal governments of FSM.

  14. Toward a National System of Postsecondary Education in the Federated States of Micronesia. A Special Report on Postsecondary Education.

    ERIC Educational Resources Information Center

    Lerner, Max J.; Drier, Harry N.

    In 1989 the Center on Education and Training for Employment at Ohio State University was asked by the government of the Federated States of Micronesia (FSM) to conduct a study on the postsecondary educational system within the FSM. During the course of the study, the survey team's postsecondary specialist visited community college campuses and…

  15. Distribution of Mosquito Larvae on Kosrae Island, Kosrae State, the Federated States of Micronesia

    PubMed Central

    Noda, Shinichi; Yamamoto, Sota; Toma, Takako; Taulung, Livinson

    2013-01-01

    Surveys of mosquito larvae were carried out in six areas of Kosrae Island, Kosrae State, the Federated States of Micronesia in December 2009 and June 2012. A total of 962 larvae of six species were collected from 106 natural and artificial habitats. They were identified as Aedes aegypti, Ae. albopictus, Ae. marshallensis, Culex quinquefasciatus, Cx. annulirostris, and Cx. kusaiensis. This is the first report from Kosrae Island for three of these species—Ae. marshallensis, Cx. quinquefasciatus, and Cx. annulirostris. The most abundant species was Ae. albopictus, followed by Ae. marshallensis, and these two species were found in all areas. Relatively large numbers of Cx. quinquefasciatus and Cx. kusaiensis were found in five areas. Fewer Cx. annulirostris were found, and only in three areas. Aedes aegypti larvae were collected from a single habitat at Tafunsak in 2009. To prevent the outbreak of dengue fever, environmental management should focus on the destruction, alteration, disposal and recycling of containers that produce larger numbers of adult Aedes mosquitoes. PMID:24478593

  16. Language Dictionaries and Grammars of Guam and Micronesia.

    ERIC Educational Resources Information Center

    Goetzfridt, Nicholas J.; Goniwiecha, Mark C.

    The study of language reference materials, particularly dictionaries and grammar works, for languages of Guam and Micronesia includes a brief history of their evolution and an annotated bibliography. An introductory section describes the geographic situation of Micronesia and chronicles numerous periods of foreign influence: Spanish Colonization…

  17. A Model for Experiential Learning: Coastal Ecosystems of Micronesia in a Changing Climate

    NASA Astrophysics Data System (ADS)

    Maloney, A. E.; Ladd, N.; Sachs, J. P.

    2013-12-01

    An intensive undergraduate course taught in Pohnpei (Federated States of Micronesia) June 22nd - July 19, 2013 through the University of Washington Study Abroad Program allowed students to intimately explore estuary, mangrove, seagrass, and coral habitat from a systems perspective. The curriculum was developed in 2010 and 2011 during a similar course taught in nearby Kosrae (Federated States of Micronesia). The course was based on field surveys of several sites from each habitat with assistance from local non-profit groups and Pohnpei government partners. Field surveys were supplemented by lectures from these local agencies or the course instructors. Classroom activities explored the connectivity of coastal ecosystems and how each habitat may be impacted by climate change. The instructors' tropical paleoclimate research objectives further supplemented the curriculum. Additionally, cultural activities facilitated an understanding of social interactions with coastal ecosystems. Students wrote field reports for each habitat and communicated the data to local agencies in an oral presentation. The class activities allowed students to engage in data analysis, interpretation, and communication while being immersed in the unique culture and environment of Micronesia.

  18. Education and Cultural Change: A View from Micronesia

    ERIC Educational Resources Information Center

    O'Neill, Jon G.; Spennemann, Dirk H.R.

    2008-01-01

    Traditionally, transmission of cultural knowledge between generations in Micronesia was the role of family, in particular parents and grand parents. To what extent is that role still important today? In this article, we draw on data obtained from questionnaires distributed to high school and primary school children throughout Micronesia in 2002…

  19. Cytoplasmatic and Nuclear YAP1 and pYAP1 Staining in Urothelial Bladder Cancer.

    PubMed

    Latz, Stefan; Umbach, Tine; Goltz, Diane; Kristiansen, Glen; Müller, Stephan C; Ellinger, Jörg

    2016-01-01

    Yes-associated protein 1 (YAP1), the nuclear effector of the Hippo pathway, plays an important role in many tumor entities. We evaluated staining and clinical significance of YAP1 and phosphorylated YAP1 (pYAP1) in urothelial bladder cancer (BCA). We used a tissue micorarray with samples of patients with muscle-invasive bladder cancer (MIBC, n = 192), non-muscle-invasive bladder cancer (NMIBC, n = 192) and normal urothelial bladder tissue (CTRL, n = 38) to determine the immunhistochemical staining of YAP1 and pYAP1. Cytoplasmatic and nuclear levels were evaluated. The t test was used for comparative analysis. Overall survival and progression-free survival were evaluated by Kaplan-Meier estimates and the Cox proportional hazard regression model. Nuclear YAP1 as well as cytoplasmatic pYAP1 levels were higher in CTRL than in BCA, whereby both--NMIBC and MIBC--had lower levels than CTRL. Among patients with MIBC, cytoplasmatic YAP1 and pYAP1 staining decreased with advanced stage. YAP1 and pYAP1 staining did not correlate with the recurrence rate, progression-free, cancer-specific or overall survival. Immunhistochemical staining and subcellular localization of YAP1 and pYAP1 are different for BCA, NMIBC, MIBC and CTRL, indicating that the Hippo pathway is involved in urothelial carcinogenesis. © 2015 S. Karger AG, Basel.

  20. Atoll-scale patterns in coral reef community structure: Human signatures on Ulithi Atoll, Micronesia.

    PubMed

    Crane, Nicole L; Nelson, Peter; Abelson, Avigdor; Precoda, Kristin; Rulmal, John; Bernardi, Giacomo; Paddack, Michelle

    2017-01-01

    The dynamic relationship between reefs and the people who utilize them at a subsistence level is poorly understood. This paper characterizes atoll-scale patterns in shallow coral reef habitat and fish community structure, and correlates these with environmental characteristics and anthropogenic factors, critical to conservation efforts for the reefs and the people who depend on them. Hierarchical clustering analyses by site for benthic composition and fish community resulted in the same 3 major clusters: cluster 1-oceanic (close proximity to deep water) and uninhabited (low human impact); cluster 2-oceanic and inhabited (high human impact); and cluster 3-lagoonal (facing the inside of the lagoon) and inhabited (highest human impact). Distance from village, reef exposure to deep water and human population size had the greatest effect in predicting the fish and benthic community structure. Our study demonstrates a strong association between benthic and fish community structure and human use across the Ulithi Atoll (Yap State, Federated States of Micronesia) and confirms a pattern observed by local people that an 'opportunistic' scleractinian coral (Montipora sp.) is associated with more highly impacted reefs. Our findings suggest that small human populations (subsistence fishing) can nevertheless have considerable ecological impacts on reefs due, in part, to changes in fishing practices rather than overfishing per se, as well as larger global trends. Findings from this work can assist in building local capacity to manage reef resources across an atoll-wide scale, and illustrates the importance of anthropogenic impact even in small communities.

  1. Hazard analysis of landslides triggered by Typhoon Chata'an on July 2, 2002, in Chuuk State, Federated States of Micronesia

    USGS Publications Warehouse

    Harp, Edwin L.; Reid, Mark E.; Michael, John A.

    2004-01-01

    More than 250 landslides were triggered across the eastern volcanic islands of Chuuk State in the Federated States of Micronesia by torrential rainfall from tropical storm Chata?an on July 2, 2002. Landslides triggered during nearly 20 inches of rainfall in less than 24 hours caused 43 fatalities and the destruction or damage of 231 structures, including homes, schools, community centers, and medical dispensaries. Landslides also buried roads, crops, and water supplies. The landslides ranged in volume from a few cubic meters to more than 1 million cubic meters. Most of the failures began as slumps and transformed into debris flows, some of which traveled several hundred meters across coastal flatlands into populated areas. A landslide-inventory map produced after the storm shows that the island of Tonoas had the largest area affected by landslides, although the islands of Weno, Fefan, Etten, Uman, Siis, Udot, Eot, and Fanapanges also had significant landslides. Based on observations since the storm, we estimate the continuing hazard from landslides triggered by Chata?an to be relatively low. However, tropical storms and typhoons similar to Chata?an frequently develop in Micronesia and are likely to affect the islands of Chuuk in the future. To assess the landslide hazard from future tropical storms, we produced a hazard map that identifies landslide-source areas of high, moderate, and low hazard. This map can be used to identify relatively safe areas for relocating structures or establishing areas where people could gather for shelter in relative safety during future typhoons or tropical storms similar to Chata?an.

  2. Atoll-scale patterns in coral reef community structure: Human signatures on Ulithi Atoll, Micronesia

    PubMed Central

    Nelson, Peter; Abelson, Avigdor; Precoda, Kristin; Rulmal, John; Bernardi, Giacomo; Paddack, Michelle

    2017-01-01

    The dynamic relationship between reefs and the people who utilize them at a subsistence level is poorly understood. This paper characterizes atoll-scale patterns in shallow coral reef habitat and fish community structure, and correlates these with environmental characteristics and anthropogenic factors, critical to conservation efforts for the reefs and the people who depend on them. Hierarchical clustering analyses by site for benthic composition and fish community resulted in the same 3 major clusters: cluster 1–oceanic (close proximity to deep water) and uninhabited (low human impact); cluster 2–oceanic and inhabited (high human impact); and cluster 3–lagoonal (facing the inside of the lagoon) and inhabited (highest human impact). Distance from village, reef exposure to deep water and human population size had the greatest effect in predicting the fish and benthic community structure. Our study demonstrates a strong association between benthic and fish community structure and human use across the Ulithi Atoll (Yap State, Federated States of Micronesia) and confirms a pattern observed by local people that an ‘opportunistic’ scleractinian coral (Montipora sp.) is associated with more highly impacted reefs. Our findings suggest that small human populations (subsistence fishing) can nevertheless have considerable ecological impacts on reefs due, in part, to changes in fishing practices rather than overfishing per se, as well as larger global trends. Findings from this work can assist in building local capacity to manage reef resources across an atoll-wide scale, and illustrates the importance of anthropogenic impact even in small communities. PMID:28489903

  3. Micronesian agroforestry: evidence from the past, implications for the future

    Treesearch

    Marjorie V. C. Falanruw

    1993-01-01

    Traditional agroforest systems exist throughout Micronesia. The system found on one Micronesian group of islands, Yap, is described and evaluated in ecological terms. Implications for future development of agriculture in Micronesia are discussed and some specific recommendations are given.

  4. Directory of Pacific Professionals for Educational Improvement. First Edition.

    ERIC Educational Resources Information Center

    Noguchi, Kay P., Comp.

    The Pacific Region Educational Laboratory (PREL) is a nonprofit corporation for educational research and improvement, serving Pacific children and educators in American Samoa, Commonwealth of the Northern Mariana Island, Federated States of Micronesia (Chuuk, Kosrae, Pohnpei, Yap), Guam, Hawaii, Republic of the Marshall Islands, and Republic of…

  5. SKP2- and OTUD1-regulated non-proteolytic ubiquitination of YAP promotes YAP nuclear localization and activity.

    PubMed

    Yao, Fan; Zhou, Zhicheng; Kim, Jongchan; Hang, Qinglei; Xiao, Zhenna; Ton, Baochau N; Chang, Liang; Liu, Na; Zeng, Liyong; Wang, Wenqi; Wang, Yumeng; Zhang, Peijing; Hu, Xiaoyu; Su, Xiaohua; Liang, Han; Sun, Yutong; Ma, Li

    2018-06-11

    Dysregulation of YAP localization and activity is associated with pathological conditions such as cancer. Although activation of the Hippo phosphorylation cascade is known to cause cytoplasmic retention and inactivation of YAP, emerging evidence suggests that YAP can be regulated in a Hippo-independent manner. Here, we report that YAP is subject to non-proteolytic, K63-linked polyubiquitination by the SCF SKP2 E3 ligase complex (SKP2), which is reversed by the deubiquitinase OTUD1. The non-proteolytic ubiquitination of YAP enhances its interaction with its nuclear binding partner TEAD, thereby inducing YAP's nuclear localization, transcriptional activity, and growth-promoting function. Independently of Hippo signaling, mutation of YAP's K63-linkage specific ubiquitination sites K321 and K497, depletion of SKP2, or overexpression of OTUD1 retains YAP in the cytoplasm and inhibits its activity. Conversely, overexpression of SKP2 or loss of OTUD1 leads to nuclear localization and activation of YAP. Altogether, our study sheds light on the ubiquitination-mediated, Hippo-independent regulation of YAP.

  6. Taking Responsibility for Our Schools: A Series of Four Articles on Education in Micronesia.

    ERIC Educational Resources Information Center

    Hezel, Francis X.

    Mobilizing communities to support educational improvements is one of the challenges confronting educators in the Freely Associated States (FAS), which consists of the Federated States of Micronesia, the Republic of the Marshall Islands, and the Republic of Palau. This booklet aims to establish a consensus on broad educational goals and to rebuild…

  7. Retention and Attrition of Pacific School Teachers and Administrators (RAPSTA) Study: Republic of Palau. Research Series.

    ERIC Educational Resources Information Center

    Research and Development Cadre, Honolulu, HI.

    Pacific Resources for Education and Learning (PREL) works with 10 American-affiliated Pacific entities: American Samoa, the Commonwealth of Northern Mariana Islands, the Federated States of Micronesia (Chuuk, Kosrae, Pohnpei, Yap), Guam, Hawaii, the Republic of the Marshall Islands, and the Republic of Palau. The survey raises awareness of the…

  8. The Status of the Preparation and Hiring of School Principals in the U.S.-Affiliated Pacific Region. REL Technical Brief. REL 2008-No. 006

    ERIC Educational Resources Information Center

    Camblin, Sharon; Keir, Scott

    2008-01-01

    This technical brief describes the current status of the preparation and hiring of school principals in the Pacific Region--American Samoa, Guam, Hawaii, Republic of the Marshall Islands, Federated States of Micronesia (Chuuk, Kosrae, Pohnpei, and Yap), Commonwealth of the Northern Mariana Islands, and Republic of Palau. The brief answers the…

  9. Retention and Attrition of Pacific School Teachers and Administrators (RAPSTA) Study: Republic of the Marshall Islands (RMI). Research Series.

    ERIC Educational Resources Information Center

    Research and Development Cadre, Honolulu, HI.

    Pacific Resources for Education and Learning (PREL) works with 10 American-affiliated Pacific entities: American Samoa, the Commonwealth of Northern Mariana Islands, the Federated States of Micronesia (Chuuk, Kosrae, Pohnpei, Yap), Guam, Hawaii, the Republic of the Marshall Islands, and the Republic of Palau. The survey raises awareness of the…

  10. Retention and Attrition of Pacific School Teachers and Administrators (RAPSTA) Study: American Samoa. Research Series.

    ERIC Educational Resources Information Center

    Research and Development Cadre, Honolulu, HI.

    Pacific Resources for Education and Learning (PREL) works with 10 American-affiliated Pacific entities: American Samoa, the Commonwealth of Northern Mariana Islands, the Federated States of Micronesia (Chuuk, Kosrae, Pohnpei, Yap), Guam, Hawaii, the Republic of the Marshall Islands, and the Republic of Palau. This survey raises awareness of the…

  11. Guam and Micronesia Reference Sources.

    ERIC Educational Resources Information Center

    Goetzfridt, Nicholas J.; Goniwiecha, Mark C.

    1993-01-01

    This article lists reference sources for studying Guam and Micronesia. The entries are arranged alphabetically by main entry within each section in the categories of: (1) bibliographical works; (2) travel and guide books; (3) handbooks and surveys; (4) dictionaries; (5) yearbooks; (6) periodical and newspaper publications; and (7) audiovisual…

  12. A tour of forest nurseries in the Pacific Islands of Micronesia and American Samoa

    Treesearch

    Leonard A. Newell

    2002-01-01

    Forestry programs in the American-affiliated islands of Micronesia and American Samoa are relatively young, compared to those of mainland states. American Samoa and Guam have been American Flag Territories since 1899, but neither had a forestry program before 1970. American Samoa had no forestry program until 1987. After World War II, the United States was the de facta...

  13. A snapshot of agroforestry in Terminalia carolinensis wetlands in Kosrae, Federated States of Micronesia

    Treesearch

    Nobuko K. Conroy; Ali Fares; Katherine C. Ewel; Tomoaki Miura; Halina M. Zaleski

    2011-01-01

    Traditional food and its supporting agricultural and agroforestry systems still play a large part in people’s daily lives in Federated Sates of Micronesia (FSM). To date, however, there are few publications on details of these systems in the country. On Kosrae Island, the easternmost island of FSM, one type of agroforestry has been practiced for centuries in coastal...

  14. Retention and Attrition of Pacific School Teachers and Administrators (RAPSTA) Study: Guam. Research Series.

    ERIC Educational Resources Information Center

    Research and Development Cadre, Honolulu, HI.

    Pacific Resources for Education and Learning (PREL) works closely with 10 American-affiliated Pacific entities: (1) American Samoa; (2) the Commonwealth of Northern Mariana Islands; (3) the Federated States of Micronesia (Chuuk, Kosrae, Pohnpei, Yap); (4) Guam; (5) Hawaii; (6) the Republic of the Marshall Islands; and (7) the Republic of Palau.…

  15. Retention and Attrition of Pacific School Teachers and Administrators (RAPSTA) Study: Hawai'i. Research Series.

    ERIC Educational Resources Information Center

    Research and Development Cadre, Honolulu, HI.

    Pacific Resources for Education and Learning (PREL) works closely with 10 American-affiliated Pacific entities: (1)American Samoa; (2) the Commonwealth of Northern Mariana Islands; (3) the Federated States of Micronesia (Chuuk, Kosrae, Pohnpei, Yap); (4) Guam; (5) Hawaii; (6) the Republic of the Marshall Islands; and (7) the Republic of Palau.…

  16. Presented by REL Pacific at McREL: Available Resources and Work in Progress. Research Digest. [Volume 1

    ERIC Educational Resources Information Center

    Regional Educational Laboratory Pacific, 2014

    2014-01-01

    REL Pacific at McREL, one of 10 Regional Educational Laboratories (RELs) funded by the Institute of Education Sciences (IES), serves educators in American Samoa, the Commonwealth of the Northern Mariana Islands, the Federated States of Micronesia (Chuuk, Kosrae, Pohnpei, and Yap), Guam, Hawai'i, the Republic of the Marshall Islands, and the…

  17. Water resources of the Yap Islands

    USGS Publications Warehouse

    Van der Brug, Otto

    1984-01-01

    The Yap Islands consist of four major islands, Yap, Gagil-Tamil, Maap, and Rumung. Of these, Yap Island has more than half the total land area, most of the population, and almost all of the economic development. The islands of Maap and Rumung together compose only 15 percent of the land area and population. Average annual rainfall over the Yap Islands amounts to 122 inches. Rainfall-runoff comparisons indicate that about half of the annual rainfall runs off to the ocean on Yap Island and Gagil-Tamil. Streams on Gagil-Tamil are perennial but streams on Yap Island are dry an average of 3 months per year due to geologic differences. Analyses of water samples from 23 sources show the good quality and the chemical similarity of surface and ground water. This report summarizes the hydrologic data collected and provides interpretations that can be used by the planning and public works officials of Yap to make decisions concerning development and management of their water resources.

  18. Biogeography of marine podocopid ostracodes in Micronesia

    USGS Publications Warehouse

    Weissleader, L.S.; Gilinsky, N.L.; Ross, R.M.; Cronin, T. M.

    1989-01-01

    Bottom lagoonal sediment samples from 12 islands and atolls yielded >70 species representing >32 ostracode genera. All or most samples from a particular lagoon generally form distinct subgroups (Jaccard =0.45-0.50). At lower levels, 5 groups delineate faunal regions within Micronesia: the Gilbert Islands (Onotoa) in the SE part of the region, the N Marshall Islands (Enewetak, Rongelap, Bikini), the SE Marshall Islands (Kwajalein, Jaluit, Majuro, Arno), the Marianas and Caroline Islands (Guam, Truk, Pohnpei) and Pingelap. Pingelap, Kwajalein and Onotoa have the highest species richness (S=32-42) and Shannon-Wiener diversity values (H(S)=2.62-3.02) in the study area. Enewetak, Jaluit, Majuro and Arno show lower values (S=23-27, H(S)=2.29-2.70). Of the ostracode species living in Micronesia, 64.3% have Indo-West Pacific affinities, 7.1% are circumtropical, 5.7% have East Pacific-Caribbean affinities, 11.4% are endemic to Micronesia, and 11.4% have unknown affinities. If the SE Asian region is a primary species-source, results show that each Micronesian lagoon is equally likely to be colonized by dispersal from the source region, despite differences in distance from a hypothetical source. However, each lagoon has a distinct ostracode assemblage, probably the result of unique history of random colonization events, local extinctions and environmental disturbances. -from Authors

  19. Presented by REL Pacific at McREL: A Summary of Cross-Regional Educational Laboratory Studies. Research Digest

    ERIC Educational Resources Information Center

    Regional Educational Laboratory Pacific, 2013

    2013-01-01

    REL Pacific at McREL, 1 of 10 Regional Educational Laboratories (RELs) funded by the Institute of Education Sciences (IES), serves educators in American Samoa, the Commonwealth of the Northern Mariana Islands, the Federated States of Micronesia (Chuuk, Kosrae, Pohnpei, and Yap), Guam, Hawai'i, the Republic of the Marshall Islands, and the Republic…

  20. Presented by REL Pacific at McREL: Available Resources and Work in Progress. Research Digest. Volume 2

    ERIC Educational Resources Information Center

    Regional Educational Laboratory Pacific, 2014

    2014-01-01

    REL Pacific at McREL, one of 10 Regional Educational Laboratories (RELs) funded by the U.S. Department of Education's Institute of Education Sciences (IES), serves educators in American Samoa, the Commonwealth of the Northern Mariana Islands, the Federated States of Micronesia (Chuuk, Kosrae, Pohnpei, and Yap), Guam, Hawai'i, the Republic of the…

  1. Yap reprograms glutamine metabolism to increase nucleotide biosynthesis and enable liver growth.

    PubMed

    Cox, Andrew G; Hwang, Katie L; Brown, Kristin K; Evason, Kimberley; Beltz, Sebastian; Tsomides, Allison; O'Connor, Keelin; Galli, Giorgio G; Yimlamai, Dean; Chhangawala, Sagar; Yuan, Min; Lien, Evan C; Wucherpfennig, Julia; Nissim, Sahar; Minami, Akihiro; Cohen, David E; Camargo, Fernando D; Asara, John M; Houvras, Yariv; Stainier, Didier Y R; Goessling, Wolfram

    2016-08-01

    The Hippo pathway is an important regulator of organ size and tumorigenesis. It is unclear, however, how Hippo signalling provides the cellular building blocks required for rapid growth. Here, we demonstrate that transgenic zebrafish expressing an activated form of the Hippo pathway effector Yap1 (also known as YAP) develop enlarged livers and are prone to liver tumour formation. Transcriptomic and metabolomic profiling identify that Yap1 reprograms glutamine metabolism. Yap1 directly enhances glutamine synthetase (glul) expression and activity, elevating steady-state levels of glutamine and enhancing the relative isotopic enrichment of nitrogen during de novo purine and pyrimidine biosynthesis. Genetic or pharmacological inhibition of GLUL diminishes the isotopic enrichment of nitrogen into nucleotides, suppressing hepatomegaly and the growth of liver cancer cells. Consequently, Yap-driven liver growth is susceptible to nucleotide inhibition. Together, our findings demonstrate that Yap1 integrates the anabolic demands of tissue growth during development and tumorigenesis by reprogramming nitrogen metabolism to stimulate nucleotide biosynthesis.

  2. Yap reprograms glutamine metabolism to increase nucleotide biosynthesis and enable liver growth

    PubMed Central

    Brown, Kristin K.; Evason, Kimberley; Beltz, Sebastian; Tsomides, Allison; O'Connor, Keelin; Galli, Giorgio G.; Yimlamai, Dean; Chhangawala, Sagar; Yuan, Min; Lien, Evan C.; Wucherpfennig, Julia; Nissim, Sahar; Minami, Akihiro; Cohen, David E.; Camargo, Fernando D.; Asara, John M.; Houvras, Yariv; Stainier, Didier Y.R.; Goessling, Wolfram

    2016-01-01

    The Hippo pathway is an important regulator of organ size and tumorigenesis. It is unclear, however, how Hippo signaling provides the cellular building blocks required for rapid growth. Here, we demonstrate that transgenic zebrafish expressing an activated form of the Hippo pathway effector Yap1 (also known as YAP) develop enlarged livers and are prone to liver tumor formation. Transcriptomic and metabolomic profiling identify that Yap1 reprograms glutamine metabolism. Yap1 directly enhances glutamine synthetase (glul) expression and activity, elevating steady-state levels of glutamine and enhancing the relative isotopic enrichment of nitrogen during de novo purine and pyrimidine biosynthesis. Genetic or pharmacological inhibition of GLUL diminishes the isotopic enrichment of nitrogen into nucleotides, suppresses hepatomegaly and the growth of liver cancer cells. Consequently, Yap-driven liver growth is susceptible to nucleotide inhibition. Together, our findings demonstrate that Yap1 integrates the anabolic demands of tissue growth during development and tumorigenesis by reprogramming nitrogen metabolism to stimulate nucleotide biosynthesis. PMID:27428308

  3. Downed Wood in micronesian mangrove Forests

    Treesearch

    James A. Allen; Katherine C. Ewel; Bobby D. Keeland; Tara Tara; Thomas J. Smith

    2000-01-01

    Dead, downed wood is an important component of upland forest and aquatic ecosystems, but its role in wetland ecosystems, including mangroves, is poorly understood. We measured downed wood in ten sites on the western Pacific islands of Kosrae, Pohnpei, and Yap, all located within the Federated States of Micronesia. Our goals were to examine patterns of variability in...

  4. Getting to Know Education in the Pacific Region

    ERIC Educational Resources Information Center

    Regional Educational Laboratory Pacific, 2014

    2014-01-01

    The Pacific region is comprised of American Samoa, the Commonwealth of the Northern Mariana Islands (CNMI); the Federated States of Micronesia (FSM)-Chuuk, Kosrae, Pohnpei, and Yap; Guam; Hawai'i; the Republic of the Marshall Islands; and the Republic of Palau. This document begins by providing a map of the REL Pacific region overlaid on a map of…

  5. We Are the Neocolonialists of Micronesia.

    ERIC Educational Resources Information Center

    Schmitz, Stephen; Pono, M. Odette

    Examining the fragmentation and Americanization that pervades education in Micronesia, this paper explores the causes of the fragmentation, which represent a local attempt to modernize education, and the local belief in the superiority of American culture. The consequences of a fragmented world view have been confusion between educational aims and…

  6. The Hippo-YAP signaling pathway and contact inhibition of growth

    PubMed Central

    Gumbiner, Barry M.; Kim, Nam-Gyun

    2014-01-01

    ABSTRACT The Hippo-YAP pathway mediates the control of cell proliferation by contact inhibition as well as other attributes of the physical state of cells in tissues. Several mechanisms sense the spatial and physical organization of cells, and function through distinct upstream modules to stimulate Hippo-YAP signaling: adherens junction or cadherin–catenin complexes, epithelial polarity and tight junction complexes, the FAT-Dachsous morphogen pathway, as well as cell shape, actomyosin or mechanotransduction. Soluble extracellular factors also regulate Hippo pathway signaling, often inhibiting its activity. Indeed, the Hippo pathway mediates a reciprocal relationship between contact inhibition and mitogenic signaling. As a result, cells at the edges of a colony, a wound in a tissue or a tumor are more sensitive to ambient levels of growth factors and more likely to proliferate, migrate or differentiate through a YAP and/or TAZ-dependent process. Thus, the Hippo-YAP pathway senses and responds to the physical organization of cells in tissues and coordinates these physical cues with classic growth-factor-mediated signaling pathways. This Commentary is focused on the biological significance of Hippo-YAP signaling and how upstream regulatory modules of the pathway interact to produce biological outcomes. PMID:24532814

  7. Aerobic glycolysis tunes YAP/TAZ transcriptional activity

    PubMed Central

    Enzo, Elena; Santinon, Giulia; Pocaterra, Arianna; Aragona, Mariaceleste; Bresolin, Silvia; Forcato, Mattia; Grifoni, Daniela; Pession, Annalisa; Zanconato, Francesca; Guzzo, Giulia; Bicciato, Silvio; Dupont, Sirio

    2015-01-01

    Increased glucose metabolism and reprogramming toward aerobic glycolysis are a hallmark of cancer cells, meeting their metabolic needs for sustained cell proliferation. Metabolic reprogramming is usually considered as a downstream consequence of tumor development and oncogene activation; growing evidence indicates, however, that metabolism on its turn can support oncogenic signaling to foster tumor malignancy. Here, we explored how glucose metabolism regulates gene transcription and found an unexpected link with YAP/TAZ, key transcription factors regulating organ growth, tumor cell proliferation and aggressiveness. When cells actively incorporate glucose and route it through glycolysis, YAP/TAZ are fully active; when glucose metabolism is blocked, or glycolysis is reduced, YAP/TAZ transcriptional activity is decreased. Accordingly, glycolysis is required to sustain YAP/TAZ pro-tumorigenic functions, and YAP/TAZ are required for the full deployment of glucose growth-promoting activity. Mechanistically we found that phosphofructokinase (PFK1), the enzyme regulating the first committed step of glycolysis, binds the YAP/TAZ transcriptional cofactors TEADs and promotes their functional and biochemical cooperation with YAP/TAZ. Strikingly, this regulation is conserved in Drosophila, where phosphofructokinase is required for tissue overgrowth promoted by Yki, the fly homologue of YAP. Moreover, gene expression regulated by glucose metabolism in breast cancer cells is strongly associated in a large dataset of primary human mammary tumors with YAP/TAZ activation and with the progression toward more advanced and malignant stages. These findings suggest that aerobic glycolysis endows cancer cells with particular metabolic properties and at the same time sustains transcription factors with potent pro-tumorigenic activities such as YAP/TAZ. PMID:25796446

  8. YAP promotes tumorigenesis and cisplatin resistance in neuroblastoma.

    PubMed

    Yang, Chao; Tan, Juan; Zhu, Jun; Wang, Shan; Wei, Guanghui

    2017-06-06

    The transcriptional co-activator Yes-associated protein (YAP) is essential for Hippo pathway-driven tumorigenesis in various cancers. However, the expression and function of YAP in neuroblastoma remains elusive. Here, we show that YAP was highly expressed in Neuroblastoma (NB) and expression levels correlated with advanced tumor staging. Knockdown of YAP significantly impaired neuroblastoma proliferation, tumorigenesis, and invasion in vitro. Injection of the YAP inhibitor, Peptide 17, dramatically prevented neuroblastoma subcutaneous tumor growth by efficiently downregulating YAP expression in tumors. Additionally, less proliferative and more apoptotic cells were found in the Peptide 17 treatment group. Furthermore, YAP inhibition significantly inhibited cisplatin-resistant neuroblastoma proliferation, tumorigenesis, and invasion in vitro. The combination of Peptide 17 with low-dose cisplatin efficiently impaired cisplatin-resistant NB subcutaneous tumor growth, being as effective as high-dose cisplatin. Notably, the combination therapy caused lesser liver toxicity in mice compared to the high-dose cisplatin treatment group. Collectively, this work identifies YAP as a novel regulator of neuroblastoma proliferation, tumorigenesis, and invasion and indicates that YAP is a potential therapeutic target for cisplatin-resistant neuroblastoma.

  9. Environments. Basic Edition. Science for Micronesia.

    ERIC Educational Resources Information Center

    Trust Territory of the Pacific Islands Dept. of Education, Saipan.

    Presented is a teacher's guide to an elementary science unit designed for use with fourth grade, or higher, students in the Trust Territory of Micronesia. Although there is a degree of similarity to curriculum materials developed for the Science Curriculum Improvement Study, this Micronesian unit does not purport to be an adaption or edition of…

  10. Populations. Basic Edition. Science for Micronesia.

    ERIC Educational Resources Information Center

    Trust Territory of the Pacific Islands Dept. of Education, Saipan.

    This teacher's guide is for an elementary school science unit designed for use with third grade (or older) children in the Trust Territory of Micronesia. Although there is a degree of similarity to curriculum materials developed for the Science Curriculum Improvement Study, this Micronesian unit does not purport to be an adaptation or edition of…

  11. YAP/TAZ Orchestrate VEGF Signaling during Developmental Angiogenesis.

    PubMed

    Wang, Xiaohong; Freire Valls, Aida; Schermann, Géza; Shen, Ying; Moya, Ivan M; Castro, Laura; Urban, Severino; Solecki, Gergely M; Winkler, Frank; Riedemann, Lars; Jain, Rakesh K; Mazzone, Massimilano; Schmidt, Thomas; Fischer, Tamás; Halder, Georg; Ruiz de Almodóvar, Carmen

    2017-09-11

    Vascular endothelial growth factor (VEGF) is a major driver of blood vessel formation. However, the signal transduction pathways culminating in the biological consequences of VEGF signaling are only partially understood. Here, we show that the Hippo pathway effectors YAP and TAZ work as crucial signal transducers to mediate VEGF-VEGFR2 signaling during angiogenesis. We demonstrate that YAP/TAZ are essential for vascular development as endothelium-specific deletion of YAP/TAZ leads to impaired vascularization and embryonic lethality. Mechanistically, we show that VEGF activates YAP/TAZ via its effects on actin cytoskeleton and that activated YAP/TAZ induce a transcriptional program to further control cytoskeleton dynamics and thus establish a feedforward loop that ensures a proper angiogenic response. Lack of YAP/TAZ also results in altered cellular distribution of VEGFR2 due to trafficking defects from the Golgi apparatus to the plasma membrane. Altogether, our study identifies YAP/TAZ as central mediators of VEGF signaling and therefore as important regulators of angiogenesis. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Characterization of the coccoid cyanobacterium Myxosarcina sp. KIOST-1 isolated from mangrove forest in Chuuk State, Federated States of Micronesia

    NASA Astrophysics Data System (ADS)

    Kim, Ji Hyung; Lee, JunMo; Affan, Md-Abu; Lee, Dae-Won; Kang, Do-Hyung

    2017-09-01

    Mangrove forests are known to be inhabited by diverse symbiotic cyanobacterial communities that are capable of N2 fixation. To investigate its biodiversity, root sediments were collected from a mangrove forest in Chuuk State, Federated States of Micronesia (FSM), and an entangled yellow-brown coccoid cyanobacterium was isolated. The isolated cyanobacterium was reproduced by multiple fission and eventually produced baeocytes. Phylogenetic analysis revealed that the isolate was most similar to the genera Myxosarcina and Chroococcidiopsis in the order Pleurocapsales. Compositions of protein, lipid and carbohydrate in the cyanobacterial cells were estimated to be 19.4 ± 0.1%, 18.8 ± 0.4% and 31.5 ± 0.1%, respectively. Interestingly, total fatty acids in the isolate were mainly composed of saturated fatty acids and monounsaturated fatty acids, whereas polyunsaturated fatty acids were not detected. Based on the molecular and biochemical characteristics, the isolate was finally classified in the genus Myxosarcina, and designated as Myxosarcina sp. KIOST-1. These results will contribute to better understanding of cyanobacterial biodiversity in the mangrove forest in FSM as well as the genus Myxosarcina, and also will allow further exploitation of its biotechnological potential on the basis of its cellular characteristics.

  13. Proteolytic processing of the Yersinia pestis YapG autotransporter by the omptin protease Pla and the contribution of YapG to murine plague pathogenesis

    PubMed Central

    Lane, M. Chelsea; Lenz, Jonathan D.

    2013-01-01

    Autotransporter protein secretion represents one of the simplest forms of secretion across Gram-negative bacterial membranes. Once secreted, autotransporter proteins either remain tethered to the bacterial surface or are released following proteolytic cleavage. Autotransporters possess a diverse array of virulence-associated functions such as motility, cytotoxicity, adherence and autoaggregation. To better understand the role of autotransporters in disease, our research focused on the autotransporters of Yersinia pestis, the aetiological agent of plague. Y. pestis strain CO92 has nine functional conventional autotransporters, referred to as Yaps for Yersinia autotransporter proteins. Three Yaps have been directly implicated in virulence using established mouse models of plague infection (YapE, YapJ and YapK). Whilst previous studies from our laboratory have shown that most of the CO92 Yaps are cell associated, YapE and YapG are processed and released by the omptin protease Pla. In this study, we identified the Pla cleavage sites in YapG that result in many released forms of YapG in Y. pestis, but not in the evolutionarily related gastrointestinal pathogen, Yersinia pseudotuberculosis, which lacks Pla. Furthermore, we showed that YapG does not contribute to Y. pestis virulence in established mouse models of bubonic and pneumonic infection. As Y. pestis has a complex life cycle involving a wide range of mammalian hosts and a flea vector for transmission, it remains to be elucidated whether YapG has a measurable role in any other stage of plague disease. PMID:23657527

  14. Docking analysis of verteporfin with YAP WW domain.

    PubMed

    Kandoussi, Ilham; Lakhlili, Wiame; Taoufik, Jamal; Ibrahimi, Azeddine

    2017-01-01

    The YAP oncogene is a known cancer target. Therefore, it is of interest to understand the molecular docking interaction of verteporfin (a derivative of benzo-porphyrin) with the WW domain of YAP (clinically used for photo-dynamic therapy in macular degeneration) as a potential WW domain-ligand modulator by inhibition. A homology protein SWISS MODEL of the human YAP protein was constructed to dock (using AutoDock vina) with the PubChem verteporfin structure for interaction analysis. The docking result shows the possibilities of verteporfin interaction with the oncogenic transcription cofactor YAP having WW1 and WW2 domains. Thus, the ability of verteporfin to bind with the YAP WW domain having modulator activity is implied in this analysis.

  15. Material Objects. Basic Edition. Science for Micronesia.

    ERIC Educational Resources Information Center

    Trust Territory of the Pacific Islands Dept. of Education, Saipan.

    Presented is a teacher's guide for an elementary science unit designed for use with first grade students in the Trust Territory of Micronesia. Although there is a degree of similarity to the curriculum materials developed for the Science Curriculum Improvement Study, this Micronesian unit does not purport to be an adaptation or edition of the SCIS…

  16. Docking analysis of verteporfin with YAP WW domain

    PubMed Central

    Kandoussi, Ilham; Lakhlili, Wiame; Taoufik, Jamal; Ibrahimi, Azeddine

    2017-01-01

    The YAP oncogene is a known cancer target. Therefore, it is of interest to understand the molecular docking interaction of verteporfin (a derivative of benzo-porphyrin) with the WW domain of YAP (clinically used for photo-dynamic therapy in macular degeneration) as a potential WW domain-ligand modulator by inhibition. A homology protein SWISS MODEL of the human YAP protein was constructed to dock (using AutoDock vina) with the PubChem verteporfin structure for interaction analysis. The docking result shows the possibilities of verteporfin interaction with the oncogenic transcription cofactor YAP having WW1 and WW2 domains. Thus, the ability of verteporfin to bind with the YAP WW domain having modulator activity is implied in this analysis. PMID:28943729

  17. YAP regulates neuronal differentiation through Sonic hedgehog signaling pathway

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Lin, Yi-Ting; Ding, Jing-Ya; Li, Ming-Yang

    2012-09-10

    Tight regulation of cell numbers by controlling cell proliferation and apoptosis is important during development. Recently, the Hippo pathway has been shown to regulate tissue growth and organ size in Drosophila. In mammalian cells, it also affects cell proliferation and differentiation in various tissues, including the nervous system. Interplay of several signaling cascades, such as Notch, Wnt, and Sonic Hedgehog (Shh) pathways, control cell proliferation during neuronal differentiation. However, it remains unclear whether the Hippo pathway coordinates with other signaling cascades in regulating neuronal differentiation. Here, we used P19 cells, a mouse embryonic carcinoma cell line, as a model tomore » study roles of YAP, a core component of the Hippo pathway, in neuronal differentiation. P19 cells can be induced to differentiate into neurons by expressing a neural bHLH transcription factor gene Ascl1. Our results showed that YAP promoted cell proliferation and inhibited neuronal differentiation. Expression of Yap activated Shh but not Wnt or Notch signaling activity during neuronal differentiation. Furthermore, expression of Yap increased the expression of Patched homolog 1 (Ptch1), a downstream target of the Shh signaling. Knockdown of Gli2, a transcription factor of the Shh pathway, promoted neuronal differentiation even when Yap was over-expressed. We further demonstrated that over-expression of Yap inhibited neuronal differentiation in primary mouse cortical progenitors and Gli2 knockdown rescued the differentiation defect in Yap over-expressing cells. In conclusion, our study reveals that Shh signaling acts downstream of YAP in regulating neuronal differentiation. -- Highlights: Black-Right-Pointing-Pointer YAP promotes cell proliferation and inhibits neuronal differentiation in P19 cells. Black-Right-Pointing-Pointer YAP promotes Sonic hedgehog signaling activity during neuronal differentiation. Black-Right-Pointing-Pointer Knockdown of Gli2 rescues the

  18. Cancer, reproductive abnormalities, and diabetes in Micronesia: the effect of nuclear testing.

    PubMed

    Yamada, Seiji

    2004-09-01

    Many suggest that cancer and other diseases in Micronesia have been caused by nuclear testing in the Pacific. The 50-year commemoration of the March 1, 1954 Bravo thermonuclear test has rekindled interest in this area. This paper explores the documentation for, and the plausibility of, claims for disease causation by nuclear testing. Given the sheer volume of testing that the US conducted in the Pacific, it appears plausible that excess cancer would have occurred in areas of Micronesia other than the Marshall Islands. An excess of birth abnormalities in the Marshall Islands has been documented. While diabetes is not a radiogenic disease, and other cancers are generally less radiogenic than leukemia or thyroid cancer, the social and cultural effects of nuclear testing specifically, and the strategic uses to which Micronesia has been put generally, have had roles in the social production of disease. Integration into a globalized, cosmopolitan economy-with attendant phenomena such as the importation of tobacco, alcohol, foods of poor nutritional value, and new cultural morés-are also factors.

  19. Yap1 is dispensable for self-renewal but required for proper differentiation of mouse embryonic stem (ES) cells.

    PubMed

    Chung, HaeWon; Lee, Bum-Kyu; Uprety, Nadima; Shen, Wenwen; Lee, Jiwoon; Kim, Jonghwan

    2016-04-01

    Yap1 is a transcriptional co-activator of the Hippo pathway. The importance of Yap1 in early cell fate decision during embryogenesis has been well established, though its role in embryonic stem (ES) cells remains elusive. Here, we report that Yap1 plays crucial roles in normal differentiation rather than self-renewal of ES cells. Yap1-depleted ES cells maintain undifferentiated state with a typical colony morphology as well as robust alkaline phosphatase activity. These cells also retain comparable levels of the core pluripotent factors, such as Pou5f1 and Sox2, to the levels in wild-type ES cells without significant alteration of lineage-specific marker genes. Conversely, overexpression of Yap1 in ES cells promotes nuclear translocation of Yap1, resulting in disruption of self-renewal and triggering differentiation by up-regulating lineage-specific genes. Moreover, Yap1-deficient ES cells show impaired induction of lineage markers during differentiation. Collectively, our data demonstrate that Yap1 is a required factor for proper differentiation of mouse ES cells, while remaining dispensable for self-renewal. © 2016 The Authors.

  20. A role for Hippo/YAP-signaling in FGF-induced lens epithelial cell proliferation and fibre differentiation.

    PubMed

    Dawes, L J; Shelley, E J; McAvoy, J W; Lovicu, F J

    2018-04-01

    Recent studies indicate an important role for the transcriptional co-activator Yes-associated protein (YAP), and its regulatory pathway Hippo, in controlling cell growth and fate during lens development; however, the exogenous factors that promote this pathway are yet to be identified. Given that fibroblast growth factor (FGF)-signaling is an established regulator of lens cell behavior, the current study investigates the relationship between this pathway and Hippo/YAP-signaling during lens cell proliferation and fibre differentiation. Rat lens epithelial explants were cultured with FGF2 to induce epithelial cell proliferation or fibre differentiation. Immunolabeling methods were used to detect the expression of Hippo-signaling components, Total and Phosphorylated YAP, as well as fibre cell markers, Prox-1 and β-crystallin. FGF-induced lens cell proliferation was associated with a strong nuclear localisation of Total-YAP and low-level immuno-staining for phosphorylated-YAP. FGF-induced lens fibre differentiation was associated with a significant increase in cytoplasmic phosphorylated YAP (inactive state) and enhanced expression of core Hippo-signaling components. Inhibition of YAP with Verteporfin suppressed FGF-induced lens cell proliferation and ablated cell elongation during lens fibre differentiation. Inhibition of either FGFR- or MEK/ERK-signaling suppressed FGF-promoted YAP nuclear translocation. Here we propose that FGF promotes Hippo/YAP-signaling during lens cell proliferation and differentiation, with FGF-induced nuclear-YAP expression playing an essential role in promoting the proliferation of lens epithelial cells. An FGF-induced switch from proliferation to differentiation, hence regulation of lens growth, may play a key role in mediating Hippo suppression of YAP transcriptional activity. Copyright © 2018 Elsevier Ltd. All rights reserved.

  1. Mass poisoning after consumption of a hawksbill turtle, Federated States of Micronesia, 2010.

    PubMed

    Pavlin, Boris I; Musto, Jennie; Pretrick, Moses; Sarofalpiy, Joannes; Sappa, Perpetua; Shapucy, Siana; Kool, Jacobus

    2015-01-01

    Marine turtles of all species are capable of being toxic. On 17 October 2010, health authorities in the Federated States of Micronesia were notified of the sudden death of three children and the sickening of approximately 20 other people on Murilo Atoll in Chuuk State. The illnesses were suspected to be the result of mass consumption of a hawksbill turtle (Eretmochelys imbricata). An investigation team was assembled to confirm the cause of the outbreak, describe the epidemiology of cases and provide recommendations for control. We conducted chart reviews, interviewed key informants, collected samples for laboratory analysis, performed environmental investigations and conducted a cohort study. Four children and two adults died in the outbreak and 95 others were sickened; 84% of those who ate the turtle became ill (n = 101). The relative risk for developing illness after consuming the turtle was 11.1 (95% confidence inteval: 4.8-25.9); there was a dose-dependent relationship between amount of turtle meat consumed and risk of illness. Environmental and epidemiological investigations revealed no alternative explanation for the mass illness. Laboratory testing failed to identify a causative agent. We concluded that turtle poisoning (also called chelonitoxism) was the cause of the outbreak on Murilo. The range of illness described in this investigation is consistent with previously reported cases of chelonitoxism. This devastating incident highlights the dangers, particularly to children, of consuming turtle meat. Future incidents are certain to occur unless action is taken to alter turtle-eating behaviour in coastal communities throughout the world.

  2. Mass poisoning after consumption of a hawksbill turtle, Federated States of Micronesia, 2010

    PubMed Central

    Musto, Jennie; Pretrick, Moses; Sarofalpiy, Joannes; Sappa, Perpetua; Shapucy, Siana; Kool, Jacobus

    2015-01-01

    Background Marine turtles of all species are capable of being toxic. On 17 October 2010, health authorities in the Federated States of Micronesia were notified of the sudden death of three children and the sickening of approximately 20 other people on Murilo Atoll in Chuuk State. The illnesses were suspected to be the result of mass consumption of a hawksbill turtle (Eretmochelys imbricata). An investigation team was assembled to confirm the cause of the outbreak, describe the epidemiology of cases and provide recommendations for control. Methods We conducted chart reviews, interviewed key informants, collected samples for laboratory analysis, performed environmental investigations and conducted a cohort study. Results Four children and two adults died in the outbreak and 95 others were sickened; 84% of those who ate the turtle became ill (n = 101). The relative risk for developing illness after consuming the turtle was 11.1 (95% confidence inteval: 4.8–25.9); there was a dose-dependent relationship between amount of turtle meat consumed and risk of illness. Environmental and epidemiological investigations revealed no alternative explanation for the mass illness. Laboratory testing failed to identify a causative agent. Conclusion We concluded that turtle poisoning (also called chelonitoxism) was the cause of the outbreak on Murilo. The range of illness described in this investigation is consistent with previously reported cases of chelonitoxism. This devastating incident highlights the dangers, particularly to children, of consuming turtle meat. Future incidents are certain to occur unless action is taken to alter turtle-eating behaviour in coastal communities throughout the world. PMID:26045970

  3. Libraries, Archives, and Museums Helping Create Futures: Building on Culture, Knowledge, and Information through Collaboration and Resource Sharing. Selected Papers from PIALA 2010, Pacific Islands Association of Libraries, Archives, and Museums Annual Conference (20th, Weno, Chuuk State, Federated States of Micronesia, November 15-19, 2010)

    ERIC Educational Resources Information Center

    Drake, Paul B., Ed.

    2012-01-01

    This publication follows the tradition of publishing selected papers from Pacific Islands Association of Libraries, Archives and Museums (PIALA) annual conferences. This 20th annual conference was held in Weno, Chuuk State, Federated States of Micronesia, November 15-19, 2010. The volume begins with a listing of the members of the PIALA 2010…

  4. Yes-Associated Protein (YAP) Promotes the Nuclear Import of p73

    NASA Astrophysics Data System (ADS)

    Zhang, Heng; Wu, Shengnan

    2011-01-01

    p73 has been identified as a structural and functional homolog of the tumor suppressor p53. However, mechanisms that regulate the localization of p73 have not been fully clarified. The Yes-associated protein (YAP) is a transcriptional coactivator. As a transcriptional coactivator, YAP needs to bind transcription factors to stimulate gene expression. p73 is a reported YAP target transcription factors and YAP has been shown to positively regulate p73 in promoting apoptosis. Previous studies show that p73 interacts with YAP through its PPPY motif, and increases p73 transactivation of apoptotic genes. In this study, we focused on YAP's regulation of the localization of p73. After transient transfection into Rat pheochromocytoma (PC12) cells and Human embryonic kidney 293T cells with GFP-YAP and/or YFP-p73, and incubated for 24 hours expression. p73 was fused to YFP to allow the examination of its subcellular localization. When expressed alone, YFP-p73 was distributed throughout the cell. When coexpressed with YAP, nuclear accumulation of YFP-p73 became evident. We quantitated the effect of YAP on the redistribution of YFP-p73 by counting cells with nuclear-only YFP signal. We found that YAP can influence the subcellular distribution of p73. Altogether, coexpression with YAP affected the subcellular distribution of the p73 protein. Our studies attribute a central role to YAP in regulating p73 accumulation and YAP, at least in part, might promote the nuclear import of p73.

  5. Systems and Variables. Basic Edition. Science for Micronesia.

    ERIC Educational Resources Information Center

    Trust Territory of the Pacific Islands Dept. of Education, Saipan.

    This teacher's guide is for an elementary school science unit designed for use with third grade (or older) children in the schools of the Trust Territory of Micronesia. Although there is a degree of similarity to curriculum materials developed for the Science Curriculum Improvement Study, this Micronesian unit does not purport to be an adaptation…

  6. Evolution and virulence contributions of the autotransporter proteins YapJ and YapK of Yersinia pestis CO92 and their homologs in Y. pseudotuberculosis IP32953.

    PubMed

    Lenz, Jonathan D; Temple, Brenda R S; Miller, Virginia L

    2012-10-01

    Yersinia pestis, the causative agent of plague, evolved from the gastrointestinal pathogen Yersinia pseudotuberculosis. Both species have numerous type Va autotransporters, most of which appear to be highly conserved. In Y. pestis CO92, the autotransporter genes yapK and yapJ share a high level of sequence identity. By comparing yapK and yapJ to three homologous genes in Y. pseudotuberculosis IP32953 (YPTB0365, YPTB3285, and YPTB3286), we show that yapK is conserved in Y. pseudotuberculosis, while yapJ is unique to Y. pestis. All of these autotransporters exhibit >96% identity in the C terminus of the protein and identities ranging from 58 to 72% in their N termini. By extending this analysis to include homologous sequences from numerous Y. pestis and Y. pseudotuberculosis strains, we determined that these autotransporters cluster into a YapK (YPTB3285) class and a YapJ (YPTB3286) class. The YPTB3286-like gene of most Y. pestis strains appears to be inactivated, perhaps in favor of maintaining yapJ. Since autotransporters are important for virulence in many bacterial pathogens, including Y. pestis, any change in autotransporter content should be considered for its impact on virulence. Using established mouse models of Y. pestis infection, we demonstrated that despite the high level of sequence identity, yapK is distinct from yapJ in its contribution to disseminated Y. pestis infection. In addition, a mutant lacking both of these genes exhibits an additive attenuation, suggesting nonredundant roles for yapJ and yapK in systemic Y. pestis infection. However, the deletion of the homologous genes in Y. pseudotuberculosis does not seem to impact the virulence of this organism in orogastric or systemic infection models.

  7. Activation of β-catenin and Yap1 in human hepatoblastoma and induction of hepatocarcinogenesis in mice.

    PubMed

    Tao, Junyan; Calvisi, Diego F; Ranganathan, Sarangarajan; Cigliano, Antonio; Zhou, Lili; Singh, Sucha; Jiang, Lijie; Fan, Biao; Terracciano, Luigi; Armeanu-Ebinger, Sorin; Ribback, Silvia; Dombrowski, Frank; Evert, Matthias; Chen, Xin; Monga, Satdarshan P S

    2014-09-01

    Aberrant activation of β-catenin and Yes-associated protein 1 (Yap1) signaling pathways have been associated with the development of multiple tumor types. Yap functions as a transcriptional coactivator by interacting with TEA domain DNA binding proteins. We investigated the interactions among these pathways during hepatic tumorigenesis. We used immunohistochemical analysis to determine expression of β-catenin and Yap1 in liver cancer specimens collected from patients in Europe and the United States, consisting of 104 hepatocellular carcinoma, 62 intrahepatic cholangiocarcinoma, and 94 hepatoblastoma samples. We assessed β-catenin and Yap1 signaling and interactions in hepatoblastoma cell lines ((HuH6, HepG2, HepT1, HC-AFW1, HepG2, and HC-AFW1); proteins were knocked down with small interfering RNAs, and effects on proliferation and cell death were measured. Sleeping beauty-mediated hydrodynamic transfection was used to overexpress constitutively active forms of β-catenin (ΔN90/β-catenin) and Yap1 (YapS127A) in livers of mice; tissues were collected, and histological and immunohistochemical analyses were performed. We observed nuclear localization of β-catenin and Yap1 in 79% of hepatoblastoma samples but not in most hepatocellular carcinoma or intrahepatic cholangiocarcinoma samples. Yap1 and β-catenin coprecipitated in hepatoblastoma but not hepatocellular carcinoma cells. Small interfering RNA-mediated knockdown of Yap1 or β-catenin in hepatoblastoma cells reduced proliferation in an additive manner. Knockdown of Yap1 reduced its ability to coactivate transcription with β-catenin; β-catenin inhibitors inactivated Yap1. Overexpression of constitutively active forms of Yap1 and β-catenin in mouse liver led to rapid tumorigenesis, with 100% mortality by 11 weeks. Tumor cells expressed both proteins, and human hepatoblastoma cells expressed common targets of their 2 signaling pathways. Yap1 binding of TEA domain factors was required for tumorigenesis in

  8. Yap4 PKA- and GSK3-dependent phosphorylation affects its stability but not its nuclear localization.

    PubMed

    Pereira, Jorge; Pimentel, Catarina; Amaral, Catarina; Menezes, Regina A; Rodrigues-Pousada, Claudina

    2009-12-01

    Yap4 is a nuclear-resident transcription factor induced in Saccharomyces cerevisiae when exposed to several stress conditions, which include mild hyperosmotic and oxidative stress, temperature shift or metal exposure. This protein is also phosphorylated. Here we report that this modification is driven by PKA and GSK3. In order to ascertain whether Yap4 is directly or indirectly phosphorylated by PKA, we searched for stress and PKA-related kinases that could phosphorylate Yap4. We show that phosphorylation is independent of the kinases Rim15, Yak1, Sch9, Slt2, Ste20 and Ptk2. In addition, we showed that Yap4 phosphorylation is also abrogated in the triple GSK3 mutant mck1 rim11 yol128c. Furthermore, our data reveal that Yap4 nuclear localization is independent of its phosphorylation state. This protein has several putative phosphorylation sites, but only the mutation of residues T192 and S196 impairs its phosphorylation under different stress conditions. The ability of the non-phosphorylated forms of Yap4 to partially rescue the hog1 severe sensitivity phenotype is not affected, suggesting that Yap4 activity is maintained in the absence of phosphorylation. However, this modification seems to be required for stability of the protein, as the non-phosphorylated form has a shorter half-life than the phosphorylated one.

  9. YAP activation protects urothelial cell carcinoma from treatment-induced DNA damage

    PubMed Central

    Ciamporcero, Eric; Shen, He; Ramakrishnan, Swathi; Ku, Sheng Yu; Chintala, Sreenivasulu; Shen, Li; Adelaiye, Remi; Miles, Kiersten Marie; Ullio, Chiara; Pizzimenti, Stefania; Daga, Martina; Azabdaftari, Gissou; Attwood, Kris; Johnson, Candace; Zhang, Jianmin; Barrera, Giuseppina; Pili, Roberto

    2015-01-01

    Current standard of care for muscle-invasive urothelial cell carcinoma (UCC) is surgery along with perioperative platinum-based chemotherapy. UCC is sensitive to cisplatin-based regimens, but acquired resistance eventually occurs, and a subset of tumors is intrinsically resistant. Thus, there is an unmet need for new therapeutic approaches to target chemotherapy-resistant UCC. Yes-associated protein (YAP) is a transcriptional co-activator that has been associated with bladder cancer progression and cisplatin resistance in ovarian cancer. In contrast, YAP has been shown to induce DNA damage associated apoptosis in non-small cell lung carcinoma. However, no data have been reported on the YAP role in UCC chemo-resistance. Thus, we have investigated the potential dichotomous role of YAP in UCC response to chemotherapy utilizing two patient-derived xenograft models recently established. Constitutive expression and activation of YAP inversely correlated with in vitro and in vivo cisplatin sensitivity. YAP overexpression protected while YAP knock-down sensitized UCC cells to chemotherapy and radiation effects via increased accumulation of DNA damage and apoptosis. Furthermore, pharmacological YAP inhibition with verteporfin inhibited tumor cell proliferation and restored sensitivity to cisplatin. In addition, nuclear YAP expression was associated with poor outcome in UCC patients who received perioperative chemotherapy. In conclusion, these results suggest that YAP activation exerts a protective role and represents a pharmacological target to enhance the anti-tumor effects of DNA damaging modalities in the treatment of UCC. PMID:26119935

  10. YAP activation protects urothelial cell carcinoma from treatment-induced DNA damage.

    PubMed

    Ciamporcero, E; Shen, H; Ramakrishnan, S; Yu Ku, S; Chintala, S; Shen, L; Adelaiye, R; Miles, K M; Ullio, C; Pizzimenti, S; Daga, M; Azabdaftari, G; Attwood, K; Johnson, C; Zhang, J; Barrera, G; Pili, R

    2016-03-24

    Current standard of care for muscle-invasive urothelial cell carcinoma (UCC) is surgery along with perioperative platinum-based chemotherapy. UCC is sensitive to cisplatin-based regimens, but acquired resistance eventually occurs, and a subset of tumors is intrinsically resistant. Thus, there is an unmet need for new therapeutic approaches to target chemotherapy-resistant UCC. Yes-associated protein (YAP) is a transcriptional co-activator that has been associated with bladder cancer progression and cisplatin resistance in ovarian cancer. In contrast, YAP has been shown to induce DNA damage associated apoptosis in non-small cell lung carcinoma. However, no data have been reported on the YAP role in UCC chemo-resistance. Thus, we have investigated the potential dichotomous role of YAP in UCC response to chemotherapy utilizing two patient-derived xenograft models recently established. Constitutive expression and activation of YAP inversely correlated with in vitro and in vivo cisplatin sensitivity. YAP overexpression protected while YAP knockdown sensitized UCC cells to chemotherapy and radiation effects via increased accumulation of DNA damage and apoptosis. Furthermore, pharmacological YAP inhibition with verteporfin inhibited tumor cell proliferation and restored sensitivity to cisplatin. In addition, nuclear YAP expression was associated with poor outcome in UCC patients who received perioperative chemotherapy. In conclusion, these results suggest that YAP activation exerts a protective role and represents a pharmacological target to enhance the anti-tumor effects of DNA damaging modalities in the treatment of UCC.

  11. Cytoplasmic ASPP1 inhibits apoptosis through the control of YAP

    PubMed Central

    Vigneron, Arnaud M.; Ludwig, Robert L.; Vousden, Karen H.

    2010-01-01

    The ASPP (apoptosis-stimulating protein of p53) family of proteins can function in the nucleus to modulate the transcriptional activity of p53, with ASPP1 and ASPP2 contributing to the expression of apoptotic target genes. In this study, we describe a new function for cytoplasmic ASPP1 in controlling YAP (Yes-associated protein)/TAZ. ASPP1 can inhibit the interaction of YAP with LATS1 (large tumor suppressor 1), a kinase that phosphorylates YAP/TAZ and promotes cytoplasmic sequestration and protein degradation. This function of ASPP1 therefore enhances nuclear accumulation of YAP/TAZ and YAP/TAZ-dependent transcriptional regulation. The consequence of YAP/TAZ activation by ASPP1 is to inhibit apoptosis, in part through the down-regulation of Bim expression, leading to resistance to anoikis and enhanced cell migration. These results reveal a potential oncogenic role for cytoplasmic ASPP1, in contrast to the tumor-suppressive activity described previously for nuclear ASPP1. PMID:21041411

  12. Two-signal requirement for growth-promoting function of Yap in hepatocytes

    PubMed Central

    Su, Tian; Bondar, Tanya; Zhou, Xu; Zhang, Cuiling; He, Hang; Medzhitov, Ruslan

    2015-01-01

    The transcriptional coactivator Yes-associated protein (Yap) promotes proliferation and inhibits apoptosis, suggesting that Yap functions as an oncogene. Most oncogenes, however, require a combination of at least two signals to promote proliferation. In this study, we present evidence that Yap activation is insufficient to promote growth in the otherwise normal tissue. Using a mosaic mouse model, we demonstrate that Yap overexpression in a fraction of hepatocytes does not lead to their clonal expansion, as proliferation is counterbalanced by increased apoptosis. To shift the activity of Yap towards growth, a second signal provided by tissue damage or inflammation is required. In response to liver injury, Yap drives clonal expansion, suppresses hepatocyte differentiation, and promotes a progenitor phenotype. These results suggest that Yap activation is insufficient to promote growth in the absence of a second signal thus coordinating tissue homeostasis and repair. DOI: http://dx.doi.org/10.7554/eLife.02948.001 PMID:25667983

  13. Fluid shear stress activates YAP1 to promote cancer cell motility

    NASA Astrophysics Data System (ADS)

    Lee, Hyun Jung; Diaz, Miguel F.; Price, Katherine M.; Ozuna, Joyce A.; Zhang, Songlin; Sevick-Muraca, Eva M.; Hagan, John P.; Wenzel, Pamela L.

    2017-01-01

    Mechanical stress is pervasive in egress routes of malignancy, yet the intrinsic effects of force on tumour cells remain poorly understood. Here, we demonstrate that frictional force characteristic of flow in the lymphatics stimulates YAP1 to drive cancer cell migration; whereas intensities of fluid wall shear stress (WSS) typical of venous or arterial flow inhibit taxis. YAP1, but not TAZ, is strictly required for WSS-enhanced cell movement, as blockade of YAP1, TEAD1-4 or the YAP1-TEAD interaction reduces cellular velocity to levels observed without flow. Silencing of TEAD phenocopies loss of YAP1, implicating transcriptional transactivation function in mediating force-enhanced cell migration. WSS dictates expression of a network of YAP1 effectors with executive roles in invasion, chemotaxis and adhesion downstream of the ROCK-LIMK-cofilin signalling axis. Altogether, these data implicate YAP1 as a fluid mechanosensor that functions to regulate genes that promote metastasis.

  14. MicroRNA-590-5p Inhibits Intestinal Inflammation by Targeting YAP.

    PubMed

    Yu, Minhao; Luo, Yang; Cong, Zhijie; Mu, Yifei; Qiu, Yier; Zhong, Ming

    2018-04-18

    Hippo signaling is an evolutionarily conserved pathway that controls organ size by regulating cell proliferation, survival, apoptosis, and stem cell self-renewal. In addition, Hippo signaling is profoundly implicated in intestinal regeneration and cancer. However, its roles in the pathogenesis of Crohn's disease (CD) remain largely unexplored. Quantitative real-time PCR was performed to identify the deregulated molecules in Hippo signaling. Expression of the highly upregulated Yes Associated Protein 1 (YAP) was subsequently examined by qRT-PCR, western blotting and immunohistochemistry in the intestinal tissues of CD patients and the colons of 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced colitis mice. The miRNAs predicted to target YAP were explored by transfection of miR-590-5p mimics or inhibitors and analyzed by luciferase reporter assay. The role of the miR-590-5p/YAP axis in CD and colorectal cancer were studied in experimental colitis mice and colorectal cancer cell lines. YAP mRNA was significantly upregulated in intestinal epithelial cells in CD patients and TNBS-induced colitis mice. MiR-590-5p suppressed YAP expression by directly targeting the YAP 3'-untranslated region in Caco-2 cells and SW620 cells. Upregulation of miR-590-5p in colon reduced YAP level and its downstream targets in IECs. Treatment of miR-590-5p or YAP inhibitor Verteporfin alleviated experimental colitis. Targeting the miR-590-5p/YAP axis inhibited cell proliferation and invasiveness of CRC cells in vitro. Our results suggest that miR-590-5p inhibits intestinal inflammation in mouse colon and tumorigenesis of colorectal cancer cells by inhibiting YAP. The miR-590-5p/YAP axis may be an important novel mechanism in the pathogenesis of CD and colorectal cancer.

  15. Mechanosignaling through YAP and TAZ drives fibroblast activation and fibrosis

    PubMed Central

    Liu, Fei; Lagares, David; Choi, Kyoung Moo; Stopfer, Lauren; Marinković, Aleksandar; Vrbanac, Vladimir; Probst, Clemens K.; Hiemer, Samantha E.; Sisson, Thomas H.; Horowitz, Jeffrey C.; Rosas, Ivan O.; Fredenburgh, Laura E.; Feghali-Bostwick, Carol; Varelas, Xaralabos; Tager, Andrew M.

    2014-01-01

    Pathological fibrosis is driven by a feedback loop in which the fibrotic extracellular matrix is both a cause and consequence of fibroblast activation. However, the molecular mechanisms underlying this process remain poorly understood. Here we identify yes-associated protein (YAP) (homolog of drosophila Yki) and transcriptional coactivator with PDZ-binding motif (TAZ) (also known as Wwtr1), transcriptional effectors of the Hippo pathway, as key matrix stiffness-regulated coordinators of fibroblast activation and matrix synthesis. YAP and TAZ are prominently expressed in fibrotic but not healthy lung tissue, with particularly pronounced nuclear expression of TAZ in spindle-shaped fibroblastic cells. In culture, both YAP and TAZ accumulate in the nuclei of fibroblasts grown on pathologically stiff matrices but not physiologically compliant matrices. Knockdown of YAP and TAZ together in vitro attenuates key fibroblast functions, including matrix synthesis, contraction, and proliferation, and does so exclusively on pathologically stiff matrices. Profibrotic effects of YAP and TAZ operate, in part, through their transcriptional target plasminogen activator inhibitor-1, which is regulated by matrix stiffness independent of transforming growth factor-β signaling. Immortalized fibroblasts conditionally expressing active YAP or TAZ mutant proteins overcome soft matrix limitations on growth and promote fibrosis when adoptively transferred to the murine lung, demonstrating the ability of fibroblast YAP/TAZ activation to drive a profibrotic response in vivo. Together, these results identify YAP and TAZ as mechanoactivated coordinators of the matrix-driven feedback loop that amplifies and sustains fibrosis. PMID:25502501

  16. Mediator, SWI/SNF and SAGA complexes regulate Yap8-dependent transcriptional activation of ACR2 in response to arsenate.

    PubMed

    Menezes, Regina Andrade; Pimentel, Catarina; Silva, Ana Rita Courelas; Amaral, Catarina; Merhej, Jawad; Devaux, Frédéric; Rodrigues-Pousada, Claudina

    2017-04-01

    Response to arsenic stress in Saccharomyces cerevisiae is orchestrated by the regulatory protein Yap8, which mediates transcriptional activation of ACR2 and ACR3. This study contributes to the state of art knowledge of the molecular mechanisms underlying yeast stress response to arsenate as it provides the genetic and biochemical evidences that Yap8, through cysteine residues 132, 137, and 274, is the sensor of presence of arsenate in the cytosol. Moreover, it is here reported for the first time the essential role of the Mediator complex in the transcriptional activation of ACR2 by Yap8. Based on our data, we propose an order-of-function map to recapitulate the sequence of events taking place in cells injured with arsenate. Modification of the sulfhydryl state of these cysteines converts Yap8 in its activated form, triggering the recruitment of the Mediator complex to the ACR2/ACR3 promoter, through the interaction with the tail subunit Med2. The Mediator complex then transfers the regulatory signals conveyed by Yap8 to the core transcriptional machinery, which culminates with TBP occupancy, ACR2 upregulation and cell adaptation to arsenate stress. Additional co-factors are required for the transcriptional activation of ACR2 by Yap8, particularly the nucleosome remodeling activity of SWI/SNF and SAGA complexes. Copyright © 2017. Published by Elsevier B.V.

  17. Evaluation of a "traditional food for health" intervention in Pohnpei, Federated States of Micronesia.

    PubMed

    Kaufer, Laura; Englberger, Lois; Cue, Roger; Lorens, Adelino; Albert, Kiped; Pedrus, Podis; Kuhnlein, Harriet V

    2010-04-01

    Federated States of Micronesia (FSM) faces increasing rates of non-communicable diseases related to the neglect of the traditional food system and the shift to consumption of imported food and adoption of sedentary lifestyles. To reverse this trend, a two-year, food-based intervention in one Pohnpeian community in FSM promoted local food production and consumption using a variety of approaches including education, training, agriculture and social marketing following a "Go Local" message. Foods promoted were banana, giant swamp taro, breadfruit and pandanus varieties, green leafy vegetables and fruits for their provitamin A and total carotenoids, vitamins, minerals and fiber content. An evaluation was conducted in a random sample of households (n=47) to examine the extent of dietary changes following the intervention. Results indicated increased (110%) provitamin A carotenoid intake; increased frequency of consumption of local banana (53%), giant swamp taro (475%), and local vegetables (130%); and increased dietary diversity from local food. Exposure to intervention activities was high and there were positive changes in attitudes towards local food. The intervention approaches appear to have been successful in this short period. It is likely that similar approaches in additional communities in Pohnpei and other parts of the Pacific would also be successful in promoting local food. Evidence gathering should continue to document the long-term health outcomes of increased reliance on local food.

  18. Adhesive Properties of YapV and Paralogous Autotransporter Proteins of Yersinia pestis

    PubMed Central

    Nair, Manoj K. M.; De Masi, Leon; Yue, Min; Galván, Estela M.; Chen, Huaiqing; Wang, Fang

    2015-01-01

    Yersinia pestis is the causative agent of plague. This bacterium evolved from an ancestral enteroinvasive Yersinia pseudotuberculosis strain by gene loss and acquisition of new genes, allowing it to use fleas as transmission vectors. Infection frequently leads to a rapidly lethal outcome in humans, a variety of rodents, and cats. This study focuses on the Y. pestis KIM yapV gene and its product, recognized as an autotransporter protein by its typical sequence, outer membrane localization, and amino-terminal surface exposure. Comparison of Yersinia genomes revealed that DNA encoding YapV or each of three individual paralogous proteins (YapK, YapJ, and YapX) was present as a gene or pseudogene in a strain-specific manner and only in Y. pestis and Y. pseudotuberculosis. YapV acted as an adhesin for alveolar epithelial cells and specific extracellular matrix (ECM) proteins, as shown with recombinant Escherichia coli, Y. pestis, or purified passenger domains. Like YapV, YapK and YapJ demonstrated adhesive properties, suggesting that their previously related in vivo activity is due to their capacity to modulate binding properties of Y. pestis in its hosts, in conjunction with other adhesins. A differential host-specific type of binding to ECM proteins by YapV, YapK, and YapJ suggested that these proteins participate in broadening the host range of Y. pestis. A phylogenic tree including 36 Y. pestis strains highlighted an association between the gene profile for the four paralogous proteins and the geographic location of the corresponding isolated strains, suggesting an evolutionary adaption of Y. pestis to specific local animal hosts or reservoirs. PMID:25690102

  19. Proceedings of the workshop on research methodologies and applications for Pacific Island agroforestry; July 16-20, 1990; Kolonia, Pohnpei, Federated States of Micronesia

    Treesearch

    Bill Raynor; Roger R. Bay

    1993-01-01

    Includes 19 papers presented at the workshop, covering such topics as sampling techniques and statistical considerations, indigenous agricultural and agroforestry systems, crop testing and evaluation, and agroforestry practices in the Pacific Islands, including Micronesia, Northern Marianas Islands, Palau, and American Samoa.

  20. Mass gathering enhanced syndromic surveillance for the 8th Micronesian Games in 2014, Pohnpei State, Federated States of Micronesia.

    PubMed

    White, Paul; Saketa, Salanieta; Johnson, Eliaser; Gopalani, Sameer V; Edward, Eliashib; Loney, Charles; Mercier, Alize; Toatu, Tebuka; Wojcik, Richard; Lewis, Sheri; Hoy, Damian

    2018-01-01

    Pohnpei State's Division of Primary Health Care implemented enhanced surveillance for early warning and detection of disease to support the 8th Micronesian Games (the Games) in July 2014. The surveillance comprised 11 point-of-care sentinel sites around Pohnpei, Federated States of Micronesia, collecting data daily for eight syndromes using standard case definitions. Each sentinel site reported total acute care encounters, total syndrome cases and the total for each syndrome. A public health response, including epidemiological investigation and laboratory testing, followed when syndrome counts reached predetermined threshold levels. The surveillance was implemented using the web-based Suite for Automated Global Electronic bioSurveillance Open-ESSENCE (SAGES-OE) application that was customized for the Games. Data were summarized in daily situation reports (SitReps) issued to key stakeholders and posted on PacNet, a Pacific public health e-mail network. Influenza-like illness (ILI) was the most common syndrome reported (55%, n  = 225). Most syndrome cases (75%) were among people from Pohnpei. Only 30 cases out of a total of 408 syndrome cases (7%) presented with acute fever and rash, despite the large and ongoing measles outbreak at the time. No new infectious disease outbreak was recorded during the Games. Peaks in diarrhoeal and ILI cases were followed up and did not result in widespread transmission. The technology was a key feature of the enhanced surveillance. The introduction of the web-based tool greatly improved the timeliness of data entry, analysis and SitRep dissemination, providing assurance to the Games organizers that communicable diseases would not adversely impact the Games.

  1. Pharmacokinetics and Dosing of Levofloxacin in Children Treated for Active or Latent Multidrug-resistant Tuberculosis, Federated States of Micronesia and Republic of the Marshall Islands.

    PubMed

    Mase, Sundari R; Jereb, John A; Gonzalez, Daniel; Martin, Fatma; Daley, Charles L; Fred, Dorina; Loeffler, Ann M; Menon, Lakshmy R; Bamrah Morris, Sapna; Brostrom, Richard; Chorba, Terence; Peloquin, Charles A

    2016-04-01

    In the Federated States of Micronesia and then the Republic of the Marshall Islands (RMI), levofloxacin pharmacokinetics were studied in children receiving directly observed once-daily regimens (10 mg/kg, age >5 years; 15-20 mg/kg, age ≤5 years) for either multidrug-resistant tuberculosis disease or latent infection after multidrug-resistant tuberculosis exposure, to inform future dosing strategies. Blood samples were collected at 0 (RMI only), 1, 2 and 6 hours (50 children, aged 6 months to 15 years) after oral levofloxacin at >6 weeks of treatment. Clinical characteristics and maximal drug concentration (Cmax) of levofloxacin, elimination half-life and area under the curve from 0 to 24 hours (AUC0-24 hours × μg/mL) were correlated to determine the optimal dosage and to examine associations. Population pharmacokinetics and target attainment were modeled. With results from the Federated States of Micronesia, dosages were increased in RMI toward the target Cmax for Mycobacterium tuberculosis, 8-12 µg/mL. Cmax correlated linearly with per-weight dosage. Neither Cmax nor half-life was associated with gender, age, body mass index, concurrent medications or predose meals. At levofloxacin dosage of 15-20 mg/kg, Cmax ≥8 µg/mL was observed, and modeling corroborated a high target attainment across the ratio of the area under the free concentration versus time curve to minimum inhibitory concentration (fAUCss,0-24/MIC) values. Levofloxacin dosage should be 15-20 mg/kg for Cmax ≥8 µg/mL and a high target attainment across fAUCss,0-24/MIC values in children ≥2 years of age.

  2. Impact of routine hepatitis B immunization on the prevalence of chronic hepatitis B virus infection in the marshall islands and the federated States of micronesia.

    PubMed

    Bialek, Stephanie R; Helgenberger, Louisa; Fischer, Gayle E; Bower, William A; Konelios, Mailynn; Chaine, Jean-Paul; Armstrong, Gregory; Williams, Ian T; Bell, Beth P

    2010-01-01

    To evaluate the impact of routine hepatitis B (HB) vaccination on the prevalence of chronic hepatitis B virus (HBV) infection among children in Pacific Island countries where HBV infection was highly endemic, we conducted HB serosurveys during 2000 to 2007 among women of childbearing age born before implementation of HB vaccination and among children born after its implementation. Serum specimens were collected from children aged 2 to 6 years and their mothers in Chuuk, Federated States of Micronesia in 2000, children aged 2 to 9 years and their mothers in Pohnpei, Federated States of Micronesia in 2005, and 5- to 9-year-old children and prenatal clinic patients in 2007 in Republic of the Marshall Islands (RMI). Specimens were tested for HB surface antigen (HBsAg) and antibodies to HB core antigen (total anti-HBc). HB vaccination coverage was determined from health department vaccination registries. We defined chronic HBV infection as the presence of HBsAg. Birthdose and 3 dose HB vaccination coverage was 48% and 87%, respectively, in Chuuk, 87% and 90% in Pohnpei, and 49% and 93% in RMI. Chronic HBV infection prevalence among children was 2.5% (9/362) in Chuuk, 1.5% (7/478) in Pohnpei and 1.8% (6/331) in RMI. Chronic HBV infection prevalence among women was 9.2% (21/229) in Chuuk, 4.4% (10/229) in Pohnpei, and 9.5% (11/116) in RMI. Hepatitis B vaccination has resulted in a substantial decline in chronic infection in children in the Pacific Islands. HB vaccine effectiveness is high in this region, despite challenges in providing HB vaccine at birth and completing vaccination series on schedule.

  3. Palliative Care and Traditional Practices of Death and Dying in Wa'ab (Yap Proper) and in the Outer Islands of Yap

    PubMed Central

    Yalmadau, Kelly; Maluchmai, Maryann R; Tun, Petra; Yinnifel, Cyril; Hancock, W Thane

    2011-01-01

    Background Death remains one of the most important and significant activities in Yap, an event that involves the entire island. A death of a Yapese not only unites the family, it initiates a complex series of reaffirmed kinship ties, rituals and exchanges that refocus the entire community and create new social identities for the participants. How these ties, exchanges, and identities are changing due to new economic challenges and new social pressures were the focus of this preliminary study, which sought to document the resiliency or fragility of traditional structures, measured in the efforts around death and dying in Yap and to identify ways that the health care system can intervene to improve palliative care. Methods 226 persons (49 on Wa'ab - Yap Proper - and 177 on the Outer Islands) participated in 16 focus groups, of which eight were on Wa'ab and eight on four Outer Islands: Fais, Falalop, Fetherai, and Mogmog. We additionally conducted 6 semi-structured open-ended key informant interviews, added to capture more of Yap's enormous sociocultural diversity. Results The islands of Yap, particularly the Outer Islands, continue to support one of the world's best traditional palliative care involving the immediate family, more distant relatives and in many cases the entire community. However, participants showed considerable concern for ways that this system is weakening and offered numerous suggestions for improving and strengthening palliative care in Yap. Discussion Although caution must be exercised not to undermine the existing system, six recommendations on how the health system can intervene can be identified. These involve identifying a key resource person on each island; supplying small, practical “comfort care” kits; making more pain medication available; conducting regular home visits; improving patient-physician and physician-family communication; designing a suicide intervention strategy; and documenting existing variations of how the dying are

  4. YAP:Ce scintillator characteristics for neutron detection

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Viererbl, L.; Klupak, V.; Vins, M.

    2015-07-01

    YAP:Ce (YAlO{sub 3}:Ce{sup +}, Yttrium Aluminum Perovskite, Ce{sup +} doped) crystals with appropriate converters seem like prospective scintillators for neutron detection. An important aspect for neutron detection with inorganic scintillators is the ability to discriminate neutron radiation from gamma radiation by pulse height of signals. For a detailed measurement of the aspect, a YAP:Ce crystal scintillator with lithium or hydrogen converters and a photomultiplier was used. A plutonium-beryllium neutron source and horizontal neutron channel beams of the LVR-15 research reactor were used as neutron sources. The measurement confirmed the possibility to use the YAP:Ce scintillator for neutron radiation detection. Themore » degree of discrimination between neutron and gamma radiation for different detection configurations was studied. (authors)« less

  5. Structural and functional analysis of the YAP-binding domain of human TEAD2

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Tian, Wei; Yu, Jianzhong; Tomchick, Diana R.

    2010-06-15

    The Hippo pathway controls organ size and suppresses tumorigenesis in metazoans by blocking cell proliferation and promoting apoptosis. The TEAD1-4 proteins (which contain a DNA-binding domain but lack an activation domain) interact with YAP (which lacks a DNA-binding domain but contains an activation domain) to form functional heterodimeric transcription factors that activate proliferative and prosurvival gene expression programs. The Hippo pathway inhibits the YAP-TEAD hybrid transcription factors by phosphorylating and promoting cytoplasmic retention of YAP. Here we report the crystal structure of the YAP-binding domain (YBD) of human TEAD2. TEAD2 YBD adopts an immunoglobulin-like {beta}-sandwich fold with two extra helix-turn-helixmore » inserts. NMR studies reveal that the TEAD-binding domain of YAP is natively unfolded and that TEAD binding causes localized conformational changes in YAP. In vitro binding and in vivo functional assays define an extensive conserved surface of TEAD2 YBD as the YAP-binding site. Therefore, our studies suggest that a short segment of YAP adopts an extended conformation and forms extensive contacts with a rigid surface of TEAD. Targeting a surface-exposed pocket of TEAD might be an effective strategy to disrupt the YAP-TEAD interaction and to reduce the oncogenic potential of YAP.« less

  6. Glutamine-utilizing transaminases are a metabolic vulnerability of TAZ/YAP-activated cancer cells.

    PubMed

    Yang, Chih-Sheng; Stampouloglou, Eleni; Kingston, Nathan M; Zhang, Liye; Monti, Stefano; Varelas, Xaralabos

    2018-06-01

    The transcriptional regulators TAZ and YAP (TAZ/YAP) have emerged as pro-tumorigenic factors that drive many oncogenic traits, including induction of cell growth, resistance to cell death, and activation of processes that promote migration and invasion. Here, we report that TAZ/YAP reprogram cellular energetics to promote the dependence of breast cancer cell growth on exogenous glutamine. Rescue experiments with glutamine-derived metabolites suggest an essential role for glutamate and α-ketoglutarate (AKG) in TAZ/YAP-driven cell growth in the absence of glutamine. Analysis of enzymes that mediate the conversion of glutamate to AKG shows that TAZ/YAP induce glutamic-oxaloacetic transaminase (GOT1) and phosphoserine aminotransferase (PSAT1) expression and that TAZ/YAP activity positively correlates with transaminase expression in breast cancer patients. Notably, we find that the transaminase inhibitor aminooxyacetate (AOA) represses cell growth in a TAZ/YAP-dependent manner, identifying transamination as a potential vulnerable metabolic requirement for TAZ/YAP-driven breast cancer. © 2018 The Authors.

  7. Integrin signalling regulates YAP and TAZ to control skin homeostasis

    PubMed Central

    Elbediwy, Ahmed; Vincent-Mistiaen, Zoé I.; Spencer-Dene, Bradley; Stone, Richard K.; Boeing, Stefan; Wculek, Stefanie K.; Cordero, Julia; Tan, Ee H.; Ridgway, Rachel; Brunton, Val G.; Sahai, Erik; Gerhardt, Holger; Behrens, Axel; Malanchi, Ilaria; Sansom, Owen J.; Thompson, Barry J.

    2016-01-01

    ABSTRACT The skin is a squamous epithelium that is continuously renewed by a population of basal layer stem/progenitor cells and can heal wounds. Here, we show that the transcription regulators YAP and TAZ localise to the nucleus in the basal layer of skin and are elevated upon wound healing. Skin-specific deletion of both YAP and TAZ in adult mice slows proliferation of basal layer cells, leads to hair loss and impairs regeneration after wounding. Contact with the basal extracellular matrix and consequent integrin-Src signalling is a key determinant of the nuclear localisation of YAP/TAZ in basal layer cells and in skin tumours. Contact with the basement membrane is lost in differentiating daughter cells, where YAP and TAZ become mostly cytoplasmic. In other types of squamous epithelia and squamous cell carcinomas, a similar control mechanism is present. By contrast, columnar epithelia differentiate an apical domain that recruits CRB3, Merlin (also known as NF2), KIBRA (also known as WWC1) and SAV1 to induce Hippo signalling and retain YAP/TAZ in the cytoplasm despite contact with the basal layer extracellular matrix. When columnar epithelial tumours lose their apical domain and become invasive, YAP/TAZ becomes nuclear and tumour growth becomes sensitive to the Src inhibitor Dasatinib. PMID:26989177

  8. YAP is essential for Treg mediated suppression of anti-tumor immunity.

    PubMed

    Ni, Xuhao; Tao, Jinhui; Barbi, Joseph; Chen, Qian; Park, Benjamin V; Li, Zhiguang; Zhang, Nailing; Lebid, Andriana; Ramaswamy, Anjali; Wei, Ping; Zheng, Ying; Zhang, Xuehong; Wu, Xingmei; Vignali, Paolo D A; Yang, Cuiping; Li, Huabin; Pardoll, Drew; Lu, Ling; Pan, Duojia; Pan, Fan

    2018-06-15

    Regulatory T cells (Tregs) are critical for maintaining self-tolerance and immune homeostasis, but their suppressive function can impede effective anti-tumor immune responses. Foxp3 is a transcription factor expressed in Tregs that is required for their function. However, the pathways and microenvironmental cues governing Foxp3 expression and Treg function are not completely understood. Herein, we report that Yes-associated protein (YAP), a co-activator of the Hippo pathway, is highly expressed in Tregs and bolsters Foxp3 expression and Treg function in vitro and in vivo. This potentiation stemmed from YAP-dependent upregulation of Activin signaling which amplifies TGFβ/SMAD activation in Tregs. YAP-deficiency resulted in dysfunctional Tregs unable to suppress anti-tumor immunity or promote tumor growth in mice. Chemical YAP antagonism and knockout or blockade of the YAP-regulated Activin Receptor similarly improved anti-tumor immunity. Thus we identify YAP as an unexpected amplifier of a Treg-reinforcing pathway with significant potential as an anti-cancer immunotherapeutic target. Copyright ©2018, American Association for Cancer Research.

  9. YAP expression in normal and neoplastic breast tissue: an immunohistochemical study.

    PubMed

    Jaramillo-Rodríguez, Yolanda; Cerda-Flores, Ricardo M; Ruiz-Ramos, Ruben; López-Márquez, Francisco C; Calderón-Garcidueñas, Ana Laura

    2014-04-01

    Yes-associated protein (YAP) is a transcriptional factor involved in normal cell proliferation, apoptosis and carcinogenesis; however, its contribution to breast cancer (BC) is still controversial. We undertook this study to compare the expression of YAP by immunohistochemistry (IHC) in normal breast tissue of women without breast cancer (BC) (controls), non-neoplastic breast tissue in women with cancer (internal controls) and in four different subtypes of invasive ductal carcinoma. There were 17 controls and 105 tumor cases (53 luminal A, 15 luminal B, 20 overexpression of HER2 and 17 triple negative cases) studied by IHC. Statistical analysis included χ(2) for linear trend (Extended Mantel-Haenszel). There were 40% of internal controls that showed expression of YAP in myoepithelial cells, whereas in controls expression was 100%. In controls, 3/17 (17.6%) showed cytoplasmic staining in luminal cells. There was a significant difference in nuclear expression between the ductal BC subtypes. Luminal A had 4% of positive cases with <10% of cells affected in each case; in contrast, there were 17-20% of positive cases in the other groups with 50% or more of stained cells. YAP expression in stromal cells was not observed in controls or in triple-negative cases, and luminal B pattern had the highest YAP nuclear expression (20%). YAP showed decreased expression in tumor cells compared with normal breast tissue. These findings are consistent with a role of YAP as a suppressor gene in BC and show differences in YAP expression in different patterns of ductal BC. Copyright © 2014 IMSS. Published by Elsevier Inc. All rights reserved.

  10. Discover the Hidden Jewels in Your Library and Sharing the Wealth through Collaboration. Selected Papers from PIALA 2011, Pacific Islands Association of Libraries, Archives, and Museums Annual Conference (21st, Kosrae, Federated States of Micronesia, November 14-17, 2011)

    ERIC Educational Resources Information Center

    Drake, Paul B., Ed.

    2012-01-01

    This publication follows the tradition of publishing selected papers from Pacific Islands Association of Libraries, Archives and Museums (PIALA) annual conferences. This 21st annual conference was held in Kosrae, Federated States of Micronesia, November 14-17, 2011. The volume begins with a listing of the members of the PIALA 2011 Planning…

  11. Pacific Visions: Finding, Selecting, and Using Resources for Your Libraries, Archives, and Museums. Selected Papers from PIALA 2009, Pacific Islands Association of Libraries, Archives, and Museums Annual Conference (19th, Pohnpei, Federated States of Micronesia, November 16-21, 2009)

    ERIC Educational Resources Information Center

    Drake, Paul B., Ed.

    2011-01-01

    This publication follows the tradition of publishing selected papers from Pacific Islands Association of Libraries, Archives and Museums (PIALA) annual conferences. This 19th annual conference was held in Pohnpei, Federated States of Micronesia, November 16-21, 2009. The volume begins with a listing of the members of the PIALA 2009 Planning…

  12. YAP/TAZ regulates sprouting angiogenesis and vascular barrier maturation

    PubMed Central

    Kim, Yoo Hyung; Kim, Jaeryung; Park, Do Young; Bae, Hosung; Lee, Da-Hye; Kim, Kyun Hoo; Hong, Seon Pyo; Jang, Seung Pil; Kwon, Young-Guen; Lim, Dae-Sik

    2017-01-01

    Angiogenesis is a multistep process that requires coordinated migration, proliferation, and junction formation of vascular endothelial cells (ECs) to form new vessel branches in response to growth stimuli. Major intracellular signaling pathways that regulate angiogenesis have been well elucidated, but key transcriptional regulators that mediate these signaling pathways and control EC behaviors are only beginning to be understood. Here, we show that YAP/TAZ, a transcriptional coactivator that acts as an end effector of Hippo signaling, is critical for sprouting angiogenesis and vascular barrier formation and maturation. In mice, endothelial-specific deletion of Yap/Taz led to blunted-end, aneurysm-like tip ECs with fewer and dysmorphic filopodia at the vascular front, a hyper-pruned vascular network, reduced and disarranged distributions of tight and adherens junction proteins, disrupted barrier integrity, subsequent hemorrhage in growing retina and brain vessels, and reduced pathological choroidal neovascularization. Mechanistically, YAP/TAZ activates actin cytoskeleton remodeling, an important component of filopodia formation and junction assembly. Moreover, YAP/TAZ coordinates EC proliferation and metabolic activity by upregulating MYC signaling. Overall, these results show that YAP/TAZ plays multifaceted roles for EC behaviors, proliferation, junction assembly, and metabolism in sprouting angiogenesis and barrier formation and maturation and could be a potential therapeutic target for treating neovascular diseases. PMID:28805663

  13. An Assessment of Non-Communicable Diseases, Diabetes, and Related Risk Factors in the Federated States of Micronesia, State of Kosrae: A Systems Perspective

    PubMed Central

    Tolenoa, Nena; Taulung, Livinson; Mongkeya, Maria; Lippwe, Kipier; Aitaoto, Nia

    2013-01-01

    Non-communicable diseases (NCD) have been identified as a health emergency in the US-affiliated Pacific Islands (USAPI).1 This assessment, funded by the National Institutes of Health, was conducted in the Federated States of Micronesia, State of Kosrae and describes the burdens due to NCDs, including diabetes, and assesses the system of service capacity and current activities for service delivery, data collection and reporting as well as identifying the issues that need to be addressed. There has been a 13.9% decline in the population between 2000 and 2010. Findings reveal that the risk factors of poor diet, lack of physical activity, and lifestyle behaviors lead to overweight and obesity and subsequent NCD that are a significant factor in the morbidity and mortality of the population. Leading causes of death were due to nutrition and metabolic diseases followed by diseases of the circulatory system. Data from selected community programs show that the prevalence of overweight and obese participants ranged between 82% and 95% and the rate of reported diabetes ranged from 13% to 14%. Other findings show significant gaps in the system of administrative, clinical, data, and support services to address these NCD. There is no functional data system that is able to identify, register, or track patients with diabetes. Priority administrative and clinical issues were identified that need to be addressed to begin to mitigate the burdens of NCDs among the residents of Kosrae State. PMID:23900387

  14. An assessment of non-communicable diseases, diabetes, and related risk factors in the Federated States of Micronesia, State of Kosrae: a systems perspective.

    PubMed

    Ichiho, Henry M; Tolenoa, Nena; Taulung, Livinson; Mongkeya, Maria; Lippwe, Kipier; Aitaoto, Nia

    2013-05-01

    Non-communicable diseases (NCD) have been identified as a health emergency in the US-affiliated Pacific Islands (USAPI). This assessment, funded by the National Institutes of Health, was conducted in the Federated States of Micronesia, State of Kosrae and describes the burdens due to NCDs, including diabetes, and assesses the system of service capacity and current activities for service delivery, data collection and reporting as well as identifying the issues that need to be addressed. There has been a 13.9% decline in the population between 2000 and 2010. Findings reveal that the risk factors of poor diet, lack of physical activity, and lifestyle behaviors lead to overweight and obesity and subsequent NCD that are a significant factor in the morbidity and mortality of the population. Leading causes of death were due to nutrition and metabolic diseases followed by diseases of the circulatory system. Data from selected community programs show that the prevalence of overweight and obese participants ranged between 82% and 95% and the rate of reported diabetes ranged from 13% to 14%. Other findings show significant gaps in the system of administrative, clinical, data, and support services to address these NCD. There is no functional data system that is able to identify, register, or track patients with diabetes. Priority administrative and clinical issues were identified that need to be addressed to begin to mitigate the burdens of NCDs among the residents of Kosrae State.

  15. YAP Inhibition Restores Hepatocyte Differentiation in Advanced HCC, Leading to Tumor Regression.

    PubMed

    Fitamant, Julien; Kottakis, Filippos; Benhamouche, Samira; Tian, Helen S; Chuvin, Nicolas; Parachoniak, Christine A; Nagle, Julia M; Perera, Rushika M; Lapouge, Marjorie; Deshpande, Vikram; Zhu, Andrew X; Lai, Albert; Min, Bosun; Hoshida, Yujin; Avruch, Joseph; Sia, Daniela; Campreciós, Genís; McClatchey, Andrea I; Llovet, Josep M; Morrissey, David; Raj, Lakshmi; Bardeesy, Nabeel

    2015-03-10

    Defective Hippo/YAP signaling in the liver results in tissue overgrowth and development of hepatocellular carcinoma (HCC). Here, we uncover mechanisms of YAP-mediated hepatocyte reprogramming and HCC pathogenesis. YAP functions as a rheostat in maintaining metabolic specialization, differentiation, and quiescence within the hepatocyte compartment. Increased or decreased YAP activity reprograms subsets of hepatocytes to different fates associated with deregulation of the HNF4A, CTNNB1, and E2F transcriptional programs that control hepatocyte quiescence and differentiation. Importantly, treatment with small interfering RNA-lipid nanoparticles (siRNA-LNPs) targeting YAP restores hepatocyte differentiation and causes pronounced tumor regression in a genetically engineered mouse HCC model. Furthermore, YAP targets are enriched in an aggressive human HCC subtype characterized by a proliferative signature and absence of CTNNB1 mutations. Thus, our work reveals Hippo signaling as a key regulator of the positional identity of hepatocytes, supports targeting of YAP using siRNA-LNPs as a paradigm of differentiation-based therapy, and identifies an HCC subtype that is potentially responsive to this approach. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  16. Integrin signalling regulates YAP and TAZ to control skin homeostasis.

    PubMed

    Elbediwy, Ahmed; Vincent-Mistiaen, Zoé I; Spencer-Dene, Bradley; Stone, Richard K; Boeing, Stefan; Wculek, Stefanie K; Cordero, Julia; Tan, Ee H; Ridgway, Rachel; Brunton, Val G; Sahai, Erik; Gerhardt, Holger; Behrens, Axel; Malanchi, Ilaria; Sansom, Owen J; Thompson, Barry J

    2016-05-15

    The skin is a squamous epithelium that is continuously renewed by a population of basal layer stem/progenitor cells and can heal wounds. Here, we show that the transcription regulators YAP and TAZ localise to the nucleus in the basal layer of skin and are elevated upon wound healing. Skin-specific deletion of both YAP and TAZ in adult mice slows proliferation of basal layer cells, leads to hair loss and impairs regeneration after wounding. Contact with the basal extracellular matrix and consequent integrin-Src signalling is a key determinant of the nuclear localisation of YAP/TAZ in basal layer cells and in skin tumours. Contact with the basement membrane is lost in differentiating daughter cells, where YAP and TAZ become mostly cytoplasmic. In other types of squamous epithelia and squamous cell carcinomas, a similar control mechanism is present. By contrast, columnar epithelia differentiate an apical domain that recruits CRB3, Merlin (also known as NF2), KIBRA (also known as WWC1) and SAV1 to induce Hippo signalling and retain YAP/TAZ in the cytoplasm despite contact with the basal layer extracellular matrix. When columnar epithelial tumours lose their apical domain and become invasive, YAP/TAZ becomes nuclear and tumour growth becomes sensitive to the Src inhibitor Dasatinib. © 2016. Published by The Company of Biologists Ltd.

  17. Yap is required for ependymal integrity and is suppressed in LPA-induced hydrocephalus

    PubMed Central

    Park, Raehee; Moon, Uk Yeol; Park, Jun Young; Hughes, Lucinda J.; Johnson, Randy L.; Cho, Seo-Hee; Kim, Seonhee

    2016-01-01

    Timely generation and normal maturation of ependymal cells along the aqueduct are critical for preventing physical blockage between the third and fourth ventricles and the development of fetal non-communicating hydrocephalus. Our study identifies Yap, the downstream effector of the evolutionarily conserved Hippo pathway, as a central regulator for generating developmentally controlled ependymal cells along the ventricular lining of the aqueduct. Yap function is necessary for proper proliferation of progenitors and apical attachment of ependymal precursor cells. Importantly, an injury signal initiated by lysophosphatidic acid (LPA), an upstream regulator of Yap that can cause fetal haemorrhagic hydrocephalus, deregulates Yap in the developing aqueduct. LPA exposure leads to the loss of N-cadherin concentrations at the apical endfeet, which can be partially restored by forced Yap expression and more efficiently by phosphomimetic Yap. These results reveal a novel function of Yap in retaining tissue junctions during normal development and after fetal brain injury. PMID:26754915

  18. Reciprocal regulation of YAP/TAZ by the Hippo pathway and the Small GTPase pathway.

    PubMed

    Jang, Ju-Won; Kim, Min-Kyu; Bae, Suk-Chul

    2018-04-20

    Yes-associated protein 1 (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) (YAP/TAZ) are transcriptional coactivators that regulate genes involved in proliferation and transformation by interacting with DNA-binding transcription factors. Remarkably, YAP/TAZ are essential for cancer initiation or growth of most solid tumors. Their activation induces cancer stem cell attributes, proliferation, and metastasis. The oncogenic activity of YAP/TAZ is inhibited by the Hippo cascade, an evolutionarily conserved pathway that is governed by two kinases, mammalian Ste20-like kinases 1/2 (MST1/2) and Large tumor suppressor kinase 1/2 (LATS1/2), corresponding to Drosophila's Hippo (Hpo) and Warts (Wts), respectively. One of the most influential aspects of YAP/TAZ biology is that these factors are transducers of cell structural features, including polarity, shape, and cytoskeletal organization. In turn, these features are intimately related to the cell's ability to attach to other cells and to the surrounding extracellular matrix (ECM), and are also influenced by the cell's microenvironment. Thus, YAP/TAZ respond to changes that occur at the level of whole tissues. Notably, small GTPases act as master organizers of the actin cytoskeleton. Recent studies provided convincing genetic evidence that small GTPase signaling pathways activate YAP/TAZ, while the Hippo pathway inhibits them. Biochemical studies showed that small GTPases facilitate the YAP-Tea domain transcription factor (TEAD) interaction by inhibiting YAP phosphorylation in response to serum stimulation, while the Hippo pathway facilitates the YAP-RUNX3 interaction by increasing YAP phosphorylation. Therefore, small GTPase pathways activate YAP/TAZ by switching its DNA-binding transcription factors. In this review, we summarize the relationship between the Hippo pathway and small GTPase pathways in the regulation of YAP/TAZ.

  19. The Hippo-YAP Pathway Regulates 3D Organ Formation and Homeostasis.

    PubMed

    Ishihara, Erika; Nishina, Hiroshi

    2018-04-17

    The vertebrate body shape is formed by the specific sizes and shapes of its resident tissues and organs, whose alignments are essential for proper functioning. To maintain tissue and organ shape, and thereby function, it is necessary to remove senescent, transformed, and/or damaged cells, which impair function and can lead to tumorigenesis. However, the molecular mechanisms underlying three-dimensional (3D) organ formation and homeostasis are not fully clear. Yes-associated protein (YAP) is a transcriptional co-activator that is involved in organ size control and tumorigenesis. Recently, we reported that YAP is essential for proper 3D body shape through regulation of cell tension by using a unique medaka fish mutant, hirame ( hir ). In Madin–Darby canine kidney (MDCK) epithelial cells, active YAP-transformed cells are eliminated apically when surrounded by normal cells. Furthermore, in a mosaic mouse model, active YAP-expressing damaged hepatocytes undergo apoptosis and are eliminated from the liver. Thus, YAP functions in quantitative and quality control in organogenesis. In this review, we describe the various roles of YAP in vertebrates, including in the initiation of liver cancer.

  20. Two new species of the genus Arrenurus from Pohnpei, Federated States of Micronesia (Acari: Hydrchnidia: Arrenuridae)

    Treesearch

    Harry Smit

    2010-01-01

    Few specimens of water mites have been collected from Pacific Island streams, especially higher elevation, head water streams. Uchida (1935, 1939) and Cook & Bright (1983) published 11 species of water mites from the Palau Islands, while Cook (1957) reported two Arrenurus species from the main island of Yap in the Caroline Island chain. Viets (...

  1. Voyaging from the Past, to the Present, and into the Future: Knowing Your Heritage. Selected Papers from PIALA 2003, Pacific Islands Association of Libraries, Archives and Museums Annual Conference (13th, Pohnpei, Federated States of Micronesia, November 4-6, 2003)

    ERIC Educational Resources Information Center

    Drake, Paul B., Ed.

    2003-01-01

    This publication follows the tradition of publishing selected papers from Pacific Islands Association of Libraries, Archives and Museums (PIALA) annual conferences. This 13th annual conference was held in Pohnpei, Federated States of Micronesia, November 4-6, 2003. The volume begins with a listing of the members of the PIALA 2003 Planning &…

  2. Force Triggers YAP Nuclear Entry by Regulating Transport across Nuclear Pores.

    PubMed

    Elosegui-Artola, Alberto; Andreu, Ion; Beedle, Amy E M; Lezamiz, Ainhoa; Uroz, Marina; Kosmalska, Anita J; Oria, Roger; Kechagia, Jenny Z; Rico-Lastres, Palma; Le Roux, Anabel-Lise; Shanahan, Catherine M; Trepat, Xavier; Navajas, Daniel; Garcia-Manyes, Sergi; Roca-Cusachs, Pere

    2017-11-30

    YAP is a mechanosensitive transcriptional activator with a critical role in cancer, regeneration, and organ size control. Here, we show that force applied to the nucleus directly drives YAP nuclear translocation by decreasing the mechanical restriction of nuclear pores to molecular transport. Exposure to a stiff environment leads cells to establish a mechanical connection between the nucleus and the cytoskeleton, allowing forces exerted through focal adhesions to reach the nucleus. Force transmission then leads to nuclear flattening, which stretches nuclear pores, reduces their mechanical resistance to molecular transport, and increases YAP nuclear import. The restriction to transport is further regulated by the mechanical stability of the transported protein, which determines both active nuclear transport of YAP and passive transport of small proteins. Our results unveil a mechanosensing mechanism mediated directly by nuclear pores, demonstrated for YAP but with potential general applicability in transcriptional regulation. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Profile of Pacific Higher Education.

    ERIC Educational Resources Information Center

    Research and Development Cadre, Honolulu, HI.

    Comparative data concerning institutions of higher education in the Pacific Islands are tabulated and summarized to aid in program planning, development, and implementation in that region. The jurisdictions covered are: American Samoa; Palau; the Northern Mariana Islands; Micronesia; Kosrae; Pohnpei; Truk; Yap; Guam; Hawaii; and the Marshall…

  4. Quantitative Analysis Reveals that Actin and Src-Family Kinases Regulate Nuclear YAP1 and Its Export.

    PubMed

    Ege, Nil; Dowbaj, Anna M; Jiang, Ming; Howell, Michael; Hooper, Steven; Foster, Charles; Jenkins, Robert P; Sahai, Erik

    2018-06-08

    The transcriptional regulator YAP1 is critical for the pathological activation of fibroblasts. In normal fibroblasts, YAP1 is located in the cytoplasm, while in activated cancer-associated fibroblasts, it is nuclear and promotes the expression of genes required for pro-tumorigenic functions. Here, we investigate the dynamics of YAP1 shuttling in normal and activated fibroblasts, using EYFP-YAP1, quantitative photobleaching methods, and mathematical modeling. Imaging of migrating fibroblasts reveals the tight temporal coupling of cell shape change and altered YAP1 localization. Both 14-3-3 and TEAD binding modulate YAP1 shuttling, but neither affects nuclear import. Instead, we find that YAP1 nuclear accumulation in activated fibroblasts results from Src and actomyosin-dependent suppression of phosphorylated YAP1 export. Finally, we show that nuclear-constrained YAP1, upon XPO1 depletion, remains sensitive to blockade of actomyosin function. Together, these data place nuclear export at the center of YAP1 regulation and indicate that the cytoskeleton can regulate YAP1 within the nucleus. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

  5. A Novel Notch-YAP Circuit Drives Stemness and Tumorigenesis in Embryonal Rhabdomyosarcoma.

    PubMed

    Slemmons, Katherine K; Crose, Lisa E S; Riedel, Stefan; Sushnitha, Manuela; Belyea, Brian; Linardic, Corinne M

    2017-12-01

    Rhabdomyosarcoma (RMS), a cancer characterized by skeletal muscle features, is the most common soft-tissue sarcoma of childhood. While low- and intermediate-risk groups have seen improved outcomes, high-risk patients still face a 5-year survival rate of <30%, a statistic that has not changed in over 40 years. Understanding the biologic underpinnings of RMS is critical. The developmental pathways of Notch and YAP have been identified as potent but independent oncogenic signals that support the embryonal variant of RMS (eRMS). Here, the cross-talk between these pathways and the impact on eRMS tumorigenesis is reported. Using human eRMS cells grown as three-dimensional (3D) rhabdospheres, which enriches in stem cells, it was found that Notch signaling transcriptionally upregulates YAP1 gene expression and YAP activity. Reciprocally, YAP transcriptionally upregulates the Notch ligand genes JAG1 and DLL1 and the core Notch transcription factor RBPJ This bidirectional circuit boosts expression of key stem cell genes, including SOX2 , which is functionally required for eRMS spheres. Silencing this circuit for therapeutic purposes may be challenging, because the inhibition of one node (e.g., pharmacologic Notch blockade) can be rescued by upregulation of another (constitutive YAP expression). Instead, dual inhibition of Notch and YAP is necessary. Finally, supporting the existence of this circuit beyond a model system, nuclear Notch and YAP protein expression are correlated in human eRMS tumors, and YAP suppression in vivo decreases Notch signaling and SOX2 expression. Implications: This study identifies a novel oncogenic signaling circuit driving eRMS stemness and tumorigenesis, and provides evidence and rationale for combination therapies co-targeting Notch and YAP. Mol Cancer Res; 15(12); 1777-91. ©2017 AACR . ©2017 American Association for Cancer Research.

  6. Arsenic Directly Binds to and Activates the Yeast AP-1-Like Transcription Factor Yap8

    PubMed Central

    Kumar, Nallani Vijay; Yang, Jianbo; Pillai, Jitesh K.; Rawat, Swati; Solano, Carlos; Kumar, Abhay; Grøtli, Morten; Stemmler, Timothy L.; Rosen, Barry P.

    2015-01-01

    The AP-1-like transcription factor Yap8 is critical for arsenic tolerance in the yeast Saccharomyces cerevisiae. However, the mechanism by which Yap8 senses the presence of arsenic and activates transcription of detoxification genes is unknown. Here we demonstrate that Yap8 directly binds to trivalent arsenite [As(III)] in vitro and in vivo and that approximately one As(III) molecule is bound per molecule of Yap8. As(III) is coordinated by three sulfur atoms in purified Yap8, and our genetic and biochemical data identify the cysteine residues that form the binding site as Cys132, Cys137, and Cys274. As(III) binding by Yap8 does not require an additional yeast protein, and Yap8 is regulated neither at the level of localization nor at the level of DNA binding. Instead, our data are consistent with a model in which a DNA-bound form of Yap8 acts directly as an As(III) sensor. Binding of As(III) to Yap8 triggers a conformational change that in turn brings about a transcriptional response. Thus, As(III) binding to Yap8 acts as a molecular switch that converts inactive Yap8 into an active transcriptional regulator. This is the first report to demonstrate how a eukaryotic protein couples arsenic sensing to transcriptional activation. PMID:26711267

  7. Arsenic Directly Binds to and Activates the Yeast AP-1-Like Transcription Factor Yap8

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kumar, Nallani Vijay; Yang, Jianbo; Pillai, Jitesh K.

    The AP-1-like transcription factor Yap8 is critical for arsenic tolerance in the yeastSaccharomyces cerevisiae. However, the mechanism by which Yap8 senses the presence of arsenic and activates transcription of detoxification genes is unknown. Here we demonstrate that Yap8 directly binds to trivalent arsenite [As(III)]in vitroandin vivoand that approximately one As(III) molecule is bound per molecule of Yap8. As(III) is coordinated by three sulfur atoms in purified Yap8, and our genetic and biochemical data identify the cysteine residues that form the binding site as Cys132, Cys137, and Cys274. As(III) binding by Yap8 does not require an additional yeast protein, and Yap8more » is regulated neither at the level of localization nor at the level of DNA binding. Instead, our data are consistent with a model in which a DNA-bound form of Yap8 acts directly as an As(III) sensor. Binding of As(III) to Yap8 triggers a conformational change that in turn brings about a transcriptional response. Thus, As(III) binding to Yap8 acts as a molecular switch that converts inactive Yap8 into an active transcriptional regulator. This is the first report to demonstrate how a eukaryotic protein couples arsenic sensing to transcriptional activation.« less

  8. Unusual Rocks of the Yap Ridge - Metamorphosed Basal Cumulates of an Arc ?

    NASA Astrophysics Data System (ADS)

    Hawkins, J. W.; Castillo, P. R.; Batiza, R.

    2002-12-01

    The 8 to 9 km deep Yap trench, and adjacent Yap Ridge, extend from the southwest end of the Mariana Trench near 11o N, to near 7o 15' N where the trench swings west to intersect the Palau Trench. Unlike other western Pacific subduction systems, the Yap Ridge rises directly from the trench, it has no forearc, neither a remnant nor active volcanic arc, and no inclined seismic zone. The few seismic events recorded are mainly < 70 km depth. Yap Ridge crest depths range from 2.5 km to emergent; there are no emergent volcanoes. Rocks from the islands Yap and Map, are mainly strongly schistose, amphibole-rich, mafic and ultramafic rocks. Metamorphic lineations, and meter-sized mullions having lenticular cross-sections, define inclined (15o southerly dip) tectonic transport. Yap and Map schists are in greenschist facies (actinolite - chlorite - Na-plagioclase, rare titanite and epidote). Talc - tremolite schists, serpentinite, and chlorite-pyroxenite are less common. Small areas of altered andesite are present; quartz diorite and hornblende-rich gabbro occur as clasts in breccias, bomb craters yielded fragments of basalt and diabase. Scattered blankets of laterite several meters thick, and jungle, obscure many details. Deeper crustal rocks exposed on inner wall of Yap Trench, (5 - 2.5 km depths) include amphibolite (Al-hornblende-andesine-titanite) interlayered with calcite- diopside - grossularite marble, and calc-silicate gneisses. Rocks dredged from Yap Ridge include metabasite similar toYap schists, island arc tholeiite series basalt, basaltic andesite, and 2-PX gabbro. These have late Miocene ages (Beccaluva et al., AGU Mon. 23, 1980). Assuming isochemical behavior for immobile elements, protolith for mafic and ultramafic schists had high Mg# (52-83), CaO/Al2O3 0.7-6, Cr 288-1490, Ni 64-609, Zr 13-145, Y 3-28 (ppm).These data suggest picrite, high-Mg basalt, boninite, or OL-PX rich ultramafic cumulates as parents. REE data, e.g. negative slope and (La/Sm)N 0

  9. A hairpin within YAP mRNA 3′UTR functions in regulation at post-transcription level

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Gao, Yuen; Wang, Yuan; Feng, Jinyan

    2015-04-03

    The central dogma of gene expression is that DNA is transcribed into messenger RNAs, which in turn serve as the template for protein synthesis. Recently, it has been reported that mRNAs display regulatory roles that rely on their ability to compete for microRNA binding, independent of their protein-coding function. However, the regulatory mechanism of mRNAs remains poorly understood. Here, we report that a hairpin within YAP mRNA 3′untranslated region (3′UTR) functions in regulation at post-transcription level through generating endogenous siRNAs (esiRNAs). Bioinformatics analysis for secondary structure showed that YAP mRNA displayed a hairpin structure (termed standard hairpin, S-hairpin) within itsmore » 3′UTR. Surprisingly, we observed that the overexpression of S-hairpin derived from YAP 3′UTR (YAP-sh) increased the luciferase reporter activities of transcriptional factor NF-κB and AP-1 in 293T cells. Moreover, we identified that a fragment from YAP-sh, an esiRNA, was able to target mRNA 3′UTR of NF2 (a member of Hippo-signaling pathway) and YAP mRNA 3′UTR itself in hepatoma cells. Thus, we conclude that the YAP-sh within YAP mRNA 3′UTR may serve as a novel regulatory element, which functions in regulation at post-transcription level. Our finding provides new insights into the mechanism of mRNAs in regulatory function. - Highlights: • An S-hairpin within YAP mRNA 3′UTR possesses regulatory function. • YAP-sh acts as a regulatory element for YAP at post-transcription level. • YAP-sh-3p20, an esiRNA derived from YAP-sh, targets mRNAs of YAP and NF2. • YAP-sh-3p20 depresses the proliferation of HepG2 cells in vitro.« less

  10. YAP/TAZ enhance mammalian embryonic neural stem cell characteristics in a Tead-dependent manner

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Han, Dasol; Byun, Sung-Hyun; Park, Soojeong

    Mammalian brain development is regulated by multiple signaling pathways controlling cell proliferation, migration and differentiation. Here we show that YAP/TAZ enhance embryonic neural stem cell characteristics in a cell autonomous fashion using diverse experimental approaches. Introduction of retroviral vectors expressing YAP or TAZ into the mouse embryonic brain induced cell localization in the ventricular zone (VZ), which is the embryonic neural stem cell niche. This change in cell distribution in the cortical layer is due to the increased stemness of infected cells; YAP-expressing cells were colabeled with Sox2, a neural stem cell marker, and YAP/TAZ increased the frequency and sizemore » of neurospheres, indicating enhanced self-renewal- and proliferative ability of neural stem cells. These effects appear to be TEA domain family transcription factor (Tead)–dependent; a Tead binding-defective YAP mutant lost the ability to promote neural stem cell characteristics. Consistently, in utero gene transfer of a constitutively active form of Tead2 (Tead2-VP16) recapitulated all the features of YAP/TAZ overexpression, and dominant negative Tead2-EnR resulted in marked cell exit from the VZ toward outer cortical layers. Taken together, these results indicate that the Tead-dependent YAP/TAZ signaling pathway plays important roles in neural stem cell maintenance by enhancing stemness of neural stem cells during mammalian brain development. - Highlights: • Roles of YAP and Tead in vivo during mammalian brain development are clarified. • Expression of YAP promotes embryonic neural stem cell characteristics in vivo in a cell autonomous fashion. • Enhancement of neural stem cell characteristics by YAP depends on Tead. • Transcriptionally active form of Tead alone can recapitulate the effects of YAP. • Transcriptionally repressive form of Tead severely reduces stem cell characteristics.« less

  11. Yes-associated protein homolog, YAP-1, is involved in the thermotolerance and aging in the nematode Caenorhabditis elegans

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Iwasa, Hiroaki; Maimaiti, Sainawaer; Department of Psychotherapy, The Fourth People's Hospital of Urumqi, Urumqi 830000

    2013-04-15

    The mammalian Hippo pathway comprises mammalian Ste20-like kinases (MST1/2) and large tumor suppressor kinases (LATS1/2). LATS1/2, which are activated by MST1/2, phosphorylate a transcriptional co-activator, yes-associated protein (YAP), and induce the recruitment of YAP by 14-3-3 to cytoplasm, so that the TEAD-dependent gene transcriptions are turned off. Although the core components of the Hippo pathway are well conserved in metazoans, it has been discussed that Caenorhabditis elegans lacks YAP ortholog, we found that F13E6.4 gene encodes a protein that shows sequence similarities to YAP in the N-terminal TEAD-binding domain and in the WW domain. We designated this gene as yap-1.more » YAP-1 is widely expressed in various cells such as epithelial cells, muscles, hypodermal cells, gonadal sheath cells, spermatheca, and hypodermal cells. YAP-1 is distributed in cytoplasm and nuclei. wts-1 (LATS ortholog) and ftt-2 (14-3-3 ortholog) knockdowns cause nuclear accumulation of YAP-1, supporting that the subcellular localization of YAP-1 is regulated in a similar way as that of YAP. Heat shock also causes the nuclear accumulation of YAP-1 but after heat shock, YAP-1 translocates to cytoplasm. Knockdowns of DAF-21 (HSP90 ortholog) and HSF-1block the nuclear export of YAP-1 during this recovery. YAP-1 overexpression is beneficial for thermotolerance, whereas YAP-1 hyperactivity induced by wts-1 and ftt-2 knockdowns is deleterious on thermal response and yap-1 deficiency promotes health aging. In short, YAP-1 partially shares basal characters with mammalian YAP and plays a role in thermal stress response and healthy aging. - Highlights: ► We named Caenorhabditis elegans F13E6.4 gene yap-1 as a putative YAP homolog. ► The localization of YAP-1 is regulated by WTS-1 and FTT-2. ► YAP-1 is involved in healthy aging and thermosensitivity.« less

  12. Atypical protein kinase C induces cell transformation by disrupting Hippo/Yap signaling

    PubMed Central

    Archibald, Andrew; Al-Masri, Maia; Liew-Spilger, Alyson; McCaffrey, Luke

    2015-01-01

    Epithelial cells are major sites of malignant transformation. Atypical protein kinase C (aPKC) isoforms are overexpressed and activated in many cancer types. Using normal, highly polarized epithelial cells (MDCK and NMuMG), we report that aPKC gain of function overcomes contact inhibited growth and is sufficient for a transformed epithelial phenotype. In 2D cultures, aPKC induced cells to grow as stratified epithelia, whereas cells grew as solid spheres of nonpolarized cells in 3D culture. aPKC associated with Mst1/2, which uncoupled Mst1/2 from Lats1/2 and promoted nuclear accumulation of Yap1. Of importance, Yap1 was necessary for aPKC-mediated overgrowth but did not restore cell polarity defects, indicating that the two are separable events. In MDCK cells, Yap1 was sequestered to cell–cell junctions by Amot, and aPKC overexpression resulted in loss of Amot expression and a spindle-like cell phenotype. Reexpression of Amot was sufficient to restore an epithelial cobblestone appearance, Yap1 localization, and growth control. In contrast, the effect of aPKC on Hippo/Yap signaling and overgrowth in NMuMG cells was independent of Amot. Finally, increased expression of aPKC in human cancers strongly correlated with increased nuclear accumulation of Yap1, indicating that the effect of aPKC on transformed growth by deregulating Hippo/Yap1 signaling may be clinically relevant. PMID:26269582

  13. YAP forms autocrine loops with the ERBB pathway to regulate ovarian cancer initiation and progression.

    PubMed

    He, C; Lv, X; Hua, G; Lele, S M; Remmenga, S; Dong, J; Davis, J S; Wang, C

    2015-12-10

    Mechanisms underlying ovarian cancer initiation and progression are unclear. Herein, we report that the Yes-associated protein (YAP), a major effector of the Hippo tumor suppressor pathway, interacts with ERBB signaling pathways to regulate the initiation and progression of ovarian cancer. Immunohistochemistry studies indicate that YAP expression is associated with poor clinical outcomes in patients. Overexpression or constitutive activation of YAP leads to transformation and tumorigenesis in human ovarian surface epithelial cells, and promotes growth of cancer cells in vivo and in vitro. YAP induces the expression of epidermal growth factor (EGF) receptors (EGFR, ERBB3) and production of EGF-like ligands (HBEGF, NRG1 and NRG2). HBEGF or NRG1, in turn, activates YAP and stimulates cancer cell growth. Knockdown of ERBB3 or HBEGF eliminates YAP effects on cell growth and transformation, whereas knockdown of YAP abrogates NRG1- and HBEGF-stimulated cell proliferation. Collectively, our study demonstrates the existence of HBEGF & NRGs/ERBBs/YAP/HBEGF & NRGs autocrine loop that controls ovarian cell tumorigenesis and cancer progression.

  14. YAP forms autocrine loops with the ERBB pathway to regulate ovarian cancer initiation and progression

    PubMed Central

    He, Chunbo; Lv, Xiangmin; Hua, Guohua; Lele, Subodh M; Remmenga, Steven; Dong, Jixin; Davis, John S; Wang, Cheng

    2014-01-01

    Mechanisms underlying ovarian cancer initiation and progression are unclear. Herein, we report that the Yes-associated protein (YAP), a major effector of the Hippo tumor suppressor pathway, interacts with ERBB signaling pathways to regulate the initiation and progression of ovarian cancer. Immunohistochemistry studies indicate that YAP expression is associated with poor clinical outcomes in patients. Overexpression or constitutive activation of YAP leads to transformation and tumorigenesis in human ovarian surface epithelial cells, and promotes growth of cancer cells in vivo and in vitro. YAP induces expression of EGF receptors (EGFR, ERBB3) and production of EGF-like ligands (HBEGF, NRG1 and NRG2). HBEGF or NRG1, in turn, activates YAP and stimulates cancer cell growth. Knockdown of ERBB3 or HBEGF eliminates YAP effects on cell growth and transformation, while knockdown of YAP abrogates NRG1- and HBEGF-stimulated cell proliferation. Collectively, our study demonstrates the existence of HBEGF&NRGs/ERBBs/YAP/HBEGF&NRGs autocrine loop that controls ovarian cell tumorigenesis and cancer progression. PMID:25798835

  15. Efficient 2-μm Tm:YAP Q-switched and CW lasers

    NASA Astrophysics Data System (ADS)

    Hays, A. D.; Cole, Brian; King, Vernon; Goldberg, Lew

    2018-02-01

    Highly efficient, diode pumped Tm:YAP lasers generating emission in the 1.85-1.94 μm range are demonstrated and characterized. Laser optical efficiencies of 51% and 45%, and electrical efficiencies of 31% and 25% are achieved under CW and Q-switched operation, respectively. Laser performance was characterized for maximum average powers up to 20W with various cavity configurations, all using an intra-cavity lens to compensate for thermal lensing in the Tm:YAP crystal. Q-switched lasers incorportating a Cr:ZnS saturable absorber (SA), resonant mechanical mirror scanner, or acousto-optic modulator were characterized. To enable higher average output powers, measurements of the thermal lens were conducted for the Tm:YAP crystal as a function of pump power and were compared to values predicted by a finiteelement- analysis (FEA) thermal-optical model of the Tm:YAP crystal. A resonator model is developed to incorporate this calculated thermal lens and its effect on laser performance. This paper will address approaches for improving the performance of Tm:YAP lasers, and means for achieving increased average output powers while maintaining high optical efficiency for both SA and mechanical Q-switching.

  16. YAP1 Is a Driver of Myofibroblast Differentiation in Normal and Diseased Fibroblasts.

    PubMed

    Piersma, Bram; de Rond, Saskia; Werker, Paul M N; Boo, Stellar; Hinz, Boris; van Beuge, Marike M; Bank, Ruud A

    2015-12-01

    Dupuytren disease is a fibrotic disorder characterized by contraction of myofibroblast-rich cords and nodules in the hands. The Hippo member Yes-associated protein 1 (YAP1) is activated by tissue stiffness and the profibrotic transforming growth factor-β1, but its role in cell fibrogenesis is yet unclear. We hypothesized that YAP1 regulates the differentiation of dermal fibroblasts into highly contractile myofibroblasts and that YAP1 governs the maintenance of a myofibroblast phenotype in primary Dupuytren cells. Knockdown of YAP1 in transforming growth factor-β1-stimulated dermal fibroblasts decreased the formation of contractile smooth muscle α-actin stress fibers and the deposition of collagen type I, which are hallmark features of myofibroblasts. Translating our findings to a clinically relevant model, we found that YAP1 deficiency in Dupuytren disease myofibroblasts resulted in decreased expression of ACTA2, COL1A1, and CCN2 mRNA, but this did not result in decreased protein levels. YAP1-deficient Dupuytren myofibroblasts showed decreased contraction of a collagen hydrogel. Finally, we showed that YAP1 levels and nuclear localization were elevated in affected Dupuytren disease tissue compared with matched control tissue and partly co-localized with smooth muscle α-actin-positive cells. In conclusion, our data show that YAP1 is a regulator of myofibroblast differentiation and contributes to the maintenance of a synthetic and contractile phenotype, in both transforming growth factor-β1-induced myofibroblast differentiation and primary Dupuytren myofibroblasts. Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  17. Yap1 Protein Regulates Vascular Smooth Muscle Cell Phenotypic Switch by Interaction with Myocardin*

    PubMed Central

    Xie, Changqing; Guo, Yanhong; Zhu, Tianqing; Zhang, Jifeng; Ma, Peter X.; Chen, Y. Eugene

    2012-01-01

    The Hippo-Yap (Yes-associated protein) signaling pathway has emerged as one of the critical pathways regulating cell proliferation, differentiation, and apoptosis in response to environmental and developmental cues. However, Yap1 roles in vascular smooth muscle cell (VSMC) biology have not been investigated. VSMCs undergo phenotypic switch, a process characterized by decreased gene expression of VSMC contractile markers and increased proliferation, migration, and matrix synthesis. The goals of the present studies were to investigate the relationship between Yap1 and VSMC phenotypic switch and to determine the molecular mechanisms by which Yap1 affects this essential process in VSMC biology. Results demonstrated that the expression of Yap1 was rapidly up-regulated by stimulation with PDGF-BB (a known inducer of phenotypic switch in VSMCs) and in the injured vessel wall. Knockdown of Yap1 impaired VSMC proliferation in vitro and enhanced the expression of VSMC contractile genes as well by increasing serum response factor binding to CArG-containing regions of VSMC-specific contractile genes within intact chromatin. Conversely, the interaction between serum response factor and its co-activator myocardin was reduced by overexpression of Yap1 in a dose-dependent manner. Taken together, these results indicate that down-regulation of Yap1 promotes VSMC contractile phenotype by both up-regulating myocardin expression and promoting the association of the serum response factor-myocardin complex with VSMC contractile gene promoters and suggest that the Yap1 signaling pathway is a central regulator of phenotypic switch of VSMCs. PMID:22411986

  18. Reproductive characteristics of the humbug damselfish, Dascyllus aruanus, in Chuuk Lagoon, Micronesia

    NASA Astrophysics Data System (ADS)

    Choi, Young-Ung; Park, Miae; Lee, Kyun-Woo; Oh, Chulhong; Park, Heung-Sik

    2014-12-01

    This study was conducted to investigate the reproductive characteristics of the humbug damselfish, Dascyllus aruanus, through the measurement of gonadosomatic indices (GSI) and histological examination of the gonads. Fish were collected from Chuuk Lagoon, Micronesia (7°27'N; 151°53'E), between August 2009 and July 2010. Overall, the functional sex ratio was approximately 1:1; however, there was a female bias in the smaller size range (35-40 mm standard length [SL]) and male bias in the larger size range (45-60 mm in SL). The process of oocyte development exhibited a group synchronous pattern, from the vitellogenic phase oocytes in the gonads following the two clutches of oocytes, as the primary growth stage and yolk vesicle stage. The testis with an ovarian lumen exists as a central slit, and the sperm ducts extend into the medial hilar region of the gonads, indicating that males of D. aruanus have a secondary testis of protogynous species. Monthly variations in the GSI and evolution of gonad status indicated that reproductive activity in this species occurs throughout the year in Chuuk Lagoon, Micronesia.

  19. Hippo pathway coactivators Yap and Taz are required to coordinate mammalian liver regeneration

    PubMed Central

    Lu, Li; Finegold, Milton J; Johnson, Randy L

    2018-01-01

    The mammalian liver has a remarkable capacity for repair following injury. Removal of up to two-third of liver mass results in a series of events that include extracellular matrix remodeling, coordinated hepatic cell cycle re-entry, restoration of liver mass and tissue remodeling to return the damaged liver to its normal state. Although there has been considerable advancement of our knowledge concerning the regenerative capacity of the mammalian liver, many outstanding questions remaining, such as: how does the regenerating liver stop proliferating when appropriate mass is restored and how do these mechanisms relate to normal regulation of organ size during development? Hippo pathway has been proposed to be central in mediating both events: organ size control during development and following regeneration. In this report, we examined the role of Yap and Taz, key components of the Hippo pathway in liver organ size regulation, both in the context of development and homeostasis. Our studies reveal that contrary to the current paradigms that Yap/Taz are not required for developmental regulation of liver size but are required for proper liver regeneration. In livers depleted of Yap and Taz, liver mass is elevated in neonates and adults. However, Yap/Taz-depleted livers exhibit profound defects in liver regeneration, including an inability to restore liver mass and to properly coordinate cell cycle entry. Taken together, our results highlight requirements for the Hippo pathway during liver regeneration and indicate that there are additional pathways that cooperate with Hippo signaling to control liver size during development and in the adult. PMID:29303509

  20. Activation of β Catenin and Yap1 in Human Hepatoblastoma and Induction of Hepatocarcinogenesis in Mice

    PubMed Central

    Cigliano, Antonio; Zhou, Lili; Singh, Sucha; Jiang, Lijie; Fan, Biao; Terracciano, Luigi; Armeanu-Ebinger, Sorin; Ribback, Silvia; Dombrowski, Frank; Evert, Matthias; Chen, Xin; Monga, Satdarshan P. S.

    2014-01-01

    Background & Aims Aberrant activation of βcatenin and Yes-associated protein 1 (Yap1) signaling pathways have been associated with development of multiple tumor types. Yap functions as a transcriptional co-activator by interacting with TEAD DNA binding proteins. We investigated the interactions among these pathways during hepatic tumorigenesis. Methods We used immunohistochemical analysis to determine expression of β-catenin and Yap1 in liver cancer specimens collected from patients in Europe and the US, consisting of 104 hepatocellular carcinoma (HCC), 62 intrahepatic cholangiocarcinoma (ICC), and 94 hepatoblastoma samples. We assessed βcatenin and Yap1 signaling and interactions in hepatoblastoma cell lines ((HuH6, HepG2, HepT1, HC-AFW1, HepG2, and HC-AFW1); proteins were knocked down with small interfering (si)RNAs and effects on proliferation and cell death were measured. Sleeping beauty-mediated hydrodynamic transfection was used to overexpress constitutively active forms of β catenin ( N90-βcatenin) and Yap1 (YapS127A) in livers of mice; tissues were collected and histologic and immunohistochemical analyses were performed. Results We observed nuclear localization of βcatenin and Yap1 in 79% of hepatoblastoma samples, but not in most HCC or ICC tissues. Yap1 and β catenin co-precipitated in hepatoblastoma but not HCC cells. siRNA-mediated knockdown of Yap1 or β catenin in hepatoblastoma cells reduced proliferation in an additive manner. Knockdown of Yap1 reduced its ability to co-activate transcription with βcatenin; βcatenin inhibitors inactivated Yap1. Overexpression of constitutively active forms of Yap1 and βcatenin in mouse liver led to rapid tumorigenesis, with 100% mortality by 11 weeks. Tumors cells expressed both proteins, and human hepatoblastoma cells expressed common targets of their 2 signaling pathways. Yap1 binding of TEAD factors was required for tumorigenesis in mice. Conclusions β catenin and the transcriptional regulator Yap1

  1. Regulation of the Hippo-YAP Pathway by Glucose Sensor O-GlcNAcylation.

    PubMed

    Peng, Changmin; Zhu, Yue; Zhang, Wanjun; Liao, Qinchao; Chen, Yali; Zhao, Xinyuan; Guo, Qiang; Shen, Pan; Zhen, Bei; Qian, Xiaohong; Yang, Dong; Zhang, Jin-San; Xiao, Dongguang; Qin, Weijie; Pei, Huadong

    2017-11-02

    The Hippo pathway is crucial in organ size control and tissue homeostasis, with deregulation leading to cancer. An extracellular nutrition signal, such as glucose, regulates the Hippo pathway activation. However, the mechanisms are still not clear. Here, we found that the Hippo pathway is directly regulated by the hexosamine biosynthesis pathway (HBP) in response to metabolic nutrients. Mechanistically, the core component of Hippo pathway (YAP) is O-GlcNAcylated by O-GlcNAc transferase (OGT) at serine 109. YAP O-GlcNAcylation disrupts its interaction with upstream kinase LATS1, prevents its phosphorylation, and activates its transcriptional activity. And this activation is not dependent on AMPK. We also identified OGT as a YAP-regulated gene that forms a feedback loop. Finally, we confirmed that glucose-induced YAP O-GlcNAcylation and activation promoted tumorigenesis. Together, our data establish a molecular mechanism and functional significance of the HBP in directly linking extracellular glucose signal to the Hippo-YAP pathway and tumorigenesis. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Role of YAP activation in nuclear receptor CAR-mediated proliferation of mouse hepatocytes.

    PubMed

    Abe, Taiki; Amaike, Yuto; Shizu, Ryota; Takahashi, Miki; Kano, Makoto; Hosaka, Takuomi; Sasaki, Takamitsu; Kodama, Susumu; Matsuzawa, Atsushi; Yoshinari, Kouichi

    2018-06-08

    Constitutive androstane receptor (CAR) is a xenobiotic-responsive nuclear receptor that is highly expressed in the liver. CAR activation induces hepatocyte proliferation and hepatocarcinogenesis in rodents, but the mechanisms remain unclear. In this study, we investigated the association of CAR-dependent cell proliferation with Yes-associated protein (YAP), which is a transcriptional cofactor controlling organ size and cell growth through the interaction with various transcriptional factors including TEAD. In mouse livers, TCPOBOP (a mouse CAR activator) treatment increased the nuclear YAP accumulation and mRNA levels of YAP target genes as well as cell-cycle related genes along with liver hypertrophy and verteporfin (an inhibitor of YAP/TEAD interaction) cotreatment tended to attenuate them. Furthermore, in cell-based reporter gene assays, CAR activation enhanced the YAP/TEAD-dependent transcription. To investigate the role of YAP/TEAD activation in the CAR-dependent hepatocyte proliferation, we sought to establish an in vitro system completely reproducing CAR-dependent cell proliferation. Since CAR was only slightly expressed in cultured mouse primary hepatocytes compared to mouse livers and no proliferation was observed after treatment with TCPOBOP, we overexpressed CAR using mouse CAR expressing adenovirus (Ad-mCAR-V5) in mouse primary hepatocytes. Ad-mCAR-V5 infection and TCPOBOP treatment induced hepatocyte proliferation. Similar results were obtained with immortalized normal mouse hepatocytes as well. In the established in vitro system, CAR-dependent proliferation was strongly inhibited by Yap knockdown and completely abolished by verteporfin treatment. Our present results obtained in in vivo and in vitro experiments suggest that YAP/TEAD activation plays key roles in CAR-dependent proliferation of murine hepatocytes.

  3. Pi3kcb links Hippo-YAP and PI3K-AKT signaling pathways to promote cardiomyocyte proliferation and survival.

    PubMed

    Lin, Zhiqiang; Zhou, Pingzhu; von Gise, Alexander; Gu, Fei; Ma, Qing; Chen, Jinghai; Guo, Haidong; van Gorp, Pim R R; Wang, Da-Zhi; Pu, William T

    2015-01-02

    Yes-associated protein (YAP), the nuclear effector of Hippo signaling, regulates cellular growth and survival in multiple organs, including the heart, by interacting with TEA (transcriptional enhancer activator)-domain sequence-specific DNA-binding proteins. Recent studies showed that YAP stimulates cardiomyocyte proliferation and survival. However, the direct transcriptional targets through which YAP exerts its effects are poorly defined. To identify direct YAP targets that mediate its mitogenic and antiapoptotic effects in the heart. We identified direct YAP targets by combining differential gene expression analysis in YAP gain- and loss-of-function with genome-wide identification of YAP-bound loci using chromatin immunoprecipitation and high throughput sequencing. This screen identified Pik3cb, encoding p110β, a catalytic subunit of phosphoinositol-3-kinase, as a candidate YAP effector that promotes cardiomyocyte proliferation and survival. YAP and TEA-domain occupied a conserved enhancer within the first intron of Pik3cb, and this enhancer drove YAP-dependent reporter gene expression. Yap gain- and loss-of-function studies indicated that YAP is necessary and sufficient to activate the phosphoinositol-3-kinase-Akt pathway. Like Yap, Pik3cb gain-of-function stimulated cardiomyocyte proliferation, and Pik3cb knockdown dampened YAP mitogenic activity. Reciprocally, impaired heart function in Yap loss-of-function was significantly rescued by adeno-associated virus-mediated Pik3cb expression. Pik3cb is a crucial direct target of YAP, through which the YAP activates phosphoinositol-3-kinase-AKT pathway and regulates cardiomyocyte proliferation and survival. © 2014 American Heart Association, Inc.

  4. Nf2-Yap signaling controls the expansion of DRG progenitors and glia during DRG development.

    PubMed

    Serinagaoglu, Yelda; Paré, Joshua; Giovannini, Marco; Cao, Xinwei

    2015-02-01

    Molecular mechanisms governing the maintenance and proliferation of dorsal root ganglia (DRG) progenitors are largely unknown. Here we reveal that the Hippo pathway regulates the expansion of DRG progenitors and glia during mammalian DRG development. The key effectors of this pathway, transcriptional coactivators Yap and Taz, are expressed in DRG progenitors and glia during DRG development but are at least partially inhibited from activating transcription. Aberrant YAP activation leads to overexpansion of DRG progenitor and glial populations. We further show that the Neurofibromatosis 2 (Nf2) tumor suppressor inhibits Yap during DRG development. Loss of Nf2 leads to similar phenotypes as does YAP hyperactivation, and deleting Yap suppresses these phenotypes. Our study demonstrates that Nf2-Yap signaling plays important roles in controlling the expansion of DRG progenitors and glia during DRG development. Copyright © 2014 Elsevier Inc. All rights reserved.

  5. Nf2-Yap signaling controls the expansion of DRG progenitors and glia during DRG development

    PubMed Central

    Serinagaoglu, Yelda; Paré, Joshua; Giovannini, Marco; Cao, Xinwei

    2014-01-01

    Molecular mechanisms governing the maintenance and proliferation of dorsal root ganglia (DRG) progenitors are largely unknown. Here we reveal that the Hippo pathway regulates the expansion of DRG progenitors and glia during mammalian DRG development. The key effectors of this pathway, transcriptional coactivators Yap and Taz, are expressed in DRG progenitors and glia during DRG development but are at least partially inhibited from activating transcription. Aberrant YAP activation leads to overexpansion of DRG progenitor and glial populations. We further show that the Neurofibromatosis 2 (Nf2) tumor suppressor inhibits Yap during DRG development. Loss of Nf2 leads to similar phenotypes as does YAP hyperactivation, and deleting Yap suppresses these phenotypes. Our study demonstrates that Nf2-Yap signaling plays important roles in controlling the expansion of DRG progenitors and glia during DRG development. PMID:25433207

  6. Claudin-18-mediated YAP activity regulates lung stem and progenitor cell homeostasis and tumorigenesis.

    PubMed

    Zhou, Beiyun; Flodby, Per; Luo, Jiao; Castillo, Dan R; Liu, Yixin; Yu, Fa-Xing; McConnell, Alicia; Varghese, Bino; Li, Guanglei; Chimge, Nyam-Osor; Sunohara, Mitsuhiro; Koss, Michael N; Elatre, Wafaa; Conti, Peter; Liebler, Janice M; Yang, Chenchen; Marconett, Crystal N; Laird-Offringa, Ite A; Minoo, Parviz; Guan, Kunliang; Stripp, Barry R; Crandall, Edward D; Borok, Zea

    2018-03-01

    Claudins, the integral tight junction (TJ) proteins that regulate paracellular permeability and cell polarity, are frequently dysregulated in cancer; however, their role in neoplastic progression is unclear. Here, we demonstrated that knockout of Cldn18, a claudin family member highly expressed in lung alveolar epithelium, leads to lung enlargement, parenchymal expansion, increased abundance and proliferation of known distal lung progenitors, the alveolar epithelial type II (AT2) cells, activation of Yes-associated protein (YAP), increased organ size, and tumorigenesis in mice. Inhibition of YAP decreased proliferation and colony-forming efficiency (CFE) of Cldn18-/- AT2 cells and prevented increased lung size, while CLDN18 overexpression decreased YAP nuclear localization, cell proliferation, CFE, and YAP transcriptional activity. CLDN18 and YAP interacted and colocalized at cell-cell contacts, while loss of CLDN18 decreased YAP interaction with Hippo kinases p-LATS1/2. Additionally, Cldn18-/- mice had increased propensity to develop lung adenocarcinomas (LuAd) with age, and human LuAd showed stage-dependent reduction of CLDN18.1. These results establish CLDN18 as a regulator of YAP activity that serves to restrict organ size, progenitor cell proliferation, and tumorigenesis, and suggest a mechanism whereby TJ disruption may promote progenitor proliferation to enhance repair following injury.

  7. The Hippo pathway member Yap plays a key role in influencing fate decisions in muscle satellite cells

    PubMed Central

    Judson, Robert N.; Tremblay, Annie M.; Knopp, Paul; White, Robert B.; Urcia, Roby; De Bari, Cosimo; Zammit, Peter S.; Camargo, Fernando D.; Wackerhage, Henning

    2012-01-01

    Summary Satellite cells are the resident stem cells of skeletal muscle. Mitotically quiescent in mature muscle, they can be activated to proliferate and generate myoblasts to supply further myonuclei to hypertrophying or regenerating muscle fibres, or self-renew to maintain the resident stem cell pool. Here, we identify the transcriptional co-factor Yap as a novel regulator of satellite cell fate decisions. Yap expression increases during satellite cell activation and Yap remains highly expressed until after the differentiation versus self-renewal decision is made. Constitutive expression of Yap maintains Pax7+ and MyoD+ satellite cells and satellite cell-derived myoblasts, promotes proliferation but prevents differentiation. In contrast, Yap knockdown reduces the proliferation of satellite cell-derived myoblasts by ≈40%. Consistent with the cellular phenotype, microarrays show that Yap increases expression of genes associated with Yap inhibition, the cell cycle, ribosome biogenesis and that it represses several genes associated with angiotensin signalling. We also identify known regulators of satellite cell function such as BMP4, CD34 and Myf6 (Mrf4) as genes whose expression is dependent on Yap activity. Finally, we confirm in myoblasts that Yap binds to Tead transcription factors and co-activates MCAT elements which are enriched in the proximal promoters of Yap-responsive genes. PMID:23038772

  8. Experimental Model for Successful Liver Cell Therapy by Lenti TTR-YapERT2 Transduced Hepatocytes with Tamoxifen Control of Yap Subcellular Location

    PubMed Central

    Yovchev, Mladen; Jaber, Fadi L.; Lu, Zhonglei; Patel, Shachi; Locker, Joseph; Rogler, Leslie E.; Murray, John W.; Sudol, Marius; Dabeva, Mariana D.; Zhu, Liang; Shafritz, David A.

    2016-01-01

    Liver repopulation by transplanted hepatocytes has not been achieved previously in a normal liver microenvironment. Here we report that adult rat hepatocytes transduced ex vivo with a lentivirus expressing a human YapERT2 fusion protein (hYapERT2) under control of the hepatocyte-specific transthyretin (TTR) promoter repopulate normal rat liver in a tamoxifen-dependent manner. Transplanted hepatocytes expand very slowly but progressively to produce 10% repopulation at 6 months, showing clusters of mature hepatocytes that are fully integrated into hepatic parenchyma, with no evidence for dedifferentiation, dysplasia or malignant transformation. Thus, we have developed the first vector designed to regulate the growth control properties of Yap that renders it capable of producing effective cell therapy. The level of liver repopulation achieved has significant translational implications, as it is 2-3x the level required to cure many monogenic disorders of liver function that have no underlying hepatic pathology and is potentially applicable to diseases of other tissues and organs. PMID:26763940

  9. Mass gathering enhanced syndromic surveillance for the 8th Micronesian Games in 2014, Pohnpei State, Federated States of Micronesia

    PubMed Central

    Saketa, Salanieta; Johnson, Eliaser; Gopalani, Sameer V.; Edward, Eliashib; Loney, Charles; Mercier, Alize; Toatu, Tebuka; Wojcik, Richard; Lewis, Sheri; Hoy, Damian

    2018-01-01

    Pohnpei State’s Division of Primary Health Care implemented enhanced surveillance for early warning and detection of disease to support the 8th Micronesian Games (the Games) in July 2014. The surveillance comprised 11 point-of-care sentinel sites around Pohnpei, Federated States of Micronesia, collecting data daily for eight syndromes using standard case definitions. Each sentinel site reported total acute care encounters, total syndrome cases and the total for each syndrome. A public health response, including epidemiological investigation and laboratory testing, followed when syndrome counts reached predetermined threshold levels. The surveillance was implemented using the web-based Suite for Automated Global Electronic bioSurveillance Open-ESSENCE (SAGES-OE) application that was customized for the Games. Data were summarized in daily situation reports (SitReps) issued to key stakeholders and posted on PacNet, a Pacific public health e-mail network. Influenza-like illness (ILI) was the most common syndrome reported (55%, n = 225). Most syndrome cases (75%) were among people from Pohnpei. Only 30 cases out of a total of 408 syndrome cases (7%) presented with acute fever and rash, despite the large and ongoing measles outbreak at the time. No new infectious disease outbreak was recorded during the Games. Peaks in diarrhoeal and ILI cases were followed up and did not result in widespread transmission. The technology was a key feature of the enhanced surveillance. The introduction of the web-based tool greatly improved the timeliness of data entry, analysis and SitRep dissemination, providing assurance to the Games organizers that communicable diseases would not adversely impact the Games. PMID:29666748

  10. Hippo/Yap signaling controls epithelial progenitor cell proliferation and differentiation in the embryonic and adult lung

    PubMed Central

    Lange, Alexander W.; Sridharan, Anusha; Xu, Yan; Stripp, Barry R.; Perl, Anne-Karina; Whitsett, Jeffrey A.

    2015-01-01

    The Hippo/Yap pathway is a well-conserved signaling cascade that regulates cell proliferation and differentiation to control organ size and stem/progenitor cell behavior. Following airway injury, Yap was dynamically regulated in regenerating airway epithelial cells. To determine the role of Hippo signaling in the lung, the mammalian Hippo kinases, Mst1 and Mst2, were deleted in epithelial cells of the embryonic and mature mouse lung. Mst1/2 deletion in the fetal lung enhanced proliferation and inhibited sacculation and epithelial cell differentiation. The transcriptional inhibition of cell proliferation and activation of differentiation during normal perinatal lung maturation were inversely regulated following embryonic Mst1/2 deletion. Ablation of Mst1/2 from bronchiolar epithelial cells in the adult lung caused airway hyperplasia and altered differentiation. Inhibitory Yap phosphorylation was decreased and Yap nuclear localization and transcriptional targets were increased after Mst1/2 deletion, consistent with canonical Hippo/Yap signaling. YAP potentiated cell proliferation and inhibited differentiation of human bronchial epithelial cells in vitro. Loss of Mst1/2 and expression of YAP regulated transcriptional targets controlling cell proliferation and differentiation, including Ajuba LIM protein. Ajuba was required for the effects of YAP on cell proliferation in vitro. Hippo/Yap signaling regulates Ajuba and controls proliferation and differentiation of lung epithelial progenitor cells. PMID:25480985

  11. An evaluation of a nutrition intervention in Kapinga Village on Pohnpei, Federated States of Micronesia.

    PubMed

    Hanson, Michelle; Englberger, Lois; Duncan, Burris; Taren, Douglas; Mateak, Henrich; Johnson, Emihner

    2011-03-01

    The people of Kapinga Village are suffering from chronic diseases as a result of their lifestyles and eating habits, similar to many Pohnpeians. Kapinga Village is an urban area on the island of Pohnpei, Federated States of Micronesia, settled by people from Kapingamarangi, a remote atoll. The villagers have limited access to traditional staple foods, including breadfruit, banana, and taro, fruits, vegetables, and other healthy foods. The Island Food Community of Pohnpei (IFCP) carried out several nutrition interventions in Kapinga Village to prevent disease, including promotion of physical activity through growing local food, a nutritious diet of local foods, cooking classes, container gardening, and charcoal oven workshops. This study evaluated the effect of those interventions on dietary intake. A 7-day Food Frequency Questionnaire (FFQ) was administered in June-July, 2010 to participants from 68 households and data were compared to 2009 baseline data. Qualitative data were collected and analyzed to identify salient themes that were associated with changes in dietary intake. The FFQ data indicated that there was an increase in consumption of local fruits and vegetables compared with the baseline. Qualitative data revealed that participants viewed the interventions positively. The data also revealed that some of the new foods and drinks consumed were those already available in the village, but for which their uses had not previously been known (such as banana flower and hibiscus tea). Such improvements are likely to be sustainable. Recommendations are for more education, in the Kapingan language if possible, and future research to determine what culturally appropriate interventions are still needed to improve nutrition in Kapinga Village.

  12. YAP is essential for mechanical force production and epithelial cell proliferation during lung branching morphogenesis

    PubMed Central

    Lin, Chuwen; Yao, Erica; Zhang, Kuan; Jiang, Xuan; Croll, Stacey; Thompson-Peer, Katherine; Chuang, Pao-Tien

    2017-01-01

    Branching morphogenesis is a fundamental program for tissue patterning. We show that active YAP, a key mediator of Hippo signaling, is distributed throughout the murine lung epithelium and loss of epithelial YAP severely disrupts branching. Failure to branch is restricted to regions where YAP activity is removed. This suggests that YAP controls local epithelial cell properties. In support of this model, mechanical force production is compromised and cell proliferation is reduced in Yap mutant lungs. We propose that defective force generation and insufficient epithelial cell number underlie the branching defects. Through genomic analysis, we also uncovered a feedback control of pMLC levels, which is critical for mechanical force production, likely through the direct induction of multiple regulators by YAP. Our work provides a molecular pathway that could control epithelial cell properties required for proper morphogenetic movement and pattern formation. DOI: http://dx.doi.org/10.7554/eLife.21130.001 PMID:28323616

  13. YAP controls retinal stem cell DNA replication timing and genomic stability

    PubMed Central

    Cabochette, Pauline; Vega-Lopez, Guillermo; Bitard, Juliette; Parain, Karine; Chemouny, Romain; Masson, Christel; Borday, Caroline; Hedderich, Marie; Henningfeld, Kristine A; Locker, Morgane; Bronchain, Odile; Perron, Muriel

    2015-01-01

    The adult frog retina retains a reservoir of active neural stem cells that contribute to continuous eye growth throughout life. We found that Yap, a downstream effector of the Hippo pathway, is specifically expressed in these stem cells. Yap knock-down leads to an accelerated S-phase and an abnormal progression of DNA replication, a phenotype likely mediated by upregulation of c-Myc. This is associated with an increased occurrence of DNA damage and eventually p53-p21 pathway-mediated cell death. Finally, we identified PKNOX1, a transcription factor involved in the maintenance of genomic stability, as a functional and physical interactant of YAP. Altogether, we propose that YAP is required in adult retinal stem cells to regulate the temporal firing of replication origins and quality control of replicated DNA. Our data reinforce the view that specific mechanisms dedicated to S-phase control are at work in stem cells to protect them from genomic instability. DOI: http://dx.doi.org/10.7554/eLife.08488.001 PMID:26393999

  14. Hippo/Yap signaling controls epithelial progenitor cell proliferation and differentiation in the embryonic and adult lung.

    PubMed

    Lange, Alexander W; Sridharan, Anusha; Xu, Yan; Stripp, Barry R; Perl, Anne-Karina; Whitsett, Jeffrey A

    2015-02-01

    The Hippo/Yap pathway is a well-conserved signaling cascade that regulates cell proliferation and differentiation to control organ size and stem/progenitor cell behavior. Following airway injury, Yap was dynamically regulated in regenerating airway epithelial cells. To determine the role of Hippo signaling in the lung, the mammalian Hippo kinases, Mst1 and Mst2, were deleted in epithelial cells of the embryonic and mature mouse lung. Mst1/2 deletion in the fetal lung enhanced proliferation and inhibited sacculation and epithelial cell differentiation. The transcriptional inhibition of cell proliferation and activation of differentiation during normal perinatal lung maturation were inversely regulated following embryonic Mst1/2 deletion. Ablation of Mst1/2 from bronchiolar epithelial cells in the adult lung caused airway hyperplasia and altered differentiation. Inhibitory Yap phosphorylation was decreased and Yap nuclear localization and transcriptional targets were increased after Mst1/2 deletion, consistent with canonical Hippo/Yap signaling. YAP potentiated cell proliferation and inhibited differentiation of human bronchial epithelial cells in vitro. Loss of Mst1/2 and expression of YAP regulated transcriptional targets controlling cell proliferation and differentiation, including Ajuba LIM protein. Ajuba was required for the effects of YAP on cell proliferation in vitro. Hippo/Yap signaling regulates Ajuba and controls proliferation and differentiation of lung epithelial progenitor cells. © The Author (2014). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS. All rights reserved.

  15. The Hippo/YAP pathway interacts with EGFR signaling and HPV oncoproteins to regulate cervical cancer progression

    PubMed Central

    He, Chunbo; Mao, Dagan; Hua, Guohua; Lv, Xiangmin; Chen, Xingcheng; Angeletti, Peter C; Dong, Jixin; Remmenga, Steven W; Rodabaugh, Kerry J; Zhou, Jin; Lambert, Paul F; Yang, Peixin; Davis, John S; Wang, Cheng

    2015-01-01

    The Hippo signaling pathway controls organ size and tumorigenesis through a kinase cascade that inactivates Yes-associated protein (YAP). Here, we show that YAP plays a central role in controlling the progression of cervical cancer. Our results suggest that YAP expression is associated with a poor prognosis for cervical cancer. TGF-α and amphiregulin (AREG), via EGFR, inhibit the Hippo signaling pathway and activate YAP to induce cervical cancer cell proliferation and migration. Activated YAP allows for up-regulation of TGF-α, AREG, and EGFR, forming a positive signaling loop to drive cervical cancer cell proliferation. HPV E6 protein, a major etiological molecule of cervical cancer, maintains high YAP protein levels in cervical cancer cells by preventing proteasome-dependent YAP degradation to drive cervical cancer cell proliferation. Results from human cervical cancer genomic databases and an accepted transgenic mouse model strongly support the clinical relevance of the discovered feed-forward signaling loop. Our study indicates that combined targeting of the Hippo and the ERBB signaling pathways represents a novel therapeutic strategy for prevention and treatment of cervical cancer. PMID:26417066

  16. Microenvironment rigidity modulates responses to the HER2 receptor tyrosine kinase inhibitor lapatinib via YAP and TAZ transcription factors

    DOE PAGES

    Lin, Chun-Han; Pelissier, Fanny A.; Zhang, Hui; ...

    2015-09-02

    Stiffness is a biophysical property of the extracellular matrix that modulates cellular functions, including proliferation, invasion, and differentiation, and it also may affect therapeutic responses. Therapeutic durability in cancer treatments remains a problem for both chemotherapies and pathway-targeted drugs, but the reasons for this are not well understood. Tumor progression is accompanied by changes in the biophysical properties of the tissue, and we asked whether matrix rigidity modulated the sensitive versus resistant states in HER2-amplified breast cancer cell responses to the HER2-targeted kinase inhibitor lapatinib. The antiproliferative effect of lapatinib was inversely proportional to the elastic modulus of the adhesivemore » substrata. Down-regulation of the mechanosensitive transcription coactivators YAP and TAZ, either by siRNA or with the small-molecule YAP/TEAD inhibitor verteporfin, eliminated modulus-dependent lapatinib resistance. Reduction of YAP in vivo in mice also slowed the growth of implanted HER2-amplified tumors, showing a trend of increasing sensitivity to lapatinib as YAP decreased. Thus we address the role of stiffness in resistance to and efficacy of a HER2 pathway–targeted therapeutic via the mechanotransduction arm of the Hippo pathway.« less

  17. Microenvironment rigidity modulates responses to the HER2 receptor tyrosine kinase inhibitor lapatinib via YAP and TAZ transcription factors

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Lin, Chun-Han; Pelissier, Fanny A.; Zhang, Hui

    Stiffness is a biophysical property of the extracellular matrix that modulates cellular functions, including proliferation, invasion, and differentiation, and it also may affect therapeutic responses. Therapeutic durability in cancer treatments remains a problem for both chemotherapies and pathway-targeted drugs, but the reasons for this are not well understood. Tumor progression is accompanied by changes in the biophysical properties of the tissue, and we asked whether matrix rigidity modulated the sensitive versus resistant states in HER2-amplified breast cancer cell responses to the HER2-targeted kinase inhibitor lapatinib. The antiproliferative effect of lapatinib was inversely proportional to the elastic modulus of the adhesivemore » substrata. Down-regulation of the mechanosensitive transcription coactivators YAP and TAZ, either by siRNA or with the small-molecule YAP/TEAD inhibitor verteporfin, eliminated modulus-dependent lapatinib resistance. Reduction of YAP in vivo in mice also slowed the growth of implanted HER2-amplified tumors, showing a trend of increasing sensitivity to lapatinib as YAP decreased. Thus we address the role of stiffness in resistance to and efficacy of a HER2 pathway–targeted therapeutic via the mechanotransduction arm of the Hippo pathway.« less

  18. Upland forests of the American/Pacific Islands: research opportunities in Micronesia and American Samoa

    Treesearch

    Dean S. DeBell; Craig D. Whitesell

    1993-01-01

    Upland forests of Micronesia and American Samoa can provide many social, ecological, and esthetic benefits for island inhabitants. Substantial upland areas (the majority of acreage on some islands) are now occupied by secondary and grassland/savanna vegetation; such areas represent opportunities for restoration, with both native forest cover and plantations of...

  19. Effects of season, rainfall, and hydrogeomorphic setting on mangrove tree growth in Micronesia

    USGS Publications Warehouse

    Krauss, K.W.; Keeland, B.D.; Allen, J.A.; Ewel, K.C.; Johnson, Daniel J.

    2007-01-01

    Seasonal patterns of tree growth are often related to rainfall, temperature, and relative moisture regimes. We asked whether diameter growth of mangrove trees in Micronesia, where seasonal changes are minimal, is continuous throughout a year or conforms to an annual cycle. We installed dendrometer bands on Sonneratia alba and Bruguiera gymnorrhiza trees growing naturally within mangrove swamps on the islands of Kosrae, Federated States of Micronesia (FSM), Pohnpei, FSM, and Butaritari, Republic of Kiribati, in the eastern Caroline Islands of the western Pacific Ocean. Trees were remeasured monthly or quarterly for as long as 6 yr. Annual mean individual tree basal area increments ranged from 7.0 to 79.6 cm2/yr for all S. alba trees and from 4.8 to 27.4 cm2/yr for all B. gymnorrhiza trees from Micronesian high islands. Diameter increment for S. alba on Butaritari Atoll was lower at 7.8 cm 2/yr for the one year measured. Growth rates differed significantly by hydrogeomorphic zone. Riverine and interior zones maintained up to seven times the annual diameter growth rate of fringe forests, though not on Pohnpei, where basal area increments for both S. alba and B. gymnorrhiza were approximately 1.5 times greater in the fringe zone than in the interior zone. Time-series modeling indicated that there were no consistent and statistically significant annual diameter growth patterns. Although rainfall has some seasonality in some years on Kosrae and Pohnpei and overall growth of mangroves was sometimes related positively to quarterly rainfall depths, seasonal diameter growth patterns were not distinctive. A reduced chance of moisture-related stress in high-rainfall, wetland environments may serve to buffer growth of Micronesian mangroves from climatic extremes. ?? 2007 The Author(s) Journal compilation ?? 2007 by The Association for Tropical Biology and Conservation.

  20. Targeting YAP/TAZ-TEAD protein-protein interactions using fragment-based and computational modeling approaches

    PubMed Central

    Verma, Chandra

    2017-01-01

    The Hippo signaling pathway, which is implicated in the regulation of organ size, has emerged as a potential target for the development of cancer therapeutics. YAP, TAZ (transcription co-activators) and TEAD (transcription factor) are the downstream transcriptional machinery and effectors of the pathway. Formation of the YAP/TAZ-TEAD complex leads to transcription of growth-promoting genes. Conversely, disrupting the interactions of the complex decreases cell proliferation. Herein, we screened a 1000-member fragment library using Thermal Shift Assay and identified a hit fragment. We confirmed its binding at the YAP/TAZ-TEAD interface by X-ray crystallography, and showed that it occupies the same hydrophobic pocket as a conserved phenylalanine of YAP/TAZ. This hit fragment serves as a scaffold for the development of compounds that have the potential to disrupt YAP/TAZ-TEAD interactions. Structure-activity relationship studies and computational modeling were also carried out to identify more potent compounds that may bind at this validated druggable binding site. PMID:28570566

  1. YAP1 enhances cell proliferation, migration, and invasion of gastric cancer in vitro and in vivo.

    PubMed

    Sun, Dan; Li, Xiaoting; He, Yingjian; Li, Wenhui; Wang, Ying; Wang, Huan; Jiang, Shanshan; Xin, Yan

    2016-12-06

    Yes-associated protein 1 (YAP1) plays an important role in the development of carcinomas such as breast, colorectal, and gastric (GC) cancers, but the role of YAP1 in GC has not been investigated comprehensively. The present study strongly suggests that YAP1 and P62 were significantly up-regulated in GC specimens, compared with normal gastric mucosa. In addition, the YAP1high P62high expression was independently associated with poor prognosis in GC (hazard ratio: 1.334, 95% confidence interval: 1.045-1.704, P = 0.021). Stable YAP1 silencing inhibited the proliferation, migration, and invasion of BGC-823 GC cells in vitro and inhibited the growth of xenograft tumor and hematogenous metastasis of BGC-823 GC cells in vivo. The mechanism was associated with inhibited extracellular signal-regulated kinases (ERK)1/2 phosphorylation, elevated E-cadherin protein expression and decreased vimentin protein expression, down-regulated β-catenin protein expression and elevated α-catenin protein expression, and down-regulated long non-coding RNA (lncRNA) expressions including HOX transcript antisense RNA (HOTAIR), H19, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), human large tumor suppressor-2 (LATS2)-AS1-001, and LATS2. YAP1 over-expression promoted the proliferation, migration, and invasion of human immortalized normal gastric mucosa GES-1 cells in vitro by reversing the above signal molecules. Subcutaneous inoculation of GES-1 cells and YAP1-over-expressing GES-1 cells into nude mice did not generate tumors. We successfully established the xenograft tumor models using MKN-45 GC cells, but immunochemistry showed that there was no YAP1 expression in MKN-45 cells. These results suggest that YAP1 is not a direct factor affecting tumor formation, but could accelerate tumor growth and metastasis. Collectively, this study highlights an important role for YAP1 as a promoter of GC growth and metastasis, and suggests that YAP1 could possibly be a potential

  2. YAP and TAZ in epithelial stem cells: A sensor for cell polarity, mechanical forces and tissue damage.

    PubMed

    Elbediwy, Ahmed; Vincent-Mistiaen, Zoé I; Thompson, Barry J

    2016-07-01

    The YAP/TAZ family of transcriptional co-activators drives cell proliferation in epithelial tissues and cancers. Yet, how YAP and TAZ are physiologically regulated remains unclear. Here we review recent reports that YAP and TAZ act primarily as sensors of epithelial cell polarity, being inhibited when cells differentiate an apical membrane domain, and being activated when cells contact the extracellular matrix via their basal membrane domain. Apical signalling occurs via the canonical Crumbs/CRB-Hippo/MST-Warts/LATS kinase cascade to phosphorylate and inhibit YAP/TAZ. Basal signalling occurs via Integrins and Src family kinases to phosphorylate and activate YAP/TAZ. Thus, YAP/TAZ is localised to the nucleus in basal stem/progenitor cells and cytoplasm in differentiated squamous cells or columnar cells. In addition, other signals such as mechanical forces, tissue damage and possibly receptor tyrosine kinases (RTKs) can influence MST-LATS or Src family kinase activity to modulate YAP/TAZ activity. © 2016 The Authors BioEssays Published by WILEY Periodicals, Inc.

  3. Cost of a measles outbreak in a remote island economy: 2014 Federated States of Micronesia measles outbreak.

    PubMed

    Pike, Jamison; Tippins, Ashley; Nyaku, Mawuli; Eckert, Maribeth; Helgenberger, Louisa; Underwood, J Michael

    2017-10-13

    After 20years with no reported measles cases, on May 15, 2014 the Centers for Disease Control and Prevention (CDC) was notified of two cases testing positive for measles-specific immunoglobulin M (IgM) antibodies in the Federated States of Micronesia (FSM). Under the Compact of Free Association, FSM receives immunization funding and technical support from the United States (US) domestic vaccination program managed by the Centers for Disease Control and Prevention (CDC). In a collaborative effort, public health officials and volunteers from FSM and the US government worked to respond and contain the measles outbreak through an emergency mass vaccination campaign, contact tracing, and other outbreak investigation activities. Contributions were also made by United Nations Children's Emergency Fund (UNICEF) and World Health Organization (WHO). Total costs incurred as a result of the outbreak were nearly $4,000,000; approximately $10,000 per case. Direct medical costs (≈$141,000) were incurred in the treatment of those individuals infected, as well as lost productivity of the infected and informal caregivers (≈$250,000) and costs to contain the outbreak (≈$3.5 million). We assessed the economic burden of the 2014 measles outbreak to FSM, as well as the economic responsibilities of the US. Although the US paid the majority of total costs of the outbreak (≈67%), examining each country's costs relative to their respective economy illustrates a far greater burden to FSM. We demonstrate that while FSM was heavily assisted by the US in responding to the 2014 Measles Outbreak, the outbreak significantly impacted their economy. FSM's economic burden from the outbreak is approximately equivalent to their entire 2016 Fiscal Year budget dedicated to education. Published by Elsevier Ltd.

  4. YAP Tyrosine Phosphorylation and Nuclear Localization in Cholangiocarcinoma Cells is Regulated by LCK and Independent of LATS Activity.

    PubMed

    Sugihara, Takaaki; Werneburg, Nathan W; Hernandez, Matthew C; Yang, Lin; Kabashima, Ayano; Hirsova, Petra; Yohanathan, Lavanya; Sosa, Carlos; Truty, Mark Joseph; Vasmatzis, George; Gores, Gregory J; Smoot, Rory L

    2018-06-14

    The hippo pathway effector, Yes-associated protein (YAP) is a transcriptional co-activator implicated in cholangiocarcinoma (CCA) pathogenesis. YAP is known to be regulated by a serine/threonine kinase relay module (MST1/2 - LATS1/2) culminating in phosphorylation of YAP at Serine 127 (S127) and cytoplasmic sequestration. However, YAP also undergoes tyrosine phosphorylation, and the role of tyrosine phosphorylation in YAP regulation remains unclear. Herein, YAP regulation by tyrosine phosphorylation was examined in human and mouse CCA cells, as well as patient-derived xenograft (PDX) models. YAP was phosphorylated on tyrosine 357 (Y357) in CCA cell lines and PDX models. SRC family kinase (SFK) inhibition with dasatinib resulted in loss of YAPY357 phosphorylation, promoted its translocation from the nucleus to the cytoplasm, and reduced YAP target gene expression; including cell lines expressing a LATS1/2-resistant YAP mutant in which all serine residues were mutated to alanine. Consistent with these observations, precluding YAPY357 phosphorylation by site-directed mutagenesis (YAPY357F) excluded YAP from the nucleus. Targeted siRNA experiments identified LCK as the SFK that most potently mediated YAPY357 phosphorylation. Likewise, inducible CRISPR/Cas9-targeted LCK deletion decreased YAPY357 phosphorylation and its nuclear localization. The importance of LCK in CCA biology was demonstrated by clinical observations suggesting LCK expression levels were associated with early tumor recurrence following resection of CCA. Finally, dasatinib displayed therapeutic efficacy in PDX models. Demonstration of targetable, LCK-mediated YAP tyrosine phosphorylation in CCA regulating YAP's nuclear retention and oncogenic activity. Copyright ©2018, American Association for Cancer Research.

  5. Two residues in the basic region of the yeast transcription factor Yap8 are crucial for its DNA-binding specificity.

    PubMed

    Amaral, Catarina; Pimentel, Catarina; Matos, Rute G; Arraiano, Cecília M; Matzapetakis, Manolis; Rodrigues-Pousada, Claudina

    2013-01-01

    In Saccharomyces cerevisiae, the transcription factor Yap8 is a key determinant in arsenic stress response. Contrary to Yap1, another basic region-leucine zipper (bZIP) yeast regulator, Yap8 has a very restricted DNA-binding specificity and only orchestrates the expression of ACR2 and ACR3 genes. In the DNA-binding basic region, Yap8 has three distinct amino acids residues, Leu26, Ser29 and Asn31, at sites of highly conserved positions in the other Yap family of transcriptional regulators and Pap1 of Schizosaccharomyces pombe. To evaluate whether these residues are relevant to Yap8 specificity, we first built a homology model of the complex Yap8bZIP-DNA based on Pap1-DNA crystal structure. Several Yap8 mutants were then generated in order to confirm the contribution of the residues predicted to interact with DNA. Using bioinformatics analysis together with in vivo and in vitro approaches, we have identified several conserved residues critical for Yap8-DNA binding. Moreover, our data suggest that Leu26 is required for Yap8 binding to DNA and that this residue together with Asn31, hinder Yap1 response element recognition by Yap8, thus narrowing its DNA-binding specificity. Furthermore our results point to a role of these two amino acids in the stability of the Yap8-DNA complex.

  6. Transcriptional integration of mitogenic and mechanical signals by Myc and YAP.

    PubMed

    Croci, Ottavio; De Fazio, Serena; Biagioni, Francesca; Donato, Elisa; Caganova, Marieta; Curti, Laura; Doni, Mirko; Sberna, Silvia; Aldeghi, Deborah; Biancotto, Chiara; Verrecchia, Alessandro; Olivero, Daniela; Amati, Bruno; Campaner, Stefano

    2017-10-15

    Mammalian cells must integrate environmental cues to determine coherent physiological responses. The transcription factors Myc and YAP-TEAD act downstream from mitogenic signals, with the latter responding also to mechanical cues. Here, we show that these factors coordinately regulate genes required for cell proliferation. Activation of Myc led to extensive association with its genomic targets, most of which were prebound by TEAD. At these loci, recruitment of YAP was Myc-dependent and led to full transcriptional activation. This cooperation was critical for cell cycle entry, organ growth, and tumorigenesis. Thus, Myc and YAP-TEAD integrate mitogenic and mechanical cues at the transcriptional level to provide multifactorial control of cell proliferation. © 2017 Croci et al.; Published by Cold Spring Harbor Laboratory Press.

  7. The Hippo/YAP pathway interacts with EGFR signaling and HPV oncoproteins to regulate cervical cancer progression.

    PubMed

    He, Chunbo; Mao, Dagan; Hua, Guohua; Lv, Xiangmin; Chen, Xingcheng; Angeletti, Peter C; Dong, Jixin; Remmenga, Steven W; Rodabaugh, Kerry J; Zhou, Jin; Lambert, Paul F; Yang, Peixin; Davis, John S; Wang, Cheng

    2015-11-01

    The Hippo signaling pathway controls organ size and tumorigenesis through a kinase cascade that inactivates Yes-associated protein (YAP). Here, we show that YAP plays a central role in controlling the progression of cervical cancer. Our results suggest that YAP expression is associated with a poor prognosis for cervical cancer. TGF-α and amphiregulin (AREG), via EGFR, inhibit the Hippo signaling pathway and activate YAP to induce cervical cancer cell proliferation and migration. Activated YAP allows for up-regulation of TGF-α, AREG, and EGFR, forming a positive signaling loop to drive cervical cancer cell proliferation. HPV E6 protein, a major etiological molecule of cervical cancer, maintains high YAP protein levels in cervical cancer cells by preventing proteasome-dependent YAP degradation to drive cervical cancer cell proliferation. Results from human cervical cancer genomic databases and an accepted transgenic mouse model strongly support the clinical relevance of the discovered feed-forward signaling loop. Our study indicates that combined targeting of the Hippo and the ERBB signaling pathways represents a novel therapeutic strategy for prevention and treatment of cervical cancer. © 2015 The Authors. Published under the terms of the CC BY 4.0 license.

  8. Emerging evidence on the role of the Hippo/YAP pathway in liver physiology and cancer.

    PubMed

    Yimlamai, Dean; Fowl, Brendan H; Camargo, Fernando D

    2015-12-01

    The Hippo pathway and its regulatory target, YAP, has recently emerged as an important biochemical signaling pathway that tightly governs epithelial tissue growth. Initially defined in Drosophilia, this pathway has shown remarkable conservation in vertebrate systems with many components of the Hippo/YAP pathway showing biochemical and functional conservation. The liver is particularly sensitive to changes in Hippo/YAP signaling with rapid increases in liver size becoming manifest on the order of days to weeks after perturbation. The first identified direct targets of Hippo/YAP signaling were pro-proliferative and anti-apoptotic gene programs, but recent work has now implicated this pathway in cell fate choice, stem cell maintenance/renewal, epithelial to mesenchymal transition, and oncogenesis. The mechanisms by which Hippo/YAP signaling is changed endogenously are beginning to come to light as well as how this pathway interacts with other signaling pathways, and important details for designing new therapeutic interventions. This review focuses on the known roles for Hippo/YAP signaling in the liver and promising avenues for future study. Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  9. PAR1 participates in the ability of multidrug resistance and tumorigenesis by controlling Hippo-YAP pathway.

    PubMed

    Fujimoto, Daisuke; Ueda, Yuki; Hirono, Yasuo; Goi, Takanori; Yamaguchi, Akio

    2015-10-27

    The Hippo pathway significantly correlates with organ size control and tumorigenesis. The activity of YAP/TAZ, a transducer of the Hippo pathway, is required to sustain self-renewal and tumor-initiation capacities in cancer stem cells (CSCs). But, upstream signals that control the mammalian Hippo pathway have not been well understood. Here, we reveal a connection between the Protease-activated receptor 1 (PAR1) signaling pathway and the Hippo-YAP pathway in gastric cancer stem-like cells. The selective PAR1 agonist TFLLR-NH2 induces an increase in the fraction of side population cells which is enriched in CSCs, and promotes tumorigenesis, multi cancer drug resistance, cell morphological change, and cell invasion which are characteristics of CSCs. In addition, PAR1 activation inhibits the Hippo-YAP pathway kinase Lats via Rho GTPase. Lats kinase inhibition in turn results in increased nuclear localization of dephosphorylated YAP. Furthermore, PAR1 activation confers CSCs related traits via the Hippo-YAP pathway, and the Hippo-YAP pathway correlates with epithelial mesenchymal transition which is induced by PAR1 activation. Our research suggests that the PAR1 signaling deeply participates in the ability of multi drug resistance and tumorigenesis through interactions with the Hippo-YAP pathway signaling in gastric cancer stem-like cells. We presume that inhibited YAP is a new therapeutic target in the treatment human gastric cancer invasion and metastasis by dysregulated PAR1 or its agonists.

  10. Acquisition of omptin reveals cryptic virulence function of autotransporter YapE in Yersinia pestis

    PubMed Central

    Pennington, Jarrod; Miller, Virginia L.

    2013-01-01

    SUMMARY Autotransporters, the largest family of secreted proteins in Gram negative bacteria, perform a variety of functions, including adherence, cytotoxicity, and immune evasion. In Yersinia pestis the autotransporter YapE has adhesive properties and contributes to bubonic infection of the mouse model. Here, we demonstrate that omptin cleavage of Y. pestis YapE is required to mediate bacterial aggregation and adherence to eukaryotic cells. We demonstrate that omptin cleavage is specific for the Y. pestis and Y. pseudotuberculosis YapE orthologs but is not conserved in the Y. enterocolitica protein. We also show that cleavage of YapE occurs in Y. pestis but not in the enteric Yersinia species, and requires the omptin Pla (plasminogen activator protease), which is encoded on the Y. pestis-specific plasmid pPCP1. Together, these data show that post-translation modification of YapE appears to be specific to Y. pestis, was acquired along with the acquisition of pPCP1 during the divergence of Y. pestis from Y. pseudotuberculosis, and are the first evidence of a novel mechanism to regulate bacterial adherence. PMID:23701256

  11. Tectono-sedimentary features in the Yap subduction zone, Western Pacific: constraints from latest integrated geophysical survey

    NASA Astrophysics Data System (ADS)

    Dong, D.; Zhang, G.; Bai, Y.; Fan, J.; Zhang, Z.

    2017-12-01

    The Yap subduction zone, western Pacific, is a typical structure related to the ridge subduction, but comparative shortage of the geophysical data makes the structural details unknown in this area. In this study, we present the latest and high-quality multi-beam swath bathymetry and multi-channel seismic data acquired synchronously in the year 2015 across the Yap subduction zone. Multichannel seismic and multi-beam data are mainly applied to investigate the topography of major tectonic units and stratigraphic structure in the Yap subduction zone and discuss the tectonic characteristics controlled by ridge subduction. It suggests that, Parece Vela Basin, as the regional sedimentary center, developed sedimentary layers nearly 800 meters thick. On the contrast, the horizontal sedimentary layers were not obviously identified in the Yap trench, where subduction erosion occurred. Caroline ridge changed the tectonic characteristics of subduction zone, and influenced magmatism of the Yap arc because of the special topography. The seismic profile clearly reveals landslide deposits at the upper slope break of the forearc, north of the Yap Island, which was identified as the fault notch denoting a lithological boundary in previous work. Detailed topography and geological structure of horst and graben in the north of Yap are depicted, and topographic high of Caroline ridge is supposed to bring greater bending and tension and the subsequent horst and graben belt. Multichannel seismic evidence has been provided for interpreting the expansion of Sorol Trough and its inferred age. A modified model for the Yap subduction zone evolution is proposed, incorporating three major tectonic events: proto-Yap Arc rupture in the Oligocene, collision of the Caroline Ridge and the Yap Trench in the Late Oligocene or Middle Miocene, and onset of the Sorol Trough rifting in the Late Miocene. Acknowledge: This study was supported by the Strategic Priority Research Program of the Chinese Academy

  12. Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control

    PubMed Central

    Zhao, Bin; Wei, Xiaomu; Li, Weiquan; Udan, Ryan S.; Yang, Qian; Kim, Joungmok; Xie, Joe; Ikenoue, Tsuneo; Yu, Jindan; Li, Li; Zheng, Pan; Ye, Keqiang; Chinnaiyan, Arul; Halder, Georg; Lai, Zhi-Chun; Guan, Kun-Liang

    2007-01-01

    The Hippo pathway plays a key role in organ size control by regulating cell proliferation and apoptosis in Drosophila. Although recent genetic studies have shown that the Hippo pathway is regulated by the NF2 and Fat tumor suppressors, the physiological regulations of this pathway are unknown. Here we show that in mammalian cells, the transcription coactivator YAP (Yes-associated protein), is inhibited by cell density via the Hippo pathway. Phosphorylation by the Lats tumor suppressor kinase leads to cytoplasmic translocation and inactivation of the YAP oncoprotein. Furthermore, attenuation of this phosphorylation of YAP or Yorkie (Yki), the Drosophila homolog of YAP, potentiates their growth-promoting function in vivo. Moreover, YAP overexpression regulates gene expression in a manner opposite to cell density, and is able to overcome cell contact inhibition. Inhibition of YAP function restores contact inhibition in a human cancer cell line bearing deletion of Salvador (Sav), a Hippo pathway component. Interestingly, we observed that YAP protein is elevated and nuclear localized in some human liver and prostate cancers. Our observations demonstrate that YAP plays a key role in the Hippo pathway to control cell proliferation in response to cell contact. PMID:17974916

  13. YAP regulates the expression of Hoxa1 and Hoxc13 in mouse and human oral and skin epithelial tissues.

    PubMed

    Liu, Ming; Zhao, Shuangyun; Lin, Qingjie; Wang, Xiu-Ping

    2015-04-01

    Yes-associated protein (YAP) is a Hippo signaling transcriptional coactivator that plays pivotal roles in stem cell proliferation, organ size control, and tumor development. The downstream targets of YAP have been shown to be highly context dependent. In this study, we used the embryonic mouse tooth germ as a tool to search for the downstream targets of YAP in ectoderm-derived tissues. Yap deficiency in the dental epithelium resulted in a small tooth germ with reduced epithelial cell proliferation. We compared the gene expression profiles of embryonic day 14.5 (E14.5) Yap conditional knockout and YAP transgenic mouse tooth germs using transcriptome sequencing (RNA-Seq) and further confirmed the differentially expressed genes using real-time PCR and in situ hybridization. We found that YAP regulates the expression of Hoxa1 and Hoxc13 in oral and dental epithelial tissues as well as in the epidermis of skin during embryonic and adult stages. Sphere formation assay suggested that Hoxa1 and Hoxc13 are functionally involved in YAP-regulated epithelial progenitor cell proliferation, and chromatin immunoprecipitation (ChIP) assay implies that YAP may regulate Hoxa1 and Hoxc13 expression through TEAD transcription factors. These results provide mechanistic insights into abnormal YAP activities in mice and humans. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  14. RUNX1 and RUNX3 protect against YAP-mediated EMT, stem-ness and shorter survival outcomes in breast cancer

    PubMed Central

    Kulkarni, Madhura; Tan, Tuan Zea; Syed Sulaiman, Nurfarhanah Bte; Lamar, John M.; Bansal, Prashali; Cui, Jianzhou; Qiao, Yiting; Ito, Yoshiaki

    2018-01-01

    Hippo pathway target, YAP has emerged as an important player in solid tumor progression. Here, we identify RUNX1 and RUNX3 as novel negative regulators of oncogenic function of YAP in the context of breast cancer. RUNX proteins are one of the first transcription factors identified to interact with YAP. RUNX1 or RUNX3 expression abrogates YAP-mediated pro-tumorigenic properties of mammary epithelial cell lines in an interaction dependent manner. RUNX1 and RUNX3 inhibit YAP-mediated migration and stem-ness properties of mammary epithelial cell lines by co-regulating YAP-mediated gene expression. Analysis of whole genome expression profiles of breast cancer samples revealed significant co-relation between YAP–RUNX1/RUNX3 expression levels and survival outcomes of breast cancer patients. High RUNX1/RUNX3 expression proved protective towards YAP-dependent patient survival outcomes. High YAP in breast cancer patients’ expression profiles co-related with EMT and stem-ness gene signature enrichment. High RUNX1/RUNX3 expression along with high YAP reflected lower enrichment of EMT and stem-ness signatures. This antagonistic activity of RUNX1 and RUNX3 towards oncogenic function of YAP identified in mammary epithelial cells as well as in breast cancer expression profiles gives a novel mechanistic insight into oncogene–tumor suppressor interplay in the context of breast cancer progression. The novel interplay between YAP, RUNX1 and RUNX3 and its significance in breast cancer progression can serve as a prognostic tool to predict cancer recurrence. PMID:29581836

  15. YAP Version 4.0

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Nelson, Eric M.

    2004-05-20

    The YAP software library computes (1) electromagnetic modes, (2) electrostatic fields, (3) magnetostatic fields and (4) particle trajectories in 2d and 3d models. The code employs finite element methods on unstructured grids of tetrahedral, hexahedral, prism and pyramid elements, with linear through cubic element shapes and basis functions to provide high accuracy. The novel particle tracker is robust, accurate and efficient, even on unstructured grids with discontinuous fields. This software library is a component of the MICHELLE 3d finite element gun code.

  16. Colon cancer cells escape 5FU chemotherapy-induced cell death by entering stemness and quiescence associated with the c-Yes/YAP axis.

    PubMed

    Touil, Yasmine; Igoudjil, Wassila; Corvaisier, Matthieu; Dessein, Anne-Frédérique; Vandomme, Jérôme; Monté, Didier; Stechly, Laurence; Skrypek, Nicolas; Langlois, Carole; Grard, Georges; Millet, Guillaume; Leteurtre, Emmanuelle; Dumont, Patrick; Truant, Stéphanie; Pruvot, François-René; Hebbar, Mohamed; Fan, Fan; Ellis, Lee M; Formstecher, Pierre; Van Seuningen, Isabelle; Gespach, Christian; Polakowska, Renata; Huet, Guillemette

    2014-02-15

    Metastasis and drug resistance are the major limitations in the survival and management of patients with cancer. This study aimed to identify the mechanisms underlying HT29 colon cancer cell chemoresistance acquired after sequential exposure to 5-fluorouracil (5FU), a classical anticancer drug for treatment of epithelial solid tumors. We examined its clinical relevance in a cohort of patients with colon cancer with liver metastases after 5FU-based neoadjuvant chemotherapy and surgery. We show that a clonal 5F31 cell population, resistant to 1 μmol/L 5FU, express a typical cancer stem cell-like phenotype and enter into a reversible quiescent G0 state upon reexposure to higher 5FU concentrations. These quiescent cells overexpressed the tyrosine kinase c-Yes that became activated and membrane-associated upon 5FU exposure. This enhanced signaling pathway induced the dissociation of the Yes/YAP (Yes-associated protein) molecular complex and depleted nuclear YAP levels. Consistently, YES1 silencing decreased nuclear YAP accumulation and induced cellular quiescence in 5F31 cells cultured in 5FU-free medium. Importantly, YES1 and YAP transcript levels were higher in liver metastases of patients with colon cancer after 5FU-based neoadjuvant chemotherapy. Moreover, the YES1 and YAP transcript levels positively correlated with colon cancer relapse and shorter patient survival (P < 0.05 and P < 0.025, respectively). We identified c-Yes and YAP as potential molecular targets to eradicate quiescent cancer cells and dormant micrometastases during 5FU chemotherapy and resistance and as predictive survival markers for colon cancer. ©2013 AACR

  17. Colon cancer cells escape 5FU chemotherapy-induced cell death by entering stemness and quiescence associated with the c-Yes/YAP axis

    PubMed Central

    Touil, Yasmine; Igoudjil, Wassila; Corvaisier, Matthieu; Dessein, Anne-Frédérique; Vandomme, Jérôme; Monté, Didier; Stechly, Laurence; Skrypek, Nicolas; Langlois, Carole; Grard, Georges; Millet, Guillaume; Leteurtre, Emmanuelle; Dumont, Patrick; Truant, Stéphanie; Pruvot, François-René; Hebbar, Mohamed; Fan, Fan; Ellis, Lee M.; Formstecher, Pierre; Van Seuningen, Isabelle; Gespach, Christian; Polakowska, Renata; Huet, Guillemette

    2015-01-01

    Purpose Metastasis and drug resistance are the major limitations in the survival and management of cancer patients. This study aimed to identify the mechanisms underlying HT29 colon cancer cell chemoresistance acquired after sequential exposure to 5-fluorouracil (5FU), a classical anticancer drug for treatment of epithelial solid tumors. We examined its clinical relevance in a cohort of colon cancer patients with liver metastases after 5FU-based neoadjuvant chemotherapy and surgery. Results We show that a clonal 5F31 cell population, resistant to 1μM 5FU, express a typical cancer stem cell-like phenotype and enter into a reversible quiescent G0-state upon re-exposure to higher 5FU concentrations. These quiescent cells overexpressed the tyrosine kinase c-Yes that became activated and membrane-associated upon 5FU exposure. This enhanced signaling pathway induced the dissociation of the Yes/YAP (Yes-associated protein) molecular complex and depleted nuclear YAP levels. Consistently, c-Yes silencing decreased nuclear YAP accumulation and induced cellular quiescence in 5F31 cells cultured in 5FU-free medium. Importantly, c-Yes and YAP transcript levels were higher in liver metastases of colon cancer patients after 5FU-based neoadjuvant chemotherapy. Moreover, the c-Yes and YAP levels positively correlated with colon cancer relapse and shorter patient survival (p<0.05 and p<0.025, respectively). Conclusions We identified c-Yes and YAP as potential molecular targets to eradicate quiescent cancer cells and dormant micrometastases during 5FU chemotherapy and resistance and as predictive survival markers for colon cancer. PMID:24323901

  18. Indigenous Fallow Management on Yap Island

    Treesearch

    M.V.C. Falanruw; Francis Ruegorong

    2002-01-01

    On Yap Island, indigenous management of the fallow in shifting agriculture has resulted in the development of site-stable taro patch and tree garden agroforestry systems. These systems are relatively sustainable and supportive of household economies , with some surplus for local market sales. however, a broad range of crops whose harvest is complementary to those...

  19. Hippo Signaling Regulates Pancreas Development through Inactivation of Yap

    PubMed Central

    Day, Caroline E.; Boerner, Brian P.; Johnson, Randy L.; Sarvetnick, Nora E.

    2012-01-01

    The mammalian pancreas is required for normal metabolism, with defects in this vital organ commonly observed in cancer and diabetes. Development must therefore be tightly controlled in order to produce a pancreas of correct size, cell type composition, and physiologic function. Through negative regulation of Yap-dependent proliferation, the Hippo kinase cascade is a critical regulator of organ growth. To investigate the role of Hippo signaling in pancreas biology, we deleted Hippo pathway components in the developing mouse pancreas. Unexpectedly, the pancreas from Hippo-deficient offspring was reduced in size, with defects evident throughout the organ. Increases in the dephosphorylated nuclear form of Yap are apparent throughout the exocrine compartment and correlate with increases in levels of cell proliferation. However, the mutant exocrine tissue displays extensive disorganization leading to pancreatitis-like autodigestion. Interestingly, our results suggest that Hippo signaling does not directly regulate the pancreas endocrine compartment as Yap expression is lost following endocrine specification through a Hippo-independent mechanism. Altogether, our results demonstrate that Hippo signaling plays a crucial role in pancreas development and provide novel routes to a better understanding of pathological conditions that affect this organ. PMID:23071096

  20. Chemical Characteristics of Seawater and Sediment in the Yap Trench

    NASA Astrophysics Data System (ADS)

    Ding, H.; Sun, C.; Yang, G.

    2017-12-01

    In June 2016, seawater samples at sediment-seawater interface and sediment samples were collected by the he Jiaolong, China's manned submersible, at four sampling sites located in the Yap Trench. Seawater samples from different depths of the trench were also collected by CTD. Chemical parameters, including pH, alkanility, concentrations of dissolved inorganic carbon, dissolved and total organic carbon, methane, dimethylsulfoniopropionate, nutrients, carbohydrates, and amino acids were analyzed in the seawater samples. Concentrations of total organic carbon, six constant elements and nine trace elements were determined in the sediment samples. All the vertical profiles of the chemical parameters in the seawater have unique characteristics. Our resluts also showed that the carbonate compensation depth (CCD) was between 4500 m and 5000 m in the trench. The hadal sediment at 6500 m depth under the CCD line was siliceous ooze favored for the burial of orgaic carbon, attributed to accumulation of surface sediment by gravity flow. The abyssal sediment at the 4500 m depth was calcareous ooze. Various microfossils, such as discoasters and diatoms, were identified in different sediment layers of the sediment samples.Based on the ratios of Fe/Al and Ti/Al, and the correlation between different elements, the sediment in the Yap Trench were derived from biogenic, terrestrial, volcanic and autogenic sources. The ratios of Ni/Co and V/Cr showed that the deposition environment of the trench should be oxidative, arributed to inflow of the Antractic bottom oxygen-rich seawater.The high concentraiont of Ca in the sediment from the station 371-Yap-S02 below 4 cm depth indicated that there was no large-scale volcanic eruption in the research area and the volcanic materials in the sediment might orginated from the Mariana Volcanic Arc, and the Carolyn Ridge has been slowly sinking on the east side of the trench due to plate subduction. This study is the first systematic study of

  1. MicroRNA-375 targets Hippo-signaling effector YAP in liver cancer and inhibits tumor properties

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Liu, Angela M.; Department of Pharmacology and Department of Surgery, National University of Singapore, Singapore 117597; Poon, Ronnie T.P.

    2010-04-09

    Hepatocellular carcinoma (HCC) is a malignant form of liver cancer that ranks the second leading cause of cancer-related deaths in China and many Asia regions. The dismal outcome reflects the need for a better understanding of the transcriptional control of oncogenic signaling pathway. Our recent findings have identified yes-associated protein (YAP) is a potent oncogenic driver and independent prognostic risk factor of HCC. The present study aims to elucidate the transcriptional regulation of YAP targeted by microRNA (miRNA). miR-375 is a putative target and was found significantly down-regulated in the tumor versus adjacent non-tumor tissues of HCC patients (n =more » 48). As determined by luciferase reporter assay, we found ectopic expression of miR-375 could diminish the transcriptional activity of YAP. Furthermore, immunoblotting revealed miR-375 suppressed endogenous YAP protein level. Functional assays showed that miR-375 was able to inhibit proliferation and invasion of HCC cells. Conclusion: miR-375 is an important regulator of YAP oncogene, implicating a potential therapeutic role in HCC treatment.« less

  2. Multiple Mechanisms Cooperate to Constitutively Exclude the Transcriptional Co-Activator YAP from the Nucleus During Murine Oogenesis1

    PubMed Central

    Abbassi, Laleh; Malki, Safia; Cockburn, Katie; Macaulay, Angus; Robert, Claude; Rossant, Janet; Clarke, Hugh J.

    2016-01-01

    Reproduction depends on the generation of healthy oocytes. Improving therapeutic strategies to prolong or rescue fertility depends on identifying the inter- and intracellular mechanisms that direct oocyte development under physiological conditions. Growth and proliferation of multiple cell types is regulated by the Hippo signaling pathway, whose chief effectors are the transcriptional co-activator YAP and its paralogue WWTR1. To resolve conflicting results concerning the potential role of Hippo in mammalian oocyte development, we systematically investigated the expression and localization of YAP in mouse oocytes. We report that that YAP is expressed in the germ cells beginning as early as Embryonic Day 15.5 and subsequently throughout pre- and postnatal oocyte development. However, YAP is restricted to the cytoplasm at all stages. YAP is phosphorylated at serine-112 in growing and fully grown oocytes, identifying a likely mechanistic basis for its nuclear exclusion, and becomes dephosphorylated at this site during meiotic maturation. Phosphorylation at serine-112 is regulated by a mechanism dependent on cyclic AMP and protein kinase A, which is known to be active in oocytes prior to maturation. Growing oocytes also contain a subpopulation of YAP, likely dephosphorylated, that is able enter the oocyte nucleus, but it is not retained there, implying that oocytes lack the cofactors required to retain YAP in the nucleus. Thus, although YAP is expressed throughout oocyte development, phosphorylation-dependent and -independent mechanisms cooperate to ensure that it does not accumulate in the nucleus. We conclude that nuclear YAP does not play a significant physiological role during oocyte development in mammals. PMID:26985001

  3. A genome-wide screen identifies YAP/WBP2 interplay conferring growth advantage on human epidermal stem cells

    PubMed Central

    Walko, Gernot; Woodhouse, Samuel; Pisco, Angela Oliveira; Rognoni, Emanuel; Liakath-Ali, Kifayathullah; Lichtenberger, Beate M.; Mishra, Ajay; Telerman, Stephanie B.; Viswanathan, Priyalakshmi; Logtenberg, Meike; Renz, Lisa M.; Donati, Giacomo; Quist, Sven R.; Watt, Fiona M.

    2017-01-01

    Individual human epidermal cells differ in their self-renewal ability. To uncover the molecular basis for this heterogeneity, we performed genome-wide pooled RNA interference screens and identified genes conferring a clonal growth advantage on normal and neoplastic (cutaneous squamous cell carcinoma, cSCC) human epidermal cells. The Hippo effector YAP was amongst the top positive growth regulators in both screens. By integrating the Hippo network interactome with our data sets, we identify WW-binding protein 2 (WBP2) as an important co-factor of YAP that enhances YAP/TEAD-mediated gene transcription. YAP and WPB2 are upregulated in actively proliferating cells of mouse and human epidermis and cSCC, and downregulated during terminal differentiation. WBP2 deletion in mouse skin results in reduced proliferation in neonatal and wounded adult epidermis. In reconstituted epidermis YAP/WBP2 activity is controlled by intercellular adhesion rather than canonical Hippo signalling. We propose that defective intercellular adhesion contributes to uncontrolled cSCC growth by preventing inhibition of YAP/WBP2. PMID:28332498

  4. Structural features and ligand binding properties of tandem WW domains from YAP and TAZ, nuclear effectors of the Hippo pathway.

    PubMed

    Webb, Claire; Upadhyay, Abhishek; Giuntini, Francesca; Eggleston, Ian; Furutani-Seiki, Makoto; Ishima, Rieko; Bagby, Stefan

    2011-04-26

    The paralogous multifunctional adaptor proteins YAP and TAZ are the nuclear effectors of the Hippo pathway, a central mechanism of organ size control and stem cell self-renewal. WW domains, mediators of protein-protein interactions, are essential for YAP and TAZ function, enabling interactions with PPxY motifs of numerous partner proteins. YAP has single and double WW domain isoforms (YAP1 and YAP2) whereas only a single WW domain isoform of TAZ has been described to date. Here we identify the first example of a double WW domain isoform of TAZ. Using NMR, we have characterized conformational features and peptide binding of YAP and TAZ tandem WW domains (WW1-WW2). The solution structure of YAP WW2 confirms that it has a canonical three-stranded antiparallel β-sheet WW domain fold. While chemical shift-based analysis indicates that the WW domains in the tandem WW pairs retain the characteristic WW domain fold, 15N relaxation data show that, within the respective WW pairs, YAP WW1 and both WW1 and WW2 of TAZ undergo conformational exchange. 15N relaxation data also indicate that the linker between the WW domains is flexible in both YAP and TAZ. Within both YAP and TAZ tandem WW pairs, WW1 and WW2 bind single PPxY-containing peptide ligand concurrently and noncooperatively with sub-mM affinity. YAP and TAZ WW1-WW2 bind a dual PPxY-containing peptide with approximately 6-fold higher affinity. Our results indicate that both WW domains in YAP and TAZ are functional and capable of enhanced affinity binding to multi-PPxY partner proteins such as LATS1, ErbB4, and AMOT.

  5. The geochemical characteristics and sedimentary environment of abyss and hadal sediments of Yap-trench

    NASA Astrophysics Data System (ADS)

    Huang, Y.; Wang, M.; Sun, C.; Yang, G.; Ding, H.

    2017-12-01

    Based on ICP-ES analysis, concentrations of 6 constant elements and 9 trace elements in five sediment columnar samples collected from Yap-trench by the Jiaolong Submersiblein June, 2016, were determined. According to the distribution of elements, the sources of sediment and the implications on sedimentary environment were investigated through the correlation of elements and the ratios between special elements. The results showed that the carbonate compensation depthwas between 4500m and 5000m, and the depth of 5000m should be an ideal condition for the formation of iron and manganese nodules. Based on the ratios of Fe/Al and Ti/Al, and the correlation of elements, we inferred that Yap-trench sediments were mainly derived from biogenic, terrestrial, volcanic and autogenic source. The values of Ni/Co and V/Cr indicated that the depositional environment belongs to the oxidative environment and might have inflow of the Antarctic bottom oxygen-rich water. The high content of Ca in the 371-Yap-S02 station below 4cm indicated that this area should be no large-scale volcanic eruption, and volcanic material in the sediment may come from the Mariana volcanic arc. The Caroline ridge located in the east of Yap-trench keep sinking due to plate subduction.

  6. YAP and TAZ regulate adherens junction dynamics and endothelial cell distribution during vascular development

    PubMed Central

    Neto, Filipa; Klaus-Bergmann, Alexandra; Ong, Yu Ting; Alt, Silvanus; Vion, Anne-Clémence; Szymborska, Anna; Carvalho, Joana R; Hollfinger, Irene; Bartels-Klein, Eireen; Franco, Claudio A

    2018-01-01

    Formation of blood vessel networks by sprouting angiogenesis is critical for tissue growth, homeostasis and regeneration. How endothelial cells arise in adequate numbers and arrange suitably to shape functional vascular networks is poorly understood. Here we show that YAP/TAZ promote stretch-induced proliferation and rearrangements of endothelial cells whilst preventing bleeding in developing vessels. Mechanistically, YAP/TAZ increase the turnover of VE-Cadherin and the formation of junction associated intermediate lamellipodia, promoting both cell migration and barrier function maintenance. This is achieved in part by lowering BMP signalling. Consequently, the loss of YAP/TAZ in the mouse leads to stunted sprouting with local aggregation as well as scarcity of endothelial cells, branching irregularities and junction defects. Forced nuclear activity of TAZ instead drives hypersprouting and vascular hyperplasia. We propose a new model in which YAP/TAZ integrate mechanical signals with BMP signaling to maintain junctional compliance and integrity whilst balancing endothelial cell rearrangements in angiogenic vessels. PMID:29400648

  7. Phellinus noxius in Guam, Saipan, Yap, Palau, Pohnpei and Kosrae [Chapter IV

    Treesearch

    Phil G. Cannon; Ned B. Klopfenstein; Mee-Sook Kim; Yuko Ota; Norio Sahashi; Robert L. Schlub; Gibson Santos; Rodasio Samuel; Francis Ruegorong; Maxson Nithan; Blair Charley; Erick Waguk; Roland Quitugua; Ashley Lehman; Konrad Engleberger; Victor Guerrero; Sid Cabrerra; Manny Tenorio; Arnold Route

    2014-01-01

    Phellinus noxius has a reputation of being an aggressive root rot pathogen on many forest tree species in parts of Southeast Asia and its symptoms and signs have been well documented. Previous reports from Micronesia indicated that this fungal pathogen is responsible for considerable damage in Saipan and likely present in Kosrae and Pohnpei. In this present...

  8. Assessing Landslide Mobility Using GIS: Application to Kosrae, Micronesia

    NASA Astrophysics Data System (ADS)

    Reid, M. E.; Brien, D. L.; Godt, J.; Schmitt, R. G.; Harp, E. L.

    2015-12-01

    Deadly landslides are often mobile landslides, as exemplified by the disastrous landslide that occurred near Oso, Washington in 2014 killing 43. Despite this association, many landslide susceptibility maps do not identify runout areas. We developed a simple, GIS-based method for identifying areas potentially overrun by mobile slides and debris flows. Our method links three processes within a DEM landscape: landslide initiation, transport, and debris-flow inundation (from very mobile slides). Given spatially distributed shear strengths, we first identify initiation areas using an infinite-slope stability analysis. We then delineate transport zones, or regions of potential entrainment and/or deposition, using a height/length runout envelope. Finally, where these transport zones intersect the channel network, we start debris-flow inundation zones. The extent of inundation is computed using the USGS model Laharz, modified to include many debris-flow locations throughout a DEM. Potential debris-flow volumes are computed from upslope initiation areas and typical slide thicknesses. We applied this approach to the main island of Kosrae State, Federated States of Micronesia (FSM). In 2002, typhoon Chata'an triggered numerous landslides on the neighboring islands of Chuuk State, FSM, resulting in 43 fatalities. Using an infinite-slope stability model calibrated to the Chuuk event, we identified potential landslide initiation areas on Kosrae. We then delineated potential transport zones using a 20º runout envelope, based on runout observations from Chuuk. Potential debris-flow inundation zones were then determined using Laharz. Field inspections on Kosrae revealed that our resulting susceptibility map correctly classified areas covered by previous debris-flow deposits and did not include areas covered by fluvial deposits. Our map has the advantage of providing a visual tool to portray initiation, transport, and runout zones from mobile landslides.

  9. Cryogenic Tm:YAP microchip laser

    NASA Astrophysics Data System (ADS)

    Hubka, Zbyněk.; Å ulc, Jan; Jelínková, Helena; Nejezchleb, Karel; Å koda, Václav

    2016-04-01

    The spectral characteristics of laser active media, and thus those of the laser output, are temperature dependent. Specifically, in almost every crystal host, cooling to low temperatures leads to better heat removal, a higher efficiency and output power, and a reduced lasing threshold. Tm-ion doped lasers have an emission wavelength around 2 μm and are important in medicine for soft tissue cutting and hemostasis, as well as in LIDAR or atmosphere sensing technology. This paper presents the performance-temperature dependency of a 4 at. % doped Tm:YAP microchip. During the experiment the Tm:YAP crystal was placed inside an evacuated liquid nitrogen cryostat on a cooling finger. As its temperature was varied from 80 K to 340 K, changes were observed in the absorption spectrum, ranging from 750 nm to 2000 nm and in the fluorescence spectrum from 1600 nm to 2050 nm. Fluorescence lifetime was seen to rise and fall with decreasing temperature. The laser was pumped by a 792 nm laser diode and at 80 K the maximum output peak power of the laser was 4.6 W with 23 % slope efficiency and 0.6 W threshold, compared to 2.4 W output peak power, 13 % slope efficiency and 3.3 W threshold when at 340 K. The laser emission wavelength changed from 1883 nm to 1993 nm for 80 K and 300 K, respectively.

  10. Yap1 promotes the survival and self-renewal of breast tumor initiating cells via inhibiting Smad3 signaling

    PubMed Central

    Sun, Jian-Guo; Chen, Xie-Wan; Zhang, Lu-Ping; Wang, Jiang; Diehn, Max

    2016-01-01

    Tumor initiating cells (TICs) serve as the root of tumor growth. After identifying TICs in spontaneous breast tumors of the MMTV-Wnt1 mouse model, we confirmed the specific expression and activation of Yes-associated protein 1 (Yap1) within TICs. To investigate the role of Yap1 in the self-renewal of breast TICs and the underlying mechanism, we sorted CD49fhighEpCAMlow cells as breast TICs. Active Yap1 with ectopic expression in breast TICs promoted their colony formation in vitro (p< 0.01) and self-renewal in vivo (p< 0.01), and led to a 4-fold increase in TIC frequency (p< 0.05). A conditional knock-out mouse was reconstructed to generate Yap1 knock-out breast tumors. The loss of Yap1 led to a dramatic growth disadvantage of breast TICs in vitro (p< 0.01) and in vivo (p< 0.01), and it also led to an over 200-fold decrease in TIC frequency (p< 0.01). The expression of active Yap1 was negatively correlated with that of phosphorylated Smad3 (p-Smad3). Transforming growth factor β (TGF-β) served as a strong enhancer of Smad3 and an inhibitor of clonogenesis of TICs. The presence of SIS3, a specific inhibitor of Smad3, could rescue the TGF-β -induced growth inhibition and reverse the Smad3 inhibition by Yap1. Analysis of a database containing 2,072 human breast cancer samples showed that higher expressions of Yap1 correlated with a poorer outcome of a 15-year survival rate and median overall survival (mOS)in patients, especially in those with basal breast tumors without estrogen receptor 1 (ER) expression. The findings indicate that active Yap1 promotes the self-renewal of breast TICs by inhibiting Smad3 signaling. PMID:26695440

  11. Dysregulation of YAP by the Hippo pathway is involved in intervertebral disc degeneration, cell contact inhibition, and cell senescence.

    PubMed

    Zhang, Cong; Wang, Feng; Xie, Zhiyang; Chen, Lu; Sinkemani, Arjun; Yu, Haomin; Wang, Kun; Mao, Lu; Wu, Xiaotao

    2018-01-05

    The Hippo pathway plays important roles in wound healing, tissue repair and regeneration, and in the treatment of degenerative diseases, by regulating cell proliferation and apoptosis in mammals. Intervertebral disc degeneration (IDD) is one of the major causes of low back pain, a widespread issue associated with a heavy economic burden. However, the mechanism underlying how the Hippo pathway regulates IDD is not well understood. Here, we demonstrate that the Hippo pathway is involved in natural IDD. Activation and dephosphorylation of yes-associated protein (YAP) were observed in younger rat discs, and decreased gradually with age. Surprisingly, Hippo pathway suppression was accompanied by overexpression of YAP, caused by acute disc injury, suggesting a limited ability for self-repair in IDD. We also demonstrated that YAP is inhibited by cell-to-cell contact via the Hippo pathway in vitro . Phosphorylation by large tumor suppressor kinases 1/2 (LATS1/2) led to cytoplasmic translocation and inactivation of YAP. YAP dephosphorylation was mainly localized in the nucleus and regulated by the Hippo pathway, whereas YAP dephosphorylation occurred in the cytoplasm and was associated with nucleus pulposus cell (NPC) senescence. Moreover, NPCs were transfected with shYAP and it accelerates the premature senescence of cells by interfered Hippo pathway through YAP. Therefore, our results indicate that the Hippo pathway plays an important role in maintaining the homeostasis of intervertebral discs and controlling NPC proliferation.

  12. YAP is essential for tissue tension to ensure vertebrate 3D body shape.

    PubMed

    Porazinski, Sean; Wang, Huijia; Asaoka, Yoichi; Behrndt, Martin; Miyamoto, Tatsuo; Morita, Hitoshi; Hata, Shoji; Sasaki, Takashi; Krens, S F Gabriel; Osada, Yumi; Asaka, Satoshi; Momoi, Akihiro; Linton, Sarah; Miesfeld, Joel B; Link, Brian A; Senga, Takeshi; Shimizu, Nobuyoshi; Nagase, Hideaki; Matsuura, Shinya; Bagby, Stefan; Kondoh, Hisato; Nishina, Hiroshi; Heisenberg, Carl-Philipp; Furutani-Seiki, Makoto

    2015-05-14

    Vertebrates have a unique 3D body shape in which correct tissue and organ shape and alignment are essential for function. For example, vision requires the lens to be centred in the eye cup which must in turn be correctly positioned in the head. Tissue morphogenesis depends on force generation, force transmission through the tissue, and response of tissues and extracellular matrix to force. Although a century ago D'Arcy Thompson postulated that terrestrial animal body shapes are conditioned by gravity, there has been no animal model directly demonstrating how the aforementioned mechano-morphogenetic processes are coordinated to generate a body shape that withstands gravity. Here we report a unique medaka fish (Oryzias latipes) mutant, hirame (hir), which is sensitive to deformation by gravity. hir embryos display a markedly flattened body caused by mutation of YAP, a nuclear executor of Hippo signalling that regulates organ size. We show that actomyosin-mediated tissue tension is reduced in hir embryos, leading to tissue flattening and tissue misalignment, both of which contribute to body flattening. By analysing YAP function in 3D spheroids of human cells, we identify the Rho GTPase activating protein ARHGAP18 as an effector of YAP in controlling tissue tension. Together, these findings reveal a previously unrecognised function of YAP in regulating tissue shape and alignment required for proper 3D body shape. Understanding this morphogenetic function of YAP could facilitate the use of embryonic stem cells to generate complex organs requiring correct alignment of multiple tissues.

  13. Tumor-selective proteotoxicity of verteporfin inhibits colon cancer progression independently of YAP1#

    PubMed Central

    Zhang, Huabing; Ramakrishnan, Sadeesh K.; Triner, Daniel; Centofanti, Brook; Maitra, Dhiman; Győrffy, Balázs; Sebolt-Leopold, Judith S.; Dame, Michael K.; Varani, James; Brenner, Dean E.; Fearon, Eric R.; Omary, M. Bishr; Shah, Yatrik M.

    2016-01-01

    Yes-associated protein 1 (YAP1) is a transcriptional coactivator in the Hippo signaling pathway. Increased YAP1- activity promotes the growth of tumors, including that of colorectal cancer (CRC). Verteporfin, a drug that enhances phototherapy to treat neovascular macular degeneration, is an inhibitor of YAP1. Here, we found that verteporfin inhibited tumor growth independently of its effects on YAP1 or the related protein TAZ in genetic or chemical-induced mouse models of CRC, in patient-derived xenografts and in enteroid models of CRC. Instead, verteporfin exhibited in vivo selectivity for killing tumor cells in part by impairing the global clearance of high molecular weight oligomerized proteins, particularly p62 (a sequestrome involved in autophagy) and STAT3 (a transcription factor). Verteporfin inhibited cytokine-induced STAT3 activity and cell proliferation and reduced the viabilty of cultured CRC cells. Although verteporfin accumulated to a greater extent in normal cells than in tumor cells in vivo, experiments with cultured cells indicated that the normal cells efficiently cleared verteporfin-induced protein oligomers through autophagic and proteasomal pathways. Culturing CRC cells in hypoxic or nutrient-deprived conditions (modeling a typical CRC microenvironment) impaired the clearance of protein oligomers and resulted in cell death; whereas culturing cells in normoxic or glucose-replete conditions protected cell viability and proliferation in the presence of verteporfin. Furthermore, verteporfin suppressed the proliferation of other cancer cell lines even in the absence of YAP1, suggesting that verteporfin may be effective against multiple types of solid cancers. PMID:26443705

  14. Sub-cellular localisation studies may spuriously detect the Yes-associated protein, YAP, in nucleoli leading to potentially invalid conclusions of its function.

    PubMed

    Finch, Megan L; Passman, Adam M; Strauss, Robyn P; Yeoh, George C; Callus, Bernard A

    2015-01-01

    The Yes-associated protein (YAP) is a potent transcriptional co-activator that functions as a nuclear effector of the Hippo signaling pathway. YAP is oncogenic and its activity is linked to its cellular abundance and nuclear localisation. Activation of the Hippo pathway restricts YAP nuclear entry via its phosphorylation by Lats kinases and consequent cytoplasmic retention bound to 14-3-3 proteins. We examined YAP expression in liver progenitor cells (LPCs) and surprisingly found that transformed LPCs did not show an increase in YAP abundance compared to the non-transformed LPCs from which they were derived. We then sought to ascertain whether nuclear YAP was more abundant in transformed LPCs. We used an antibody that we confirmed was specific for YAP by immunoblotting to determine YAP's sub-cellular localisation by immunofluorescence. This antibody showed diffuse staining for YAP within the cytosol and nuclei, but, noticeably, it showed intense staining of the nucleoli of LPCs. This staining was non-specific, as shRNA treatment of cells abolished YAP expression to undetectable levels by Western blot yet the nucleolar staining remained. Similar spurious YAP nucleolar staining was also seen in mouse embryonic fibroblasts and mouse liver tissue, indicating that this antibody is unsuitable for immunological applications to determine YAP sub-cellular localisation in mouse cells or tissues. Interestingly nucleolar staining was not evident in D645 cells suggesting the antibody may be suitable for use in human cells. Given the large body of published work on YAP in recent years, many of which utilise this antibody, this study raises concerns regarding its use for determining sub-cellular localisation. From a broader perspective, it serves as a timely reminder of the need to perform appropriate controls to ensure the validity of published data.

  15. Arsenic-induced cutaneous hyperplastic lesions are associated with the dysregulation of Yap, a Hippo signaling-related protein

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Li, Changzhao; Srivastava, Ritesh K.; Elmets, Craig A.

    2013-09-06

    Highlights: •Arsenic activates canonical Hippo signaling pathway and up-regulates αCatenin in the skin. •Arsenic activates transcriptional activity of Yap by its nuclear translocation. •Yap is involved in the disruption of tight/adherens junctions in arsenic-exposed animals. -- Abstract: Arsenic exposure in humans causes a number of toxic manifestations in the skin including cutaneous neoplasm. However, the mechanism of these alterations remains elusive. Here, we provide novel observations that arsenic induced Hippo signaling pathway in the murine skin. This pathway plays crucial roles in determining organ size during the embryonic development and if aberrantly activated in adults, contributes to the pathogenesis ofmore » epithelial neoplasm. Arsenic treatment enhanced phosphorylation-dependent activation of LATS1 kinase and other Hippo signaling regulatory proteins Sav1 and MOB1. Phospho-LATS kinase is known to catalyze the inactivation of a transcriptional co-activator, Yap. However, in arsenic-treated epidermis, we did not observed its inactivation. Thus, as expected, unphosphorylated-Yap was translocated to the nucleus in arsenic-treated epidermis. Yap by binding to the transcription factors TEADs induces transcription of its target genes. Consistently, an up-regulation of Yap-dependent target genes Cyr61, Gli2, Ankrd1 and Ctgf was observed in the skin of arsenic-treated mice. Phosphorylated Yap is important in regulating tight and adherens junctions through its binding to αCatenin. We found disruption of these junctions in the arsenic-treated mouse skin despite an increase in αCatenin. These data provide evidence that arsenic-induced canonical Hippo signaling pathway and Yap-mediated disruption of tight and adherens junctions are independently regulated. These effects together may contribute to the carcinogenic effects of arsenic in the skin.« less

  16. The Hippo component YAP localizes in the nucleus of human papilloma virus positive oropharyngeal squamous cell carcinoma.

    PubMed

    Alzahrani, Faisal; Clattenburg, Leanne; Muruganandan, Shanmugam; Bullock, Martin; MacIsaac, Kaitlyn; Wigerius, Michael; Williams, Blair A; Graham, M Elise R; Rigby, Matthew H; Trites, Jonathan R B; Taylor, S Mark; Sinal, Christopher J; Fawcett, James P; Hart, Robert D

    2017-02-22

    HPV infection causes cervical cancer, mediated in part by the degradation of Scribble via the HPV E6 oncoprotein. Recently, Scribble has been shown to be an important regulator of the Hippo signaling cascade. Deregulation of the Hippo pathway induces an abnormal cellular transformation, epithelial to mesenchymal transition, which promotes oncogenic progression. Given the recent rise in oropharyngeal HPV squamous cell carcinoma we sought to determine if Hippo signaling components are implicated in oropharyngeal squamous cell carcinoma. Molecular and cellular techniques including immunoprecipiations, Western blotting and immunocytochemistry were used to identify the key Hippo pathway effector Yes-Associated Protein (YAP)1. Oropharyngeal tissue was collected from CO 2 laser resections, and probed with YAP1 antibody in tumor and pre-malignant regions of HPV positive OPSCC tissue. This study reveals that the Scribble binding protein Nitric Oxide Synthase 1 Adaptor Protein (NOS1AP) forms a complex with YAP. Further, the NOS1APa and NOS1APc isoforms show differential association with activated and non-activated YAP, and impact cellular proliferation. Consistent with deregulated Hippo signaling in OPSCC HPV tumors, we see a delocalization of Scribble and increased nuclear accumulation of YAP1 in an HPV-positive OPSCC. Our preliminary data indicates that NOS1AP isoforms differentially associate with YAP1, which, together with our previous findings, predicts that loss of YAP1 enhances cellular transformation. Moreover, YAP1 is highly accumulated in the nucleus of HPV-positive OPSCC, implying that Hippo signaling and possibly NOS1AP expression are de-regulated in OPSCC. Further studies will help determine if NOS1AP isoforms, Scribble and Hippo components will be useful biomarkers in OPSCC tumor biology.

  17. Topographic and sedimentary features in the Yap subduction zone and their implications for the Caroline Ridge subduction

    NASA Astrophysics Data System (ADS)

    Dong, Dongdong; Zhang, Zhengyi; Bai, Yongliang; Fan, Jianke; Zhang, Guangxu

    2018-01-01

    The Yap subduction zone in the western Pacific presents some unique features compared to normal intra-oceanic subduction zones such as the subduction of an oceanic plateau. However, due to the relative paucity of geophysical data, the detailed structure remains unknown in this area. In this study, we present the latest high-quality swath bathymetry and multi-channel seismic data acquired synchronously in 2015 across the Yap subduction zone. The topographic and sedimentary features are intensively investigated and a modified evolutionary model of the Yap subduction zone is proposed. The two-stage evolution of the Parece Vela Basin (PVB) produced fabrics that are N-S trending and NW-SE trending. Our seismic data clearly reveal landslide deposits at the upper slope break of the forearc, to the north of the Yap Island, which was identified as the fault notch denoting a lithological boundary in previous work. The swath bathymetry and seismic profile reveal detailed horst and graben structures, including a crescent-shaped fault zone near the contact between the Yap Trench and the Caroline Ridge. A simple geometric model is proposed to explain the structure formation, indicating that the higher topography of the Caroline Ridge resulted in enhanced bending-related extension. A seismic angular unconformity (named R1) is identified in the Sorol Trough, marking the onset of rifting in the trough. Based on the sequence thickness and deposition rate by Deep Sea Drilling Project (DSDP), it is deduced that the Sorol Trough formed at 10 Ma or even earlier. A modified model for the Yap subduction zone evolution is proposed, incorporating three major tectonic events: the proto-Yap Arc rupture in the Oligocene, the collision of the Caroline Ridge and the Yap Trench in the late Oligocene or middle Miocene, and the onset of the Sorol Trough rifting in the late Miocene.

  18. Shikonin regulates C-MYC and GLUT1 expression through the MST1-YAP1-TEAD1 axis

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Vališ, Karel, E-mail: karel.valis@biomed.cas.cz; Faculty of Science, Charles University, Prague; Talacko, Pavel

    The general mechanism underlying the tumor suppressor activity of the Hippo signaling pathway remains unclear. In this study, we explore the molecular mechanisms connecting the Hippo signaling pathway with glucose metabolism. We have found that two key regulators of glycolysis, C-MYC and GLUT1, are targets of the Hippo signaling pathway in human leukemia cells. Our results revealed that activation of MST1 by the natural compound shikonin inhibited the expression of GLUT1 and C-MYC. Furthermore, RNAi experiments confirmed the regulation of GLUT1 and C-MYC expression via the MST1-YAP1-TEAD1 axis. Surprisingly, YAP1 was found to positively regulate C-MYC mRNA levels in complexmore » with TEAD1, while it negatively regulates C-MYC levels in cooperation with MST1. Hence, YAP1 serves as a rheostat for C-MYC, which is regulated by MST1. In addition, depletion of MST1 stimulates lactate production, whereas the specific depletion of TEAD1 has an opposite effect. The inhibition of lactate production and cellular proliferation induced by shikonin also depends on the Hippo pathway activity. Finally, a bioinformatic analysis revealed conserved TEAD-binding motifs in the C-MYC and GLUT1 promoters providing another molecular data supporting our observations. In summary, regulation of glucose metabolism could serve as a new tumor suppressor mechanism orchestrated by the Hippo signaling pathway. - Highlights: • Shikonin inhibits C-MYC and GLUT1 expression in MST1 and YAP1 dependent manner. • YAP1-TEAD1 interaction activates C-MYC and GLUT1 expression. • MST1 in cooperation with YAP1 inhibits C-MYC and GLUT1 expression. • MST1-YAP1-TEAD1 axis regulates lactate production by leukemic cells. • MST1 and YAP1 proteins block proliferation of leukemic cells.« less

  19. Modulated and continuous-wave operations of low-power thulium (Tm:YAP) laser in tissue welding

    NASA Astrophysics Data System (ADS)

    Bilici, Temel; Tabakoğlu, Haşim Özgür; Topaloğlu, Nermin; Kalaycıoğlu, Hamit; Kurt, Adnan; Sennaroglu, Alphan; Gülsoy, Murat

    2010-05-01

    Our aim is to explore the welding capabilities of a thulium (Tm:YAP) laser in modulated and continuous-wave (CW) modes of operation. The Tm:YAP laser system developed for this study includes a Tm:YAP laser resonator, diode laser driver, water chiller, modulation controller unit, and acquisition/control software. Full-thickness incisions on Wistar rat skin were welded by the Tm:YAP laser system at 100 mW and 5 s in both modulated and CW modes of operation (34.66 W/cm2). The skin samples were examined during a 21-day healing period by histology and tensile tests. The results were compared with the samples closed by conventional suture technique. For the laser groups, immediate closure at the surface layers of the incisions was observed. Full closures were observed for both modulated and CW modes of operation at day 4. The tensile forces for both modulated and CW modes of operation were found to be significantly higher than the values found by conventional suture technique. The 1980-nm Tm:YAP laser system operating in both modulated and CW modes maximizes the therapeutic effect while minimizing undesired side effects of laser tissue welding. Hence, it is a potentially important alternative tool to the conventional suturing technique.

  20. Ligand Binding to WW Tandem Domains of YAP2 Transcriptional Regulator Is Under Negative Cooperativity

    PubMed Central

    Schuchardt, Brett J.; Mikles, David C.; Hoang, Lawrence M.; Bhat, Vikas; McDonald, Caleb B.; Sudol, Marius; Farooq, Amjad

    2014-01-01

    YAP2 transcriptional regulator drives a multitude of cellular processes, including the newly discovered Hippo tumor suppressor pathway, by virtue of the ability of its WW domains to bind and recruit PPXY-containing ligands to specific subcellular compartments. Herein, we employ an array of biophysical tools to investigate allosteric communication between the WW tandem domains of YAP2. Our data show that the WW tandem domains of YAP2 negatively cooperate when binding to their cognate ligands. Moreover, the molecular origin of such negative cooperativity lies in an unfavorable entropic contribution to the overall free energy relative to ligand binding to isolated WW domains. Consistent with this notion, the WW tandem domains adopt a fixed spatial orientation such that the WW1 domain curves outwards and stacks onto the binding groove of WW2 domain, thereby sterically hindering ligand binding to both itself and its tandem partner. Although ligand binding to both WW domains disrupts such interdomain stacking interaction, they reorient themselves and adopt an alternative fixed spatial orientation in the liganded state by virtue of their ability to engage laterally so as to allow their binding grooves to point outwards and away from each other. In short, while the ability of WW tandem domains to aid ligand binding is well-documented, our demonstration that they may also be subject to negative binding cooperativity represents a paradigm shift in our understanding of the molecular action of this ubiquitous family of protein modules. PMID:25283809

  1. Tanshinone IIA inhibits cervix carcinoma stem cells migration and invasion via inhibiting YAP transcriptional activity.

    PubMed

    Qin, Jinghao; Shi, Hongbing; Xu, Yanjie; Zhao, Fang; Wang, Qing

    2018-06-14

    This study aims to explore the effects and related mechanisms of Tanshinone IIA in cervix carcinoma (CC) stemness-like cells migration, invasion, stemness and chemotherapeutical sensitivity. Here, we found that Tanshinone IIA suppressed CC stemness-like cells migration and invasion in a concentration- and time-dependent manner. And consistent results were obtained in CC cells stemness characterized as the decrease of CC stemness markers expression and cells spheroid formation ability. Mechanistically, we found that Tanshinone IIA suppressed RNA binding protein HuR translocation from nuclear to cytoplasm, and thus reduced YAP mRNAs stability and transcriptional activity. Importantly, overexpression YAP-5SA rescued the inhibition of Tanshinone IIA on CC cells stemness. Furthermore, Tanshinone IIA enhanced adriamycin sensitivity in CC stemness-like cells, this effect was attenuated by YAP-5SA overexpression too. Therefore, Tanshinone IIA could suppress CC stemness-like cells migration and invasion by inhibiting YAP transcriptional activity. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  2. Subduction erosion and implication for evolution model of the Yap trench: new evidence from the latest geophysical survey

    NASA Astrophysics Data System (ADS)

    Zhang, Z.; Dong, D.; Bai, Y.; Zhang, G.

    2017-12-01

    The subduction of oceanic plateau, including the ridge and seamount, with buoyant feature will lead to the occurrence of subduction erosion. Yap Trench is a unique structure related to the Caroline Ridge subduction, but with lower research degree. Previous studies lacked the investigation of crustal structure and subduction erosion model based on integrated geophysical data in Yap Trench. In 2015, Institute of Oceanology, Chinese Academy of Sciences acquired swath bathymetric, multi-channel seismic and gravity data by research vessel "Kexue" in the Yap Trench and its adjacent area, providing the chance to further explore this subduction system. For this research, we mainly used the latest data to analyze the topography and crustal structure in Yap subduction system, which is significant for the construction of subduction erosion model. We reveal that, (1) The mean value of arc-ward slope is 8° according with bathymetric slope features in erosive margins(>3°). The increasing trend to dip angles in arc-ward slope shows the control of subducting plate with different elevation from north to south; (2) The horst and graben structures and different scales of seamounts display the rough features in the subducting plate, facilitating the overlying Yap Arc erosion. In the front of the Yap Arc, collision scars identified on the bathymetric map indicates the seamount subducting; (3) The horst and graben structures, with thinner crust of 2-4 km thick, in subducting plate, possibly eroded the Yap Arc basement and made it thinner during subduction. The subducted seamounts with high topography underplated the Yap Arc, which uplifted and thickened the overlying plate crust. Therefore, it is suggested that. subduction erosion model is varied in Yap subduction sysytem which is affected by topography and crust structure of subducting plate. The two types of subduction erosion models in Yap Trench exhibit a good case to reveal the process and mode of plate subducting in subduction

  3. YAP1 Regulates OCT4 Activity and SOX2 Expression to Facilitate Self-Renewal and Vascular Mimicry of Stem-Like Cells.

    PubMed

    Bora-Singhal, Namrata; Nguyen, Jonathan; Schaal, Courtney; Perumal, Deepak; Singh, Sandeep; Coppola, Domenico; Chellappan, Srikumar

    2015-06-01

    Non-small cell lung cancer (NSCLC) is highly correlated with smoking and has very low survival rates. Multiple studies have shown that stem-like cells contribute to the genesis and progression of NSCLC. Our results show that the transcriptional coactivator yes-associated protein 1 (YAP1), which is the oncogenic component of the Hippo signaling pathway, is elevated in the stem-like cells from NSCLC and contributes to their self-renewal and ability to form angiogenic tubules. Inhibition of YAP1 by a small molecule or depletion of YAP1 by siRNAs suppressed self-renewal and vascular mimicry of stem-like cells. These effects of YAP1 were mediated through the embryonic stem cell transcription factor, Sox2. YAP1 could transcriptionally induce Sox2 through a physical interaction with Oct4; Sox2 induction occurred independent of TEAD2 transcription factor, which is the predominant mediator of YAP1 functions. The binding of Oct4 to YAP1 could be detected in cell lines as well as tumor tissues; the interaction was elevated in NSCLC samples compared to normal tissue as seen by proximity ligation assays. YAP1 bound to Oct4 through the WW domain, and a peptide corresponding to this region could disrupt the interaction. Delivery of the WW domain peptide to stem-like cells disrupted the interaction and abrogated Sox2 expression, self-renewal, and vascular mimicry. Depleting YAP1 reduced the expression of multiple epithelial-mesenchymal transition genes and prevented the growth and metastasis of tumor xenografts in mice; overexpression of Sox2 in YAP1 null cells rescued these functions. These results demonstrate a novel regulation of stem-like functions by YAP1, through the modulation of Sox2 expression. © 2015 AlphaMed Press.

  4. Mechano-growth factor protects against mechanical overload induced damage and promotes migration of growth plate chondrocytes through RhoA/YAP pathway.

    PubMed

    Jing, Xingzhi; Ye, Yaping; Bao, Yuan; Zhang, Jinming; Huang, Junming; Wang, Rui; Guo, Jiachao; Guo, Fengjing

    2018-05-15

    Epiphyseal growth plate is highly dynamic tissue which is controlled by a variety of endocrine, paracrine hormones, and by complex local signaling loops and mechanical loading. Mechano growth factor (MGF), the splice variant of the IGF-I gene, has been discovered to play important roles in tissue growth and repair. However, the effect of MGF on the growth plate remains unclear. In the present study, we found that MGF mRNA expression of growth plate chondrocytes was upregulated in response to mechanical stimuli. Treatment of MGF had no effect on growth plate chondrocytes proliferation and differentiation. But it could inhibit growth plate chondrocytes apoptosis and inflammation under mechanical overload. Moreover, both wound healing and transwell assay indicated that MGF could significantly enhance growth plate chondrocytes migration which was accompanied with YAP activation and nucleus translocation. Knockdown of YAP with YAP siRNA suppressed migration induced by MGF, indicating the essential role of YAP in MGF promoting growth plate chondrocytes migration. Furthermore, MGF promoted YAP activation through RhoA GTPase mediated cytoskeleton reorganization, RhoA inhibition using C3 toxin abrogated MGF induced YAP activation. Importantly, we found that MGF promoted focal adhesion(FA) formation and knockdown of YAP with YAP siRNA partially suppressed the activation of FA kinase, implying that YAP is associated with FA formation. In conclusion, MGF is an autocrine growth factor which is regulated by mechanical stimuli. MGF could not only protect growth plate chondrocytes against damage by mechanical overload, but also promote migration through activation of RhoA/YAP signaling axis. Most importantly, our findings indicate that MGF promote cell migration through YAP mediated FA formation to determine the FA-cytoskeleton remodeling. Copyright © 2018. Published by Elsevier Inc.

  5. Sub-Cellular Localisation Studies May Spuriously Detect the Yes-Associated Protein, YAP, in Nucleoli Leading to Potentially Invalid Conclusions of Its Function

    PubMed Central

    Finch, Megan L.; Passman, Adam M.; Strauss, Robyn P.; Yeoh, George C.; Callus, Bernard A.

    2015-01-01

    The Yes-associated protein (YAP) is a potent transcriptional co-activator that functions as a nuclear effector of the Hippo signaling pathway. YAP is oncogenic and its activity is linked to its cellular abundance and nuclear localisation. Activation of the Hippo pathway restricts YAP nuclear entry via its phosphorylation by Lats kinases and consequent cytoplasmic retention bound to 14-3-3 proteins. We examined YAP expression in liver progenitor cells (LPCs) and surprisingly found that transformed LPCs did not show an increase in YAP abundance compared to the non-transformed LPCs from which they were derived. We then sought to ascertain whether nuclear YAP was more abundant in transformed LPCs. We used an antibody that we confirmed was specific for YAP by immunoblotting to determine YAP’s sub-cellular localisation by immunofluorescence. This antibody showed diffuse staining for YAP within the cytosol and nuclei, but, noticeably, it showed intense staining of the nucleoli of LPCs. This staining was non-specific, as shRNA treatment of cells abolished YAP expression to undetectable levels by Western blot yet the nucleolar staining remained. Similar spurious YAP nucleolar staining was also seen in mouse embryonic fibroblasts and mouse liver tissue, indicating that this antibody is unsuitable for immunological applications to determine YAP sub-cellular localisation in mouse cells or tissues. Interestingly nucleolar staining was not evident in D645 cells suggesting the antibody may be suitable for use in human cells. Given the large body of published work on YAP in recent years, many of which utilise this antibody, this study raises concerns regarding its use for determining sub-cellular localisation. From a broader perspective, it serves as a timely reminder of the need to perform appropriate controls to ensure the validity of published data. PMID:25658431

  6. Hippo-YAP signaling pathway: A new paradigm for cancer therapy.

    PubMed

    Ma, Yanlei; Yang, Yongzhi; Wang, Feng; Wei, Qing; Qin, Huanlong

    2015-11-15

    In the past decades, the Hippo signaling pathway has been delineated and shown to play multiple roles in the control of organ size in both Drosophila and mammals. In mammals, the Hippo pathway is a kinase cascade leading from Mst1/2 to YAP and its paralog TAZ. Several studies have demonstrated that YAP/TAZ is a candidate oncogene and that other members of the Hippo pathway are tumor suppressive genes. The dysregulation of the Hippo pathway has been observed in a variety of cancers. This review chronicles the recent progress in elucidating the function of Hippo signaling in tumorigenesis and provide a rich source of potential targets for cancer therapy. © 2014 UICC.

  7. Preparedness for Threat of Chikungunya in the Pacific

    PubMed Central

    Hoy, Damian; Horwood, Paul F.; Ropa, Berry; Hancock, Thane; Guillaumot, Laurent; Rickart, Keith; Frison, Pascal; Pavlin, Boris; Souares, Yvan

    2014-01-01

    Chikungunya virus (CHIKV) caused significant outbreaks of illness during 2005–2007 in the Indian Ocean region. Chikungunya outbreaks have also occurred in the Pacific region, including in Papua New Guinea in 2012; New Caledonia in April 2013; and Yap State, Federated States of Micronesia, in August 2013. CHIKV is a threat in the Pacific, and the risk for further spread is high, given several similarities between the Pacific and Indian Ocean chikungunya outbreaks. Island health care systems have difficulties coping with high caseloads, which highlights the need for early multidisciplinary preparedness. The Pacific Public Health Surveillance Network has developed several strategies focusing on surveillance, case management, vector control, laboratory confirmation, and communication. The management of this CHIKV threat will likely have broad implications for global public health. PMID:25062306

  8. YAP and MRTF-A, transcriptional co-activators of RhoA-mediated gene expression, are critical for glioblastoma tumorigenicity.

    PubMed

    Yu, Olivia M; Benitez, Jorge A; Plouffe, Steven W; Ryback, Daniel; Klein, Andrea; Smith, Jeff; Greenbaum, Jason; Delatte, Benjamin; Rao, Anjana; Guan, Kun-Liang; Furnari, Frank B; Chaim, Olga Meiri; Miyamoto, Shigeki; Brown, Joan Heller

    2018-06-11

    The role of YAP (Yes-associated protein 1) and MRTF-A (myocardin-related transcription factor A), two transcriptional co-activators regulated downstream of GPCRs (G protein-coupled receptors) and RhoA, in the growth of glioblastoma cells and in vivo glioblastoma multiforme (GBM) tumor development was explored using human glioblastoma cell lines and tumor-initiating cells derived from patient-derived xenografts (PDX). Knockdown of these co-activators in GSC-23 PDX cells using short hairpin RNA significantly attenuated in vitro self-renewal capability assessed by limiting dilution, oncogene expression, and neurosphere formation. Orthotopic xenografts of the MRTF-A and YAP knockdown PDX cells formed significantly smaller tumors and were of lower morbidity than wild-type cells. In vitro studies used PDX and 1321N1 glioblastoma cells to examine functional responses to sphingosine 1-phosphate (S1P), a GPCR agonist that activates RhoA signaling, demonstrated that YAP signaling was required for cell migration and invasion, whereas MRTF-A was required for cell adhesion; both YAP and MRTF-A were required for proliferation. Gene expression analysis by RNA-sequencing of S1P-treated MRTF-A or YAP knockout cells identified 44 genes that were induced through RhoA and highly dependent on YAP, MRTF-A, or both. Knockdown of F3 (tissue factor (TF)), a target gene regulated selectively through YAP, blocked cell invasion and migration, whereas knockdown of HBEGF (heparin-binding epidermal growth factor-like growth factor), a gene selectively induced through MRTF-A, prevented cell adhesion in response to S1P. Proliferation was sensitive to knockdown of target genes regulated through either or both YAP and MRTF-A. Expression of TF and HBEGF was also selectively decreased in tumors from PDX cells lacking YAP or MRTF-A, indicating that these transcriptional pathways are regulated in preclinical GBM models and suggesting that their activation through GPCRs and RhoA contributes to growth and

  9. Yes-associated protein (YAP) in pancreatic cancer: at the epicenter of a targetable signaling network associated with patient survival.

    PubMed

    Rozengurt, Enrique; Sinnett-Smith, James; Eibl, Guido

    2018-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is generally a fatal disease with no efficacious treatment modalities. Elucidation of signaling mechanisms that will lead to the identification of novel targets for therapy and chemoprevention is urgently needed. Here, we review the role of Yes-associated protein (YAP) and WW-domain-containing Transcriptional co-Activator with a PDZ-binding motif (TAZ) in the development of PDAC. These oncogenic proteins are at the center of a signaling network that involves multiple upstream signals and downstream YAP-regulated genes. We also discuss the clinical significance of the YAP signaling network in PDAC using a recently published interactive open-access database (www.proteinatlas.org/pathology) that allows genome-wide exploration of the impact of individual proteins on survival outcomes. Multiple YAP/TEAD-regulated genes, including AJUBA , ANLN , AREG , ARHGAP29 , AURKA , BUB1 , CCND1 , CDK6, CXCL5 , EDN2 , DKK1 , FOSL1,FOXM1 , HBEGF , IGFBP2 , JAG1 , NOTCH2 , RHAMM , RRM2 , SERP1 , and ZWILCH , are associated with unfavorable survival of PDAC patients. Similarly, components of AP-1 that synergize with YAP ( FOSL1 ), growth factors (TGFα, EPEG, and HBEGF), a specific integrin ( ITGA2 ), heptahelical receptors ( P2Y 2 R , GPR87 ) and an inhibitor of the Hippo pathway ( MUC1 ), all of which stimulate YAP activity, are associated with unfavorable survival of PDAC patients. By contrast, YAP inhibitory pathways (STRAD/LKB-1/AMPK, PKA/LATS, and TSC/mTORC1) indicate a favorable prognosis. These associations emphasize that the YAP signaling network correlates with poor survival of pancreatic cancer patients. We conclude that the YAP pathway is a major determinant of clinical aggressiveness in PDAC patients and a target for therapeutic and preventive strategies in this disease.

  10. Overexpression of YAP1 in EGFR mutant lung adenocarcinoma prior to tyrosine kinase inhibitor therapy is associated with poor survival.

    PubMed

    Hong, Soon Auck; Jang, Si-Hyong; Oh, Mee-Hye; Kim, Sung Joon; Kang, Jin-Hyung; Hong, Sook-Hee

    2018-03-01

    EGFR tyrosine kinase inhibitor (EGFR TKI) is approved as first-line treatment for advanced-stage EGFR mutant lung adenocarcinoma (LADC). Yes-associated protein 1 (YAP1), a main effector of the Hippo pathway, is associated with adverse prognosis and disruption of EGFR TKI modulation of non-small cell lung cancer. In this study, we demonstrated a prognostic role of YAP1 in EGFR mutant LADC and efficacy of EGFR TKI therapy. A total of 63 patients, including 41 with paired lung cancer specimens before and after EGFR TKI therapy and 22 with non-paired lung cancer specimens prior to EGFR TKI, were enrolled for examination. Expression of YAP1 protein was evaluated using immunohistochemistry. Fifteen paired cases (36.6%) with high nuclear YAP1 expression were detected in the pre-EGFR TKI LADC group and 21 paired cases (52.5%) after treatment with EGFR TKI. Nuclear YAP1 expression was significantly upregulated after EGFR TKI therapy (P = .002). Fifteen paired cases with high nuclear YAP1 expression before EGFR TKI LADCs showed poorer overall survival (OS) (P = .023) and progression-free survival (PFS) (P = .041). Among the 63 patients under study, those with high nuclear YAP1 expression before EGFR TKI showed shorter OS (P = .038) and PFS (P < .001). High nuclear YAP1 expression in cases with acquired EGFR exon 20 T790 M mutant LADCs showed poorer OS (P < .001). We demonstrated that YAP1 burden before clinical application of EGFR TKI plays a crucial role in prognosis of EGFR mutant LADC treated using EGFR TKI. Copyright © 2018 Elsevier GmbH. All rights reserved.

  11. Yap5 Protein-regulated Transcription of the TYW1 Gene Protects Yeast from High Iron Toxicity*

    PubMed Central

    Li, Liangtao; Jia, Xuan; Ward, Diane M.; Kaplan, Jerry

    2011-01-01

    The budding yeast Saccharomyces cerevisiae responds to high cytosolic iron by inducing Yap5-mediated transcription. We identified genes regulated by Yap5 in response to iron and show that one of the genes induced is TYW1, which encodes an iron-sulfur cluster enzyme that participates in the synthesis of wybutosine-modified tRNA. Strains deleted for TYW1 do not show a phenotype in standard yeast medium. In contrast, overexpression of TYW1 results in decreased cell growth and induction of the iron regulon, leading to increased expression of the high affinity iron transporters. We identified a minimal domain of S. cerevisiae Tyw1 that is sufficient to induce the iron regulon. CCC1, a vacuolar iron importer, is a Yap5-regulated gene, and deletion of either CCC1 or YAP5 resulted in high iron sensitivity. Deletion of TYW1 in a Δccc1 strain led to increased iron sensitivity. The increased iron sensitivity of Δccc1Δtyw1 could be suppressed by overexpression of iron-sulfur cluster enzymes. We conclude that the Yap5-mediated induction of TYW1 provides protection from high iron toxicity by the consumption of free cytosolic iron through the formation of protein-bound iron-sulfur clusters. PMID:21917924

  12. Description of nests, eggs, and nestlings of the endangered nightingale reed-warbler on Saipan, Micronesia

    USGS Publications Warehouse

    Mosher, S.M.; Fancy, S.G.

    2002-01-01

    We describe the first verified nests, eggs, and nestlings of the Nightingale Reed-Warbler (Acrocephalus luscinia), an endangered species endemic to the Mariana Islands, Micronesia. Nest composition, nest dimensions, and eggs were studied on the island of Saipan. Nests were located within three habitat types: upland introduced tangantangan (Leucaena leucocephala) forest, a native mangrove (Bruguiera gymnorrhiza) wetland, and a native reed (Phragmites karka) wetland. Nesting substrates included five native and two introduced tree species and one native reed species. Nests were composed primarily of dry vine stems, needle-like branchlets of ironwood (Casuarina equisetifolia), and tangantangan petioles. Nests were compact to bulky in construction and were secured to a forked arrangement of branches or stems. The background color of eggs ranged from white to cream to ivory-buff. Eggs were spotted, speckled, and blotched with gray, brown, black, and rust colored markings. Clutch size was 2-4, with a mode of two. Hatchlings were altricial with closed eyelids and devoid of natal down with dark gray to black skin. Nestlings examined prior to fledging resembled the adult plumage, except for the lack of the yellow supercilium found in adults. The nests and eggs have some characteristics similar to those of other Acrocephaline warblers found throughout Micronesia and Polynesia.

  13. The unexpected discovery of blind snakes (Serpentes: Typhlopidae) in Micronesia: two new species of Ramphotyphlops from the Caroline Islands

    Treesearch

    Addison H. Wynn; Robert P. Reynolds; Donald W. Buden; Marjorie Falanruw; Brian. Lunch

    2012-01-01

    Two new blind snakes in the genus Ramphotyphlops are described from Ulithi (R. hatmaliyeb sp. nov.) and Ant Atoll (R.adocetus sp. nov.) in the Caroline Islands, the first blind snake species known from Micronesia east of Palau (excludingRamphotyphlops braminus). Both species are unusual in...

  14. Molecular Basis of the Binding of YAP Transcriptional Regulator to the ErbB4 Receptor Tyrosine Kinase

    PubMed Central

    Schuchardt, Brett J.; Bhat, Vikas; Mikles, David C.; McDonald, Caleb B.; Sudol, Marius; Farooq, Amjad

    2014-01-01

    The newly discovered transactivation function of ErbB4 receptor tyrosine kinase is believed to be mediated by virtue of the ability of its proteolytically-cleaved intracellular domain (ICD) to physically associate with YAP2 transcriptional regulator. In an effort to unearth the molecular basis of YAP2-ErbB4 interaction, we have conducted a detailed biophysical analysis of the binding of WW domains of YAP2 to PPXY motifs located within the ICD of ErbB4. Our data show that the WW1 domain of YAP2 binds to PPXY motifs within the ICD in a differential manner and that this behavior is by and large replicated by the WW2 domain. Remarkably, while both WW domains absolutely require the integrity of the PPXY consensus sequence, non-consensus residues within and flanking this motif do not appear to be critical for binding. In spite of this shared mode of binding, the WW domains of YAP2 display distinct conformational dynamics in complex with PPXY motifs derived from ErbB4. Collectively, our study lends new insights into the molecular basis of a key protein-protein interaction involved in a diverse array of cellular processes. PMID:24472438

  15. Ligand binding to WW tandem domains of YAP2 transcriptional regulator is under negative cooperativity.

    PubMed

    Schuchardt, Brett J; Mikles, David C; Hoang, Lawrence M; Bhat, Vikas; McDonald, Caleb B; Sudol, Marius; Farooq, Amjad

    2014-12-01

    YES-associated protein 2 (YAP2) transcriptional regulator drives a multitude of cellular processes, including the newly discovered Hippo tumor suppressor pathway, by virtue of the ability of its WW domains to bind and recruit PPXY-containing ligands to specific subcellular compartments. Herein, we employ an array of biophysical tools to investigate allosteric communication between the WW tandem domains of YAP2. Our data show that the WW tandem domains of YAP2 negatively cooperate when binding to their cognate ligands. Moreover, the molecular origin of such negative cooperativity lies in an unfavorable entropic contribution to the overall free energy relative to ligand binding to isolated WW domains. Consistent with this notion, the WW tandem domains adopt a fixed spatial orientation such that the WW1 domain curves outwards and stacks onto the binding groove of the WW2 domain, thereby sterically hindering ligand binding to both itself and its tandem partner. Although ligand binding to both WW domains disrupts such interdomain stacking interaction, they reorient themselves and adopt an alternative fixed spatial orientation in the liganded state by virtue of their ability to engage laterally so as to allow their binding grooves to point outwards and away from each other. In short, while the ability of WW tandem domains to aid ligand binding is well documented, our demonstration that they may also be subject to negative binding cooperativity represents a paradigm shift in our understanding of the molecular action of this ubiquitous family of protein modules. © 2014 FEBS.

  16. Self-mode-locking operation of a diode-end-pumped Tm:YAP laser with watt-level output power

    NASA Astrophysics Data System (ADS)

    Zhang, Su; Zhang, Xinlu; Huang, Jinjer; Wang, Tianhan; Dai, Junfeng; Dong, Guangzong

    2018-03-01

    We report on a high power continuous wave (CW) self-mode-locked Tm:YAP laser pumped by a 792 nm laser diode. Without any additional mode-locking elements in the cavity, stable and self-starting mode-locking operation has been realized. The threshold pump power of the CW self-mode-locked Tm:YAP laser is only 5.4 W. The maximum average output power is as high as 1.65 W at the pump power of 12 W, with the repetition frequency of 468 MHz and the center wavelength of 1943 nm. To the best of our knowledge, this is the first CW self-mode-locked Tm:YAP laser. The experiment results show that the Tm:YAP crystal is a promising gain medium for realizing the high power self-mode-locking operation at 2 µm.

  17. YAP(Ce) crystal characterization with proton beam up to 60 MeV

    NASA Astrophysics Data System (ADS)

    Randazzo, N.; Sipala, V.; Aiello, S.; Lo Presti, D.; Cirrone, G. A. P.; Cuttone, G.; Di Rosa, F.

    2008-02-01

    A YAP(Ce) crystal was characterized with a proton beam up to 60 MeV. Tests were performed to investigate the possibility of using this detector as a proton calorimeter. The size of the crystal was chosen so that the proton energy is totally lost inside the medium. The authors propose to use the YAP(Ce) crystal in medical applications for proton therapy. In particular, in proton computed tomography (pCT) project it is necessary as a calorimeter in order to measure the proton residual energy after the phantom. Energy resolution, linearity, and light yield were measured in the Laboratori Nazionali del Sud with the CATANA proton beam [ http://www.lns.infn.it/CATANA/CATANA] and the results are shown in this paper. The crystal shows a good resolution (3% at 60 MeV proton beam) and it shows good linearity for different proton beam energies (1% at 30-60 MeV energy range). The crystal performances confirm that the YAP(Ce) crystal represents a good solution for these kinds of application.

  18. Cr:ZnSe laser pumped with Tm:YAP microchip laser

    NASA Astrophysics Data System (ADS)

    Koranda, Petr; Sulc, Jan; Doroshenko, Maxim; Jelinková, Helena; Basiev, Tasoltan T.; Osiko, Vjatcheslav; Badikov, V. V.; Badikov, D.

    2010-02-01

    Cr:ZnSe laser coherently longitudinally pumped with Tm:YAP microchip laser was realised. The pumping laser consisted of Tm:YAP crystal (3x3 mm) with resonator mirrors deposited directly on its faces (on rear face the dielectric layer with high reflectance for 1998 nm wavelength and high transmittance for 790 nm pumping radiation wavelength; on output face the dielectric layer with reflectance 97% at 1998 nm wavelength). The maximal output power was 5.5 W and the generated radiation wavelength was 1998 nm. The main advantage of this pumping was stable and still output without relaxation spikes (non-spiking). The Tm:YAP laser radiation was collimated and focused by the set of two CaF2 lenses. The pumping beam spot diameter inside the Cr:ZnSe crystal was 300 μm. The Cr:ZnSe laser resonator consisted of flat rear mirror (HT at 1998 nm and HR at 2100 - 2900 nm) and curved output coupler (r = -150 mm, R = 95% at 2100 - 2700 nm). The maximal output energy of stable radiation was 4 mJ (pulse duration 10 ms, repetition rate 10 Hz). For wavelength tuning the Lyott filter (quartz plate under Brewster angle) was placed between the Cr:ZnSe crystal and output coupler. The generated radiation wavelength was continuously tunable from 2246 - 2650 nm.

  19. Biophysical studies and NMR structure of YAP2 WW domain - LATS1 PPxY motif complexes reveal the basis of their interaction.

    PubMed

    Verma, Apoorva; Jing-Song, Fan; Finch-Edmondson, Megan L; Velazquez-Campoy, Adrian; Balasegaran, Shanker; Sudol, Marius; Sivaraman, Jayaraman

    2018-01-30

    YES-associated protein (YAP) is a major effector protein of the Hippo tumor suppressor pathway, and is phosphorylated by the serine/threonine kinase LATS. Their binding is mediated by the interaction between WW domains of YAP and PPxY motifs of LATS. Their isoforms, YAP2 and LATS1 contain two WW domains and two PPxY motifs respectively. Here, we report the study of the interaction of these domains both in vitro and in human cell lines, to better understand the mechanism of their binding. We show that there is a reciprocal binding preference of YAP2-WW1 with LATS1-PPxY2, and YAP2-WW2 with LATS1-PPxY1. We solved the NMR structures of these complexes and identified several conserved residues that play a critical role in binding. We further created a YAP2 mutant by swapping the WW domains, and found that YAP2 phosphorylation at S127 by LATS1 is not affected by the spatial configuration of its WW domains. This is likely because the region between the PPxY motifs of LATS1 is unstructured, even upon binding with its partner. Based on our observations, we propose possible models for the interaction between YAP2 and LATS1.

  20. Biophysical studies and NMR structure of YAP2 WW domain - LATS1 PPxY motif complexes reveal the basis of their interaction

    PubMed Central

    Verma, Apoorva; Jing-Song, Fan; Finch-Edmondson, Megan L.; Velazquez-Campoy, Adrian; Balasegaran, Shanker; Sudol, Marius; Sivaraman, Jayaraman

    2018-01-01

    YES-associated protein (YAP) is a major effector protein of the Hippo tumor suppressor pathway, and is phosphorylated by the serine/threonine kinase LATS. Their binding is mediated by the interaction between WW domains of YAP and PPxY motifs of LATS. Their isoforms, YAP2 and LATS1 contain two WW domains and two PPxY motifs respectively. Here, we report the study of the interaction of these domains both in vitro and in human cell lines, to better understand the mechanism of their binding. We show that there is a reciprocal binding preference of YAP2-WW1 with LATS1-PPxY2, and YAP2-WW2 with LATS1-PPxY1. We solved the NMR structures of these complexes and identified several conserved residues that play a critical role in binding. We further created a YAP2 mutant by swapping the WW domains, and found that YAP2 phosphorylation at S127 by LATS1 is not affected by the spatial configuration of its WW domains. This is likely because the region between the PPxY motifs of LATS1 is unstructured, even upon binding with its partner. Based on our observations, we propose possible models for the interaction between YAP2 and LATS1. PMID:29487715

  1. The Freely Associated States and the United States 2004-2005: Holding Firm

    DTIC Science & Technology

    Marshall Islands (RMI), and the Republic of Palau have all too often had their contribution to the U.S. global security architecture minimized...Association establishes the U.S. obligation to defend the Marshall Islands and the Federated States of Micronesia and their peoples from attack or

  2. The Micronesia Challenge: Assessing the Relative Contribution of Stressors on Coral Reefs to Facilitate Science-to-Management Feedback.

    PubMed

    Houk, Peter; Camacho, Rodney; Johnson, Steven; McLean, Matthew; Maxin, Selino; Anson, Jorg; Joseph, Eugene; Nedlic, Osamu; Luckymis, Marston; Adams, Katrina; Hess, Don; Kabua, Emma; Yalon, Anthony; Buthung, Eva; Graham, Curtis; Leberer, Trina; Taylor, Brett; van Woesik, Robert

    2015-01-01

    Fishing and pollution are chronic stressors that can prolong recovery of coral reefs and contribute to ecosystem decline. While this premise is generally accepted, management interventions are complicated because the contributions from individual stressors are difficult to distinguish. The present study examined the extent to which fishing pressure and pollution predicted progress towards the Micronesia Challenge, an international conservation strategy initiated by the political leaders of 6 nations to conserve at least 30% of marine resources by 2020. The analyses were rooted in a defined measure of coral-reef-ecosystem condition, comprised of biological metrics that described functional processes on coral reefs. We report that only 42% of the major reef habitats exceeded the ecosystem-condition threshold established by the Micronesia Challenge. Fishing pressure acting alone on outer reefs, or in combination with pollution in some lagoons, best predicted both the decline and variance in ecosystem condition. High variances among ecosystem-condition scores reflected the large gaps between the best and worst reefs, and suggested that the current scores were unlikely to remain stable through time because of low redundancy. Accounting for the presence of marine protected area (MPA) networks in statistical models did little to improve the models' predictive capabilities, suggesting limited efficacy of MPAs when grouped together across the region. Yet, localized benefits of MPAs existed and are expected to increase over time. Sensitivity analyses suggested that (i) grazing by large herbivores, (ii) high functional diversity of herbivores, and (iii) high predator biomass were most sensitive to fishing pressure, and were required for high ecosystem-condition scores. Linking comprehensive fisheries management policies with these sensitive metrics, and targeting the management of pollution, will strengthen the Micronesia Challenge and preserve ecosystem services that coral

  3. The Micronesia Challenge: Assessing the Relative Contribution of Stressors on Coral Reefs to Facilitate Science-to-Management Feedback

    PubMed Central

    Houk, Peter; Camacho, Rodney; Johnson, Steven; McLean, Matthew; Maxin, Selino; Anson, Jorg; Joseph, Eugene; Nedlic, Osamu; Luckymis, Marston; Adams, Katrina; Hess, Don; Kabua, Emma; Yalon, Anthony; Buthung, Eva; Graham, Curtis; Leberer, Trina; Taylor, Brett; van Woesik, Robert

    2015-01-01

    Fishing and pollution are chronic stressors that can prolong recovery of coral reefs and contribute to ecosystem decline. While this premise is generally accepted, management interventions are complicated because the contributions from individual stressors are difficult to distinguish. The present study examined the extent to which fishing pressure and pollution predicted progress towards the Micronesia Challenge, an international conservation strategy initiated by the political leaders of 6 nations to conserve at least 30% of marine resources by 2020. The analyses were rooted in a defined measure of coral-reef-ecosystem condition, comprised of biological metrics that described functional processes on coral reefs. We report that only 42% of the major reef habitats exceeded the ecosystem-condition threshold established by the Micronesia Challenge. Fishing pressure acting alone on outer reefs, or in combination with pollution in some lagoons, best predicted both the decline and variance in ecosystem condition. High variances among ecosystem-condition scores reflected the large gaps between the best and worst reefs, and suggested that the current scores were unlikely to remain stable through time because of low redundancy. Accounting for the presence of marine protected area (MPA) networks in statistical models did little to improve the models’ predictive capabilities, suggesting limited efficacy of MPAs when grouped together across the region. Yet, localized benefits of MPAs existed and are expected to increase over time. Sensitivity analyses suggested that (i) grazing by large herbivores, (ii) high functional diversity of herbivores, and (iii) high predator biomass were most sensitive to fishing pressure, and were required for high ecosystem-condition scores. Linking comprehensive fisheries management policies with these sensitive metrics, and targeting the management of pollution, will strengthen the Micronesia Challenge and preserve ecosystem services that coral

  4. Radon gamma-ray spectrometry with YAP:Ce scintillator

    NASA Astrophysics Data System (ADS)

    Plastino, Wolfango; De Felice, Pierino; de Notaristefani, Francesco

    2002-06-01

    The detection properties of a YAP:Ce scintillator (YAlO 3:Ce crystal) optically coupled to a Hamamatsu H5784 photomultiplier with standard bialkali photocathode have been analyzed. In particular, the application to radon and radon-daughters gamma-ray spectrometry was investigated. The crystal response has been studied under severe extreme conditions to simulate environments of geophysical interest, particularly those found in geothermal and volcanic areas. Tests in water up to a temperature of 100°C and in acids solutions such as HCl (37%), H 2SO 4 (48%) and HNO 3 (65%) have been performed. The measurements with standard radon sources provided by the National Institute for Metrology of Ionizing Radiations (ENEA) have emphasized the non-hygroscopic properties of the scintillator and a small dependence of the light yield on temperature and HNO 3. The data collected in this first step of our research have pointed out that the YAP:Ce scintillator can allow high response stability for radon gamma-ray spectrometry in environments with large temperature gradients and high acid concentrations.

  5. Areca (betel) nut chewing habit among high-school children in the Commonwealth of the Northern Mariana Islands (Micronesia).

    PubMed Central

    Oakley, Eric; Demaine, L.; Warnakulasuriya, Saman

    2005-01-01

    OBJECTIVE: To investigate the prevalence of its use by high-school children in Saipan in Micronesia. Usage of the areca nut is indigenous to south Asia and the western and south Pacific. Some serious health effects of areca nut chewing are recognized and the International Agency for Research on Cancer has recently classified regular use of areca nut as being carcinogenic to humans. Information on usage by young people, however, is scarce. METHODS: Data on consumption of areca nut were obtained by a self-administered questionnaire. Following an oral mucosal examination using WHO criteria any detectable oral mucosal diseases were recorded. FINDINGS: Of 309 schoolchildren surveyed (mean age 16.3 +/- 1.5 years), 63.4% claimed regular use, the highest level recorded in any school population survey. Significant oral diseases detected were oral leukoplakia in 13% and oral submucous fibrosis in 8.8% of children. CONCLUSION: These findings from Saipan suggest that areca nut chewing starts at a young age in Micronesia. As many users develop dependency this raises important concerns regarding its consequences for oral health. PMID:16211156

  6. Areca (betel) nut chewing habit among high-school children in the Commonwealth of the Northern Mariana Islands (Micronesia).

    PubMed

    Oakley, Eric; Demaine, L; Warnakulasuriya, Saman

    2005-09-01

    To investigate the prevalence of its use by high-school children in Saipan in Micronesia. Usage of the areca nut is indigenous to south Asia and the western and south Pacific. Some serious health effects of areca nut chewing are recognized and the International Agency for Research on Cancer has recently classified regular use of areca nut as being carcinogenic to humans. Information on usage by young people, however, is scarce. Data on consumption of areca nut were obtained by a self-administered questionnaire. Following an oral mucosal examination using WHO criteria any detectable oral mucosal diseases were recorded. Of 309 schoolchildren surveyed (mean age 16.3 +/- 1.5 years), 63.4% claimed regular use, the highest level recorded in any school population survey. Significant oral diseases detected were oral leukoplakia in 13% and oral submucous fibrosis in 8.8% of children. These findings from Saipan suggest that areca nut chewing starts at a young age in Micronesia. As many users develop dependency this raises important concerns regarding its consequences for oral health.

  7. Yap-Hippo pathway regulates cerebral hypoxia-reoxygenation injury in neuroblastoma N2a cells via inhibiting ROCK1/F-actin/mitochondrial fission pathways.

    PubMed

    Geng, Chizi; Wei, Jianchao; Wu, Chengsi

    2018-05-23

    Yes-associated protein (Yap), a regulator of cellular apoptosis, has been demonstrated to be involved in cerebral ischemia-reperfusion (IR) injury through poorly defined mechanisms. The present study aimed to explore the role of Yap in regulating cerebral IR injury in vitro, with a focus on mitochondrial fission and ROCK1/F-actin pathways. Our data demonstrated that Yap was actually downregulated in N2a cells after cerebral hypoxia-reoxygenation (HR) injury, and that lower expression of Yap was closely associated with increased cell death. However, the reintroduction of Yap was able to suppress the HR-mediated N2a cells death via blocking the mitochondria-related apoptotic signal. At the molecular levels, Yap overexpression sustained mitochondrial potential, normalized the mitochondrial respiratory function, reduced ROS overproduction, limited HtrA2/Omi release from mitochondria into the nucleus, and suppressed pro-apoptotic proteins activation. Subsequently, functional studies have further illustrated that HR-mediated mitochondrial apoptosis was highly regulated by mitochondrial fission, whereas Yap overexpression was able to attenuate HR-mediated mitochondrial fission and, thus, promote N2a cell survival in the context of HR injury. At last, we demonstrated that Yap handled mitochondrial fission via closing ROCK1/F-actin signaling pathways. Activation of ROCK1/F-actin pathways abrogated the protective role of Yap overexpression on mitochondrial homeostasis and N2a cell survival in the setting of HR injury. Altogether, our data identified Yap as the endogenous defender to relieve HR-mediated nerve damage via antagonizing ROCK1/F-actin/mitochondrial fission pathways.

  8. Molecular basis of the binding of YAP transcriptional regulator to the ErbB4 receptor tyrosine kinase.

    PubMed

    Schuchardt, Brett J; Bhat, Vikas; Mikles, David C; McDonald, Caleb B; Sudol, Marius; Farooq, Amjad

    2014-06-01

    The newly discovered transactivation function of ErbB4 receptor tyrosine kinase is believed to be mediated by virtue of the ability of its proteolytically-cleaved intracellular domain (ICD) to physically associate with YAP2 transcriptional regulator. In an effort to unearth the molecular basis of YAP2-ErbB4 interaction, we have conducted a detailed biophysical analysis of the binding of WW domains of YAP2 to PPXY motifs located within the ICD of ErbB4. Our data show that the WW1 domain of YAP2 binds to PPXY motifs within the ICD in a differential manner and that this behavior is by and large replicated by the WW2 domain. Remarkably, while both WW domains absolutely require the integrity of the PPXY consensus sequence, non-consensus residues within and flanking this motif do not appear to be critical for binding. In spite of this shared mode of binding, the WW domains of YAP2 display distinct conformational dynamics in complex with PPXY motifs derived from ErbB4. Collectively, our study lends new insights into the molecular basis of a key protein-protein interaction involved in a diverse array of cellular processes. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  9. The Completion of Non-Steady-State Queue Model on The Queue System in Dr. Yap Eye Hospital Yogyakarta

    NASA Astrophysics Data System (ADS)

    Helmi Manggala Putri, Arum; Subekti, Retno; Binatari, Nikenasih

    2017-06-01

    Dr Yap Eye Hospital Yogyakarta is one of the most popular reference eye hospitals in Yogyakarta. There are so many patients coming from other cities and many of them are BPJS (Badan Penyelenggara Jaminan Sosial, Social Security Administrative Bodies) patients. Therefore, it causes numerous BPJS patients were in long queue at counter C of the registration section so that it needs to be analysed using queue system. Queue system analysis aims to give queue model overview and determine its effectiveness measure. The data collecting technique used in this research are by interview and observation. After getting the arrival data and the service data of BPJS patients per 5 minutes, the next steps are investigating steady-state condition, examining the Poisson distribution, determining queue models, and counting the effectiveness measure. Based on the result of data observation on Tuesday, February 16th, 2016, it shows that the queue system at counter C has (M/M/1):(GD/∞/∞) queue model. The analysis result in counter C shows that the queue system is a non-steady-state condition. Three ways to cope a non-steady-state problem on queue system are proposed in this research such as bounding the capacity of queue system, adding the servers, and doing Monte Carlo simulation. The queue system in counter C will reach steady-state if the capacity of patients is not more than 52 BPJS patients or adding one more server. By using Monte Carlo simulation, it shows that the effectiveness measure of the average waiting time for BPJS patients in counter C is 36 minutes 65 seconds. In addition, the average queue length of BPJS patients is 11 patients.

  10. Near-IR, blue, and UV generation by frequency conversion of a Tm:YAP laser

    NASA Astrophysics Data System (ADS)

    Cole, Brian; Goldberg, Lew; Chinn, Steve

    2018-02-01

    We describe generation of near-infrared (944nm, 970nm), blue (472nm, 485nm), and UV (236 nm) light by frequency up-conversion of 2 μm output of a compact and efficient passively Q-switched Tm:YAP laser. The Tm:YAP laser source was near diffraction limited with maximum Q-switched pulse peak power of 190 kW. For second harmonic generation (SHG) of NIR, both periodically poled lithium niobate (PPLN) and lithium tri-borate (LBO) were evaluated, with 58% conversion efficiency and 3.1 W of 970 nm power achieved with PPLN. The PPLN 970nm emission was frequency doubled in 20mm long type I LBO, generating 1.1 W at 485nm with a conversion efficiency of 34%. With LBO used for frequency doubling of 2.3 W of 1888 nm Tm:YAP output to 944nm, 860mW was generated, with 37% conversion efficiency. Using a second LBO crystal to generate the 4th harmonic, 545mW of 472nm power was generated, corresponding to 64% conversion efficiency. To generate the 8th harmonic of Tm:YAP laser emission, the 472nm output of the second LBO was frequency doubled in a 7mm long BBO crystal, generating 110 mW at 236nm, corresponding to 21% conversion efficiency.

  11. Yap is essential for retinal progenitor cell cycle progression and RPE cell fate acquisition in the developing mouse eye.

    PubMed

    Kim, Jin Young; Park, Raehee; Lee, Jin Hwan J; Shin, Jinyeon; Nickas, Jenna; Kim, Seonhee; Cho, Seo-Hee

    2016-11-15

    Yap functions as a transcriptional regulator by acting together with sequence-specific DNA binding factors and transcription cofactors to mediate cell proliferation in developing epithelial tissues and tumors. An upstream kinase cascade controls nuclear localization and function in response to partially identified exogenous signals, including cell-to-cell contact. Nevertheless, its role in CNS development is poorly understood. In order to investigate Yap function in developing CNS, we characterized the cellular outcomes after selective Yap gene ablation in developing ocular tissues. When Yap was lost, presumptive retinal pigment epithelium acquired anatomical and molecular characteristics resembling those of the retinal epithelium rather than of RPE, including loss of pigmentation, pseudostratified epithelial morphology and ectopic induction of markers for retinal progenitor cells, like Chx10, and neurons, like β-Tubulin III. In addition, developing retina showed signs of progressive degeneration, including laminar folding, thinning and cell loss, which resulted from multiple defects in cell proliferation and survival, and in junction integrity. Furthermore, Yap-deficient retinal progenitors displayed decreased S-phase cells and altered cell cycle progression. Altogether, our studies not only illustrate the canonical function of Yap in promoting the proliferation of progenitors, but also shed new light on its evolutionarily conserved, instructive role in regional specification, maintenance of junctional integrity and precise regulation of cell proliferation during neuroepithelial development. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. The receptor tyrosine kinase EphA2 promotes glutamine metabolism in tumors by activating the transcriptional coactivators YAP and TAZ.

    PubMed

    Edwards, Deanna N; Ngwa, Verra M; Wang, Shan; Shiuan, Eileen; Brantley-Sieders, Dana M; Kim, Laura C; Reynolds, Albert B; Chen, Jin

    2017-12-05

    Malignant tumors reprogram cellular metabolism to support cancer cell proliferation and survival. Although most cancers depend on a high rate of aerobic glycolysis, many cancer cells also display addiction to glutamine. Glutamine transporters and glutaminase activity are critical for glutamine metabolism in tumor cells. We found that the receptor tyrosine kinase EphA2 activated the TEAD family transcriptional coactivators YAP and TAZ (YAP/TAZ), likely in a ligand-independent manner, to promote glutamine metabolism in cells and mouse models of HER2-positive breast cancer. Overexpression of EphA2 induced the nuclear accumulation of YAP and TAZ and increased the expression of YAP/TAZ target genes. Inhibition of the GTPase Rho or the kinase ROCK abolished EphA2-dependent YAP/TAZ nuclear localization. Silencing YAP or TAZ substantially reduced the amount of intracellular glutamate through decreased expression of SLC1A5 and GLS , respectively, genes that encode proteins that promote glutamine uptake and metabolism. The regulatory DNA elements of both SLC1A5 and GLS contain TEAD binding sites and were bound by TEAD4 in an EphA2-dependent manner. In patient breast cancer tissues, EphA2 expression positively correlated with that of YAP and TAZ , as well as that of GLS and SLC1A5 Although high expression of EphA2 predicted enhanced metastatic potential and poor patient survival, it also rendered HER2-positive breast cancer cells more sensitive to glutaminase inhibition. The findings define a previously unknown mechanism of EphA2-mediated glutaminolysis through YAP/TAZ activation in HER2-positive breast cancer and identify potential therapeutic targets in patients. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

  13. The Characteristic of S100A7 Induction by the Hippo-YAP Pathway in Cervical and Glossopharyngeal Squamous Cell Carcinoma.

    PubMed

    Kong, Fei; Li, Yunguang; Hu, Enze; Wang, Rui; Wang, Junhao; Liu, Jin; Zhang, Jinsan; He, Dacheng; Xiao, Xueyuan

    2016-01-01

    S100A7 is expressed in many squamous cell carcinomas (SCCs). Our previous study revealed that S100A7 was dramatically induced in several SCC cells and activation of the Hippo pathway significantly promoted S100A7 in epidermoid carcinoma cells. However, whether the Hippo pathway regulates S100A7 expression in SCCs remains largely unknown. Here, we uncover that S100A7 induction by the Hippo-YAP pathway displays different characteristic in cervical and glossopharyngeal SCC. In well differentiated HCC94 cervical cells and FaDu pharyngeal cells, S100A7 is easily induced by both suspension and dense culture, which is accompanied by an increase in YAP phosphorylation and a decrease in nuclear YAP. Strikingly, these correlations of S100A7 and YAP reverse after recovery of cell attachment or relief from dense culture. Further examination finds that S100A7 induction is significantly repressed by nuclear YAP, which is validated by activation or inhibition of the Hippo pathway via loss- and/or gain-of- LATS1 and MST1 function. Subsequently, we prove that TEAD1 is required for YAP transcriptional repression of S100A7. However, S100A7 is hardly induced in poorly differentiated SiHa cervical cells and NCI-H226 pulmonary cells even in suspension or activation of the Hippo pathway. More importantly, cervical and lingual SCC tissues array analyses show that S100A7 expression displays the positive correlation with pYAP-S127 and the negative correlation with nuclear YAP in the majority of well differentiated but not in poorly differentiated tissues. Collectively, our findings demonstrate that the different induction of S100A7 toward activation of the Hippo pathway mainly depends on the degree of cell differentiation in cervical and glossopharyngeal SCC.

  14. Temperature influence on spectroscopic properties and 2.7-μm lasing of Er:YAP crystal

    NASA Astrophysics Data System (ADS)

    Švejkar, Richard; Šulc, Jan; Němec, Michal; Jelínková, Helena; Nejezchleb, Karel; Čech, Miroslav

    2018-02-01

    The spectroscopic and laser properties of Er:YAP crystal, that is appropriate for generation at 2.7 μm, in temperature range 78 - 400 K are presented. The sample of Er:YAP (1 at. % of Er3+) had face-polished plan-parallel faces without anti-reflection coatings (thickness 4.47 mm). During experiments the Er:YAP was attached to temperature controlled copper holder and it was placed in vacuum chamber. The transmission and emission spectra together with the fluorescence decay time were measured depending on temperature. The Er:YAP crystal was longitudinally pumped by radiation from laser diode that works in pulse regime (repetition rate 66.6 Hz, pulse duration 1.5 ms, pump wavelength 972.5 nm) or in CW regime. Laser resonator was hemispherical, 145 mm in length with flat pumping mirror (HR @ 2.7 μm) and spherical output coupler (r = 150 mm, R = 95 % @ 2.5 - 2.8 μm). The fluorescence decay time of manifold 4I11/2 (upper laser level) became shorter and intensity of up-conversion radiation was increasing with decreasing temperature. In pulsed regime, the highest slope efficiency with respect to absorbed mean power was 1.27 % at 78 K. The maximum output of mean power was 3.5 mW at 78 K, i.e. 8.7 times higher than measured this value at 300 K. The maximal output power 27 mW with slope efficiency up to 3.5 % was achieved in CW. The radiation generated by Er:YAP laser (2.73 μm) is close to absorption peak of water (3 μm) thus this wavelength can be use in medicine and spectroscopy.

  15. Tumor-propagating cells and Yap/Taz activity contribute to lung tumor progression and metastasis

    PubMed Central

    Lau, Allison N; Curtis, Stephen J; Fillmore, Christine M; Rowbotham, Samuel P; Mohseni, Morvarid; Wagner, Darcy E; Beede, Alexander M; Montoro, Daniel T; Sinkevicius, Kerstin W; Walton, Zandra E; Barrios, Juliana; Weiss, Daniel J; Camargo, Fernando D; Wong, Kwok-Kin; Kim, Carla F

    2014-01-01

    Metastasis is the leading cause of morbidity for lung cancer patients. Here we demonstrate that murine tumor propagating cells (TPCs) with the markers Sca1 and CD24 are enriched for metastatic potential in orthotopic transplantation assays. CD24 knockdown decreased the metastatic potential of lung cancer cell lines resembling TPCs. In lung cancer patient data sets, metastatic spread and patient survival could be stratified with a murine lung TPC gene signature. The TPC signature was enriched for genes in the Hippo signaling pathway. Knockdown of the Hippo mediators Yap1 or Taz decreased in vitro cellular migration and transplantation of metastatic disease. Furthermore, constitutively active Yap was sufficient to drive lung tumor progression in vivo. These results demonstrate functional roles for two different pathways, CD24-dependent and Yap/Taz-dependent pathways, in lung tumor propagation and metastasis. This study demonstrates the utility of TPCs for identifying molecules contributing to metastatic lung cancer, potentially enabling the therapeutic targeting of this devastating disease. PMID:24497554

  16. Network-based expression analyses and experimental validations revealed high co-expression between Yap1 and stem cell markers compared to differentiated cells.

    PubMed

    Dehghanian, Fariba; Hojati, Zohreh; Esmaeili, Fariba; Masoudi-Nejad, Ali

    2018-05-21

    The Hippo signaling pathway is identified as a potential regulatory pathway which plays critical roles in differentiation and stem cell self-renewal. Yap1 is a primary transcriptional effector of this pathway. The importance of Yap1 in embryonic stem cells (ESCs) and differentiation procedure remains a challenging question, since two different observations have been reported. To answer this question we used co-expression network and differential co-expression analyses followed by experimental validations. Our results indicate that Yap1 is highly co-expressed with stem cell markers in ESCs but not in differentiated cells (DCs). The significant Yap1 down-regulation and also translocation of Yap1 into the cytoplasm during P19 differentiation was also detected. Moreover, our results suggest the E2f7, Lin28a and Dppa4 genes as possible regulatory nuclear factors of Hippo pathway in stem cells. The present findings are actively consistent with studies that suggested Yap1 as an essential factor for stem cell self-renewal. Copyright © 2018 Elsevier Inc. All rights reserved.

  17. The Basic Leucine Zipper Stress Response Regulator Yap5 Senses High-Iron Conditions by Coordination of [2Fe-2S] Clusters

    PubMed Central

    Rietzschel, Nicole; Pierik, Antonio J.; Bill, Eckhard; Mühlenhoff, Ulrich

    2014-01-01

    Iron is an essential, yet at elevated concentrations toxic trace element. To date, the mechanisms of iron sensing by eukaryotic iron-responsive transcription factors are poorly understood. The Saccharomyces cerevisiae transcription factor Yap5, a member of the Yap family of bZIP stress response regulators, administrates the adaptive response to high-iron conditions. Despite the central role of the iron-sensing process for cell viability, the molecule perceived by Yap5 and the underlying regulatory mechanisms are unknown. Here, we show that Yap5 senses high-iron conditions by two Fe/S clusters bound to its activator domain (Yap5-AD). The more stable iron-regulatory Fe/S cluster at the N-terminal cysteine-rich domain (n-CRD) of Yap5 is detected in vivo and in vitro. The second cluster coordinated by the C-terminal CRD can only be shown after chemical reconstitution, since it is bound in a labile fashion. Both clusters are of the [2Fe-2S] type as characterized by UV/visible (UV/Vis), circular dichroism, electron paramagnetic resonance (EPR), and Mössbauer spectroscopy. Fe/S cluster binding to Yap5-AD induces a conformational change that may activate transcription. The cluster-binding motif of the n-CRD domain is highly conserved in HapX-like transcription factors of pathogenic fungi and thus may represent a general sensor module common to many eukaryotic stress response regulators. PMID:25368382

  18. ω-3 PUFAs ameliorate liver fibrosis and inhibit hepatic stellate cells proliferation and activation by promoting YAP/TAZ degradation.

    PubMed

    Zhang, Kun; Chang, Yanan; Shi, Zhemin; Han, Xiaohui; Han, Yawei; Yao, Qingbin; Hu, Zhimei; Cui, Hongmei; Zheng, Lina; Han, Tao; Hong, Wei

    2016-07-20

    Elevated levels of the transcriptional regulators Yes-associated protein (YAP) and transcriptional coactivators with PDZ-binding motif (TAZ), key effectors of the Hippo pathway, have been shown to play essential roles in controlling liver cell fate and the activation of hepatic stellate cells (HSCs). The dietary intake of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) has been positively associated with a number of health benefits including prevention and reduction of cardiovascular diseases, inflammation and cancers. However, little is known about the impact of ω-3 PUFAs on liver fibrosis. In this study, we used CCl4-induced liver fibrosis mouse model and found that YAP/TAZ is over-expressed in the fibrotic liver and activated HSCs. Fish oil administration to the model mouse attenuates CCl4-induced liver fibrosis. Further study revealed that ω-3 PUFAs down-regulate the expression of pro-fibrogenic genes in activated HSCs and fibrotic liver, and the down-regulation is mediated via YAP, thus identifying YAP as a target of ω-3 PUFAs. Moreover, ω-3 PUFAs promote YAP/TAZ degradation in a proteasome-dependent manner. Our data have identified a mechanism of ω-3 PUFAs in ameliorating liver fibrosis.

  19. Augmentation of the therapeutic efficacy of WEE1 kinase inhibitor AZD1775 by inhibiting the YAP-E2F1-DNA damage response pathway axis.

    PubMed

    Oku, Yusuke; Nishiya, Naoyuki; Tazawa, Takaaki; Kobayashi, Takaya; Umezawa, Nanami; Sugawara, Yasuyo; Uehara, Yoshimasa

    2018-06-01

    The main reasons for failure of cancer chemotherapy are intrinsic and acquired drug resistance. The Hippo pathway effector Yes-associated protein (YAP) is associated with resistance to both cytotoxic and molecular targeted drugs. Several lines of evidence indicate that YAP activates transcriptional programmes to promote cell cycle progression and DNA damage responses. Therefore, we hypothesised that YAP is involved in the sensitivity of cancer cells to small-molecule agents targeting cell cycle-related proteins. Here, we report that the inactivation of YAP sensitises the OVCAR-8 ovarian cancer cell line to AZD1775, a small-molecule WEE1 kinase inhibitor. The accumulation of DNA damage and mitotic failures induced by AZD1775-based therapy were further enhanced by YAP depletion. YAP depletion reduced the expression of the Fanconi anaemia (FA) pathway components required for DNA repair and their transcriptional regulator E2F1. These results suggest that YAP activates the DNA damage response pathway, exemplified by the FA pathway and E2F1. Furthermore, we aimed to apply this finding to combination chemotherapy against ovarian cancers. The regimen containing dasatinib, which inhibits the nuclear localisation of YAP, improved the response to AZD1775-based therapy in the OVCAR-8 ovarian cancer cell line. We propose that dasatinib acts as a chemosensitiser for a subset of molecular targeted drugs, including AZD1775, by targeting YAP.

  20. Local Food Policies Can Help Promote Local Foods and Improve Health: A Case Study from the Federated States of Micronesia

    PubMed Central

    Lorens, Adelino; Pretrick, Moses; Tara, Mona J; Johnson, Emihner

    2011-01-01

    The Federated States of Micronesia (FSM) and other countries throughout the Pacific are facing an epidemic of non-communicable disease health problems. These are directly related to the increased consumption of unhealthy imported processed foods, the neglect of traditional food systems, and lifestyle changes, including decreased physical activity. The FSM faces the double burden of malnutrition with both non-communicable diseases and micronutrient deficiencies, including vitamin A deficiency and anemia. To help increase the use of traditional island foods and improve health, the Island Food Community of Pohnpei has initiated a program in the FSM to support and promote local food policies, along with its Go Local awareness campaign. Such local food policies are defined broadly and include individual and family commitments, community group local food policies and policies established by government, including presidential proclamations and increased taxation on soft drinks. The aim of this paper is to describe this work. An inter-agency, community- and research-based, participatory and media approach was used. Partners are both non-governmental and governmental. The use of continuing awareness work along with local food policy establishment and the acknowledgement of the individuals and groups involved are essential. The work is still in the preliminary stage but ad hoc examples show that this approach has had success in increased awareness on health issues and improving dietary intake on both an individual and group basis. This indicates that further use of local food policies could have an instrumental impact in FSM as well as other Pacific Island countries in promoting local foods and improving dietary intake and health, including the control of non-communicable diseases and other dietary-related health problems. PMID:22235156

  1. Local food policies can help promote local foods and improve health: a case study from the Federated States of Micronesia.

    PubMed

    Englberger, Lois; Lorens, Adelino; Pretrick, Moses; Tara, Mona J; Johnson, Emihner

    2011-11-01

    The Federated States of Micronesia (FSM) and other countries throughout the Pacific are facing an epidemic of non-communicable disease health problems. These are directly related to the increased consumption of unhealthy imported processed foods, the neglect of traditional food systems, and lifestyle changes, including decreased physical activity. The FSM faces the double burden of malnutrition with both non-communicable diseases and micronutrient deficiencies, including vitamin A deficiency and anemia. To help increase the use of traditional island foods and improve health, the Island Food Community of Pohnpei has initiated a program in the FSM to support and promote local food policies, along with its Go Local awareness campaign. Such local food policies are defined broadly and include individual and family commitments, community group local food policies and policies established by government, including presidential proclamations and increased taxation on soft drinks. The aim of this paper is to describe this work. An inter-agency, community- and research-based, participatory and media approach was used. Partners are both non-governmental and governmental. The use of continuing awareness work along with local food policy establishment and the acknowledgement of the individuals and groups involved are essential. The work is still in the preliminary stage but ad hoc examples show that this approach has had success in increased awareness on health issues and improving dietary intake on both an individual and group basis. This indicates that further use of local food policies could have an instrumental impact in FSM as well as other Pacific Island countries in promoting local foods and improving dietary intake and health, including the control of non-communicable diseases and other dietary-related health problems.

  2. Hippo-independent activation of YAP by the GNAQ uveal melanoma oncogene through a trio-regulated rho GTPase signaling circuitry.

    PubMed

    Feng, Xiaodong; Degese, Maria Sol; Iglesias-Bartolome, Ramiro; Vaque, Jose P; Molinolo, Alfredo A; Rodrigues, Murilo; Zaidi, M Raza; Ksander, Bruce R; Merlino, Glenn; Sodhi, Akrit; Chen, Qianming; Gutkind, J Silvio

    2014-06-16

    Mutually exclusive activating mutations in the GNAQ and GNA11 oncogenes, encoding heterotrimeric Gαq family members, have been identified in ∼ 83% and ∼ 6% of uveal and skin melanomas, respectively. However, the molecular events underlying these GNAQ-driven malignancies are not yet defined, thus limiting the ability to develop cancer-targeted therapies. Here, we focused on the transcriptional coactivator YAP, a critical component of the Hippo signaling pathway that controls organ size. We found that Gαq stimulates YAP through a Trio-Rho/Rac signaling circuitry promoting actin polymerization, independently of phospholipase Cβ and the canonical Hippo pathway. Furthermore, we show that Gαq promotes the YAP-dependent growth of uveal melanoma cells, thereby identifying YAP as a suitable therapeutic target in uveal melanoma, a GNAQ/GNA11-initiated human malignancy. Copyright © 2014 Elsevier Inc. All rights reserved.

  3. Prevalence of obesity and acanthosis nigricans among young children in the children's healthy living program in the United States Affiliated Pacific.

    PubMed

    Novotny, Rachel; Li, Fenfang; Fialkowski, Marie Kainoa; Bersamin, Andrea; Tufa, Aifili; Deenik, Jonathan; Coleman, Patricia; Guerrero, Rachael Leon; Wilkens, Lynne R

    2016-09-01

    Estimate prevalence of obesity and acanthosis nigricans (AN) among children in United States Affiliated Pacific (USAP) jurisdictions.Cross-sectional measurement of weight, height, and AN in 5775, 2 to 8 years old in 51 communities-Hawai'i, Alaska, Commonwealth of the Northern Mariana Islands, Guam, American Samoa, Palau, Republic of the Marshall Islands (RMI), 4 Federated States of Micronesia (Pohnpei, Yap, Kosrae, Chuuk). Analyses weighted to jurisdiction-specific sex and age distributions accounting for clustering of communities within jurisdictions.Prevalence of obesity was 14.0%, overweight 14.4%, healthy weight 68.9%, and underweight 2.6%, higher in males (16.3%) than females (11.6%), higher among 6 to 8 years old (16.3%) than 2 to 5 years old (12.9%), highest in American Samoa (21.7%), and absent in RMI. In total, 4.7% of children had AN, with no sex difference, higher in 6 to 8 years old (6.8%) than 2 to 5 years old (3.5%) and highest in Pohnpei (11.9%), and absent in Alaska. Obesity was highly associated with AN (odds ratio = 9.25, 95% confidence interval = 6.69-12.80), with the strongest relationships among Asians, followed by Native Hawaiians and Pacific Islanders (NHPI).Obesity, age, and Asian and NHPI race were positively associated with AN.

  4. Prevalence of obesity and acanthosis nigricans among young children in the children's healthy living program in the United States Affiliated Pacific

    PubMed Central

    Novotny, Rachel; Li, Fenfang; Fialkowski, Marie Kainoa; Bersamin, Andrea; Tufa, Aifili; Deenik, Jonathan; Coleman, Patricia; Guerrero, Rachael Leon; Wilkens, Lynne R.

    2016-01-01

    Abstract Estimate prevalence of obesity and acanthosis nigricans (AN) among children in United States Affiliated Pacific (USAP) jurisdictions. Cross-sectional measurement of weight, height, and AN in 5775, 2 to 8 years old in 51 communities—Hawai‘i, Alaska, Commonwealth of the Northern Mariana Islands, Guam, American Samoa, Palau, Republic of the Marshall Islands (RMI), 4 Federated States of Micronesia (Pohnpei, Yap, Kosrae, Chuuk). Analyses weighted to jurisdiction-specific sex and age distributions accounting for clustering of communities within jurisdictions. Prevalence of obesity was 14.0%, overweight 14.4%, healthy weight 68.9%, and underweight 2.6%, higher in males (16.3%) than females (11.6%), higher among 6 to 8 years old (16.3%) than 2 to 5 years old (12.9%), highest in American Samoa (21.7%), and absent in RMI. In total, 4.7% of children had AN, with no sex difference, higher in 6 to 8 years old (6.8%) than 2 to 5 years old (3.5%) and highest in Pohnpei (11.9%), and absent in Alaska. Obesity was highly associated with AN (odds ratio = 9.25, 95% confidence interval = 6.69–12.80), with the strongest relationships among Asians, followed by Native Hawaiians and Pacific Islanders (NHPI). Obesity, age, and Asian and NHPI race were positively associated with AN. PMID:27631218

  5. WW Domains of the Yes-Kinase-Associated-Protein (YAP) Transcriptional Regulator Behave as Independent Units with Different Binding Preferences for PPxY Motif-Containing Ligands

    PubMed Central

    Iglesias-Bexiga, Manuel; Castillo, Francisco; Cobos, Eva S.; Oka, Tsutomu; Sudol, Marius; Luque, Irene

    2015-01-01

    YAP is a WW domain-containing effector of the Hippo tumor suppressor pathway, and the object of heightened interest as a potent oncogene and stemness factor. YAP has two major isoforms that differ in the number of WW domains they harbor. Elucidating the degree of co-operation between these WW domains is important for a full understanding of the molecular function of YAP. We present here a detailed biophysical study of the structural stability and binding properties of the two YAP WW domains aimed at investigating the relationship between both domains in terms of structural stability and partner recognition. We have carried out a calorimetric study of the structural stability of the two YAP WW domains, both isolated and in a tandem configuration, and their interaction with a set of functionally relevant ligands derived from PTCH1 and LATS kinases. We find that the two YAP WW domains behave as independent units with different binding preferences, suggesting that the presence of the second WW domain might contribute to modulate target recognition between the two YAP isoforms. Analysis of structural models and phage-display studies indicate that electrostatic interactions play a critical role in binding specificity. Together, these results are relevant to understand of YAP function and open the door to the design of highly specific ligands of interest to delineate the functional role of each WW domain in YAP signaling. PMID:25607641

  6. Merlin controls the repair capacity of Schwann cells after injury by regulating Hippo/YAP activity

    PubMed Central

    Doddrell, Robin D.S.; Edwards, Philip; Morrison, Helen

    2017-01-01

    Loss of the Merlin tumor suppressor and activation of the Hippo signaling pathway play major roles in the control of cell proliferation and tumorigenesis. We have identified completely novel roles for Merlin and the Hippo pathway effector Yes-associated protein (YAP) in the control of Schwann cell (SC) plasticity and peripheral nerve repair after injury. Injury to the peripheral nervous system (PNS) causes a dramatic shift in SC molecular phenotype and the generation of repair-competent SCs, which direct functional repair. We find that loss of Merlin in these cells causes a catastrophic failure of axonal regeneration and remyelination in the PNS. This effect is mediated by activation of YAP expression in Merlin-null SCs, and loss of YAP restores axonal regrowth and functional repair. This work identifies new mechanisms that control the regenerative potential of SCs and gives new insight into understanding the correct control of functional nerve repair in the PNS. PMID:28137778

  7. β-Catenin destruction complex-independent regulation of Hippo–YAP signaling by APC in intestinal tumorigenesis

    PubMed Central

    Cai, Jing; Maitra, Anirban; Anders, Robert A.; Taketo, Makoto M.; Pan, Duojia

    2015-01-01

    Mutations in Adenomatous polyposis coli (APC) underlie familial adenomatous polyposis (FAP), an inherited cancer syndrome characterized by the widespread development of colorectal polyps. APC is best known as a scaffold protein in the β-catenin destruction complex, whose activity is antagonized by canonical Wnt signaling. Whether other effector pathways mediate APC's tumor suppressor function is less clear. Here we report that activation of YAP, the downstream effector of the Hippo signaling pathway, is a general hallmark of tubular adenomas from FAP patients. We show that APC functions as a scaffold protein that facilitates the Hippo kinase cascade by interacting with Sav1 and Lats1. Consistent with the molecular link between APC and the Hippo signaling pathway, genetic analysis reveals that YAP is absolutely required for the development of APC-deficient adenomas. These findings establish Hippo–YAP signaling as a critical effector pathway downstream from APC, independent from its involvement in the β-catenin destruction complex. PMID:26193883

  8. Next logical steps in forest pathology activities for Guam, Saipan, Yap, Palau, Pohnpei, and Kosrae [Chapter X

    Treesearch

    Phil G. Cannon; Francis Ruegorong; Puis Liegel; Victor Guerrero; Robert L. Schlub; Leonard Sigrah; Maxon Nithan; Blair Charley; Sara M. Ashiglar; Ned B. Klopfenstein; Mee-Sook Kim; Bob Gavenda; Katie Friday; Erick Waguk; Yuko Ota; Norio Sahashi; Gibson Santos; Rodasio Samuel

    2014-01-01

    As a result of the forest pathology trip that occurred during September of 2013, advances were made on several important fronts, and future activities were also identified as critical for addressing threats to forest health in Micronesia. The purpose of this chapter is to list and briefly describe each of these activities.

  9. Sheep YAP1 temporal and spatial expression trend and its relation with MyHCs expression.

    PubMed

    Gao, W; Sun, W; Su, R; Lv, X Y; Wang, Q Z; Li, D; Musa, H H; Chen, L; Zhou, H; Xu, H S; Hua, W H

    2016-04-04

    RT-PCR was used to study the temporal and spatial pattern of Yes-associated protein 1 (YAP1) and myosin heavy chain (MyHC) expression in four different skeletal muscles (i.e., longissimus dorsi muscle, soleus muscle, gastrocnemius muscle, and extensor digitorum longus) and three growth stages (i.e., 2 days old, 2 and 6 months old) of Hu Sheep. The results showed that YAP1 was differentially expressed in skeletal muscles of sheep, that expression increased gradually with age, and that there were high levels of expression in the gastrocnemius muscle and lower levels in the longissimus dorsi muscle. MyHCI was expressed at high levels in the soleus muscle and at lower levels in the longissimus dorsi muscle. In contrast, MyHCIIA and MyHCIIX were expressed at high levels in the extensor digitorum longus and at lower levels in the soleus muscle. The expression of MyHCI and MyHCIIA decreased with increasing age while that of MyHCIIX increased. YAP1 expression was negatively correlated with MyHCII (P < 0.01) and positively correlated with MyHCIIX (P < 0.01) across all growth stages and skeletal muscle types studied. We speculate that after birth, the thicker muscle fiber diameter is associated with the high expression of MyHCIIX. Therefore, we conclude that YAP1 expression affects sheep muscle fiber development after birth and provides important genetic information for the selection candidate genes for sheep muscle growth.

  10. Cdc42 deficiency induces podocyte apoptosis by inhibiting the Nwasp/stress fibers/YAP pathway

    PubMed Central

    Huang, Z; Zhang, L; Chen, Y; Zhang, H; Zhang, Q; Li, R; Ma, J; Li, Z; Yu, C; Lai, Y; Lin, T; Zhao, X; Zhang, B; Ye, Z; Liu, S; Wang, W; Liang, X; Liao, R; Shi, W

    2016-01-01

    Podocyte apoptosis is a major mechanism that leads to proteinuria in many chronic kidney diseases. However, the concert mechanisms that cause podocyte apoptosis in these kidney diseases are not fully understood. The Rho family of small GTPases has been shown to be required in maintaining podocyte structure and function. Recent studies have indicated that podocyte-specific deletion of Cdc42 in vivo, but not of RhoA or Rac1, leads to congenital nephrotic syndrome and glomerulosclerosis. However, the underlying cellular events in podocyte controlled by Cdc42 remain unclear. Here, we assessed the cellular mechanisms by which Cdc42 regulates podocyte apoptosis. We found that the expression of Cdc42 and its activity were significantly decreased in high glucose-, lipopolysaccharide- or adriamycin-injured podocytes. Reduced Cdc42 expression in vitro and in vivo by small interfering RNA and selective Cdc42 inhibitor ML-141, respectively, caused podocyte apoptosis and proteinuria. Our results further demonstrated that insufficient Cdc42 or Nwasp, its downstream effector, could decrease the mRNA and protein expression of YAP, which had been regarded as an anti-apoptosis protein in podocyte. Moreover, our data indicated that the loss of stress fibers caused by Cdc42/Nwasp deficiency also decreased Yes-associated protein (YAP) mRNA and protein expression, and induced podocyte apoptosis. Podocyte apoptosis induced by Cdc42/Nwasp/stress fiber deficiency was significantly inhibited by overexpressing-active YAP. Thus, the Cdc42/Nwasp/stress fibers/YAP signal pathway may potentially play an important role in regulating podocyte apoptosis. Maintaining necessary Cdc42 would be one potent way to prevent proteinuria kidney diseases. PMID:26986510

  11. A Role for Iron-Sulfur Clusters in the Regulation of Transcription Factor Yap5-dependent High Iron Transcriptional Responses in Yeast*

    PubMed Central

    Li, Liangtao; Miao, Ren; Bertram, Sophie; Jia, Xuan; Ward, Diane M.; Kaplan, Jerry

    2012-01-01

    Yeast respond to increased cytosolic iron by activating the transcription factor Yap5 increasing transcription of CCC1, which encodes a vacuolar iron importer. Using a genetic screen to identify genes involved in Yap5 iron sensing, we discovered that a mutation in SSQ1, which encodes a mitochondrial chaperone involved in iron-sulfur cluster synthesis, prevented expression of Yap5 target genes. We demonstrated that mutation or reduced expression of other genes involved in mitochondrial iron-sulfur cluster synthesis (YFH1, ISU1) prevented induction of the Yap5 response. We took advantage of the iron-dependent catalytic activity of Pseudaminobacter salicylatoxidans gentisate 1,2-dioxygenase expressed in yeast to measure changes in cytosolic iron. We determined that reductions in iron-sulfur cluster synthesis did not affect the activity of cytosolic gentisate 1,2-dioxygenase. We show that loss of activity of the cytosolic iron-sulfur cluster assembly complex proteins or deletion of cytosolic glutaredoxins did not reduce expression of Yap5 target genes. These results suggest that the high iron transcriptional response, as well as the low iron transcriptional response, senses iron-sulfur clusters. PMID:22915593

  12. Biphasic Regulation of Yes-associated Protein (YAP) Cellular Localization, Phosphorylation, and Activity by G Protein-coupled Receptor Agonists in Intestinal Epithelial Cells: A NOVEL ROLE FOR PROTEIN KINASE D (PKD).

    PubMed

    Wang, Jia; Sinnett-Smith, James; Stevens, Jan V; Young, Steven H; Rozengurt, Enrique

    2016-08-19

    We examined the regulation of Yes-associated protein (YAP) localization, phosphorylation, and transcriptional activity in intestinal epithelial cells. Our results show that stimulation of intestinal epithelial IEC-18 cells with the G protein-coupled receptor (GPCR) agonist angiotensin II, a potent mitogen for these cells, induced rapid translocation of YAP from the nucleus to the cytoplasm (within 15 min) and a concomitant increase in YAP phosphorylation at Ser(127) and Ser(397) Angiotensin II elicited YAP phosphorylation and cytoplasmic accumulation in a dose-dependent manner (ED50 = 0.3 nm). Similar YAP responses were provoked by stimulation with vasopressin or serum. Treatment of the cells with the protein kinase D (PKD) family inhibitors CRT0066101 and kb NB 142-70 prevented the increase in YAP phosphorylation on Ser(127) and Ser(397) via Lats2, YAP cytoplasmic accumulation, and increase in the mRNA levels of YAP/TEAD-regulated genes (Ctgf and Areg). Furthermore, siRNA-mediated knockdown of PKD1, PKD2, and PKD3 markedly attenuated YAP nuclear-cytoplasmic shuttling, phosphorylation at Ser(127), and induction of Ctgf and Areg expression in response to GPCR activation. These results identify a novel role for the PKD family in the control of biphasic localization, phosphorylation, and transcriptional activity of YAP in intestinal epithelial cells. In turn, YAP and TAZ are necessary for the stimulation of the proliferative response of intestinal epithelial cells to GPCR agonists that act via PKD. The discovery of interaction between YAP and PKD pathways identifies a novel cross-talk in signal transduction and demonstrates, for the first time, that the PKDs feed into the YAP pathway. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  13. Targeting Signaling to YAP for the Therapy of NF2

    DTIC Science & Technology

    2016-12-01

    at any step of our newly identified pathway, and to test the preclinical efficacy of lead compounds in xenograft models of NF2. During this grant...Pathway Component AMOTL2 by the mTORC2 Kinase Promotes YAP Signaling, Resulting in Enhanced Glioblastoma Growth and Invasiveness. The Journal of Biological Chemistry. 2015. 290(32):19387-401.

  14. Characterization and management of the commercial sector of the Pohnpei coral reef fishery, Micronesia

    NASA Astrophysics Data System (ADS)

    Rhodes, K. L.; Tupper, M. H.; Wichilmel, C. B.

    2008-06-01

    Commercial coral reef fisheries in Pohnpei (Micronesia) extract approximately 1,521 kg of reef fish daily (˜500 MT year-1) from 152 km2 of surrounding reef. More than 153 species were represented during surveys, with 25 species very common or common within combined-gear catch. Acanthurids contributed the greatest to catch volume, with bluespine unicornfish, Naso unicornis, and orangespine unicornfish, Naso lituratus, among the most frequently observed herbivores. Nighttime spearfishing was the dominant fishing method and inner lagoon areas were primarily targeted. A seasonal sales ban (March April), intended to reduce pressure on reproductively active serranids, significantly increased the capture volume of other families. Catch was significantly greater during periods of low lunar illumination, suggesting higher fishing success or greater effort, or both. The marketed catch was dominated by juveniles and small adults, based on fishes of known size at sexual maturity. Artificially depressed market prices appear to be catalyzing (potential or realized) overfishing by increasing the volume of fish needed to offset rising fuel prices. These results support the need for comprehensive fisheries management that produces sustainable fishing and marketing practices and promotes shared management and enforced responsibilities between communities and the state. To be effective, management should prohibit nighttime spearfishing.

  15. LD end pumped mode locked and cavity dumped Nd:YAP laser at 1.34 μm

    NASA Astrophysics Data System (ADS)

    Wang, X.; Wang, S.; Rhee, H.; Eichler, H. J.; Meister, S.

    2011-06-01

    We report a LD end pumped actively mode locked, passively Q switched and cavity dumped Nd:YAP laser at 1.34 μm. The dumped output pulse energy of 160 μJ is obtained at a repetition rate of 10 Hz. Passing through a LD end pumped, double-passed Nd:YAP amplifier the pulse energy is amplified to 1.44 mJ. The corresponding amplification factor is 9. Stimulated Raman scattering experiment is taken with a 9 mm long PbWO4 Raman crystal. Maximum of 20% Raman conversion is reached.

  16. Antitumor activity of curcumin is involved in down-regulation of YAP/TAZ expression in pancreatic cancer cells.

    PubMed

    Zhou, Xiuxia; Su, Jingna; Feng, Shaoyan; Wang, Lixia; Yin, Xuyuan; Yan, Jingzhe; Wang, Zhiwei

    2016-11-29

    Pancreatic cancer (PC) is one of the most aggressive human malignancies worldwide and is the fourth leading cause of cancer-related deaths. Curcumin (diferuloylmethane) is a polyphenol derived from the Curcuma longa plant. Certain studies have demonstrated that curcumin exerts its anti-tumor function in a variety of human cancers including PC, via targeting multiple therapeutically important cancer signaling pathways. However, the detailed molecular mechanisms are not fully understood. Two transcriptional co-activators, YAP (Yes-associated protein) and its close paralog TAZ (transcriptional coactivator with PDZ-binding motif) exert oncogenic activities in various cancers. Therefore, in this study we aimed to determine the molecular basis of curcumin-induced cell proliferation inhibition in PC cells. First, we detected the anti-tumor effects of curcumin on PC cell lines using CTG assay, Flow cytometry, clonogenic assay, wound healing assay and Transwell invasion assay. We found that curcumin significantly suppressed cell growth, weakened clonogenic potential, inhibited migration and invasion, and induced apoptosis and cell cycle arrest in PC cells. We further measured that overexpression of YAP enhanced cell proliferation and abrogated the cytotoxic effects of curcumin on PC cells. Moreover, we found that curcumin markedly down-regulated YAP and TAZ expression and subsequently suppressed Notch-1 expression. Collectively, these findings suggest that pharmacological inhibition of YAP and TAZ activity may be a promising anticancer strategy for the treatment of PC patients.

  17. Antitumor activity of curcumin is involved in down-regulation of YAP/TAZ expression in pancreatic cancer cells

    PubMed Central

    Wang, Lixia; Yin, Xuyuan; Yan, Jingzhe; Wang, Zhiwei

    2016-01-01

    Pancreatic cancer (PC) is one of the most aggressive human malignancies worldwide and is the fourth leading cause of cancer-related deaths. Curcumin (diferuloylmethane) is a polyphenol derived from the Curcuma longa plant. Certain studies have demonstrated that curcumin exerts its anti-tumor function in a variety of human cancers including PC, via targeting multiple therapeutically important cancer signaling pathways. However, the detailed molecular mechanisms are not fully understood. Two transcriptional co-activators, YAP (Yes-associated protein) and its close paralog TAZ (transcriptional coactivator with PDZ-binding motif) exert oncogenic activities in various cancers. Therefore, in this study we aimed to determine the molecular basis of curcumin-induced cell proliferation inhibition in PC cells. First, we detected the anti-tumor effects of curcumin on PC cell lines using CTG assay, Flow cytometry, clonogenic assay, wound healing assay and Transwell invasion assay. We found that curcumin significantly suppressed cell growth, weakened clonogenic potential, inhibited migration and invasion, and induced apoptosis and cell cycle arrest in PC cells. We further measured that overexpression of YAP enhanced cell proliferation and abrogated the cytotoxic effects of curcumin on PC cells. Moreover, we found that curcumin markedly down-regulated YAP and TAZ expression and subsequently suppressed Notch-1 expression. Collectively, these findings suggest that pharmacological inhibition of YAP and TAZ activity may be a promising anticancer strategy for the treatment of PC patients. PMID:27738325

  18. Novel NEK8 Mutations Cause Severe Syndromic Renal Cystic Dysplasia through YAP Dysregulation

    PubMed Central

    Grampa, Valentina; Odye, Gweltas; Thomas, Sophie; Elkhartoufi, Nadia; Filhol, Emilie; Niel, Olivier; Silbermann, Flora; Lebreton, Corinne; Collardeau-Frachon, Sophie; Rouvet, Isabelle; Alessandri, Jean-Luc; Devisme, Louise; Dieux-Coeslier, Anne; Cordier, Marie-Pierre; Capri, Yline; Khung-Savatovsky, Suonavy; Sigaudy, Sabine; Salomon, Rémi; Antignac, Corinne; Gubler, Marie-Claire; Benmerah, Alexandre; Terzi, Fabiola; Attié-Bitach, Tania; Jeanpierre, Cécile; Saunier, Sophie

    2016-01-01

    Ciliopathies are a group of genetic multi-systemic disorders related to dysfunction of the primary cilium, a sensory organelle present at the cell surface that regulates key signaling pathways during development and tissue homeostasis. In order to identify novel genes whose mutations would cause severe developmental ciliopathies, >500 patients/fetuses were analyzed by a targeted high throughput sequencing approach allowing exome sequencing of >1200 ciliary genes. NEK8/NPHP9 mutations were identified in five cases with severe overlapping phenotypes including renal cystic dysplasia/hypodysplasia, situs inversus, cardiopathy with hypertrophic septum and bile duct paucity. These cases highlight a genotype-phenotype correlation, with missense and nonsense mutations associated with hypodysplasia and enlarged cystic organs, respectively. Functional analyses of NEK8 mutations in patient fibroblasts and mIMCD3 cells showed that these mutations differentially affect ciliogenesis, proliferation/apoptosis/DNA damage response, as well as epithelial morphogenesis. Notably, missense mutations exacerbated some of the defects due to NEK8 loss of function, highlighting their likely gain-of-function effect. We also showed that NEK8 missense and loss-of-function mutations differentially affect the regulation of the main Hippo signaling effector, YAP, as well as the expression of its target genes in patient fibroblasts and renal cells. YAP imbalance was also observed in enlarged spheroids of Nek8-invalidated renal epithelial cells grown in 3D culture, as well as in cystic kidneys of Jck mice. Moreover, co-injection of nek8 MO with WT or mutated NEK8-GFP RNA in zebrafish embryos led to shortened dorsally curved body axis, similar to embryos injected with human YAP RNA. Finally, treatment with Verteporfin, an inhibitor of YAP transcriptional activity, partially rescued the 3D spheroid defects of Nek8-invalidated cells and the abnormalities of NEK8-overexpressing zebrafish embryos

  19. Yap1 as a New Therapeutic Target in Neurofibromatosis Type 2

    DTIC Science & Technology

    2013-09-01

    Hedgehog and Notch has particularly contributed to the understanding and treatment of cancer1. A more recently discovered signalling cascade is the...Wnt, Notch, and Hedgehog pathways. Nat. Rev. Clin. Oncol. 8, 97–106 (2011). 2. Zhao, B., Lei, Q. Y. & Guan, K. L. The Hippo-YAP pathway: new

  20. Targeting Signaling to YAP for the Therapy of NF2

    DTIC Science & Technology

    2016-12-01

    any step of our newly identified pathway, and to test the preclinical efficacy of lead compounds in xenograft models of NF2. During this grant, we have...Phosphorylation of the Hippo Pathway Component AMOTL2 by the mTORC2 Kinase Promotes YAP Signaling, Resulting in Enhanced Glioblastoma Growth and Invasiveness. The Journal of Biological Chemistry. 2015. 290(32):19387-401.

  1. A full Monte Carlo simulation of the YAP-PEM prototype for breast tumor detection

    NASA Astrophysics Data System (ADS)

    Motta, A.; Righi, S.; Del Guerra, A.; Belcari, N.; Vaiano, A.; De Domenico, G.; Zavattini, G.; Campanini, R.; Lanconelli, N.; Riccardi, A.

    2004-07-01

    A prototype for Positron Emission Mammography, the YAP-PEM, is under development within a collaboration of the Italian Universities of Pisa, Ferrara, and Bologna. The aim is to detect breast lesions, with dimensions of 5 mm in diameter, and with a specific activity ratio of 10:1 between the cancer and breast tissue. The YAP-PEM is composed of two stationary detection heads of 6×6 cm 2, composed of a matrix of 30×30 YAP:Ce finger crystals of 2×2×30 mm 3 each. The EGSnrc Monte Carlo code has been used to simulate several characteristics of the prototype. A fast EM algorithm has been adapted to reconstruct all of the collected lines of flight, also at large incidence angles, by achieving 3D positioning capability of the lesion in the FOV. The role of the breast compression has been studied. The performed study shows that a 5 mm diameter tumor of 37 kBq/cm 3 (1 μCi/cm 3), embedded in active breast tissue with 10:1 tumor/background specific activity ratio, is detected in 10 min with a Signal-to-Noise Ratio of 8.7±1.0. Two hot lesions in the active breast phantom are clearly visible in the reconstructed image.

  2. Fbxw7 Deletion Accelerates KrasG12D-Driven Pancreatic Tumorigenesis via Yap Accumulation.

    PubMed

    Zhang, Qiang; Zhang, Yaqing; Parsels, Joshua D; Lohse, Ines; Lawrence, Theodore S; Pasca di Magliano, Marina; Sun, Yi; Morgan, Meredith A

    2016-11-01

    Pancreatic cancers driven by KRAS mutations require additional mutations for tumor progression. The tumor suppressor FBXW7 is altered in pancreatic cancers, but its contribution to pancreatic tumorigenesis is unknown. To determine potential cooperation between Kras mutation and Fbxw7 inactivation in pancreatic tumorigenesis, we generated P48-Cre;LSL-Kras G12D ;Fbxw7 fl/fl (KFC fl/fl ) compound mice. We found that KFC fl/fl mice displayed accelerated tumorigenesis: all mice succumbed to pancreatic ductal adenocarcinoma (PDA) by 40 days of age, with PDA onset occurring by 2 weeks of age. PDA in KFC fl/fl mice was preceded by earlier onset of acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) lesions, and associated with chromosomal instability and the accumulation of Fbxw7 substrates Yes-associated protein (Yap), c-Myc, and Notch. Using KFC fl/fl and FBXW7-deficient human pancreatic cancer cells, we found that Yap silencing attenuated growth promotion by Fbxw7 deletion. Our data demonstrate that Fbxw7 is a potent suppressor of Kras G12D -induced pancreatic tumorigenesis due, at least in part, to negative regulation of Yap. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  3. Measurement of x-ray spectra using a recent YAP(Ce)-MPPC detector

    NASA Astrophysics Data System (ADS)

    Sato, Eiichi; Oda, Yasuyuki; Yoshida, Sohei; Yamaguchi, Satoshi; Sato, Yuichi; Ishii, Tomotaka; Hagiwara, Osahiko; Matsukiyo, Hiroshi; Enomoto, Toshiyuki; Watanabe, Manabu; Kusachi, Shinya

    2017-09-01

    To measure X-ray spectra with high count rates, we developed a detector consisting of a cerium-doped yttrium aluminum perovskite [YAP(Ce)] crystal and a recent multipixel photon counter (MPPC). Scintillation photons are detected using the MPPC, and the photocurrents flowing through the MPPC are converted into voltages and amplified using a high-speed current-voltage (I-V) amplifier. The MPPC bias voltage was set to a value at the pre-Geiger mode to perform zero-dark counting. The event-pulse widths were approximately 200 ns, and the widths were extend to approximately 1 μs. X-ray spectra were measured using a multichannel analyzer (MCA) for pulse-height analysis. The photon energy was roughly determined by the two-point calibration using tungsten K photons and iodine K fluorescence. Using the YAP(Ce)-MPPC detector, first-generation dual-energy computed tomography was accomplished using iodine and gadolinium contrast media.

  4. Transmission potential of Zika virus infection in the South Pacific.

    PubMed

    Nishiura, Hiroshi; Kinoshita, Ryo; Mizumoto, Kenji; Yasuda, Yohei; Nah, Kyeongah

    2016-04-01

    Zika virus has spread internationally through countries in the South Pacific and Americas. The present study aimed to estimate the basic reproduction number, R0, of Zika virus infection as a measurement of the transmission potential, reanalyzing past epidemic data from the South Pacific. Incidence data from two epidemics, one on Yap Island, Federal State of Micronesia in 2007 and the other in French Polynesia in 2013-2014, were reanalyzed. R0 of Zika virus infection was estimated from the early exponential growth rate of these two epidemics. The maximum likelihood estimate (MLE) of R0 for the Yap Island epidemic was in the order of 4.3-5.8 with broad uncertainty bounds due to the small sample size of confirmed and probable cases. The MLE of R0 for French Polynesia based on syndromic data ranged from 1.8 to 2.0 with narrow uncertainty bounds. The transmissibility of Zika virus infection appears to be comparable to those of dengue and chikungunya viruses. Considering that Aedes species are a shared vector, this finding indicates that Zika virus replication within the vector is perhaps comparable to dengue and chikungunya. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  5. Needs Assessment of International Students at Eastern Oregon State College.

    ERIC Educational Resources Information Center

    Eid, Mamoud Taha; Jordan-Domschot, Theresa

    The purpose of the research project was to assess the needs, satisfaction, and concerns of international students attending Eastern Oregon State College. The international student population consisted of students from Micronesia, Netherlands, Somalia, Saudi Arabia, Jordan, Iran, Japan, Thailand, Zimbabwe, Belgium, Canada, Nigeria, China,…

  6. The YAP1/SIX2 axis is required for DDX3-mediated tumor aggressiveness and cetuximab resistance in KRAS-wild-type colorectal cancer

    PubMed Central

    Wu, De-Wei; Lin, Po-Lin; Wang, Lee; Huang, Chi-Chou; Lee, Huei

    2017-01-01

    The mechanism underlying tumor aggressiveness and cetuximab (CTX) resistance in KRAS-wild-type (KRAS -WT) colorectal cancer remains obscure. We here provide evidence that DDX3 promoted soft agar growth and invasiveness of KRAS-WT cells, as already confirmed in KRAS-mutated cells. Mechanistically, increased KRAS expression induced ROS production, which elevated HIF-1α and YAP1 expression. Increased HIF-1α persistently promoted DDX3 expression via a KRAS/ROS/HIF-1α feedback loop. DDX3-mediated aggressiveness and CTX resistance were regulated by the YAP1/SIX2 axis in KRAS-WT cells and further confirmed in animal models. Kaplan-Meier and Cox regression analysis indicated that DDX3, KRAS, and YAP1 expression had prognostic value for OS and RFS in KRAS-WT and KRAS-mutated tumors, but SIX2 and YAP1/SIX2 were prognostic value only in KRAS-WT patients. The observation from patients seemed to support the mechanistic action of cell and animal models. We therefore suggest that combining YAP1 inhibitors with CTX may therefore suppress DDX3-mediated tumor aggressiveness and enhance CTX sensitivity in KRAS-WT colorectal cancer. PMID:28435452

  7. Elevated YAP and its downstream targets CCN1 and CCN2 in basal cell carcinoma: impact on keratinocyte proliferation and stromal cell activation.

    PubMed

    Quan, Taihao; Xu, Yiru; Qin, Zhaoping; Robichaud, Patrick; Betcher, Stephanie; Calderone, Ken; He, Tianyuan; Johnson, Timothy M; Voorhees, John J; Fisher, Gary J

    2014-04-01

    Yes-associated protein (YAP) is a transcriptional co-activator of hippo signaling pathway, which plays an important role in organ size control and tumorigenesis. Here we report that YAP and its downstream transcriptional targets CCN1 and CCN2 are markedly elevated in keratinocytes in human skin basal cell carcinoma tumor islands. In human keratinocytes, knockdown of YAP significantly reduced expression of CCN1 and CCN2, and repressed proliferation and survival. This inhibition of proliferation and survival was rescued by restoration of CCN1 expression, but not by CCN2 expression. In basal cell carcinoma stroma, CCN2-regulated genes type I collagen, fibronectin, and α-smooth muscle actin were highly expressed. Furthermore, atomic force microscopy revealed increased tissue stiffness in basal cell carcinoma stroma compared to normal dermis. These data provide evidence that up-regulation of YAP in basal cell carcinoma impacts both aberrant keratinocyte proliferation, via CCN1, and tumor stroma cell activation and stroma remodeling, via CCN2. Targeting YAP and/or CCN1 and CCN2 may provide clinical benefit in basal cell carcinoma. Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  8. Dracograllus trukensis sp. nov. (Draconematidae: Nematoda) from a seagrass bed ( Zostera spp.) in Chuuk Islands, Micronesia, Central Western Pacific Ocean

    NASA Astrophysics Data System (ADS)

    Min, Wongi; Kim, Dongsung; Decraemer, Wilfrida; Rho, Hyun Soo

    2016-09-01

    A new species of free-living marine draconematid nematode, Dracograllus trukensis sp. nov., is described based on the specimens collected from the sediments of a intertidal seagrass bed from Chuuk Islands, Micronesia. Dracograllus trukensis sp. nov. differs from other species of the genus by the combination of the following characteristics: the presence of numerous minute spiny ornamented body cuticular annules in both sexes, eight cephalic adhesion tubes inserted on the head capsule in both sexes, the presence of stiff posteriorly directed setae anterior to posterior adhesion tubes in both sexes, the shape (large, elongated, open loop-shaped in male and large, elongated, closed loop-shaped in female) and position (longer ventral arm extending to the first body annule in male) of amphideal fovea, shorter spicule length (34-42 μm), the presence of sexual dimorphism in shape and length of the non-annulated tail terminus, and number of posterior sublateral adhesion tubes (10 in male and 13-15 in female) and posterior subventral adhesion tubes (8-10 in male and 9-11 in female). A comparative table on the biogeographical and ecological characteristics of the species of Dracograllus is presented. This is the first taxonomic report on the genus Dracograllus from Chuuk Islands, Micronesia, central western Pacific Ocean.

  9. TEAD and YAP regulate the enhancer network of human embryonic pancreatic progenitors.

    PubMed

    Cebola, Inês; Rodríguez-Seguí, Santiago A; Cho, Candy H-H; Bessa, José; Rovira, Meritxell; Luengo, Mario; Chhatriwala, Mariya; Berry, Andrew; Ponsa-Cobas, Joan; Maestro, Miguel Angel; Jennings, Rachel E; Pasquali, Lorenzo; Morán, Ignasi; Castro, Natalia; Hanley, Neil A; Gomez-Skarmeta, Jose Luis; Vallier, Ludovic; Ferrer, Jorge

    2015-05-01

    The genomic regulatory programmes that underlie human organogenesis are poorly understood. Pancreas development, in particular, has pivotal implications for pancreatic regeneration, cancer and diabetes. We have now characterized the regulatory landscape of embryonic multipotent progenitor cells that give rise to all pancreatic epithelial lineages. Using human embryonic pancreas and embryonic-stem-cell-derived progenitors we identify stage-specific transcripts and associated enhancers, many of which are co-occupied by transcription factors that are essential for pancreas development. We further show that TEAD1, a Hippo signalling effector, is an integral component of the transcription factor combinatorial code of pancreatic progenitor enhancers. TEAD and its coactivator YAP activate key pancreatic signalling mediators and transcription factors, and regulate the expansion of pancreatic progenitors. This work therefore uncovers a central role for TEAD and YAP as signal-responsive regulators of multipotent pancreatic progenitors, and provides a resource for the study of embryonic development of the human pancreas.

  10. Mitochondrial Superoxide Dismutase and Yap1p Act as a Signaling Module Contributing to Ethanol Tolerance of the Yeast Saccharomyces cerevisiae.

    PubMed

    Zyrina, Anna N; Smirnova, Ekaterina A; Markova, Olga V; Severin, Fedor F; Knorre, Dmitry A

    2017-02-01

    There are two superoxide dismutases in the yeast Saccharomyces cerevisiae-cytoplasmic and mitochondrial enzymes. Inactivation of the cytoplasmic enzyme, Sod1p, renders the cells sensitive to a variety of stresses, while inactivation of the mitochondrial isoform, Sod2p, typically has a weaker effect. One exception is ethanol-induced stress. Here we studied the role of Sod2p in ethanol tolerance of yeast. First, we found that repression of SOD2 prevents ethanol-induced relocalization of yeast hydrogen peroxide-sensing transcription factor Yap1p, one of the key stress resistance proteins. In agreement with this, the levels of Trx2p and Gsh1p, proteins encoded by Yap1 target genes, were decreased in the absence of Sod2p. Analysis of the ethanol sensitivities of the cells lacking Sod2p, Yap1p, or both indicated that the two proteins act in the same pathway. Moreover, preconditioning with hydrogen peroxide restored the ethanol resistance of yeast cells with repressed SOD2 Interestingly, we found that mitochondrion-to-nucleus signaling by Rtg proteins antagonizes Yap1p activation. Together, our data suggest that hydrogen peroxide produced by Sod2p activates Yap1p and thus plays a signaling role in ethanol tolerance. Baker's yeast harbors multiple systems that ensure tolerance to high concentrations of ethanol. Still, the role of mitochondria under severe ethanol stress in yeast is not completely clear. Our study revealed a signaling function of mitochondria which contributes significantly to the ethanol tolerance of yeast cells. We found that mitochondrial superoxide dismutase Sod2p and cytoplasmic hydrogen peroxide sensor Yap1p act together as a module of the mitochondrion-to-nucleus signaling pathway. We also report cross talk between this pathway and the conventional retrograde signaling cascade activated by dysfunctional mitochondria. Copyright © 2017 American Society for Microbiology.

  11. Mitochondrial Superoxide Dismutase and Yap1p Act as a Signaling Module Contributing to Ethanol Tolerance of the Yeast Saccharomyces cerevisiae

    PubMed Central

    Zyrina, Anna N.; Smirnova, Ekaterina A.; Markova, Olga V.; Severin, Fedor F.

    2016-01-01

    ABSTRACT There are two superoxide dismutases in the yeast Saccharomyces cerevisiae—cytoplasmic and mitochondrial enzymes. Inactivation of the cytoplasmic enzyme, Sod1p, renders the cells sensitive to a variety of stresses, while inactivation of the mitochondrial isoform, Sod2p, typically has a weaker effect. One exception is ethanol-induced stress. Here we studied the role of Sod2p in ethanol tolerance of yeast. First, we found that repression of SOD2 prevents ethanol-induced relocalization of yeast hydrogen peroxide-sensing transcription factor Yap1p, one of the key stress resistance proteins. In agreement with this, the levels of Trx2p and Gsh1p, proteins encoded by Yap1 target genes, were decreased in the absence of Sod2p. Analysis of the ethanol sensitivities of the cells lacking Sod2p, Yap1p, or both indicated that the two proteins act in the same pathway. Moreover, preconditioning with hydrogen peroxide restored the ethanol resistance of yeast cells with repressed SOD2. Interestingly, we found that mitochondrion-to-nucleus signaling by Rtg proteins antagonizes Yap1p activation. Together, our data suggest that hydrogen peroxide produced by Sod2p activates Yap1p and thus plays a signaling role in ethanol tolerance. IMPORTANCE Baker's yeast harbors multiple systems that ensure tolerance to high concentrations of ethanol. Still, the role of mitochondria under severe ethanol stress in yeast is not completely clear. Our study revealed a signaling function of mitochondria which contributes significantly to the ethanol tolerance of yeast cells. We found that mitochondrial superoxide dismutase Sod2p and cytoplasmic hydrogen peroxide sensor Yap1p act together as a module of the mitochondrion-to-nucleus signaling pathway. We also report cross talk between this pathway and the conventional retrograde signaling cascade activated by dysfunctional mitochondria. PMID:27864171

  12. Muscle contraction is required to maintain the pool of muscle progenitors via YAP and NOTCH during fetal myogenesis.

    PubMed

    Esteves de Lima, Joana; Bonnin, Marie-Ange; Birchmeier, Carmen; Duprez, Delphine

    2016-08-24

    The importance of mechanical activity in the regulation of muscle progenitors during chick development has not been investigated. We show that immobilization decreases NOTCH activity and mimics a NOTCH loss-of-function phenotype, a reduction in the number of muscle progenitors and increased differentiation. Ligand-induced NOTCH activation prevents the reduction of muscle progenitors and the increase of differentiation upon immobilization. Inhibition of NOTCH ligand activity in muscle fibers suffices to reduce the progenitor pool. Furthermore, immobilization reduces the activity of the transcriptional co-activator YAP and the expression of the NOTCH ligand JAG2 in muscle fibers. YAP forced-activity in muscle fibers prevents the decrease of JAG2 expression and the number of PAX7+ cells in immobilization conditions. Our results identify a novel mechanism acting downstream of muscle contraction, where YAP activates JAG2 expression in muscle fibers, which in turn regulates the pool of fetal muscle progenitors via NOTCH in a non-cell-autonomous manner.

  13. YAP-dependent Mechanotransduction is Required for Proliferation and Migration on Native-like Substrate Topography

    PubMed Central

    Mascharak, Shamik; Benitez, Patrick L.; Proctor, Amy C.; Madl, Christopher M.; Hu, Kenneth H.; Dewi, Ruby E.; Butte, Manish J.; Heilshorn, Sarah C.

    2017-01-01

    Native vascular extracellular matrices (vECM) consist of elastic fibers that impart varied topographical properties, yet most in vitro models designed to study the effects of topography on cell behavior are not representative of native architecture. Here, we engineer an electrospun elastin-like protein (ELP) system with independently tunable, vECM-mimetic topography and demonstrate that increasing topographical variation causes loss of endothelial cell-cell junction organization. This loss of VE-cadherin signaling and increased cytoskeletal contractility on more topographically varied ELP substrates in turn promote YAP activation and nuclear translocation, resulting in significantly increased endothelial cell migration and proliferation. Our findings identify YAP as a required signaling factor through which fibrous substrate topography influences cell behavior and highlights topography as a key design parameter for engineered biomaterials. PMID:27889666

  14. Management of fruit bats on Yap, Caroline Islands: past and future challenges

    Treesearch

    Marjorie C. Falanruw

    1988-01-01

    Increased hunting pressure for export, commencing about 1975, resulted in a serious decline in the populations of the Yap fruit bat (pieropus mariannus yapensis). Factors causing this pressure included an export market in the U.S. Territory of Guam and in Saipan, Commonwealth of the Northern Mariana Islands and increased use of firearms. Research...

  15. YAP-dependent mechanotransduction is required for proliferation and migration on native-like substrate topography.

    PubMed

    Mascharak, Shamik; Benitez, Patrick L; Proctor, Amy C; Madl, Christopher M; Hu, Kenneth H; Dewi, Ruby E; Butte, Manish J; Heilshorn, Sarah C

    2017-01-01

    Native vascular extracellular matrices (vECM) consist of elastic fibers that impart varied topographical properties, yet most in vitro models designed to study the effects of topography on cell behavior are not representative of native architecture. Here, we engineer an electrospun elastin-like protein (ELP) system with independently tunable, vECM-mimetic topography and demonstrate that increasing topographical variation causes loss of endothelial cell-cell junction organization. This loss of VE-cadherin signaling and increased cytoskeletal contractility on more topographically varied ELP substrates in turn promote YAP activation and nuclear translocation, resulting in significantly increased endothelial cell migration and proliferation. Our findings identify YAP as a required signaling factor through which fibrous substrate topography influences cell behavior and highlights topography as a key design parameter for engineered biomaterials. Copyright © 2016 Elsevier Ltd. All rights reserved.

  16. v-Src-induced nuclear localization of YAP is involved in multipolar spindle formation in tetraploid cells.

    PubMed

    Kakae, Keiko; Ikeuchi, Masayoshi; Kuga, Takahisa; Saito, Youhei; Yamaguchi, Naoto; Nakayama, Yuji

    2017-01-01

    The protein-tyrosine kinase, c-Src, is involved in a variety of signaling events, including cell division. We have reported that v-Src, which is a mutant variant of the cellular proto-oncogene, c-Src, causes delocalization of Aurora B kinase, resulting in a furrow regression in cytokinesis and the generation of multinucleated cells. However, the effect of v-Src on mitotic spindle formation is unknown. Here we show that v-Src-expressing HCT116 and NIH3T3 cells undergo abnormal cell division, in which cells separate into more than two cells. Upon v-Src expression, the proportion of multinucleated cells is increased in a time-dependent manner. Flow cytometry analysis revealed that v-Src increases the number of cells having a ≥4N DNA content. Microscopic analysis showed that v-Src induces the formation of multipolar spindles with excess centrosomes. These results suggest that v-Src induces multipolar spindle formation by generating multinucleated cells. Tetraploidy activates the tetraploidy checkpoint, leading to a cell cycle arrest of tetraploid cells at the G1 phase, in which the nuclear exclusion of the transcription co-activator YAP plays a critical role. In multinucleated cells that are induced by cytochalasin B and the Plk1 inhibitor, YAP is excluded from the nucleus. However, v-Src prevents this nuclear exclusion of YAP through a decrease in the phosphorylation of YAP at Ser127 in multinucleated cells. Furthermore, v-Src decreases the expression level of p53, which also plays a critical role in the cell cycle arrest of tetraploid cells. These results suggest that v-Src promotes abnormal spindle formation in at least two ways: generation of multinucleated cells and a weakening of the tetraploidy checkpoint. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Novel wine yeast with mutations in YAP1 that produce less acetic acid during fermentation.

    PubMed

    Cordente, Antonio G; Cordero-Bueso, Gustavo; Pretorius, Isak S; Curtin, Christopher D

    2013-02-01

    Acetic acid, a byproduct formed during yeast alcoholic fermentation, is the main component of volatile acidity (VA). When present in high concentrations in wine, acetic acid imparts an undesirable 'vinegary' character that results in a significant reduction in quality and sales. Previously, it has been shown that saké yeast strains resistant to the antifungal cerulenin produce significantly lower levels of VA. In this study, we used a classical mutagenesis method to isolate a series of cerulenin-resistant strains, derived from a commercial diploid wine yeast. Four of the selected strains showed a consistent low-VA production phenotype after small-scale fermentation of different white and red grape musts. Specific mutations in YAP1, a gene encoding a transcription factor required for oxidative stress tolerance, were found in three of the four low-VA strains. When integrated into the genome of a haploid wine strain, the mutated YAP1 alleles partially reproduced the low-VA production phenotype of the diploid cerulenin-resistant strains, suggesting that YAP1 might play a role in (regulating) acetic acid production during fermentation. This study offers prospects for the development of low-VA wine yeast starter strains that could assist winemakers in their effort to consistently produce wine to definable quality specifications. © 2012 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.

  18. Prostaglandin E2 Activates YAP and a Positive-Signaling Loop to Promote Colon Regeneration After Colitis but Also Carcinogenesis in Mice.

    PubMed

    Kim, Han-Byul; Kim, Minchul; Park, Young-Soo; Park, Intae; Kim, Tackhoon; Yang, Sung-Yeun; Cho, Charles J; Hwang, DaeHee; Jung, Jin-Hak; Markowitz, Sanford D; Hwang, Sung Wook; Yang, Suk-Kyun; Lim, Dae-Sik; Myung, Seung-Jae

    2017-02-01

    Prostaglandin E 2 (PGE 2 ) is mediator of inflammation that regulates tissue regeneration, but its continual activation has been associated with carcinogenesis. Little is known about factors in the PGE 2 signaling pathway that contribute to tumor formation. We investigated whether yes-associated protein 1 (YAP1), a transcriptional co-activator in the Hippo signaling pathway, mediates PGE 2 function. DLD-1 and SW480 colon cancer cell lines were transfected with vectors expressing transgenes or small hairpin RNAs and incubated with recombinant PGE 2 , with or without pharmacologic inhibitors of signaling proteins, and analyzed by immunoblot, immunofluorescence, quantitative reverse-transcription polymerase chain reaction, transcriptional reporter, and proliferation assays. Dextran sodium sulfate (DSS) was given to induce colitis in C57/BL6 (control) mice, as well as in mice with disruption of the hydroxyprostaglandin dehydrogenase 15 gene (15-PGDH-knockout mice), Yap1 gene (YAP-knockout mice), and double-knockout mice. Some mice also were given indomethacin to block PGE 2 synthesis. 15-PGDH knockout mice were crossed with mice with intestine-specific disruption of the salvador family WW domain containing 1 gene (Sav1), which encodes an activator of Hippo signaling. We performed immunohistochemical analyses of colon biopsy samples from 26 patients with colitis-associated cancer and 51 age-and sex-matched patients with colorectal cancer (without colitis). Incubation of colon cancer cell lines with PGE 2 led to phosphorylation of cyclic adenosine monophosphate-responsive element binding protein 1 and increased levels of YAP1 messenger RNA, protein, and YAP1 transcriptional activity. This led to increased transcription of the prostaglandin-endoperoxide synthase 2 gene (PTGS2 or cyclooxygenase 2) and prostaglandin E-receptor 4 gene (PTGER4 or EP4). Incubation with PGE 2 promoted proliferation of colon cancer cell lines, but not cells with knockdown of YAP1. Control mice

  19. Traditional adaptation to natural processes of erosion and sedimentation on Yap Island

    Treesearch

    Marjorie C. Falanruw

    1990-01-01

    Yap is a high island with a mean annual rainfall of 3040 mm and considerable potential for erosion. The island once supported a dense population with a nature-intensive technology. The traditional food production system incorporated tree gardens which mimic natural forests in intercepting rainfall and holding the soil, and taro patch system which mimic swamp forests...

  20. A Study of Risk Factors among High School Students in Kosrae State.

    ERIC Educational Resources Information Center

    Kawakami, Alice J.; And Others

    A profile of variables related to the status of students at risk of failure in Kosrae State, Federated States of Micronesia in 1993-94 is presented as part of a study of at-risk high school students in some of the American-affiliated Pacific political entities. Data collection was a challenge in Kosrae because of inadequate records, but data were…

  1. Muscle contraction is required to maintain the pool of muscle progenitors via YAP and NOTCH during fetal myogenesis

    PubMed Central

    Esteves de Lima, Joana; Bonnin, Marie-Ange; Birchmeier, Carmen; Duprez, Delphine

    2016-01-01

    The importance of mechanical activity in the regulation of muscle progenitors during chick development has not been investigated. We show that immobilization decreases NOTCH activity and mimics a NOTCH loss-of-function phenotype, a reduction in the number of muscle progenitors and increased differentiation. Ligand-induced NOTCH activation prevents the reduction of muscle progenitors and the increase of differentiation upon immobilization. Inhibition of NOTCH ligand activity in muscle fibers suffices to reduce the progenitor pool. Furthermore, immobilization reduces the activity of the transcriptional co-activator YAP and the expression of the NOTCH ligand JAG2 in muscle fibers. YAP forced-activity in muscle fibers prevents the decrease of JAG2 expression and the number of PAX7+ cells in immobilization conditions. Our results identify a novel mechanism acting downstream of muscle contraction, where YAP activates JAG2 expression in muscle fibers, which in turn regulates the pool of fetal muscle progenitors via NOTCH in a non-cell-autonomous manner. DOI: http://dx.doi.org/10.7554/eLife.15593.001 PMID:27554485

  2. The unexpected discovery of blind snakes (Serpentes: Typhlopidae) in Micronesia: Two new species of Ramphotyphlops from the Caroline Islands

    USGS Publications Warehouse

    Wynn, A.H.; Reynolds, R.P.; Buden, D.W.; Falanruw, M.; Lynch, B.

    2012-01-01

    Two new blind snakes in the genus Ramphotyphlops are described from Ulithi (R. hatmaliyeb sp. nov.) and Ant Atoll (R. adocetus sp. nov.) in the Caroline Islands, the first blind snake species known from Micronesia east of Palau (excluding Ramphotyphlops braminus). Both species are unusual in being known only from small, low-lying atolls. They can be distinguished from other Ramphotyphlops by the combination of 22 scale rows over the length of the body; a wedge-shaped snout, without a keratinized keel; and a broad, pyriform (R. adocetus) or ovate (R. hatmaliyeb) rostral scale.

  3. The unexpected discovery of blind snakes (Serpentes: Typhlopidae) in Micronesia: two new species of Ramphotyphlops from the Caroline Islands

    USGS Publications Warehouse

    Wynn, Addison H.; Reynolds, Robert P.; Buden, Donald W.; Falanruw, Marjorie; Lynch, Brian

    2012-01-01

    Two new blind snakes in the genus Ramphotyphlops are described from Ulithi (R. hatmaliyeb sp. nov.) and Ant Atoll (R. adocetus sp. nov.) in the Caroline Islands, the first blind snake species known from Micronesia east of Palau (excluding Ramphotyphlops braminus). Both species are unusual in being known only from small, low-lying atolls. They can be distinguished from other Ramphotyphlops by the combination of 22 scale rows over the length of the body; a wedge-shaped snout, without a keratinized keel; and a broad, pyriform (R. adocetus) or ovate (R. hatmaliyeb) rostral scale.

  4. Shifting reef fish assemblages along a depth gradient in Pohnpei, Micronesia

    PubMed Central

    Copus, Joshua M.; Coffey, Daniel M.; Whitton, Robert K.; Bowen, Brian W.

    2018-01-01

    Mesophotic coral ecosystems (MCEs) continue to be understudied, especially in island locations spread across the Indo-Pacific Ocean. Pohnpei is the largest island in the Federated States of Micronesia, with a well-developed barrier reef, and steep slopes that descend to more than 1,000 m. Here we conducted visual surveys along a depth gradient of 0 to 60 m in addition to video surveys that extend to 130 m, with 72 belt transects and 12 roving surveys using closed-circuit rebreathers, to test for changes in reef fish composition from shallow to mesophotic depths. We observed 304 fish species across 47 families with the majority confined to shallow habitat. Taxonomic and trophic positions at 30 m showed similar compositions when compared against all other depths. However, assemblages were comprised of a distinct shallow (<30 m) and deep (>30 m) group, suggesting 30 m as a transition zone between these communities. Shallow specialists had a high probability of being herbivores and deep specialists had a higher probability of being planktivores. Acanthuridae (surgeonfishes), Holocentridae (soldierfishes), and Labridae (wrasses) were associated primarily with shallow habitat, while Pomacentridae (damselfishes) and Serranidae (groupers) were associated with deep habitat. Four species may indicate Central Pacific mesophotic habitat: Chromis circumaurea, Luzonichthys seaver, Odontanthias borbonius, and an undescribed slopefish (Symphysanodon sp.). This study supports the 30 m depth profile as a transition zone between shallow and mesophotic ecosystems (consistent with accepted definitions of MCEs), with evidence of multiple transition zones below 30 m. Disturbances restricted to either region are not likely to immediately impact the other and both ecosystems should be considered separately in management of reefs near human population centers. PMID:29707432

  5. The solar diameter on 9 March 2016, from the total eclipse in Micronesia: at its standard value

    NASA Astrophysics Data System (ADS)

    Sigismondi, Costantino; Castiglioni, Francesco; Cicogna, Domenico; Cardoso, Felipe

    2016-05-01

    The total eclipse of 9 March 2016 has been observed in Woleai atoll (Micronesia) by the Exploratorium team and posted in youtube. Exploiting the ghost images of that video we overcome the overexposition problems when dealing with the transition photosphere/chromosphere, dealing with Baily's beads around totality comparable with the intensity of the corona. A correction to the standard value of the solar radius R=959.63" of ΔR=+0.01"±0.02" has been found, contrarily to the recent values near 960.0" with the last eclipses and transit of Venus. Perspectives for the measures to be done during the forthcoming transit of Mercury are drafted.

  6. State of the Art of Pacific Bilingual Education. Bilingual Education Paper Series Vol. 4 No. 10.

    ERIC Educational Resources Information Center

    Gibson, Robert E.

    A discussion of the state of bilingual education in the Pacific islands administered by the United States (Guam, American Samoa, and Micronesia) begins with background information on the patterns of education and language use in the region and in each separate area. The current status of bilingual education programs and support projects is…

  7. Yap1 as a New Therapeutic Target in Neurofibromatosis Type 2

    DTIC Science & Technology

    2014-05-01

    binding sites (bold and underlined) present in the NOTCH2 promoter. Red box indicates area of genomic sequence (WT Notch2 prom) that was cloned into... Drosophila homolog of YAP. Cell 122, 421–434 22 Tao, W. et al. (1999) Human homologue of the Drosophila melanogaster lats tumour suppressor modulates... the hippo pathway basics The Hippo signaling cascade was first identified in Drosophila Melanogaster as an important regulator of organ size. The high

  8. Gross and Microscopic Lesions in Corals from Micronesia.

    PubMed

    Work, T M; Aeby, G S; Hughen, K A

    2016-01-01

    The authors documented gross and microscopic morphology of lesions in corals on 7 islands spanning western, southern, and eastern Micronesia, sampling 76 colonies comprising 30 species of corals among 18 genera, with Acropora, Porites, and Montipora dominating. Tissue loss comprised the majority of gross lesions sampled (41%), followed by discoloration (30%) and growth anomaly (29%). Of 31 cases of tissue loss, most lesions were subacute (48%), followed by acute and chronic (26% each). Of 23 samples with discoloration, most were dark discoloration (40%), with bleaching and other discoloration each constituting 30%. Of 22 growth anomalies, umbonate growth anomalies composed half, with exophytic, nodular, and rugose growth anomalies composing the remainder. On histopathology, for 9 cases of dark discoloration, fungal infections predominated (77%); for 7 bleached corals, depletion of zooxanthellae from the gastrodermis made up a majority of microscopic diagnoses (57%); and for growth anomalies other than umbonate, hyperplasia of the basal body wall was the most common microscopic finding (63%). For the remainder of the gross lesions, no single microscopic finding constituted >50% of the total. Host response varied with the agent present on histology. Fragmentation of tissues was most often associated with algae (60%), whereas necrosis dominated (53%) for fungi. Two newly documented potentially symbiotic tissue-associated metazoans were seen in Porites and Montipora. Findings of multiple potential etiologies for a given gross lesion highlight the importance of incorporating histopathology in coral disease surveys. This study also expands the range of corals infected with cell-associated microbial aggregates. © The Author(s) 2015.

  9. Gross and microscopic lesions in corals from Micronesia

    USGS Publications Warehouse

    Work, Thierry M.; Aeby, Greta S.; Hughen, Konrad A.

    2015-01-01

    The authors documented gross and microscopic morphology of lesions in corals on 7 islands spanning western, southern, and eastern Micronesia, sampling 76 colonies comprising 30 species of corals among 18 genera, with Acropora, Porites, and Montipora dominating. Tissue loss comprised the majority of gross lesions sampled (41%), followed by discoloration (30%) and growth anomaly (29%). Of 31 cases of tissue loss, most lesions were subacute (48%), followed by acute and chronic (26% each). Of 23 samples with discoloration, most were dark discoloration (40%), with bleaching and other discoloration each constituting 30%. Of 22 growth anomalies, umbonate growth anomalies composed half, with exophytic, nodular, and rugose growth anomalies composing the remainder. On histopathology, for 9 cases of dark discoloration, fungal infections predominated (77%); for 7 bleached corals, depletion of zooxanthellae from the gastrodermis made up a majority of microscopic diagnoses (57%); and for growth anomalies other than umbonate, hyperplasia of the basal body wall was the most common microscopic finding (63%). For the remainder of the gross lesions, no single microscopic finding constituted >50% of the total. Host response varied with the agent present on histology. Fragmentation of tissues was most often associated with algae (60%), whereas necrosis dominated (53%) for fungi. Two newly documented potentially symbiotic tissue-associated metazoans were seen in Porites and Montipora. Findings of multiple potential etiologies for a given gross lesion highlight the importance of incorporating histopathology in coral disease surveys. This study also expands the range of corals infected with cell-associated microbial aggregates.

  10. Pharmacokinetics and Dosing of Levofloxacin in Children Treated for Active or Latent Multidrug-Resistant Tuberculosis, Federated States of Micronesia and Republic of the Marshall Islands

    PubMed Central

    Mase, Sundari R.; Jereb, John A.; Gonzalez, Daniel; Martin, Fatma; Daley, Charles L.; Fred, Dorina; Loeffler, Ann; Menon, Lakshmy; Morris, Sapna Bamrah; Brostrom, Richard; Chorba, Terence; Peloquin, Charles A.

    2016-01-01

    Background In the Federated States of Micronesia (FSM) and then the Republic of the Marshall Islands (RMI), levofloxacin pharmacokinetics (PK) were studied in children receiving directly observed once-daily regimens (10 mg/kg, age >5 years; 15–20 mg/kg, age ≤5 years) for either multidrug-resistant tuberculosis (MDR TB) disease or latent infection after MDR TB exposure, to inform future dosing strategies. Methods Blood samples were collected at 0 (RMI only), 1, 2, and 6 hours (50 children, aged 6 months to 15 years) after oral levofloxacin at >6 weeks of treatment. Clinical characteristics and levofloxacin Cmax, elimination half-life (t1/2), and area under the curve from 0 to 24 hours (AUC0–24 hours * µg/mL) were correlated to determine optimal dosage and to examine associations. Population PK and target attainment were modeled. With results from FSM, dosages were increased in RMI toward the target maximal drug concentration (Cmax) for Mycobacterium tuberculosis, 8–12 µg/ml. Results Cmax correlated linearly with per-weight dosage. Neither Cmax nor t1/2 was associated with gender, age, body mass index, concurrent medications, or pre-dose meals. At levofloxacin dosage of 15–20 mg/kg, Cmax ≥ 8 µg/ml was observed, and modeling corroborated a high target attainment across the ratio of the area under the free-concentration-versus-time curve to minimum inhibitory concentration (fAUCss,0–24/MIC) values. Conclusions Levofloxacin dosage should be 15–20 mg/kg for Cmax ≥ 8 µg/ml and a high target attainment across fAUCss,0–24/MIC values in children ≥2 years of age. PMID:26658531

  11. Microhardness evaluations of CAD/CAM ceramics irradiated with CO2 or Nd:YAP laser

    PubMed Central

    Rocca, Jean Paul; Fornaini, Carlo; Medioni, Etienne; Brulat-Bouchard, Nathalie

    2017-01-01

    Background and aims The aim of this study was to measure the microhardness values of irradiated computer-aided design/computer-aided manufacturing (CAD/CAM) ceramics surfaces before and after thermal treatment. Materials and Methods Sixty CAD/CAM ceramic discs were prepared and grouped by material, i.e. lithium disilicate ceramic (Emax CAD) and zirconia ceramic (Emax ZirCAD). Laser irradiation at the material surface was performed with a carbon dioxide laser at 5 Watt (W) or 10 W power in continuous mode (CW mode), or with a neodymium:yttrium aluminum perovskite (Nd:YAP) laser at 10 W on graphite and non-graphite surfaces. Vickers hardness was tested at 0.3 kgf for lithium disilicate and 1 kgf for zirconia. Results Emax CAD irradiated with CO2 at 5 W increased microhardness by 6.32 GPa whereas Emax ZirCAD irradiated with Nd:YAP decreased microhardness by 17.46 GPa. Conclusion CO2 laser effectively increases the microhardness of lithium disilicate ceramics (Emax CAD). PMID:28740324

  12. Zika virus: history of a newly emerging arbovirus.

    PubMed

    Wikan, Nitwara; Smith, Duncan R

    2016-07-01

    Zika virus was originally identified in a sentinel rhesus monkey in the Zika Forest of Uganda in 1947. The virus is a member of the family Flaviviridae, genus Flavivirus, and is transmitted to humans by Aedes species mosquitoes. The first report of Zika virus outside Africa and Asia was in 2007 when the virus was associated with a small outbreak in Yap State, part of the Federated States of Micronesia. Since then, Zika virus infections have been reported around the world, including in southeast Asia; French Polynesia and other islands in the Pacific Ocean; and parts of South, Central, and North America. Symptomatic infection in human beings normally results in a mild and self-limiting febrile disease, although recent reports have suggested a possible association with more serious sequelae such as Guillain-Barré syndrome, and microcephaly in newborn infants of mothers infected with Zika virus during pregnancy. In this Review, we summarise the history of Zika virus from its first detection to its current worldwide distribution. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. Zika Virus Spreads to New Areas - Region of the Americas, May 2015-January 2016.

    PubMed

    Hennessey, Morgan; Fischer, Marc; Staples, J Erin

    2016-01-29

    Zika virus is a mosquito-borne flavivirus that was first identified in Uganda in 1947 (1). Before 2007, only sporadic human disease cases were reported from countries in Africa and Asia. In 2007, the first documented outbreak of Zika virus disease was reported in Yap State, Federated States of Micronesia; 73% of the population aged ≥3 years is estimated to have been infected (2). Subsequent outbreaks occurred in Southeast Asia and the Western Pacific (3). In May 2015, the World Health Organization reported the first local transmission of Zika virus in the Region of the Americas (Americas), with autochthonous cases identified in Brazil (4). In December, the Ministry of Health estimated that 440,000-1,300,000 suspected cases of Zika virus disease had occurred in Brazil in 2015 (5). By January 20, 2016, locally-transmitted cases had been reported to the Pan American Health Organization from Puerto Rico and 19 other countries or territories in the Americas* (Figure) (6). Further spread to other countries in the region is being monitored closely.

  14. TEAD1 mediates the oncogenic activities of Hippo-YAP1 signaling in osteosarcoma.

    PubMed

    Chai, Jiwei; Xu, Shijie; Guo, Fengbo

    2017-06-24

    Hippo signaling pathway is an evolutionarily conserved developmental network that governs the downstream transcriptional co-activators, YAP and TAZ, which bind to and activate the output of TEADs that responsible for cell proliferation, apoptosis, and stem cell self renewal. Emerging evidence has shown the tumor suppressor properties of Hippo signaling. However, limited knowledge is available concerning the downstream transcription factors of Hippo pathway in osteosarcoma (OS). In this study, we demonstrated that TEAD1 was the major transcription factor of Hippo signaling pathway in OS. Genetic silencing of TEAD1 suppressed multiple malignant phenotypes of OS cells including cell proliferation, apoptosis resistance, and invasive potential. Mechanistically, we showed that TEAD1 largely exerted its transcriptional control of its functional targets, PTGS2 and CYR61. Collectively, this work identifies the YAP1/TEAD1 complex as the representative dysregulated profile of Hippo signaling in OS and provides proof-of-principle that targeting TEAD1 may be a therapeutic strategy of osteosarcoma. Copyright © 2017. Published by Elsevier Inc.

  15. Dual-wavelength waveguide lasers at 1064 and 1079 nm in Nd:YAP crystal by direct femtosecond laser writing.

    PubMed

    Nie, Weijie; Cheng, Chen; Jia, Yuechen; Romero, Carolina; Vázquez de Aldana, Javier R; Chen, Feng

    2015-05-15

    Low-loss depressed cladding waveguides have been produced in Nd:YAP laser crystal by using direct femtosecond laser writing. Under optical pump at 812 nm at room temperature, continuous-wave simultaneous dual-wavelength laser oscillations at 1064 and 1079 nm, both along TM polarization, have been realized in the waveguiding structures. It has been found that, with the variation of pump polarization, the intensity ratio of 1064 and 1079 nm emissions varies periodically, while the polarization of output dual-wavelength laser remains unchanged. The maximum output power achieved for the Nd:YAP waveguide lasers is ∼200  mW with a slope efficiency of 33.4%.

  16. Collecting, Preserving & Sharing Information in Micronesia. Proceedings of the Annual Pacific Islands Association of Libraries and Archives Conference (3rd, Saipan, Northern Mariana Islands, October 13-15, 1993).

    ERIC Educational Resources Information Center

    Pacific Islands Association of Libraries and Archives, Guam.

    Participants from Washington, Hawaii, Majuro, Palau, Guam and other points in the Northern Mariana Islands came together to share information relating to the functions of libraries and archives as information banks and as preservers of the cultural heritage of Micronesia. Papers presented were: (1) "Reading Motivation in the Pacific"…

  17. Enhanced osteogenic differentiation of MC3T3-E1 cells on grid-topographic surface and evidence for involvement of YAP mediator.

    PubMed

    Zhang, Yingying; Gong, He; Sun, Yan; Huang, Yan; Fan, Yubo

    2016-05-01

    Numerous studies have shown that surface topography can promote cell-substrate associations and deeply influence cell fate. The intracellular mechanism or how micro- or nano-patterned extracellular signal is ultimately linked to activity of nuclear transcription factors remains unknown. It has been reported that Yes-associated protein (YAP) can respond to extracellular matrix microenvironment signals, thus regulates stem cell differentiation process. We propose that YAP may play a role in mediating the topography induced cell differentiation. To this end, we fabricated polydimethylsiloxane (PDMS) micropatterns with grid topology (GT) (3 μm pattern width, 2 μm pattern interval length, 7 μm pattern height); nonpatterned PDMS substrates were used as the planar controls. The MC3T3-E1 cells were then cultured on these surfaces, respectively, in osteogenic inducing medium. Cell differentiation in terms of osteogenesis related gene expression, protein levels, alkaline phosphatase activity and extracellular matrix mineralization was assessed. It was shown that the cells on GT surfaces had stronger osteogenesis capacity. In addition, expression level of YAP was increased when MC3T3-E1 cells grew on GT substrates, which was similar to the levels of osteogenic differentiation markers. It was also shown that YAP knockdown attenuated GT substrates-induced MC3T3-E1 differentiation, which reduced the osteogenic differentiation effect of the GT substrates. Collectively, our findings indicate that GT substrates-induced MC3T3-E1 differentiation may be associated with YAP. This paper provides new target points for transcriptional mechanism research of microenvironment induced cell differentiation and a useful approach to obtain more biofunctionalization scaffolds for tissue engineering. © 2016 Wiley Periodicals, Inc.

  18. The causes of mangrove death on Yap, Palau, Pohnpei and Kosrae [Chapter II

    Treesearch

    Phil G. Cannon; Margie Falanruw; Francis Ruegorong; Rich MacKenzie; Katie Friday; Amy L. Ross-Davis; Sara M. Ashiglar; Ned B. Klopfenstein; Zhangfeng Liu; Mohammad Golabi; Chancy Thomas Iyekar

    2014-01-01

    The area of a massive mangrove dieback in Yinuf Mn Island, Yap, was selected as the first location to study mangrove dieback problems. Seawater and soil samples were collected from plots where the mangrove trees were dead/dying and these samples were analyzed for eight different seawater and soil floor properties. Seawater and soil properties from dead/dying/...

  19. Diode end-pumped passively Q-switched Tm:YAP laser with 1.85-mJ pulse energy.

    PubMed

    Sebbag, Daniel; Korenfeld, Arik; Ben-Ami, Udi; Elooz, David; Shalom, Eran; Noach, Salman

    2015-04-01

    Passive Q switching of a Tm:YAP solid-state laser at 1935 nm with Cr:ZnSe and Cr:ZnS polycrystalline saturable absorbers is demonstrated for the first time, to the best of our knowledge. With Cr:ZnS, a maximum pulse energy of 1.85 mJ is obtained for a pulse duration of 35.8 ns, resulting in a peak power of 51.7 kW. With Cr:ZnSe, the achieved pulse energy of 1.55 mJ with a pulse duration of 42.2 ns leads to 36.7-kW peak power. These high pulse energies, together with the unique lasing wavelength at 1935 nm, make this laser a promising tool for biomedical and microsurgery applications.

  20. Geology and geochemistry of epithermal precious metal vein systems in the intra-oceanic arcs of Palau and Yap, western Pacific

    USGS Publications Warehouse

    Rytuba, J.J.; Miller, W.R.

    1990-01-01

    The Palau and Yap arcs are part of an intra-oceanic island-arc-trench system which separates the Pacific and Philippine plates in the western Pacific Ocean. The 350-km-long Palau arc consists of over 200 islands while the 400-km-long Yap arc located to the north has only four major islands exposed. Four of the largest islands in Palau are composed primarily of early Eocene to mid-Miocene volcanic rocks and the four islands comprising Yap contain only Miocene volcanic rocks. Basalt and basaltic andesites of the Babelthuap Formation are the oldest volcanic rocks in Palau and are characterized by high MgO, Ni and Cr and low TiO2 and have a boninitic affinity. They form the central and southeastern parts of Babelthuap Island. Oligocene arc tholeiite flows having an age of 34-35.5 Ma comprise most of the three smaller volcanic islands in Palau and the western part of Babelthuap. The youngest volcanic rocks are dacitic intrusions having an age of 22.7-23.2 Ma. The Yap arc is unusual in that metamorphic rocks up to amphibolite grade form most of the islands. These are underlain by a melange composed of igneous and volcanic clasts as well as clasts from a dismembered copper-gold skarn deposit. Miocene volcanic rocks consisting of flows and volcaniclastic deposits overlie the melange and metamorphic complex. An epithermal precious-metal vein system hosted by flows and flow breccias of the Babelthuap Formation occurs in an area 1.5 km by 1 km on the southeast side of Babelthuap Island. Over 50 veins and mineralized breccias ranging up to 2 m in width and having a strike length up to 500 m contain from trace to 13.0 ppm gold. The veins consist of quartz with varying amounts of sulfides and iron oxides after sulfides and the mineralized breccias consist of brecciated country rock cemented by quartz and iron oxides after sulfides. The veins and mineralized breccias generally dip within 15?? of vertical and have two preferred orientations, north-northwest and north

  1. Academic Achievement and Classification of Students from the Freely Associated States in Guam Schools. REL 2017-260

    ERIC Educational Resources Information Center

    Stewart, Joshua; Stringer, Katie; Arens, Sheila A.; Cicchinelli, Louis F.; San Nicolas, Heidi; Flores, Nieves

    2017-01-01

    Guam is home to the largest population of migrants from the Freely Associated States (FAS): the Federated States of Micronesia, the Republic of the Marshall Islands, and the Republic of Palau. FAS students made up 22 percent of total student enrollment in Guam public schools in 2012. FAS students face a number of challenges when they enter Guam…

  2. Type I collagen-induced YAP nuclear expression promotes primary cilia growth and contributes to cell migration in confluent mouse embryo fibroblast 3T3-L1 cells.

    PubMed

    Xu, Qian; Liu, Xiaoling; Liu, Weiwei; Hayashi, Toshihiko; Yamato, Masayuki; Fujisaki, Hitomi; Hattori, Shunji; Tashiro, Shin-Ichi; Onodera, Satoshi; Ikejima, Takashi

    2018-05-30

    The extracellular matrix (ECM) is a major biomechanical environment for all cells in vivo, and tightly controls wound healing and cancer progression. Type I collagen (Col I) is the most abundant component in ECM and plays an essential role for cell motility control and migration beyond structural support. Our previous results showed that Col I increased the length of primary cilia and the expression of primary cilia-associated proteins in 3T3-L1 cells. The Hippo/YAP pathway serves as a major integrator of cell surface-mediated signals and regulates key processes for the development and maintenance of tissue functions. In this study, we investigated the role of Hippo/YAP signaling in primary cilia growth of cells cultured on Col I-coated plate, as well as the potential link between primary cilia and migration. At 2-day post-confluence, YAP localization in the nucleus was dramatically increased when the cells were cultured on Col I-coated plate, accompanied by cilia growth. YAP inhibitor verteporfin repressed the growth of primary cilia as well as the expressions of ciliogenesis-associated proteins in confluent 3T3-L1 cells cultured on Col I-coated plate. Moreover, knockdown of either YAP or IFT88, one of the ciliogenesis-associated proteins, reversed the migration of confluent 3T3-L1 cells promoted by Col I-coating. In conclusion, activation of YAP pathway by Col I-coating of culture plate for confluent 3T3-L1 cells is positively associated with the primary cilia growth, which eventually results in promoted migration.

  3. The effect of CO2 and Nd:YAP lasers on CAD/CAM Ceramics: SEM, EDS and thermal studies.

    PubMed

    El Gamal, Ahmed; Fornaini, Carlo; Rocca, Jean Paul; Muhammad, Omid H; Medioni, Etienne; Cucinotta, Annamaria; Brulat-Bouchard, Nathalie

    2016-03-31

    The objective of this study was to investigate the interaction of infrared laser light on Computer Aided Design and Computer Aided Manufacturing (CAD/CAM) ceramic surfaces. Sixty CAD/CAM ceramic discs were prepared and divided into two different groups: lithiumdisilicate ceramic (IPSe.maxCADs) and Zirconia ceramic (IPSe.maxZirCADs). The laser irradiation was performed on graphite and non-graphite surfaces with a Carbon Dioxide laser at 5W and 10W power in continuous mode (CW mode) and with Neodymium Yttrium Aluminum Perovskite (Nd:YAP) laser at 10W. Surface textures and compositions were examined using Scanning Electron Microscopy (SEM), and Energy Dispersive Spectroscopy (EDS). Thermal elevation was measured by thermocouple during laser irradiation. The SEM observation showed a rough surface plus cracks and fissures on CO2 10W samples and melting areas in Nd:YAP samples; moreover, with CO2 5W smooth and shallow surfaces were observed. EDS analysis revealed that laser irradiation does not result in modifications of the chemical composition even if minor changes in the atomic mass percentage of the components were registered. Thermocouple showed several thermal changes during laser irradiation. CO2 and Nd:YAP lasers modify CAD/CAM ceramic surface without chemical composition modifications.

  4. The effect of CO2 and Nd:YAP lasers on CAD/CAM Ceramics: SEM, EDS and thermal studies

    PubMed Central

    Fornaini, Carlo; Rocca, Jean Paul; Muhammad, Omid H; Medioni, Etienne; Cucinotta, Annamaria; Brulat-Bouchard, Nathalie

    2016-01-01

    Background and aims: The objective of this study was to investigate the interaction of infrared laser light on Computer Aided Design and Computer Aided Manufacturing (CAD/CAM) ceramic surfaces. Material and Methods: Sixty CAD/CAM ceramic discs were prepared and divided into two different groups: lithiumdisilicate ceramic (IPSe.maxCADs) and Zirconia ceramic (IPSe.maxZirCADs). The laser irradiation was performed on graphite and non-graphite surfaces with a Carbon Dioxide laser at 5W and 10W power in continuous mode (CW mode) and with Neodymium Yttrium Aluminum Perovskite (Nd:YAP) laser at 10W. Surface textures and compositions were examined using Scanning Electron Microscopy (SEM), and Energy Dispersive Spectroscopy (EDS). Thermal elevation was measured by thermocouple during laser irradiation. Results: The SEM observation showed a rough surface plus cracks and fissures on CO2 10W samples and melting areas in Nd:YAP samples; moreover, with CO2 5W smooth and shallow surfaces were observed. EDS analysis revealed that laser irradiation does not result in modifications of the chemical composition even if minor changes in the atomic mass percentage of the components were registered. Thermocouple showed several thermal changes during laser irradiation. Conclusion: CO2 and Nd:YAP lasers modify CAD/CAM ceramic surface without chemical composition modifications. PMID:27141152

  5. A study of response of a LuYAP:Ce array with innovative assembling for PET

    NASA Astrophysics Data System (ADS)

    Pani, Roberto; Cinti, Maria Nerina; Scafè, Raffaele; Bennati, Paolo; Lo Meo, Sergio; Preziosi, Enrico; Pellegrini, Rosanna; De Vincentis, Giuseppe; Sacco, Donatella; Fabbri, Andrea

    2015-09-01

    We propose the characterization of a first array of 10×10 Lutetium Yttrium Orthoaluminate Perovskite (LuYAP:Ce) crystals, 2 mm×2 mm×10 mm pixel size, with an innovative assembling designed to enhance light output, uniformity and detection efficiency. The innovation consists of the use of 0.015 mm thick dielectric coating as inter-pixel light-insulators, manufactured by Crytur (Czech Republic) intended to improve crystal insulation and then light collection. Respect to the traditional treatment with 0.2 mm of white epoxy, a thinner pixel gap enhances packing fraction up to 98% with a consequent improvement of detection efficiency. Spectroscopic characterization of the array was performed by a Hamamatsu R6231 photomultiplier tube. A pixel-by-pixel scanning with a collimated 99mTc radioisotope (140 keV photon energy) highlighted a deviation in pulse height close to 3.5% respect to the overall mean value. Meanwhile, in term of energy resolution a difference between the response of single pixel and the array of about 10% was measured. Results were also supported and validated by Monte Carlo simulations performed with GEANT4. Although the dielectric coating pixel insulator cannot overcome the inherent limitations of LuYAP crystal due to its self-absorption of light (still present), this study demonstrated that the new coating treatment allows better light collection (nearly close to the expected one) with in addition a very good uniformity between different pixels. These results confirm the high potentiality of this coating for any other crystal array suited for imaging application and new expectations for the use of LuYAP for PET systems.

  6. All-trans-retinoic acid activates the pro-invasive Src-YAP-Interleukin 6 axis in triple-negative MDA-MB-231 breast cancer cells while cerivastatin reverses this action.

    PubMed

    Mezquita, Belén; Mezquita, Pau; Pau, Montserrat; Gasa, Laura; Navarro, Lourdes; Samitier, Mireia; Pons, Miquel; Mezquita, Cristóbal

    2018-05-04

    All-trans-retinoic acid (RA), the active metabolite of vitamin A, can reduce the malignant phenotype in some types of cancer and paradoxically also can promote cancer growth and invasion in others. For instance, it has been reported that RA induces tumor suppression in tumor xenografts of MDA-MB-468 breast cancer cells while increasing tumor growth and metastases in xenografts of MDA-MB-231 breast cancer cells. The signaling pathways involved in the pro-invasive action of retinoic acid remain mostly unknown. We show here that RA activates the pro-invasive axis Src-YAP-Interleukin 6 (Src-YAP-IL6) in triple negative MDA-MB-231 breast cancer cells, yielding to increased invasion of these cells. On the contrary, RA inhibits the Src-YAP-IL6 axis of triple-negative MDA-MB-468 cells, which results in decreased invasion phenotype. In both types of cells, inhibition of the Src-YAP-IL6 axis by the Src inhibitor PP2 drastically reduces migration and invasion. Src inhibition also downregulates the expression of a pro-invasive isoform of VEGFR1 in MDA-MB-231 breast cancer cells. Furthermore, interference of YAP nuclear translocation using the statin cerivastatin reverses the upregulation of Interleukin 6 (IL-6) and the pro-invasive effect of RA on MDA-MB-231 breast cancer cells and also decreases invasion and viability of MDA-MB-468 breast cancer cells. These results altogether suggest that RA induces pro-invasive or anti-invasive actions in two triple-negative breast cancer cell lines due to its ability to activate or inhibit the Src-YAP-IL6 axis in different cancer cells. The pro-invasive effect of RA can be reversed by the statin cerivastatin.

  7. Roles of the Yap1 Transcription Factor and Antioxidants in Saccharomyces cerevisiae's Tolerance to Furfural and 5-Hydroxymethylfurfural, Which Function as Thiol-Reactive Electrophiles Generating Oxidative Stress

    PubMed Central

    Kim, Daehee

    2013-01-01

    Development of the tolerance of Saccharomyces cerevisiae strains to furfural and 5-hydroxymethylfurfural (HMF) is an important issue for cellulosic ethanol production. Although furfural and HMF are known to induce oxidative stress, the underlying mechanisms are largely unknown. In this study, we show that both furfural and HMF act as thiol-reactive electrophiles, thus directly activating the Yap1 transcription factor via the H2O2-independent pathway, depleting cellular glutathione (GSH) levels, and accumulating reactive oxygen species in Saccharomyces cerevisiae. However, furfural showed higher reactivity than did HMF toward GSH in vitro and in vivo. In line with such toxic mechanisms, overexpression of YAP1C620F, a constitutively active mutant of YAP1, and Yap1 target genes encoding catalases (CTA1 and CTT1) increased tolerance to furfural and HMF. However, increasing GSH levels by overexpression of genes for GSH biosynthesis (GSH1 and GLR1) or by the exogenous addition of GSH to the culture medium enhanced tolerance to furfural but not to HMF. PMID:23793623

  8. Roles of the Yap1 transcription factor and antioxidants in Saccharomyces cerevisiae's tolerance to furfural and 5-hydroxymethylfurfural, which function as thiol-reactive electrophiles generating oxidative stress.

    PubMed

    Kim, Daehee; Hahn, Ji-Sook

    2013-08-01

    Development of the tolerance of Saccharomyces cerevisiae strains to furfural and 5-hydroxymethylfurfural (HMF) is an important issue for cellulosic ethanol production. Although furfural and HMF are known to induce oxidative stress, the underlying mechanisms are largely unknown. In this study, we show that both furfural and HMF act as thiol-reactive electrophiles, thus directly activating the Yap1 transcription factor via the H2O2-independent pathway, depleting cellular glutathione (GSH) levels, and accumulating reactive oxygen species in Saccharomyces cerevisiae. However, furfural showed higher reactivity than did HMF toward GSH in vitro and in vivo. In line with such toxic mechanisms, overexpression of YAP1(C620F), a constitutively active mutant of YAP1, and Yap1 target genes encoding catalases (CTA1 and CTT1) increased tolerance to furfural and HMF. However, increasing GSH levels by overexpression of genes for GSH biosynthesis (GSH1 and GLR1) or by the exogenous addition of GSH to the culture medium enhanced tolerance to furfural but not to HMF.

  9. PPARγ agonists promote differentiation of cancer stem cells by restraining YAP transcriptional activity

    PubMed Central

    Rattanakorn, Kirk; Gadi, Abhilash; Verma, Narendra; Maurizi, Giulia; Gunaratne, Preethi H.; Coarfa, Cristian; Kennedy, Oran D.; Garabedian, Michael J.; Basilico, Claudio; Mansukhani, Alka

    2016-01-01

    Osteosarcoma (OS) is a highly aggressive pediatric bone cancer in which most tumor cells remain immature and fail to differentiate into bone-forming osteoblasts. However, OS cells readily respond to adipogenic stimuli suggesting they retain mesenchymal stem cell-like properties. Here we demonstrate that nuclear receptor PPARγ agonists such as the anti-diabetic, thiazolidinedione (TZD) drugs induce growth arrest and cause adipogenic differentiation in human, mouse and canine OS cells as well as in tumors in mice. Gene expression analysis reveals that TZDs induce lipid metabolism pathways while suppressing targets of the Hippo-YAP pathway, Wnt signaling and cancer-related proliferation pathways. Significantly, TZD action appears to be restricted to the high Sox2 expressing cancer stem cell population and is dependent on PPARγ expression. TZDs also affect growth and cell fate by causing the cytoplasmic sequestration of the transcription factors SOX2 and YAP that are required for tumorigenicity. Finally, we identify a TZD-regulated gene signature based on Wnt/Hippo target genes and PPARγ that predicts patient outcomes. Together, this work highlights a novel connection between PPARγ agonist in inducing adipogenesis and mimicking the tumor suppressive hippo pathway. It also illustrates the potential of drug repurposing for TZD-based differentiation therapy for osteosarcoma. PMID:27528232

  10. YAP and TAZ: a nexus for Hippo signaling and beyond

    PubMed Central

    Guan, Kun-Liang

    2015-01-01

    The Hippo pathway is a potent regulator of cellular proliferation, differentiation, and tissue homeostasis. Here we review the regulatory mechanisms of the Hippo pathway and discuss the function of Yes-associated protein (YAP)/transcriptional coactivator with a PDZ-binding domain (TAZ), the prime mediators of the Hippo pathway, in stem cell biology and tissue regeneration. We highlight their activities in both the nucleus and the cytoplasm and discuss their role as a signaling nexus and integrator of several other prominent signaling pathways such as the Wnt, G protein-coupled receptor (GPCR), epidermal growth factor (EGF), BMP/transforming growth factor beta (TGFβ), and Notch pathways. PMID:26045258

  11. Cancer of the oral cavity- a growing concern in the Micronesia: a case report from the Marshall Islands.

    PubMed

    Bhandary, Sangita; Bhandary, Prahlad

    2003-03-01

    Cancer of the oral cavity is of growing concern worldwide. In the Micronesia, there has been a recent increase in use of betel nut and tobacco chewing in addition to already existing problem of smoking and alcohol drinking. These deleterious habits have further added the risk for development of oral cancers in the Marshall Islands. The oral cancers have good prognosis, which is directly related to the early diagnosis and treatment. Advanced staged cancers need mutilating surgery in addition to radiotherapy and carry high mortality rate. The epidemiology, etiology and recent approaches in the management of oral cavity cancer has been discussed along with a case report of advanced cancer of the floor of the mouth from the Marshall Islands.

  12. Integrated analysis identifies microRNA-195 as a suppressor of Hippo-YAP pathway in colorectal cancer.

    PubMed

    Sun, Min; Song, Haibin; Wang, Shuyi; Zhang, Chunxiao; Zheng, Liang; Chen, Fangfang; Shi, Dongdong; Chen, Yuanyuan; Yang, Chaogang; Xiang, Zhenxian; Liu, Qing; Wei, Chen; Xiong, Bin

    2017-03-29

    With persistent inconsistencies in colorectal cancer (CRC) miRNAs expression data, it is crucial to shift toward inclusion of a "pre-laboratory" integrated analysis to expedite effective precision medicine and translational research. Aberrant expression of hsa-miRNA-195 (miR-195) which is distinguished as a clinically noteworthy miRNA has previously been observed in multiple cancers, yet its role in CRC remains unclear. In this study, we performed an integrated analysis of seven CRC miRNAs expression datasets. The expression of miR-195 was validated in The Cancer Genome Atlas (TCGA) datasets, and an independent validation sample cohort. Colon cancer cells were transfected with miR-195 mimic and inhibitor, after which cell proliferation, colony formation, migration, invasion, and dual luciferase reporter were assayed. Xenograft mouse models were used to determine the role of miR-195 in CRC tumorigenicity in vivo. Four downregulated miRNAs (hsa-let-7a, hsa-miR-125b, hsa-miR-145, and hsa-miR-195) were demonstrated to be potentially useful diagnostic markers in the clinical setting. CRC patients with a decreased level of miR-195-5p in tumor tissues had significantly shortened survival as revealed by the TCGA colon adenocarcinoma (COAD) dataset and our CRC cohort. Overexpression of miR-195-5p in DLD1 and HCT116 cells repressed cell growth, colony formation, invasion, and migration. Inhibition of miR-195-5p function contributed to aberrant cell proliferation, migration, invasion, and epithelial mesenchymal transition (EMT). We identified miR-195-5p binding sites within the 3'-untranslated region (3'-UTR) of the human yes-associated protein (YAP) mRNA. YAP1 expression was downregulated after miR-195-5p treatment by qRT-PCR analysis and western blot. Four downregulated miRNAs were shown to be prime candidates for a panel of biomarkers with sufficient diagnostic accuracy for CRC in a clinical setting. Our integrated microRNA profiling approach identified miR-195-5p

  13. Methylglyoxal, a glycolysis side-product, induces Hsp90 glycation and YAP-mediated tumor growth and metastasis

    PubMed Central

    Nokin, Marie-Julie; Durieux, Florence; Peixoto, Paul; Chiavarina, Barbara; Peulen, Olivier; Blomme, Arnaud; Turtoi, Andrei; Costanza, Brunella; Smargiasso, Nicolas; Baiwir, Dominique; Scheijen, Jean L; Schalkwijk, Casper G; Leenders, Justine; De Tullio, Pascal; Bianchi, Elettra; Thiry, Marc; Uchida, Koji; Spiegel, David A; Cochrane, James R; Hutton, Craig A; De Pauw, Edwin; Delvenne, Philippe; Belpomme, Dominique; Castronovo, Vincent; Bellahcène, Akeila

    2016-01-01

    Metabolic reprogramming toward aerobic glycolysis unavoidably induces methylglyoxal (MG) formation in cancer cells. MG mediates the glycation of proteins to form advanced glycation end products (AGEs). We have recently demonstrated that MG-induced AGEs are a common feature of breast cancer. Little is known regarding the impact of MG-mediated carbonyl stress on tumor progression. Breast tumors with MG stress presented with high nuclear YAP, a key transcriptional co-activator regulating tumor growth and invasion. Elevated MG levels resulted in sustained YAP nuclear localization/activity that could be reverted using Carnosine, a scavenger for MG. MG treatment affected Hsp90 chaperone activity and decreased its binding to LATS1, a key kinase of the Hippo pathway. Cancer cells with high MG stress showed enhanced growth and metastatic potential in vivo. These findings reinforce the cumulative evidence pointing to hyperglycemia as a risk factor for cancer incidence and bring renewed interest in MG scavengers for cancer treatment. DOI: http://dx.doi.org/10.7554/eLife.19375.001 PMID:27759563

  14. Circular RNA hsa_circ_0023404 exerts an oncogenic role in cervical cancer through regulating miR-136/TFCP2/YAP pathway.

    PubMed

    Zhang, Jianhua; Zhao, Xinyuan; Zhang, Jin; Zheng, Xuerong; Li, Fenxia

    2018-06-22

    Cervical cancer (CC) is one of the most prevalent malignances among women. However, the mechanism underlying CC development remains elusive. Recently, circular RNAs (circRNAs) have been known as important regulators in tumorigenesis. Whether circRNAs are involved in CC requires to be determined. In the present study, we found that circRNA hsa_circ_0023404 was significantly upregulated in CC tissues compared to adjacent normal tissues. And its overexpression was correlated with poor prognosis in CC patients. Functionally, we showed that knockdown of hsa_circ_0023404 significantly suppressed the proliferation, arrested the cell-cycle progression and inhibited cell migration and invasion in CC. In terms of mechanism, we found that hsa_circ_0023404 acted as a sponge of miR-136 and miR-136 targeted TFCP2, which is an activator of YAP signaling pathway. We showed that hsa_circ_0023404 activated YAP pathway in CC via promoting TFCP2 expression by sponging miR-136, leading to CC development and progression. Taken together, our study for the first time demonstrated the pivot role of hsa_circ_0023404 and revealed a novel regulatory loop of hsa_circ_0023404/miR-136/TFCP2/YAP axis in CC progression. Copyright © 2018 Elsevier Inc. All rights reserved.

  15. YAP and the Hippo pathway in pediatric cancer

    PubMed Central

    Mohamed, Abdalla D.; Gener, Melissa; Li, Weijie; Taboada, Eugenio

    2017-01-01

    ABSTRACT 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. PMID:28616573

  16. YAP and the Hippo pathway in pediatric cancer.

    PubMed

    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.

  17. Distribution and composition of dissolved amino acids in seawater at the Yap Trench

    NASA Astrophysics Data System (ADS)

    Yan, Y.; Xie, L.; Sun, C.; Yang, G.; Ding, H.

    2017-12-01

    The distributions and compositions of total hydrolyzed amino acids ( THAA) , dissolved combined amino acids ( DCAA) and dissolved free amino acids ( DFAA) were investigated after analyzing seawater samples collected from different depths by CTD and from the sediment-seawater interface by the Jiaolong submersible, at 4 stations located in the Yap Trench in June, 2016. The results showed that the average concentration of THAA was (2.44±0.85) μmol /L, while the average concentrations of DCAA and DFAA were (1.97±0.82) μmol /L and (0.47±0.34)μmol /L, respectively.The concentrations of THAA and DCAA displayed a decreasing trend from surface layer to deep layer. In the vertical distribution, the concentrations of THAA varied differently in superficial layer (above 1000 meters). THAA, DFAA and DCAA had a similar concentrations below 1000 meter depth. In the study area, major constituents of dissolved amino acids were methionine, threonine , histidine, glutamic acid , valine and glycine. At the Yap Trench, neutral dissolved amino acids were dominant in total dissolved amino acids. The trend of vertical distributions of various types of THAA, DFAA, and DCAA were similar with the total THAA, DFAA, and DCAA. In sediment-seawater interface, the seawater in the northwest of the trench has high concentrations of THAA and DCAA, while the concentrations of DFAA were similar in the seawater at the sediment-seawater interface.

  18. Transcriptomic profiling of chemical exposure reveals roles of Yap1 in protecting yeast cells from oxidative and other types of stresses.

    PubMed

    Zhang, Chao; Li, Zhouquan; Zhang, Xiaohua; Yuan, Li; Dai, Heping; Xiao, Wei

    2016-01-01

    Transcriptomic profiles are generated by comparing wild-type and the yeast yap1 mutant to various chemicals in an attempt to establish a correlation between this gene mutation and chemical exposure. Test chemicals include ClonNAT as a non-genotoxic agent, methyl methanesulphonate (MMS) as an alkylating agent, tert-butyl hydroperoxide (t-BHP) as an oxidative agent and the mixture of t-BHP and MMS to reflect complex natural exposure. Differentially expressed genes (DEGs) were identified and specific DEGs were obtained by excluding overlapping DEGs with the control group. In the MMS exposure group, deoxyribonucleotide biosynthetic processes were upregulated, while oxidation-reduction processes were downregulated. In the t-BHP exposure group, metabolic processes were upregulated while peroxisome and ion transport pathways were downregulated. In the mixture exposure group, the proteasome pathway was upregulated, while the aerobic respiration was downregulated. Homologue analysis of DEGs related to human diseases showed that many of DEGs were linked to cancer, ageing and neuronal degeneration. These observations confirm that the yap1 mutant is more sensitive to chemicals than wild-type cells and that the susceptible individuals carrying the YAP1-like gene defect may enhance risk to chemical exposure. Hence, this study offers a novel approach to environmental risk assessment, based on the genetic backgrounds of susceptible individuals. Copyright © 2015 John Wiley & Sons, Ltd.

  19. Transcriptional integration of mitogenic and mechanical signals by Myc and YAP

    PubMed Central

    Croci, Ottavio; De Fazio, Serena; Biagioni, Francesca; Donato, Elisa; Caganova, Marieta; Curti, Laura; Doni, Mirko; Sberna, Silvia; Aldeghi, Deborah; Biancotto, Chiara; Verrecchia, Alessandro; Olivero, Daniela; Amati, Bruno

    2017-01-01

    Mammalian cells must integrate environmental cues to determine coherent physiological responses. The transcription factors Myc and YAP–TEAD act downstream from mitogenic signals, with the latter responding also to mechanical cues. Here, we show that these factors coordinately regulate genes required for cell proliferation. Activation of Myc led to extensive association with its genomic targets, most of which were prebound by TEAD. At these loci, recruitment of YAP was Myc-dependent and led to full transcriptional activation. This cooperation was critical for cell cycle entry, organ growth, and tumorigenesis. Thus, Myc and YAP–TEAD integrate mitogenic and mechanical cues at the transcriptional level to provide multifactorial control of cell proliferation. PMID:29141911

  20. Fine root productivity varies along nitrogen and phosphorus gradients in high-rainfall mangrove forests of Micronesia

    USGS Publications Warehouse

    Cormier, Nicole; Twilley, Robert R.; Ewel, Katherine C.; Krauss, Ken W.

    2015-01-01

    Belowground biomass is thought to account for much of the total biomass in mangrove forests and may be related to soil fertility. The Yela River and the Sapwalap River, Federated States of Micronesia, contain a natural soil resource gradient defined by total phosphorus (P) density ranging from 0.05 to 0.42 mg cm−3 in different hydrogeomorphic settings. We used this fertility gradient to test the hypothesis that edaphic conditions constrain mangrove productivity through differential allocation of biomass to belowground roots. We removed sequential cores and implanted root ingrowth bags to measure in situ biomass and productivity, respectively. Belowground root biomass values ranged among sites from 0.448 ± 0.096 to 2.641 ± 0.534 kg m−2. Root productivity (roots ≤20 mm) did not vary significantly along the gradient (P = 0.3355) or with P fertilization after 6 months (P = 0.2968). Fine root productivity (roots ≤2 mm), however, did vary significantly among sites (P = 0.0363) and ranged from 45.88 ± 21.37 to 118.66 ± 38.05 g m−2 year−1. The distribution of total standing root biomass and fine root productivity followed patterns of N:P ratios as hypothesized, with larger root mass generally associated with lower relative P concentrations. Many of the processes of nutrient acquisition reported from nutrient-limited mangrove forests may also occur in forests of greater biomass and productivity when growing along soil nutrient gradients.

  1. aPKCζ-dependent Repression of Yap is Necessary for Functional Restoration of Irradiated Salivary Glands with IGF-1.

    PubMed

    Chibly, Alejandro M; Wong, Wen Yu; Pier, Maricela; Cheng, Hongqiang; Mu, Yongxin; Chen, Ju; Ghosh, Sourav; Limesand, Kirsten H

    2018-04-20

    Xerostomia and salivary hypofunction often result as a consequence of radiation therapy for head and neck cancers, which are diagnosed in roughly 60,000 individuals every year in the U.S. Due to the lack of effective treatments for radiation-induced salivary hypofunction, stem cell-based therapies have been suggested to regenerate the irradiated salivary glands. Pharmacologically, restoration of salivary gland function has been accomplished in mice by administering IGF-1 shortly after radiation treatment, but it is not known if salivary stem and progenitor cells play a role. We show that radiation inactivates aPKCζ and promotes nuclear redistribution of Yap in a population of label-retaining cells in the acinar compartment of the parotid gland (PG)- which comprises a heterogeneous pool of salivary progenitors. Administration of IGF-1 post-radiation maintains activation of aPKCζ and partially rescues Yap's cellular localization in label retaining cells, while restoring salivary function. Finally, IGF-1 fails to restore saliva production in mice lacking aPKCζ, demonstrating the importance of the kinase as a potential therapeutic target.

  2. Investigative study of a diode-pumped continuous-wave Tm:YAP laser as an efficient 1.94 μm pump source

    NASA Astrophysics Data System (ADS)

    Kwiatkowski, Jacek; Zendzian, Waldemar; Jabczynski, Jan K.

    2016-12-01

    A detailed study of a Tm:YAP laser in continuous-wave (CW), single-pass end-pumped by a 793 nm diode laser is presented. The laser based on c-cut 3 at. % Tm:YAP crystal was experimentally examined and presented in the dependence on transmittance and radius of curvature of output coupling mirrors. A detailed spectral analysis was presented. The influence of a heat-sink cooling water temperature on the laser performance was studied. At room temperature, for an output coupling transmission of 19.5%, the maximum CW output power of 4.53 W was achieved, corresponding to a slope efficiency of 41.5% and an optical-to-optical conversion efficiency of 25.7% with respect to the incident pump power, respectively. We have shown that the output spectrum at a certain wavelength (e.g. 1940 nm) for a given pump power can be realized via the change of resonator parameters (OC transmittance, mode size).

  3. A tropical freshwater wetland: I Structure, growth, and regeneration

    Treesearch

    James A. Allen; Ken W. Krauss; Katherine C. Ewel; Bobby D Keeland; Erick E. Waguk

    2005-01-01

    Forested wetlands dominated by (Terminalia carolinensis) are endemic to Micronesia but common only on the island of Kosrae, Federated States of Micronesia. On Kosrae, these forests occur on Nansepsep, Inkosr, and Sonahnpil soil types, which differ in degree of flooding and soil saturation. We compared forest structure, growth, nutrition, and...

  4. Trust Territory of the Pacific Islands. 1978 Annual Report.

    ERIC Educational Resources Information Center

    Department of the Interior, Washington, DC.

    Social, political, and economic advances in Micronesia during fiscal year 1978 are highlighted in this annual report to the United States Secretary of the Interior. Introductory chapters summarize the year's achievements and present major events in chronological order. Items include creation of a 200-mile fishery zone for Micronesia and provision…

  5. Emerging role of Hippo signalling in pancreatic biology: YAP re-expression and plausible link to islet cell apoptosis and replication.

    PubMed

    Sharma, Anjana; Yerra, Veera Ganesh; Kumar, Ashutosh

    2017-02-01

    Diabetes mellitus is an ailment that develops when the functional capacity of the pancreas does not meet the metabolic requirements of the whole body, either due to insulin insufficiency or resistance to insulin action. Current therapies that control glycaemia are limited by their unwanted effects or their inability to prevent the development of long-term complications. Regeneration and replacement of beta cell therapies are shaping the goals of future management of diabetes. The Hippo pathway, first discovered in Drosophila melanogaster, plays a vital role in controlling the organ size. Nuclear recruitment of YAP/TAZ (Yes-associated protein/transcriptional co-activator with PDZ-binding motif), a mammalian analogue of Yorkie protein found in Drosophila, activates cell proliferation and inhibits apoptosis. YAP was found to regulate early pancreatic development followed by downregulation during Ngn3-specific endocrine lineage maturation corresponding to their mitotic quiescence. Recent evidences have shown that optimum modulation of upstream kinases in the Hippo signalling pathway may lead to apoptosis inhibition and renewal of progenitor as well as stem cells in case of tissue or cell injury. This article reviews the evidences linking the role of various components of the Hippo pathway to pancreatic regeneration. In particular, the focus is on the beneficial role of induced YAP expression and its nuclear distribution on apoptosis and replication of adult pancreatic β islets. This approach may be of immense significance towards our fight against diabetes; thus, more insightful research is warranted in the area of Hippo signalling pathway and its involvement in pancreatic regeneration. Copyright © 2016 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

  6. Zika Virus in the Americas: A Review for Clinicians.

    PubMed

    Sampathkumar, Priya; Sanchez, Joyce L

    2016-04-01

    Zika virus has recently emerged as a new public health threat. An arthropod-borne virus named after the Zika forest in Uganda, it was first discovered in 1947. The virus caused only sporadic cases of Zika infection in Africa and Southeast Asia until 2007, when the first large outbreak occurred in the Yap State in the Federated States of Micronesia. Another outbreak in French Polynesia in 2013 was notable for being associated temporally with an increase in cases of Guillain-Barré syndrome. In 2015, the virus was first reported in Brazil and since then has spread explosively through several additional countries in South and Central America and the Caribbean. Simultaneously, several of these countries have seen a dramatic increase in the incidence of infants born with microcephaly. The rapid spread of Zika virus through the Americas, together with the association of infection with microcephaly and Guillain-Barré syndrome, has resulted in the World Health Organization declaring a public health emergency. Zika virus has the potential to spread to new areas where the Aedes mosquito vector is present and therefore presents a risk to the United States. This concise review describes the clinical features of Zika virus infection and provides advice for clinicians on counseling travelers and others about the disease. Copyright © 2016 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

  7. Mcps-range photon-counting X-ray computed tomography system utilizing an oscillating linear-YAP(Ce) photon detector

    NASA Astrophysics Data System (ADS)

    Oda, Yasuyuki; Sato, Eiichi; Abudurexiti, Abulajiang; Hagiwara, Osahiko; Osawa, Akihiro; Matsukiyo, Hiroshi; Enomoto, Toshiyuki; Watanabe, Manabu; Kusachi, Shinya; Sugimura, Shigeaki; Endo, Haruyuki; Sato, Shigehiro; Ogawa, Akira; Onagawa, Jun

    2011-07-01

    High-speed X-ray photon counting is useful for discriminating photon energy, and the counting can be used for constructing an X-ray computed tomography (CT) system. A photon-counting X-ray CT system consists of an X-ray generator, a turntable, an oscillation linear detector, a two-stage controller, a multipixel photon counter (MPPC) module, a 1.0 mm-thick crystal (scintillator) of YAP(Ce) (cerium-doped yttrium aluminum perovskite), a counter card (CC), and a personal computer (PC). Tomography is accomplished by repeating the linear scanning and the rotation of an object, and projection curves of the object are obtained by the linear scanning using the detector consisting of an MPPC module, the YAP(Ce), and a scan stage. The pulses of the event signal from the module are counted by the CC in conjunction with the PC. Because the lower level of the photon energy was roughly determined by a comparator in the module, the average photon energy of the X-ray spectra increased with increase in the lower-level voltage of the comparator at a constant tube voltage. The maximum count rate was approximately 3 Mcps (mega counts per second), and photon-counting CT was carried out.

  8. Micronesian Texts for the K-12 Reader. A Selection Guide.

    ERIC Educational Resources Information Center

    Carriveau, Kenneth L., Jr., Comp.; Cunningham, Lawrence J., Comp.

    Micronesia is an ethno-geographical grouping of over 2000 islands spread out over 7,000,000 square kilometers of the Pacific Ocean and includes the Republic of Kiribati, the Republic of Nauru, the Republic of the Marshall Islands, the Republic of Palau, the Federated States of Micronesia, the Commonwealth of the Northern Mariana Islands, and Guam,…

  9. The response of a fast scintillator screen (YAP:Ce) to low energy ions (0-40 keV) and its use to detect fast-ion-loss in stellarator TJ-II

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Martínez, M., E-mail: marcos.martinez@externos.ciemat.es; Zurro, B.; Baciero, A.

    2016-11-15

    A systematic study of scintillation materials was undertaken to improve the time resolution of the fast ion diagnostic currently installed at TJ-II stellarator. It was found that YAP:Ce (formula YAlO{sub 3}:Ce, Yttrium Aluminum Perovskite doped with Cerium) ionoluminescence offers better sensitivity and time response compared to the standard detector material, SrGa{sub 2}S{sub 4}:Eu (TG-Green), currently used in TJ-II. A comparison between both materials was carried out by irradiating them with H{sup +} ions of up to 40 keV using a dedicated laboratory setup. It is found that for the low energy ions of interest at TJ-II, YAP:Ce offers 20 timesmore » higher sensitivity than TG-Green and much faster decay time, 27 ns versus 540 ns. It is expected that the use of YAP:Ce in combination with a faster data acquisition and an ion counting software as part of the TJ-II ion luminescent probe will provide 20 times faster data on ion loss.« less

  10. Morin impedes Yap nuclear translocation and fosters apoptosis through suppression of Wnt/β-catenin and NF-κB signaling in Mst1 overexpressed HepG2 cells

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Perumal, NaveenKumar; Perumal, MadanKumar; Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390

    Recent clinical and experimental evidences strongly acclaim Yes-associated protein (Yap), a key oncogenic driver in liver carcinogenesis, as a therapeutic target. Of the known multiple schemes to inhibit Yap activity, activation of Mammalian Sterile 20-like Kinase 1 (Mst1), an upstream regulator of Yap, appears to be a promising one. In this study, we hypothesize that morin, a bioflavonoid, mediates its anti-cancer effect through the activation of Mst1/hippo signaling in liver cancer cells. To test this hypothesis, both full length Mst1 (F-Mst1) and kinase active N-terminal Mst1 (N-Mst1)-overexpressed HepG2 cells were used. Exposure of F-Mst1 overexpressed HepG2 cells to morin activatedmore » Mst1 by caspase-3 cleavage and thereby inhibited Yap nuclear translocation and fostered apoptosis. Morin suppressed NF-κB p65 and Wnt/β-catenin signaling through Mst1 activation via cleavage and phosphorylation, leading to cell death. Annexin-V/PI staining further confirmed the induction of apoptosis in morin treated F-Mst1 overexpressed cells. The present study shows that morin targets cell survival molecules such as NF-κB p65 and β-catenin through activation of hippo signaling. Therefore, morin could be considered as a potential anti-cancer agent against liver cancer. - Highlights: • Morin induced cytotoxicity in cultured HepG2 cells. • Morin activated hippo pathway via Mst1 activation in transfected HepG2 cells. • Morin suppressed Wnt/β-catenin signaling and induced G0/G1 cell cycle arrest. • Morin inhibited NF-κB signaling through Mst1 activation in transfected HepG2 cells. • Morin potentiates apoptosis through Mst1-JNK-caspase mediated mechanism in HepG2 cells.« less

  11. Silibinin Induced Human Glioblastoma Cell Apoptosis Concomitant with Autophagy through Simultaneous Inhibition of mTOR and YAP.

    PubMed

    Bai, Zhuan-Li; Tay, Vincent; Guo, Shu-Zhong; Ren, Juan; Shu, Mao-Guo

    2018-01-01

    Silibinin, also known as silybin, is the major flavonolignan isolated from Silybum marianum . Although previous reports demonstrated that silibinin exhibits significant tumor suppressor activities in various cancers by promoting cell apoptosis, it was also shown to trigger autophagy to counteract apoptosis induced by exogenous stresses in several types of cells. However, there is no report to address the role of silibinin induced autophagy in human A172 and SR glioblastoma cells. Our study showed that silibinin treatment not only inhibited the metabolic activities of glioblastoma cells but also promoted their apoptosis through the regulation of caspase 3 and PARP-1 in concentration- and time-dependent manners. Meanwhile, silibinin induced autophagy through upregulation of microtubule-associated protein a light chain 3- (LC3-) II. And autophagy inhibition with chloroquine, a lysosomotropic agent, significantly enhanced silibinin induced glioblastoma cell apoptosis. Moreover, silibinin dose-dependently downregulated the phosphorylation levels of mTOR at Ser-2448, p70S6K at Thr-389, and 4E-BP1 at Thr-37/46. Furthermore, the expression of YAP, the downstream effector of Hippo signal pathway, was also suppressed by silibinin. These results suggested that silibinin induced glioblastoma cell apoptosis concomitant with autophagy which might be due to simultaneous inhibition of mTOR and YAP and silibinin induced autophagy exerted a protective role against cell apoptosis in both A172 and SR cells.

  12. Coral skeletal Tin and Copper Concentration at Pohnpei, Micronesia, as a potential proxy for marine pollution

    NASA Astrophysics Data System (ADS)

    Inoue, M.; Suzuki, A.; Nohara, M.; Kan, H.; Edward, A.; Kawahata, H.

    2002-12-01

    Coral reefs are increasingly threatened by human activities such as industrialization, sewage discharge, dredging, deforestation and so on. The annually-banded coral (Porites sp.) collected from Pohnpei Island, Micronesia, recorded fluctuations of copper (Cu) and tin (Sn) contents in ambient seawater for about last 40 years. Both the elements are present in antifouling marine paints. Especially, Sn has often been used in the form of tributyltin (TBT) compound. In general, pretreatment of coral skeleton is conducted in order to remove contaminations due to coral coring and/or sample storage and then lattice-bound metals are determined as a potential proxy for marine pollution. We conducted a preliminary experimental treatment consisting of 9 cleaning steps. Based on a stepwise pretreatment examination, we found that skeletal Sn and Cu, not only inside but also outside of aragonite lattice, have potential for use as pollution indicators. High values of extra-skeletal Cu/Ca and Sn/Ca atomic ratios were found between late 1960s and late 1980s during a period of active use of TBT-based antifouling paints worldwide. However, significant decrease in both the ratios since the beginning of 1990s can be attributed to regulation of use of TBT on cargo ships by the developed countries such as the USA, Japan and Australia.

  13. Thermal effect of diode-pumped solid state lasers based on composite crystals

    NASA Astrophysics Data System (ADS)

    Hao, Ming-ming; Lu, Guo-guang; Zhu, Hong-bo; Huang, Yun; En, Yun-fei

    2013-12-01

    Thermal effect of diode-pumped solid-state lasers (DPSSL) based on YAP/Tm:YAP composite crystal is studied by using of finite element method (FEM). It is found that the peak temperature in a composite rod decreases to less than 80% of that in a non-composite crystal. Thermal stress of composite rod is obviously reduced to less than 70% comparing with non-composite crystal. It is also demonstrated that length of thermal lens unchanged with increasing of un-doped crystal length, which means that beam quality of composite laser wouldn't be improved by non-composite crystal. Therefore, it is concluded that using composite crystal would benefit for the properties of temperature and heat stress while insignificance for beam quality of DPSSL.

  14. Role of YAP/TAZ in cell-matrix adhesion-mediated signalling and mechanotransduction

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Dupont, Sirio, E-mail: sirio.dupont@unipd.it

    2016-04-10

    Signalling from the extracellular matrix (ECM) is a fundamental cellular input that sustains proliferation, opposes cell death and regulates differentiation. Through integrins, cells perceive both the chemical composition and physical properties of the ECM. In particular, cell behaviour is profoundly influenced by the mechanical elasticity or stiffness of the ECM, which regulates the ability of cells to develop forces through their contractile actomyosin cytoskeleton and to mature focal adhesions. This mechanosensing ability affects fundamental cellular functions, such that alterations of ECM stiffness is nowadays considered not a simple consequence of pathology, but a causative input driving aberrant cell behaviours. Wemore » here discuss recent advances on how mechanical signals intersect nuclear transcription and in particular the activity of YAP/TAZ transcriptional coactivators, known downstream transducers of the Hippo pathway and important effectors of ECM mechanical cues.« less

  15. YAP1 and VGLL3, encoding two cofactors of TEAD transcription factors, are amplified and overexpressed in a subset of soft tissue sarcomas.

    PubMed

    Hélias-Rodzewicz, Zofia; Pérot, Gaëlle; Chibon, Frédéric; Ferreira, Céline; Lagarde, Pauline; Terrier, Philippe; Coindre, Jean-Michel; Aurias, Alain

    2010-12-01

    In a series of 404 adult soft tissue sarcomas, analyzed by array-CGH, we have observed in approximately 10% of them a genomic amplification of either chromosome bands 11q22 or 3p12. These two amplicons likely target the YAP1 and VGLL3 genes, respectively. Both genes encode proteins that are cofactors of the TEAD family of transcription factors. Very good correlations between amplification and expression levels were observed. Welch test analyses of transcriptome data demonstrate that tumors with amplicons share a large set of upregulated and downregulated genes. Inhibition of YAP1 and VGLL3 in cell lines with these amplifications/overexpressions leads to similar phenotypes: decrease of proliferation rate, and to a lesser extent decrease of migration properties. These data, and the fact that these amplicons are observed either in de-differentiated liposarcomas or in undifferentiated pleomorphic sarcomas, suggest that these genetics events could be involved in oncogenesis and progression of soft tissue sarcomas. © 2010 Wiley-Liss, Inc.

  16. Downed wood in Micronesian mangrove forests

    USGS Publications Warehouse

    Allen, J.A.; Ewel, K.C.; Keeland, B.D.; Tara, T.; Smith, T. J.

    2000-01-01

    Dead, downed wood is an important component of upland forest and aquatic ecosystems, but its role in wetland ecosystems, including mangroves, is poorly understood. We measured downed wood in ten sites on the western Pacific islands of Kosrae, Pohnpei, and Yap, all located within the Federated States of Micronesia. Our goals were to examine patterns of variability in the quantity of downed wood in these mangrove ecosystems, provide a general characterization of downed wood in a region with no previously published accounts, and investigate the relationship between harvesting practices and the amount of downed wood. The overall mean volume of downed wood at our study sites was estimated to be 60.8 m3 ha-1 (20.9 t ha-1), which is greater than most published data for forested wetlands. There were significant differences among islands, with the sites on Kosrae (104.2 m3 ha-1) having a much greater mean volume of downed wood than those on Pohnpei (43.1 m3 ha-1) or Yap (35.1 m3 ha-1). Part of the difference among islands may be attributable to differences in stand age and structure, but the most important factor seems to be the greater amount of wood harvesting on Kosrae, coupled with a low efficiency of use of cut trees. Of a total of 45 cut trees examined on Kosrae, no wood had been removed from 18 (40%); these are believed to be trees cut down because other, more valuable, trees were caught on them as they were felled. Of the other 27 trees, only 24 to 42% of the stem volume (to a 10 cm top) was removed from the forest, the amount varying by species. The impacts of current harvesting practices are unknown but may include important effects on tree regeneration and the abundance and species composition of crab populations.

  17. Exploiting RhoA Mutations in Diffuse Gastric Adenocarcinoma and Targeting Intertwined RhoA and Yap1 Pathways for Therapeutic Advantage

    DTIC Science & Technology

    2017-10-01

    fluorescent marker mOrange into MIT’s Dr. Zhang’s pLenti- Crispr -v2, making transfection into mammalian cells easier and visible under fluorescent...microscope, it the same time, those cells under Crispr editing are also selectable with puromycin. We have successfully knocked-out RhoA expression in cell...15. SUBJECT TERMS RHOA, YAP1, mouse model, CRISPR -CAS9, plasmid, cell lines, diffuse gastric adenocarcinoma, mutations, gastric adenocarcinoma 16

  18. ZO-2 silencing induces renal hypertrophy through a cell cycle mechanism and the activation of YAP and the mTOR pathway

    PubMed Central

    Domínguez-Calderón, Alaide; Ávila-Flores, Antonia; Ponce, Arturo; López-Bayghen, Esther; Calderón-Salinas, José-Víctor; Luis Reyes, José; Chávez-Munguía, Bibiana; Segovia, José; Angulo, Carla; Ramírez, Leticia; Gallego-Gutiérrez, Helios; Alarcón, Lourdes; Martín-Tapia, Dolores; Bautista-García, Pablo; González-Mariscal, Lorenza

    2016-01-01

    Renal compensatory hypertrophy (RCH) restores normal kidney function after disease or loss of kidney tissue and is characterized by an increase in organ size due to cell enlargement and not to cell proliferation. In MDCK renal epithelial cells, silencing of the tight junction protein zona occludens 2 (ZO-2 KD) induces cell hypertrophy by two mechanisms: prolonging the time that cells spend at the G1 phase of the cell cycle due to an increase in cyclin D1 level, and augmenting the rate of protein synthesis. The latter is triggered by the nuclear accumulation and increased transcriptional activity of Yes-associated protein (YAP), the main target of the Hippo pathway, which results in decreased expression of phosphatase and tensin homologue. This in turn increased the level of phosphatidylinositol (3,4,5)-triphosphate, which transactivates the Akt/mammalian target of rapamycin pathway, leading to activation of the kinase S6K1 and increased synthesis of proteins and cell size. In agreement, in a rat model of uninephrectomy, RCH is accompanied by decreased expression of ZO-2 and nuclear expression of YAP. Our results reveal a novel role of ZO-2 as a modulator of cell size. PMID:27009203

  19. Aedes hensilli as a Potential Vector of Chikungunya and Zika Viruses

    PubMed Central

    Ledermann, Jeremy P.; Guillaumot, Laurent; Yug, Lawrence; Saweyog, Steven C.; Tided, Mary; Machieng, Paul; Pretrick, Moses; Marfel, Maria; Griggs, Anne; Bel, Martin; Duffy, Mark R.; Hancock, W. Thane; Ho-Chen, Tai; Powers, Ann M.

    2014-01-01

    An epidemic of Zika virus (ZIKV) illness that occurred in July 2007 on Yap Island in the Federated States of Micronesia prompted entomological studies to identify both the primary vector(s) involved in transmission and the ecological parameters contributing to the outbreak. Larval and pupal surveys were performed to identify the major containers serving as oviposition habitat for the likely vector(s). Adult mosquitoes were also collected by backpack aspiration, light trap, and gravid traps at select sites around the capital city. The predominant species found on the island was Aedes (Stegomyia) hensilli. No virus isolates were obtained from the adult field material collected, nor did any of the immature mosquitoes that were allowed to emerge to adulthood contain viable virus or nucleic acid. Therefore, laboratory studies of the probable vector, Ae. hensilli, were undertaken to determine the likelihood of this species serving as a vector for Zika virus and other arboviruses. Infection rates of up to 86%, 62%, and 20% and dissemination rates of 23%, 80%, and 17% for Zika, chikungunya, and dengue-2 viruses respectively, were found supporting the possibility that this species served as a vector during the Zika outbreak and that it could play a role in transmitting other medically important arboviruses. PMID:25299181

  20. 7 CFR 3575.2 - Definitions.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... closely related by blood or by marriage, or within the same household, such as a spouse, parent, child... Federated States of Micronesia. State Bond Banks and State Bond Pools. An entity authorized by the State to...

  1. CO2 and Nd:YAP laser interaction with lithium disilicate and Zirconia dental ceramics: A preliminary study

    NASA Astrophysics Data System (ADS)

    Rocca, Jean-Paul; Fornaini, Carlo; Brulat-Bouchard, Nathalie; Bassel Seif, Samy; Darque-Ceretti, Evelyne

    2014-04-01

    Lithium disilicate and Zirconia ceramics offer a high level of accuracy when used in prosthetic dentistry. Their bonding using different resins is highly dependent on micro-mechanical interlocking and adhesive chemical bonding. Investigation of the performances of high strength ceramics when their surface is modified for chemical and mechanical bonding is then required. The aim of this study is to investigate the possibility of using laser for surface treatment of different high strength CAD/CAM ceramics and thus to improve their mechanical and chemical properties. Thirty two CAD/CAM ceramic discs were divided into two different groups: lithium disilicate ceramics (IPS e.max CAD®, Ivoclar, Vivadent, Italy) and Zirconia ceramics (IPS e.max ZirCAD®, Ivoclar, Vivadent, Italy). The Laser surface treatment was performed by Carbon Dioxide laser (Dream Pulse Laser®, Daeshin Enterprise Corp., Korea) at 20 W, 25 W and 30 W CW and by Neodymium Yttrium Aluminum Perovskite laser (Nd:YAP Lokki®, Lobel Medical, France) at 10 W and 30 Hz. Physical modifications of the irradiated ceramic discs were observed by scanning electron microscopy (SEM) and chemically analyzed by Energy-Dispersive Spectroscopy (EDS). Surface wettability was tested using the water drop test and the crystalline structure was investigated using X-ray diffraction (XRD). The macroscopic observation showed a shinier structure in all the groups, while at the SEM observation only CO2 25 W and 30 W treated groups showed cracks and fissures. In the conditions of this study, CO2 laser and Nd:YAP laser with the parameters used create chemical and physical surface modifications of the ceramics, indicating the possibility of an improvement in adhesion of the tested ceramics.

  2. Hippo/YAP-mediated rigidity-dependent motor neuron differentiation of human pluripotent stem cells

    NASA Astrophysics Data System (ADS)

    Sun, Yubing; Yong, Koh Meng Aw; Villa-Diaz, Luis G.; Zhang, Xiaoli; Chen, Weiqiang; Philson, Renee; Weng, Shinuo; Xu, Haoxing; Krebsbach, Paul H.; Fu, Jianping

    2014-06-01

    Our understanding of the intrinsic mechanosensitive properties of human pluripotent stem cells (hPSCs), in particular the effects that the physical microenvironment has on their differentiation, remains elusive. Here, we show that neural induction and caudalization of hPSCs can be accelerated by using a synthetic microengineered substrate system consisting of poly(dimethylsiloxane) micropost arrays (PMAs) with tunable mechanical rigidities. The purity and yield of functional motor neurons derived from hPSCs within 23 days of culture using soft PMAs were improved more than fourfold and tenfold, respectively, compared with coverslips or rigid PMAs. Mechanistic studies revealed a multi-targeted mechanotransductive process involving Smad phosphorylation and nucleocytoplasmic shuttling, regulated by rigidity-dependent Hippo/YAP activities and actomyosin cytoskeleton integrity and contractility. Our findings suggest that substrate rigidity is an important biophysical cue influencing neural induction and subtype specification, and that microengineered substrates can thus serve as a promising platform for large-scale culture of hPSCs.

  3. Bayerotrochus delicatus, a new species of pleurotomariid from Yap Seamount, near Palau, Western Pacific (Gastropoda: Pleurotomariidae).

    PubMed

    Zhang, Suping; Zhang, Shuqian; Wei, Peng

    2016-09-05

    A new pleurotomariid species, Bayerotrochus delicatus sp. nov., collected from the Yap Seamount, near Palau, Western Pacific (8°51'N, 137°47'E), is described and illustrated. The generic assignment is based on morphology and molecular evidence. The new species is characterized by a small, depressed trochoid shell sculptured with delicate spiral threads and axial riblets; the shell surface is lustrous orange mottled with iridescence. The radula has a formula of R + 3 + 23 + (ca. 30) + (ca. 65) + 9. These features can separate Bayerotrochus delicatus sp. nov. from its congeners. To determine the relationships of Bayerotrochus delicatus sp. nov. with other pleurotomariids, a neighbor-joining (NJ) tree was established using available sequences of cytochrome c oxidase I gene (COI) from this study and GenBank.

  4. Mapping of hazard from rainfall-triggered landslides in developing countries: Examples from Honduras and Micronesia

    USGS Publications Warehouse

    Harp, E.L.; Reid, M.E.; McKenna, J.P.; Michael, J.A.

    2009-01-01

    Loss of life and property caused by landslides triggered by extreme rainfall events demonstrates the need for landslide-hazard assessment in developing countries where recovery from such events often exceeds the country's resources. Mapping landslide hazards in developing countries where the need for landslide-hazard mitigation is great but the resources are few is a challenging, but not intractable problem. The minimum requirements for constructing a physically based landslide-hazard map from a landslide-triggering storm, using the simple methods we discuss, are: (1) an accurate mapped landslide inventory, (2) a slope map derived from a digital elevation model (DEM) or topographic map, and (3) material strength properties of the slopes involved. Provided that the landslide distribution from a triggering event can be documented and mapped, it is often possible to glean enough topographic and geologic information from existing databases to produce a reliable map that depicts landslide hazards from an extreme event. Most areas of the world have enough topographic information to provide digital elevation models from which to construct slope maps. In the likely event that engineering properties of slope materials are not available, reasonable estimates can be made with detailed field examination by engineering geologists or geotechnical engineers. Resulting landslide hazard maps can be used as tools to guide relocation and redevelopment, or, more likely, temporary relocation efforts during severe storm events such as hurricanes/typhoons to minimize loss of life and property. We illustrate these methods in two case studies of lethal landslides in developing countries: Tegucigalpa, Honduras (during Hurricane Mitch in 1998) and the Chuuk Islands, Micronesia (during Typhoon Chata'an in 2002).

  5. Notch3 inhibits epithelial–mesenchymal transition by activating Kibra-mediated Hippo/YAP signaling in breast cancer epithelial cells

    PubMed Central

    Zhang, X; Liu, X; Luo, J; Xiao, W; Ye, X; Chen, M; Li, Y; Zhang, G-J

    2016-01-01

    Invasion, metastasis and chemoresistance are leading causes of death in breast cancer patients. A vital change of epithelial cells, epithelial–mesenchymal transition (EMT), is involved in these processes. Unfortunately, the molecular mechanisms controlling EMT remain to be elucidated. Our previous studies have shown that ectopic N3ICD expression inhibits EMT in MDA-MB-231, a triple-negative breast cancer (TNBC) epithelial cell line. To decipher the mechanism, we performed in-depth studies. Specifically, we found that overexpressing N3ICD transcriptionally upregulated the expression of Kibra, an upstream member of the Hippo pathway. Correspondingly, we also observed that phosphorylated Hippo pathway core kinases, including Lats1/2 and MST1/2, were increased and decreased by overexpressing and knocking down Notch3, respectively. Furthermore, we found that the oncogenic transcriptional coactivator yes-associated protein (YAP), which is negatively regulated by the Hippo pathway, was inhibited by overexpressing N3ICD in breast cancer epithelial cells. The ability of Kibra to inhibit EMT has been previously reported. We thus speculated that Notch3 inhibition of EMT is mediated by upregulated Kibra. To verify this hypothesis, a rescue experiment was performed. Evidently, the ability of Notch3 to inhibit EMT can be countered by knocking down Kibra expression. These data suggest that Notch3 inhibits EMT by activating the Hippo/YAP pathway by upregulating Kibra in breast cancer epithelial cells, and Kibra may be a downstream effector of Notch3. These findings deepen our understanding of EMT in both development and disease, and will undoubtedly help to provide new therapeutic strategies for interfering with cancer invasion and metastasis, especially for TNBC. PMID:27841855

  6. The reproductive cycle of the humbug damselfish Dascyllus aruanus according to the changes in lunar phase in Micronesia

    NASA Astrophysics Data System (ADS)

    Choi, Ji Yong; Kim, Na Na; Lee, Dae-Won; Choi, Young-Ung; Choi, Cheol Young

    2017-09-01

    The moon is known to be an environmental factor that controls the reproductive cycle of fish, and fish have evolved a variety of reproduction patterns depending on the lunar phase. In this study, we examined the relationship between lunar phases and the reproductive cycle of the humbug damselfish Dascyllus aruanus inhabiting Weno Island, Chuuk Lagoon, Micronesia. We divided the one-month lunar cycle into eight phases, and measured the features of moonlight (peak wavelength and intensity) and indicators of fish maturity [gonadosomatic index (GSI) and sex hormones] in relation to the eight lunar phases. In addition, we investigated the daily rhythms of sex hormones in fish ovaries during the full moon phase. The results showed that the peak wavelength of moonlight was 430 nm (blue wavelength region) regardless of the lunar phase, and that moonlight intensity was highest during a full moon at 02:00. Furthermore, the GSI and sex hormones were both higher around the full moon phase. These findings support the hypothesis that humbug damselfish spawn once a month and that this event occurs at full moon, which is the phase of the moon with the strongest intensity. Based on these findings, we predict that blue wavelength, the dominant wavelength of moonlight, is one of the environmental factors influencing the monthly spawning of D. aruanus.

  7. Afro-derived Brazilian populations: male genetic constitution estimated by Y-chromosomes STRs and AluYAP element polymorphisms.

    PubMed

    Ribeiro, Guilherme Galvarros Bueno Lobo; De Lima, Reginaldo Ramos; Wiezel, Cláudia Emília Vieira; Ferreira, Luzitano Brandão; Sousa, Sandra Mara Bispo; Rocha, Dulce Maria Sucena; Canas, Maria do Carmo Tomitão; Nardelli-Costa, Juliana; Klautau-Guimarães, Maria De Nazaré; Simões, Aguinaldo Luiz; Oliveira, Silviene Fabiana

    2009-01-01

    The genetic constitution of Afro-derived Brazilian populations is barely studied. To improve that knowledge, we investigated the AluYAP element and five Y-chromosome STRs (DYS19, DYS390, DYS391, DYS392, and DYS393) to estimate ethnic male contribution in the constitution of four Brazilian quilombos remnants: Mocambo, Rio das Rãs, Kalunga, and Riacho de Sacutiaba. Results indicated significant differences among communities, corroborating historical information about the Brazilian settlement. We concluded that besides African contribution, there was a great European participation in the constitution of these four populations and that observed haplotype variability could be explained by gene flow to quilombos remnants and mutational events in microsatellites (STRs). (c) 2009 Wiley-Liss, Inc.

  8. The resistance of the yeast Saccharomyces cerevisiae to the biocide polyhexamethylene biguanide: involvement of cell wall integrity pathway and emerging role for YAP1.

    PubMed

    Elsztein, Carolina; de Lucena, Rodrigo M; de Morais, Marcos A

    2011-08-19

    Polyhexamethylene biguanide (PHMB) is an antiseptic polymer that is mainly used for cleaning hospitals and pools and combating Acantamoeba infection. Its fungicide activity was recently shown by its lethal effect on yeasts that contaminate the industrial ethanol process, and on the PE-2 strain of Saccharomyces cerevisiae, one of the main fermenting yeasts in Brazil. This pointed to the need to know the molecular mechanism that lay behind the cell resistance to this compound. In this study, we examined the factors involved in PHMB-cell interaction and the mechanisms that respond to the damage caused by this interaction. To achieve this, two research strategies were employed: the expression of some genes by RT-qPCR and the analysis of mutant strains. Cell Wall integrity (CWI) genes were induced in the PHMB-resistant Saccharomyces cerevisiae strain JP-1, although they are poorly expressed in the PHMB-sensitive Saccharomyces cerevisiae PE2 strain. This suggested that PHMB damages the glucan structure on the yeast cell wall. It was also confirmed by the observed sensitivity of the yeast deletion strains, Δslg1, Δrom2, Δmkk2, Δslt2, Δknr4, Δswi4 and Δswi4, which showed that the protein kinase C (PKC) regulatory mechanism is involved in the response and resistance to PHMB. The sensitivity of the Δhog1 mutant was also observed. Furthermore, the cytotoxicity assay and gene expression analysis showed that the part played by YAP1 and CTT1 genes in cell resistance to PHMB is unrelated to oxidative stress response. Thus, we suggested that Yap1p can play a role in cell wall maintenance by controlling the expression of the CWI genes. The PHMB treatment of the yeast cells activates the PKC1/Slt2 (CWI) pathway. In addition, it is suggested that HOG1 and YAP1 can play a role in the regulation of CWI genes.

  9. The resistance of the yeast Saccharomyces cerevisiae to the biocide polyhexamethylene biguanide: involvement of cell wall integrity pathway and emerging role for YAP1

    PubMed Central

    2011-01-01

    Background Polyhexamethylene biguanide (PHMB) is an antiseptic polymer that is mainly used for cleaning hospitals and pools and combating Acantamoeba infection. Its fungicide activity was recently shown by its lethal effect on yeasts that contaminate the industrial ethanol process, and on the PE-2 strain of Saccharomyces cerevisiae, one of the main fermenting yeasts in Brazil. This pointed to the need to know the molecular mechanism that lay behind the cell resistance to this compound. In this study, we examined the factors involved in PHMB-cell interaction and the mechanisms that respond to the damage caused by this interaction. To achieve this, two research strategies were employed: the expression of some genes by RT-qPCR and the analysis of mutant strains. Results Cell Wall integrity (CWI) genes were induced in the PHMB-resistant Saccharomyces cerevisiae strain JP-1, although they are poorly expressed in the PHMB-sensitive Saccharomyces cerevisiae PE2 strain. This suggested that PHMB damages the glucan structure on the yeast cell wall. It was also confirmed by the observed sensitivity of the yeast deletion strains, Δslg1, Δrom2, Δmkk2, Δslt2, Δknr4, Δswi4 and Δswi4, which showed that the protein kinase C (PKC) regulatory mechanism is involved in the response and resistance to PHMB. The sensitivity of the Δhog1 mutant was also observed. Furthermore, the cytotoxicity assay and gene expression analysis showed that the part played by YAP1 and CTT1 genes in cell resistance to PHMB is unrelated to oxidative stress response. Thus, we suggested that Yap1p can play a role in cell wall maintenance by controlling the expression of the CWI genes. Conclusion The PHMB treatment of the yeast cells activates the PKC1/Slt2 (CWI) pathway. In addition, it is suggested that HOG1 and YAP1 can play a role in the regulation of CWI genes. PMID:21854579

  10. Future wave and wind projections for United States and United-States-affiliated Pacific Islands

    USGS Publications Warehouse

    Storlazzi, Curt D.; Shope, James B.; Erikson, Li H.; Hegermiller, Christine A.; Barnard, Patrick L.

    2015-01-01

    throughout the study area during other seasons. Extreme wave directions in equatorial Micronesia during June-August undergo an approximate 30° clockwise rotation from primarily west to northwest. September-November RCP4.5 extreme mean wave directions rotate counterclockwise by approximately 30 to 45° in equatorial Micronesia; September-November RCP8.5 extreme mean wave directions within equatorial Micronesia rotate clockwise by approximately 20 to 30°. Extreme wind speeds decreased within both scenarios, with the largest decreases occurring in the September-November season. Extreme wind directions under RCP4.5 rotated clockwise by more than 60° in equatorial Micronesia during the September-November season and by approximately 30° during June-August. RCP8.5 extreme wind directions rotated counterclockwise during September-November within the same region by 30 to 50° and clockwise by 30 to 40° at one island. The spatial patterns and trends are similar between the two different greenhouse gas emission scenarios, with the magnitude and extent of the trends generally greater for the higher (RCP8.5) scenario.

  11. Spatial, temporal, and environmental dynamics of a multi-species epinephelid spawning aggregation in Pohnpei, Micronesia

    NASA Astrophysics Data System (ADS)

    Rhodes, K. L.; Nemeth, R. S.; Kadison, E.; Joseph, E.

    2014-09-01

    Long-term and short-term underwater visual censuses using SCUBA, technical Nitrox, and closed circuit rebreathers (CCR) were carried out in Pohnpei, Micronesia, to define spatial and temporal dynamics within a semi-protected multi-species epinephelid (fish) spawning aggregation (FSA) of brown-marbled grouper, Epinephelus fuscoguttatus, camouflage grouper, Epinephelus polyphekadion, and squaretail coralgrouper, Plectropomus areolatus. Results identified species-specific patterns of habitat use, abundance, residency, and dispersal of FSAs. Fish spawning aggregations formed and dispersed monthly within a 21-160-d period after winter solstice within adjacent yet distinct outer reef habitats. The reproductive season coincided with periods of seasonally low sub-surface seawater temperature. Peaks in density varied among species both within the calendar year and relative to the winter solstice. Significant long-term declines in FSA density were observed for all three species, suggesting population-level fishery-induced impacts, similar to those previously reported for E. polyphekadion. Differences in density estimates were also observed between dive gear, with a threefold difference in densities measured by CCR for E. polyphekadion versus SCUBA that suggest a disturbance effect from exhaled SCUBA bubbles for this species. CCR also allowed surveys to be conducted over a larger area in a single dive, thereby improving the potential to gauge actual abundance and density within FSAs. Based on these findings, a combination of long-term and intensive short-term monitoring strategies is recommended to fully characterize trends in seasonal abundance and habitat use for aggregating species at single or multi-species FSA sites. Inherent variations in the timing and distribution of species within FSA make fine-scale temporal management protocols less effective than blanket protective coverage of these species at (e.g., marine protected areas covering FSAs and adjacent migratory

  12. Dark-count-less photon-counting x-ray computed tomography system using a YAP-MPPC detector

    NASA Astrophysics Data System (ADS)

    Sato, Eiichi; Sato, Yuich; Abudurexiti, Abulajiang; Hagiwara, Osahiko; Matsukiyo, Hiroshi; Osawa, Akihiro; Enomoto, Toshiyuki; Watanabe, Manabu; Kusachi, Shinya; Sato, Shigehiro; Ogawa, Akira; Onagawa, Jun

    2012-10-01

    A high-sensitive X-ray computed tomography (CT) system is useful for decreasing absorbed dose for patients, and a dark-count-less photon-counting CT system was developed. X-ray photons are detected using a YAP(Ce) [cerium-doped yttrium aluminum perovskite] single crystal scintillator and an MPPC (multipixel photon counter). Photocurrents are amplified by a high-speed current-voltage amplifier, and smooth event pulses from an integrator are sent to a high-speed comparator. Then, logical pulses are produced from the comparator and are counted by a counter card. Tomography is accomplished by repeated linear scans and rotations of an object, and projection curves of the object are obtained by the linear scan. The image contrast of gadolinium medium slightly fell with increase in lower-level voltage (Vl) of the comparator. The dark count rate was 0 cps, and the count rate for the CT was approximately 250 kcps.

  13. Generation of multiple spectral bands in a diode-pumped self-mode-locked Nd:YAP laser

    NASA Astrophysics Data System (ADS)

    Huang, Y. J.; Tzeng, Y. S.; Cho, H. H.; Chen, Y. F.; Chen, W. D.; Zhang, G.; Chen, T. C.

    2016-02-01

    A single- and multispectral-band diode end-pumped self-mode-locked Nd:YAP laser is originally demonstrated with an intracavity etalon to properly control the gain-to-loss ratios among the intermanifold lines on the 4F3/2  →  4I11/2 transition level. With a pulse repetition rate of 5.07 GHz, the shortest pulse durations under the single-spectral-band operation are achieved to be 11.1 ps at 1073 nm, 10.9 ps at 1080 nm, and 15.1 ps at 1084 nm, respectively. Moreover, the temporal overlapping of the multispectral-band pulses is experimentally found to lead to the generation of an intensity fringe pattern in the autocorrelation trace with the optical-beat frequency reaching several terahertz. A simple mathematical model is developed to elucidate the formation of a train of optical-beat pulses.

  14. Child and Adolescent Psychiatrist Finder

    MedlinePlus

    ... Connecticut Delaware District of Columbia Federated States of Micronesia Florida Georgia Guam Hawaii Idaho Illinois Indiana Iowa Kansas Kentucky Louisiana Maine Manitoba Marshall Islands Maryland Massachusetts Michigan Minnesota Mississippi Missouri Montana Nebraska ...

  15. Concentration-Dependent Effects of Rhodiola Rosea on Long-Term Survival and Stress Resistance of Yeast Saccharomyces Cerevisiae: The Involvement of YAP 1 and MSN2/4 Regulatory Proteins

    PubMed Central

    Bayliak, Maria M.; Burdyliuk, Nadia I.; Izers’ka, Lilia I.; Lushchak, Volodymyr I.

    2014-01-01

    Concentration-dependent effects of aqueous extract from R. rosea root on long-term survival and stress resistance of budding yeast Saccharomyces cerevisiae were studied. At low concentrations, R. rosea aqueous extract extended yeast chronological lifespan, enhanced oxidative stress resistance of stationary-phase cells and resistance to number stressors in exponentially growing cultures. At high concentrations, R. rosea extract sensitized yeast cells to stresses and shortened yeast lifespan. These biphasic concentration-responses describe a common hormetic phenomenon characterized by a low-dose stimulation and a high-dose inhibition. Yeast pretreatment with low doses of R. rosea extract enhanced yeast survival and prevented protein oxidation under H2O2-induced oxidative stress. Positive effect of R. rosea extract on yeast survival under heat shock exposure was not accompanied with changes in antioxidant enzyme activities and levels of oxidized proteins. The deficiency in transcriptional regulators, Msn2/Msn4 and Yap1, abolished the positive effect of low doses of R. rosea extract on yeast viability under stress challenges. Potential involvement of Msn2/Msn4 and Yap1 regulatory proteins in realization of R. rosea beneficial effects is discussed. PMID:24659935

  16. Culture and Education in Micronesia.

    ERIC Educational Resources Information Center

    Conklin, Nancy Faires

    By focusing on social and cultural backgrounds of the five U.S.-affiliated Micronesian states, this document highlight issues that pertain to education in this region. The first sections deal with the political history of the region, emphasizing the period of U.S. administration from the 1940's to the 1970's. The history of instititonalized…

  17. GI Locator Service

    MedlinePlus

    ... North Dakota Nebraska New Hampshire New Jersey New Mexico Nevada New York Ohio Oklahoma Oregon Pennsylvania Puerto ... MARIANA ISLANDS MARSHALL ISLANDS Martinique MAURITANIA MAURITIUS MAYOTTE MEXICO MICRONESIA, FEDERATED STATES OF MOLDOVA, REPUBLIC OF MONACO ...

  18. Compacts of Free Association: Improvements Needed to Assess and Address Growing Migration. Report to Congressional Requesters. GAO-12-64

    ERIC Educational Resources Information Center

    US Government Accountability Office, 2011

    2011-01-01

    U.S. compacts with the freely associated states (FAS)--the Federated States of Micronesia (FSM), the Marshall Islands, and Palau--permit FAS citizens to migrate to the United States and its territories (U.S. areas) without regard to visa and labor certification requirements. Thousands of FAS citizens have migrated to U.S. areas (compact…

  19. Effects of the Compact of Free Association on Sovereignty in the Federated States of Micronesia

    DTIC Science & Technology

    2017-06-01

    limited authority to the United States, backed by the FSM’s international legal standing. In return, the FSM should gain the political and economic ...the FSM’s international legal standing. In return, the FSM should gain the political and economic capacity to be more effectively sovereign than it...FSM’S ECONOMIC AND POLITICAL CHALLENGES ..........4 D. POTENTIAL EXPLANATIONS AND HYPOTHESES .......................7 1. Explanations for the

  20. Compact and efficient 2μm Tm:YAP lasers with mechanical or passive Q-switching

    NASA Astrophysics Data System (ADS)

    Cole, Brian; Goldberg, Lew

    2017-02-01

    We describe compact and efficient Q-switched diode-pumped, Tm:YAP lasers operating at 1.94μm. Laser CW and Q-switched performance is compared, using both compact mechanical as well as passive Q-switching. For passive Q-switching using a Cr:ZnS saturable absorber (unsaturated transmission of 95%), the laser produced 0.5mJ pulses with an average power of 4.4W and 6.5kW peak power, and had an optical efficiency of 30%. A resonant mirror mechanical Q-switch resulted in a 4 kHz PRF pulse train, with an optical slope efficiency of 52% and an optical-to-optical conversion efficiency of 41%. The laser generated 1.5 mJ, 45 ns FWHM, 33kW peak power pulses, and 6.2W of average output. A second mechanically Q-switched laser operating at 10 kHz PRF produced 1mJ, 35kW peak power pulses, generating 11W average power with an optical efficiency of 46%, and a beam quality of 1.4x diffraction limit.

  1. 41 CFR 102-36.300 - How do we report the furnishing of personal property to non-federal recipients?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... U.S. Virgin Islands, American Samoa, Guam, Puerto Rico, the Federated States of Micronesia, the... recipient, by type of property (two-digit FSC groups). [65 FR 31218, May 16, 2000, as amended at 71 FR 53572...

  2. Performance of continuous wave and acousto-optically Q-switched Tm, Ho: YAP laser pumped by diode laser

    NASA Astrophysics Data System (ADS)

    Li, Guoxing; Xie, Wenqiang; Yang, Xining; Zhang, Ziqiu; Zhang, Hongda; Zhang, Liang

    2018-02-01

    A two-end-pumped a-cut Tm(0.5%), Ho(0.5%):YAP laser output at 2119nm is reported under cryogenic temperature. The maximum output power reached to 7.76W with the incident pump power of 24.2W in CW mode. With the acousto-optically Q-switch, an average power of 7.3W can be obtained, when the pulse repetition frequency was 7.5 kHz. The corresponding optical-to-optical conversion efficiency was 30.2% and the slope efficiency was 31.4%. Then, the laser output characteristics in the repetition frequency of 7.5 kHz and 10kHz were researched. The output power, the optical-to-optical conversion efficiency and slope efficiency were increased with the increase of the repetition frequency. In the same repetition frequency, the pulse duration was decreasing with the growth of the incident pump power.

  3. Biophysical Analysis of the Binding of WW Domains of YAP2 Transcriptional Regulator to PPXY Motifs within WBP1 and WBP2 Adaptors

    PubMed Central

    McDonald, Caleb B.; McIntosh, Samantha K. N.; Mikles, David C.; Bhat, Vikas; Deegan, Brian J.; Seldeen, Kenneth L.; Saeed, Ali M.; Buffa, Laura; Sudol, Marius; Nawaz, Zafar; Farooq, Amjad

    2011-01-01

    YAP2 transcriptional regulator mediates a plethora of cellular functions, including the newly discovered Hippo tumor suppressor pathway, by virtue of its ability to recognize WBP1 and WBP2 signaling adaptors among a wide variety of other ligands. Herein, using isothermal titration calorimery (ITC) and circular dichroism (CD) in combination with molecular modeling (MM) and molecular dynamics (MD), we provide evidence that the WW1 and WW2 domains of YAP2 recognize various PPXY motifs within WBP1 and WBP2 in a highly promiscuous and subtle manner. Thus, although both WW domains strictly require the integrity of the consensus PPXY sequence, non-consensus residues within and flanking this motif are not critical for high-affinity binding, implying that they most likely play a role in stabilizing the polyproline type II (PPII) helical conformation of the PPXY ligands. Of particular interest is the observation that both WW domains bind to a PPXYXG motif with highest affinity, implicating a preference for a non-bulky and flexible glycine one-residue C-terminal to the consensus tyrosine. Importantly, a large set of residues within both WW domains and the PPXY motifs appear to undergo rapid fluctuations on a nanosecond time scale, arguing that WW-ligand interactions are highly dynamic and that such conformational entropy may be an integral part of the reversible and temporal nature of cellular signaling cascades. Collectively, our study sheds light on the molecular determinants of a key WW-ligand interaction pertinent to cellular functions in health and disease. PMID:21981024

  4. Biophysical analysis of binding of WW domains of the YAP2 transcriptional regulator to PPXY motifs within WBP1 and WBP2 adaptors.

    PubMed

    McDonald, Caleb B; McIntosh, Samantha K N; Mikles, David C; Bhat, Vikas; Deegan, Brian J; Seldeen, Kenneth L; Saeed, Ali M; Buffa, Laura; Sudol, Marius; Nawaz, Zafar; Farooq, Amjad

    2011-11-08

    The YAP2 transcriptional regulator mediates a plethora of cellular functions, including the newly discovered Hippo tumor suppressor pathway, by virtue of its ability to recognize WBP1 and WBP2 signaling adaptors among a wide variety of other ligands. Herein, using isothermal titration calorimery and circular dichroism in combination with molecular modeling and molecular dynamics, we provide evidence that the WW1 and WW2 domains of YAP2 recognize various PPXY motifs within WBP1 and WBP2 in a highly promiscuous and subtle manner. Thus, although both WW domains strictly require the integrity of the consensus PPXY sequence, nonconsensus residues within and flanking this motif are not critical for high-affinity binding, implying that they most likely play a role in stabilizing the polyproline type II helical conformation of the PPXY ligands. Of particular interest is the observation that both WW domains bind to a PPXYXG motif with highest affinity, implicating a preference for a nonbulky and flexible glycine one residue to the C-terminal side of the consensus tyrosine. Importantly, a large set of residues within both WW domains and the PPXY motifs appear to undergo rapid fluctuations on a nanosecond time scale, suggesting that WW-ligand interactions are highly dynamic and that such conformational entropy may be an integral part of the reversible and temporal nature of cellular signaling cascades. Collectively, our study sheds light on the molecular determinants of a key WW-ligand interaction pertinent to cellular functions in health and disease.

  5. Planarian yorkie/YAP functions to integrate adult stem cell proliferation, organ homeostasis and maintenance of axial patterning.

    PubMed

    Lin, Alexander Y T; Pearson, Bret J

    2014-03-01

    During adult homeostasis and regeneration, the freshwater planarian must accomplish a constant balance between cell proliferation and cell death, while also maintaining proper tissue and organ size and patterning. How these ordered processes are precisely modulated remains relatively unknown. Here we show that planarians use the downstream effector of the Hippo signaling cascade, yorkie (yki; YAP in vertebrates) to control a diverse set of pleiotropic processes in organ homeostasis, stem cell regulation, regeneration and axial patterning. We show that yki functions to maintain the homeostasis of the planarian excretory (protonephridial) system and to limit stem cell proliferation, but does not affect the differentiation process or cell death. Finally, we show that Yki acts synergistically with WNT/β-catenin signaling to repress head determination by limiting the expression domains of posterior WNT genes and that of the WNT-inhibitor notum. Together, our data show that yki is a key gene in planarians that integrates stem cell proliferation control, organ homeostasis, and the spatial patterning of tissues.

  6. Sustainability of rainwater catchment systems for small island communities

    NASA Astrophysics Data System (ADS)

    Bailey, Ryan T.; Beikmann, Alise; Kottermair, Maria; Taboroši, Danko; Jenson, John W.

    2018-02-01

    Communities living on atolls and similar low-lying islands in the tropical Pacific rely on rainwater and shallow groundwater to meet domestic water needs. Rainwater, generally captured and stored using rooftop rainwater catchment systems, is the preferred water source due to higher quality and convenience of access. This study assesses the performance of rainwater catchment systems (RWCS) on Ifalik Atoll, located in Yap State, Federated States of Micronesia in the western Pacific. A field survey was conducted in August 2015 to evaluate RWCS features (guttered roof area, storage tank size, gutter leakage conditions), determine numbers of users, and estimate daily water use via household surveys. All 152 RWCS were surveyed. Water balance modeling was applied to the RWCS to estimate end-of-day stored rainwater volumes for each day of the 1997-1999 time period, during which an El Niño-induced drought occurred. Results indicate that the community is resilient to drought, although the majority of RWCS were depleted of rainwater and hence community sharing was required. Scenario testing indicates that increasing guttered roof area is the optimal strategy for enhancing system reliability. For example, the volume of water maintained at the peak of a drought can be tripled if the available roof areas for the RWCS are guttered. Design curves, which provide a set of roof area - tank volume combinations that achieve specified levels of reliability, were created and can be used to plan new RWCS. Besides offering insights into community-wide water storage and usage patterns and resiliency for Ifalik Atoll, this study presents methods that can be applied to other atoll island communities throughout the Indo-Pacific region.

  7. Water-quality reconnaissance of ground water in the inhabited outer islands of Chuuk State, Federated States of Micronesia, 1984-85

    USGS Publications Warehouse

    Hamlin, S.N.; Takasaki, K.J.

    1996-01-01

    A reconnaissance of ground-water quality in 24 inhabited outer islands in Chuuk State was made between January 1984 and October 1985. Most of the islands are part of low-lying coral atolls within the Western, Namonuito, Hall, and Mortlock Island Groups. A total of 648 wells were located and sampled for temperature and specific conductance. A few miscellaneous sites such as taro patches also were sampled. The nitrate concentration was determined for 308 water samples. To develop a relation between specific conductance and chloride concentration, the chloride concentration was determined for 63 water samples. In addition, 21 water samples were analyzed for major and trace constituent ion concentrations. Chloride and nitrate are the primary constituents affecting the potability of ground water in the inhabited outer islands of Chuuk State. The source of chloride in ground water is seawater, whereas nitrate is derived fro plant and animal waste materials. The chloride concentrations in many well waters exceed the World Health Organization guideline for drinking water, particularly in wells near the shoreline or on small islands. In addition, the nitrate concentrations in some well waters exceeded the World Health Organization guideline for drinking water.

  8. Profile of Pacific Schools.

    ERIC Educational Resources Information Center

    Northwest Regional Educational Lab., Portland, OR.

    This profile contains tables and charts which provide baseline information on the Pacific Region school systems. The Region comprises the State of Hawaii, the Territories of American Samoa and Guam, the Commonwealth of the Northern Marianas, the Federated States of Micronesia, the Republic of Belau, and the Republic of the Marshall Islands.…

  9. Construction Carpentry. Secondary Schools. Curriculum Guide.

    ERIC Educational Resources Information Center

    Tellei, Patrick U.

    This document is intended to help construction carpentry instructors in the State of Truk, Truk, Federated States of Micronesia, to prepare their senior high school students uniformly to design and build residential structures capable of withstanding typhoons. Because of the threat of typhoons, the carpentry curriculum contained in the guide has a…

  10. The Secretary's Seventh Annual Report on Teacher Quality: A Highly Qualified Teacher in Every Classroom

    ERIC Educational Resources Information Center

    Office of Postsecondary Education, US Department of Education, 2010

    2010-01-01

    This seventh report on the quality of America's teacher preparation programs and novice teachers presents data reported to the U.S. Department of Education (the Department) in October 2007 by all 50 states, the District of Columbia, Puerto Rico and the outlying areas, which include American Samoa, the Federated States of Micronesia, Guam, the…

  11. Disruption of adherens junction and alterations in YAP-related proliferation behavior as part of the underlying cell transformation process of alcohol-induced oral carcinogenesis.

    PubMed

    Husari, Ayman; Hülter-Hassler, Diana; Steinberg, Thorsten; Schulz, Simon Daniel; Tomakidi, Pascal

    2018-01-01

    Accumulating evidences indicate that alcohol might play a causative in oral cancer. Unfortunately, in vitro cell systems, uncovering the molecular background of the underlying cell transformation process, are rare. Therefore, this study was conducted, to identify molecular changes and characterize their putative cell behavioral consequences in epitheloid (EPI) and fibroblastoid (FIB) oral keratinocyte phenotypes, arising from chronical alcohol treatment. Concerning adherens junctions (AJs), both EPI and FIB showed membrane-bound β-catenin, but exhibited differences for E-cadherin and zyxin. While EPI revealed E-cadherin/β-catenin membrane co-localization, which in parts also applied for zyxin, FIB membranes were devoid of E-cadherin and exhibited marginal zyxin expression. Fetal calf serum (FCS) administration in starved cells promoted proliferation in both keratinocyte phenotypes, whereat EPI and FIB yielded a strikingly modified FCS sensitivity on the temporal scale. Impedance measurement-based cell index detection yielded proliferation stimulation occurring much earlier in FIB (<20h) compared to EPI (>45h). Nuclear preference of the proliferation-associated YAP co-transcription factor in FIB was FCS independent, while it required FCS in EPI. Taken together, the lack of membrane-inherent E-cadherin/β-catenin co-localization together with low zyxin - reveals perturbation of AJ integrity in FIB. Regarding cell behavior, perturbed AJs in FIB correlate with temporal proliferation sensitivity towards FCS. CYF of 5.6 strongly suggests involvement of chromatin-bound YAP in FIB's proliferation temperosensitivity. These molecular differences detected for EPI and FIB are part of the underlying cell transformation process of alcohol-induced oral carcinogenesis, and indicate FIB being in a more advanced transformation stage. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Consortia Building: A Handshake and a Smile, Island Style.

    ERIC Educational Resources Information Center

    Cutright, Patricia J.

    2000-01-01

    Discussion of library consortia focuses on the collaborative efforts in the Federated States of Micronesia that will enhance library services through staff training and educating while utilizing innovative technology. Highlights include background and socioeconomic overview; a project that addresses automation and Internet connectivity issues; and…

  13. Wnt, RSPO and Hippo Signalling in the Intestine and Intestinal Stem Cells.

    PubMed

    Kriz, Vitezslav; Korinek, Vladimir

    2018-01-08

    In this review, we address aspects of Wnt, R-Spondin (RSPO) and Hippo signalling, in both healthy and transformed intestinal epithelium. In intestinal stem cells (ISCs), the Wnt pathway is essential for intestinal crypt formation and renewal, whereas RSPO-mediated signalling mainly affects ISC numbers. In human colorectal cancer (CRC), aberrant Wnt signalling is the driving mechanism initiating this type of neoplasia. The signalling role of the RSPO-binding transmembrane proteins, the leucine-rich-repeat-containing G-protein-coupled receptors (LGRs), is possibly more pleiotropic and not only limited to the enhancement of Wnt signalling. There is growing evidence for multiple crosstalk between Hippo and Wnt/β-catenin signalling. In the ON state, Hippo signalling results in serine/threonine phosphorylation of Yes-associated protein (YAP1) and tafazzin (TAZ), promoting formation of the β-catenin destruction complex. In contrast, YAP1 or TAZ dephosphorylation (and YAP1 methylation) results in β-catenin destruction complex deactivation and β-catenin nuclear localization. In the Hippo OFF state, YAP1 and TAZ are engaged with the nuclear β-catenin and participate in the β-catenin-dependent transcription program. Interestingly, YAP1/TAZ are dispensable for intestinal homeostasis; however, upon Wnt pathway hyperactivation, the proteins together with TEA domain (TEAD) transcription factors drive the transcriptional program essential for intestinal cell transformation. In addition, in many CRC cells, YAP1 phosphorylation by YES proto-oncogene 1 tyrosine kinase (YES1) leads to the formation of a transcriptional complex that includes YAP1, β-catenin and T-box 5 (TBX5) DNA-binding protein. YAP1/β-catenin/T-box 5-mediated transcription is necessary for CRC cell proliferation and survival. Interestingly, dishevelled (DVL) appears to be an important mediator involved in both Wnt and Hippo (YAP1/TAZ) signalling and some of the DVL functions were assigned to the nuclear DVL

  14. Availability, usage, and threats to freshwater resources on low carbonate islands in Micronesia

    NASA Astrophysics Data System (ADS)

    Taboroši, Danko; Jenson, John W.; Sánchez Collazo, Maricruz; Zega, Mojca

    2010-05-01

    Federated States of Micronesia (FSM) is an insular nation in the western Pacific. It consists of 4 high volcanic islands and 37 low carbonate units, mostly coral atolls. The high islands are relatively large, and are developing socioeconomic centers of the country, whereas low islands are small and remote outposts of traditional subsistence lifestyle. The latter are inhabited by a fifth of the nation's population of 107,000 people. Total land area of a typical low island is a fraction of a km2, yet may be home to hundreds of people, creating some of the highest population densities in the Pacific. The resultant extreme pressures on natural resources are exacerbated by severe weather hazards, especially typhoons and unusually high tides which have recently flooded some islands in entirety, damaging homes and food sources. Freshwater resources are particularly sensitive. Crowded low islands have some of the world's most unfavorable relationships between population density and freshwater availability. As there are no communal or municipal facilities and government operated infrastructure, people have only two sources of water available for consumption: rainwater and groundwater. Rain is captured by individual households' thatch or corrugated iron roofs and transferred by gutters to concrete or fiberglass tanks. It is used for drinking, cooking, and dishwashing, and depending on availability, for laundry and showering. Such arrangement are highly unreliable, because they depend on sufficient rainfall and islanders' ability to capture and store it. Some communities have actually run out of water in the past, as a result of prolonged droughts or typhoons' damage to the catchment systems. In addition, tropical climate and pervasive organic matter and microorganisms make the tanks' maintenance difficult, because even most conscientious cleaning cannot ensure that stored water remains potable. Stomach problems and more serious health complications are common. Groundwater

  15. Epidemiologic update on the dengue situation in the Western Pacific Region, 2011.

    PubMed

    Arima, Yuzo; Edelstein, Zoe Rebecca; Han, Hwi Kwang; Matsui, Tamano

    2013-01-01

    Dengue is an emerging vectorborne infectious disease that is a major public health concern in the Asia and the Pacific. Official dengue surveillance data for 2011 provided by ministries of health were summarized as part of routine activities of the World Health Organization Regional Office for the Western Pacific. Based on officially reported surveillance data, dengue continued to show sustained activity in the Western Pacific Region. In 2011, Member States reported a total of 244,855 cases of which 839 died for a case fatality rate of 0.34%. More than 1000 cases were reported each from Cambodia, the Federated States of Micronesia, the Lao People's Democratic Republic, Malaysia, the Philippines, the Marshall Islands, Singapore and Viet Nam. Cambodia, the Federated States of Micronesia and the Marshall Islands reported higher activity relative to 2010. There continues to be great variability among the dengue-endemic countries and areas in the Region in the number of cases and serotype distribution. The continued high notification rate and complex dengue epidemiology in the Region highlight the need for information-sharing on a routine and timely basis.

  16. The Adoption of Innovation in Youth Organizations: Creating the Conditions for Youth-Adult Partnerships

    ERIC Educational Resources Information Center

    Zeldin, Shepherd; Camino, Linda; Mook, Carrie

    2005-01-01

    Youth-adult partnerships (Y-APs) for organizational and community change represent an innovative practice in the United States. Innovations are typically a challenge to implement, so it is not surprising that youth organizations are seeking guidance on how to adopt and sustain Y-APs. This article brings contemporary scholarship to bear on the…

  17. X-ray induced luminescence properties of (Y,Eu)AlO3 single crystals

    NASA Astrophysics Data System (ADS)

    Kuro, Tomoaki; Nakauchi, Daisuke; Okada, Go; Kawaguchi, Noriaki; Yanagida, Takayuki

    2017-02-01

    We investigated photoluminescence, scintillation and dosimeter properties of (Y1-x Eux)AlO3 (x = 0.001, 0.5 and 1) single crystals (hereafter denoted as Eu:YAP for x = 0.001, EYAP for x = 0.5 and EAP for x = 1). The samples were prepared by the Floating Zone method. In photoluminescence (PL), we observed a broad emission around 300-400 nm due to host under excitation of 280 nm, and emissions due to the 4f state transitions of Eu3+ appeared around 590 nm and 615 nm. Scintillation spectra also show emission peaks around 590 and 615 nm due to the 4f state transitions of Eu3+ in all the samples. In addition, emissions around 300-400 nm due to YAP host and around 550-700 nm due to 5d-4f transitions of Eu2+ appeared in Eu:YAP. The PL and scintillation decay time profiles consisted of several exponential decay components. The fast (ns) component group was possibly due to host emission, and especially Eu:YAP demonstrated a very fast PL decay time of 16 ns. The intermediate (μs) component group was due to the 5d-4f transitions of Eu2+. The slow (ms) component group was ascribed to the 4f state transitions of Eu3+ ion. The Eu:YAP sample showed intense thermally-stimulated luminescence (TSL) with peaks at 46, 155, 255 and 443 °C. The intensity was much higher than those of EAP and EYAP. In particular, the peak at 254 °C, which showed the highest intensity, was due to doping with Eu. The TSL dose response function showed a good linearity (R2 > 0.99) over a wide dose range from 0.1 mGy to 100 mGy for Eu:YAP, which showed the highest sensitivity among the present samples.

  18. Assistive Technology in the Pacific: Symposium Proceedings. Leading the Challenge (San Diego, California, May 14-16, 1995) [and] Future Directions (Agana, Guam, December 3-6, 1995).

    ERIC Educational Resources Information Center

    Farley, Tania Huff, Comp.

    This monograph presents the proceedings of two symposia on assistive technology for people with disabilities in Hawaii, American Samoa, Guam, the Federated States of Micronesia, Commonwealth of the Northern Mariana Islands, Republic of the Marshall Islands, and Palau. Following an overview, Sections 1 and 2 contain the presentations and…

  19. PIALA '94. Pacific Information Liberation: The Wave of the Future. Proceedings of the Annual Pacific Islands Association of Libraries and Archives Conference (4th, Tamuning, Guam, November 4-9, 1994).

    ERIC Educational Resources Information Center

    Cohen, Arlene, Ed.

    Over 100 participants from Micronesia, Australia, Japan, Hawaii, and other United States convened to hear presenters speaking on various topics of interest to librarians, archivists, and educators in the Pacific islands. The proceedings include a welcoming speech, remarks acknowledging conference exhibitors, and a keynote address by Dr. John…

  20. 7 CFR 4290.50 - Definition of terms.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... primary purpose is to manage and invest non-Federal funds on behalf of at least three Institutional... Commonwealth of Puerto Rico, the island is considered rural and eligible for Business Programs assistance... States of Micronesia, and the Republic of the Marshall Islands, the USDA shall determine what constitutes...

  1. Deteriorated Stress Response in Stationary-Phase Yeast: Sir2 and Yap1 Are Essential for Hsf1 Activation by Heat Shock and Oxidative Stress, Respectively

    PubMed Central

    Cohen, Aviv; Bar-Nun, Shoshana

    2014-01-01

    Stationary-phase cultures have been used as an important model of aging, a complex process involving multiple pathways and signaling networks. However, the molecular processes underlying stress response of non-dividing cells are poorly understood, although deteriorated stress response is one of the hallmarks of aging. The budding yeast Saccharomyces cerevisiae is a valuable model organism to study the genetics of aging, because yeast ages within days and are amenable to genetic manipulations. As a unicellular organism, yeast has evolved robust systems to respond to environmental challenges. This response is orchestrated largely by the conserved transcription factor Hsf1, which in S. cerevisiae regulates expression of multiple genes in response to diverse stresses. Here we demonstrate that Hsf1 response to heat shock and oxidative stress deteriorates during yeast transition from exponential growth to stationary-phase, whereas Hsf1 activation by glucose starvation is maintained. Overexpressing Hsf1 does not significantly improve heat shock response, indicating that Hsf1 dwindling is not the major cause for Hsf1 attenuated response in stationary-phase yeast. Rather, factors that participate in Hsf1 activation appear to be compromised. We uncover two factors, Yap1 and Sir2, which discretely function in Hsf1 activation by oxidative stress and heat shock. In Δyap1 mutant, Hsf1 does not respond to oxidative stress, while in Δsir2 mutant, Hsf1 does not respond to heat shock. Moreover, excess Sir2 mimics the heat shock response. This role of the NAD+-dependent Sir2 is supported by our finding that supplementing NAD+ precursors improves Hsf1 heat shock response in stationary-phase yeast, especially when combined with expression of excess Sir2. Finally, the combination of excess Hsf1, excess Sir2 and NAD+ precursors rejuvenates the heat shock response. PMID:25356557

  2. Deteriorated stress response in stationary-phase yeast: Sir2 and Yap1 are essential for Hsf1 activation by heat shock and oxidative stress, respectively.

    PubMed

    Nussbaum, Inbal; Weindling, Esther; Jubran, Ritta; Cohen, Aviv; Bar-Nun, Shoshana

    2014-01-01

    Stationary-phase cultures have been used as an important model of aging, a complex process involving multiple pathways and signaling networks. However, the molecular processes underlying stress response of non-dividing cells are poorly understood, although deteriorated stress response is one of the hallmarks of aging. The budding yeast Saccharomyces cerevisiae is a valuable model organism to study the genetics of aging, because yeast ages within days and are amenable to genetic manipulations. As a unicellular organism, yeast has evolved robust systems to respond to environmental challenges. This response is orchestrated largely by the conserved transcription factor Hsf1, which in S. cerevisiae regulates expression of multiple genes in response to diverse stresses. Here we demonstrate that Hsf1 response to heat shock and oxidative stress deteriorates during yeast transition from exponential growth to stationary-phase, whereas Hsf1 activation by glucose starvation is maintained. Overexpressing Hsf1 does not significantly improve heat shock response, indicating that Hsf1 dwindling is not the major cause for Hsf1 attenuated response in stationary-phase yeast. Rather, factors that participate in Hsf1 activation appear to be compromised. We uncover two factors, Yap1 and Sir2, which discretely function in Hsf1 activation by oxidative stress and heat shock. In Δyap1 mutant, Hsf1 does not respond to oxidative stress, while in Δsir2 mutant, Hsf1 does not respond to heat shock. Moreover, excess Sir2 mimics the heat shock response. This role of the NAD+-dependent Sir2 is supported by our finding that supplementing NAD+ precursors improves Hsf1 heat shock response in stationary-phase yeast, especially when combined with expression of excess Sir2. Finally, the combination of excess Hsf1, excess Sir2 and NAD+ precursors rejuvenates the heat shock response.

  3. Glimpses into Pacific Lives: Some Outstanding Women (Revised).

    ERIC Educational Resources Information Center

    Simon-McWilliams, Ethel, Comp.; Green, Karen Reed, Ed.

    This booklet provides brief biographies of women who have made outstanding contributions to the social and economic development of these Pacific islands: American Samoa, the Republic of Belau, the Federated States of Micronesia, Guam, Hawaii, the Marshall islands, and the Northern Mariana Islands. The 66 women profiled include educators, health…

  4. The Evolution of Epidemic Suicide on Guam: Context and Contagion

    ERIC Educational Resources Information Center

    Booth, Heather

    2010-01-01

    Thirty years of suicide rates for Guam were analyzed by age, sex, period, and cohort. Youth suicide increased rapidly in the 1990s; certain cohorts have higher rates. Four explanatory factors are discussed, including ecological factors and migration from the Federated States of Micronesia. Direct and indirect suicide contagion followed the death…

  5. School Finance and Facilities Study.

    ERIC Educational Resources Information Center

    Kawakami, Alice J., Ed.

    1994-01-01

    This document presents findings of a Pacific Region Educational Laboratory (PREL) study on the status of school finance and facilities in the 10 entities of the Pacific region served by PREL--American Samoa, Commonwealth of the Northern Mariana Islands (CNMI), Federated States of Micronesia, Guam, Hawaii, Republic of the Marshall Islands, and the…

  6. 7 CFR 4280.302 - Definitions and abbreviations.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... with combined hours of at least 35 hours in a work week equals one FTE, and three seasonal jobs equals... granted by the State. (ii) For the Commonwealth of Puerto Rico, the island is considered rural and... Micronesia, and the Republic of the Marshall Islands, the Agency shall determine what constitutes rural and...

  7. 7 CFR 4280.302 - Definitions and abbreviations.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... with combined hours of at least 35 hours in a work week equals one FTE, and three seasonal jobs equals... granted by the State. (ii) For the Commonwealth of Puerto Rico, the island is considered rural and... Micronesia, and the Republic of the Marshall Islands, the Agency shall determine what constitutes rural and...

  8. 7 CFR 4280.302 - Definitions and abbreviations.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... with combined hours of at least 35 hours in a work week equals one FTE, and three seasonal jobs equals... granted by the State. (ii) For the Commonwealth of Puerto Rico, the island is considered rural and... Micronesia, and the Republic of the Marshall Islands, the Agency shall determine what constitutes rural and...

  9. 7 CFR 4280.302 - Definitions and abbreviations.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... with combined hours of at least 35 hours in a work week equals one FTE, and three seasonal jobs equals... granted by the State. (ii) For the Commonwealth of Puerto Rico, the island is considered rural and... Micronesia, and the Republic of the Marshall Islands, the Agency shall determine what constitutes rural and...

  10. Suvanine analogs from a Coscinoderma sp. marine sponge and their cytotoxicities against human cancer cell lines.

    PubMed

    Lee, Jeong-Woo; Lee, Hyi-Seung; Shin, Jongheon; Kang, Jong Soon; Yun, Jieun; Shin, Hee Jae; Lee, Jong Seok; Lee, Yeon-Ju

    2015-06-01

    Nine suvanine analogs including suvanine phenethylammonium salt and two new compounds were isolated from the marine sponge Coscinoderma sp., collected from Chuuk State, Federated States of Micronesia. The structures of the new compounds were elucidated by 2D NMR and HRMS analyses. Suvanine and a new analog exhibited weak but selective cytotoxicity against colon (HCT-15), lung (NCI-H23), stomach (NUGC-3), and prostate (PC-3) cancer cell lines.

  11. An updated review of Zika virus.

    PubMed

    Abushouk, Abdelrahman Ibrahim; Negida, Ahmed; Ahmed, Hussien

    2016-11-01

    The current outbreak of Zika virus (ZIKV) in South America is one of the most serious public health emergencies since the Ebola outbreak of West Africa [2014]. ZIKV belongs to the flaviviridae family and has two lineages (Asian and African). The virus was first discovered in Uganda [1947] and the first human infection was identified in Nigeria [1952]. The current epidemic is the third of its type after that of Yap Island, Micronesia [2007] and French Polynesia [2013]. Phylogenetic studies revealed that the current strain shares about 99.7% of nucleotides and 99.9% of amino acids with the strain of French Polynesia epidemic [2013], suggesting that it has spread across the Pacific Ocean to invade South America. Aedes Aegypti mosquito is the main vector for ZIKV and there are some reports describing possible sexual and maternal to fetal transmission. ZIKV infection is known to be self-limited. However, recent reports suggested that it can be associated with neurological manifestations as Guillan-Barrè Syndrome and microcephaly in the newborn population. Currently, vector control seems to be the most effective available preventive measure against ZIKV spread. The development of broad spectrum antivirals and ZIKV vaccines should be a priority of future research. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. Hippo signaling in the kidney: the good and the bad.

    PubMed

    Wong, Jenny S; Meliambro, Kristin; Ray, Justina; Campbell, Kirk N

    2016-08-01

    The Hippo signaling pathway is an evolutionarily conserved kinase cascade, playing multiple roles in embryonic development that controls organ size, cell proliferation, and apoptosis. At the center of this network lie the Hippo kinase target and downstream pathway effector Yes-associated protein (YAP) and its paralog TAZ. In its phosphorylated form, cytoplasmic YAP is sequestered in an inactive state. When it is dephosphorylated, YAP, a potent oncogene, is activated and relocates to the nucleus to interact with a number of transcription factors and signaling regulators that promote cell growth, differentiation, and survival. The identification of YAP activation in human cancers has made it an attractive target for chemotherapeutic drug development. Little is known to date about the function of the Hippo pathway in the kidney, but that is rapidly changing. Recent studies have shed light on the role of Hippo-YAP signaling in glomerular and lower urinary tract embryonic development, maintenance of podocyte homeostasis, the integrity of the glomerular filtration barrier, regulation of renal tubular cyst growth, renal epithelial injury in diabetes, and renal fibrogenesis. This review summarizes the current knowledge of the Hippo-YAP signaling axis in the kidney under normal and disease conditions. Copyright © 2016 the American Physiological Society.

  13. Epidemiologic update on the dengue situation in the Western Pacific Region, 2011

    PubMed Central

    Edelstein, Zoe Rebecca; Han, Hwi Kwang; Matsui, Tamano

    2013-01-01

    Dengue is an emerging vectorborne infectious disease that is a major public health concern in the Asia and the Pacific. Official dengue surveillance data for 2011 provided by ministries of health were summarized as part of routine activities of the World Health Organization Regional Office for the Western Pacific. Based on officially reported surveillance data, dengue continued to show sustained activity in the Western Pacific Region. In 2011, Member States reported a total of 244 855 cases of which 839 died for a case fatality rate of 0.34%. More than 1000 cases were reported each from Cambodia, the Federated States of Micronesia, the Lao People's Democratic Republic, Malaysia, the Philippines, the Marshall Islands, Singapore and Viet Nam. Cambodia, the Federated States of Micronesia and the Marshall Islands reported higher activity relative to 2010. There continues to be great variability among the dengue-endemic countries and areas in the Region in the number of cases and serotype distribution. The continued high notification rate and complex dengue epidemiology in the Region highlight the need for information-sharing on a routine and timely basis. PMID:24015372

  14. Appendix 1: Regional summaries - Hawaii and U.S Affiliated Pacific Islands

    Treesearch

    Christian Giardina

    2012-01-01

    Hawaii and the U.S.-affiliated Pacific islands, including Guam, American Samoa, Commonwealth of Northern Mariana Islands, Federated States of Micronesia, Republic of Palau, and the Marshall Islands (fig. A1-3), contain a high diversity of flora, fauna, ecosystems, geographies, and cultures, with climates ranging from lowland tropical to alpine desert. Forest ecosystems...

  15. Eliminating tobacco-related disparities among Pacific Islanders through leadership and capacity building: promising practices and lessons learned.

    PubMed

    David, Annette M; Lew, Rod; Lyman, Annabel K; Otto, Caleb; Robles, Rebecca; Cruz, George J

    2013-09-01

    Tobacco remains a major risk factor for premature death and ill health among Pacific Islanders, and tobacco-related disparities persist. Eliminating these disparities requires a comprehensive approach to transform community norms about tobacco use through policy change, as contained in the World Health Organization international Framework Convention on Tobacco Control. Three of the six U.S.-affiliated Pacific Islands-the Federated States of Micronesia, Palau, and the Marshall Islands-are Parties to the Framework; the remaining three territories-American Samoa, the Commonwealth of the Northern Mariana Islands, and Guam-are excluded from the treaty by virtue of U.S. nonratification. Capacity building and leadership development are essential in achieving policy change and health equity within Pacific Islander communities. We describe promising practices from American Samoa, the Commonwealth of the Northern Mariana Islands, the Federated States of Micronesia, Guam, and Palau and highlight some of the key lessons learned in supporting and sustaining the reduction in tobacco use among Pacific Islanders as the first step toward eliminating tobacco-related disparities in these populations.

  16. Culturally Responsive Schools for Micronesian Immigrant Students. PREL Briefing Paper.

    ERIC Educational Resources Information Center

    Heine, Hilda C.

    This paper provides background information about the geography, language, culture, and political history of the Micronesian region, noting that Hawaii's public schools are experiencing an increase in the enrollment of children from Micronesia. Micronesia includes the Commonwealth of the Northern Mariana Islands; the three Freely Associated States…

  17. Control of proliferation and cancer growth by the Hippo signaling pathway

    PubMed Central

    Ehmer, Ursula; Sage, Julien

    2015-01-01

    The control of cell division is essential for normal development and the maintenance of cellular homeostasis. Abnormal cell proliferation is associated with multiple pathological states, including cancer. While the Hippo/YAP signaling pathway was initially thought to control organ size and growth, increasing evidence indicates that this pathway also plays a major role in the control of proliferation independent of organ size control. In particular, accumulating evidence indicates that the Hippo/YAP signaling pathway functionally interacts with multiple other cellular pathways and serves as a central node in the regulation of cell division, especially in cancer cells. Here recent observations are highlighted that connect Hippo/YAP signaling to transcription, the basic cell cycle machinery, and the control of cell division. Furthermore, the oncogenic and tumor suppressive attributes of YAP/TAZ are reviewed which emphasizes the relevance of the Hippo pathway in cancer. PMID:26432795

  18. Appreciating tropical coastal wetlands from a landscape perspective

    Treesearch

    Katherine C. Ewel

    2010-01-01

    Freshwater forested wetlands are often found just upslope from mangrove forests in both high- and low-rainfall areas in the tropics. A case study on the island of Kosrae, Federated States of Micronesia, demonstrates how important both wetland types are to each other hydrologically and to local economies as well. Together, these wetlands form a landscape that provides...

  19. Research on the ecology and management of Micronesian mangroves

    Treesearch

    J.A. Allen

    1999-01-01

    Mangroves are a vitally important natural resource on the high islands of Micronesia. This importance is especially valid in the Federated States of Micronisa (FSM) and the Republic of Palau, where mangroves cover 10-15% of the total land area and are used heavily by islanders as sources of wood, crabs, fish, thatching material, and other products.

  20. Increasing Access to Effective Education across Oceania

    ERIC Educational Resources Information Center

    Hogan, Robert; Nimmer, Natalie

    2013-01-01

    The history of education in many developing nations is a template of ineffectual and expensive instruction. Despite nearly half a century of higher education in the Pacific, up to 50% of the teachers in many countries such as the Federated States of Micronesia and the Republic of the Marshall Islands still have no more than a high school…

  1. Resistant starch in Micronesian banana cultivars offers health benefits.

    PubMed

    Thakorlal, J; Perera, C O; Smith, B; Englberger, L; Lorens, A

    2010-04-01

    Resistant Starch (RS) is a type of starch that is resistant to starch hydrolyzing enzymes in the stomach and thus behaves more like dietary fibre. RS has been shown to have beneficial effects in disease prevention including modulation of glycaemic index diabetes, cholesterol lowering capability and weight management, which are critically important for many people in the Federated States of Micronesia. Green bananas are known to contain substantial concentrations of RS and are a common part of the Micronesian diet. Therefore the aim of this study was to determine the RS content in banana cultivars from Pohnpei, Micronesia: Daiwang, Inahsio, Karat, Utin Kerenis and Utin Ruk, for which no such information was available. Utin Kerenis, Inahsio and Utin Ruk were found to contain the highest amounts of RS. The fate of RS after incorporation into a food product (i.e., pancakes) was also studied and a significant reduction in the RS content was found for each cultivar after cooking. Microscopy of the banana samples indicated that the overall morphology of the cultivars was similar. In conclusion, green banana, including these varieties, should be promoted in Micronesia and other places for their rich RS content and related health benefits including diabetes control. Further research is needed to more clearly determine the effects of cooking and food processing on RS.

  2. One Step Combustion Synthesis Of YAG:Ce Phosphor For Solid State Lighting

    NASA Astrophysics Data System (ADS)

    Yadav, Pooja; Gupta, K. Vijay Kumar; Muley, Aarti; Joshi, C. P.; Moharil, S. V.

    2011-10-01

    YAG:Ce is an important phosphor having applications in various fields ranging from solid state lighting to scintillation detectors. YAG phosphors doped with activators are mainly synthesized by solid state reaction techniques that require high sintering temperatures (above 1500°C) to eliminate YAM and YAP phases. Though several soft chemical routes have been explored for synthesis of YAG, most of these methods are complex and phase pure materials are not obtained in one step, but prolonged annealing at temperatures around 1000 C or above becomes necessary. One step combustion synthesis of YAG:Ce3+ and related phosphors carried out at 500 C furnace temperature is reported here. Activation with Ce3+ could be achieved during the synthesis without taking recourse to any post-combustion thermal treatment. LEDs prepared from the combustion synthesized YAG:Ce3+, exhibited properties comparable to those produced from the commercial phosphor.

  3. Whole-island carbon stocks in the tropical Pacific: implications for mangrove conservation and upland restoration.

    PubMed

    Donato, D C; Kauffman, J B; Mackenzie, R A; Ainsworth, A; Pfleeger, A Z

    2012-04-30

    Management of forest carbon (C) stocks is an increasingly prominent land-use issue. Knowledge of carbon storage in tropical forests is improving, but regional variations are still poorly understood, and this constrains forest management and conservation efforts associated with carbon valuation mechanisms (e.g., carbon markets). This deficiency is especially pronounced in tropical islands and low-lying coastal areas where climate change impacts are expected to be among the most severe. This study presents the first field estimate of island-wide carbon storage in ecosystems of Oceania, with special attention to the regional role of coastal mangroves, which occur on islands and coastal zones throughout the tropics. On two island groups of Micronesia (Yap and Palau), we sampled all above- and belowground C pools, including soil and vegetation, in 24 sites distributed evenly among the three major vegetation structural types: mangroves, upland forests, and open savannas (generally on degraded lands formerly forested). Total C stocks were estimated to be 3.9 and 15.2 Tg C on Yap and Palau, respectively. Mangroves contained by far the largest per-hectare C pools (830-1218 Mg C ha(-1)), with deep organic-rich soils alone storing more C (631-754 Mg C ha(-1)) than all pools combined in upland systems. Despite covering just 12-13% of land area, mangroves accounted for 24-34% of total island C stocks. Savannas (156-203 Mg C ha(-1)) contained significantly lower C stocks than upland forests (375-437 Mg C ha(-1)), suggesting that reforesting savannas where appropriate has high potential for carbon-based funding to aid restoration objectives. For mangroves, these results demonstrate the key role of these systems within the broader context of C storage in island and coastal landscapes. Sustainable management of mangrove forests and their large C stocks is of high importance at the regional scale, and climate change mitigation programs such as REDD+ could play a large role in

  4. Patterns of natural and anthropogenic disturbance of the mangroves on a small Pacific island.

    Treesearch

    James A. Allen; Katherine C. Ewel; Jason Jack

    2001-01-01

    Mangroves in many parts of the world are subjected to frequent, large-scale disturbances. A possible exception is Kosrae, Federated States of Micronesia (FSM), a small volcanic island in the west-central Pacific Ocean. Relative sea level has been stable for most of the last 1000 years and the last tropical cyclone to affect the island was in 1905. Many trees on Kosrae...

  5. Shriners Hospitals for Children, Honolulu's experience with telemedicine: program implementation, maintenance, growth, and lessons learned.

    PubMed

    Ono, Craig M; Lindsey, Jana L

    2004-10-01

    Shriners Hospitals for Children, Honolulu Telemedicine Program conducts real-time video consultations with remotes sites in Hawaii, Guam, Saipan, American Samoa, the Federated States of Micronesia, and the Republic of the Marshall Islands. The program began in 1999 and has provided over 240 consultations. This report is a summary of the Shriners Hospitals experience and lessons learned regarding program implementation and maintenance.

  6. Zika virus infection: Past and present of another emerging vector-borne disease.

    PubMed

    Sakkas, Hercules; Economou, Vangelis; Papadopoulou, Chrissanthy

    2016-01-01

    Zika virus infection is an emerging mosquito-borne disease, first identified in Uganda in 1947. It is caused by the Zika arbovirus, and transmitted by the bites of infected mosquitoes of the genus Aedes. For almost half a century, the Zika virus was reported as the causative agent of sporadic human infections. In 2007, the Zika virus emerged outside Asia and Africa causing an epidemic on the Island of Yap in Micronesia. The manifestation of the newly acquired human infection varies from asymptomatic to self-limiting acute febrile illness with symptoms and clinical features similar to those caused by the Dengue virus ('Dengue-like syndrome'). The real-time PCR and serological methods have been successfully applied for the diagnosis of the disease. The treatment is symptomatic, since there is no specific antiviral treatment or a vaccine. During the recent outbreaks in French Polynesia and Brazil, incidents of Guillain-Barrι syndrome and microcephaly were associated with Zika virus infection, giving rise to fears of further global spread of the virus. Prevention and vector control strategies have to be urgently implemented by national health authorities in order to contain future outbreaks in vulnerable populations. This review summarizes the existing information on Zika virus characteristics, pathogenesis and epidemiology, the available methods for the diagnosis of Zika virus infection and recent approaches for prevention and control.

  7. Two distinct roles of the yorkie/yap gene during homeostasis in the planarian Dugesia japonica.

    PubMed

    Hwang, Byulnim; An, Yang; Agata, Kiyokazu; Umesono, Yoshihiko

    2015-04-01

    Adult planarians possess somatic pluripotent stem cells called neoblasts that give rise to all missing cell types during regeneration and homeostasis. Recent studies revealed that the Yorkie (Yki)/Yes-associated protein (YAP) transcriptional coactivator family plays an important role in the regulation of tissue growth during development and regeneration, and therefore we investigated the role of a planarian yki-related gene (termed Djyki) during regeneration and homeostasis of the freshwater planarian Dugesia japonica. We found that knockdown of the function of Djyki by RNA interference (RNAi) downregulated neoblast proliferation and caused regeneration defects after amputation. In addition, Djyki RNAi caused edema during homeostasis. These seemingly distinct defects induced by Djyki RNAi were rescued by simultaneous RNAi of a planarian mats-related gene (termed Djmats), suggesting an important role of Djmats in the negative regulation of Djyki, in accordance with the conservation of the functional relationship of these two genes during the course of evolution. Interestingly, Djyki RNAi did not prevent normal protonephridial structure, suggesting that Djyki RNAi induced the edema phenotype without affecting the excretory system. Further analyses revealed that increased expression of the D. japonica gene DjaquaporinA (DjaqpA), which belongs to a large gene family that encodes a water channel protein for the regulation of transcellular water flow, promoted the induction of edema, but not defects in neoblast dynamics, in Djyki(RNAi) animals. Thus, we conclude that Djyki plays two distinct roles in the regulation of active proliferation of stem cells and in osmotic water transport across the body surface in D. japonica. © 2015 The Authors Development, Growth & Differentiation published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Society of Developmental Biologists.

  8. Training competent and effective Primary Health Care Workers to fill a void in the outer islands health service delivery of the Marshall Islands of Micronesia.

    PubMed

    Keni, Bhalachandra H

    2006-12-15

    Human resources for health are non-existent in many parts of the world and the outer islands of Marshall Islands in Micronesia are prime examples. While the more populated islands with hospital facilities are often successful in recruiting qualified health professionals from overseas, the outer islands generally have very limited health resources, and are thus less successful. In an attempt to provide reasonable health services to these islands, indigenous people were trained as Health Assistants (HA) to service their local communities. In an effort to remedy the effectiveness of health care delivery to these islands, a program to train mid-level health care workers (Hospital Assistants) was developed and implemented by the Ministry of Health in conjunction with the hospital in Majuro, the capital city of the Marshall Islands. A physician instructor with experience and expertise in primary health care in these regions conducted the program. The curriculum included training in basic health science, essentials of endemic disorders and their clinical management appropriate to the outer islands. Emphasis was given to prevention and health promotion as well as to the curative aspects. For clinical observation, the candidates were assigned to clinical departments of the Majuro hospital for 1 year during their training, as assistants to the nursing staff. This paper discusses the details of the training, the modalities used to groom the candidates, and an assessment of the ultimate effectiveness of the program. Out of 16 boys who began training, 14 candidates were successful in completing the program. In 1998 a similar program was conducted exclusively for women under the auspices of Asian Development Bank funding, hence women were not part of this program. For developing countries of the Pacific, appropriately trained human resources are an essential component of economic progress, and the health workforce is an important part of human resources for sustainable progress

  9. The PDZ-binding motif of Yes-associated protein is required for its co-activation of TEAD-mediated CTGF transcription and oncogenic cell transforming activity

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Shimomura, Tadanori; Miyamura, Norio; Hata, Shoji

    2014-01-17

    Highlights: •Loss of the PDZ-binding motif inhibits constitutively active YAP (5SA)-induced oncogenic cell transformation. •The PDZ-binding motif of YAP promotes its nuclear localization in cultured cells and mouse liver. •Loss of the PDZ-binding motif inhibits YAP (5SA)-induced CTGF transcription in cultured cells and mouse liver. -- Abstract: YAP is a transcriptional co-activator that acts downstream of the Hippo signaling pathway and regulates multiple cellular processes, including proliferation. Hippo pathway-dependent phosphorylation of YAP negatively regulates its function. Conversely, attenuation of Hippo-mediated phosphorylation of YAP increases its ability to stimulate proliferation and eventually induces oncogenic transformation. The C-terminus of YAP contains amore » highly conserved PDZ-binding motif that regulates YAP’s functions in multiple ways. However, to date, the importance of the PDZ-binding motif to the oncogenic cell transforming activity of YAP has not been determined. In this study, we disrupted the PDZ-binding motif in the YAP (5SA) protein, in which the sites normally targeted by Hippo pathway-dependent phosphorylation are mutated. We found that loss of the PDZ-binding motif significantly inhibited the oncogenic transformation of cultured cells induced by YAP (5SA). In addition, the increased nuclear localization of YAP (5SA) and its enhanced activation of TEAD-dependent transcription of the cell proliferation gene CTGF were strongly reduced when the PDZ-binding motif was deleted. Similarly, in mouse liver, deletion of the PDZ-binding motif suppressed nuclear localization of YAP (5SA) and YAP (5SA)-induced CTGF expression. Taken together, our results indicate that the PDZ-binding motif of YAP is critical for YAP-mediated oncogenesis, and that this effect is mediated by YAP’s co-activation of TEAD-mediated CTGF transcription.« less

  10. A novel acetylation cycle of transcription co-activator Yes-associated protein that is downstream of Hippo pathway is triggered in response to SN2 alkylating agents.

    PubMed

    Hata, Shoji; Hirayama, Jun; Kajiho, Hiroaki; Nakagawa, Kentaro; Hata, Yutaka; Katada, Toshiaki; Furutani-Seiki, Makoto; Nishina, Hiroshi

    2012-06-22

    Yes-associated protein (YAP) is a transcriptional co-activator that acts downstream of the Hippo signaling pathway and regulates multiple cellular processes. Although cytoplasmic retention of YAP is known to be mediated by Hippo pathway-dependent phosphorylation, post-translational modifications that regulate YAP in the nucleus remain unclear. Here we report the discovery of a novel cycle of acetylation/deacetylation of nuclear YAP induced in response to S(N)2 alkylating agents. We show that after treatment of cells with the S(N)2 alkylating agent methyl methanesulfonate, YAP phosphorylation mediated by the Hippo pathway is markedly reduced, leading to nuclear translocation of YAP and its acetylation. This YAP acetylation occurs on specific and highly conserved C-terminal lysine residues and is mediated by the nuclear acetyltransferases CBP (CREB binding protein) and p300. Conversely, the nuclear deacetylase SIRT1 is responsible for YAP deacetylation. Intriguingly, we found that YAP acetylation is induced specifically by S(N)2 alkylating agents and not by other DNA-damaging stimuli. These results identify a novel YAP acetylation cycle that occurs in the nucleus downstream of the Hippo pathway. Intriguingly, our findings also indicate that YAP acetylation is involved in responses to a specific type of DNA damage.

  11. A Novel Acetylation Cycle of Transcription Co-activator Yes-associated Protein That Is Downstream of Hippo Pathway Is Triggered in Response to SN2 Alkylating Agents*

    PubMed Central

    Hata, Shoji; Hirayama, Jun; Kajiho, Hiroaki; Nakagawa, Kentaro; Hata, Yutaka; Katada, Toshiaki; Furutani-Seiki, Makoto; Nishina, Hiroshi

    2012-01-01

    Yes-associated protein (YAP) is a transcriptional co-activator that acts downstream of the Hippo signaling pathway and regulates multiple cellular processes. Although cytoplasmic retention of YAP is known to be mediated by Hippo pathway-dependent phosphorylation, post-translational modifications that regulate YAP in the nucleus remain unclear. Here we report the discovery of a novel cycle of acetylation/deacetylation of nuclear YAP induced in response to SN2 alkylating agents. We show that after treatment of cells with the SN2 alkylating agent methyl methanesulfonate, YAP phosphorylation mediated by the Hippo pathway is markedly reduced, leading to nuclear translocation of YAP and its acetylation. This YAP acetylation occurs on specific and highly conserved C-terminal lysine residues and is mediated by the nuclear acetyltransferases CBP (CREB binding protein) and p300. Conversely, the nuclear deacetylase SIRT1 is responsible for YAP deacetylation. Intriguingly, we found that YAP acetylation is induced specifically by SN2 alkylating agents and not by other DNA-damaging stimuli. These results identify a novel YAP acetylation cycle that occurs in the nucleus downstream of the Hippo pathway. Intriguingly, our findings also indicate that YAP acetylation is involved in responses to a specific type of DNA damage. PMID:22544757

  12. Keeping up with sea-level rise: Carbonate production rates in Palau and Yap, western Pacific Ocean.

    PubMed

    van Woesik, Robert; Cacciapaglia, Christopher William

    2018-01-01

    Coral reefs protect islands from tropical storm waves and provide goods and services for millions of islanders worldwide. Yet it is unknown how coral reefs in general, and carbonate production in particular, will respond to sea-level rise and thermal stress associated with climate change. This study compared the reef-building capacity of different shallow-water habitats at twenty-four sites on each of two islands, Palau and Yap, in the western Pacific Ocean. We were particularly interested in estimating the inverse problem of calculating the value of live coral cover at which net carbonate production becomes negative, and whether that value varied across habitats. Net carbonate production varied among habitats, averaging 10.2 kg CaCO3 m-2 y-1 for outer reefs, 12.7 kg CaCO3 m-2 y-1 for patch reefs, and 7.2 kg CaCO3 m-2 y-1 for inner reefs. The value of live coral cover at which net carbonate production became negative varied across habitats, with highest values on inner reefs. These results suggest that some inner reefs tend to produce less carbonate, and therefore need higher coral cover to produce enough carbonate to keep up with sea-level rise than outer and patch reefs. These results also suggest that inner reefs are more vulnerable to sea-level rise than other habitats, which stresses the need for effective land-use practices as the climate continues to change. Averaging across all reef habitats, the rate of carbonate production was 9.7 kg CaCO3 m-2 y-1, or approximately 7.9 mm y-1 of potential vertical accretion. Such rates of vertical accretion are higher than projected averages of sea-level rise for the representative concentration pathway (RCP) climate-change scenarios 2.6, 4.5, and 6, but lower than for the RCP scenario 8.5.

  13. Geology and water-resources reconnaissance of Lenger Island, State of Pohnpei, Federated States of Micronesia, 1991

    USGS Publications Warehouse

    Anthony, Stephen S.; Spengler, Steven R.

    1996-01-01

    Lenger is a small (less than 0.2 square miles) volcanic island located within the lagoon of Pohnpei Island. Ground water on Lenger moves as shallow subsurface flow through weathered bedrock slopes into low-lying areas near the coast before discharging into the surrounding lagoon. Estimated ground-water recharge to the island from rainfall is 506,000 gallons per day on the basis of a mean annual rainfall of 140 inches. The basal part of Lenger is composed of a relatively low- permeability post-shield-building lava flow. This flow is overlain by a more permeable conglomerate of stream deposits which is in turn overlain by a relatively low-permeability columnar-jointed lava flow. The limited land mass and relatively low-permeability lava flows that form the bedrock of Lenger are not favorable to the formation of well-defined drainage basins or large basal ground-water bodies. Numerous springs and seeps discharge shallow subsurface flow at the contact between water-bearing weathered bedrock and underlying less-permeable bedrock. Because the amount of water stored in these shallow subsurface ground-water bodies is limited, springflow and seepflow rates are directly related to rainfall. Barbosa Pond, the largest surface-water body on Lenger, contained 162,000 gallons of water on June 19, 1991. On June 20, 1991, springflow into the pond increased from 0.6 gallons per minute during base-flow conditions to 21 gallons per minute during a 4-hour period of rain that totaled 0.74 inches. The water from Barbosa Pond contains iron and manganese in concentrations that may cause problems in a water-supply system. Small-scale development of ground water, such as was done at Barbosa Pond by the Japanese, is possible by tapping water stored in colluvial talus deposits that flank the base of Mosher hill. The source of water in these deposits is from seeps and springs that have low base flows; however, additional quantities of water could be obtained from these deposits by widening or deepening the capture area of wells used to develop these deposits. If sufficient storage facilities are built, water from these deposits would be available during drought conditions.

  14. A pathogenesis assay using Saccharomyces cerevisiae and Caenorhabditis elegans reveals novel roles for yeast AP-1, Yap1, and host dual oxidase BLI-3 in fungal pathogenesis.

    PubMed

    Jain, Charu; Yun, Meijiang; Politz, Samuel M; Rao, Reeta Prusty

    2009-08-01

    Treatment of systemic fungal infections is difficult because of the limited number of antimycotic drugs available. Thus, there is an immediate need for simple and innovative systems to assay the contribution of individual genes to fungal pathogenesis. We have developed a pathogenesis assay using Caenorhabditis elegans, an established model host, with Saccharomyces cerevisiae as the invading fungus. We have found that yeast infects nematodes, causing disease and death. Our data indicate that the host produces reactive oxygen species (ROS) in response to fungal infection. Yeast mutants sod1Delta and yap1Delta, which cannot withstand ROS, fail to cause disease, except in bli-3 worms, which carry a mutation in a dual oxidase gene. Chemical inhibition of the NADPH oxidase activity abolishes ROS production in worms exposed to yeast. This pathogenesis assay is useful for conducting systematic, whole-genome screens to identify fungal virulence factors as alternative targets for drug development and exploration of host responses to fungal infections.

  15. Current Zika virus epidemiology and recent epidemics.

    PubMed

    Ioos, S; Mallet, H-P; Leparc Goffart, I; Gauthier, V; Cardoso, T; Herida, M

    2014-07-01

    The Zika virus (ZIKV) is a mosquito-borne flavivirus (Aedes), similar to other arboviruses, first identified in Uganda in 1947. Few human cases were reported until 2007, when a Zika outbreak occurred in Yap, Micronesia, even though ZIKV activity had been reported in Africa and in Asia through virological surveillance and entomological studies. French Polynesia has recorded a large outbreak since October 2013. A great number of cases and some with neurological and autoimmune complications have been reported in a context of concurrent circulation of dengue viruses. The clinical presentation is a "dengue-like syndrome". Until the epidemic in French Polynesia, no severe ZIKV disease had been described so far. The diagnosis is confirmed by viral genome detection by genomic amplification (RT- PCR) and viral isolation. These two large outbreaks occurred in a previously unaffected area in less than a decade. They should raise awareness as to the potential for ZIKV to spread especially since this emergent disease is not well known and that some questions remain on potential reservoirs and transmission modes as well as on clinical presentations and complications. ZIKV has the potential to spread to new areas where the Aedes mosquito vector is present and could be a risk for Southern Europe. Strategies for the prevention and control of ZIKV disease should include the use of insect repellent and mosquito vector eradication. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  16. Characterizing Peptide β-HAIRPIN Loops via Cold Ion Spectroscopy of Model Compounds

    NASA Astrophysics Data System (ADS)

    Lawler, John T.; DeBlase, Andrew F.; Harrilal, Christopher P.; Fischer, Joshua L.; McLuckey, Scott A.; Zwier, Timothy S.

    2017-06-01

    The introduction of non-native D-amino acids into peptides is known to reduce conformational entropy in peptides. D-proline has been shown to promote the formation of β-hairpin loops when paired with Gly, providing a framework for building these loops with different lengths of anti-parallel beta-sheet. This study seeks to characterize and compare the conformational preferences of a model protonated pentapeptide containing DPG, [YAP^{D}GA+H]^{+}, with its L-Pro counterpart via conformation specific cold ion spectroscopy as a foundation for future consideration of larger beta-hairpin models. The UV spectrum of YAP^{D}GA of the Tyr chromophore is beautifully sharp, but contains a complicated set of transitions that could arise from the presence of more than one conformer. To assess this possibility, we recorded non-conformation specific IR "gain" spectra in the hydride stretch region. The IR spectrum so obtained displays a set of five strong IR transitions that bear a close resemblance to those found in one of the conformers of its close analog, [YAP^{D}AA+H]^{+}, signaling that a single conformer dominates the population. Two transitions at 3392 and 3464 cm-1 are slightly shifted versions of the C10 and C14 hydrogen bonds found in one of the conformers of [YAP^{D}AA+H]^{+}, and are characteristic of formation of a β-hairpin loop. Notably, in [YAP^{D}GA+H]^{+}, there is at most a minor second conformer with a free carboxylic acid OH, appearing weakly in the IR "gain" spectrum. As expected, the UV spectrum of YAP^{L}GA is more congested, which suggests the presence of multiple conformers. Further investigation into this peptide will reveal the conformational preferences of the L-pro containing molecule. Preliminary data affirms that D-proline containing peptides show reduced conformational states when compared to their natural counterparts.

  17. Yes-Associated Protein Promotes Angiogenesis via Signal Transducer and Activator of Transcription 3 in Endothelial Cells.

    PubMed

    He, Jinlong; Bao, Qiankun; Zhang, Yan; Liu, Mingming; Lv, Huizhen; Liu, Yajin; Yao, Liu; Li, Bochuan; Zhang, Chenghu; He, Shuang; Zhai, Guijin; Zhu, Yan; Liu, Xin; Zhang, Kai; Wang, Xiu-Jie; Zou, Ming-Hui; Zhu, Yi; Ai, Ding

    2018-02-16

    Angiogenesis is a complex process regulating endothelial cell (EC) functions. Emerging lines of evidence support that YAP (Yes-associated protein) plays an important role in regulating the angiogenic activity of ECs. The objective of this study was to specify the effect of EC YAP on angiogenesis and its underlying mechanisms. In ECs, vascular endothelial growth factor reduced YAP phosphorylation time and dose dependently and increased its nuclear accumulation. Using Tie2Cre-mediated YAP transgenic mice, we found that YAP promoted angiogenesis in the postnatal retina and tumor tissues. Mass spectrometry revealed signal transducer and activator of transcription 3 (STAT3) as a potential binding partner of YAP in ECs. Western blot and immunoprecipitation assays indicated that binding with YAP prolonged interleukin 6-induced STAT3 nuclear accumulation by blocking chromosomal maintenance 1-mediated STAT3 nuclear export without affecting its phosphorylation. Moreover, angiopoietin-2 expression induced by STAT3 was enhanced by YAP overexpression in ECs. Finally, a selective STAT3 inhibitor or angiopoietin-2 blockage partly attenuated retinal angiogenesis in Tie2Cre-mediated YAP transgenic mice. YAP binding sustained STAT3 in the nucleus to enhance the latter's transcriptional activity and promote angiogenesis via regulation of angiopoietin-2. © 2018 American Heart Association, Inc.

  18. The Hippo Pathway as Drug Targets in Cancer Therapy and Regenerative Medicine.

    PubMed

    Nagashima, Shunta; Bao, Yijun; Hata, Yutaka

    2017-01-01

    Yes-associated protein 1 (YAP1) and transcriptional co-activator with PDZ-binding motif (TAZ) co-operate with numerous transcription factors to regulate gene transcriptions. YAP1 and TAZ are negatively regulated by the tumor suppressive Hippo pathway. In human cancers, the Hippo pathway is frequently deregulated and YAP1 and TAZ escape the inhibition by the Hippo pathway. The upregulation of YAP1 and TAZ induces epithelial-mesenchymal transition and increases drug resistance in cancer cells. TAZ is implicated in cancer stemness. In consequence cancers with hyperactive YAP1 and TAZ are associated with poor clinical prognosis. Inhibitors of YAP1 and TAZ are reasoned to be beneficial in cancer therapy. On the other hand, since YAP1 and TAZ play important roles in the regulation of various tissue stem cells and in tissue repair, activators of YAP1 and TAZ are useful in the regenerative medicine. We discuss the potential application of inhibitors and activators of YAP1 and TAZ in human diseases and review the progress of drug screenings to search for them. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  19. Promyelocytic leukemia protein enhances apoptosis of gastric cancer cells through Yes-associated protein.

    PubMed

    Xu, Zhipeng; Chen, Jiamin; Shao, Liming; Ma, Wangqian; Xu, Dingting

    2015-09-01

    It has been shown that Yes-associated protein (YAP) acts as a transcriptional co-activator to regulate p73-dependent apoptosis in response to DNA damage in some cell types, and promyelocytic leukemia (PML) protein is involved in the regulation loop through stabilization of YAP through sumoylation. Although YAP has been shown to be significantly upregulated in gastric cancer, whether the YAP/PML/p73 regulation loop also functions in gastric cancer is unknown. Here, we show significantly higher levels of YAP and significantly lower levels of PML in the gastric cancer specimen. Overexpression of YAP in gastric cancer cells significantly increased cell growth, but did not affect apoptosis. However, overexpression of PML in gastric cancer cells significantly increased cell apoptosis, resulting in decreases in cell growth, which seemed to require the presence of YAP. The effect of PML on apoptosis appeared to be conducted through p73-mediated modulation of apoptosis-associated genes, Bcl-2, Bak, and caspase9. Thus, our study suggests the presence of a YAP/PML/p73 regulatory loop in gastric cancer, and highlights PML as a promising tumor suppressor in gastric cancer through YAP-coordinated cancer cell apoptosis.

  20. Training competent and effective Primary Health Care Workers to fill a void in the outer islands health service delivery of the Marshall Islands of Micronesia

    PubMed Central

    Keni, Bhalachandra H

    2006-01-01

    Background Human resources for health are non-existent in many parts of the world and the outer islands of Marshall Islands in Micronesia are prime examples. While the more populated islands with hospital facilities are often successful in recruiting qualified health professionals from overseas, the outer islands generally have very limited health resources, and are thus less successful. In an attempt to provide reasonable health services to these islands, indigenous people were trained as Health Assistants (HA) to service their local communities. In an effort to remedy the effectiveness of health care delivery to these islands, a program to train mid-level health care workers (Hospital Assistants) was developed and implemented by the Ministry of Health in conjunction with the hospital in Majuro, the capital city of the Marshall Islands. Methods A physician instructor with experience and expertise in primary health care in these regions conducted the program. The curriculum included training in basic health science, essentials of endemic disorders and their clinical management appropriate to the outer islands. Emphasis was given to prevention and health promotion as well as to the curative aspects. For clinical observation, the candidates were assigned to clinical departments of the Majuro hospital for 1 year during their training, as assistants to the nursing staff. This paper discusses the details of the training, the modalities used to groom the candidates, and an assessment of the ultimate effectiveness of the program. Results Out of 16 boys who began training, 14 candidates were successful in completing the program. In 1998 a similar program was conducted exclusively for women under the auspices of Asian Development Bank funding, hence women were not part of this program. Conclusion For developing countries of the Pacific, appropriately trained human resources are an essential component of economic progress, and the health workforce is an important part of

  1. Pairing Coral Geochemical Analyses with an Ecosystem Services Model to Assess Drivers and Impacts of Sediment Delivery within Micronesia's Largest Estuary, Ngeremeduu Bay

    NASA Astrophysics Data System (ADS)

    Lewis, S.; Dunbar, R. B.; Mucciarone, D.; Barkdull, M.

    2017-12-01

    Scientific tools assessing impacts to watershed and coastal ecosystem services, like those from land-use land conversion (LULC), are critical for sustainable land management strategies. Small island nations are particularly vulnerable to LULC threats, especially sediment delivery, given their small spatial size and reliance on natural resources. In the Republic of Palau, a small Pacific island country, three major land-use activities—construction, fires, and agriculture— have increased sediment delivery to important estuarine and coastal habitats (i.e., rivers, mangroves, coral reefs) over the past 30 years. This project examines the predictive capacity of an ecosystem services model, Natural Capital Project's InVEST, for sediment delivery using historic land-use and coral geochemical analysis. These refined model projections are used to assess ecosystem services tradeoffs under different future land development and management scenarios. Coral cores (20-41cm in length) were sampled along a high-to-low sedimentation gradient (i.e., near major rivers (high-impact) and ocean (low-impact)) in Micronesia's largest estuary, Ngeremeduu Bay. Isotopic indicators of seasonality (δ18O and δ13C values (% VPDB)) were used to construct the age model for each core. Barium, Manganese, and Yttrium were used as trace metal proxies for sedimentation and measured in each core using a laser ablation ICP-MS. Finally, the Natural Capital Project's InVEST sediment delivery model was paired with Geospatial data to examine the drivers of sediment delivery (i.e., construction, farms and fires) within these two watersheds. A thirty-year record of trace metal to calcium ratios in coral skeletons show a peak in sedimentation during 2006 and 2007, and in 2012. These results suggest historic peaks in sediment delivery correlating to large-scale road construction and support previous findings that Ngeremeduu Bay has reached a tipping point of retaining sediment. Natural Capital's project In

  2. Compact intra-cavity pumped low-threshold passively Q-switched Ho:Sc2SiO5 laser by a LD-pumped Tm:YAP laser at room temperature

    NASA Astrophysics Data System (ADS)

    Yang, Xiao-tao; Xie, Wen-qiang; Liu, Long; Li, Lin-jun

    2017-08-01

    A compact intra-cavity pumped low-threshold passively Q-switched (PQS) Ho:Sc2SiO5 (Ho:SSO) laser is reported for the first time. The Tm:YAlO3 (Tm:YAP) crystal and the Ho:SSO crystal are placed in the same laser cavity. A laser diode with a central wavelength of 793 nm is used to realize the output of the Ho:SSO laser. Both the continuous wave (CW) and PQS operation are investigated. A Cr2+:ZnSe is used as the saturable absorber in the PQS Ho:SSO laser. For the CW mode, the laser threshold is only 750 mW, which is 980 mW in the PQS mode. A maximum pulse energy of 699 µJ is primarily obtained, corresponding to the pulse width of 96 ns. The maximum repetition frequency is 1.46 kHz. The maximum pulse peak power can be calculated to be 7.28 kW. The beam quality factor M 2 is calculated to be 1.4 with the maximum output power.

  3. Activated Hippo/Yes-Associated Protein Pathway Promotes Cell Proliferation and Anti-apoptosis in Endometrial Stromal Cells of Endometriosis.

    PubMed

    Song, Yong; Fu, Jing; Zhou, Min; Xiao, Li; Feng, Xue; Chen, Hengxi; Huang, Wei

    2016-04-01

    The imbalance in cell proliferation and apoptosis is considered an important role in the pathogenesis of endometriosis, but the exact mechanisms remains unclear. A newly established signaling pathway–Hippo/Yes-associated protein (YAP) pathway plays a critical role in the proliferation and apoptosis processes. However, studies focusing on Hippo/YAP pathway and endometriosis are lacking. The objective was to explore the function of the Hippo/YAP pathway in endometriosis. The expression of YAP was first investigated in endometrium of women with or without endometriosis. The role of YAP in cell proliferation and apoptosis is identified by transfection of endometrial stromal cells (ESCs) in vitro, subsequent Verteporfin treatments in eutopic ESCs in vitro, and endometriosis animal model of nude mice in vivo. Our results revealed that increased expression of YAP and decreased expression of p-YAP in ectopic and eutopic endometrium compared with normal endometrium. YAP knockdown in eutopic ESCs decreased cell proliferation and enhanced cell apoptosis companied with decreased expression of TEAD1, CTGF, and B-cell lymphoma/leukemia (BCL)-2; whereas overexpression of YAP resulted in increased proliferation and decreased apoptosis of normal ESCs with increased expression of TEAD1, CTGF, and BCL-2. By chromatin immunoprecipitation qPCR CTGF and BCL-2 were identified as directly downstream target genes of YAP-TEAD1 active complex. Eutopic ESCs treated with Verteporfin revealed decreased proliferation and enhanced apoptosis whereas in endometriosis animal models of nude mice treated with Verteporfin, the size of endometriotic lesions was significantly reduced. Our study suggests that the Hippo/YAP-signaling pathway plays a critical role in the pathogenesis of endometriosis and should present a novel therapeutic method against endometriosis.

  4. Hydrogeology and ground-water resources of Ngatik Island, Sapwuahfik Atoll, State of Pohnpei, Federated States of Micronesia

    USGS Publications Warehouse

    Anthony, S.S.

    1996-01-01

    The lens of fresh ground water on Ngatik Island contains about 509 million gallons of potable water. Recharge to the freshwater lens is estimated to be 990,000 gallons per day on the basis of an estimated mean annual rainfall of 160 inches. The long-term average sustainable yield is estimated to be about 280,000 gallons per day. The estimated demand for water is about 30,000 gallons per day. Shallow-vertical-tube-wells or horizontal-infiltration wells could be used to develop the freshwater lens. The effect of development on the lens can be determined by monitoring the chloride concentration of water from a network of shallow-water-table wells and deep driven wells. The ground-water resource on Ngatik can be used in conjunction with individual rainwater-catchment systems: rainwater can be used for drinking and cooking and ground water can be used for sanitary purposes. When rainwater- catchment systems fail during extended dry periods, ground water would be available to meet the total demand.

  5. Hydrogeology and ground-water resources of Pingelap Island, Pingelap Atoll, State of Pohnpei, Federated States of Micronesia

    USGS Publications Warehouse

    Anthony, S.S.

    1996-01-01

    The lens of fresh ground water on Pingelap Island, Pingelap Atoll contains about 384 million gallons of potable water. Recharge to the freshwater lens is estimated to be 230,000 gallons per day on the basis of an average annual rainfall of 160 inches. The long-term average sustainable yield is estimated to be about 69,000 gallons per day. The estimated demand for water is about 50,000 gallons per day. Shallow-vertical-tube wells or horizontal-infiltration wells could be used to develop the freshwater lens. The effect of development on the lens can be determined by monitoring the chloride concentration of water from a network of shallow-water-table wells and deep driven wells. The ground-water resource on Pingelap can be used in conjunction with individual rainwater-catchment systems: rainwater can be used for drinking and cooking, and ground water can be used for sanitary uses. When rainwater-catchment systems fail during extended dry periods, ground water would be available to meet the total demand.

  6. Hydrogeology and ground-water resources of Kahlap Island, Mwoakilloa Atoll, State of Pohnpei, Federated States of Micronesia

    USGS Publications Warehouse

    Anthony, S.S.

    1996-01-01

    The lens of fresh ground water on Kahlap Island contains about 21.3 million gallons of potable water. Recharge to the freshwater lens is estimated to be 125,000 gallons per day on the basis of a mean annual rainfall of 120 inches. The long-term average sustainable yield is estimated to be about 17,300 gallons per day. The estimated demand for water is about 13,500 gallons per day. Shallow-vertical-tube wells or horizontal- infiltration wells could be used to develop the freshwater lens. The effect of development on the lens can be determined by monitoring the chloride concentration of water from a network of shallow- water-table and deep driven wells. The ground- water resource on Kahlap can be used in conjunc- tion with individual rainwater-catchment systems: rainwater can be used for drinking and cooking, and ground water can be used for sanitary uses. When rainwater-catchment systems fail during extended dry periods, ground water would be available to meet the total demand.

  7. Preparation and characterization of chitosan film incorporated with thinned young apple polyphenols as an active packaging material.

    PubMed

    Sun, Lijun; Sun, Jiaojiao; Chen, Lei; Niu, Pengfei; Yang, Xingbin; Guo, Yurong

    2017-05-01

    The objective of this study was to characterize the physical, mechanical and bioactive properties of chitosan film incorporated with thinned young apple polyphenols (YAP). The results indicated that the addition of YAP resulted in a significant increase in the thickness, density, swelling degree, solubility and opacity of chitosan film, but the water content, water vapor permeability and mechanical properties of the film were decreased. Besides, the antioxidant and antimicrobial properties of chitosan film were significantly enhanced by YAP. Both the NMR and FTIR spectra indicated the interactions between YAP and chitosan were likely to be non-covalent. Furthermore, the thermal stability of the film was decreased by YAP addition, suggested by DSC. Interestingly, the changing tendency of crystalline degree indicated by X-ray kept pace with that of thermal stability for YAP-chitosan films. Overall, YAP-chitosan film was shown a potential as a bioactive packaging material to extend food shelf-life. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. Targeting the Hippo Signaling Pathway for Tissue Regeneration and Cancer Therapy.

    PubMed

    Juan, Wen Chun; Hong, Wanjin

    2016-08-30

    The Hippo signaling pathway is a highly-conserved developmental pathway that plays an essential role in organ size control, tumor suppression, tissue regeneration and stem cell self-renewal. The YES-associated protein (YAP) and the transcriptional co-activator with PDZ-binding motif (TAZ) are two important transcriptional co-activators that are negatively regulated by the Hippo signaling pathway. By binding to transcription factors, especially the TEA domain transcription factors (TEADs), YAP and TAZ induce the expression of growth-promoting genes, which can promote organ regeneration after injury. Therefore, controlled activation of YAP and TAZ can be useful for regenerative medicine. However, aberrant activation of YAP and TAZ due to deregulation of the Hippo pathway or overexpression of YAP/TAZ and TEADs can promote cancer development. Hence, pharmacological inhibition of YAP and TAZ may be a useful approach to treat tumors with high YAP and/or TAZ activity. In this review, we present the mechanisms regulating the Hippo pathway, the role of the Hippo pathway in tissue repair and cancer, as well as a detailed analysis of the different strategies to target the Hippo signaling pathway and the genes regulated by YAP and TAZ for regenerative medicine and cancer therapy.

  9. Micronesian mangrove forest structure and tree responses to a severe typhoon

    Treesearch

    J. Boone Kauffman; Thomas G. Cole

    2010-01-01

    Tropical cyclones are common disturbances that have strong effects on mangrove composition and structure. Because there are numerous ecosystem services provided by mangroves, it is important to understand their adaptations and responses to these climatic events. In April 2004, Typhoon Sudal, a category 3-4 cyclone, passed over the state of Yap, Federated States of...

  10. Micronesian mangrove forest structure and tree responses to a severe typhoon

    Treesearch

    J. Boone Kauffman; Thomas G. Cole

    2010-01-01

    Tropical cyclones are common disturbances that have strong effects on mangrove composition and structure. Because there are numerous ecosystem services provided by mangroves, it is important to understand their adaptations and responses to these climatic events. In April 2004, Typhoon Sudal, a category 3–4 cyclone, passed over the state of Yap, Federated States of...

  11. Targeting the Hippo Signaling Pathway for Tissue Regeneration and Cancer Therapy

    PubMed Central

    Juan, Wen Chun; Hong, Wanjin

    2016-01-01

    The Hippo signaling pathway is a highly-conserved developmental pathway that plays an essential role in organ size control, tumor suppression, tissue regeneration and stem cell self-renewal. The YES-associated protein (YAP) and the transcriptional co-activator with PDZ-binding motif (TAZ) are two important transcriptional co-activators that are negatively regulated by the Hippo signaling pathway. By binding to transcription factors, especially the TEA domain transcription factors (TEADs), YAP and TAZ induce the expression of growth-promoting genes, which can promote organ regeneration after injury. Therefore, controlled activation of YAP and TAZ can be useful for regenerative medicine. However, aberrant activation of YAP and TAZ due to deregulation of the Hippo pathway or overexpression of YAP/TAZ and TEADs can promote cancer development. Hence, pharmacological inhibition of YAP and TAZ may be a useful approach to treat tumors with high YAP and/or TAZ activity. In this review, we present the mechanisms regulating the Hippo pathway, the role of the Hippo pathway in tissue repair and cancer, as well as a detailed analysis of the different strategies to target the Hippo signaling pathway and the genes regulated by YAP and TAZ for regenerative medicine and cancer therapy. PMID:27589805

  12. A novel autotransporter adhesin is required for efficient colonization during bubonic plague.

    PubMed

    Lawrenz, Matthew B; Lenz, Jonathan D; Miller, Virginia L

    2009-01-01

    Many proteins secreted by the type V secretion system (autotransporters) have been linked to virulence in gram-negative bacteria. Several putative conventional autotransporters are present in the Yersinia pestis genome, but only one, YapE, is conserved in the other pathogenic Yersinia species. Here, we introduce YapE and demonstrate that it is secreted via a type V mechanism. Inactivation of yapE in Y. pestis results in decreased efficiency in colonization of tissues during bubonic infection. Coinfection with wild-type bacteria only partially compensates for this defect. Analysis of the host immune response suggests that YapE is required for either efficient colonization at the inoculation site or dissemination to draining lymph nodes. YapE also demonstrates adhesive properties capable of mediating interactions with bacteria and eukaryotic cells. These findings support a role for YapE in modulating host-pathogen interactions that are important for colonization of the mammalian host.

  13. Targeting loss of the Hippo signaling pathway in NF2-deficient papillary kidney cancers

    PubMed Central

    Ricketts, Christopher J.; Wei, Darmood; Yang, Youfeng; Baranes, Sarah M.; Gibbs, Benjamin K.; Ohanjanian, Lernik; Spencer Krane, L.; Scroggins, Bradley T.; Keith Killian, J.; Wei, Ming-Hui; Kijima, Toshiki; Meltzer, Paul S.; Citrin, Deborah E.; Neckers, Len; Vocke, Cathy D.; Marston Linehan, W.

    2018-01-01

    Papillary renal cell carcinomas (PRCC) are a histologically and genetically heterogeneous group of tumors that represent 15–20% of all kidney neoplasms and may require diverse therapeutic approaches. Alteration of the NF2 tumor suppressor gene, encoding a key regulator of the Hippo signaling pathway, is observed in 22.5% of PRCC. The Hippo signaling pathway controls cell proliferation by regulating the transcriptional activity of Yes-Associated Protein, YAP1. Loss of NF2 results in aberrant YAP1 activation. The Src family kinase member Yes also regulates YAP1 transcriptional activity. This study investigated the importance of YAP and Yes activity in three NF2-deficient PRCC cell lines. NF2-deficency correlated with increased expression of YAP1 transcriptional targets and siRNA-based knockdown of YAP1 and Yes1 downregulated this pathway and dramatically reduced cell viability. Dasatinib and saracatinib have potent inhibitory effects on Yes and treatment with either resulted in downregulation of YAP1 transcription targets, reduced cell viability, and G0-G1 cell cycle arrest. Xenograft models for NF2-deficient PRCC also demonstrated reduced tumor growth in response to dasatinib. Thus, inhibiting Yes and the subsequent transcriptional activity of YAP1 had a substantial anti-tumor cell effect both in vitro and in vivo and may provide a viable therapeutic approach for patients with NF2-deficient PRCC. PMID:29535838

  14. The Geographic Distribution of Human Y Chromosome Variation

    PubMed Central

    Hammer, M. F.; Spurdle, A. B.; Karafet, T.; Bonner, M. R.; Wood, E. T.; Novelletto, A.; Malaspina, P.; Mitchell, R. J.; Horai, S.; Jenkins, T.; Zegura, S. L.

    1997-01-01

    We examined variation on the nonrecombining portion of the human Y chromosome to investigate human evolution during the last 200,000 years. The Y-specific polymorphic sites included the Y Alu insertional polymorphism or ``YAP'' element (DYS287), the poly(A) tail associated with the YAP element, three point mutations in close association with the YAP insertion site, an A-G polymorphic transition (DYS271), and a tetranucleotide microsatellite (DYS19). Global variation at the five bi-allelic sites (DYS271, DYS287, and the three point mutations) gave rise to five ``YAP haplotypes'' in 60 populations from Africa, Europe, Asia, Australasia, and the New World (n = 1500). Combining the multi-allelic variation at the microsatellite loci (poly(A) tail and DYS19) with the YAP haplotypes resulted in a total of 27 ``combination haplotypes''. All five of the YAP haplotypes and 21 of the 27 combination haplotypes were found in African populations, which had greater haplotype diversity than did populations from other geographical locations. Only subsets of the five YAP haplotypes were found outside of Africa. Patterns of observed variation were compatible with a variety of hypotheses, including multiple human migrations and range expansions. PMID:9055088

  15. [Polymorphism of DYS287 on Y chromosome in 28 ethnic populations of China].

    PubMed

    Chen, Yang; Chu, Jia-you; Yu, Jian-kun; Yu, Liang; Sun, Hao; Lin, Ke-qin; Tao, Yu-fen; Shi, Lei; Huang, Xiao-qin; Shi, Tie-liu; Fu, Song-bin

    2006-04-01

    To investigate the polymorphism of DYS287 among 28 ethnic populations in 9 provinces of China. YAP element was detected by Touchdown PCR amplification and 2% agarose gel electrophoresis. YAP+ frequencies in these ethnic populations were as follows: Zang 36.7%, Tu 23.8%, Yi 18.4%, Pumi 11.3%, Tajik 7.4%, Bai 6.7%, Jino 5.1%, Shandong Han 4%, Mulao 2.7%, and Maonan 1.3%. The rest ethnic populations in our study, including Gansu Han, Yunnan Han, Zhuangzu, Daizu, Lizu, Nuzu, Lisu, Naxi, Lahu, Dulong, Hani, Shezu, Weiwuer, Sala, Kerkizi, Dongxiang, Vazu, and Korea didn't carry YAP + element. Zangzu, Tuzu, Yizu, Pumi, Jino, and Baizu, which belong to Sino-Tibetan language family, carry a high YAP + frequency. Sala, Tuzu, and Tajik, regarded as Central Asia by origin in history and linguistics, also have a high YAP + frequency. Mulao and Maonan, which origin from "Baiyue" ancient ethnic groups, also have a considerable YAP + frequency.

  16. Effects of thinned young apple polyphenols on the quality of grass carp (Ctenopharyngodon idellus) surimi during cold storage.

    PubMed

    Sun, Lijun; Sun, Jiaojiao; Thavaraj, Pridhuvi; Yang, Xingbin; Guo, Yurong

    2017-06-01

    The aim of this study was to investigate the effects of young apple polyphenols (YAP) on the quality of grass cap surimi (GCS) during storage at 4°C. The addition of YAP into GCS was found to be effective in delaying lipid oxidation, soluble myofibrillar protein (SMP) degradation and changes of L ∗ , a ∗ and b ∗ values of GCS. Chlorogenic acid was screened to be the primary component showing preservative effects. YAP was shown to protect the functional properties of SMP during cold storage, retarding both the decrease in emulsifying activity and stability, and the increase in surface hydrophobicity of SMP. Additionally, the loss of gel strength and texture of GCS with YAP were significantly (P<0.05) lower than that of GCS without YAP during cold storage. Therefore, YAP may be developed as a natural antioxidant to maintain the quality and to extend the shelf life of freshwater fish surimi. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. Risk factors for mortality during the 2002 landslides in Chuuk, Federated States of Micronesia.

    PubMed

    Sanchez, Carlos; Lee, Tze-San; Young, Stacy; Batts, Dahna; Benjamin, Jefferson; Malilay, Josephine

    2009-10-01

    This study examines health effects resulting from landslides in Chuuk during Tropical Storm Chata'an in July 2002, and suggests strategies to prevent future mortality. In August 2002, we conducted a cross-sectional survey to identify risk factors for mortality during landslides, which included 52 survivors and 40 surrogates for 43 decedents to identify risk factors for death. Findings suggest that 1) females had a higher mortality rate from this event than males, and 2) children aged 5-14 years had a 10-fold increase in mortality when compared with annual mortality rates from all causes. Awareness of landslides occurring elsewhere and knowledge of natural warning signs were significantly associated with lower risks of death; being outside during landslides was not associated with reduced mortality. In Chuuk, improving communication systems during tropical storms and increasing knowledge of natural warnings can reduce the risk for mortality during landslides.

  18. A tropical freshwater wetlands: I. Structure, growth, and regeneration

    USGS Publications Warehouse

    Allen, J.A.; Krauss, K.W.; Ewel, K.C.; Keeland, B.D.; Waguk, E.E.

    2005-01-01

    Forested wetlands dominated by Terminalia carolinensis are endemic to Micronesia but common only on the island of Kosrae, Federated States of Micronesia. On Kosrae, these forests occur on Nansepsep, Inkosr, and Sonahnpil soil types, which differ in degree of flooding and soil saturation. We compared forest structure, growth, nutrition, and regeneration on two sites each on Nansepsep and Inkosr soils and one site on the much less common Sonahnpil soil type. Terminalia tree sizes were similar on all three soil types, but forests differed in total basal area, species of smaller trees, and total plant species diversity. Terminalia regeneration was found only on the Inkosr soil type, which had the highest water table levels. Other Terminalia species are relatively light demanding, and T. carolinensis exhibited similar characteristics. It is therefore likely that Terminalia requires periodic, but perhaps naturally rare, stand-replacing disturbances (e.g., typhoons) in order to maintain its dominanace, except on the wettest sites, where competition from other species is reduced. Terminalia swamps in the Nansepsep soil type appeared to be at the greatest risk of conversion to other uses, but swamps on all three types may face reater pressure as Kosrae's population increases and the island's infrastrucure becomes more developed.

  19. Youth-Driven Youth-Adult Partnerships: A Phenomenological Exploration of Agricultural Education Teachers' Experiences

    ERIC Educational Resources Information Center

    Watson, Jennifer M.; Mazur, Joan M.; Vincent, Stacy K.

    2015-01-01

    This phenomenological study explores the dimensions of youth-adult partnerships (YAPs) in agricultural mechanics classrooms in three rural schools. YAPs presume a positive learning collaboration between young people and adults who work together to achieve meaningful community-based change. Previous research on the development of YAPs has focused…

  20. Induction of Chromosome Instability by Activation of Yes-Associated Protein and Forkhead Box M1 in Liver Cancer.

    PubMed

    Weiler, Sofia M E; Pinna, Federico; Wolf, Thomas; Lutz, Teresa; Geldiyev, Aman; Sticht, Carsten; Knaub, Maria; Thomann, Stefan; Bissinger, Michaela; Wan, Shan; Rössler, Stephanie; Becker, Diana; Gretz, Norbert; Lang, Hauke; Bergmann, Frank; Ustiyan, Vladimir; Kalin, Tatiana V; Singer, Stephan; Lee, Ju-Seog; Marquardt, Jens U; Schirmacher, Peter; Kalinichenko, Vladimir V; Breuhahn, Kai

    2017-06-01

    Many different types of cancer cells have chromosome instability. The hippo pathway leads to phosphorylation of the transcriptional activator yes-associated protein 1 (YAP1, YAP), which regulates proliferation and has been associated with the development of liver cancer. We investigated the effects of hippo signaling via YAP on chromosome stability and hepatocarcinogenesis in humans and mice. We analyzed transcriptome data from 242 patients with hepatocellular carcinoma (HCC) to search for gene signatures associated with chromosomal instability (CIN); we investigated associations with overall survival time and cancer recurrence using Kaplan-Meier curves. We analyzed changes in expression of these signature genes, at mRNA and protein levels, after small interfering RNA-mediated silencing of YAP in Sk-Hep1, SNU182, HepG2, or pancreatic cancer cells, as well as incubation with thiostrepton (an inhibitor of forkhead box M1 [FOXM1]) or verteporfin (inhibitor of the interaction between YAP and TEA domain transcription factor 4 [TEAD4]). We performed co-immunoprecipitation and chromatin immunoprecipitation experiments. We collected liver tissues from mice that express a constitutively active form of YAP (YAP S127A ) and analyzed gene expression signatures and histomorphologic parameters associated with chromosomal instability. Mice were given injections of thiostrepton and livers were collected and analyzed by immunoblotting, immunohistochemistry, histology, and real-time polymerase chain reaction. We performed immunohistochemical analyses on tissue microarrays of 105 HCCs and 7 nontumor liver tissues. Gene expression patterns associated with chromosome instability, called CIN25 and CIN70, were detected in HCCs from patients with shorter survival time or early cancer recurrence. TEAD4 and YAP were required for CIN25 and CIN70 signature expression via induction and binding of FOXM1. Disrupting the interaction between YAP and TEAD4 with verteporfin, or inhibiting FOXM1

  1. The Hippo Signaling Pathway Regulates Ovarian Function via the Proliferation of Ovarian Germline Stem Cells.

    PubMed

    Ye, Haifeng; Li, Xiaoyan; Zheng, Tuochen; Hu, Chuan; Pan, Zezheng; Huang, Jian; Li, Jia; Li, Wei; Zheng, Yuehui

    2017-01-01

    To improve the separation, identification and cultivation of ovarian germline stem cells (OGSCs), to clarify the relationship between the Hippo signaling pathway effector YAP1 and the proliferation and differentiation of OGSCs in vitro and to identify the major contribution of Hippo signaling to ovarian function. Two-step enzymatic separation processes and magnetic separation were used to isolate and identify OGSCs by determining the expression of Mvh, Oct4, Nanog, Fragilis and Stella markers. Then, YAP1, as the main effector molecule in the Hippo signaling pathway, was chosen as the target gene of the study. Lentivirus containing overexpressed YAP1 or a YAP1-targeted shRNA was transduced into OGSCs. The effects of modulating the Hippo signaling pathway on the proliferation, differentiation, reproduction and endocrine function of ovaries were observed by microinjecting the lentiviral vectors with overexpressed YAP1 or YAP1 shRNA into infertile mouse models or natural mice of reproductive age. (1) The specific expression of Mvh, Oct4, Nanog, Fragilis and Stella markers was observed in isolated stem cells. Thus, the isolated cells were preliminarily identified as OGSCs. (2) The co-expression of LATS2, MST1, YAP1 and MVH was observed in isolated OGSCs. Mvh and Oct4 expression levels were significantly increased in OGSCs overexpressing YAP1 compared to GFP controls. Consistently, Mvh and Oct4 levels were significantly decreased in cells expressing YAP1-targeted shRNA. (3) After 14-75 days of YAP1 overexpression in infertile mouse models, we detected follicle regeneration in ovaries, the activation of primordial follicles and increased birth rate, accompanied by increasing levels of E2 and FSH. (4) However, we detected decreasing follicles in ovaries, lower birth rate, and decreasing E2 and FSH in serum from healthy mice of reproductive age following YAP1 shRNA expression. Methods for the isolation, identification and culture of OGSCs were successfully established

  2. The two faces of Hippo: targeting the Hippo pathway for regenerative medicine and cancer treatment

    PubMed Central

    Johnson, Randy; Halder, Georg

    2014-01-01

    The Hippo signaling pathway is an emerging growth control and tumor suppressor pathway that regulates cell proliferation and stem cell functions. Defects in Hippo signaling and hyperactivation of its downstream effectors YAP and TAZ contribute to the development of cancer, suggesting that pharmacological inhibition of YAP and TAZ activity may be an effective anticancer strategy. Conversely, YAP and TAZ can also play beneficial roles in stimulating tissue repair and regeneration following injury, therefore activation of YAP and TAZ may be useful in these contexts. Recently, a complex network of intracellular and extracellular signaling pathways that modulate YAP and TAZ activities have been identified. Here we review the regulation of the Hippo signaling pathway, its functions in normal homeostasis and disease, and recent progress in the identification of small molecule pathway modulators. PMID:24336504

  3. Disruption of mechanical stress in extracellular matrix is related to Stanford type A aortic dissection through down-regulation of Yes-associated protein.

    PubMed

    Jiang, Wen-Jian; Ren, Wei-Hong; Liu, Xu-Jie; Liu, Yan; Wu, Fu-Jian; Sun, Li-Zhong; Lan, Feng; Du, Jie; Zhang, Hong-Jia

    2016-09-05

    In this study, we assessed whether the down-regulation of Yes-associated protein (YAP) is involved in the pathogenesis of extracellular matrix (ECM) mechanical stress-induced Stanford type A aortic dissection (STAAD). Human aortic samples were obtained from heart transplantation donors as normal controls and from STAAD patients undergoing surgical replacement of the ascending aorta. Decreased maximum aortic wall velocity, ECM disorders, increased VSMC apoptosis, and YAP down-regulation were identified in STAAD samples. In a mouse model of STAAD, YAP was down-regulated over time during the development of ECM damage, and increased VSMC apoptosis was also observed. YAP knockdown induced VSMC apoptosis under static conditions in vitro , and the change in mechanical stress induced YAP down-regulation and VSMC apoptosis. This study provides evidence that YAP down-regulation caused by the disruption of mechanical stress is associated with the development of STAAD via the induction of apoptosis in aortic VSMCs. As STAAD is among the most elusive and life-threatening vascular diseases, better understanding of the molecular pathogenesis of STAAD is critical to improve clinical outcome.

  4. Protein kinase A activates the Hippo pathway to modulate cell proliferation and differentiation

    PubMed Central

    Yu, Fa-Xing; Zhang, Yifan; Park, Hyun Woo; Jewell, Jenna L.; Chen, Qian; Deng, Yaoting; Pan, Duojia; Taylor, Susan S.; Lai, Zhi-Chun; Guan, Kun-Liang

    2013-01-01

    The Hippo tumor suppressor pathway plays an important role in tissue homeostasis that ensures development of functional organs at proper size. The YAP transcription coactivator is a major effector of the Hippo pathway and is phosphorylated and inactivated by the Hippo pathway kinases Lats1/2. It has recently been shown that YAP activity is regulated by G-protein-coupled receptor signaling. Here we demonstrate that cyclic adenosine monophosphate (cAMP), a second messenger downstream from Gαs-coupled receptors, acts through protein kinase A (PKA) and Rho GTPases to stimulate Lats kinases and YAP phosphorylation. We also show that inactivation of YAP is crucial for PKA-induced adipogenesis. In addition, PKA activation in Drosophila inhibits the expression of Yorki (Yki, a YAP ortholog) target genes involved in cell proliferation and death. Taken together, our study demonstrates that Hippo–YAP is a key signaling branch of cAMP and PKA and reveals new insight into mechanisms of PKA in regulating a broad range of cellular functions. PMID:23752589

  5. Efficacy evaluation of an anti-caries varnish: protocol for a phase II randomised controlled trial

    PubMed Central

    Tut, Ohnmar; Rothen, Marilynn; Mancl, Lloyd; Gallen, Marcelle; Tanzer, Jason M

    2017-01-01

    Introduction Dental caries (tooth decay) is a common disease in which the products of sugar metabolism by certain bacteria that populate the tooth surface induce the development and progression of lesions (cavities). This is a phase II single-centre randomised, double-blind, active-controlled, parallel-group trial to assess the efficacy of a combination povidone iodine and sodium fluoride dental varnish to determine if it is superior to a varnish containing only sodium fluoride in the prevention of new caries lesions. The objective of this report is to describe the rationale and protocol for the trial. Methods and analysis The study site is Pohnpei State, Federated States of Micronesia. The study population is 284 children 48–84 months old. The primary outcome will be the surface-level primary molar caries increment (d2-3mfs/DMFS) at 2 years post baseline. The incremental dental caries at 1 year will also be compared between the two interventions. The secondary outcome is the Facial Image Scale after the initial treatment and after the fifth treatment at 1 year that gauges the child’s response to the treatment. Ethics and dissemination The Western Institutional Review Board (designated IRB) and the Institutional Review Board of the College of Micronesia-FSM approved all study procedures. The US Food and Drug Administration (FDA) has issued IND 128835 covering this study. The study results will be published and submitted to the FDA in support of a new drug application. Trialregistration number NCT03082196. PMID:28667230

  6. Pan-mTOR inhibitor MLN0128 is effective against intrahepatic cholangiocarcinoma in mice.

    PubMed

    Zhang, Shanshan; Song, Xinhua; Cao, Dan; Xu, Zhong; Fan, Biao; Che, Li; Hu, Junjie; Chen, Bin; Dong, Mingjie; Pilo, Maria G; Cigliano, Antonio; Evert, Katja; Ribback, Silvia; Dombrowski, Frank; Pascale, Rosa M; Cossu, Antonio; Vidili, Gianpaolo; Porcu, Alberto; Simile, Maria M; Pes, Giovanni M; Giannelli, Gianluigi; Gordan, John; Wei, Lixin; Evert, Matthias; Cong, Wenming; Calvisi, Diego F; Chen, Xin

    2017-12-01

    Intrahepatic cholangiocarcinoma (ICC) is a lethal malignancy without effective treatment options. MLN0128, a second generation pan-mTOR inhibitor, shows efficacy for multiple tumor types. We evaluated the therapeutic potential of MLN0128 vs. gemcitabine/oxaliplatin in a novel ICC mouse model. We established a novel ICC mouse model via hydrodynamic transfection of activated forms of AKT (myr-AKT) and Yap (YapS127A) protooncogenes (that will be referred to as AKT/YapS127A). Genetic approaches were applied to study the requirement of mTORC1 and mTORC2 in mediating AKT/YapS127A driven tumorigenesis. Gemcitabine/oxaliplatin and MLN0128 were administered in AKT/YapS127A tumor-bearing mice to study their anti-tumor efficacy in vivo. Multiple human ICC cell lines were used for in vitro experiments. Hematoxylin and eosin staining, immunohistochemistry and immunoblotting were applied for the characterization and mechanistic study. Co-expression of myr-AKT and YapS127A promoted ICC development in mice. Both mTORC1 and mTORC2 complexes were required for AKT/YapS127A ICC development. Gemcitabine/oxaliplatin had limited efficacy in treating late stage AKT/YapS127A ICC. In contrast, partial tumor regression was achieved when MLN0128 was applied in the late stage of AKT/YapS127A cholangiocarcinogenesis. Furthermore, when MLN0128 was administered in the early stage of AKT/YapS127A carcinogenesis, it led to disease stabilization. Mechanistically, MLN0128 efficiently inhibited AKT/mTOR signaling both in vivo and in vitro, inducing strong ICC cell apoptosis and only marginally affecting proliferation. This study suggests that mTOR kinase inhibitors may be beneficial for the treatment of ICC, even in tumors that are resistant to standard of care chemotherapeutics, such as gemcitabine/oxaliplatin-based regimens, especially in the subset of tumors exhibiting activated AKT/mTOR cascade. Lay summary: We established a novel mouse model of intrahepatic cholangiocarcinoma (ICC). Using this

  7. Repression of the Low Affinity Iron Transporter Gene FET4

    PubMed Central

    Caetano, Soraia M.; Menezes, Regina; Amaral, Catarina; Rodrigues-Pousada, Claudina; Pimentel, Catarina

    2015-01-01

    Cadmium is a well known mutagenic metal that can enter cells via nonspecific metal transporters, causing several cellular damages and eventually leading to death. In the yeast Saccharomyces cerevisiae, the transcription factor Yap1 plays a key role in the regulation of several genes involved in metal stress response. We have previously shown that Yap1 represses the expression of FET4, a gene encoding a low affinity iron transporter able to transport metals other than iron. Here, we have studied the relevance of this repression in cell tolerance to cadmium. Our results indicate that genomic deletion of Yap1 increases FET4 transcript and protein levels. In addition, the cadmium toxicity exhibited by this strain is completely reversed by co-deletion of FET4 gene. These data correlate well with the increased intracellular levels of cadmium observed in the mutant yap1. Rox1, a well known aerobic repressor of hypoxic genes, conveys the Yap1-mediated repression of FET4. We further show that, in a scenario where the activity of Yap1 or Rox1 is compromised, cells activate post-transcriptional mechanisms, involving the exoribonuclease Xrn1, to compensate the derepression of FET4. Our data thus reveal a novel protection mechanism against cadmium toxicity mediated by Yap1 that relies on the aerobic repression of FET4 and results in the impairment of cadmium uptake. PMID:26063801

  8. Leadership Development: A Handbook from the Youth Action Program of the East Harlem Block Schools.

    ERIC Educational Resources Information Center

    Stoneman, Dorothy; Bell, John

    This manual is written for adults who work with teenagers and young adults. It is based on the experience of building the Youth Action Program (YAP) of the East Harlem (New York City) Block Schools. The manual begins with background information on the accomplishments and plans of YAP on its 10th anniversary, followed by a section on YAP's basic…

  9. Transcriptional regulators in the Hippo signaling pathway control organ growth in Xenopus tadpole tail regeneration.

    PubMed

    Hayashi, Shinichi; Ochi, Haruki; Ogino, Hajime; Kawasumi, Aiko; Kamei, Yasuhiro; Tamura, Koji; Yokoyama, Hitoshi

    2014-12-01

    The size and shape of tissues are tightly controlled by synchronized processes among cells and tissues to produce an integrated organ. The Hippo signaling pathway controls both cell proliferation and apoptosis by dual signal-transduction states regulated through a repressive kinase cascade. Yap1 and Tead, transcriptional regulators that act downstream of the Hippo signaling kinase cascade, have essential roles in regulating cell proliferation. In amphibian limb or tail regeneration, the local tissue outgrowth terminates when the correct size is reached, suggesting that organ size is strictly controlled during epimorphic organ-level regeneration. We recently demonstrated that Yap1 is required for the regeneration of Xenopus tadpole limb buds (Hayashi et al., 2014, Dev. Biol. 388, 57-67), but the molecular link between the Hippo pathway and organ size control in vertebrate epimorphic regeneration is not fully understood. To examine the requirement of Hippo pathway transcriptional regulators in epimorphic regeneration, including organ size control, we inhibited these regulators during Xenopus tadpole tail regeneration by overexpressing a dominant-negative form of Yap (dnYap) or Tead4 (dnTead4) under a heat-shock promoter in transgenic animal lines. Each inhibition resulted in regeneration defects accompanied by reduced cell mitosis and increased apoptosis. Single-cell gene manipulation experiments indicated that Tead4 cell-autonomously regulates the survival of neural progenitor cells in the regenerating tail. In amphibians, amputation at the proximal level of the tail (deep amputation) results in faster regeneration than that at the distal level (shallow amputation), to restore the original-sized tail with similar timing. However, dnTead4 overexpression abolished the position-dependent differential growth rate of tail regeneration. These results suggest that the transcriptional regulators in the Hippo pathway, Tead4 and Yap1, are required for general vertebrate

  10. Actin cytoskeletal remodeling with protrusion formation is essential for heart regeneration in Hippo-deficient mice

    PubMed Central

    Morikawa, Yuka; Zhang, Min; Heallen, Todd; Leach, John; Tao, Ge; Xiao, Yang; Bai, Yan; Li, Wei; Willerson, James T.; Martin, James F.

    2015-01-01

    The mammalian heart regenerates poorly, and damage commonly leads to heart failure. Hippo signaling is an evolutionarily conserved kinase cascade that regulates organ size during development and prevents adult mammalian cardiomyocyte regeneration by inhibiting the transcriptional coactivator Yap, which also responds to mechanical signaling in cultured cells to promote cell proliferation. To identify Yap target genes that are activated during cardiomyocyte renewal and regeneration, we performed Yap chromatin immunoprecipitation sequencing (ChIP-Seq) and mRNA expression profiling in Hippo signaling-deficient mouse hearts. We found that Yap directly regulated genes encoding cell cycle progression proteins, as well as genes encoding proteins that promote F-actin polymerization and that link the actin cytoskeleton to the extracellular matrix. Included in the latter group were components of the dystrophin glycoprotein complex (DGC), a large molecular complex that, when defective, results in muscular dystrophy in humans. Cardiomyocytes near scar tissue of injured Hippo signaling-deficient mouse hearts showed cellular protrusions suggestive of cytoskeletal remodeling. The hearts of mdx mutant mice, which lack functional dystrophin and are a model for muscular dystrophy, showed impaired regeneration and cytoskeleton remodeling, but normal cardiomyocyte proliferation after injury. Our data showed that, in addition to genes encoding cell cycle progression proteins, Yap regulated genes that enhance cytoskeletal remodeling Thus, blocking the Hippo pathway input to Yap may tip the balance so that Yap responds to the mechanical changes associated with heart injury to promote repair. PMID:25943351

  11. USP21 regulates Hippo pathway activity by mediating MARK protein turnover.

    PubMed

    Nguyen, Hung Thanh; Kugler, Jan-Michael; Loya, Anand C; Cohen, Stephen M

    2017-09-08

    The Hippo pathway, which acts to repress the activity of YAP and TAZ trancriptional co-activators, serve as a barrier for oncogenic transformation. Unlike other oncoproteins, YAP and TAZ are rarely activated by mutations or amplified in cancer. However, elevated YAP/TAZ activity is frequently observed in cancer and often correlates with worse survival. The activity and stability of Hippo pathway components, including YAP/TAZ, AMOT and LATS1/2, are regulated by ubiquitin-mediated protein degradation. Aberrant expression of ubiquitin ligase complexes that regulate the turnover of Hippo components and deubiquitylating enzymes that counteract these ubiquitin ligases have been implicated in human cancer. Here we identify the USP21 deubiquitylating enzyme as a novel regulator of Hippo pathway activity. We provide evidence that USP21 regulates YAP/TAZ activity by controlling the stability of MARK kinases, which promote Hippo signaling. Low expression of USP21 in early stage renal clear cell carcinoma suggests that USP21 may be a useful biomarker.

  12. 77 FR 26734 - Notice of Intent To Extend a Currently Approved Information Collection

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-05-07

    ... American Samoa, Guam, Micronesia, Northern Marianas, Puerto Rico, and the Virgin Islands. The objectives of... practices; (2) youth group participants; and (3) staff. NEERS consists of separate software sub-systems for...

  13. LIM-domain protein AJUBA suppresses malignant mesothelioma cell proliferation via Hippo signaling cascade.

    PubMed

    Tanaka, I; Osada, H; Fujii, M; Fukatsu, A; Hida, T; Horio, Y; Kondo, Y; Sato, A; Hasegawa, Y; Tsujimura, T; Sekido, Y

    2015-01-02

    Malignant mesothelioma (MM) is one of the most aggressive neoplasms usually associated with asbestos exposure and is highly refractory to current therapeutic modalities. MMs show frequent activation of a transcriptional coactivator Yes-associated protein (YAP), which is attributed to the neurofibromatosis type 2 (NF2)-Hippo pathway dysfunction, leading to deregulated cell proliferation and acquisition of a malignant phenotype. However, the whole mechanism of disordered YAP activation in MMs has not yet been well clarified. In the present study, we investigated various components of the NF2-Hippo pathway, and eventually found that MM cells frequently showed downregulation of LIM-domain protein AJUBA, a binding partner of large tumor suppressor type 2 (LATS2), which is one of the last-step kinases of the NF2-Hippo pathway. Although loss of AJUBA expression was independent of the alteration status of other Hippo pathway components, MM cell lines with AJUBA inactivation showed a more dephosphorylated (activated) level of YAP. Immunohistochemical analysis showed frequent downregulation of AJUBA in primary MMs, which was associated with YAP constitutive activation. We found that AJUBA transduction into MM cells significantly suppressed promoter activities of YAP-target genes, and the suppression of YAP activity by AJUBA was remarkably canceled by knockdown of LATS2. In connection with these results, transduction of AJUBA-expressing lentivirus significantly inhibited the proliferation and anchorage-independent growth of the MM cells that harbored ordinary LATS family expression. Taken together, our findings indicate that AJUBA negatively regulates YAP activity through the LATS family, and inactivation of AJUBA is a novel key mechanism in MM cell proliferation.

  14. Satellite communications application to Pacific countries above Ku band

    NASA Technical Reports Server (NTRS)

    Iida, Takashi

    1992-01-01

    An application of satellite communications above the Ku band to the Pacific region is described, focusing on: (1) Lightsat system and (2) a high capacity satellite system. A small geostationary satellite system using Ku band for the Federated States of Micronesia is shown as an example. A concept of multi-gigabits/second high capacity communications system using two satellites in the Ka band is described. The onboard bit-by-bit processing is very useful in the low link margin environment due to rain attenuation. These topics were obtained by the Asia Pacific Telecommunications Study granted by NASA conducted by the University of Colorado at Boulder.

  15. The Hippo signal transduction network for exercise physiologists

    PubMed Central

    Hamilton, D. Lee; Tremblay, Annie M.

    2016-01-01

    The ubiquitous transcriptional coactivators Yap (gene symbol Yap1) and Taz (gene symbol Wwtr1) regulate gene expression mainly by coactivating the Tead transcription factors. Being at the center of the Hippo signaling network, Yap and Taz are regulated by the Hippo kinase cassette and additionally by a plethora of exercise-associated signals and signaling modules. These include mechanotransduction, the AKT-mTORC1 network, the SMAD transcription factors, hypoxia, glucose homeostasis, AMPK, adrenaline/epinephrine and angiotensin II through G protein-coupled receptors, and IL-6. Consequently, exercise should alter Hippo signaling in several organs to mediate at least some aspects of the organ-specific adaptations to exercise. Indeed, Tead1 overexpression in muscle fibers has been shown to promote a fast-to-slow fiber type switch, whereas Yap in muscle fibers and cardiomyocytes promotes skeletal muscle hypertrophy and cardiomyocyte adaptations, respectively. Finally, genome-wide association studies in humans have linked the Hippo pathway members LATS2, TEAD1, YAP1, VGLL2, VGLL3, and VGLL4 to body height, which is a key factor in sports. PMID:26940657

  16. The Hippo signaling pathway provides novel anti-cancer drug targets

    PubMed Central

    Bae, June Sung; Kim, Sun Mi; Lee, Ho

    2017-01-01

    The Hippo signaling pathway plays a crucial role in cell proliferation, apoptosis, differentiation, and development. Major effectors of the Hippo signaling pathway include the transcriptional co-activators Yes-associated protein 1 (YAP) and WW domain-containing transcription regulator protein 1 (TAZ). The transcriptional activities of YAP and TAZ are affected by interactions with proteins from many diverse signaling pathways as well as responses to the external environment. High YAP and TAZ activity has been observed in many cancer types, and functional dysregulation of Hippo signaling enhances the oncogenic properties of YAP and TAZ and promotes cancer development. Many biological elements, including mechanical strain on the cell, cell polarity/adhesion molecules, other signaling pathways (e.g., G-protein-coupled receptor, epidermal growth factor receptor, Wnt, Notch, and transforming growth factor β/bone morphogenic protein), and cellular metabolic status, can promote oncogenesis through synergistic association with components of the Hippo signaling pathway. Here, we review the signaling networks that interact with the Hippo signaling pathway and discuss the potential of using drugs that inhibit YAP and TAZ activity for cancer therapy. PMID:28035075

  17. The Hippo signaling pathway provides novel anti-cancer drug targets.

    PubMed

    Bae, June Sung; Kim, Sun Mi; Lee, Ho

    2017-02-28

    The Hippo signaling pathway plays a crucial role in cell proliferation, apoptosis, differentiation, and development. Major effectors of the Hippo signaling pathway include the transcriptional co-activators Yes-associated protein 1 (YAP) and WW domain-containing transcription regulator protein 1 (TAZ). The transcriptional activities of YAP and TAZ are affected by interactions with proteins from many diverse signaling pathways as well as responses to the external environment. High YAP and TAZ activity has been observed in many cancer types, and functional dysregulation of Hippo signaling enhances the oncogenic properties of YAP and TAZ and promotes cancer development. Many biological elements, including mechanical strain on the cell, cell polarity/adhesion molecules, other signaling pathways (e.g., G-protein-coupled receptor, epidermal growth factor receptor, Wnt, Notch, and transforming growth factor β/bone morphogenic protein), and cellular metabolic status, can promote oncogenesis through synergistic association with components of the Hippo signaling pathway. Here, we review the signaling networks that interact with the Hippo signaling pathway and discuss the potential of using drugs that inhibit YAP and TAZ activity for cancer therapy.

  18. Find an Allergist/Immunologist

    MedlinePlus

    ... Nevada New Brunswick New Hampshire New Jersey New Mexico New York Newfoundland North Carolina North Dakota Northwest ... Mali Malta Marshall Islands Martinique Mauritania Mauritius Mayotte Mexico Micronesia Moldova Monaco Mongolia Montenegro Montserrat Morocco Mozambique ...

  19. Low-Intensity Pulsed Ultrasound Protects Retinal Ganglion Cell From Optic Nerve Injury Induced Apoptosis via Yes Associated Protein

    PubMed Central

    Zhou, Jia-Xing; Liu, Yun-Jia; Chen, Xi; Zhang, Xi; Xu, Jie; Yang, Ke; Wang, Dong; Lin, Sen; Ye, Jian

    2018-01-01

    Background: Low-intensity pulsed ultrasound (LIPUS) has been used in clinical studies. But little is known about its effects on the central nervous system (CNS), or its mechanism of action. Retinal ganglion cells (RGCs) are CNS neuronal cells that can be utilized as a classic model system to evaluate outcomes of LIPUS protection from external trauma-induced retinal injury. In this study, we aim to: (1) determine the pulse energy and the capability of LIPUS in RGC viability, (2) ascertain the protective role of LIPUS in optic nerve (ON) crush-induced retinal injury, and 3) explore the cellular mechanisms of RGC apoptosis prevention by LIPUS. Methods: An ON crush model was set up to induce RGC death. LIPUS was used to treat mice eyes daily, and the retina samples were dissected for immunostaining and Western blot. The expression of yes-associated protein (YAP) and apoptosis-related proteins was detected by immunostaining and Western blot in vitro and in vivo. Apoptosis of RGCs was evaluated by TUNEL staining, the survival of RGCs and retained axons were labeled by Fluoro-gold and Tuj1 antibody, respectively. Rotenone was used to set up an in vitro cellular degenerative model and siYAP was used to interfering the expression of YAP to detect the LIPUS protective function. Results: LIPUS protected RGC from loss and apoptosis in vivo and in vitro. The ratio of cleaved/pro-caspase3 also decreased significantly under LIPUS treatment. As a cellular mechanical sensor, YAP expression increased and YAP translocated to nucleus in LIPUS stimulation group, however, phospho-YAP was found to be decreased. When YAP was inhibited, the LIPUS could not protect RGC from caspase3-dependent apoptosis. Conclusion: LIPUS prevented RGCs from apoptosis in an ON crush model and in vitro cellular degenerative model, which indicates a potential treatment for further traumatic ON injury. The mechanism of protection is dependent on YAP activation and correlated with caspase-3 signaling.

  20. Symptoms with betel nut and betel nut with tobacco among Micronesian youth.

    PubMed

    Milgrom, Peter; Tut, Ohnmar K; Gallen, Marcelle; Mancl, Lloyd; Spillane, Nichea; Chi, Donald L; Ramsay, Douglas S

    2016-02-01

    Betel nut has been stated to be addictive, but evidence is lacking. This study describes dependence symptoms among adolescents using betel alone or with tobacco. In the first study, participants were 151 9th graders in Saipan. In the second study, participants were 269 9th graders in Pohnpei and Yap. Participants completed a confidential questionnaire adapted from the U.S. National Survey of Drug Use and Health, which measured dependence symptoms. The 15 items were summed to form a scale, with a range of 0-15, where higher scores indicated greater endorsement of dependence symptoms. In the first study, 39.1% had used betel. More than two-thirds of all users (69.5%) used betel in the previous month: 87.8% also used tobacco with the betel. The mean (SD) dependence symptoms scale score among tobacco users was 8.2±4.0 versus 3.4±2.9 among those who used betel alone [t(7)=3.3, p=0.015]. In the second study, 38% from Pohnpei and 85% from Yap had used betel and most of the current users used it in the previous month (67% from Pohnpei, 91% from Yap). Among those who had used betel in the previous month, 90% from Pohnpei and 64% from Yap were using betel with tobacco. The dependence score was positively associated with frequency of tobacco use (e.g., mean (SD)=11.3 (±2.4) among most frequent users versus a mean (SD)=4.8 (±3.5) among the never users [F(3109)=28.8, p<0.001]). Betel nut users who also use tobacco may benefit from tobacco cessation strategies. Copyright © 2015 Elsevier Ltd. All rights reserved.

  1. Litigation and Community Advocacy to Ensure Health Access for Micronesian Migrants in Hawai'i.

    PubMed

    Hagiwara, Megan Kiyomi; Yamada, Seiji; Tanaka, Wayne; Ostrowski, Deja Marie

    2015-05-01

    The Federated States of Micronesia and the Republics of Palau and the Marshall Islands signed a series of treaties known as the Compacts of Free Association (COFA) with the United States (U.S.). While the islands became independent nations, certain rights and responsibilities were assigned to the U.S. However since the signing of the treaties, U.S. federal and Hawai'i state policies have reduced health care coverage for COFA migrants living in the U.S. and its territories. This commentary reports the ongoing efforts of the Micronesian community and its allies to rectify a legacy of unjust policies. We outline the need for sound policies that support appropriate health care to all members of society, and highlight the community's strength and ability to mobilize for political action. If health is a human right, providing adequate, equitable health care to all members of society is not up for debate.

  2. The Reconstruction of Condition-Specific Transcriptional Modules Provides New Insights in the Evolution of Yeast AP-1 Proteins

    PubMed Central

    Goudot, Christel; Etchebest, Catherine

    2011-01-01

    AP-1 proteins are transcription factors (TFs) that belong to the basic leucine zipper family, one of the largest families of TFs in eukaryotic cells. Despite high homology between their DNA binding domains, these proteins are able to recognize diverse DNA motifs. In yeasts, these motifs are referred as YRE (Yap Response Element) and are either seven (YRE-Overlap) or eight (YRE-Adjacent) base pair long. It has been proposed that the AP-1 DNA binding motif preference relies on a single change in the amino acid sequence of the yeast AP-1 TFs (an arginine in the YRE-O binding factors being replaced by a lysine in the YRE-A binding Yaps). We developed a computational approach to infer condition-specific transcriptional modules associated to the orthologous AP-1 protein Yap1p, Cgap1p and Cap1p, in three yeast species: the model yeast Saccharomyces cerevisiae and two pathogenic species Candida glabrata and Candida albicans. Exploitation of these modules in terms of predictions of the protein/DNA regulatory interactions changed our vision of AP-1 protein evolution. Cis-regulatory motif analyses revealed the presence of a conserved adenine in 5′ position of the canonical YRE sites. While Yap1p, Cgap1p and Cap1p shared a remarkably low number of target genes, an impressive conservation was observed in the YRE sequences identified by Yap1p and Cap1p. In Candida glabrata, we found that Cgap1p, unlike Yap1p and Cap1p, recognizes YRE-O and YRE-A motifs. These findings were supported by structural data available for the transcription factor Pap1p (Schizosaccharomyces pombe). Thus, whereas arginine and lysine substitutions in Cgap1p and Yap1p proteins were reported as responsible for a specific YRE-O or YRE-A preference, our analyses rather suggest that the ancestral yeast AP-1 protein could recognize both YRE-O and YRE-A motifs and that the arginine/lysine exchange is not the only determinant of the specialization of modern Yaps for one motif or another. PMID:21695268

  3. Wnt/Yes-Associated Protein Interactions During Neural Tissue Patterning of Human Induced Pluripotent Stem Cells.

    PubMed

    Bejoy, Julie; Song, Liqing; Zhou, Yi; Li, Yan

    2018-04-01

    Human induced pluripotent stem cells (hiPSCs) have special ability to self-assemble into neural spheroids or mini-brain-like structures. During the self-assembly process, Wnt signaling plays an important role in regional patterning and establishing positional identity of hiPSC-derived neural progenitors. Recently, the role of Wnt signaling in regulating Yes-associated protein (YAP) expression (nuclear or cytoplasmic), the pivotal regulator during organ growth and tissue generation, has attracted increasing interests. However, the interactions between Wnt and YAP expression for neural lineage commitment of hiPSCs remain poorly explored. The objective of this study is to investigate the effects of Wnt signaling and YAP expression on the cellular population in three-dimensional (3D) neural spheroids derived from hiPSCs. In this study, Wnt signaling was activated using CHIR99021 for 3D neural spheroids derived from human iPSK3 cells through embryoid body formation. Our results indicate that Wnt activation induces nuclear localization of YAP and upregulates the expression of HOXB4, the marker for hindbrain/spinal cord. By contrast, the cells exhibit more rostral forebrain neural identity (expression of TBR1) without Wnt activation. Cytochalasin D was then used to induce cytoplasmic YAP and the results showed the decreased HOXB4 expression. In addition, the incorporation of microparticles in the neural spheroids was investigated for the perturbation of neural patterning. This study may indicate the bidirectional interactions of Wnt signaling and YAP expression during neural tissue patterning, which have the significance in neurological disease modeling, drug screening, and neural tissue regeneration.

  4. Molecular chaperone Hsp27 regulates the Hippo tumor suppressor pathway in cancer.

    PubMed

    Vahid, Sepideh; Thaper, Daksh; Gibson, Kate F; Bishop, Jennifer L; Zoubeidi, Amina

    2016-08-24

    Heat shock protein 27 (Hsp27) is a molecular chaperone highly expressed in aggressive cancers, where it is involved in numerous pro-tumorigenic signaling pathways. Using functional genomics we identified for the first time that Hsp27 regulates the gene signature of transcriptional co-activators YAP and TAZ, which are negatively regulated by the Hippo Tumor Suppressor pathway. The Hippo pathway inactivates YAP by phosphorylating and increasing its cytoplasmic retention with the 14.3.3 proteins. Gain and loss of function experiments in prostate, breast and lung cancer cells showed that Hsp27 knockdown induced YAP phosphorylation and cytoplasmic localization while overexpression of Hsp27 displayed opposite results. Mechanistically, Hsp27 regulates the Hippo pathway by accelerating the proteasomal degradation of ubiquitinated MST1, the core Hippo kinase, resulting in reduced phosphorylation/activity of LATS1 and MOB1, its downstream effectors. Importantly, our in vitro results were supported by data from human tumors; clinically, high expression of Hsp27 in prostate tumors is correlated with increased expression of YAP gene signature and reduced phosphorylation of YAP in lung and invasive breast cancer clinical samples. This study reveals for the first time a link between Hsp27 and the Hippo cascade, providing a novel mechanism of deregulation of this tumor suppressor pathway across multiple cancers.

  5. Environmental Prime Movers for Prehistoric Colonization of Islands in Remote Oceania

    NASA Astrophysics Data System (ADS)

    Montenegro, Alvaro; Callaghan, Richard T.; Fitzpatrick, Scott M.

    2016-04-01

    The peopling of Remote Oceania was one of the last great waves of human migration in the ancient past. Beginning around 3500 BP, peoples from Island Southeast Asia began colonizing western Micronesia, and shortly thereafter ca. 3400 BP, Lapita groups began moving east from Near Oceania (e.g., the Solomons and Bismarck Archipelago) to islands in Eastern Melanesia and West Polynesia, including Vanuatu, Fiji, Tonga, and Samoa. It is remarkable that over the next 2500 years, even the most remote islands, known now to represent the distant nodes of the Polynesian triangle (New Zealand, Hawaii, and Easter Island), were eventually visited by Austronesian speakers and their descendants across this seemingly boundless ocean. One of the more enduring questions - and one that has perplexed scholars for decades - is how and when these ancient seafarers were able to develop navigational/wayfinding techniques and seafaring technologies to overcome a number of environmental challenges. This would ultimately help determine what combination of social and environmental stimuli forced or encouraged people to colonize some of the most isolated patches of land on earth. To advance our understanding of ancient Pacific colonization strategies, we integrate seafaring simulation models, ease of eastward travel estimates based on land distribution and wind pattern analysis, and new climatic datasets for precipitation in Micronesia and Polynesia to examine intra-annual variations in wind and precipitation that would have influenced travel. Combined with statistical modeling of winds and currents, we argue that: land distribution could have contributed to the pause in eastward expansion seen at about 3000 BP; simple downwind sailing and downwind sailing during eastward spells are viable navigation strategies for reaching islands to the east; seasonality of eastward winds would facilitate voyage planning and increase chances of success; knowledge of annual and interannual variability

  6. Growth and anisotropic thermal properties of biaxial Ho:YAlO3 crystal

    NASA Astrophysics Data System (ADS)

    Dong, Qin; Zhao, Guangjun; Chen, Jianyu; Ding, Yuchong; Zhao, Chengchun

    2010-07-01

    Ho:YAlO3 (YAP) crystal with large size and good optical quality has been grown by the Czochralski method. Thermal properties of the as-grown Ho:YAP crystal have been investigated by measuring the temperature-dependent, anisotropic thermal expansion, specific heat, thermal diffusion, and thermal conductivity. The results show that Ho:YAP crystal possesses a large anisotropic thermal expansion and good thermal conductivity. The calculated average thermal expansion coefficients along a, b, and c axis are αa=9.18×10-6/K, αb=1.94×10-6/K, and αc=7.61×10-6/K from 293.15 to 770.15 K. The thermal conductivities along a, b, and c axis are up to 11.6, 9.9, and 12.3 W m-1 K-1 at 298.15 K. Compared with Ho: Y3Al5O12 (YAG), Ho:YAP crystal has a larger thermal conductivity along a axis from 298.15 to 568.15 K.

  7. Hippo signaling regulates Microprocessor and links cell density-dependent miRNA biogenesis to cancer

    PubMed Central

    Mori, Masaki; Triboulet, Robinson; Mohseni, Morvarid; Schlegelmilch, Karin; Shrestha, Kriti; Camargo, Fernando D.; Gregory, Richard I.

    2014-01-01

    SUMMARY Global downregulation of microRNAs (miRNAs) is commonly observed in human cancers and can have a causative role in tumorigenesis. The mechanisms responsible for this phenomenon remain poorly understood. Here we show that YAP, the downstream target of the tumor-suppressive Hippo signaling pathway regulates miRNA biogenesis in a cell density-dependent manner. At low cell density, nuclear YAP binds and sequesters p72 (DDX17), a regulatory component of the miRNA processing machinery. At high cell density, Hippo-mediated cytoplasmic retention of YAP facilitates p72 association with Microprocessor and binding to a specific sequence motif in pri-miRNAs. Inactivation of the Hippo pathway or expression of constitutively active YAP causes widespread miRNA suppression in cells and tumors and a corresponding post-transcriptional induction of MYC expression. Thus, the Hippo pathway links contact-inhibition regulation to miRNA biogenesis and may be responsible for the widespread miRNA repression observed in cancer. PMID:24581491

  8. Identification of an Endogenously Generated Cryptic Collagen Epitope (XL313) That May Selectively Regulate Angiogenesis by an Integrin Yes-associated Protein (YAP) Mechano-transduction Pathway*

    PubMed Central

    Ames, Jacquelyn J.; Contois, Liangru; Caron, Jennifer M.; Tweedie, Eric; Yang, Xuehui; Friesel, Robert; Vary, Calvin; Brooks, Peter C.

    2016-01-01

    Extracellular matrix (ECM) remodeling regulates angiogenesis. However, the precise mechanisms by which structural changes in ECM proteins contribute to angiogenesis are not fully understood. Integrins are molecules with the ability to detect compositional and structural changes within the ECM and integrate this information into a network of signaling circuits that coordinate context-dependent cell behavior. The role of integrin αvβ3 in angiogenesis is complex, as evidence exists for both positive and negative functions. The precise downstream signaling events initiated by αvβ3 may depend on the molecular characteristics of its ligands. Here, we identified an RGD-containing cryptic collagen epitope that is generated in vivo. Surprisingly, rather than inhibiting αvβ3 signaling, this collagen epitope promoted αvβ3 activation and stimulated angiogenesis and inflammation. An antibody directed to this RGDKGE epitope but not other RGD collagen epitopes inhibited angiogenesis and inflammation in vivo. The selective ability of this RGD epitope to promote angiogenesis and inflammation depends in part on its flanking KGE motif. Interestingly, a subset of macrophages may represent a physiologically relevant source of this collagen epitope. Here, we define an endothelial cell mechano-signaling pathway in which a cryptic collagen epitope activates αvβ3 leading to an Src and p38 MAPK-dependent cascade that leads to nuclear accumulation of Yes-associated protein (YAP) and stimulation of endothelial cell growth. Collectively, our findings not only provide evidence for a novel mechano-signaling pathway, but also define a possible therapeutic strategy to control αvβ3 signaling by targeting a pro-angiogenic and inflammatory ligand of αvβ3 rather than the receptor itself. PMID:26668310

  9. The effect of repeated laser stimuli to ink-marked skin on skin temperature-recommendations for a safe experimental protocol in humans.

    PubMed

    Madden, Victoria J; Catley, Mark J; Grabherr, Luzia; Mazzola, Francesca; Shohag, Mohammad; Moseley, G Lorimer

    2016-01-01

    Background. Nd:YAP laser is widely used to investigate the nociceptive and pain systems, generating perpetual and laser-evoked neurophysiological responses. A major procedural concern for the use of Nd:YAP laser stimuli in experimental research is the risk of skin damage. The absorption of Nd:YAP laser stimuli is greater in darker skin, or in pale skin that has been darkened with ink, prompting some ethics boards to refuse approval to experimenters wishing to track stimulus location by marking the skin with ink. Some research questions, however, require laser stimuli to be delivered at particular locations or within particular zones, a requirement that is very difficult to achieve if marking the skin is not possible. We thoroughly searched the literature for experimental evidence and protocol recommendations for safe delivery of Nd:YAP laser stimuli over marked skin, but found nothing. Methods. We designed an experimental protocol to define safe parameters for the use of Nd:YAP laser stimuli over skin that has been marked with black dots, and used thermal imaging to assess the safety of the procedure at the forearm and the back. Results. Using thermal imaging and repeated laser stimulation to ink-marked skin, we demonstrated that skin temperature did not increase progressively across the course of the experiment, and that the small change in temperature seen at the forearm was reversed during the rest periods between blocks. Furthermore, no participant experienced skin damage due to the procedure. Conclusion. This protocol offers parameters for safe, confident and effective experimentation using repeated Nd:YAP laser on skin marked with ink, thus paving the way for investigations that depend on it.

  10. The Hippo pathway mediates inhibition of vascular smooth muscle cell proliferation by cAMP.

    PubMed

    Kimura, Tomomi E; Duggirala, Aparna; Smith, Madeleine C; White, Stephen; Sala-Newby, Graciela B; Newby, Andrew C; Bond, Mark

    2016-01-01

    Inhibition of vascular smooth muscle cell (VSMC) proliferation by intracellular cAMP prevents excessive neointima formation and hence angioplasty restenosis and vein-graft failure. These protective effects are mediated via actin-cytoskeleton remodelling and subsequent regulation of gene expression by mechanisms that are incompletely understood. Here we investigated the role of components of the growth-regulatory Hippo pathway, specifically the transcription factor TEAD and its co-factors YAP and TAZ in VSMC. Elevation of cAMP using forskolin, dibutyryl-cAMP or the physiological agonists, Cicaprost or adenosine, significantly increased phosphorylation and nuclear export YAP and TAZ and inhibited TEAD-luciferase report gene activity. Similar effects were obtained by inhibiting RhoA activity with C3-transferase, its downstream kinase, ROCK, with Y27632, or actin-polymerisation with Latrunculin-B. Conversely, expression of constitutively-active RhoA reversed the inhibitory effects of forskolin on TEAD-luciferase. Forskolin significantly inhibited the mRNA expression of the pro-mitogenic genes, CCN1, CTGF, c-MYC and TGFB2 and this was reversed by expression of constitutively-active YAP or TAZ phospho-mutants. Inhibition of YAP and TAZ function with RNAi or Verteporfin significantly reduced VSMC proliferation. Furthermore, the anti-mitogenic effects of forskolin were reversed by overexpression of constitutively-active YAP or TAZ. Taken together, these data demonstrate that cAMP-induced actin-cytoskeleton remodelling inhibits YAP/TAZ-TEAD dependent expression of pro-mitogenic genes in VSMC. This mechanism contributes novel insight into the anti-mitogenic effects of cAMP in VSMC and suggests a new target for intervention. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  11. Ubiquitin-Dependent Regulation of the Mammalian Hippo Pathway: Therapeutic Implications for Cancer

    PubMed Central

    Nguyen, Thanh Hung

    2018-01-01

    The Hippo pathway serves as a key barrier for oncogenic transformation. It acts by limiting the activity of the proto-oncogenes YAP and TAZ. Reduced Hippo signaling and elevated YAP/TAZ activities are frequently observed in various types of tumors. Emerging evidence suggests that the ubiquitin system plays an important role in regulating Hippo pathway activity. Deregulation of ubiquitin ligases and of deubiquitinating enzymes has been implicated in increased YAP/TAZ activity in cancer. In this article, we review recent insights into the ubiquitin-mediated regulation of the mammalian Hippo pathway, its deregulation in cancer, and possibilities for targeting the Hippo pathway through the ubiquitin system. PMID:29673168

  12. Ubiquitin-Dependent Regulation of the Mammalian Hippo Pathway: Therapeutic Implications for Cancer.

    PubMed

    Nguyen, Thanh Hung; Kugler, Jan-Michael

    2018-04-17

    The Hippo pathway serves as a key barrier for oncogenic transformation. It acts by limiting the activity of the proto-oncogenes YAP and TAZ. Reduced Hippo signaling and elevated YAP/TAZ activities are frequently observed in various types of tumors. Emerging evidence suggests that the ubiquitin system plays an important role in regulating Hippo pathway activity. Deregulation of ubiquitin ligases and of deubiquitinating enzymes has been implicated in increased YAP/TAZ activity in cancer. In this article, we review recent insights into the ubiquitin-mediated regulation of the mammalian Hippo pathway, its deregulation in cancer, and possibilities for targeting the Hippo pathway through the ubiquitin system.

  13. The Hippo pathway in normal development and cancer.

    PubMed

    Maugeri-Saccà, Marcello; De Maria, Ruggero

    2018-06-01

    The Hippo pathway is a central regulator of organ size and tissue homeostasis. Hippo kinases and adaptor proteins mediate the phosphorylation and inactivation of YAP and TAZ, two closely related transcription co-activators. The Hippo pathway responds to a variety of extracellular and intracellular signals, spanning from cell-cell contact and mechanical cues to ligands of G-protein-coupled receptors and metabolic avenues. In some instances, YAP/TAZ activation is tuned by forces that bypass the Hippo kinase module, adding further complexity to the biology of the pathway. Over the past two decades, the Hippo pathway has increasingly been connected with developmental processes and tissue repair, being intimately tied to the function of tissue-specific progenitor cells. Pervasive activation of YAP/TAZ has been recognized in a multitude of human tumors and connected with the acquisition of malignant traits, including resistance to anticancer therapies, distant dissemination and maintenance of cancer stem cells. On this ground, Hippo-related biomarkers are increasingly investigated in translational studies striving to identify prognostic and predictive factors. In addition, the dependency of many tumors on YAP/TAZ may be exploited for therapeutic purposes. Albeit no direct inhibitors are currently available, drug repositioning approaches provided hints that YAP/TAZ inhibition can be achieved with old drugs, such as cholesterol-lowering agents or compounds blocking bone resorption. Copyright © 2018 Elsevier Inc. All rights reserved.

  14. Molecular chaperone Hsp27 regulates the Hippo tumor suppressor pathway in cancer

    PubMed Central

    Vahid, Sepideh; Thaper, Daksh; Gibson, Kate F.; Bishop, Jennifer L.; Zoubeidi, Amina

    2016-01-01

    Heat shock protein 27 (Hsp27) is a molecular chaperone highly expressed in aggressive cancers, where it is involved in numerous pro-tumorigenic signaling pathways. Using functional genomics we identified for the first time that Hsp27 regulates the gene signature of transcriptional co-activators YAP and TAZ, which are negatively regulated by the Hippo Tumor Suppressor pathway. The Hippo pathway inactivates YAP by phosphorylating and increasing its cytoplasmic retention with the 14.3.3 proteins. Gain and loss of function experiments in prostate, breast and lung cancer cells showed that Hsp27 knockdown induced YAP phosphorylation and cytoplasmic localization while overexpression of Hsp27 displayed opposite results. Mechanistically, Hsp27 regulates the Hippo pathway by accelerating the proteasomal degradation of ubiquitinated MST1, the core Hippo kinase, resulting in reduced phosphorylation/activity of LATS1 and MOB1, its downstream effectors. Importantly, our in vitro results were supported by data from human tumors; clinically, high expression of Hsp27 in prostate tumors is correlated with increased expression of YAP gene signature and reduced phosphorylation of YAP in lung and invasive breast cancer clinical samples. This study reveals for the first time a link between Hsp27 and the Hippo cascade, providing a novel mechanism of deregulation of this tumor suppressor pathway across multiple cancers. PMID:27555231

  15. Comparison of Outcomes for Youth Apprenticeship Projects and Youth Career Development Projects. Supplementary Report.

    ERIC Educational Resources Information Center

    Richards, James M., Jr.; And Others

    The New Youth Initiatives in Apprenticeship Program (YAP) was compared with the Youth Career Development Program (YCD). Data for 1979 and 1980 came from an evaluation of YAP projects by CSR, Incorporated, and an evaluation of the YCD projects by the Educational Testing Service. A multiple regression approach was used to compare student…

  16. 77 FR 53917 - Report on Countries That Are Candidates for Millennium Challenge Account Eligibility in Fiscal...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-09-04

    ... poverty reduction. The Act requires the Millennium Challenge Corporation (MCC) to take a number of steps... its people; and (b) considering the opportunity to reduce poverty and generate economic growth in the... India Indonesia Iraq Kenya Kiribati Kyrgyz Republic Lao PDR Lesotho Liberia Malawi Mauritania Micronesia...

  17. Environmental Education in the South Pacific: An Evaluation of Progress in Three Countries.

    ERIC Educational Resources Information Center

    Taylor, Neil; Topalian, Teny

    1995-01-01

    Evaluates formal environmental education in three countries in the South Pacific Region: Fiji (Melanesia); Kiribati (Micronesia); and Niue (Polynesia). Findings reveal that environmental education is at different stages of evolution in each of these countries and only Niue appears to deliver environmental education effectively when compared with…

  18. Family Advocacy Program (FAP)

    DTIC Science & Technology

    1992-06-23

    PURPOSEiA ’. This Directive administratively reissues reference (a) to update: a. DoD policy on child abuse and neglect (hereafter referred to as...34 child abuse ") and spouse abuse. b. The Department of Defense YAP and Family Advocacy Committee (FAC). c. Responsibility for the establishment and...Notification of the local public child protective agency (in alleged child abuse cases only) in the United States and where covered by agreement overseas

  19. Radio- and VUV - Excited Luminescence of YAP:Ce, YAP:Pr and YAG:Pr

    DTIC Science & Technology

    2001-01-01

    Pr 3+ ions.", Acta Physica Polonica A, 90 pp.407-10, 1996. 6. C. Pedrini, D. Bouttet, C. Dujardin, B. Moine, I. Dafinei, P. Lecoq, M. Koselja, K...34Spectroscopy and thermoluminescence of LuAIO 3:Ce" Acta Physica Polonica A,.90, pp.377-383, 1996 17. A.J. Wojtowicz, J. Glodo, W. Drozdowski, K.R. Przegietka...Malinowski, M.F. Joubert, B. Jacquier. "Simultaneous laser action at blue and orange wavelengths in YAG:Pr 3+ Physica Status Solidi A, 140, pp.K49-52, 1993 5

  20. Measuring and Understanding Authentic Youth Engagement: The Youth-Adult Partnership Rubric

    ERIC Educational Resources Information Center

    Wu, Heng-Chieh Jamie; Kornbluh, Mariah; Weiss, John; Roddy, Lori

    2016-01-01

    Commonly described as youth-led or youth-driven, the youth-adult partnership (Y-AP) model has gained increasing popularity in out-of-school time (OST) programs in the past two decades (Larson, Walker, & Pearce, 2005; Zeldin, Christens, & Powers, 2013). The Y-AP model is defined as "the practice of (a) multiple youth and multiple…

  1. Endocardial Hippo signaling regulates myocardial growth and cardiogenesis.

    PubMed

    Artap, Stanley; Manderfield, Lauren J; Smith, Cheryl L; Poleshko, Andrey; Aghajanian, Haig; See, Kelvin; Li, Li; Jain, Rajan; Epstein, Jonathan A

    2018-08-01

    The Hippo signaling pathway has been implicated in control of cell and organ size, proliferation, and endothelial-mesenchymal transformation. This pathway impacts upon two partially redundant transcription cofactors, Yap and Taz, that interact with other factors, including members of the Tead family, to affect expression of downstream genes. Yap and Taz have been shown to regulate, in a cell-autonomous manner, myocardial proliferation, myocardial hypertrophy, regenerative potential, and overall size of the heart. Here, we show that Yap and Taz also play an instructive, non-cell-autonomous role in the endocardium of the developing heart to regulate myocardial growth through release of the paracrine factor, neuregulin. Without endocardial Yap and Taz, myocardial growth is impaired causing early post-natal lethality. Thus, the Hippo signaling pathway regulates cell size via both cell-autonomous and non-cell-autonomous mechanisms. Furthermore, these data suggest that Hippo may regulate organ size via a sensing and paracrine function in endothelial cells. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

  2. Hippo signaling pathway in liver and pancreas: the potential drug target for tumor therapy.

    PubMed

    Kong, Delin; Zhao, Yicheng; Men, Tong; Teng, Chun-Bo

    2015-02-01

    Cell behaviors, including proliferation, differentiation and apoptosis, are intricately controlled during organ development and tissue regeneration. In the past 9 years, the Hippo signaling pathway has been delineated to play critical roles in organ size control, tissue regeneration and tumorigenesis through regulating cell behaviors. In mammals, the core modules of the Hippo signaling pathway include the MST1/2-LATS1/2 kinase cascade and the transcriptional co-activators YAP/TAZ. The activity of YAP/TAZ is suppressed by cytoplasmic retention due to phosphorylation in the canonical MST1/2-LATS1/2 kinase cascade-dependent manner or the non-canonical MST1/2- and/or LATS1/2-independent manner. Hippo signaling pathway, which can be activated or inactivated by cell polarity, contact inhibition, mechanical stretch and extracellular factors, has been demonstrated to be involved in development and tumorigenesis of liver and pancreas. In addition, we have summarized several small molecules currently available that can target Hippo-YAP pathway for potential treatment of hepatic and pancreatic cancers, providing clues for other YAP initiated cancers therapy as well.

  3. Thesaurus of DDC Descriptors

    DTIC Science & Technology

    1966-06-01

    BIRDS BLASTOMYCES BLATTIDAE BOVINES CANDIDA CANNABIS CARNIVORA CATS CEPHALOPODA CEREALS CETACEA CHICKENS CHILDREN CHIMPANZEES CHLORELLA...POLIOMYELITIS VIRUS POX VIRUSES PROTEUS PROTEUS VULGAR1S PROTOZOA PSEUOOMONADACEAE PSEUUOMONADALES PSEUDOMONAS PSEUDOMONAS AEROGINOSA RABIES VIRUS...ISLANUS MARYLAND MASSACHUSETTS MASSACHUSETTS BAY MEDITERRANEAN SEA MEDITERRANEAN SEA ISLANDS MELANESIA MEXICO MEXICO GULF MICHIGAN MICRONESIA

  4. Glimpses into Pacific Lives: Some Outstanding Women.

    ERIC Educational Resources Information Center

    Simon-McWilliams, Ethel, Comp.; Green, Karen Reed, Ed.

    This document presents profiles of women who have contributed significantly to governmental changes, social and economic development, and general efforts toward change in Guam, Hawaii, American Samoa, Micronesia, the Republic of the Marshall Islands, the Commonwealth of the Northern Mariana Islands, and Palau. Each profile provides a brief…

  5. Diving beneath the Surface: Underwater Robotics Lessons Bring STEM to Life for Teachers in Guam

    ERIC Educational Resources Information Center

    Tweed, Anne; Arndt, Laura

    2017-01-01

    In spring 2014, education leaders from across Micronesia came together on the island of Guam to learn about underwater robotics and Marine Advanced Technology Education (MATE), a program based at Monterey Peninsula College in Monterey, California. Participants listened intently as they learned about building and participating in competitions with…

  6. Marianas Islands seen during STS-103 mission

    NASA Image and Video Library

    1999-12-24

    S103-E-5361 (24 December 1999) --- This vertical view from the Space Shuttle Discovery shows two small islands of the Marianas Islands (Saipan and Tinian) in Micronesia in the Pacific Ocean. The STS-103 crew recorded this electronic still image at 28:05:53 GMT, December 24, 1999.

  7. Union List of Serials in Pacific Island Libraries.

    ERIC Educational Resources Information Center

    Cohen, Arlene G., Comp.; Yoshida, Patricia, Comp.

    This union list contains the serial holdings from Pacific Island libraries, including the University of the South Pacific Library (Fiji), the University of Guam Robert F. Kennedy Library, Guam Public Library, College of Micronesia-FSM Library, College of the Marshall Islands Library, Micronesian Seminar Library, Palau Community College Library,…

  8. Yapese land classification and use in relation to agroforests

    Treesearch

    Pius Liyagel

    1993-01-01

    Traditional land use classification on Yap Island, especially in regards to agroforestry, is described. Today there is a need to classify land on Yap to protect culturally significant areas and to make the best possible use of the land to support a rapidly growing population. Any new uses of land should be evaluated to assure that actions in one area, even private...

  9. A review of traditional agroforestry in Micronesia

    Treesearch

    Harley I. Manner

    1993-01-01

    For the many Micronesian islands, agroforestry was a sustainable land use system, and an integral component of the traditional subsistence system which provided the people with many of the necessities of life. Given the increasing pressures on limited land resources, the social and environmental problems associated with modern agriculture, particularly its use of...

  10. Chamorro Reference Grammar. Pali Language Texts: Micronesia.

    ERIC Educational Resources Information Center

    Topping, Donald M.; Dungca, Bernadita C.

    This detailed reference grammar of Chamorro, the native Malayo-Polynesian language spoken in Guam and the other Mariana Islands (Saipan, Rota, Tinian), differs from earlier grammars of the language in that: (1) it includes new data; (2) it offers a different interpretation of some of the data based on more recent linguistic concepts; and (3) it is…

  11. The Hippo signal transduction pathway in soft tissue sarcomas.

    PubMed

    Mohamed, Abdalla D; Tremblay, Annie M; Murray, Graeme I; Wackerhage, Henning

    2015-08-01

    Sarcomas are rare cancers (≈1% of all solid tumours) usually of mesenchymal origin. Here, we review evidence implicating the Hippo pathway in soft tissue sarcomas. Several transgenic mouse models of Hippo pathway members (Nf2, Mob1, LATS1 and YAP1 mutants) develop various types of sarcoma. Despite that, Hippo member genes are rarely point mutated in human sarcomas. Instead, WWTR1-CAMTA1 and YAP1-TFE3 fusion genes are found in almost all cases of epithelioid haemangioendothelioma. Also copy number gains of YAP1 and other Hippo members occur at low frequencies but the most likely cause of perturbed Hippo signalling in sarcoma is the cross-talk with commonly mutated cancer genes such as KRAS, PIK3CA, CTNNB1 or FBXW7. Current Hippo pathway-targeting drugs include compounds that target the interaction between YAP and TEAD G protein-coupled receptors (GPCR) and the mevalonate pathway (e.g. statins). Given that many Hippo pathway-modulating drugs are already used in patients, this could lead to early clinical trials testing their efficacy in different types of sarcoma. Crown Copyright © 2015. Published by Elsevier B.V. All rights reserved.

  12. Interactions between polyphenols in thinned young apples and porcine pancreatic α-amylase: Inhibition, detailed kinetics and fluorescence quenching.

    PubMed

    Sun, Lijun; Chen, Weiqi; Meng, Yonghong; Yang, Xingbin; Yuan, Li; Guo, Yurong; Warren, Frederick J; Gidley, Michael J

    2016-10-01

    Young apple polyphenols (YAP) and nine types of phenolic compounds were investigated regarding the inhibitory activity against porcine pancreatic α-amylase (PPA) in vitro. Tannic acid, chlorogenic acid and caffeic acid in YAP showed relatively high inhibition with the IC50 values of 0.30, 1.96 and 3.69mg/mL, respectively. A detailed kinetics of inhibition study revealed that YAP and tannic acid were competitive inhibitors of PPA, whereas chlorogenic acid and caffeic acid were mixed inhibitors, exhibiting both competitive and uncompetitive characteristics. The fluorescence of PPA could be significantly quenched by YAP and the three polyphenols, and their quenching constants were determined. The results showed that for the polyphenols investigated, the order of the apparent static quenching constants (KFQ) was in agreement with that of the reciprocal competitive inhibition constants (1/Kic) (tannic acid>chlorogenic acid>caffeic acid>epicatechin); both of the parameters were contrary to the order of the IC50 values. Thus, combining detailed kinetics and fluorescence quenching studies can be applied to characterise the interactions between polyphenols in young apples and α-amylase. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. Old Ponape. Pohnpei Ni Mwehin Kawa.

    ERIC Educational Resources Information Center

    Lawrence, Pensile, Comp.; And Others

    This book presents English and Ponape versions of the stories, legends, and histories originally transcribed by anthropologists attached to the Thilenius South Sea Expedition of 1908-1910. The natives of the Marshall Islands in Micronesia who related these stories are identified, but the material is much older and represents the cultural heritage…

  14. The Language Question in Pacific Education: The Case of the Republic of the Marshall Islands. Research Brief

    ERIC Educational Resources Information Center

    Low, Marylin; Penland, Destin; Heine, Hilda

    2005-01-01

    This paper uses a sociohistorical lens to examine complex issues surrounding language-in-education policy in Micronesia. It is motivated by the realization that language policy and practice in this region, like many other parts of the world significantly impacted by outside contact, rarely align. This is especially evident in contexts where…

  15. Dynamics of an island agroecosystem: Where to now?

    Treesearch

    Marjorie V. C. Falanruw;  Francis Ruegorong

    2015-01-01

    This chapter describes past interaction of human populations with habitats on mainland Yap and the dynamics of the agroecosystem that developed. Recent changes in this system on mainland Yap are described, followed by a description of the nature and threats to agriculture in the Outer Islands. The chapter concludes by asking “Where to now?” and considers a past...

  16. Ubiquitin-specific protease 11 (USP11) functions as a tumor suppressor through deubiquitinating and stabilizing VGLL4 protein

    PubMed Central

    Zhang, Encheng; Shen, Bing; Mu, Xingyu; Qin, Yan; Zhang, Fang; Liu, Yong; Xiao, Jiantao; Zhang, Pingzhao; Wang, Chenji; Tan, Mingyue; Fan, Yu

    2016-01-01

    VGLL4 is a transcriptional repressor that interacts with transcription factors TEADs and inhibits YAP-induced overgrowth and tumorigenesis. VGLL4 protein was dramatically reduced in various types of human cancers. But how VGLL4 protein is post-transcriptional regulated is poorly understood. In this study, we identify deubiquitinating enzyme USP11 as a novel VGLL4 interactor. We reveal that the USP domain of USP11 and the N-terminal region of VGLL4 are required for mutual binding. USP11 controls VGLL4 protein stability by promoting its deubiquitination. Furthermore, our results show that knockdown of USP11 promotes cell growth, migration, and invasion in a YAP-dependent manner. Together, our results suggest that USP11 may exert its tumor suppressor role by modulating VGLL4/YAP-TEADs regulatory loop. PMID:28042509

  17. Viral hepatitis in a homeless shelter in Hawai'i.

    PubMed

    Boyce, Daniel E C; Tice, Alan D; Ona, Fernando V; Akinaka, Kenneth T; Lusk, Heather

    2009-06-01

    It is estimated that as many as 21,000 people in the state of Hawai'i may be infected with HCV Most of those infected with viral hepatitis are unaware they are infected. Complications from viral hepatitis include liver cirrhosis and hepatocellular carcinoma. Hawai'i has the highest incidence of hepatocellular carcinoma in the United States. In 2003 there were over 6000 homeless and over 155,000 people at-risk of becoming homeless living in the state of Hawai'i. Risk factors for hepatitis, such as drug use, tattoos, sexual contact, and sharing of personal hygiene equipment are more prevalent in the homeless population. To determine the incidence of hepatitis B and C among a population of homeless individuals, a health fair was held at a Honolulu area homeless shelter with approximately 200 residents. The incidence of hepatitis B and C was determined by anti-HCV and HBsAg blood tests. A survey was also conducted regarding risk factors and basic demographics. Fifty-nine homeless adults volunteered for testing and took the survey. Thirty-one (52%) volunteers were born in Micronesia, twenty-four (41%) were born in the United States, two (3%) were born in Samoa, one (2%) was born in the Philippines, and one (2%) was born in the Marshall Islands. Forty adults were tested for Hepatitis C antibody, three of which tested positive. The primary risk factor among this group was jail time (100%), followed by illegal drug injection (67%), tattoos (67%), ear/body piercing (67%), snorting drugs (33%), blood transfusions (33%), and a sex partner with hepatitis (33%). Forty adults were also tested for HBsAg, One of which tested positive. This was a recent immigrant from Micronesia. Homeless people in Hawai'i are more likely to have hepatitis B or C because risk factors are common among this population. Additionally a large proportion of Hawai'i's homeless people come from the Pacific Islands, where the prevalence of hepatitis B is one of the highest in the world. In addition there

  18. Hypothetical model for the bending of the Mariana Arc

    NASA Astrophysics Data System (ADS)

    McCabe, Robert; Uyeda, Seiya

    The southern Mariana Arc has a distinct eastward convex shape which is more pronounced than the typical arcuate structure observed above oceanic subduction zones. The Yap Trench is offset hundreds of kilometers westward from the main Izu-Bonin-Mariana trend. Between the southern Mariana Arc and the Yap Trench, the Mariana Arc has an anomalous east-west orientation and is characterized by a markedly lower seismicity than the main Mariana trend. Situated east of the Yap Trench is the ESE trending Caroline Ridge that geochemically resembles the Hawaiian hot spot trend. Paleomagnetic data from Truk and the generally increasing ages to the WNW trend of the Caroline Ridge suggest that the Caroline Ridge is part of the Pacific plate as suggested by Clague and Jarrard (1973). Pacific plate motion for the Caroline Ridge predicts that the ridge has collided with the Yap Trench during the Tertiary. Other evidence for this collision is observed on the island of Yap and by the fact that this portion of the arc has not had volcanic activity during the Neogene period. Paleomagnetic studies show that since the early Oligocene, Guam has rotated greater than 50° clockwise. During this same period, Saipan has rotated only 35° clockwise. These data, the similar bends of the west Mariana Ridge and the Mariana Ridge, and the orientation of fold axes on Guam and Saipan suggest that the clockwise rotation occurred after the initiation of spreading of the Parece Vela Basin and before the opening of the Mariana Trough. This investigation also suggests that the east-west trending portion of the Mariana Trench is a transform boundary which developed in response to the collision.

  19. A Novel NHERF1 Mutation in Human Breast Cancer and Effects on Malignant Progression.

    PubMed

    Yang, Xiaomei; Du, Guifang; Yu, Zhen; Si, Yang; Martin, Tracey A; He, Junqi; Cheng, Shan; Jiang, Wen G

    2017-01-01

    Na + /H + exchanger regulatory factor 1 (NHERF1) has been reported to interact with post-synaptic density protein/Drosophila disc large tumour suppressor/zonula occludens 1 protein (PDZ) binding proteins by its two PDZ domains. These associations have effects on cellular signal transductions. NHERF1 has also been indicated as a cancer-related gene in several solid tumour types. We identified a novel mutation (A190D), of the PDZ2 domain of NHERF1 in breast cancer tissues. NHERF1 A190D mutation abolished NHERF1 modulation of proliferation and migration. In this study, we found that NHERF1 A190D mutation increased nuclear localisation of the protein compared to wild-type NHERF1. It has been reported that YES-associated protein (YAP) interacts with NHERF1. Here we found that NHERF1 A190D mutation increased the binding affinity between NHERF1 and YAP, which inhibited the phosphorylation of YAP. These data suggest that wild-type NHERF1 acts as a tumour suppressor, while NHERF1 A190D mutation abolishes the tumour-suppressive effect in cancer cells, due to A190D mutation-mediated nuclear NHERF1 translocation and induction of YAP phosphorylation. Copyright© 2017 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  20. The Hippo pathway in disease and therapy: cancer and beyond

    PubMed Central

    2014-01-01

    The Hippo tumour suppressor pathway co-ordinates cell proliferation, cell death and cell differentiation to regulate tissue growth control. In mammals, a conserved core Hippo signalling module receives signal inputs on different levels to ensure the proper regulation of YAP/TAZ activities as transcriptional co-activators. While the core module members MST1/2, Salvador, LATS1/2 and MOB1 have been attributed tumour suppressive functions, YAP/TAZ have been mainly described to have oncogenic roles, although some reports provided evidence supporting growth suppressive roles of YAP/TAZ in certain cancer settings. Intriguingly, mammalian Hippo signalling is also implicated in non-cancer diseases and plays a role in tissue regeneration following injury. Cumulatively, these findings indicate that the pharmacological inhibition or activation of the Hippo pathway could be desirable depending on the disease context. In this review, we first summarise the functions of the mammalian Hippo pathway in tumour formation, and then discuss non-cancer diseases involving Hippo signalling core components with a specific focus on our current understanding of the non-cancer roles of MST1/2 and YAP/TAZ. In addition, the pros and cons of possible pharmacological interventions with Hippo signalling will be reviewed, with particular emphasis on anti-cancer drug development and regenerative medicine. PMID:25097725