WorldWideScience

Sample records for act opportunity knocks

  1. EPA and the Federal Technology Transfer Act: Opportunity knocks

    Gatchett, A.M.; Fradkin, L.; Moore, M.; Gorman, T.; Ehrlich, A. [Environmental Protection Agency, Washington, DC (United States)

    1990-12-31

    In 1986, the Federal Technology Transfer Act (FTTA) was established to promote a closer, collaborative relationship between federal government agencies and the private sector. With the increasing need for new cost-effective technologies to prevent and control pollution, both the US Environmental Protection Agency (EPA) and private industry are encouraged to facilitate the transfer of knowledge and technology under this Act. The FTTA removed several of the legal and institutional barriers to cooperative research that existed before the Act`s passage. Through the FTTA, the government strives to promote the movement of its products, processes, skills, and knowledge into the private sector for further development and commercialization by encouraging the exchange of technical personnel and the sharing of facilities and other resources. Collaborative efforts between industry, federal agencies, and academia are made possible through cooperative research and development agreements (CRADAs). Forty-two CRADAs and five licensing agreements have been initiated with EPA under this program. This paper provides an overview of this new and innovative program within the EPA. 1 fig., 2 tabs.

  2. Open the door whenever opportunity knocks.

    Downs, Mallery H; Kaminsky, Alexis; Lewis, Johnnye

    2006-01-01

    The Community Environmental Health Program/Community Outreach and Education Program (CEHP/COEP) New Mexico Center for Environmental Health Sciences has learned that listening and responding to opportunities that arise in local communities can be a more effective means of reaching health care providers, lay health workers, and community members than structured plans of action. While specific opportunities that have occurred in New Mexico may be unique, they are presented here with the hope that they might suggest new strategies to the reader and help to identify parallel opportunities in other communities. The paper is organized around three major opportunities to which CEHP/COEP has responded: (1) the need for more informed health care in communities with unique and complex environmental and occupational exposures due to their proximity to National Laboratories; (2) the need for resources on environmental health within local provider networks and issue-specific groups; and (3) the need for community environmental health projects within the College of Nursing. CEHP/COEP's responses, observations, and lessons learned through these experiences are discussed. In the end, the major lesson is that the ability to respond to opportunities requires flexibility and creativity; by sticking doggedly to plans, valuable-and sometimes more profitable and productive-opportunities may be missed.

  3. Biosimilars lining up to compete with Herceptin--opportunity knocks.

    Nelson, Kevin M; Gallagher, Patrick C

    2014-11-01

    Trastuzumab is a monoclonal antibody developed by Genentech as a treatment for breast cancer and gastric cancer when the cancer cells overexpress HER2, a membrane-bound receptor activated by epidermal growth factor. Now marketed by Roche under the trade name Herceptin, trastuzumab has been readily adopted as treatment for some of the most invasive types of breast cancer. The cost for Herceptin is over $50,000 for a full course of treatment. With the development of regulatory pathways for biosimilar products, and the imminent expiry of patents covering Herceptin, several companies have developed biosimilar trastuzumab products. As biosimilar manufacturers look for opportunities to market biosimilar trastuzumab products, Roche has positioned itself to protect its market by developing additional anti-HER2 products complementary to Herceptin. The advent of competition from biosimilars should bring some opportunity for cost savings for patients, as well as incentive for continued advancement in development of better treatments to fight breast cancer.

  4. Answering the Knock of Opportunity: Addressing the Data Needs for California's English Learners. Policy Brief

    Perez, Maria; Shambaugh, Larisa S.; Parrish, Tom

    2008-01-01

    California currently faces an opportunity to develop an effective data system that can assist in improving the state's future understanding of the educational progress of English learners (ELs). This policy brief outlines the needs for good data on ELs and makes recommendations for creating an effective longitudinal data system for ELs. It…

  5. Current status and future perspectives of PSMA-targeted therapy in Europe: opportunity knocks

    Pfestroff, A.; Luster, M. [University Hospital Marburg, Department of Nuclear Medicine, Marburg (Germany); Jilg, C.A. [University Hospital Freiburg, Department of Urology, Freiburg (Germany); Olbert, P.J. [University Hospital Marburg, Department of Urology, Marburg (Germany); Ohlmann, C.H. [Saarland University Hospital, Department of Urology, Homburg/Saar (Germany); Lassmann, M. [University Hospital Wuerzburg, Department of Nuclear Medicine, Wuerzburg (Germany); Maecke, H.R. [University Hospital Freiburg, Department of Nuclear Medicine and Radiopharmacy, Freiburg (Germany); Ezziddin, S. [Saarland University Hospital, Department of Nuclear Medicine, Homburg/Saar (Germany); Bodei, L. [European Institute of Oncology, Department of Nuclear Medicine, Milan (Italy); Collaboration: on behalf of the Radionuclide Therapy Committee of the European Association of Nuclear Medicine

    2015-12-15

    {sup 177}Lu-based PSMA-targeted therapy appears to be a promising treatment for advanced PCA. However, lessons should be learned from PRRT of neuroendocrine tumours, which was referred to as a ''promising'' tool for 15 years before the advent of evidence-based comparative studies. This experience strongly suggests that the communities involved with PSMA-targeted therapy, namely nuclear medicine, urology, radiochemistry, and medical physics, should capitalize without delay on the great opportunity to conduct well-designed prospective studies. Doing so should advance this modality from the proof-of principle stage to the potential standard-of-Care-stage. From our perspective, crucial components of this process are: - Harmonization of therapy protocols - Implementation of a patient selection algorithm into clinical routine - Standardization of toxicity assessment - Establishment of standardized dosimetry protocols to assess safety and efficacy - Transfer of expertise in PSMA therapy throughout Europe - Regulatory approval of {sup 177}Lu-PSMA-targeted compounds.

  6. When Opportunity Knocks Twice: Dual Living Kidney Donation, Autonomy and the Public Interest.

    Bailey, Phillippa; Huxtable, Richard

    2016-02-01

    Living kidney transplantation offers the best treatment in terms of life-expectancy and quality of life for those with end-stage renal disease. The long-term risks of living donor nephrectomy, although real, are very small, with evidence of good medium-term outcomes. Who should be entitled to donate, and in which circumstances, is nevertheless a live question. We explore the ethical dimensions of a request by an individual to donate both of their kidneys during life: 'dual living kidney donation'. Our ethical analysis is tethered to a hypothetical case study in which a father asks to donate a kidney to each of his twin boys. We explore the autonomy of the protagonists, alongside different dimensions of the public interest, such as the need to protect not only the recipients, but also the donor and even the wider community. Whilst acknowledging objections to 'dual-donation', not least by reference to the harms that the donor might be expected to endure, we suggest there is a prima facie case for permitting this, provided that both donor and recipients are willing and that due attention is paid to such considerations as the autonomy and welfare of all parties, as well as to the wider ramifications of acting on such a request. We argue for broader interpretations of the concepts of autonomy and welfare, recognizing the importance of relationships and the relevance of more than merely physical well-being. Equipped with such a holistic assessment, we suggest there is a prima facie case for allowing 'dual living kidney donation'.

  7. 75 FR 32480 - Funding Opportunity: Affordable Care Act Medicare Beneficiary Outreach and Assistance Program...

    2010-06-08

    ... HUMAN SERVICES Administration on Aging Funding Opportunity: Affordable Care Act Medicare Beneficiary...: Availability of funding opportunity announcement. Funding Opportunity Title/Program Name: Affordable Care Act... Protection and Affordable Care Act of 2010 (Affordable Care Act). Catalog of Federal Domestic......

  8. Codifying the corporate opportunity doctrine: The (UK Companies Act 2006

    John Lowry

    2012-04-01

    Full Text Available Part 10 of the UK Companies Act 2006 codifies the fiduciary and common law duties of directors as a means of addressing the key policy considerations which underpinned the company law reform project launched by the Labour Government in 1998. Focusing on the core fiduciary duty of loyalty and its corporate law manifestation in the form of the ‘corporate opportunity doctrine’, the article critically examines whether the statutory language adequately captures the totality of the duty as developed in the case law. It concludes that the formalistic language of the relevant provisions neither encompasses the breadth of the pre-existing jurisprudence nor addresses the policy objectives of the reform exercise.

  9. Msh2 acts in medium-spiny striatal neurons as an enhancer of CAG instability and mutant huntingtin phenotypes in Huntington's disease knock-in mice.

    Kovalenko, Marina; Dragileva, Ella; St Claire, Jason; Gillis, Tammy; Guide, Jolene R; New, Jaclyn; Dong, Hualing; Kucherlapati, Raju; Kucherlapati, Melanie H; Ehrlich, Michelle E; Lee, Jong-Min; Wheeler, Vanessa C

    2012-01-01

    The CAG trinucleotide repeat mutation in the Huntington's disease gene (HTT) exhibits age-dependent tissue-specific expansion that correlates with disease onset in patients, implicating somatic expansion as a disease modifier and potential therapeutic target. Somatic HTT CAG expansion is critically dependent on proteins in the mismatch repair (MMR) pathway. To gain further insight into mechanisms of somatic expansion and the relationship of somatic expansion to the disease process in selectively vulnerable MSNs we have crossed HTT CAG knock-in mice (HdhQ111) with mice carrying a conditional (floxed) Msh2 allele and D9-Cre transgenic mice, in which Cre recombinase is expressed specifically in MSNs within the striatum. Deletion of Msh2 in MSNs eliminated Msh2 protein in those neurons. We demonstrate that MSN-specific deletion of Msh2 was sufficient to eliminate the vast majority of striatal HTT CAG expansions in HdhQ111 mice. Furthermore, MSN-specific deletion of Msh2 modified two mutant huntingtin phenotypes: the early nuclear localization of diffusely immunostaining mutant huntingtin was slowed; and the later development of intranuclear huntingtin inclusions was dramatically inhibited. Therefore, Msh2 acts within MSNs as a genetic enhancer both of somatic HTT CAG expansions and of HTT CAG-dependent phenotypes in mice. These data suggest that the selective vulnerability of MSNs may be at least in part contributed by the propensity for somatic expansion in these neurons, and imply that intervening in the expansion process is likely to have therapeutic benefit.

  10. Equal Protection of the Law: The Persons with Disabilities (Equal Opportunities Act, 2014, Bahamas

    Bernadette Bain

    2016-10-01

    This analysis of the Persons with Disabilities (Equal Opportunities Act, 2014, examines the nature and scope of equal rights and whether the Act provides adequate enforcement. The aim of the provisions is to restrict discrimination against persons with disabilities by providing opportunities on an equal basis and to require persons having dealings with the disabled to accommodate their needs. It is questionable whether the Act fulfils its purpose and whether penalties for failure to comply with the Act are adequate, as there is a lacuna or gap in the law, which hinders purposeful rights.

  11. Msh2 acts in medium-spiny striatal neurons as an enhancer of CAG instability and mutant huntingtin phenotypes in Huntington's disease knock-in mice.

    Marina Kovalenko

    Full Text Available The CAG trinucleotide repeat mutation in the Huntington's disease gene (HTT exhibits age-dependent tissue-specific expansion that correlates with disease onset in patients, implicating somatic expansion as a disease modifier and potential therapeutic target. Somatic HTT CAG expansion is critically dependent on proteins in the mismatch repair (MMR pathway. To gain further insight into mechanisms of somatic expansion and the relationship of somatic expansion to the disease process in selectively vulnerable MSNs we have crossed HTT CAG knock-in mice (HdhQ111 with mice carrying a conditional (floxed Msh2 allele and D9-Cre transgenic mice, in which Cre recombinase is expressed specifically in MSNs within the striatum. Deletion of Msh2 in MSNs eliminated Msh2 protein in those neurons. We demonstrate that MSN-specific deletion of Msh2 was sufficient to eliminate the vast majority of striatal HTT CAG expansions in HdhQ111 mice. Furthermore, MSN-specific deletion of Msh2 modified two mutant huntingtin phenotypes: the early nuclear localization of diffusely immunostaining mutant huntingtin was slowed; and the later development of intranuclear huntingtin inclusions was dramatically inhibited. Therefore, Msh2 acts within MSNs as a genetic enhancer both of somatic HTT CAG expansions and of HTT CAG-dependent phenotypes in mice. These data suggest that the selective vulnerability of MSNs may be at least in part contributed by the propensity for somatic expansion in these neurons, and imply that intervening in the expansion process is likely to have therapeutic benefit.

  12. 78 FR 5800 - Clean Water Act Class II: Proposed Administrative Settlement, Penalty Assessment and Opportunity...

    2013-01-28

    ... administrative order assessing a civil penalty against any person who has violated applicable emergency planning... AGENCY Clean Water Act Class II: Proposed Administrative Settlement, Penalty Assessment and Opportunity... resolve violations of the Clean Water Act (CWA) and the Emergency Planning and Community Right-to-Know...

  13. 76 FR 41434 - Removal of Certain Requirements Related to the Prescription Drug Marketing Act; Opportunity for...

    2011-07-14

    ... prescription drug marketing and distribution. The primary purpose of the PDMA was to increase safeguards to... the Prescription Drug Marketing Act; Opportunity for Public Comment AGENCY: Food and Drug... remove a section of the Prescription Drug Marketing Act (PDMA) regulations requiring that prior to...

  14. 78 FR 80415 - To Take Certain Actions Under the African Growth and Opportunity Act and for Other Purposes

    2013-12-31

    ... Opportunity Act and for Other Purposes Presidential Documents Federal Register / Vol. 78 , No. 251 / Tuesday... December 23, 2013 To Take Certain Actions Under the African Growth and Opportunity Act and for Other... meeting the requirements described in section 506A(a)(1) of the Trade Act of 1974, as amended (the...

  15. Statistical Engine Knock Control

    Stotsky, Alexander A.

    2008-01-01

    A new statistical concept of the knock control of a spark ignition automotive engine is proposed . The control aim is associated with the statistical hy pothesis test which compares the threshold value to the average value of the max imal amplitud e of the knock sensor signal at a given freq uency...

  16. Education Issues Raised by S.744: The Border Security, Economic Opportunity, and Immigration Modernization Act

    Murphy, Garrett

    2014-01-01

    This brief report summarizes the requirements for undocumented immigrants set forth by the Border Security, Economic Opportunity, and Immigration Modernization Act (S.744). Assuming that S.744 will move forward in Congress, the report also examines issues having to do with certain language, civics and government, and education/training provisions…

  17. Opportunities for social work under the Affordable Care Act: A call for action.

    Lynch, Sean; Greeno, Catherine; Teich, Judith; Delany, Peter

    2016-10-01

    The Affordable Care Act (ACA) has profoundly restructured American health care. Numerous social work authors have commented on the importance of the ACA's reforms to social work practice, education, and research. This article summarizes the literature, adds relevant information, and makes recommendations for future actions. The policy, opinion, and peer-reviewed literatures were systematically reviewed. Sixty-three publications appeared between 2010 and 2015 are included. Five themes emerged, as follows: 1) the crucial provisions of the ACA, 2) the natural affinity of social work and the ACA reforms, 3) curricular adaptations needed to address changing workforce needs, 4) areas for continued social work advocacy, and 5) opportunities for high-impact social work research. This article provides a comprehensive introduction to the ACA, its reforms, and opportunities for social work to assume a high visibility leadership role in implementing the reforms, with particular emphasis on needed curricular changes and opportunities for research.

  18. The Affordable Care Act and the future of clinical medicine: the opportunities and challenges.

    Kocher, Robert; Emanuel, Ezekiel J; DeParle, Nancy-Ann M

    2010-10-19

    The Affordable Care Act is a once-in-a-generation change to the U.S. health system. It guarantees access to health care for all Americans, creates new incentives to change clinical practice to foster better coordination and quality, gives physicians more information to make them better clinicians and patients more information to make them more value-conscious consumers, and changes the payment system to reward value. The Act and the health information technology provisions in the American Recovery and Reinvestment Act remove many barriers to delivering high-quality care, such as unnecessary administrative complexity, inaccessible clinical data, and insufficient access to primary care and allied health providers. We hope that physicians will embrace the opportunities created by the Affordable Care Act that will enable them to provide better care for their patients and lead the U.S. health system in a more positive direction. To fully realize the benefits of the Affordable Care Act for their practices and their patients, physicians will design their offices for seamless care, employing new practice models and using technology to integrate patient information with professional society guidelines to keep patients with chronic conditions healthy and out of the hospital. Under the Affordable Care Act, physicians who effectively collaborate with other providers to improve patient outcomes, the value of medical services, and patient experiences will thrive and be the leaders of the health care system.

  19. When a Leadership Opportunity Knocks, Answer!

    DelGuidice, Margaux

    2011-01-01

    In the fall of 2010 the author received an e-mail informing her that she has been selected as a Gale/Cengage New Leader, which was a true honor. Not only would she be joining four dynamic school librarians from around the country at the School Library Journal Summit on the Future of Reading, she was also being paired with a mentor to navigate her…

  20. The Affordable Care Act: new opportunities for cardiac rehabilitation in the workplace?

    Pinkstaff, Sherry O; Arena, Ross; Myers, Jonathan; Kaminsky, Leonard; Briggs, Paige; Forman, Daniel E; Patel, Mahesh J; Cahalin, Lawrence P

    2014-08-01

    Many people affected by cardiovascular disease (CVD) are working age. Employers bear a large percentage of the costs associated with CVD. Employers pay 80 times more in diagnosis and treatment than in prevention, although there is evidence that 50% to 70% of all diseases are associated with preventable health risks. As a result, the worksite is an appealing location to deliver health care.Cardiac rehabilitation has developed a track record of delivering improved outcomes for patients with CVD. Partnerships between cardiac rehabilitation providers and worksite health programs have the potential to improve referral and participation rates of employees with CVD. The current era of health reform in the United States that has been stimulated by the Affordable Care Act provides an ideal opportunity to reconsider worksite health programs as an essential partner in the health care team.

  1. How the Sarbanes-Oxley Act Has Knocked the “SOX” off the DOJ and SEC and Kept the FCPA on Its Feet

    Laura E. Kress

    2010-04-01

    Full Text Available Congress passed both the Foreign Corrupt Practices Act (“FCPA” or “the Act” and Sarbanes-Oxley Act (“SOX” in reaction to national corruption and bribery scandals.[1]  The reputation and integrity of American companies were under attack as these scandals unraveled and made international news.  Allegations of fraud, bribery and illegal practices plagued corporate America.  Congress needed legislation to address these problems to ensure its own country, as well as the international community, that the legislature would not tolerate corrupt business practices.  The FCPA was enacted to decrease corruption and bribery and to improve the accuracy of accounting and record-keeping of companies, and the SOX was enacted for very similar purposes, yet twenty five years later.  The FCPA requires companies to report their financial information in accordance with its provisions, while the SOX requires the Chief Executive Officers and Chief Financial Officers of public companies to guarantee that their financial reports are accurate.[2]  During the first twenty five years after the FCPA was enacted, the Department of Justice (“DOJ” and Securities and Exchange Commission (“SEC” did not conduct many investigations into companies that had potentially violated the Act’s provisions.  However, in the aftermath of the Enron[3] and WorldCom[4] scandals, which lead to the enactment of the SOX in 2002 and subsequent increased international awareness of the problems of bribery and financial fraud, there has been a significant increase in FCPA enforcement.[5] [1] The FCPA was enacted in 1977 in response to the Watergate scandal, and the SOX was enacted in 2002 in response to the Enron and WorldCom scandals. Lawrence A. Cunningham, Sharing Accounting’s Burden: Business Lawyers in Enron’s Dark Shadows, 57 Bus. Law. 1421, 1427 (2002 (commenting that the Enron scandal that led to the enactment of the SOX is “akin to the straw that broke the

  2. Healthy, Hunger-Free Kids Act of 2010: An Opportunity for School Nurses to Make a Difference

    Prokop, Jessica L.; Galon, Patricia

    2011-01-01

    Implementation of the Healthy Hunger-Free Kids Act of 2010 will provide an opportunity for school nurses to intervene in the serious childhood obesity problem in the United States. Major changes in the management of the National School Lunch Program (NSLP) will likely challenge schools yet may provide the impetus for a collaborative effort by the…

  3. Exclusivity strategies and opportunities in view of the Biologics Price Competition and Innovation Act.

    Gaudry, Kate S

    2011-01-01

    Government-provided exclusivity periods provide pharmaceutical companies with incentives to invest in new drugs. Meanwhile, encouraging competition serves another worthy goal of improving the affordability of medications. Decades ago, the Hatch-Waxman Act set forth provisions attempting to balance these objectives in the context of small-molecule drugs. Recently, the Biologics Price Competition and Innovation Act was enacted to meet similar aims in the context of biologic drugs. This article presents a detailed comparison of these two Acts. While the Acts share many global similarities (e.g., providing exclusivity terms and abbreviated approval processes), many differences are also apparent when analyzing details of the provisions. One area of great departure between the Acts is the requirements of how a generic or follow-on applicant must address patents covering a reference product. After describing these differences, the article presents predictions of how reference product sponsors will adapt their patent-prosecution strategies in view of the new Biologics Act.

  4. 75 FR 70342 - Privacy Act; System of Records: Equal Employment Opportunity Records

    2010-11-17

    ... capability of printing audit trails of access from the computer media, thereby permitting regular and ad hoc monitoring of computer usage. When it is determined that a user no longer needs access, the user account is... Employment Opportunity Records, a user must first be granted access to the Department of State...

  5. 78 FR 49512 - Clean Water Act Class II: Proposed Administrative Settlement, Penalty Assessment and Opportunity...

    2013-08-14

    ... Emergency Planning and Community Right-to-Know Act (EPCRA), and their implementing regulations. The... included operating facilities, corporate offices, warehouses, and other storage locations. On October 2... Commission (SERC) and/or the Local Emergency Planning Committee (LEPC) that these facilities are subject...

  6. Deployment of ACT antimalarials for treatment of malaria: challenges and opportunities

    Leslie Toby

    2008-12-01

    Full Text Available Abstract Following a long period when the effectiveness of existing mono-therapies for antimalarials was steadily declining with no clear alternative, most malaria-endemic countries in Africa and Asia have adopted artemisinin combination therapy (ACT as antimalarial drug policy. Several ACT drugs exist and others are in the pipeline. If properly targeted, they have the potential to reduce mortality from malaria substantially. The major challenge now is to get the drugs to the right people. Current evidence suggests that most of those who need the drugs do not get them. Simultaneously, a high proportion of those who are given antimalarials do not in fact have malaria. Financial and other barriers mean that, in many settings, the majority of those with malaria, particularly the poorest, do not access formal healthcare, so the provision of free antimalarials via this route has only limited impact. The higher cost of ACT creates a market for fake drugs. Addressing these problems is now a priority. This review outlines current evidence, possible solutions and research priorities.

  7. Opportunity Design

    2012-01-01

    or development oriented, the act of ‘recognition’ is still a central part of the definition. Recently the term “Opportunity Design” has been introduced, suggesting that opportunities can be proactively and intentionally designed. However, the relatedness between the opportunity recognition process...... and opportunity design is not clear. Furthermore, there is still a lack of approaches, methods and tools, which can support entrepreneurs in designing the entrepreneurial opportunities. In this paper, we take steps towards defining opportunity design in respect to the opportunity recognition process, and identify...... some of the specific approaches applicable to the design of opportunities. By looking at industrial designers working with entrepreneurial opportunities, it becomes evident that there is a set of approaches, which can turn the opportunity recognition process into an intentional and proactive process....

  8. Evaluation of the DC Opportunity Scholarship Program: An Early Look at Applicants and Participating Schools under the SOAR Act. Year 1 Report, Executive Summary. NCEE 2015-4000

    Feldman, Jill; Lucas-McLean, Juanita; Gutmann, Babette; Dynarski, Mark; Betts, Julian

    2014-01-01

    This report explores implementation of the District of Columbia Opportunity Scholarship Program (OSP) in the first two years after Congress reauthorized it with some changes under the SOAR Act of 2011. Key findings include the following: (1) Just over half of all DC private schools participated in the OSP, with current schools more likely to have…

  9. Evaluation of the DC Opportunity Scholarship Program: An Early Look at Applicants and Participating Schools under the SOAR Act. Year 1 Report. NCEE 2015-4000

    Feldman, Jill; Lucas-McLean, Juanita; Gutmann, Babette; Dynarski, Mark; Betts, Julian

    2014-01-01

    This report explores implementation of the District of Columbia Opportunity Scholarship Program (OSP) in the first two years after Congress reauthorized it with some changes under the SOAR Act of 2011. Key findings include the following: (1) Just over half of all DC private schools participated in the OSP, with current schools more likely to have…

  10. LEARN TO LISTEN Opportunity sometimes knocks very softly

    王会慈

    2009-01-01

    我们在生活中,总会以自己的想当然去想别人.在我们的思想中总会有一些这个或是那个“不合适”。其实,只要我们有坚强的意志,有不屈不挠的精神,内心充满爱,相信自己,我们不会有克服不了的困难.不会有做不到的事情。

  11. Opportunity knocks - the sustainable energy industry and climate change

    Price, B.; Keegan, P. [International Institute for Energy Conservation, Washington, DC (United States)

    1997-12-31

    Climate change mitigation, if intelligently undertaken, can stimulate economic growth. The main tools available for this task are energy efficiency, renewable energy, and clean energy technologies and services, which are collectively known as sustainable energy. To unleash this potential, the US and other governments need the full cooperation of the sustainable energy industry. This industry knows more than most other about turning energy-related pollution prevention into profits. If engaged, they can help: (1) Identify the economic benefits of greenhouse gas mitigation; (2) Identify barriers to the implementation of greenhouse gas mitigation projects; (3) Develop policies and measures to overcome these barriers; and (4) Implement greenhouse gas mitigation projects. 7 refs.

  12. 76 FR 54773 - Notice of Intent To Award Affordable Care Act Funding, Funding Opportunity Announcement CDC-RFA...

    2011-09-02

    ... HUMAN SERVICES Centers for Disease Control and Prevention Notice of Intent To Award Affordable Care Act... Patient Protection Affordable Care Act (PPACA), Section 4002, appropriations. Recipient Reporting... law the Patient Protection and Affordable Care Act (PPACA). PPACA is designed to improve and...

  13. 76 FR 54774 - Notice of Intent To Award Affordable Care Act Funding, Funding Opportunity Announcement CDC-RFA...

    2011-09-02

    ... HUMAN SERVICES Centers for Disease Control and Prevention Notice of Intent To Award Affordable Care Act... reviewed application with Patient Protection Affordable Care Act (PPACA), Section 4002, appropriations... President signed into law the Patient Protection and Affordable Care Act (PPACA). PPACA is designed...

  14. 76 FR 54772 - Notice of Intent To Award Affordable Care Act Funding, Funding Opportunity Announcement CDC-RFA...

    2011-09-02

    ... HUMAN SERVICES Centers for Disease Control and Prevention Notice of Intent To Award Affordable Care Act... Affordable Care Act (PPACA), Section 4002, appropriations. Recipient Reporting Requirements Under PPACA... Affordable Care Act (Pub. L. 111-148). DATES: The effective date for this action is September 2, 2011...

  15. Opportunities in the American Recovery and Reinvestment Act for Supports and Services for Youth Transitioning from Foster Care

    Flynn-Khan, Margaret; Langford, Barbara Hanson

    2009-01-01

    To address the economic crisis facing the country, the President signed the American Recovery and Reinvestment Act (ARRA) into law on February 17, 2009. This sweeping legislation provides $789 billion to jumpstart the economy and boost employment. This act includes $463 billion in new spending and $326 billion in tax relief directed at those…

  16. 75 FR 81077 - To Take Certain Actions Under the African Growth and Opportunity Act, and for Other Purposes

    2010-12-27

    ... Democratic Republic of Congo (DRC) as an eligible sub-Saharan African country pursuant to section 104 of the... the authority provided to the President under section 506A(a)(1) of the 1974 Act to designate the DRC... October 31, 2003, the USTR designated the DRC as a beneficiary sub-Saharan African country (68 FR...

  17. Opportunities in the Affordable Care Act to Advance Long-Term Services and Supports: The Role of Rehabilitation Counseling

    Caldwell, Joe; Alston, Reginald J.

    2012-01-01

    The Affordable Care Act includes many new provisions for long-term services and supports (LTSS). Among these are several new options, improvements, and incentives within Medicaid to balance service systems and expand access to home and community-based services. This article discusses some of the major provisions, implementations, and implications…

  18. Genetic Contributors to Intergenerational CAG Repeat Instability in Huntington’s Disease Knock-In Mice

    Neto, João Luís; Lee, Jong-Min; Afridi, Ali; Gillis, Tammy; Guide, Jolene R.; Dempsey, Stephani; Lager, Brenda; Alonso, Isabel; Wheeler, Vanessa C.; Pinto, Ricardo Mouro

    2017-01-01

    Huntington’s disease (HD) is a neurodegenerative disorder caused by the expansion of a CAG trinucleotide repeat in exon 1 of the HTT gene. Longer repeat sizes are associated with increased disease penetrance and earlier ages of onset. Intergenerationally unstable transmissions are common in HD families, partly underlying the genetic anticipation seen in this disorder. HD CAG knock-in mouse models also exhibit a propensity for intergenerational repeat size changes. In this work, we examine intergenerational instability of the CAG repeat in over 20,000 transmissions in the largest HD knock-in mouse model breeding datasets reported to date. We confirmed previous observations that parental sex drives the relative ratio of expansions and contractions. The large datasets further allowed us to distinguish effects of paternal CAG repeat length on the magnitude and frequency of expansions and contractions, as well as the identification of large repeat size jumps in the knock-in models. Distinct degrees of intergenerational instability were observed between knock-in mice of six background strains, indicating the occurrence of trans-acting genetic modifiers. We also found that lines harboring a neomycin resistance cassette upstream of Htt showed reduced expansion frequency, indicative of a contributing role for sequences in cis, with the expanded repeat as modifiers of intergenerational instability. These results provide a basis for further understanding of the mechanisms underlying intergenerational repeat instability. PMID:27913616

  19. Opportunities for Energy Development in Water Conduits: A Report Prepared in Response to Section 7 of the Hydropower Regulatory Efficiency Act of 2013

    Sale, Michael J. [BCS, Incorporated, Laurel, MD (United States); Bishop, Norman A. [Knight Piesold, Chicago, IL (United States); Reiser, Sonya L. [Knight Piesold, Chicago, IL (United States); Johnson, Kurt [Telluride Energy LLC, Grand Junction, CO (United States); Bailey, Andrea C. [BCS, Incorporated, Laurel, MD (United States); Frank, Anthony [BCS, Incorporated, Laurel, MD (United States); Smith, Brennan T. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Environmental Sciences Division

    2014-09-01

    In Section 7 of the Hydropower Regulatory Efficiency Act (HREA) of 2013 (P.L. 113-23), Congress directed the U.S. Department of Energy (DOE) to prepare an analysis of conduit hydropower opportunities available in the United States and to present case studies that describe the potential energy generation from these types of hydropower projects. Those analyses have been included in a new DOE report to Congress, and this ORNL/TM provides additional technical details supporting that report. Conduit hydropower offers important new ways to enhance renewable energy portfolios in the United States, as well as to increase the energy efficiency of water delivery systems. Conduit hydropower projects are constructed on existing water-conveyance structures, such as irrigation canals or pressurized pipelines that deliver water to municipalities, industry, or agricultural water users. Although water conveyance infrastructures are usually designed for non-power purposes, new renewable energy can often be harvested from them without affecting their original purpose and without the need to construct new dams or diversions. Conduit hydropower differs from more conventional hydropower development in that it is generally not located on natural rivers or waterways and therefore does not involve the types of environmental impacts that are associated with hydropower. The addition of hydropower to existing water conduits can provide valuable new revenue sources from clean, renewable energy. The new energy can be used within the existing water distribution systems to offset other energy demands, or it can be sold into regional transmission systems.

  20. Challenges and opportunities in building a sustainable rural primary care workforce in alignment with the Affordable Care Act: the WWAMI program as a case study.

    Allen, Suzanne M; Ballweg, Ruth A; Cosgrove, Ellen M; Engle, Kellie A; Robinson, Lawrence R; Rosenblatt, Roger A; Skillman, Susan M; Wenrich, Marjorie D

    2013-12-01

    The authors examine the potential impact of the Patient Protection and Affordable Care Act (ACA) on a large medical education program in the Northwest United States that builds the primary care workforce for its largely rural region. The 42-year-old Washington, Wyoming, Alaska, Montana, and Idaho (WWAMI) program, hosted by the University of Washington School of Medicine, is one of the nation's most successful models for rural health training. The program has expanded training and retention of primary care health professionals for the region through medical school education, graduate medical education, a physician assistant training program, and support for practicing health professionals.The ACA and resulting accountable care organizations (ACOs) present potential challenges for rural settings and health training programs like WWAMI that focus on building the health workforce for rural and underserved populations. As more Americans acquire health coverage, more health professionals will be needed, especially in primary care. Rural locations may face increased competition for these professionals. Medical schools are expanding their positions to meet the need, but limits on graduate medical education expansion may result in a bottleneck, with insufficient residency positions for graduating students. The development of ACOs may further challenge building a rural workforce by limiting training opportunities for health professionals because of competing demands and concerns about cost, efficiency, and safety associated with training. Medical education programs like WWAMI will need to increase efforts to train primary care physicians and increase their advocacy for student programs and additional graduate medical education for rural constituents.

  1. Personal Responsibility and Work Opportunity Reconciliation Act of 1996 (PRWORA); interpretation of "federal public benefit"--HHS. Notice with comment period.

    1998-08-01

    This notice with comment period interprets the term "Federal public benefit" as used in Title IV of the Personal Responsibility and Work Opportunity Reconciliation Act of 1996 (PRWORA), Pub. L. 104-193, and identifies the HHS programs that provide such benefits under this interpretation. According to section 401 if PRWORA, aliens who are not "qualified aliens" are not eligible for any "Federal public benefit," unless the "Federal public benefit" falls within a specified exception. A "Federal public benefit" includes "any grant, contract, loan, professional license, or commercial license" provided to an individual, and also "any retirement, welfare, health, disability, public or assisted housing, postsecondary education, food assistance, unemployment benefit, or any other similar benefit for which payments or assistance are provided to an individual, household, or family eligibility unit." Under section 432, providers of a non-exempt "Federal public benefit" must verify that a person applying for the benefit is a qualified alien and is eligible to receive the benefit. The HHS programs that provide "Federal public benefits" and are not otherwise excluded from the definition by the exceptions provided in section 401(b) are: Adoption Assistance Administration on Developmental Disabilities (ADD)-State Developmental Disabilities Councils (direct services only) ADD-Special Projects (direct services only) ADD-University Affiliated Programs (clinical disability assessment services only) Adult Programs/Payments to Territories Agency for Health Care Policy and Research Dissertation Grants Child Care and Development Fund Clinical Training Grant for Faculty Development in Alcohol & Drug Abuse Foster Care Health Profession Education and Training Assistance Independent Living Program Job Opportunities for Low Income Individuals (JOLI) Low Income Home Energy Assistance Program (LIHEAP) Medicare Medicaid (except assistance for an emergency medical condition) Mental Health Clinical

  2. Characteristics of Knock in Hydrogen-Oxygen-Argon SI Engine

    Killingsworth, N; Rapp, V; Flowers, D; Aceves, S; Chen, J; Dibble, R

    2010-02-23

    A promising approach for improving the efficiency of internal combustion engines is to employ a working fluid with a high specific heat ratio such as the noble gas argon. Moreover, all harmful emissions are eliminated when the intake charge is composed of oxygen, nonreactive argon, and hydrogen fuel. Previous research demonstrated indicated thermal efficiencies greater than 45% at 5.5 compression ratio in engines operating with hydrogen, oxygen, and argon. However, knock limits spark advance and increasing the efficiency further. Conditions under which knock occurs in such engines differs from typical gasoline fueled engines. In-cylinder temperatures using hydrogen-oxygen-argon are higher due to the high specific heat ratio and pressures are lower because of the low compression ratio. Better understanding of knock under these conditions can lead to operating strategies that inhibit knock and allow operation closer to the knock limit. In this work we compare knock with a hydrogen, oxygen, and argon mixture to that of air-gasoline mixtures in a variable compression ratio cooperative fuels research (CFR) engine. The focus is on stability of knocking phenomena, as well as, amplitude and frequency of the resulting pressure waves.

  3. The Expression of TALEN before Fertilization Provides a Rapid Knock-Out Phenotype in Xenopus laevis Founder Embryos.

    Kei Miyamoto

    Full Text Available Recent advances in genome editing using programmable nucleases have revolutionized gene targeting in various organisms. Successful gene knock-out has been shown in Xenopus, a widely used model organism, although a system enabling less mosaic knock-out in founder embryos (F0 needs to be explored in order to judge phenotypes in the F0 generation. Here, we injected modified highly active transcription activator-like effector nuclease (TALEN mRNA to oocytes at the germinal vesicle (GV stage, followed by in vitro maturation and intracytoplasmic sperm injection, to achieve a full knock-out in F0 embryos. Unlike conventional injection methods to fertilized embryos, the injection of TALEN mRNA into GV oocytes allows expression of nucleases before fertilization, enabling them to work from an earlier stage. Using this procedure, most of developed embryos showed full knock-out phenotypes of the pigmentation gene tyrosinase and/or embryonic lethal gene pax6 in the founder generation. In addition, our method permitted a large 1 kb deletion. Thus, we describe nearly complete gene knock-out phenotypes in Xenopus laevis F0 embryos. The presented method will help to accelerate the production of knock-out frogs since we can bypass an extra generation of about 1 year in Xenopus laevis. Meantime, our method provides a unique opportunity to rapidly test the developmental effects of disrupting those genes that do not permit growth to an adult able to reproduce. In addition, the protocol shown here is considerably less invasive than the previously used host transfer since our protocol does not require surgery. The experimental scheme presented is potentially applicable to other organisms such as mammals and fish to resolve common issues of mosaicism in founders.

  4. The Expression of TALEN before Fertilization Provides a Rapid Knock-Out Phenotype in Xenopus laevis Founder Embryos.

    Miyamoto, Kei; Suzuki, Ken-Ichi T; Suzuki, Miyuki; Sakane, Yuto; Sakuma, Tetsushi; Herberg, Sarah; Simeone, Angela; Simpson, David; Jullien, Jerome; Yamamoto, Takashi; Gurdon, J B

    2015-01-01

    Recent advances in genome editing using programmable nucleases have revolutionized gene targeting in various organisms. Successful gene knock-out has been shown in Xenopus, a widely used model organism, although a system enabling less mosaic knock-out in founder embryos (F0) needs to be explored in order to judge phenotypes in the F0 generation. Here, we injected modified highly active transcription activator-like effector nuclease (TALEN) mRNA to oocytes at the germinal vesicle (GV) stage, followed by in vitro maturation and intracytoplasmic sperm injection, to achieve a full knock-out in F0 embryos. Unlike conventional injection methods to fertilized embryos, the injection of TALEN mRNA into GV oocytes allows expression of nucleases before fertilization, enabling them to work from an earlier stage. Using this procedure, most of developed embryos showed full knock-out phenotypes of the pigmentation gene tyrosinase and/or embryonic lethal gene pax6 in the founder generation. In addition, our method permitted a large 1 kb deletion. Thus, we describe nearly complete gene knock-out phenotypes in Xenopus laevis F0 embryos. The presented method will help to accelerate the production of knock-out frogs since we can bypass an extra generation of about 1 year in Xenopus laevis. Meantime, our method provides a unique opportunity to rapidly test the developmental effects of disrupting those genes that do not permit growth to an adult able to reproduce. In addition, the protocol shown here is considerably less invasive than the previously used host transfer since our protocol does not require surgery. The experimental scheme presented is potentially applicable to other organisms such as mammals and fish to resolve common issues of mosaicism in founders.

  5. Theoretical Analysis of Noise of Piston Knocking Cylinder Wall in Automotive Engines

    2005-01-01

    Based on the loading conditions of engine, applying difference method to solve the hydrodynamic lubrication equation of piston skirt movement, the force acting on piston skirt and the moment on wrist pin were obtained. A computer program for simulating the piston second order motion was conducted to calculate the lateral motion of the upper part and the bottom part of piston skirts of the engine of automotive model CA1091. From the simulated result, the maximal impacting phase and the maximal impacting region of the piston were obtained. The result can be used for designing engine, diagnosing the noise of piston knocking cylinder wall and explaining many practical fault phenomena in theory.

  6. Knock characteristics of dual-fuel combustion in diesel engines using natural gas as primary fuel

    O M I Nwafor

    2002-06-01

    This paper investigates the combustion knock characteristics of diesel engines running on natural gas using pilot injection as means of initiating combustion. The diesel engines knock under normal operating conditions but the knock referred to in this paper is an objectionable one. In the dual-fuel combustion process we have the ignition stage followed by the combustion stage. There are three types of knock: diesel knock, spark knock and knock due to secondary ignition delay of the primary fuel (erratic knock). Several factors have been noted to feature in defining knock characteristics of dual-fuel engines that include ignition delay, pilot quantity, engine load and speed, turbulence and gas flow rate.

  7. Knock Prediction Using a Simple Model for Ignition Delay

    Kalghatgi, Gautam

    2016-04-05

    An earlier paper has shown the ability to predict the phasing of knock onset in a gasoline PFI engine using a simple ignition delay equation for an appropriate surrogate fuel made up of toluene and PRF (TPRF). The applicability of this approach is confirmed in this paper in a different engine using five different fuels of differing RON, sensitivity, and composition - including ethanol blends. An Arrhenius type equation with a pressure correction for ignition delay can be found from interpolation of previously published data for any gasoline if its RON and sensitivity are known. Then, if the pressure and temperature in the unburned gas can be estimated or measured, the Livengood-Wu integral can be estimated as a function of crank angle to predict the occurrence of knock. Experiments in a single cylinder DISI engine over a wide operating range confirm that this simple approach can predict knock very accurately. The data presented should enable engineers to study knock or other auto-ignition phenomena e.g. in premixed compression ignition (PCI) engines without explicit chemical kinetic calculations. © Copyright 2016 SAE International.

  8. A Scholar Who Knocks at the Door to Friendship

    2004-01-01

    <正>Senegalese scholar Adama Gaye came from far away Africa to visit China in March when there was still a chill in the early spring air. He is not an ordinary scholar, but an African friend who has come to knock at the door to friendship.The government of Senegal established diplomatic relations

  9. The Computational Complexity of the Parallel Knock-Out Problem

    Broersma, H.J.; Johnson, M.; Paulusma, D.; Stewart, I.A.; Correa, J.R.; Hevia, A.; Kiwi, M.

    2006-01-01

    We consider computational complexity questions related to parallel knock-out schemes for graphs. In such schemes, in each round, each remaining vertex of a given graph eliminates exactly one of its neighbours. We show that the problem of whether, for a given graph, such a scheme can be found that el

  10. Opportunities for computer abuse

    Willison, Robert Andrew; Backhouse, James

    2005-01-01

    Systems risk refers to the likelihood that an IS is inadequately guarded against certain types of damage or loss. While risks are posed by acts of God, hackers and viruses, consideration should also be given to the `insider' threat of dishonest employees, intent on undertaking some form of computer...... for the offender. To achieve this goal a model known as the `Crime Specific Opportunity Structure' is advanced. Focussing on the opportunities for computer abuse, the model addresses the nature of such opportunities with regards to the organisational context and the threats posed by rogue employees. Drawing...

  11. Transgenic gene knock-outs: functional genomics and therapeutic target selection.

    Harris, S; Foord, S M

    2000-11-01

    The completion of the first draft of the human genome presents both a tremendous opportunity and enormous challenge to the pharmaceutical industry since the whole community, with few exceptions, will soon have access to the same pool of candidate gene sequences from which to select future therapeutic targets. The commercial imperative to select and pursue therapeutically relevant genes from within the overall content of the genome will be particularly intense for those gene families that currently represent the chemically tractable or 'drugable' gene targets. As a consequence the emphasis within exploratory research has shifted towards the evaluation and adoption of technology platforms that can add additional value to the gene selection process, either through functional studies or direct/indirect measures of disease alignment e.g., genetics, differential gene expression, proteomics, tissue distribution, comparative species data etc. The selection of biological targets for the development of potential new medicines relies, in part, on the quality of the in vivo biological data that correlates a particular molecular target with the underlying pathophysiology of a disease. Within the pharmaceutical industry, studies employing transgenic animals and, in particular, animals with specific gene deletions are playing an increasingly important role in the therapeutic target gene selection, drug candidate selection and product development phases of the overall drug discovery process. The potential of phenotypic information from gene knock-outs to contribute to a high-throughput target selection/validation strategy has hitherto been limited by the resources required to rapidly generate and characterise a large number of knock-out transgenics in a timely fashion. The offerings of several companies that provide an opportunity to overcome these hurdles, albeit at a cost, are assessed with respect to the strategic business needs of the pharmaceutical industry.

  12. American Recovery and Reinvestment Act (ARRA) Federal Energy Management Program Technical Assistance Project 282 Renewable Energy Opportunities at Fort Gordon, Georgia

    Boyd, Brian K.; Gorrissen, Willy J.; Hand, James R.; Horner, Jacob A.; Orrell, Alice C.; Russo, Bryan J.; Weimar, Mark R.; Williamson, Jennifer L.; Nesse, Ronald J.

    2010-09-30

    This document provides an overview of renewable resource potential at Fort Gordon, based primarily upon analysis of secondary data sources supplemented with limited on-site evaluations. This effort focuses on grid-connected generation of electricity from renewable energy sources and also on ground source heat pumps for heating and cooling buildings. The effort was funded by the American Recovery and Reinvestment Act (ARRA) as follow-on to the 2005 Department of Defense (DoD) Renewables Assessment. The site visit to Fort Gordon took place on March 9, 2010.

  13. Opportunity Knocks: Pipeline Programs Offer Minority Students a Path to Dentistry

    Fauteux, Nicole

    2012-01-01

    Minority students have traditionally been underrepresented in dental schools, which is why enrichment and pipeline programs aimed at helping minority students are necessary. That reality is reflected in their woeful underrepresentation among practicing dentists. Hispanics made up only 5.8 percent of practicing dentists in 2011, according to the…

  14. Is Opportunity Knocking or Slipping Away? Racial Diversity and Segregation in Pennsylvania

    Kotok, Stephen; Reed, Katherine

    2015-01-01

    Historically, Pennsylvania has struggled to integrate its public schools, especially with much of the racial diversity concentrated in urban regions. Starting in the 1960s, the Pennsylvania Human Relations Commission (PHRC) was the state's enforcing body to combat school desegregation, but since the early 1980s, when it comes to education, the…

  15. Knock Detection in a Two-Stroke Engine to be Used in the Engine Management System

    Höglund, Filip

    2014-01-01

    Engine knock has long been a well recognized phenomenon in the automotive industry. Detecting engine knock opens up the possibility for an indirect feedback of the engine's internal combustion without installing a pressure transducer inside the cylinder. Knock detection has mainly been used for spark advance control, making it possible to control the engine close to its knock limit in search for the optimal ignition timing. This application has to a lesser extent been applied to lightweight t...

  16. Super-knock Suppression Using Split Injection in a Turbo-Charged GDI Engine

    Lv Meng

    2016-01-01

    Full Text Available Super-knock, which occurs under low-speed and big load operate condition in turbo-charged gasoline direct injection (TGDI engine, is an abnormal combustion phenomenon. Due to its potential to cause degradation of the engine, super knock has become the main obstacle for increasing specific power and lowing fuel consumption of engine. In order to investigate suppress strategies of super-knock, split injection is applied on a high boosted GDI engine. The results shows that: super knock correlates to some extent with split injection; further study shows that appropriate split injection duty ratio and the end of second injection time could reduce super knock effectively.

  17. Knock Detection in Spark Ignition Engines Base on Complementary Ensemble Empirical Mode Decomposition-Hilbert Transform

    Fengrong Bi

    2016-01-01

    Full Text Available In spark ignition engines, knock onset limits the maximum spark advance. An inaccurate identification of this limit penalises the fuel conversion efficiency. Thus knock feature extraction is the key of closed-loop control of ignition in spark ignition engine. This paper reports an investigation of knock detection in spark ignition (SI engines using CEEMD-Hilbert transform based on the engine cylinder pressure signals and engine cylinder block vibration signals. Complementary Ensemble Empirical Mode Decomposition (CEEMD was used to decompose the signal and detect knock characteristic. Hilbert transform was used to analyze the frequency information of knock characteristic. The result shows that, for both of cylinder pressure signals and vibration signals, the CEEMD algorithm could extract the knock characteristic, and the Hilbert transform result shows that the energy of knock impact areas has the phenomenon of frequency concentration in both cylinder pressure signal and cylinder block vibration signal. At last, the knock window is then determined, based on which a new knock intensity evaluation factor K is propose, and it can accurately distinguish between heavy knock, light knock, and normal combustion three states.

  18. Method and device for determining the knock rating of motor fuels

    Kjuregyan, S.K.; Kazarian, S.A.; Dovlatov, I.A.

    1996-03-14

    The invention relates to the oil refining and petrochemical industry and concerns in particular techniques for determining the knock rating of motor fuels. The proposed method of determining the knock rating of motor fuels involves the thermostatic control of a reaction vessel of constant volume, feeding the fuel-air mixture into the vessel, atomization of the mixture under excess pressure, and ignition of the mixture. The knock rating is indicated by the intensity of the knocking which in turn is determined from the magnitude of the signal from a knocking sensor in the reaction vessel. The proposed device for determining the knock rating of motor fuels comprises a reaction vessel whith inlet and outlet valves and provided with means of thermostatic control. A spark plug is provided in the reaction vessel and a knock sensor is arranged opposite the spark plug. (author)

  19. Opportunity Design

    Løwe Nielsen, Suna; Lassen, Astrid Heidemann; Nielsen, Louise Møller

    2013-01-01

    design”. The framework explains how opportunities intentionally and pro-actively can be designed from methods and processes of moving-in and moving-out. An illustrative case of opportunity design within the area of sustainable energy and electric cars is presented to link the theoretical discussion...

  20. Cylinder pressure based knock control for analysis of knock control applications and automatic ignition angle applications; Zylinderdruckbasierte Klopfregelung zur Bewertung von Klopfregelungsapplikationen und automatisierten Zuendwinkelapplikationen

    Kempf, S.; Goebels, J.; Sloboda, R. [Robert Bosch GmbH, Schwieberdingen (Germany)

    2006-07-01

    Today, knock control is part of the modern standard engine management system. The trend towards higher performance, lower fuel consumption and legal limitation of emissions makes it necessary to reliably detect knocking combustions at all operating conditions during the entire service life of the vehicle. Ranges in which the knock control needs to be limited or even deactivated due to detection problems can no longer be accepted. In order to ensure this detection quality, it must be made possible to be able to evaluate independently and comprehensibly the quality of the knock control calibration. The development started out from an analog evaluation strategy for the assessment of knock sensor signals and has now reached the digital signal analysis with freely programmable digital filters and a parallel evaluation of up to three frequency ranges in the BOSCH engine management system. The use of the BOSCH Knock-Intensity-Detector 2 (KID2) and the KC-tool chain offers an efficient and productive calibration. In order to be able to perform a quality assessment that is independent of the KC-tool chain, a Matlab based tool was developed. On the one hand, this tool allows a knock-controlled engine operation based on cylinder-pressure while the knock control based on structure-borne signal is disabled and on the other hand it is capable of assessing the current knock control with an additionally enabled and calibrated knock control which is based on structure-borne signal. This assessment can be used to verify a current calibration or e. g. to assess the influence by component variations on the structure borne signal based knock detection. Furthermore, a base was thus provided to perform an automated ignition angle calibration. For this, the cylinder-pressure curve is sampled and by determining the 50% mass fraction burned or the knock limit, the optimum ignition timing will be determined. The approach to this optimum ignition timing is not done manually but automated

  1. Sympathetic hyperinnervation of the uterus in the estrogen receptor alpha knock-out mouse.

    Zoubina, E V; Smith, P G

    2001-01-01

    Uterine innervation undergoes cyclical remodeling in the adult virgin rat. Previous studies showed that ovariectomy leads to increased uterine sympathetic nerve density, and this can be reduced by estrogen administration. However, the receptor mechanism by which estrogen modulates sympathetic innervation is unknown. The present study assessed the role of the estrogen receptor alpha in establishing levels of uterine innervation by comparing the nerve abundance in mice with a null mutation of the estrogen receptor alpha with those of the wild-type cycling mouse. Immunostaining for total uterine innervation using antibodies against the pan-neuronal marker protein gene product 9.5 showed that nerve numbers in normally cycling wild-type mice were high in diestrus when circulating estrogen is at its nadir, and low at estrus, coincident with high plasma estrogen. Uteri of the estrogen receptor alpha knock-out mice were smaller than those of wild-type mice, but even when corrected for differences in size, total innervation was 188% and 355% greater than that of wild-type mice at diestrus and estrus, respectively. This hyperinnervation is associated with increased numbers of nerves immunoreactive for the noradrenergic enzyme dopamine beta-hydroxylase, without obvious differences in those containing calcitonin gene-related peptide or the vesicular acetylcholine transporter. While estrogen supplementation of the ovariectomized wild-type mice significantly reduced total uterine innervation, neither ovariectomy nor estrogen supplementation affected uterine nerve density in estrogen receptor alpha knock-out mice.We conclude that estrogen acting through the estrogen receptor alpha determines the number of sympathetic nerve terminal branches within uterine smooth muscle target. In mice with low circulating estrogen, or high estrogen but lacking the functional estrogen receptor alpha, the uterus contains abundant sympathetic nerves, whereas estrogen acts via the estrogen receptor

  2. System and method for controlling engine knock using electro-hydraulic valve actuation

    Brennan, Daniel G

    2013-12-10

    A control system for an engine includes a knock control module and a valve control module. The knock control module adjusts a period that one or more of an intake valve and an exhaust valve of a cylinder are open based on engine knock corresponding to the cylinder. The valve control module, based on the adjusted period, controls the one or more of the intake valve and the exhaust valve using one or more hydraulic actuators.

  3. HOLA: Hunt for Opportunities-Learn-Act

    Gutiérrez, Rochelle

    2015-01-01

    Most mathematics teachers know that students can be a great source for understanding what they need as thinkers, group members, mathematics learners, and future citizens. Thus, listening to students is an important teacher practice. But listening takes time, something that not all teachers feel that they have. And many attempts to listen to…

  4. Source characteristics of the underwater knocking displays of a male Pacific walrus (Odobenus rosmarus divergens)

    Hughes, William R.; Reichmuth, Colleen; Mulsow, Jason L.;

    2011-01-01

    difficulty inhibiting sound production and would often continue to emit knocks in air during haul-out and even while eating, suggesting an endogenous component to this behavior. A strong correlation between his seasonal testosterone levels and the persistence of knocking displays was confirmed. Captive...

  5. Seizing Opportunity

    2006-01-01

    After the remarkable progress of the past five years, China has entered its new five-year plan period, starting from 2006, aiming to further its economic and social development. Though some are still talking about "China threat," many others consider the country's growth a huge opportunity. In an interview with People's Daily, Bill Fischer, former President of the Sino-European International Business School in Shanghai, comments on China's current development and also talks about problems the country fac...

  6. A knock-in mouse model of congenital erythropoietic porphyria.

    Ged, C; Mendez, M; Robert, E; Lalanne, M; Lamrissi-Garcia, I; Costet, P; Daniel, J Y; Dubus, P; Mazurier, F; Moreau-Gaudry, F; de Verneuil, H

    2006-01-01

    Congenital erythropoietic porphyria (CEP) is a recessive autosomal disorder characterized by a deficiency in uroporphyrinogen III synthase (UROS), the fourth enzyme of the heme biosynthetic pathway. The severity of the disease, the lack of specific treatment except for allogeneic bone marrow transplantation, and the knowledge of the molecular lesions are strong arguments for gene therapy. An animal model of CEP has been designed to evaluate the feasibility of retroviral gene transfer in hematopoietic stem cells. We have previously demonstrated that the knockout of the Uros gene is lethal in mice (Uros(del) model). This work describes the achievement of a knock-in model, which reproduces a mutation of the UROS gene responsible for a severe UROS deficiency in humans (P248Q missense mutant). Homozygous mice display erythrodontia, moderate photosensitivity, hepatosplenomegaly, and hemolytic anemia. Uroporphyrin (99% type I isomer) accumulates in urine. Total porphyrins are increased in erythrocytes and feces, while Uros enzymatic activity is below 1% of the normal level in the different tissues analyzed. These pathological findings closely mimic the CEP disease in humans and demonstrate that the Uros(mut248) mouse represents a suitable model of the human disease for pathophysiological, pharmaceutical, and therapeutic purposes.

  7. GENE KICKED MOUSE: KNOCK OUT MOUSE AND ITS APPLICATION

    Rajashekar B

    2013-07-01

    Full Text Available A knockout mouse is a laboratory mouse in which genes are inactivated, or "knocked out," an existing gene by replacing it or disrupting it with an artificial piece of DNA. The 2007 Nobel Prize in physiology or medicine is awarded to Drs Mario R. Capecchi, Martin J. Evans and Oliver Smithies for their discoveries of principles for introducing specific gene modifications in mice by using embryonic stem cells. Progress to gene targeting using embryonic cell was developed by Evans and his co-workers. Ingenious development of gene targeting has been made by introducing recognition sites for the enzyme Cre recombinase, called loxP sites, into existing genes. When mice carrying such "floxed" genes are mated with transgenic mice expressing Cre recombinase, the target gene of the offspring is modified through Cre action. Gene targeting has transformed scientific medicine by permitting experimental testing of hypotheses regarding the function of specific genes. The first area to which experimental geneticists turned their attention after the birth of gene targeting in mammals was monogenic diseases. Gene targeting has been exceptionally useful in cancer research. A large number of protooncogenes, tumor suppressor genes, angiogenetic factors etc have been targeted in different tissues in mice to shed light on the induction and spreading of tumours. Gene-targeted mouse models have also become increasingly important in studies of host defense against pathogens. Gene targeted mice have become indispensable in virtually all aspects of medical research.

  8. Study of Knocking Effect in Compression Ignition Engine with Hydrogen as a Secondary Fuel

    R. Sivabalakrishnan

    2014-01-01

    Full Text Available The aim of this project is detecting knock during combustion of biodiesel-hydrogen fuel and also the knock is suppressed by timed injection of diethyl ether (DEE with biodiesel-hydrogen fuel for different loads. Hydrogen fuel is an effective alternate fuel in making a pollution-free environment with higher efficiency. The usage of hydrogen in compression ignition engine leads to production of knocking or detonation because of its lower ignition energy, wider flammability range, and shorter quenching distance. Knocking combustion causes major engine damage, and also reduces the efficiency. The method uses the measurement and analysis of cylinder pressure signal for various loads. The pressure signal is to be converted into frequency domain that shows the accurate knocking combustion of fuel mixtures. The variation of pressure signal is gradually increased and smoothly reduced to minimum during normal combustion. The rapid rise of pressure signal has occurred during knocking combustion. The experimental setup was mainly available for evaluating the feasibility of normal combustion by comparing with the signals from both fuel mixtures in compression ignition engine. This method provides better results in predicting the knocking feature of biodiesel-hydrogen fuel and the usage of DEE provides complete combustion of fuels with higher performance, and lower emission.

  9. Chinese M&A,Opportunities & Risks

    Tang Jintao

    2009-01-01

    @@ Recently, the cases of Chinese enterprises' merger and acquisition are emerging in multitude. It is believed that M&A will provide opportunities for China enterprises to go global and act in the global economic environment.

  10. Determination of knock characteristics in spark ignition engines: an approach based on ensemble empirical mode decomposition

    Li, Ning; Yang, Jianguo; Zhou, Rui; Liang, Caiping

    2016-04-01

    Knock is one of the major constraints to improve the performance and thermal efficiency of spark ignition (SI) engines. It can also result in severe permanent engine damage under certain operating conditions. Based on the ensemble empirical mode decomposition (EEMD), this paper proposes a new approach to determine the knock characteristics in SI engines. By adding a uniformly distributed and finite white Gaussian noise, the EEMD can preserve signal continuity in different scales and therefore alleviates the mode-mixing problem occurring in the classic empirical mode decomposition (EMD). The feasibilities of applying the EEMD to detect the knock signatures of a test SI engine via the pressure signal measured from combustion chamber and the vibration signal measured from cylinder head are investigated. Experimental results show that the EEMD-based method is able to detect the knock signatures from both the pressure signal and vibration signal, even in initial stage of knock. Finally, by comparing the application results with those obtained by short-time Fourier transform (STFT), Wigner-Ville distribution (WVD) and discrete wavelet transform (DWT), the superiority of the EEMD method in determining knock characteristics is demonstrated.

  11. IdealKnock: A framework for efficiently identifying knockout strategies leading to targeted overproduction.

    Gu, Deqing; Zhang, Cheng; Zhou, Shengguo; Wei, Liujing; Hua, Qiang

    2016-04-01

    In recent years, computer aided redesigning methods based on genome-scale metabolic network models (GEMs) have played important roles in metabolic engineering studies; however, most of these methods are hindered by intractable computing times. In particular, methods that predict knockout strategies leading to overproduction of desired biochemical are generally unable to do high level prediction because the computational time will increase exponentially. In this study, we propose a new framework named IdealKnock, which is able to efficiently evaluate potentials of the production for different biochemical in a system by merely knocking out pathways. In addition, it is also capable of searching knockout strategies when combined with the OptKnock or OptGene framework. Furthermore, unlike other methods, IdealKnock suggests a series of mutants with targeted overproduction, which enables researchers to select the one of greatest interest for experimental validation. By testing the overproduction of a large number of native metabolites, IdealKnock showed its advantage in successfully breaking through the limitation of maximum knockout number in reasonable time and suggesting knockout strategies with better performance than other methods. In addition, gene-reaction relationship is well considered in the proposed framework.

  12. Estimation of knock acoustical signal by parametric inversion method; Estimation du signal acoustique de cliquetis par inversion parametrique

    Boubal, O.; Oksman, J. [Ecole Superieure d' Electricite, 91 - Gif-sur-Yvette (France)

    1999-07-01

    Knock on spark ignition engines goes against car manufacturers efforts to reduce fuel consumption and exhaust gas emissions. This article develops a signal processing method to quantify knock. After discussing some classical techniques of knock energy estimation, an acoustical measurement technique is presented. An original signal processing method based on a parametric behavioral model for both knock and apparatus and a special inversion technique are used to get actual knock parameters. The knock related parameters are computed in a two step process. A deconvolution algorithm is used to obtain a signal made of unitary pulses, followed by an efficient inversion method. The whole process is applied to real data from a one-cylinder engine. Moreover, the results are compared to those obtained from an existing technique to suit a common industrial application. (authors)

  13. High-temperature expansion and knock-out properties of moulding sands with water glass

    Major-Gabryś K.

    2007-01-01

    Full Text Available The article focuses on the topic of improving the knock-out properties of moulding sand with water glass and ester hardener. It is settled that the cause of worse knock-out properties of moulding sand can be brought by their thermal expansion in increased temperatures. There is a presentation of the influence of different additives, containing Al2O3, on moulding sands’ expansion in increased temperatures. Within the frames of research, there was an elaboration of the influence of authors own additive- Glassex, on the expansion phenomenon of moulding sands with water glass and ester hardener. It is concluded, that the new additive stops the expansion of moulding sands and as well it improves their knock-out properties.

  14. ‘ProPIG’ Challenges and opportunities for on farm pig researchers: How to collect sound scientific data on animal health, welfare, nutrition and environmental impact AND act as a facilitator to improve these aspects at the same time ?

    2014-01-01

    Challenges and opportunities of on farm research are discussed and it is concluded, that transdisciplinary on-farm research requires from all involved parties: Understanding and willingness to learn from each other Acceptance, that own field of research is only a part of the whole “on farm picture” Sound scientific methods as well as technical tools for support (e.g. tablet PCs) Move from being/expecting “experts” towards “facilitation"

  15. The Children's Internet Protection Act and E-Rate Policies in Louisiana: A Comparison of Policy Interpretations in Region III and Their Impact on Learning Opportunities of Secondary Students

    Gautreaux, Madge L.

    2013-01-01

    In 2000, President Bill Clinton enacted the "Children's Internet Protection Act" (CIPA) which requires all K-12 schools and publicly funded libraries to use Internet filters to protect children from pornography and other obscene or potentially harmful online content as a stipulation for receiving E-Rate funding. The varying…

  16. 29 CFR 452.79 - Opportunity to campaign.

    2010-07-01

    ... 29 Labor 2 2010-07-01 2010-07-01 false Opportunity to campaign. 452.79 Section 452.79 Labor... DISCLOSURE ACT OF 1959 Campaign Safeguards § 452.79 Opportunity to campaign. There must be a reasonable... prior to the election so that he was denied an equal opportunity to campaign. Similarly, in a...

  17. ACTS 2014

    Co-curator of ACTS 2014 together with Rasmus Holmboe, Judith Schwarzbart and Sanne Kofoed. ACTS is the Museum of Contemporary Art’s international bi-annual festival. ACTS was established in 2011 and, while the primary focus is on sound and performance art, it also looks toward socially oriented art...... various possibilities and public spaces as a stage. ACTS takes place in and around the museum and diverse locations in Roskilde city. ACTS is partly curated by the museum staff and partly by guest curators. ACTS 2014 is supported by Nordea-fonden and is a part of the project The Museum goes downtown....

  18. Knocking Down Snrnp200 Initiates Demorphogenesis of Rod Photoreceptors in Zebrafish

    Yuan Liu

    2015-01-01

    Full Text Available Purpose. The small nuclear ribonucleoprotein 200 kDa (SNRNP200 gene is a fundamental component for precursor message RNA (pre-mRNA splicing and has been implicated in the etiology of autosomal dominant retinitis pigmentosa (adRP. This study aims to determine the consequences of knocking down Snrnp200 in zebrafish. Methods. Expression of the Snrnp200 transcript in zebrafish was determined via whole mount in situ hybridization. Morpholino oligonucleotide (MO aiming to knock down the expression of Snrnp200 was injected into zebrafish embryos, followed by analyses of aberrant splicing and expression of the U4/U6-U5 tri-small nuclear ribonucleoproteins (snRNPs components and retina-specific transcripts. Systemic changes and retinal phenotypes were further characterized by histological study and immunofluorescence staining. Results. Snrnp200 was ubiquitously expressed in zebrafish. Knocking down Snrnp200 in zebrafish triggered aberrant splicing of the cbln1 gene, upregulation of other U4/U6-U5 tri-snRNP components, and downregulation of a panel of retina-specific transcripts. Systemic defects were found correlated with knockdown of Snrnp200 in zebrafish. Only demorphogenesis of rod photoreceptors was detected in the initial stage, mimicking the disease characteristics of RP. Conclusions. We conclude that knocking down Snrnp200 in zebrafish could alter regular splicing and expression of a panel of genes, which may eventually trigger rod defects.

  19. A NEW METHOD FOR CHARACTERIZING THE KNOCK RESISTANCE OF LNG FUELS USED IN THE TRANSPORTATION MARKET

    Levinsky, Howard; Gersen, Sander; van Essen, Martijn; van Dijk, Gerco

    2014-01-01

    To ensure that the engines to be used in LNG-fueled vehicles are matched with the expected variations in fuel composition, the knock resistance of the fuel must be determined unambiguously. Rather than rely on empirical methods using gas mixtures and “standard” engines traditionally employed for thi

  20. Knock prediction for dual fuel engines by using a simplified combustion model

    费少梅; 刘震涛; 严兆大

    2003-01-01

    The present work used a methane-air mixture chemical kinetics scheme consisting of 119 elementary reaction steps and 41 chemical species to develop a simplified combustion model for prediction of the knock in dual fuel engines. Calculated values by the model for natural gas operation showed good agreement with corresponding experimental values over a broad range of operating conditions.

  1. CRISPR/Cas9-mediated gene knock-down in post-mitotic neurons.

    Christoph Straub

    Full Text Available The prokaryotic adaptive immune system CRISPR/Cas9 has recently been adapted for genome editing in eukaryotic cells. This technique allows for sequence-specific induction of double-strand breaks in genomic DNA of individual cells, effectively resulting in knock-out of targeted genes. It thus promises to be an ideal candidate for application in neuroscience where constitutive genetic modifications are frequently either lethal or ineffective due to adaptive changes of the brain. Here we use CRISPR/Cas9 to knock-out Grin1, the gene encoding the obligatory NMDA receptor subunit protein GluN1, in a sparse population of mouse pyramidal neurons. Within this genetically mosaic tissue, manipulated cells lack synaptic current mediated by NMDA-type glutamate receptors consistent with complete knock-out of the targeted gene. Our results show the first proof-of-principle demonstration of CRISPR/Cas9-mediated knock-down in neurons in vivo, where it can be a useful tool to study the function of specific proteins in neuronal circuits.

  2. Developing a Knock Predictive Criterion in Spark Ignition Engines Fuelled with Gaseous Fuels

    G.A.Karim

    1993-01-01

    Consideration of the chemical reaction activity of the end gas in a spark ignition and operating conditions are combined to predict the onset of knock and associated performance in an engine fuelled with methane.A two-zone predictive combustion model was developed based on an estimate of the effective duration of the combustion period and the mass burning rate for any set of operating conditions.The unburned end gas preignition chemical reaction activity is described by a detailed chemical reaction kinetic scheme for methane and air,The variation with time of the value of a formulated dimensionless knock parameter(k)is calcuated.It is shown that whenever knocking is encounteren.the value of “k” builds up to a sufficiently high value that exceeds a critical value.Under normal operating conditions,the value of “k” remains throughout the whole combustion period at comparatively very low levels.It is shown that the model and the use of this knock criterion“k” produce results that are in good agreement with experiment.

  3. Knocking Down Snrnp200 Initiates Demorphogenesis of Rod Photoreceptors in Zebrafish.

    Liu, Yuan; Chen, Xue; Qin, Bing; Zhao, Kanxing; Zhao, Qingshun; Staley, Jonathan P; Zhao, Chen

    2015-01-01

    Purpose. The small nuclear ribonucleoprotein 200 kDa (SNRNP200) gene is a fundamental component for precursor message RNA (pre-mRNA) splicing and has been implicated in the etiology of autosomal dominant retinitis pigmentosa (adRP). This study aims to determine the consequences of knocking down Snrnp200 in zebrafish. Methods. Expression of the Snrnp200 transcript in zebrafish was determined via whole mount in situ hybridization. Morpholino oligonucleotide (MO) aiming to knock down the expression of Snrnp200 was injected into zebrafish embryos, followed by analyses of aberrant splicing and expression of the U4/U6-U5 tri-small nuclear ribonucleoproteins (snRNPs) components and retina-specific transcripts. Systemic changes and retinal phenotypes were further characterized by histological study and immunofluorescence staining. Results. Snrnp200 was ubiquitously expressed in zebrafish. Knocking down Snrnp200 in zebrafish triggered aberrant splicing of the cbln1 gene, upregulation of other U4/U6-U5 tri-snRNP components, and downregulation of a panel of retina-specific transcripts. Systemic defects were found correlated with knockdown of Snrnp200 in zebrafish. Only demorphogenesis of rod photoreceptors was detected in the initial stage, mimicking the disease characteristics of RP. Conclusions. We conclude that knocking down Snrnp200 in zebrafish could alter regular splicing and expression of a panel of genes, which may eventually trigger rod defects.

  4. Physicochemical effects of varying fuel composition on knock characteristics of natural gas mixtures

    Gersen, Sander; van Essen, Martijn; van Dijk, Gerco; Levinsky, Howard

    2014-01-01

    The physicochemical origins of how changes in fuel composition affect autoignition of the end gas, leading to engine knock, are analyzed for a natural gas engine. Experiments in a lean-burn, high-speed medium-BMEP gas engine are performed using a reference natural gas with systematically varied frac

  5. Evolutionary constraints or opportunities?

    Sharov, Alexei A.

    2014-01-01

    Natural selection is traditionally viewed as a leading factor of evolution, whereas variation is assumed to be random and non-directional. Any order in variation is attributed to epigenetic or developmental constraints that can hinder the action of natural selection. In contrast I consider the positive role of epigenetic mechanisms in evolution because they provide organisms with opportunities for rapid adaptive change. Because the term “constraint” has negative connotations, I use the term “regulated variation” to emphasize the adaptive nature of phenotypic variation, which helps populations and species to survive and evolve in changing environments. The capacity to produce regulated variation is a phenotypic property, which is not described in the genome. Instead, the genome acts as a switchboard, where mostly random mutations switch “on” or “off” preexisting functional capacities of organism components. Thus, there are two channels of heredity: informational (genomic) and structure-functional (phenotypic). Functional capacities of organisms most likely emerged in a chain of modifications and combinations of more simple ancestral functions. The role of DNA has been to keep records of these changes (without describing the result) so that they can be reproduced in the following generations. Evolutionary opportunities include adjustments of individual functions, multitasking, connection between various components of an organism, and interaction between organisms. The adaptive nature of regulated variation can be explained by the differential success of lineages in macro-evolution. Lineages with more advantageous patterns of regulated variation are likely to produce more species and secure more resources (i.e., long-term lineage selection). PMID:24769155

  6. The kick-in system: a novel rapid knock-in strategy.

    Yuko Tomonoh

    Full Text Available Knock-in mouse models have contributed tremendously to our understanding of human disorders. However, generation of knock-in animals requires a significant investment of time and effort. We addressed this problem by developing a novel knock-in system that circumvents several traditional challenges by establishing stem cells with acceptor elements enveloping a particular genomic target. Once established, these acceptor embryonic stem (ES cells are efficient at directionally incorporating mutated target DNA using modified Cre/lox technology. This is advantageous, because knock-ins are not restricted to one a priori selected variation. Rather, it is possible to generate several mutant animal lines harboring desired alterations in the targeted area. Acceptor ES cell generation is the rate-limiting step, lasting approximately 2 months. Subsequent manipulations toward animal production require an additional 8 weeks, but this delimits the full period from conception of the genetic alteration to its animal incorporation. We call this system a "kick-in" to emphasize its unique characteristics of speed and convenience. To demonstrate the functionality of the kick-in methodology, we generated two mouse lines with separate mutant versions of the voltage-dependent potassium channel Kv7.2 (Kcnq2: p.Tyr284Cys (Y284C and p.Ala306Thr (A306T; both variations have been associated with benign familial neonatal epilepsy. Adult mice homozygous for Y284C, heretofore unexamined in animals, presented with spontaneous seizures, whereas A306T homozygotes died early. Heterozygous mice of both lines showed increased sensitivity to pentylenetetrazole, possibly due to a reduction in M-current in CA1 hippocampal pyramidal neurons. Our observations for the A306T animals match those obtained with traditional knock-in technology, demonstrating that the kick-in system can readily generate mice bearing various mutations, making it a suitable feeder technology toward streamlined

  7. The kick-in system: a novel rapid knock-in strategy.

    Tomonoh, Yuko; Deshimaru, Masanobu; Araki, Kimi; Miyazaki, Yasuhiro; Arasaki, Tomoko; Tanaka, Yasuyoshi; Kitamura, Haruna; Mori, Fumiaki; Wakabayashi, Koichi; Yamashita, Sayaka; Saito, Ryo; Itoh, Masayuki; Uchida, Taku; Yamada, Junko; Migita, Keisuke; Ueno, Shinya; Kitaura, Hiroki; Kakita, Akiyoshi; Lossin, Christoph; Takano, Yukio; Hirose, Shinichi

    2014-01-01

    Knock-in mouse models have contributed tremendously to our understanding of human disorders. However, generation of knock-in animals requires a significant investment of time and effort. We addressed this problem by developing a novel knock-in system that circumvents several traditional challenges by establishing stem cells with acceptor elements enveloping a particular genomic target. Once established, these acceptor embryonic stem (ES) cells are efficient at directionally incorporating mutated target DNA using modified Cre/lox technology. This is advantageous, because knock-ins are not restricted to one a priori selected variation. Rather, it is possible to generate several mutant animal lines harboring desired alterations in the targeted area. Acceptor ES cell generation is the rate-limiting step, lasting approximately 2 months. Subsequent manipulations toward animal production require an additional 8 weeks, but this delimits the full period from conception of the genetic alteration to its animal incorporation. We call this system a "kick-in" to emphasize its unique characteristics of speed and convenience. To demonstrate the functionality of the kick-in methodology, we generated two mouse lines with separate mutant versions of the voltage-dependent potassium channel Kv7.2 (Kcnq2): p.Tyr284Cys (Y284C) and p.Ala306Thr (A306T); both variations have been associated with benign familial neonatal epilepsy. Adult mice homozygous for Y284C, heretofore unexamined in animals, presented with spontaneous seizures, whereas A306T homozygotes died early. Heterozygous mice of both lines showed increased sensitivity to pentylenetetrazole, possibly due to a reduction in M-current in CA1 hippocampal pyramidal neurons. Our observations for the A306T animals match those obtained with traditional knock-in technology, demonstrating that the kick-in system can readily generate mice bearing various mutations, making it a suitable feeder technology toward streamlined phenotyping.

  8. 29 CFR 1614.203 - Rehabilitation Act.

    2010-07-01

    ... 29 Labor 4 2010-07-01 2010-07-01 false Rehabilitation Act. 1614.203 Section 1614.203 Labor... EMPLOYMENT OPPORTUNITY Provisions Applicable to Particular Complaints § 1614.203 Rehabilitation Act. (a... Rehabilitation Act of 1973, as amended (29 U.S.C. 791), has been violated in a complaint alleging...

  9. P-glycoprotein interaction with risperidone and 9-OH-risperidone studied in vitro, in knock-out mice and in drug-drug interaction experiments

    Ejsing, Thomas B.; Pedersen, Anne D.; Linnet, Kristian

    2005-01-01

    P-glycoprotein, risperidone, nortriptyline, cyclosporine A, drug-drug interaction, blood-brain barrier, knock-out mice......P-glycoprotein, risperidone, nortriptyline, cyclosporine A, drug-drug interaction, blood-brain barrier, knock-out mice...

  10. Opportunities for the integration of wind gas at new buildings into the Act on Power Generation from Renewable Energy Sources (EEWaermeG); Moeglichkeiten zur Integration des Einsatzes von Windgas bei Neubauten in das Erneuerbare-Energie-Waermegesetz

    Antoni, Oliver [Stiftung Umweltenergierecht, Wuerzburg (Germany)

    2013-02-15

    The power-to-gas technology as well as the utilization of wind gas produced by this technology is in the transitional phase from the research and development to the market maturity. Despite of sophisticated technical developments and despite of the first regulatory approaches of the financial and other promotions, further efforts are necessary in order to make the utilization of wind gas more economical and in order to facilitate the utilization of wind gas as an option for energy storage to handle the fluctuating power generation from wind power and solar energy. The author of the contribution under consideration reports on the so far only little noticed legal aspect of utilizing wind gas for heat supply and refrigeration supply of buildings as well as on the fulfilment of the obligation to use from the Act on Power Generation from Renewable Energy Sources (EEWaermeG).

  11. Equal opportunity in the workplace.

    Allen, A

    1992-04-01

    The Equal Employment Opportunity Commission (EEOC) was created by the Civil Rights Act of 1964. The commission encourages voluntary compliance with equal employment opportunity practices, and has authority to investigate complaints alleging discrimination in hiring, firing, wage rates, testing, training, apprenticeship, and other conditions of employment. In October 1991, during the Senate Judiciary Committee hearings, the confirmation of Judge Clarence Thomas for a seat on the United States Supreme Court was placed in jeopardy by a charge of sexual harassment while Thomas was head of the EEOC. This article focuses on aspects of sexual harassment in the workplace, the role of the EEOC, and offers some suggestions for keeping the work environment free of abusive behavior.

  12. Opportunity Cost: A Reexamination

    Parkin, Michael

    2016-01-01

    Is opportunity cost an ambiguous and arbitrary concept or a simple, straightforward, and fruitful one? This reexamination of opportunity cost addresses this question, and shows that opportunity cost is an ambiguous concept because "two" definitions are in widespread use. One of the definitions is indeed simple, fruitful, and one that…

  13. Rewriting the Opportunity Theory

    Korsgaard, Steffen T.

    The aim of this paper is to further the discussion of opportunity theory by discussing its ontological and epistemological underpinnings, which have been neglected in previous discussions. The idea that opportunities have an objective component is critically examined drawing on insights from social...... constructionism. It is argued that opportunity theory needs to be rewritten....

  14. A Knock-in Reporter for a Novel AR-Targeted Therapy

    2016-05-01

    MK, Gursoy-Yuzugullu O, Xu C, Xu Y, Price BD. DNA double-strand breaks promote methylation of histone H3 on lysine 9 and transient formation of...carrying FLuc in the AR gene locus and thereby bicistronically co-expressing the reporter gene with AR under the control of the endogenous AR promoter and...AR gene under the control of the endogenous AR promoter and enhancer. Such a knock-in reporter can faithfully reproduce chemical responses of the

  15. Knock-in model of Dravet syndrome reveals a constitutive and conditional reduction in sodium current

    Schutte, Ryan J.; Schutte, Soleil S.; Algara, Jacqueline; Barragan, Eden V.; Gilligan, Jeff; Staber, Cynthia; Savva, Yiannis A.; Smith, Martin A.; Reenan, Robert; O'Dowd, Diane K.

    2014-01-01

    Hundreds of mutations in the SCN1A sodium channel gene confer a wide spectrum of epileptic disorders, requiring efficient model systems to study cellular mechanisms and identify potential therapeutic targets. We recently demonstrated that Drosophila knock-in flies carrying the K1270T SCN1A mutation known to cause a form of genetic epilepsy with febrile seizures plus (GEFS+) exhibit a heat-induced increase in sodium current activity and seizure phenotype. To determine whether different SCN1A m...

  16. Combustion Analysis and Knock Detection in Single Cylinder DI-Diesel Engine Using Vibration Signature Analysis

    Y.V.V.SatyanarayanaMurthy

    2011-01-01

    The purpose of this paper is to detect the “knock” in Diesel engines which deteriorate the engine performance adversely. The methodology introduced in the present work suggests a newly developed approach towards analyzing the vibration analysis of diesel engines. The method is based on fundamental relationship between the engine vibration pattern and the relative characteristics of the combustion process in each or different cylinders. Knock in diesel engine is detected by measuring the vibra...

  17. Prelimbic cortex bdnf knock-down reduces instrumental responding in extinction

    Gourley, Shannon L.; Howell, Jessica L.; Rios, Maribel; DiLeone, Ralph J.; Taylor, Jane R

    2009-01-01

    Anatomically selective medial prefrontal cortical projections regulate the extinction of stimulus–reinforcement associations, but the mechanisms underlying extinction of an instrumental response for reward are less well-defined and may involve structures that regulate goal-directed action. We show brain-derived neurotrophic factor (bdnf) knock-down in the prelimbic, but not orbitofrontal, cortex accelerates the initial extinction of instrumental responding for food and reduces striatal BDNF p...

  18. Comparison of spectral analysis of vibration using commercial knock sensor and 3-axis acceleration sensor

    Zieliński, Ł.; Walczak, D.; Szczurowski, K.; Radkowski, S.

    2016-09-01

    With the development of internal combustion engines, engineers attempt to reduce the noise and vibration generated. Due to the high cost of fuel, are increasingly looking for new sources of power in order to reduce costs. In diesel engines, an increasingly popular method is the admixture of propane-butane. This follows because of the price of the fuel as well as to improve the efficiency of combustion. With the development of this type of dual fuel power seems to be a reasonable study of the effects of LPG to generate noise and vibration, as well as an attempt to evaluate the combustion process. Unfortunately, too much addition of LPG causes a phenomenon called knock consisting in abnormal, uneven, explosive combustion of fuels in reciprocating engines. This phenomenon may lead to a reduction in engine performance and permanent damage. Control of the knock detection uses vibration acceleration sensors recording the high frequency ranges. Within the framework of the research conducted by the team of authors, an attempt was made to compare the vibroacoustic signals originating from the commercial knocking sensor with a three-axis acceleration sensor. These signals were subject to a quick Fourier transform in the purpose of analysing the amplitude spectra.

  19. Effect of Tbxl knock-down on cardiac performance in zebrafish

    ZHANG Li-feng; GUI Yong-hao; WANG Yue-xiang; JIANG Qiu; SONG Hou-yan

    2010-01-01

    Background Tbxl is the major candidate gene for DiGeorge syndrome (DGS). Similar to defects observed in DGS patients, the structures disrupted in Tbxl-/- animal models are derived from the neural crest cells during development. Although the morphological phenotypes of some Tbxl knock-down animal models have been well described, analysis of the cardiac performance is limited. Therefore, myocardial performance was explored in Tbxl morpholino injected zebrafish embryos. Methods To elucidate these issues, Tbxl specific morpholino was used to reduce the function of Tbxl in zebrafish. The differentiation of the myocardial cells was observed using whole mount in situ hybridization. Heart rates were observed and recorded under the microscope from 24 to 72 hours post fertilization (hpf). The cardiac performance was analyzed by measuring ventricular shortening fraction and atrial shortening fraction.Results Tbxl morpholino injected embryos were characterized by defects in the pharyngeal arches, otic vesicle, aortic arches and thymus. In addition, Tbxl knock down reduced the amount of pharyngeal neural crest cells in zebrafish. Abnormal cardiac morphology was visible in nearly 20% of the Tbxl morpholino injected embryos. The hearts in these embryos did not loop or loop incompletely. Importantly, cardiac performance and heart rate were reduced in Tbxl morpholino injected embryos.Conclusions Tbxl might play an essential role in the development of pharyngeal neural crest cells in zebrafish. Cardiac performance is impaired by Tbxl knock down in zebrafish.

  20. Bounce-averaged Fokker-Planck Simulation of Runaway Avalanche from Secondary Knock-on Production

    Chiu, S. C.; Chan, V. S.; Harvey, R. W.; Rosenbluth, M. N.

    1996-11-01

    It has been pointed out that secondary production of runaway electrons by knock-on collisions with very energetic confined electrons can significantly change the runaway rate,(M.N. Rosenbluth, Bull. Amer. Phys. Soc. 40), 1804 (1995).^,(N.T. Besedin, I.M. Pankratov, Nucl. Fusion 26), 807 (1986).^,(R. Jaspers, K.H. Finden, G. Mank et al.), Nucl. Fusion 33, 1775 (1993). and is potentially a serious problem in reactors. Previous calculations of the effect have only partially included important effects such as toroidal trapping, synchrotron radiation, and bremsstrahlung. Furthermore, in a normal constant current operation, the increase of the density of runaway electrons causes a decrease of the ohmic field and all these effects can balance to a steady-state. The purpose of the present paper is to present results on bounce-averaged Fokker-Planck simulations of knock-on avalanching runaways including these effects. Initially, an energetic seed component is inserted to initiate knock-on avalanching. Results on the dependence of the steady-state runaway current on Z_eff, density, and radial location will be presented.

  1. Terpineol as a novel octane booster for extending the knock limit of gasoline

    Vallinayagam, R.

    2016-09-16

    Improving the octane number of gasoline offers the potential of improved engine combustion, as it permits spark timing advancement without engine knock. This study proposes the use of terpineol as an octane booster for gasoline in a spark ignited (SI) engine. Terpineol is a bio-derived oxygenated fuel obtained from pine tree resin, and has the advantage of higher calorific value than ethanol. The ignition delay time (IDT) of terpineol was first investigated in an ignition quality tester (IQT). The IQT results demonstrated a long ignition delay of 24.7 ms for terpineol and an estimated research octane number (RON) of 104, which was higher than commercial European (Euro V) gasoline. The octane boosting potential of terpineol was further investigated by blending it with a non-oxygenated gasoline (FACE F), which has a RON (94) lower than Euro V gasoline (RON = 97). The operation of a gasoline direct injection (GDI) SI engine fueled with terpineol-blended FACE F gasoline enabled spark timing advancement and improved engine combustion. The knock intensity of FACE F + 30% terpineol was lower than FACE F gasoline at both maximum brake torque (MBT) and knock limited spark advance (KLSA) operating points. Increasing proportions of terpineol in the blend caused peak heat release rate, in-cylinder pressure, CA50, and combustion duration to be closer to those of Euro V gasoline. Furthermore, FACE F + 30% terpineol displayed improved combustion characteristics when compared to Euro V gasoline. © 2016

  2. Recovery Act. Tapoco project. Cheoah upgrade

    Tran, Paul [Alcoa Inc., Alcoa Center, PA (United States)

    2013-10-02

    Under Funding Opportunity Announcement Number: DE-FOA-0000120, Recovery Act: Hydroelectric Facility Modernization, Alcoa Power Generating Inc. (APGI), a fully owned subsidiary of Alcoa Inc., implemented major upgrades at its Cheoah hydroelectric facility near Robbinsville, North Carolina.

  3. The Clean Air Act and the Economy

    Since 1970, cleaner air and a growing economy have gone hand in hand. The Act has created market opportunities that have helped to inspire innovation in cleaner technologies for which the United States has become a global market leader.

  4. Knock-in Mice Harboring a Ca2+ Desensitizing Mutation in Cardiac Troponin C Develop Early Onset Dilated Cardiomyopathy

    Bradley K McConnell

    2015-08-01

    Full Text Available The physiological consequences of aberrant Ca2+ binding and exchange with cardiac myofilaments are not clearly understood. In order to examine the effect of decreasing Ca2+ sensitivity of cTnC on cardiac function, we generated knock-in mice carrying a D73N mutation (not known to be associated with heart disease in human patients in cTnC. The D73N mutation was engineered into the regulatory N-domain of cTnC in order to reduce Ca2+ sensitivity of reconstituted thin filaments by increasing the rate of Ca2+ dissociation. In addition, the D73N mutation drastically blunted the extent of Ca2+ desensitization of reconstituted thin filaments induced by cTnI pseudo-phosphorylation. Compared to wild-type mice, heterozygous knock-in mice carrying the D73N mutation exhibited a substantially decreased Ca2+ sensitivity of force development in skinned ventricular trabeculae. Kaplan-Meier survival analysis revealed that median survival time for knock-in mice was twelve weeks. Echocardiographic analysis revealed that knock-in mice exhibited increased left ventricular dimensions with thinner walls. Echocardiographic analysis also revealed that measures of systolic function, such as ejection fraction and fractional shortening, were dramatically reduced in knock-in mice. In addition, knock-in mice displayed electrophysiological abnormalities, namely prolonged QRS and QT intervals. Furthermore, ventricular myocytes isolated from knock-in mice did not respond to β-adrenergic stimulation. Thus, knock-in mice developed pathological features similar to those observed in human patients with dilated cardiomyopathy (DCM. In conclusion, our results suggest that decreasing Ca2+ sensitivity of the regulatory N-domain of cTnC is sufficient to trigger the development of DCM.

  5. 20 CFR 638.541 - Job Corps training opportunities.

    2010-04-01

    ... 20 Employees' Benefits 3 2010-04-01 2010-04-01 false Job Corps training opportunities. 638.541... training opportunities. The Job Corps Director shall develop policies and requirements which will ensure... Training Partnership Act for youth programs; and services supporting participants in the Job...

  6. Rod and cone pathway signalling is altered in the P2X7 receptor knock out mouse.

    Kirstan A Vessey

    Full Text Available The P2X7 receptor (P2X7-R is expressed in the retina and brain and has been implicated in neurodegenerative diseases. However, whether it is expressed by neurons and plays a role as a neurotransmitter receptor has been the subject of controversy. In this study, we first show that the novel vesicular transporter for ATP, VNUT, is expressed in the retina, verifying the presence of the molecular machinery for ATP to act as neurotransmitter at P2X7-Rs. Secondly we show the presence of P2X7-R mRNA and protein in the retina and cortex and absence of the full length variant 1 of the receptor in the P2X7-R knock out (P2X7-KO mouse. The role of the P2X7-R in neuronal function of the retina was assessed by comparing the electroretinogram response of P2X7-KO with WT mice. The rod photoreceptor response was found to be similar, while both rod and cone pathway post-photoreceptor responses were significantly larger in P2X7-KO mice. This suggests that activation of P2X7-Rs modulates output of second order retinal neurons. In line with this finding, P2X7-Rs were found in the outer plexiform layer and on inner retinal cell classes, including horizontal, amacrine and ganglion cells. The receptor co-localized with conventional synapses in the IPL and was expressed on amacrine cells post-synaptic to rod bipolar ribbon synapses. In view of the changes in visual function in the P2X7-KO mouse and the immunocytochemical location of the receptor in the normal retina, it is likely the P2X7-R provides excitatory input to photoreceptor terminals or to inhibitory cells that shape both the rod and cone pathway response.

  7. Altmetric opportunities for Libraries

    Gerritsma, W.

    2015-01-01

    Just over five years ago the concept of altmetrics was minted. For libraries and librarians this has brought a new plethora of opportunities. In the first place there is the traditional extension role. Outreach opportunities on the subject of altmetrics are manyfold, and librarians could seize the o

  8. Equal opportunities in diversity

    Laëtitia Pedroso

    2010-01-01

    Promoting equal opportunities at CERN and advising the Director-General on all related matters is the task of the Equal Opportunities Officer, Doris Chromek-Burckhart, and Tim Smith, chair of the Equal Opportunities Advisory Panel. Changes are being introduced: in future, the focus of their work will be broadened to cover all aspects of diversity promotion.   The term "equal opportunities" has always been broader in scope than the equal treatment of men and women but this is what it has traditionally been confined to in practice. "We wanted to change how people see our mission", explains Doris Chromek-Burckhart. The word "diversity" has much wider connotations than "equal opportunities" and makes it clearer that we are also dealing with differences in nationality, religion, age, culture and physical ability”. Getting away from the old clichés is vital to ensuring equal treatment for everyone. The diversit...

  9. Sound vibration signal processing for detection and identification detonation (knock) to optimize performance Otto engine

    Sujono, A.; Santoso, B.; Juwana, W. E.

    2016-03-01

    Problems of detonation (knock) on Otto engine (petrol engine) is completely unresolved problem until now, especially if want to improve the performance. This research did sound vibration signal processing engine with a microphone sensor, for the detection and identification of detonation. A microphone that can be mounted is not attached to the cylinder block, that's high temperature, so that its performance will be more stable, durable and inexpensive. However, the method of analysis is not very easy, because a lot of noise (interference). Therefore the use of new methods of pattern recognition, through filtration, and the regression function normalized envelope. The result is quite good, can achieve a success rate of about 95%.

  10. Single Proton Knock-Out Reactions from 24,25,26F

    Thoennessen, M; Brown, B A; Enders, J; Frank, N; Hansen, P G; Heckman, P; Luther, B A; Seitz, J; Stolz, A; Tryggestad, E J

    2003-01-01

    The cross sections of the single proton knock-out reactions from 24F, 25F, and 26F on a 12C target were measured at energies of about 50 MeV/nucleon. Ground state populations of 6.6+-.9 mb, 3.8+-0.6 mb for the reactions 12C(24F,23O) and 12C(25F,24O) were extracted, respectively. The data were compared to calculations based on the many-body shell model and the eikonal theory. In the reaction 12C(26F,25O) the particle instability of 25O was confirmed.

  11. Equal Opportunities Questionnaire

    2007-01-01

    The initiative to promote Equal Opportunities at CERN started in 1993. The first Equal Opportunities Officer was appointed in 1996, which was followed by the creation of the Equal Opportunities Advisory Panel in 1998. Initially the concern was mainly the fair treatment of women in the work-place. Today the emphasis has evolved to ensuring that diversity is used to increase creativity and productivity in the work-place. In order to ensure that all aspects of Equal Opportunities and Diversity are covered, CERN’s Equal Opportunities team has prepared a survey to obtain your input. Your answers are confidential and will only be used for generating statistics. The questionnaire is on-line and can be accessed via: https://espace.cern.ch/EOQ. We hope that you will take a few minutes of your time to give your input and would be grateful if you could reply before 15/10/07. For further information about Equal Opportunities at CERN see: http://cern.ch/equal-opportunities The Equa...

  12. Equal Opportunities Questionnaire

    2007-01-01

    The initiative to promote Equal Opportunities at CERN started in 1993. The first Equal Opportunities Officer was appointed in 1996 followed by the creation of the Equal Opportunities Advisory Panel in 1998. Initially the concern was mainly the fair treatment of women in the work-place. Today the emphasis has evolved to ensuring that diversity is used to increase creativity and productivity in the work-place. In order to ensure that all aspects of Equal Opportunities and Diversity are covered, CERN’s Equal Opportunities team has prepared a survey to obtain your input. Your answers are confidential and will only be used for generating statistics. The questionnaire is on-line and can be accessed via: https://espace.cern.ch/EOQ. We hope that you will take a few minutes of your time to give your input and would be grateful if you could reply before 15/10/07. For further information about Equal Opportunities at CERN see: http://cern.ch/equal-opportunities The Equal Opportuni...

  13. Differential Bees Flux Balance Analysis with OptKnock for in silico microbial strains optimization.

    Yee Wen Choon

    Full Text Available Microbial strains optimization for the overproduction of desired phenotype has been a popular topic in recent years. The strains can be optimized through several techniques in the field of genetic engineering. Gene knockout is a genetic engineering technique that can engineer the metabolism of microbial cells with the objective to obtain desirable phenotypes. However, the complexities of the metabolic networks have made the process to identify the effects of genetic modification on the desirable phenotypes challenging. Furthermore, a vast number of reactions in cellular metabolism often lead to the combinatorial problem in obtaining optimal gene deletion strategy. Basically, the size of a genome-scale metabolic model is usually large. As the size of the problem increases, the computation time increases exponentially. In this paper, we propose Differential Bees Flux Balance Analysis (DBFBA with OptKnock to identify optimal gene knockout strategies for maximizing the production yield of desired phenotypes while sustaining the growth rate. This proposed method functions by improving the performance of a hybrid of Bees Algorithm and Flux Balance Analysis (BAFBA by hybridizing Differential Evolution (DE algorithm into neighborhood searching strategy of BAFBA. In addition, DBFBA is integrated with OptKnock to validate the results for improving the reliability the work. Through several experiments conducted on Escherichia coli, Bacillus subtilis, and Clostridium thermocellum as the model organisms, DBFBA has shown a better performance in terms of computational time, stability, growth rate, and production yield of desired phenotypes compared to the methods used in previous works.

  14. Effects of Pin1 loss in HdhQ111 knock-in mice

    Elena eAgostoni

    2016-05-01

    Full Text Available Huntington’s disease (HD is a fatal, dominantly inherited, neurodegenerative disorder due to a pathological expansion of the CAG repeat in the coding region of the HTT gene. In the quest for understanding the molecular basis of neurodegeneration, we have previously demonstrated that the prolyl isomerase Pin1 plays a crucial role in mediating p53-dependent apoptosis triggered by mutant huntingtin (mHtt in vitro. To assess the effects of the lack of Pin1 in vivo, we have bred Pin1 knock-out mice with HdhQ111 knock-in mice, a genetically precise model of HD. We show that Pin1 genetic ablation modifies a portion of HdhQ111 phenotypes in a time-dependent fashion. As an early event, Pin1 activity reduces the DNA damage response. In midlife mice, by taking advantage of next-generation sequencing technology, we show that Pin1 activity modulates a portion of the alterations triggered by mHtt, extending the role of Pin1 to two additional HdhQ111 phenotypes: the unbalance in the synthesis/concentration of hormones, as well as the alteration of Wnt/β-catenin signaling. In aging animals, Pin1 significantly increases the number of mHtt-positive nuclear inclusions while it reduces gliosis. In summary, this work provides further support for a role of Pin1 in HD pathogenesis.

  15. 77 FR 50390 - Equal Credit Opportunity Act (Regulation B)

    2012-08-21

    ... the prototype designs through an interactive tool on the Bureau's Web site or through posting the... usability testing, consisting of one-on-one cognitive interviews, over several iterations of prototype... developing a qualitative testing plan, and several prototype integrated forms for the disclosure to...

  16. Development of a rank detector for knock detection in cylinder pressure or loose part noise in internal combustion engines and of assessment methods for knock detectors. Entwicklung eines Rangdetektors zur Klopfdetektion im Zylinderdruck bzw. Koerperschall von Ottomotoren und von Bewertungsverfahren fuer Klopfdetektoren

    Yu Xiangyang.

    1990-01-01

    The operational status of an internal combustion engine (efficiency) can be controlled by a knock detector and a corresponding sparking angle regulation up to knock limit. A knock regulating system of this kind has to be highly sensitive, robust, fast and adaptable. This is a report on the principles of a knock detector of this kind (cause, effect, combustion chamber model, frequency shift compensation, engine signal spectrum) and on the development of a nonparametric adaptive knock detector (adaptation algorithm, design concept to a rank detector). In conclusion, the results of simulations with the rank detector are presented assessed (comparative experimental results, confidence intervals). (HWJ).

  17. Opportunities with thermoplastics.

    Vaahs, Tilo

    2003-04-01

    Whether as substitutes for glass and metal, or completely novel injection moulded applications, engineering polymers offer a range of opportunities for developing cost-effective, safe and smart medical devices.

  18. A High-Speed Motion-Picture Study of Normal Combustion, Knock and Preignition in a Spark-Ignition Engines

    Rothrock, A M; Spencer, R C; Miller, Cearcy D

    1941-01-01

    Combustion in a spark-ignition engine was investigated by means of the NACA high-speed motion-picture cameras. This camera is operated at a speed of 40,000 photographs a second and therefore makes possible the study of changes that take place in the intervals as short as 0.000025 second. When the motion pictures are projected at the normal speed of 16 frames a second, any rate of movement shown is slowed down 2500 times. Photographs are presented of normal combustion, of combustion from preignitions, and of knock both with and without preignition. The photographs of combustion show that knock may be preceded by a period of exothermic reaction in the end zone that persists for a time interval of as much as 0.0006 second. The knock takes place in 0.00005 second or less.

  19. Alterations in ethanol-induced behaviors and consumption in knock-in mice expressing ethanol-resistant NMDA receptors.

    Carolina R den Hartog

    Full Text Available Ethanol's action on the brain likely reflects altered function of key ion channels such as glutamatergic N-methyl-D-aspartate receptors (NMDARs. In this study, we determined how expression of a mutant GluN1 subunit (F639A that reduces ethanol inhibition of NMDARs affects ethanol-induced behaviors in mice. Mice homozygous for the F639A allele died prematurely while heterozygous knock-in mice grew and bred normally. Ethanol (44 mM; ∼0.2 g/dl significantly inhibited NMDA-mediated EPSCs in wild-type mice but had little effect on responses in knock-in mice. Knock-in mice had normal expression of GluN1 and GluN2B protein across different brain regions and a small reduction in levels of GluN2A in medial prefrontal cortex. Ethanol (0.75-2.0 g/kg; i.p. increased locomotor activity in wild-type mice but had no effect on knock-in mice while MK-801 enhanced activity to the same extent in both groups. Ethanol (2.0 g/kg reduced rotarod performance equally in both groups but knock-in mice recovered faster following a higher dose (2.5 g/kg. In the elevated zero maze, knock-in mice had a blunted anxiolytic response to ethanol (1.25 g/kg as compared to wild-type animals. No differences were noted between wild-type and knock-in mice for ethanol-induced loss of righting reflex, sleep time, hypothermia or ethanol metabolism. Knock-in mice consumed less ethanol than wild-type mice during daily limited-access sessions but drank more in an intermittent 24 h access paradigm with no change in taste reactivity or conditioned taste aversion. Overall, these data support the hypothesis that NMDA receptors are important in regulating a specific constellation of effects following exposure to ethanol.

  20. Overlap knock-out effects in the CERN intersecting storage rings (ISR)

    Gourber, J P; Myers, S

    1977-01-01

    Overlap knock-out arises from an overlap between frequencies present in a bunched beam and the betatron frequencies in a stack. The 'single ring' effect in the interaction of a bunched beam with a stack in the same ring. Here the coupling forces are fairly linear and are transmitted by machine elements. The 'two-ring' effect is the interaction of a bunched beam with a stack in the other ring. Here the coupling forces are nonlinear since they are produced by the beam-beam interaction. A brief outline of the general theory of these effects is given. The single ring and two-ring dipole effects have been observed and shown to cause a large increase in the transverse size of the stacked beam. (4 refs).

  1. RNAi-mediated knocking- down of rlpk2 gene retarded soybean leaf senescence

    LI Xiaoping; MA Yuanyuan; LI Pengli; ZHANG Liwen; WANG Yong; ZHANG Ren; WANG Ningning

    2005-01-01

    Leaf senescence that occurs in the last stage of leaf development is a genetically programmed process. It is very significant to elucidate the molecular mechanisms that control the initiation and progression of leaf senescence and the way the senescence signal is transduced. In a previous study on artificially induced soybean leaf senescence, we cloned a novel gene designated rlpk2 (Genbank Accession No. AY687391) that encodes a leucine-rich repeat (LRR) receptor like protein kinase. The expression level of rlpk2 gene was shown to be strongly up-regulated during both the natural leaf senescence process in this report and the artificially induced primary-leaf-senescence process in our previous work. The RNA interference (RNAi)-mediated knocking-down of rlpk2 dramatically retarded both the natural and nutrient deficiency-induced leaf senescence in transgenic soybean. The transgenic leaves showed more cell-aggregated surface structure and higher content of chlorophyll.

  2. Low leaded motor gasoline of high knock rating having few pollution effects

    Droste, W.; Obenaus, F.; Schoefer, W.

    1975-11-13

    A carburator gasoline has been developed that has a high knock rating and few enviromental pollution effects. The gasoline contains 0.1 to 0.4 g of lead per liter, and up to 20 percent by volume of a mixture made up of 80 to 90 percent by weight methyl-tert.-butyl ether and 20 to 10 percent by weight methanol. Through tests it has been determined that the characteristics (particularly the octane number) of a gasoline having a lead content of 0.15 g/liter and one of the above mentioned additives are better than those of a gasoline with a lead content of 0.4 g/liter, but not containing an additive. The harmful emissions were also lower. In addition, the danger of carburator icing is decreased.

  3. Opportunities for Products of New Plant Breeding Techniques.

    Schaart, Jan G; van de Wiel, Clemens C M; Lotz, Lambertus A P; Smulders, Marinus J M

    2016-05-01

    Various new plant breeding techniques (NPBT) have a similar aim, namely to produce improved crop varieties that are difficult to obtain through traditional breeding methods. Here, we review the opportunities for products created using NPBTs. We categorize products of these NPBTs into three product classes with a different degree of genetic modification. For each product class, recent examples are described to illustrate the potential for breeding new crops with improved traits. Finally, we touch upon the future applications of these methods, such as cisgenic potato genotypes in which specific combinations of Phytophthora infestans resistance genes have been stacked for use in durable cultivation, or the creation of new disease resistances by knocking out or removing S-genes using genome-editing techniques.

  4. 16 CFR 1101.21 - Form of notice and opportunity to comment.

    2010-01-01

    ... 16 Commercial Practices 2 2010-01-01 2010-01-01 false Form of notice and opportunity to comment. 1101.21 Section 1101.21 Commercial Practices CONSUMER PRODUCT SAFETY COMMISSION CONSUMER PRODUCT SAFETY ACT REGULATIONS INFORMATION DISCLOSURE UNDER SECTION 6(b) OF THE CONSUMER PRODUCT SAFETY ACT Procedure for Providing Notice and Opportunity...

  5. Knock-in model of Dravet syndrome reveals a constitutive and conditional reduction in sodium current.

    Schutte, Ryan J; Schutte, Soleil S; Algara, Jacqueline; Barragan, Eden V; Gilligan, Jeff; Staber, Cynthia; Savva, Yiannis A; Smith, Martin A; Reenan, Robert; O'Dowd, Diane K

    2014-08-15

    Hundreds of mutations in the SCN1A sodium channel gene confer a wide spectrum of epileptic disorders, requiring efficient model systems to study cellular mechanisms and identify potential therapeutic targets. We recently demonstrated that Drosophila knock-in flies carrying the K1270T SCN1A mutation known to cause a form of genetic epilepsy with febrile seizures plus (GEFS+) exhibit a heat-induced increase in sodium current activity and seizure phenotype. To determine whether different SCN1A mutations cause distinct phenotypes in Drosophila as they do in humans, this study focuses on a knock-in line carrying a mutation that causes a more severe seizure disorder termed Dravet syndrome (DS). Introduction of the DS SCN1A mutation (S1231R) into the Drosophila sodium channel gene para results in flies that exhibit spontaneous and heat-induced seizures with distinct characteristics and lower onset temperature than the GEFS+ flies. Electrophysiological studies of GABAergic interneurons in the brains of adult DS flies reveal, for the first time in an in vivo model system, that a missense DS mutation causes a constitutive and conditional reduction in sodium current activity and repetitive firing. In addition, feeding with the serotonin precursor 5-HTP suppresses heat-induced seizures in DS but not GEFS+ flies. The distinct alterations of sodium currents in DS and GEFS+ GABAergic interneurons demonstrate that both loss- and gain-of-function alterations in sodium currents are capable of causing reduced repetitive firing and seizure phenotypes. The mutation-specific effects of 5-HTP on heat-induced seizures suggest the serotonin pathway as a potential therapeutic target for DS.

  6. Measles virus-induced immunosuppression in SLAM knock-in mice.

    Koga, Ritsuko; Ohno, Shinji; Ikegame, Satoshi; Yanagi, Yusuke

    2010-05-01

    Measles virus (MV) causes transient severe immunosuppression in patients, which may lead to secondary viral and bacterial infections, largely accounting for measles-related morbidity and mortality. MV is known to infect immune cells by using the human signaling lymphocyte activation molecule (SLAM; also called CD150) as a cellular receptor, but the mechanism by which MV causes immunosuppression is not well understood. We show that MV infection of SLAM knock-in mice, in which the V domain of mouse SLAM was replaced by the V domain of human SLAM, crossed with alpha/beta-interferon receptor knockout mice, reproduced many immunological alterations observed in human patients. These included lymphopenia, inhibition of T-cell proliferation and antibody production, increased production of the Th2 cytokine interleukin-4 (IL-4) and the immunosuppressive cytokine IL-10, and suppression of contact hypersensitivity. Gross redistribution of lymphocytes among lymphoid tissues was not apparent in infected mice, nor was an increase of regulatory T cells. The numbers of lymphocytes in lymph nodes remained almost unchanged after MV infection, despite enhanced apoptosis, suggesting that lymph nodes were replenished with lymphocytes from the peripheral blood, which may have contributed to the observed lymphopenia in the spleen. Blocking of IL-10 by use of an anti-IL-10 receptor antibody ameliorated suppression of contact hypersensitivity in infected mice. These results indicate that SLAM knock-in mice lacking the expression of the alpha/beta-interferon receptor serve as a useful small animal model with which to elucidate MV-induced immunosuppression.

  7. Gene correction of a duchenne muscular dystrophy mutation by meganuclease-enhanced exon knock-in.

    Popplewell, Linda; Koo, Taeyoung; Leclerc, Xavier; Duclert, Aymeric; Mamchaoui, Kamel; Gouble, Agnés; Mouly, Vincent; Voit, Thomas; Pâques, Frédéric; Cédrone, Frédéric; Isman, Olga; Yáñez-Muñoz, Rafael J; Dickson, George

    2013-07-01

    Duchenne muscular dystrophy (DMD) is a severe inherited, muscle-wasting disorder caused by mutations in the DMD gene. Gene therapy development for DMD has concentrated on vector-based DMD minigene transfer, cell-based gene therapy using genetically modified adult muscle stem cells or healthy wild-type donor cells, and antisense oligonucleotide-induced exon-skipping therapy to restore the reading frame of the mutated DMD gene. This study is an investigation into DMD gene targeting-mediated correction of deletions in human patient myoblasts using a target-specific meganuclease (MN) and a homologous recombination repair matrix. The MN was designed to cleave within DMD intron 44, upstream of a deletion hotspot, and integration-competent lentiviral vectors expressing the nuclease (LVcMN) were generated. MN western blotting and deep gene sequencing for LVcMN-induced non-homologous end-joining InDels (microdeletions or microinsertions) confirmed efficient MN expression and activity in transduced DMD myoblasts. A homologous repair matrix carrying exons 45-52 (RM45-52) was designed and packaged into integration-deficient lentiviral vectors (IDLVs; LVdRM45-52). After cotransduction of DMD myoblasts harboring a deletion of exons 45 to 52 with LVcMN and LVdRM45-52 vectors, targeted knock-in of the RM45-52 region in the correct location in DMD intron 44, and expression of full-length, correctly spliced wild-type dystrophin mRNA containing exons 45-52 were observed. This work demonstrates that genome surgery on human DMD gene mutations can be achieved by MN-induced locus-specific genome cleavage and homologous recombination knock-in of deleted exons. The feasibility of human DMD gene repair in patient myoblasts has exciting therapeutic potential.

  8. P-gp substrate-induced neurotoxicity in an Abcb1a knock-in/Abcb1b knock-out mouse model with a mutated canine ABCB1 targeted insertion.

    Swain, M D; Orzechowski, K L; Swaim, H L; Jones, Y L; Robl, M G; Tinaza, C A; Myers, M J; Jhingory, M V; Buckely, L E; Lancaster, V A; Yancy, H F

    2013-06-01

    Certain dog breeds, especially Collies, are observed to exhibit neurotoxicity to avermectin drugs, which are P-glycoprotein (P-gp) substrates. This neurotoxicity is due to an ABCB1 gene mutation (ABCB1-1Δ) that results in non-functional P-gp expression. A developed Abcb1a knock-in/Abcb1b knock-out mouse model expressing the ABCB1-1Δ canine gene was previously reported and mice exhibited sensitivity upon ivermectin administration. Here, model and wild-type mice were administered P-gp substrates doramectin, moxidectin, and digoxin. While knock-in/knock-out mice exhibited ataxia, lethargy and tremor, wild-type mice remained unaffected. In addition, no neurotoxic clinical signs were observed in either mouse type administered domperidone, a P-gp substrate with no reported neurotoxicity in ABCB1-1Δ Collies. Overall, neurotoxic signs displayed by model mice closely paralleled those observed in ivermectin-sensitive Collies. This model can be used to identify toxic P-gp substrates with altered safety in dog populations and may reduce dog use in safety studies that are part of the drug approval process.

  9. PV opportunities in India

    Stone, Jack L.; Ullal, Harin S.

    1996-01-01

    The growing middle class in India, coupled with a need for electricity to provide basic services to the masses, provides an opportunity to deploy photovoltaic systems in cost-effective applications ranging from grid-connected to isolated location requirements. This need is being satisfied by aggressive government programs, the availability of funds from agencies such as the World Bank, and the desire of Indian industries to form joint ventures for in-country manufacturing. The relaxed restrictions on doing business in India makes today's opportunities timely indeed.

  10. Urbanization as opportunity

    Fuller, Brandon; Romer, Paul

    2014-01-01

    Urbanization deserves urgent attention from policy makers, academics, entrepreneurs, and social reformers of all stripes. Nothing else will create as many opportunities for social and economic progress. The urbanization project began roughly 1,000 years after the transition from the Pleistocene to the milder and more stable Holocene interglacial. In 2010, the urban population in developing...

  11. Investment Insight Opportunities Ahead

    2006-01-01

    Over the next five years, China will be shitting its focus to more balanced development and what it sees as quality growth. Its two main strategies are promoting innovation-with the government-backed industrial upgrading-and strengthening the rural economy. This shift will lead to massive investment and fresh, wealth-making opportunities. In the stock

  12. Expanding Student Assessment Opportunities.

    Bartscher, Beth; Carter, Andrea; Lawlor, Anna; McKelvey, Barbara

    This paper describes an approach for expanding assessment opportunities for students to demonstrate their understanding of content. The targeted population consisted of elementary and junior high school students in two schools in a growing middle-class community in north central Illinois. The elementary school enrolled 467 students and the junior…

  13. Opportunity Cost: A Reply

    Parkin, Michael

    2016-01-01

    The author's objective for this reply in reexamining opportunity cost was to draw attention to two conflicting definitions of the concept in current use and to argue the case for dropping one of them. The comments of Daniel Arce, Rod O'Donnell, and Daniel Stone might be read as demonstration that the author has failed on both counts. Such a…

  14. Land of Expat Opportunity

    2009-01-01

    The international work force continues to grow as employment opportunities entice foreigners to live in China Forty-four-year-old Daniell Goodin has spent almost two decades working abroad, calling Indonesia, Hong Kong and the United States "home" for different periods of time. In May, the Australian native arrived in China, working

  15. The Brain Proteome of the Ubiquitin Ligase Peli1 Knock-Out Mouse during Experimental Autoimmune Encephalomyelitis

    Lereim, Ragnhild Reehorst; Oveland, Eystein; Xiao, Yichuan; Torkildsen, Øivind; Wergeland, Stig; Myhr, Kjell-Morten; Sun, Shao-Cong; Berven, Frode S

    2016-01-01

    The ubiquitin ligase Peli1 has previously been suggested as a potential treatment target in multiple sclerosis. In the multiple sclerosis disease model, experimental autoimmune encephalomyelitis, Peli1 knock-out led to less activated microglia and less inflammation in the central nervous system. Despite being important in microglia, Peli1 expression has also been detected in glial and neuronal cells. In the present study the overall brain proteomes of Peli1 knock-out mice and wild-type mice were compared prior to experimental autoimmune encephalomyelitis induction, at onset of the disease and at disease peak. Brain samples from the frontal hemisphere, peripheral from the extensive inflammatory foci, were analyzed using TMT-labeling of sample pools, and the discovered proteins were verified in individual mice using label-free proteomics. The greatest proteomic differences between Peli1 knock-out and wild-type mice were observed at the disease peak. In Peli1 knock-out a higher degree of antigen presentation, increased activity of adaptive and innate immune cells and alterations to proteins involved in iron metabolism were observed during experimental autoimmune encephalomyelitis. These results unravel global effects to the brain proteome when abrogating Peli1 expression, underlining the importance of Peli1 as a regulator of the immune response also peripheral to inflammatory foci during experimental autoimmune encephalomyelitis. The proteomics data is available in PRIDE with accession PXD003710.

  16. True-breeding targeted gene knock-out in barley using designer TALE-nuclease in haploid cells.

    Maia Gurushidze

    Full Text Available Transcription activator-like effector nucleases (TALENs are customizable fusion proteins able to cleave virtually any genomic DNA sequence of choice, and thereby to generate site-directed genetic modifications in a wide range of cells and organisms. In the present study, we expressed TALENs in pollen-derived, regenerable cells to establish the generation of instantly true-breeding mutant plants. A gfp-specific TALEN pair was expressed via Agrobacterium-mediated transformation in embryogenic pollen of transgenic barley harboring a functional copy of gfp. Thanks to the haploid nature of the target cells, knock-out mutations were readily detected, and homozygous primary mutant plants obtained following genome duplication. In all, 22% of the TALEN transgenics proved knocked out with respect to gfp, and the loss of function could be ascribed to the deletions of between four and 36 nucleotides in length. The altered gfp alleles were transmitted normally through meiosis, and the knock-out phenotype was consistently shown by the offspring of two independent mutants. Thus, here we describe the efficient production of TALEN-mediated gene knock-outs in barley that are instantaneously homozygous and non-chimeric in regard to the site-directed mutations induced. This TALEN approach has broad applicability for both elucidating gene function and tailoring the phenotype of barley and other crop species.

  17. Characterizing Gaseous Fuels for Their Knock Resistance based on the Chemical and Physical Properties of the Fuel

    Levinsky, Howard; Gersen, Sander; van Essen, Martijn; van Dijk, Gerco

    2016-01-01

    A method is described to characterize the effects of changes in the composition of gaseous fuels on engine knock by computing the autoignition process during the compression and burn periods of the engine cycle. To account for the effects of fuel composition on the in-cylinder pressure and temperatu

  18. User Frustrations as Opportunities

    Michael Weiss

    2012-04-01

    Full Text Available User frustrations are an excellent source of new product ideas. Starting with this observation, this article describes an approach that entrepreneurs can use to discover business opportunities. Opportunity discovery starts with a problem that the user has, but may not be able to articulate. User-centered design techniques can help elicit those latent needs. The entrepreneur should then try to understand how users are solving their problem today, before proposing a solution that draws on the unique skills and technical capabilities available to the entrepreneur. Finally, an in-depth understanding of the user allows the entrepreneur to hone in on the points of difference and resonance that are the foundation of a strong customer value proposition.

  19. Nanoethics: Challenges and Opportunities

    Pompidou, Alain; Pompidou, Alain; Pompidou, Alain; Pompidou, Alain

    Nanoscience and its technological consequences constitute a relatively recent field of knowledge. Their rapid development around the world is characterised by an absence of specific norms and standards. Industrial applications, already promising, are not without risk, and this risk deserves to be fully and rigorously assessed. On the other hand, this vigilance and anticipation of risk does not need to deprive society as a whole of new opportunities, whether they be for developed countries and the emerging economies, or for less developed nations.

  20. Project X: Physics Opportunities

    Kronfeld, Andreas S; Al-Binni, Usama; Altmannshofer, Wolfgang; Ankenbrandt, Charles; Babu, Kaladi; Banerjee, Sunanda; Bass, Matthew; Batell, Brian; Baxter, David V; Berezhiani, Zurab; Bergevin, Marc; Bernstein, Robert; Bhattacharya, Sudeb; Bishai, Mary; Blum, Thomas; Bogacz, S Alex; Brice, Stephen J; Brod, Joachim; Bross, Alan; Buchoff, Michael; Burgess, Thomas W; Carena, Marcela; Castellanos, Luis A; Chattopadhyay, Subhasis; Chen, Mu-Chun; Cherdack, Daniel; Christ, Norman H; Chupp, Tim; Cirigliano, Vincenzo; Coloma, Pilar; Coppola, Christopher E; Cowsik, Ramanath; Crabtree, J Allen; Delahaye, Jean-Pierre; Denisov, Dmitri; deNiverville, Patrick; de Gouvêa, André; Dharmapalan, Ranjan; Dolgov, Alexander; Dvali, Georgi; Eichten, Estia; Engelfried, Jürgen; Ferguson, Phillip D; Gabriel, Tony; Gal, Avraham; Gallmeier, Franz; Ganezer, Kenneth S; Gardner, Susan; Glenzinski, Douglas; Godfrey, Stephen; Golubeva, Elena S; Gori, Stefania; Graves, Van B; Greene, Geoffrey; Griffard, Cory L; Haisch, Ulrich; Handler, Thomas; Hartfiel, Brandon; Hawari, Ayman; Heilbronn, Lawrence; Hill, James E; Huber, Patrick; Jaffe, David E; Johnson, Christian; Kamyshkov, Yuri; Kaplan, Daniel M; Kerbikov, Boris; Kiburg, Brendan; Kirk, Harold G; Klein, Andreas; Knoepfel, Kyle; Kopeliovich, Boris; Kopeliovich, Vladimir; Kopp, Joachim; Korsch, Wolfgang; Kribs, Graham; Lipton, Ronald; Liu, Chen-Yu; Lorenzon, Wolfgang; Lu, Zheng-Tian; Makins, Naomi C R; McKeen, David; Mills, Geoffrey; Mohapatra, Rabindra; Mokhov, Nikolai V; Mocko, Michael; Muhrer, Guenter; Mumm, Pieter; Okun, Lev; Neuffer, David; Palmer, Mark A; Palmer, Robert; Pattie, Robert W; Phillips, David G; Pronsikh, Vitaly; Pitts, Kevin; Pospelov, Maxim; Quigg, Chris; Ramberg, Erik; Ray, Amlan; Reimer, Paul E; Richards, David G; Ritz, Adam; Roy, Amit; Ruggles, Arthur; Ryne, Robert; Sarkar, Utpal; Saunders, Andy; Semertzidis, Yannis K; Serebrov, Anatoly; Shimizu, Hirohiko; Shrock, Robert; Snopok, Pavel V; Snow, William M; Sikdar, Arindam K; Soha, Aria; Spanier, Stefan; Striganov, Sergei; Tang, Zhaowen; Townsend, Lawrence; Urheim, Jon; Vainshtein, Arkady; Van Kooten, Richard J; Van de Water, Richard; Van de Water, Ruth S; Wehring, Bernard; Whitehead, Lisa; Wilson, Robert J; Worcester, Elizabeth; Young, Albert R; Wester, William C; Zeller, Geralyn

    2013-01-01

    Part 2 of "Project X: Accelerator Reference Design, Physics Opportunities, Broader Impacts". In this Part, we outline the particle-physics program that can be achieved with Project X, a staged superconducting linac for intensity-frontier particle physics. Topics include neutrino physics, kaon physics, muon physics, electric dipole moments, neutron-antineutron oscillations, new light particles, hadron structure, hadron spectroscopy, and lattice-QCD calculations.

  1. Equal Opportunities Advisory Panel

    HR Department

    2006-01-01

    At its meeting on 7 December 2006, the Standing Concertation Committee took note of the appointment of four new members of the Panel: Wisla Carena, Pierre Charrue, Sue Foffano and Markus Nordberg. The present composition of the Panel (appointed ad personam) is as follows: Tiziano Camporesi (Chairperson), Wisla Carena, Pierre Charrue, Sue Foffano, Josi Schinzel (Equal Opportunities Officer), Markus Nordberg, Christine Petit-Jean-Genaz et Elena Wildner. Human Resources Department Tel. 74480

  2. ERK5 knock down aggravates detrimental effects of hypothermal stimulation on cardiomyocytes via Bim upregulation.

    Wang, Yao-Sheng; Zhou, Jing; Liang, Chun; Hong, Kui; Cheng, Xiao-Shu; Wu, Zong-Gui

    2013-09-01

    Mechanism of cold induced myocardial injury remained unclear. Our study investigated the role of ERK5/Bim pathway in hypothermal stimulation-induced apoptosis or damage of cardiomyocytes (CMs). Results showed that in CMs which under hypothermal stimulation, ERK5 siRNA promoted expression of Bim protein. Bim siRNA did not influence ERK5 expression but attenuated production of p-ERK5. ERK5 siRNA induced higher apoptosis rate; intracellular Ca(2+) overload; ROS activity; ΔΨm damage in hypothermia stimulated CMs, when compared with hypothermal stimulation solely treated group, while Bim siRNA effected oppositely and canceled pro-apoptotic effect of ERK5 siRNA. In conclusion, ERK5 knock down releases inhibition to Bim expression, induces aggravated apoptosis in CMs under hypothermal stimulation, which related to higher intracellular Ca(2+) overload, ROS activity, and more severe ΔΨm damage. Results revealed regulative role of ERK5/Bim pathway in hypothermal stimulation-induced injure or apoptosis of cardiomyocytes.

  3. Schmallenberg virus infection of adult type I interferon receptor knock-out mice.

    Wernike, Kerstin; Breithaupt, Angele; Keller, Markus; Hoffmann, Bernd; Beer, Martin; Eschbaumer, Michael

    2012-01-01

    Schmallenberg virus (SBV), a novel orthobunyavirus, was discovered in Europe in late 2011. It causes mild and transient disease in adult ruminants, but fetal infection can lead to abortion or severe malformations. There is considerable demand for SBV research, but in vivo studies in large animals are complicated by their long gestation periods and the cost of high containment housing. The goal of this study was to investigate whether type I interferon receptor knock-out (IFNAR(-/-)) mice are a suitable small animal model for SBV. Twenty IFNAR(-/-) mice were inoculated with SBV, four were kept as controls. After inoculation, all were observed and weighed daily; two mice per day were sacrificed and blood, brain, lungs, liver, spleen, and intestine were harvested. All but one inoculated mouse lost weight, and two mice died spontaneously at the end of the first week, while another two had to be euthanized. Real-time RT-PCR detected large amounts of SBV RNA in all dead or sick mice; the controls were healthy and PCR-negative. IFNAR(-/-) mice are susceptible to SBV infection and can develop fatal disease, making them a handy and versatile tool for SBV vaccine research.

  4. Histopathological characteristics of a novel knock-in mouse prostate cancer model

    G. Wu

    2006-06-01

    Full Text Available Prostate cancer is relatively unique to man. There is no naturally occurring prostate cancer in the mouse. Pre-clinical studies involve the establishment of a genetically engineered mouse prostate cancer model with features close to those of the human situation. A new knock-in mouse adenocarcinoma prostate (KIMAP model was established, which showed close-to-human kinetics of tumor development. In order to determine if the similar kinetics is associated with heterogeneous tumor architecture similar to the human situation, we utilized a new mouse histological grading system (Gleason analogous grading system similar to the Gleason human grading system and flow cytometry DNA analysis to measure and compare the adenocarcinoma of the KIMAP model with human prostate cancer. Sixty KIMAP prostate cancer samples from 60 mice were measured and compared with human prostate cancer. Flow cytometry DNA analysis was performed on malignant prostate tissues obtained from KIMAP models. Mice with prostate cancer from KIMAP models showed a 53.3% compound histological score rate, which was close to the human clinical average (50% and showed a significant correlation with age (P = 0.001. Flow cytometry analyses demonstrated that most KIMAP tumor tissues were diploid, analogous to the human situation. The similarities of the KIMAP mouse model with tumors of the human prostate suggest the use of this experimental model to complement studies of human prostate cancer.

  5. Knock-in Luciferase Reporter Mice for In Vivo Monitoring of CREB Activity.

    Dmitry Akhmedov

    Full Text Available The cAMP response element binding protein (CREB is induced during fasting in the liver, where it stimulates transcription of rate-limiting gluconeogenic genes to maintain metabolic homeostasis. Adenoviral and transgenic CREB reporters have been used to monitor hepatic CREB activity non-invasively using bioluminescence reporter imaging. However, adenoviral vectors and randomly inserted transgenes have several limitations. To overcome disadvantages of the currently used strategies, we created a ROSA26 knock-in CREB reporter mouse line (ROSA26-CRE-luc. cAMP-inducing ligands stimulate the reporter in primary hepatocytes and myocytes from ROSA26-CRE-luc animals. In vivo, these animals exhibit little hepatic CREB activity in the ad libitum fed state but robust induction after fasting. Strikingly, CREB was markedly stimulated in liver, but not in skeletal muscle, after overnight voluntary wheel-running exercise, uncovering differential regulation of CREB in these tissues under catabolic states. The ROSA26-CRE-luc mouse line is a useful resource to study dynamics of CREB activity longitudinally in vivo and can be used as a source of primary cells for analysis of CREB regulatory pathways ex vivo.

  6. Schmallenberg virus infection of adult type I interferon receptor knock-out mice.

    Kerstin Wernike

    Full Text Available Schmallenberg virus (SBV, a novel orthobunyavirus, was discovered in Europe in late 2011. It causes mild and transient disease in adult ruminants, but fetal infection can lead to abortion or severe malformations. There is considerable demand for SBV research, but in vivo studies in large animals are complicated by their long gestation periods and the cost of high containment housing. The goal of this study was to investigate whether type I interferon receptor knock-out (IFNAR(-/- mice are a suitable small animal model for SBV. Twenty IFNAR(-/- mice were inoculated with SBV, four were kept as controls. After inoculation, all were observed and weighed daily; two mice per day were sacrificed and blood, brain, lungs, liver, spleen, and intestine were harvested. All but one inoculated mouse lost weight, and two mice died spontaneously at the end of the first week, while another two had to be euthanized. Real-time RT-PCR detected large amounts of SBV RNA in all dead or sick mice; the controls were healthy and PCR-negative. IFNAR(-/- mice are susceptible to SBV infection and can develop fatal disease, making them a handy and versatile tool for SBV vaccine research.

  7. LMNA knock-down affects differentiation and progression of human neuroblastoma cells.

    Giovanna Maresca

    Full Text Available BACKGROUND: Neuroblastoma (NB is one of the most aggressive tumors that occur in childhood. Although genes, such as MYCN, have been shown to be involved in the aggressiveness of the disease, the identification of new biological markers is still desirable. The induction of differentiation is one of the strategies used in the treatment of neuroblastoma. A-type lamins are components of the nuclear lamina and are involved in differentiation. We studied the role of Lamin A/C in the differentiation and progression of neuroblastoma. METHODOLOGY/PRINCIPAL FINDINGS: Knock-down of Lamin A/C (LMNA-KD in neuroblastoma cells blocked retinoic acid-induced differentiation, preventing neurites outgrowth and the expression of neural markers. The genome-wide gene-expression profile and the proteomic analysis of LMNA-KD cells confirmed the inhibition of differentiation and demonstrated an increase of aggressiveness-related genes and molecules resulting in augmented migration/invasion, and increasing the drug resistance of the cells. The more aggressive phenotype acquired by LMNA-KD cells was also maintained in vivo after injection into nude mice. A preliminary immunohistochemistry analysis of Lamin A/C expression in nine primary stages human NB indicated that this protein is poorly expressed in most of these cases. CONCLUSIONS/SIGNIFICANCE: We demonstrated for the first time in neuroblastoma cells that Lamin A/C plays a central role in the differentiation, and that the loss of this protein gave rise to a more aggressive tumor phenotype.

  8. Hmga1/Hmga2 double knock-out mice display a “superpygmy” phenotype

    Antonella Federico

    2014-04-01

    Full Text Available The HMGA1 and HMGA2 genes code for proteins belonging to the High Mobility Group A family. Several genes are negatively or positively regulated by both these proteins, but a number of genes are specifically regulated by only one of them. Indeed, knock-out of the Hmga1 and Hmga2 genes leads to different phenotypes: cardiac hypertrophy and type 2 diabetes in the former case, and a large reduction in body size and amount of fat tissue in the latter case. Therefore, to better elucidate the functions of the Hmga genes, we crossed Hmga1-null mice with mice null for Hmga2. The Hmga1−/−/Hmga2−/− mice showed reduced vitality and a very small size (75% smaller than the wild-type mice; they were even smaller than pygmy Hmga2-null mice. The drastic reduction in E2F1 activity, and consequently in the expression of the E2F-dependent genes involved in cell cycle regulation, likely accounts for some phenotypic features of the Hmga1−/−/Hmga2−/− mice.

  9. [Annual "Door Knock" Fundraising Campaign Jubilee--for the patients and against the disease].

    Robinson, Eliezer; Ziv, Miri

    2011-10-01

    Marking the annual "Door Knock" Fundraising Campaign Jubilee, this article provides an overview of the Israel Cancer Association (ICA) activity for patients and against the disease, that comply with the principles of the World Cancer Declaration (WCD) of the UICC (Union for International Cancer Control). To elucidate, as a voluntary organization, all of ICA's resources are derived exclusively from public contributions--with no funding from the government budget. This independence enables ICA to operate according to strictly professional criteria, while maintaining a global and national point of view and vision. ICA activity will be presented with respect to the international treaty, from monitoring the disease at the national level, to activity to promote research, prevention methods, early detection, enhancing treatment modalities and rehabilitation, and maintaining quality of life for patients and survivors. This presentation will also provide an overview of how ICA's initiative, in close collaboration with the Ministry of Health, and the HMO's, white relying on the volunteer activity of members of the ICA professional committees, and that of many other volunteers, leads Israel to significant accomplishments in each one of the treaty sections. These activities have resulted in concrete achievements at the national level, positioning Israel high on the global scale.

  10. Gene replacement in Mycobacterium chelonae: application to the construction of porin knock-out mutants.

    Vinicius Calado Nogueira de Moura

    Full Text Available Mycobacterium chelonae is a rapidly growing mycobacterial opportunistic pathogen closely related to Mycobacterium abscessus that causes cornea, skin and soft tissue infections in humans. Although M. chelonae and the emerging mycobacterial pathogen M. abscessus have long been considered to belong to the same species, these two microorganisms considerably differ in terms of optimum growth temperature, drug susceptibility, pathogenicity and the types of infection they cause. The whole genome sequencing of clinical isolates of M. chelonae and M. abscessus is opening the way to comparative studies aimed at understanding the biology of these pathogens and elucidating the molecular bases of their pathogenicity and biocide resistance. Key to the validation of the numerous hypotheses that this approach will raise, however, is the availability of genetic tools allowing for the expression and targeted mutagenesis of genes in these species. While homologous recombination systems have recently been described for M. abscessus, genetic tools are lacking for M. chelonae. We here show that two different allelic replacement methods, one based on mycobacteriophage-encoded recombinases and the other on a temperature-sensitive plasmid harboring the counterselectable marker sacB, can be used to efficiently disrupt genes in this species. Knock-out mutants for each of the three porin genes of M. chelonae ATCC 35752 were constructed using both methodologies, one of which displays a significantly reduced glucose uptake rate consistent with decreased porin expression.

  11. Mosquito knock-down and adulticidal activities of essential oils by vaporizer, impregnated filter paper and aerosol methods

    M. Ramar

    2014-09-01

    Full Text Available Essential oils from 12 medicinal plants were evaluated by three different bioassay methods (Vaporizer, Filter paper and Aerosol for Knock-down and adulticidal efficacy on the filarial vector mosquito, Culex quinquefasciatus. Based on screening results the effective plants were selected for investigating Knock-down and adulticidal potential against adult female of the laboratory-reared mosquito species, Cx. quinquefasciatus. In vaporizer bioassay method four different doses (1.25, 2.5, 5 and 10% were used. Four different doses (0.625, 1.25, 2.5 and 10% were used both filter paper (cm2 and aerosol (cm3 bioassay methods. Five essential oils (calamus, camphor, citronella, clove and eucalyptus were identified as potential treatments in vaporizer bioassay. The result showed that the knock down time decreased with increased concentration in clove oil treatment; the Knock-down time (KT 50 = 46.1 ± 0.1, 38.5 ± 0.1, 30.7 ± 0.2, and 20.1 ± 0.1 minutes was recorded at 1.25, 2.5, 5 and 10% /cm3 respectively. In filter paper method nine essential oils were identified as potential treatments. After 1 hr exposure period clove oil recorded the lowest median Knock-down time (KT50 which was calculated as 9.15 ± 0.1min/cm2. Followed by citronella (KT50 =11.4 ± 0.1 min and eucalyptus (KT50 =11.4 ±0.1min oils since they recorded lower median Knock-down time. All the twelve essential oils were identified as potential treatments in aerosol activity. The lethal time decreased when the concentration increased. At 5 % concentration the median lethal time (LT50 for clove oil was calculated as (LT50=3.80 ± 0.1minutes. The Cinnamon oil was effective which recorded (LT50 = 1.99 mins as median lethal time. Camphor (LT50 =19.6± 0.1 min oil were found to be less toxic by aerosol method. These results suggest that clove oil and cinnamon oil have the potential to be used as a eco-friendly approach for the control of the major important filaria vector Cx. quinquefasciatus

  12. Funding Opportunity: Genomic Data Centers

    Funding Opportunity CCG, Funding Opportunity Center for Cancer Genomics, CCG, Center for Cancer Genomics, CCG RFA, Center for cancer genomics rfa, genomic data analysis network, genomic data analysis network centers,

  13. Nanotechnology: Opportunities and Challenges

    Meyyappan, Meyya

    2003-01-01

    Nanotechnology seeks to exploit novel physical, chemical, biological, mechanical, electrical, and other properties, which arise primarily due to the nanoscale nature of certain materials. A key example is carbon nanotubes (CNTs) which exhibit unique electrical and extraordinary mechanical properties and offer remarkable potential for revolutionary applications in electronics devices, computing, and data storage technology, sensors, composites, nanoelectromechanical systems (NEMS), and as tip in scanning probe microscopy (SPM) for imaging and nanolithography. Thus the CNT synthesis, characterization, and applications touch upon all disciplines of science and engineering. This presentation will provide an overview and progress report on this and other major research candidates in Nanotechnology and address opportunities and challenges ahead.

  14. Informal Opportunity among SMEs

    Rezaei, Shahamak; Dana, Leo-Paul; Goli, Marco

    2013-01-01

    Based on interviews with (legal and illegal) immigrants to Denmark, meetings with stakeholders and with experts in the field, this article addresses issues regarding the underground economy. Our findings show that, in Denmark, the existence of an underground economy makes it possible for semi......-compliant and non-compliant immigrants to make a living. We suggest that the underground economy in Denmark will continue to provide networks of illegal residents with opportunities for informal economic activities as trust allows entrepreneurs to function below the radar, by owning enterprises registered using...

  15. Creating Innovative Opportunities

    Ljungberg, Daniel; McKelvey, Maureen; Lassen, Astrid Heidemann

    2012-01-01

    to illustrations of the processes, and the 86 case studies in knowledge intensive entrepreneurship in Europe. These case studies were developed during the European Union research project AEGIS (Advancing Knowledge-Intensive Entrepreneurship and Innovation for Economic Growth and Well-being in Europe). The case...... studies do demonstrate how the individual KIE ventures are dependent upon variables and processes in the surrounding innovation systems. The overall analysis of the cases provides insight into how KIE processes link the KIE venture and the innovation system, thereby highlighting e.g. the importance...... of knowledge networks to create innovative opportunities....

  16. Frontier Aerospace Opportunities

    Bushnell, Dennis M.

    2014-01-01

    Discussion and suggested applications of the many ongoing technology opportunities for aerospace products and missions, resulting in often revolutionary capabilities. The, at this point largely unexamined, plethora of possibilities going forward, a subset of which is discussed, could literally reinvent aerospace but requires triage of many possibilities. Such initial upfront homework would lengthen the Research and Development (R&D) time frame but could greatly enhance the affordability and performance of the evolved products and capabilities. Structural nanotubes and exotic energetics along with some unique systems approaches are particularly compelling.

  17. Analytical study to minimize the engine exhaust emissions and safe knock limit of CNG powered four-stroke SI engine

    Jeewan V. Tirkey, H.N. Gupta, S.K. Shukla

    2010-01-01

    Full Text Available In this paper, theoretical analysis has been done to minimise engine emissions and safe knock limit by changing some operational and design parameters such as equivalence ratio, spark plug location, compression ratio, and cylinder diameter by using computer simulation model. For this purpose a zero dimensional knock model, two zone combustion model(one in front and one behind the flame front, and gas dynamic model have been incorporated. Subsequently, the Nitric Oxide exhaust emission concentrations have been predicted by using the rate kinetic model in the power cycle and along the exhaust pipes. Furthermore, Carbon Monoxide is computed under chemical equilibrium condition and then empirical adjustment is made for kinetic behaviours based upon experimental results. It is inferred that the value of cylinder pressure data, BMEP, BSFC obtained by using computer simulation model based on theoretical analysis are in closer agreement with those which are obtained by previous studies.

  18. Knock-down of hypoxia-induced carbonic anhydrases IX and XII radiosensitizes tumor cells by increasing intracellular acidosis

    2013-01-01

    The relationship between acidosis within the tumor microenvironment and radioresistance of hypoxic tumor cells remains unclear. Previously we reported that hypoxia-induced carbonic anhydrases (CA) IX and CAXII constitute a robust intracellular pH (pHi)-regulating system that confers a survival advantage on hypoxic human colon carcinoma LS174Tr cells in acidic microenvironments. Here we investigate the role of acidosis, CAIX and CAXII knock-down in combination with ionizing radiation. Fibrobla...

  19. Opportunity and obligation

    2012-01-01

    As anyone in the press or VIP offices can tell you, CERN is in the spotlight like never before. In the first two months of 2012, we welcomed some 56 VIP visits and 144 media visits on site. Not long ago, those were the kind of numbers we’d have had in six months, and 2012 is not a one-off.   Ever since CERN turned 50 in 2004, our visitor numbers have been growing, and that includes teachers and members of the public as well as VIPs and the media. It’s a sign of the explosion of interest around the world in our science, and to me it means two things. Firstly, it means that I owe everyone at CERN a vote of thanks, since I know that visits impinge on everyone’s time. I can assure you all, however, that it is time well spent. That’s because the second thing it tells me is that growing interest in CERN brings opportunity. Our current visibility gives the particle physics community the opportunity to drive science up the popular and political agendas, and it...

  20. On Mars Exploration Rovers - Spirit and Opportunity

    李颖; 吴文忠

    2004-01-01

    NASA's twin Mars exploration rovers, now named Spirit and Opportunity, are designed to study the history of water on Mars. These robotic geologists are equipped with a robotic arm, a drilling tool, three spectrometers, and four pairs of cameras that allow them to have a human-like, 3D view of the terrain. Each rover could travel as far as 100 meters in one day to act as Mars scientists eyes and hands, exploring an environment where humans can't yet go.

  1. Numerical and Experimental Investigation of Combustion and Knock in a Dual Fuel Gas/Diesel Compression Ignition Engine

    A. Gharehghani

    2012-01-01

    Full Text Available Conventional compression ignition engines can easily be converted to a dual fuel mode of operation using natural gas as main fuel and diesel oil injection as pilot to initiate the combustion. At the same time, it is possible to increase the output power by increasing the diesel oil percentage. A detailed performance and combustion characteristic analysis of a heavy duty diesel engine has been studied in dual fuel mode of operation where natural gas is used as the main fuel and diesel oil as pilot. The influence of intake pressure and temperature on knock occurrence and the effects of initial swirl ratio on heat release rate, temperature-pressure and emission levels have been investigated in this study. It is shown that an increase in the initial swirl ratio lengthens the delay period for auto-ignition and extends the combustion period while it reduces NOx. There is an optimum value of the initial swirl ratio for a certain mixture intake temperature and pressure conditions that can achieve high thermal efficiency and low NOx emissions while decreases the tendency to knock. Simultaneous increase of intake pressure and initial swirl ratio could be the solution to power loss and knock in dual fuel engine.

  2. Knocking out the MFE-2 gene of Candida bombicola leads to improved medium-chain sophorolipid production.

    Van Bogaert, Inge N A; Sabirova, Julia; Develter, Dirk; Soetaert, Wim; Vandamme, Erick J

    2009-06-01

    The nonpathogenic yeast Candida bombicola synthesizes sophorolipids. These biosurfactants are composed of the disaccharide sophorose linked to a long-chain hydroxy fatty acid and have potential applications in the food, pharmaceutical, cosmetic and cleaning industries. In order to expand the range of application, a shift of the fatty acid moiety towards medium-chain lengths would be recommendable. However, the synthesis of medium-chain sophorolipids by C. bombicola is a challenging objective. First of all, these sophorolipids can only be obtained by fermentations on unconventional carbon sources, which often have a toxic effect on the cells. Furthermore, medium-chain substrates are partially metabolized in the beta-oxidation pathway. In order to redirect unconventional substrates towards sophorolipid synthesis, the beta-oxidation pathway was blocked on the genome level by knocking out the multifunctional enzyme type 2 (MFE-2) gene. The total gene sequence of the C. bombicola MFE-2 (6033 bp) was cloned (GenBank accession number EU371724), and the obtained nucleotide sequence was used to construct a knock-out cassette. Several knock-out mutants with the correct geno- and phenotype were evaluated in a fermentation on 1-dodecanol. All mutants showed a 1.7-2.9 times higher production of sophorolipids, indicating that in those strains the substrate is redirected towards the sophorolipid synthesis.

  3. Eléments d'analyse du cliquetis et de ses effets Elements for Analyzing Knocking and Its Effects

    Douaud A.

    2006-11-01

    Full Text Available On présente dans cet article une synthèse des travaux théoriques et expérimentaux relatifs à la génération du cliquetis et à ses effets sur le fonctionnement du moteur. L'apparition du cliquetis est décrite par un mécanisme global de délai d'auto-inflammation. Des exemples d'application portant sur l'identification du délai de carburants quelconques et sur l'optimisation de l'ensemble moteurs-carburants documentent cette approche. Le cliquetis a pour conséquence un accroissement de sollicitations mécaniques et thermiques des parois de la chambre de combustion. Des méthodes et résultats d'investigation de ces phénomènes sont présentés. A synthesis is presented of theoretical and experimental research concerning the generating of knocking and its effects on engine running. The appearance of knocking is described by an overall mechanism of autoignition delay. This approach is documented by applied examples concerning the identification of the delay involved with any type of fuel and the optimizing of engine-fuel systems. Knocking causes an increase in mechanical and thermal stresses on combustion-chamber walls. Investigational methods and results concerning these phenomena are described.

  4. Knock-out of nexilin in mice leads to dilated cardiomyopathy and endomyocardial fibroelastosis.

    Aherrahrou, Zouhair; Schlossarek, Saskia; Stoelting, Stephanie; Klinger, Matthias; Geertz, Birgit; Weinberger, Florian; Kessler, Thorsten; Aherrahrou, Redouane; Moreth, Kristin; Bekeredjian, Raffi; Hrabě de Angelis, Martin; Just, Steffen; Rottbauer, Wolfgang; Eschenhagen, Thomas; Schunkert, Heribert; Carrier, Lucie; Erdmann, Jeanette

    2016-01-01

    Cardiomyopathy is one of the most common causes of chronic heart failure worldwide. Mutations in the gene encoding nexilin (NEXN) occur in patients with both hypertrophic and dilated cardiomyopathy (DCM); however, little is known about the pathophysiological mechanisms and relevance of NEXN to these disorders. Here, we evaluated the functional role of NEXN using a constitutive Nexn knock-out (KO) mouse model. Heterozygous (Het) mice were inter-crossed to produce wild-type (WT), Het, and homozygous KO mice. At birth, 32, 46, and 22 % of the mice were WT, Het, and KO, respectively, which is close to the expected Mendelian ratio. After postnatal day 6, the survival of the Nexn KO mice decreased dramatically and all of the animals died by day 8. Phenotypic characterizations of the WT and KO mice were performed at postnatal days 1, 2, 4, and 6. At birth, the relative heart weights of the WT and KO mice were similar; however, at day 4, the relative heart weight of the KO group was 2.3-fold higher than of the WT group. In addition, the KO mice developed rapidly progressive cardiomyopathy with left ventricular dilation and wall thinning and decreased cardiac function. At day 6, the KO mice developed a fulminant DCM phenotype characterized by dilated ventricular chambers and systolic dysfunction. At this stage, collagen deposits and some elastin deposits were observed within the left ventricle cavity, which resembles the features of endomyocardial fibroelastosis (EFE). Overall, these results further emphasize the role of NEXN in DCM and suggest a novel role in EFE.

  5. Relevant Feature Set Estimation with a Knock-out Strategy and Random Forests

    Ganz, Melanie; Greve, Douglas N.; Fischl, Bruce; Konukoglu, Ender

    2015-01-01

    Group analysis of neuroimaging data is a vital tool for identifying anatomical and functional variations related to diseases as well as normal biological processes. The analyses are often performed on a large number of highly correlated measurements using a relatively smaller number of samples. Despite the correlation structure, the most widely used approach is to analyze the data using univariate methods followed by post-hoc corrections that try to account for the data’s multivariate nature. Although widely used, this approach may fail to recover from the adverse effects of the initial analysis when local effects are not strong. Multivariate pattern analysis (MVPA) is a powerful alternative to the univariate approach for identifying relevant variations. Jointly analyzing all the measures, MVPA techniques can detect global effects even when individual local effects are too weak to detect with univariate analysis. Current approaches are successful in identifying variations that yield highly predictive and compact models. However, they suffer from lessened sensitivity and instabilities in identification of relevant variations. Furthermore, current methods’ user-defined parameters are often unintuitive and difficult to determine. In this article, we propose a novel MVPA method for group analysis of high-dimensional data that overcomes the drawbacks of the current techniques. Our approach explicitly aims to identify all relevant variations using a “knock-out” strategy and the Random Forest algorithm. In evaluations with synthetic datasets the proposed method achieved substantially higher sensitivity and accuracy than the state-of-the-art MVPA methods, and outperformed the univariate approach when the effect size is low. In experiments with real datasets the proposed method identified regions beyond the univariate approach, while other MVPA methods failed to replicate the univariate results. More importantly, in a reproducibility study with the well-known ADNI

  6. Prevention of elastase-induced emphysema in placenta growth factor knock-out mice

    Tsao Po

    2009-11-01

    Full Text Available Abstract Background Although both animal and human studies suggested the association between placenta growth factor (PlGF and chronic obstructive pulmonary disease (COPD, especially lung emphysema, the role of PlGF in the pathogenesis of emphysema remains to be clarified. This study hypothesizes that blocking PlGF prevents the development of emphysema. Methods Pulmonary emphysema was induced in PlGF knock-out (KO and wild type (WT mice by intra-tracheal instillation of porcine pancreatic elastase (PPE. A group of KO mice was then treated with exogenous PlGF and WT mice with neutralizing anti-VEGFR1 antibody. Tumor necrosis factor alpha (TNF-α, matrix metalloproteinase-9 (MMP-9, and VEGF were quantified. Apoptosis measurement and immuno-histochemical staining for VEGF R1 and R2 were performed in emphysematous lung tissues. Results After 4 weeks of PPE instillation, lung airspaces enlarged more significantly in WT than in KO mice. The levels of TNF-α and MMP-9, but not VEGF, increased in the lungs of WT compared with those of KO mice. There was also increased in apoptosis of alveolar septal cells in WT mice. Instillation of exogenous PlGF in KO mice restored the emphysematous changes. The expression of both VEGF R1 and R2 decreased in the emphysematous lungs. Conclusion In this animal model, pulmonary emphysema is prevented by depleting PlGF. When exogenous PlGF is administered to PlGF KO mice, emphysema re-develops, implying that PlGF contributes to the pathogenesis of emphysema.

  7. Suppression of tumorigenesis in mitochondrial NADP(+)-dependent isocitrate dehydrogenase knock-out mice.

    Kim, Seontae; Kim, Sung Youl; Ku, Hyeong Jun; Jeon, Yong Hyun; Lee, Ho Won; Lee, Jaetae; Kwon, Taeg Kyu; Park, Kwon Moo; Park, Jeen-Woo

    2014-02-01

    The tumor host microenvironment is increasingly viewed as an important contributor to tumor growth and suppression. Cellular oxidative stress resulting from high levels of reactive oxygen species (ROS) contributes to various processes involved in the development and progress of malignant tumors including carcinogenesis, aberrant growth, metastasis, and angiogenesis. In this regard, the stroma induces oxidative stress in adjacent tumor cells, and this in turn causes several changes in tumor cells including modulation of the redox status, inhibition of cell proliferation, and induction of apoptotic or necrotic cell death. Because the levels of ROS are determined by a balance between ROS generation and ROS detoxification, disruption of this system will result in increased or decreased ROS level. Recently, we demonstrated that the control of mitochondrial redox balance and cellular defense against oxidative damage is one of the primary functions of mitochondrial NADP(+)-dependent isocitrate dehydrogenase (IDH2) that supplies NADPH for antioxidant systems. To explore the interactions between tumor cells and the host, we evaluated tumorigenesis between IDH2-deficient (knock-out) and wild-type mice in which B16F10 melanoma cells had been implanted. Suppression of B16F10 cell tumorigenesis was reproducibly observed in the IDH2-deficient mice along with significant elevation of oxidative stress in both the tumor and the stroma. In addition, the expression of angiogenesis markers was significantly down-regulated in both the tumor and the stroma of the IDH2-deficient mice. These results support the hypothesis that redox status-associated changes in the host environment of tumor-bearing mice may contribute to cancer progression.

  8. Generation of an estrogen receptor beta-iCre knock-in mouse.

    Cacioppo, Joseph A; Koo, Yongbum; Lin, Po-Ching Patrick; Osmulski, Sarah A; Ko, Chunjoo D; Ko, CheMyong

    2016-01-01

    A novel knock-in mouse that expresses codon-improved Cre recombinase (iCre) under regulation of the estrogen receptor beta (Esr2) promoter was developed for conditional deletion of genes and for the spatial and/or temporal localization of Esr2 expression. ESR2 is one of two classical nuclear estrogen receptors and displays a spatiotemporal expression pattern and functions that are different from the other estrogen receptor, ESR1. A cassette was constructed that contained iCre, a polyadenylation sequence, and a neomycin selection marker. This construct was used to insert iCre in front of the endogenous start codon of the Esr2 gene of a C57BL/6J embryonic stem cell line via homologous recombination. Resulting Esr2-iCre mice were bred with ROSA26-lacZ and Ai9-RFP reporter mice to visualize cells of functional iCre expression. Strong expression was observed in the ovary, the pituitary, the interstitium of the testes, the head and tail but not body of the epididymis, skeletal muscle, the coagulation gland (anterior prostate), the lung, and the preputial gland. Additional diffuse or patchy expression was observed in the cerebrum, the hypothalamus, the heart, the adrenal gland, the colon, the bladder, and the pads of the paws. Overall, Esr2-iCre mice will serve as a novel line for conditionally ablating genes in Esr2-expressing tissues, identifying novel Esr2-expressing cells, and differentiating the functions of ESR2 and ESR1.

  9. Knock down Os1bglu1 β-glucosidase in rice by Agrobacterium-mediated transformation

    Mariena Ketudat-Cairns

    2011-02-01

    Full Text Available This research attempted to study the function of Os1bglu1 by RNAi technique. The suppression of Os1bglu1genewas done using the 3’UTR region. The target gene fragment was cloned into the pHELLSGATE8 vector. The high percentagesof effective callus induction of 93% were obtained when the seeds were cultured on N6D medium for 4-6 weeks at 28°C. Thesuitable transformation conditions were to incubate the calli with Agrobacterium (OD 600 = 0.02 and blot dry to remove excessbacteria cells, then transferred to co-cultivation medium (pH 5.2 with 200 M acetosyringone and incubate for three days at25°C. The 20% transformation efficiency was obtained from the transformed calli with control plasmid, while transformationefficiency of only 15% was obtained from pHELLSGATE8 Os1bglu1 constructs. The transformed calli with control constructshowed higher growth rate than the transformed calli with pHELLSGATE8 Os1bglu1construct. The expression of Os1bglu1mRNA was not found in the transformed calli and siRNAs were found in the transformed calli. However no siRNAs weredetected in the control transformed calli. The regeneration efficiencies of 6% were obtained from only the calli transformedwith the control construct. The calli transformed with the knock down Os1bglu1 constructs were not able to regenerate. This may indicated that Os1bglu1 is involved in regeneration of rice from callus tissue.

  10. N-cadherin knock-down decreases invasiveness of esophageal squamous cell carcinoma in vitro

    Ke Li; Wei He; Na Lin; Xin Wang; Qing-Xia Fan

    2009-01-01

    AIM: To examine the expressions of N-cadherin and E-cadherin in specimens of 62 normal esophageal epithela, 31 adjacent atypical hyperplastic epithelia and 62 esophageal squamous cell carcinomas (ESCCs), and to investigate the roles of N-cadherin in the invasiveness of ESCC cell line EC9706 transfected by N-cadherin shRNA. METHODS: PV immunohistochemistry was used to detect the expression pattern of N-cadherin and E-cadherin in specimens of 62 normal esophageal epithelia, 31 adjacent atypical hyperplastic epithelia and 62 ESCCs. The invasiveness of ESCC line EC9706 was determined by transwell assay after EC9706 was transfected by N-cadherin shRNA. RESULTS: The positive rates of N-cadherin decreased in the carcinoma, adjacent atypical hyperplastic and normal esophageal tissues (75.8%, 61.3% and 29.0%, P < 0.05), respectively, while those of E-cadherin increased (40.3%, 71.0% and 95.2%, P < 0.05). The increased expression of N-cadherin and decreased expression of E-cadherin were related to invasion, differentiation, and lymph node metastasis ( P < 0.05). The expression level of N-cadherin decreased in the N-cadherin knocked down cells, and the invasiveness of those cells decreased significantly as well. The number of cells which crossed the basement membrane filter 0.05). CONCLUSION: E-cadherin and N-cadherin expression is correlated with the invasion and aggravation of ESCC. The down-regulation of N-cadherin lowers the invasiveness of EC9706 cell line.

  11. Comprehensive behavioral and molecular characterization of a new knock-in mouse model of Huntington's disease: zQ175.

    Liliana B Menalled

    Full Text Available Huntington's disease (HD is an autosomal dominant neurodegenerative disorder characterized by motor, cognitive and psychiatric manifestations. Since the mutation responsible for the disease was identified as an unstable expansion of CAG repeats in the gene encoding the huntingtin protein in 1993, numerous mouse models of HD have been generated to study disease pathogenesis and evaluate potential therapeutic approaches. Of these, knock-in models best mimic the human condition from a genetic perspective since they express the mutation in the appropriate genetic and protein context. Behaviorally, however, while some abnormal phenotypes have been detected in knock-in mouse models, a model with an earlier and more robust phenotype than the existing models is required. We describe here for the first time a new mouse line, the zQ175 knock-in mouse, derived from a spontaneous expansion of the CAG copy number in our CAG 140 knock-in colony [1]. Given the inverse relationship typically observed between age of HD onset and length of CAG repeat, since this new mouse line carries a significantly higher CAG repeat length it was expected to be more significantly impaired than the parent line. Using a battery of behavioral tests we evaluated both heterozygous and homozygous zQ175 mice. Homozygous mice showed motor and grip strength abnormalities with an early onset (8 and 4 weeks of age, respectively, which were followed by deficits in rotarod and climbing activity at 30 weeks of age and by cognitive deficits at around 1 year of age. Of particular interest for translational work, we also found clear behavioral deficits in heterozygous mice from around 4.5 months of age, especially in the dark phase of the diurnal cycle. Decreased body weight was observed in both heterozygotes and homozygotes, along with significantly reduced survival in the homozygotes. In addition, we detected an early and significant decrease of striatal gene markers from 12 weeks of age

  12. Generating innovation opportunities:

    Kallio, Anne; Bergenholtz, Carsten

    2011-01-01

    This study examines how a company can generate innovation opportunities by exploring and absorbing customer knowledge. The exploration can be performed via an in-depth or broad search for resources beyond organisational boundaries. Salespeople are an essential channel for an in-depth search...... in relation to customers, since salespeople possess rich knowledge of the customers. In order to be useful, such knowledge has to be absorbed in the company. Most of the literature on absorptive capacity has focused on R&D, while less focus has been placed on studying the role of individuals...... in the development of integrative practices. This paper demonstrates how a community of practice can enable organisations to move from potential absorptive capacity to realised absorptive capacity....

  13. Opportunities within ASTERICS

    van der Meer, Rob; Cimò, Giuseppe

    2016-04-01

    ASTERICS, The Astronomy ESFRI and Research Infrastructure Cluster project, brings together astronomers and astroparticle physicists of 22 institutes in Europe to help Europe's world-leading observatories work together to find common solutions to their Big Data challenges, their interoperability and scheduling, and their data access, searching for cross-cutting solutions with mutual and wide-ranging benefit to all concerned. ASTERICS is a four year project, funded through the European Union's Horizon 2020 Framework Programme. The facilities supported by ASTERICS include SKA, CTA, KM3NeT, E-ELT. ASTERICS aims to open up multi messenger astronomy to all scientists and the public through the Virtual Observatory and the citizen science work. I will draw a picture of the landscape in which ASTERICS operates and the possible interaction with the Very Large Volume Neutrino Telescope community. Attention will be given to emerging opportunities for the Neutrino community and how these can be recognised or created.

  14. Access to Education and Employment Opportunities: Implications for Poverty Reduction

    Adewale, T. M.

    2011-01-01

    The study examined the linkages between Education and poverty and the possibility of poverty reduction through access to education and better employment opportunities. The paper also stressed that poverty acts as both cause and effect on lack of education. In particular the paper examined whether education is contributing to poverty reduction…

  15. Healthcare.gov: Opportunity out of Disaster. Teaching Case

    Cundiff, Jacob; McCallum, Taylor; Rich, Andrew; Truax, Michael; Ward, Tamara; Havelka, Douglas

    2015-01-01

    The launch of HealthCare.gov, the website of the Affordable Care Act (AKA Obamacare), was a major public relations disaster for the Obama administration. This case examines some of the factors that contributed to the failure of the launch and then details how Optum, an information technology service provider, considered the opportunity provided by…

  16. Using strategic foresight to assess conservation opportunity.

    Cook, Carly N; Wintle, Bonnie C; Aldrich, Stephen C; Wintle, Brendan A

    2014-12-01

    The nature of conservation challenges can foster a reactive, rather than proactive approach to decision making. Failure to anticipate problems before they escalate results in the need for more costly and time-consuming solutions. Proactive conservation requires forward-looking approaches to decision making that consider possible futures without being overly constrained by the past. Strategic foresight provides a structured process for considering the most desirable future and for mapping the most efficient and effective approaches to promoting that future with tools that facilitate creative thinking. The process involves 6 steps: setting the scope, collecting inputs, analyzing signals, interpreting the information, determining how to act, and implementing the outcomes. Strategic foresight is ideal for seeking, recognizing, and realizing conservation opportunities because it explicitly encourages a broad-minded, forward-looking perspective on an issue. Despite its potential value, the foresight process is rarely used to address conservation issues, and previous attempts have generally failed to influence policy. We present the strategic foresight process as it can be used for proactive conservation planning, describing some of the key tools in the foresight tool kit and how they can be used to identify and exploit different types of conservation opportunities. Scanning is an important tool for collecting and organizing diverse streams of information and can be used to recognize new opportunities and those that could be created. Scenario planning explores how current trends, drivers of change, and key uncertainties might influence the future and can be used to identify barriers to opportunities. Backcasting is used to map out a path to a goal and can determine how to remove barriers to opportunities. We highlight how the foresight process was used to identify conservation opportunities during the development of a strategic plan to address climate change in New York

  17. Effect of dihydrofolate reductase gene knock-down on the expression of heart and neural crest derivatives expressed transcript 2 in zebrafish cardiac development

    SUN Shu-na; GUI Yong-hao; WANG Yue-xiang; QIAN Lin-xi; JIANG Qiu; LIU Dong; SONG Hou-yan

    2007-01-01

    Background Folic acid is very important for embryonic development and dihydrofolate reductase is one of the key enzymes in the process of folic acid performing its biological function. Therefore, the dysfunction of dihydrofolate reductase can inhibit the function of folic acid and finally cause the developmental malformations. In this study, we observed the abnormal cardiac phenotypes in dihydrofolate reductase (DHFR) gene knock-down zebrafish embryos,investigated the effect of DHFR on the expression of heart and neural crest derivatives expressed transcript 2 (HAND2)and explored the possible mechanism of DHFR knock-down inducing zebrafish cardiac malformations.Methods Morpholino oligonucleotides were microinjected into fertilized eggs to knock down the functions of DHFR or HAND2. Full length of HAND2 mRNA which was transcribed in vitro was microinjected into fertilized eggs to overexpress HAND2. The cardiac morphologies, the heart rates and the ventricular shortening fraction were observed and recorded under the microscope at 48 hours post fertilization. Whole-mount in situ hybridization and real-time PCR were performed to detect HAND2 expression.Results DHFR or HAND2 knock-down caused the cardiac malformation in zebrafish. The expression of HAND2 was obviously reduced in DHFR knock-down embryos (P<0.05). Microinjecting HAND2 mRNA into fertilized eggs can induce HAND2 overexpression. HAND2 overexpression rescued the cardiac malformation phenotypes of DHFR knock-down embryos.Conclusions DHFR plays a crucial role in cardiac development. The down-regulation of HAND2 caused by DHFR knock-down is the possible mechanism of DHFR knock-down inducing the cardiac malformation.

  18. The knock-down of the expression of MdMLO19 reduces susceptibility to powdery mildew (Podosphaera leucotricha) in apple (Malus domestica).

    Pessina, Stefano; Angeli, Dario; Martens, Stefan; Visser, Richard G F; Bai, Yuling; Salamini, Francesco; Velasco, Riccardo; Schouten, Henk J; Malnoy, Mickael

    2016-10-01

    Varieties resistant to powdery mildew (PM; caused by Podosphaera leucotricha) are a major component of sustainable apple production. Resistance can be achieved by knocking-out susceptibility S-genes to be singled out among members of the MLO (Mildew Locus O) gene family. Candidates are MLO S-genes of phylogenetic clade V up-regulated upon PM inoculation, such as MdMLO11 and 19 (clade V) and MdMLO18 (clade VII). We report the knock-down through RNA interference of MdMLO11 and 19, as well as the complementation of resistance with MdMLO18 in the Arabidopsis thaliana triple mlo mutant Atmlo2/6/12. The knock-down of MdMLO19 reduced PM disease severity by 75%, whereas the knock-down of MdMLO11, alone or in combination with MdMLO19, did not result in any reduction or additional reduction of susceptibility compared with MdMLO19 alone. The test in A. thaliana excluded a role for MdMLO18 in PM susceptibility. Cell wall appositions (papillae) were present in both PM-resistant and PM-susceptible plants, but were larger in resistant lines. No obvious negative phenotype was observed in plants with mlo genes knocked down. Apparently, MdMLO19 plays the pivotal role in apple PM susceptibility and its knock-down induces a very significant level of resistance.

  19. A Leadership Journey: Personal Reflections from the School of Hard Knocks

    R. Scott Pochron

    2009-12-01

    Full Text Available The following paper chronicles the evolution of the author’s thinking onleadership through the course of his work experience. Leadership is viewed as adynamical process involving both formal and informal roles. The process is initiated asan individual identifies opportunities and feels pulled to respond to emerging patterns andinitiate action to enable positive change. The dynamics between formal and informalleadership structures and leadership as a state of mind are discussed.

  20. Learning Opportunities (Editorial

    Denise Koufogiannakis

    2009-12-01

    Full Text Available We’ve reached the end of another year of publication at EBLIP, my first at the helm as Editor‐in‐Chief, and four full years of publication since we began. This year was a busy one with several changes to the editorial team, the addition of more Editorial Advisors, and new evidence summary writers joining our team. Most importantly, the journal continues to grow and thrive, with more people than ever participating in its success. This year we added a new section called Using Evidence in Practice, and in this issue there are two articles in that section which provide practical examples of applying evidence in the workplace. Putting evidence into practice is what EBLIP is all about, so it is my hope that this new section makes the application of evidence based practice more concrete for readers. As we began working on issue 4.4, the Editorial Team decided that it would be a good idea to seek out an Editorial Intern to help with some of the tasks we never seem to get to, given that we are all volunteers. We see the internship as an opportunity to give a library and information studies student a chance to get involved with an open access journal and learn about publishing in library and information studies, which will hopefully benefit them as they begin their new career. The Editorial Intern will assist with marketing and promotion of the journal, soliciting potential manuscripts, and proofreading. They will also participate in all editorial meetings and general discussions. We anticipate that they will bring a wealth of enthusiasm and fresh ideas to our conversations so that EBLIP Editors can also continue to learn and grow by having a fresh set of eyes involved with our processes. It will certainly be a win‐win situation and a learning opportunity for all involved. We are pleased to announce that Andrea Baer has accepted the position of Editorial Intern and joined our team in mid‐November. Andrea is currently attending the University of

  1. AAV-mediated knock-down of HRC exacerbates transverse aorta constriction-induced heart failure.

    Chang Sik Park

    Full Text Available Histidine-rich calcium binding protein (HRC is located in the lumen of sarcoplasmic reticulum (SR that binds to both triadin (TRN and SERCA affecting Ca(2+ cycling in the SR. Chronic overexpression of HRC that may disrupt intracellular Ca(2+ homeostasis is implicated in pathogenesis of cardiac hypertrophy. Ablation of HRC showed relatively normal phenotypes under basal condition, but exhibited a significantly increased susceptibility to isoproterenol-induced cardiac hypertrophy. In the present study, we characterized the functions of HRC related to Ca(2+ cycling and pathogenesis of cardiac hypertrophy using the in vitro siRNA- and the in vivo adeno-associated virus (AAV-mediated HRC knock-down (KD systems, respectively.AAV-mediated HRC-KD system was used with or without C57BL/6 mouse model of transverse aortic constriction-induced failing heart (TAC-FH to examine whether HRC-KD could enhance cardiac function in failing heart (FH. Initially we expected that HRC-KD could elicit cardiac functional recovery in failing heart (FH, since predesigned siRNA-mediated HRC-KD enhanced Ca(2+ cycling and increased activities of RyR2 and SERCA2 without change in SR Ca(2+ load in neonatal rat ventricular cells (NRVCs and HL-1 cells. However, AAV9-mediated HRC-KD in TAC-FH was associated with decreased fractional shortening and increased cardiac fibrosis compared with control. We found that phospho-RyR2, phospho-CaMKII, phospho-p38 MAPK, and phospho-PLB were significantly upregulated by HRC-KD in TAC-FH. A significantly increased level of cleaved caspase-3, a cardiac cell death marker was also found, consistent with the result of TUNEL assay.Increased Ca(2+ leak and cytosolic Ca(2+ concentration due to a partial KD of HRC could enhance activity of CaMKII and phosphorylation of p38 MAPK, causing the mitochondrial death pathway observed in TAC-FH. Our results present evidence that down-regulation of HRC could deteriorate cardiac function in TAC-FH through

  2. Arc of opportunity.

    Delaney, Adam Vai

    2011-07-01

    Born in Port Moresby, Papua New Guinea, the author had a 20 year career in diplomacy, political affairs, and development policy analysis at the Pacific Islands Forum, the United Nations in New York; the Prime Minister's Department in Papua New Guinea (PNG) and in the Foreign Ministry of PNG. He has also been involved in theatre for over a decade in PNG, and participated in a three-month program at the Eugene O'Neill Theatre Center in Connecticut, USA. He is currently the Business Development Manager at the Torres Strait Regional Authority (Commonwealth) on Thursday Island. Since 1975 the Australian government's overseas development policy has supported various sectoral programs in its neighbouring countries, in particular Papua New Guinea and the Solomon Islands. The "creative" field has not been prominent in this strategy. While natural resources and the sports sectors have gained much greater attention, in terms of being viable international commercial enterprises, the arts, have remained stagnant. In this paper the need for joint programs genuinely supporting "wellbeing" and promoting social enterprise throughout the "arc of opportunity" is described to harness Melanesian creativity to compete successfully in world-markets, starting with penetration of the largest economy at its door-step: Australia.

  3. Spark ignition engine performance and emissions in a high compression engine using biogas and methane mixtures without knock occurrence

    Gómez Montoya Juan Pablo

    2015-01-01

    Full Text Available With the purpose to use biogas in an internal combustion engine with high compression ratio and in order to get a high output thermal efficiency, this investigation used a diesel engine with a maximum output power 8.5 kW, which was converted to spark ignition mode to use it with gaseous fuels. Three fuels were used: Simulated biogas, biogas enriched with 25% and 50% methane by volume. After conversion, the output power of the engine decreased by 17.64% when using only biogas, where 7 kW was the new maximum output power of the engine. The compression ratio was kept at 15.5:1, and knocking did not occur during engine operation. Output thermal efficiency operating the engine in SI mode with biogas enriched with 50% methane was almost the same compared with the engine running in diesel-biogas dual mode at full load and was greater at part loads. The dependence of the diesel pilot was eliminated when biogas was used in the engine converted in SI mode. The optimum condition of experiment for the engine without knocking was using biogas enriched with 50% methane, with 12 degrees of spark timing advance and equivalence ratio of 0.95, larger output powers and higher values of methane concentration lead the engine to knock operation. The presence of CO2 allows operating engines at high compression ratios with normal combustion conditions. Emissions of nitrogen oxides, carbon monoxide and unburnt methane all in g/kWh decreased when the biogas was enriched with 50% methane.

  4. A method for stable gene knock-down by RNA interference in larvae of the salmon louse (Lepeophtheirus salmonis).

    Eichner, Christiane; Nilsen, Frank; Grotmol, Sindre; Dalvin, Sussie

    2014-05-01

    The salmon louse (Lepeophtheirus salmonis), an ectoparasitic copepod of salmonid fish, is a major threat to aquaculture in Norway, Ireland, Scotland and Canada. Due to rise in resistance against existing pesticides, development of novel drugs or vaccines is necessary. Posttranscriptional gene silencing by RNA interference (RNAi), when established in a high throughput system is a potential method for evaluation of molecular targets for new medical compounds or vaccine antigens. Successful use of RNAi has been reported in several stages of salmon lice. However, when we employed a previously described protocol for planktonic stages, no reproducible down-regulation of target genes was gained. In the present study, we describe a robust method for RNAi, where nauplius larvae are soaked in seawater added double stranded RNA (dsRNA). In order to test for when dsRNA may be introduced, and for the efficacy and duration of RNAi, we performed a series of experiments on accurately age determined larvae, ranging from the hatching egg to the copepodid with a salmon louse coatomer and a putative prostaglandin E synthase gene. Presumptive knock-down was monitored by real time PCR. Significant gene silencing was obtained only when nauplius I larvae were exposed to dsRNA during the period in which they molted to nauplius II. A knock down effect could be detected 2days after soaking, and it remained stable until the last measurement, on day 12. Soaking nauplius I larvae, knock-down was verified for six additional genes with a putative role in molting. For one chitinase, a loss-of-function phenotype with abnormal swimming was obtained. Hence, RNAi, induced in the nauplius, may facilitate studies of the molecular biology of the louse, such as the function of specific genes in developmental processes and physiology, host recognition, host-parasite interaction, and, in extension, the engineering of novel medicines.

  5. DIGITAL PAKISTAN: OPPORTUNITIES & CHALLENGES

    Ghulam Muhammad Kundi

    2008-12-01

    Full Text Available ABSTRACT IT has revolutionized the social and organizational life around the globe. Given the newness of IT as a technology, there is a lot of potential that needs to be explored. It is however, argued that as IT can revolutionize the economic development, by the same coin, although its mismanagement in adoption process can end up in problems or even straight failure of the technology at the business-end. This study was conducted with reference to opportunities and challenges in the IT adoption process in Pakistan. The aim of the study was to point out the barriers that are impeding the country’s computerization process in order to provide facts to the policy makers for smooth computerization. The primary data collected through structured questionnaires was analyzed and tested through correlation, regressions analysis and t-test. Out of 10 hypotheses, 3 were accepted while in the rest null hypotheses were not substantiated. Based on primary and secondary data analysis this study has found that all independent bureaucratic, political, education and social and cultural variables are mutually correlated and have significant impact on shaping and reshaping of IT in Pakistan, while the Pakistan IT policy is inconsistent, administrative machinery attitude is negative and non cooperative, procedures are cumbersome and implementation is weak and ineffective, not to mention the lack of IT knowledge on the bureaucratic side. The political environment is instable and law and order is worse which is discouraging the investment. Moreover, physical and legal infrastructure is insufficient and the country is lacking good quality IT professionals. IT organization alignment is another serious issue in Pakistan. However, government incentives and growing interest from the private sector indicate positive attitude towards computerization of the country.

  6. DIGITAL PAKISTAN: OPPORTUNITIES & CHALLENGES

    Ghulam Muhammad Kundi

    2008-10-01

    Full Text Available IT has revolutionized the social and organizational life around the globe. Given the newness of IT as a technology, there is a lot of potential that needs to be explored. It is however, argued that as IT can revolutionize the economic development, by the same coin, although its mismanagement in adoption process can end up in problems or even straight failure of the technology at the business-end. This study was conducted with reference to opportunities and challenges in the IT adoption process in Pakistan. The aim of the study was to point out the barriers that are impeding the country’s computerization process in order to provide facts to the policy makers for smooth computerization. The primary data collected through structured questionnaires was analyzed and tested through correlation, regressions analysis and t-test. Out of 10 hypotheses, 3 were accepted while in the rest null hypotheses were not substantiated. Based on primary and secondary data analysis this study has found that all independent bureaucratic, political, education and social and cultural variables are mutually correlated and have significant impact on shaping and reshaping of IT in Pakistan, while the Pakistan IT policy is inconsistent, administrative machinery attitude is negative and non cooperative, procedures are cumbersome and implementation is weak and ineffective, not to mention the lack of IT knowledge on the bureaucratic side. The political environment is instable and law and order is worse which is discouraging the investment. Moreover, physical and legal infrastructure is insufficient and the country is lacking good quality IT professionals. IT organization alignment is another serious issue in Pakistan. However, government incentives and growing interest from the private sector indicate positive attitude towards computerization of the country.

  7. Adult Learning Opportunities in Nepal

    Regmi, Krishna; Regmi, Sharada

    2008-01-01

    This paper presents the initial findings from a study of education system in Nepal. This paper examines the adult learning opportunities within the educational and cultural contexts by reviewing available literature relevant to Nepal. Findings show that there are wider opportunities for adult learning than those considered from education and…

  8. Oilseeds business opportunities in Ethiopia

    Wijnands, J.H.M.; Biersteker, J.; Hiel, R.

    2007-01-01

    In this study the business opportunities for Dutch companies in the Ethiopian oilseeds sector are explored. Opportunities for setting up sustainable export chains should mutually benefit Dutch companies as well as the Ethiopian oilseeds sector in particular and the Ethiopian society in general.

  9. Generating knock-in parasites: integration of an ornithine decarboxylase transgene into its chromosomal locus in Leishmania donovani.

    Roberts, Sigrid C; Kline, Chelsey; Liu, Wei; Ullman, Buddy

    2011-06-01

    Leishmania null mutants created by targeted gene replacement are typically complemented with chimeric episomes harboring the replaced gene in order to validate that the observed phenotype is due to the specific gene deletion. However, the current inventory of available episomes for complementation of genetic lesions in Leishmania is unstable in the absence of drug selection, and levels of gene expression cannot be controlled, especially in vivo. To circumvent this impediment, a strategy to re-introduce the targeted gene into the original chromosomal locus to generate "knock-in" parasites within selectable null backgrounds has been developed. A genomic fragment encompassing the ornithine decarboxylase locus and lacking heterologous DNA sequences was transfected into ornithine decarboxylase-deficient Leishmania donovani. The construct randomly integrated into either chromosomal allele by homologous recombination restoring polyamine prototrophy and revealing that LdODC was functionally expressed in the knock-in clones. This strategy offers a mechanism for complementing a genetic lesion amenable to positive selection in a manner that facilitates stable gene expression from its original locus in the absence of continuous drug pressure.

  10. Knocking out Bcsas1 in Botrytis cinerea impacts growth, development, and secretion of extracellular proteins, which decreases virulence.

    Zhang, Zhanquan; Qin, Guozheng; Li, Boqiang; Tian, Shiping

    2014-06-01

    Pathogenic fungi usually secrete a series of virulence factors to the extracellular environment to facilitate infection. Rab GTPases play a central role in the secretory pathway. To explore the function of Rab/GTPase in filamentous fungi, we knocked out a Rab/GTPase family gene, Bcsas1, in Botrytis cinerea, an aggressive fungal pathogen that infects more than 200 plant species. A detailed analysis was conducted on the virulence and the secretory capability of the mutants. The results indicated that knockout of Bcsas1 inhibited hyphal development and reduced sporulation of B. cinerea on potato dextrose agar plates resulting in reduced virulence on various fruit hosts. Knocking out the Bcsas1 gene led to an accumulation of transport vesicles at the hyphal tip, significantly reduced extracellular protein content, and lowered the activity of polygalacturonase and xylanase in the extracellular medium. However, mutation of Bcsas1 did not affect the expression of genes encoding polygalacturonase and xylanase, suggesting the secretion of these two family enzymes was suppressed in the mutant. Moreover, a comparative analysis of the secretome provided further evidence that the disruption of Bcsas1 in mutant strains significantly depressed the secretion of polysaccharide hydrolases and proteases. The results indicate that Bcsas1, the Rab8/SEC4-like gene, plays a crucial role in development, protein secretion, and virulence of B. cinerea.

  11. TALEN-mediated knock-in via non-homologous end joining in the crustacean Daphnia magna.

    Nakanishi, Takashi; Kato, Yasuhiko; Matsuura, Tomoaki; Watanabe, Hajime

    2016-11-07

    Transcription activator-like effector nucleases (TALENs) are versatile tools that enable the insertion of DNA into different organisms. Here, we confirmed TALEN-mediated knock-in via non-homologous end joining in the crustacean Daphnia magna, a model organism for ecological and toxicological genomics. We tested two different TALENs, ey1 TALEN and ey2 TALEN, both of which target the eyeless locus. The donor DNA plasmid, harbouring the H2B-GFP reporter gene, was designed to contain both TALEN target sites and was co-injected with each TALEN mRNA into eggs. The ey1 TALEN and ey2 TALEN constructs both resulted in H2B-GFP expression in Daphnia with a germline transmission efficiency of 3%. Of the three transgenic animals generated, two had donor DNA at the targeted genomic site, which suggested concurrent cleavage of the injected plasmid DNA and genome DNA. The availability of such tools that are capable of targeted knock-in of foreign genes will be extremely useful for advancing the knowledge of gene function and contribute to an increased understanding of functional genomics in Daphnia.

  12. Efficient generation of knock-in transgenic zebrafish carrying reporter/driver genes by CRISPR/Cas9-mediated genome engineering.

    Kimura, Yukiko; Hisano, Yu; Kawahara, Atsuo; Higashijima, Shin-ichi

    2014-10-08

    The type II bacterial CRISPR/Cas9 system is rapidly becoming popular for genome-engineering due to its simplicity, flexibility, and high efficiency. Recently, targeted knock-in of a long DNA fragment via homology-independent DNA repair has been achieved in zebrafish using CRISPR/Cas9 system. This raised the possibility that knock-in transgenic zebrafish could be efficiently generated using CRISPR/Cas9. However, how widely this method can be applied for the targeting integration of foreign genes into endogenous genomic loci is unclear. Here, we report efficient generation of knock-in transgenic zebrafish that have cell-type specific Gal4 or reporter gene expression. A donor plasmid containing a heat-shock promoter was co-injected with a short guide RNA (sgRNA) targeted for genome digestion, a sgRNA targeted for donor plasmid digestion, and Cas9 mRNA. We have succeeded in establishing stable knock-in transgenic fish with several different constructs for 4 genetic loci at a frequency being exceeding 25%. Due to its simplicity, design flexibility, and high efficiency, we propose that CRISPR/Cas9-mediated knock-in will become a standard method for the generation transgenic zebrafish.

  13. Biogas Opportunities Roadmap Progress Report

    None, None

    2015-12-01

    In support of the Obama Administration's Climate Action Plan, the U.S. Department of Energy, the U.S. Environmental Protection Agency, and U.S. Department of Agriculture jointly released the Biogas Opportunities Roadmap Progress Report, updating the federal government's progress to reduce methane emissions through biogas systems since the Biogas Opportunities Roadmap was completed by the three agencies in July 2014. The report highlights actions taken, outlines challenges and opportunities, and identifies next steps to the growth of a robust biogas industry.

  14. 76 FR 3926 - Notice of Funding Opportunity and Solicitation for Grant Application (SGA) for Trade Adjustment...

    2011-01-21

    ... Reconciliation Act of 2010 (Reconciliation Act) is described in further detail on ETA's Web site at http://www...). Funding Opportunity Number: SGA/DFA PY 10-03. SUMMARY: Through this notice, the Department of Labor's Employment and Training Administration (ETA) announces the availability of approximately $500 million...

  15. Evaluation of the DC Opportunity Scholarship Program: First Year Report on Participation

    Wolf, Patrick; Eissa, Nada; Puma, Michael

    2005-01-01

    The District of Columbia School Choice Incentive Act of 2003 was passed by Congress in January 2004. The Act provided funds for District of Columbia Public Schools (DCPS) improvement activities and charter school facility acquisitions. Most notably, the statute established what is now called the DC Opportunity Scholarship Program?the first federal…

  16. US Forest Service Recreation Opportunities

    US Forest Service, Department of Agriculture — A map service on the www depicting the recreation opportunity information that the Forest Service collects through the Recreation Portal and shares with the public...

  17. Employment opportunities for the disabled

    Delsen, L.W.M.

    1996-01-01

    Policy makers in the OECD Member States have developed quite different programmes and institutional arrangements to create and promote employment opportunities for the disabled. These policy approaches include legal interventions, employment support services, financial support of open employment and

  18. New Opportunities for Targeted Immunotherapy

    A team of NCI researchers has reported that several types of gastrointestinal cancer have tumor-specific mutations that can be recognized by the immune system, thereby offering a new therapeutic opportunity for patients with these tumors.

  19. Opportunity formation in social entrepreneurship

    Korsgaard, Steffen T.

    2011-01-01

    Purpose - This paper aims to explore the concept of opportunity and its role in social entrepreneurship processes. Design/methodology/approach - A single-case study of a sustainable community in Denmark. The data include interviews, documents and television programmes. Findings - The case study...... in the field of social entrepreneurship, while contributing to the development of the creation view of opportunities. Key words - Opportunity, Social entrepreneurship, Process, Sustainability, Case Study Paper type - Research paper...... finds that the opportunity takes a number of different forms in the process. These different forms are the result of a continuous mobilisation of actors. On the basis of these findings a model of social entrepreneurship processes is proposed, where the process is driven by mobilisation...

  20. Wind Technologies & Evolving Opportunities (Presentation)

    Robichaud, R.

    2014-07-01

    This presentation covers opportunities for wind technology; wind energy market trends; an overview of the National Wind Technology Center near Boulder, Colorado; wind energy price and cost trends; wind turbine technology improvements; and wind resource characterization improvements.

  1. Autism: Why Act Early?

    ... What's this? Submit Button Past Emails CDC Features Autism: Why Act Early? Language: English Español (Spanish) Recommend ... helped the world make sense." Florida teenager with Autism Spectrum Disorder "Because my parents acted early, I ...

  2. Network marketing as an opportunity

    Hakun, Peter

    2010-01-01

    The objective of this thesis is to clarify network marketing and how it works and to describe its advantages, disadvantages and opportunity which it offers to producer, distributor and consumer. The first chapter gives a definition of network marketing, explains how it works and refers to its history. In the second chapter the network marketing is compared to common distribution chain from producer's as well as consumer's point of view. Opportunities which network marketing offers to a distri...

  3. Characterisation of a C1qtnf5 Ser163Arg knock-in mouse model of late-onset retinal macular degeneration.

    Xinhua Shu

    Full Text Available A single founder mutation resulting in a Ser163Arg substitution in the C1QTNF5 gene product causes autosomal dominant late-onset retinal macular degeneration (L-ORMD in humans, which has clinical and pathological features resembling age-related macular degeneration. We generated and characterised a mouse "knock-in" model carrying the Ser163Arg mutation in the orthologous murine C1qtnf5 gene by site-directed mutagenesis and homologous recombination into mouse embryonic stem cells. Biochemical, immunological, electron microscopic, fundus autofluorescence, electroretinography and laser photocoagulation analyses were used to characterise the mouse model. Heterozygous and homozygous knock-in mice showed no significant abnormality in any of the above measures at time points up to 2 years. This result contrasts with another C1qtnf5 Ser163Arg knock-in mouse which showed most of the features of L-ORMD but differed in genetic background and targeting construct.

  4. Oversight on Community Services Administration, Child Abuse Prevention and Treatment, and Adoption Opportunities, and Native American Programs Act. Hearing before the Subcommittee on Aging, Family and Human Services of the Committee on Labor and Human Resources. United States Senate, Ninety-Seventh Congress, First Session.

    Congress of the U.S., Washington, DC. Senate Committee on Labor and Human Resources.

    Oversight hearings were conducted on April 23, 1981 in reference to social service block grants for the Community Services Administration, child abuse prevention and treatment and adoption programs, and Native American Programs Act. Testimonies for support of block grants advocated ability of States to decide how program resources can best be…

  5. Targeted Knock-Down of miR21 Primary Transcripts Using snoMEN Vectors Induces Apoptosis in Human Cancer Cell Lines.

    Motoharu Ono

    Full Text Available We have previously reported an antisense technology, 'snoMEN vectors', for targeted knock-down of protein coding mRNAs using human snoRNAs manipulated to contain short regions of sequence complementarity with the mRNA target. Here we characterise the use of snoMEN vectors to target the knock-down of micro RNA primary transcripts. We document the specific knock-down of miR21 in HeLa cells using plasmid vectors expressing miR21-targeted snoMEN RNAs and show this induces apoptosis. Knock-down is dependent on the presence of complementary sequences in the snoMEN vector and the induction of apoptosis can be suppressed by over-expression of miR21. Furthermore, we have also developed lentiviral vectors for delivery of snoMEN RNAs and show this increases the efficiency of vector transduction in many human cell lines that are difficult to transfect with plasmid vectors. Transduction of lentiviral vectors expressing snoMEN targeted to pri-miR21 induces apoptosis in human lung adenocarcinoma cells, which express high levels of miR21, but not in human primary cells. We show that snoMEN-mediated suppression of miRNA expression is prevented by siRNA knock-down of Ago2, but not by knock-down of Ago1 or Upf1. snoMEN RNAs colocalise with Ago2 in cell nuclei and nucleoli and can be co-immunoprecipitated from nuclear extracts by antibodies specific for Ago2.

  6. Synaptic function is modulated by LRRK2 and glutamate release is increased in cortical neurons of G2019S LRRK2 knock-in mice

    Dayne A Beccano-Kelly

    2014-09-01

    Full Text Available Mutations in Leucine-Rich Repeat Kinase-2 (LRRK2 result in familial Parkinson’s disease and the G2019S mutation alone accounts for up to 30% in some ethnicities. Despite this, the function of LRRK2 is largely undetermined although evidence suggests roles in phosphorylation, protein interactions, autophagy and endocytosis. Emerging reports link loss of LRRK2 to altered synaptic transmission, but the effects of the G2019S mutation upon synaptic release in mammalian neurons are unknown. To assess wild type and mutant LRRK2 in established neuronal networks, we conducted immunocytochemical, electrophysiological and biochemical characterisation of >3 week old cortical cultures of LRRK2 knock-out, wild-type overexpressing and G2019S knock-in mice. Synaptic release and synapse numbers were grossly normal in LRRK2 knock-out cells, but discretely reduced glutamatergic activity and reduced synaptic protein levels were observed. Conversely, synapse density was modestly but significantly increased in wild-type LRRK2 overexpressing cultures although event frequency was not. In knock-in cultures, glutamate release was markedly elevated, in the absence of any change to synapse density; indicating that physiological levels of G2019S LRRK2 elevate probability of release. Several presynaptic regulatory proteins shown by others to interact with LRRK2 were expressed at normal levels in knock-in cultures; however, synapsin 1 phosphorylation was significantly reduced. Thus, perturbations to the presynaptic release machinery and elevated synaptic transmission are early neuronal effects of LRRK2 G2019S. Furthermore, the comparison of knock-in and overexpressing cultures suggests that one copy of the G2019S mutation has a more pronounced effect than an ~3-fold increase in LRRK2 protein. Mutant-induced increases in transmission may convey additional stressors to neuronal physiology that may eventually contribute to the pathogenesis of Parkinson’s disease.

  7. VE-cadherin Y685F knock-in mouse is sensitive to vascular permeability in recurrent angiogenic organs.

    Sidibé, Adama; Polena, Helena; Pernet-Gallay, Karin; Razanajatovo, Jeremy; Mannic, Tiphaine; Chaumontel, Nicolas; Bama, Soumalamaya; Maréchal, Irène; Huber, Philippe; Gulino-Debrac, Danielle; Bouillet, Laurence; Vilgrain, Isabelle

    2014-08-01

    Covalent modifications such as tyrosine phosphorylation are associated with the breakdown of endothelial cell junctions and increased vascular permeability. We previously showed that vascular endothelial (VE)-cadherin was tyrosine phosphorylated in vivo in the mouse reproductive tract and that Y685 was a target site for Src in response to vascular endothelial growth factor in vitro. In the present study, we aimed to understand the implication of VE-cadherin phosphorylation at site Y685 in cyclic angiogenic organs. To achieve this aim, we generated a knock-in mouse carrying a tyrosine-to-phenylalanine point mutation of VE-cadherin Y685 (VE-Y685F). Although homozygous VE-Y685F mice were viable and fertile, the nulliparous knock-in female mice exhibited enlarged uteri with edema. This phenotype was observed in 30% of females between 4 to 14 mo old. Histological examination of longitudinal sections of the VE-Y685F uterus showed an extensive disorganization of myometrium and endometrium with highly edematous uterine glands, numerous areas with sparse cells, and increased accumulation of collagen fibers around blood vessels, indicating a fibrotic state. Analysis of cross section of ovaries showed the appearance of spontaneous cysts, which suggested increased vascular hyperpermeability. Electron microscopy analysis of capillaries in the ovary showed a slight but significant increase in the gap size between two adjacent endothelial cell membranes in the junctions of VE-Y685F mice (wild-type, 11.5 ± 0.3, n = 78; and VE-Y685F, 12.48 ± 0.3, n = 65; P = 0.045), as well as collagen fiber accumulation around capillaries. Miles assay revealed that either basal or vascular endothelial growth factor-stimulated permeability in the skin was increased in VE-Y685F mice. Since edema and fibrotic appearance have been identified as hallmarks of initial increased vascular permeability, we conclude that the site Y685 in VE-cadherin is involved in the physiological regulation of capillary

  8. Indirect Speech Acts

    李威

    2001-01-01

    Indirect speech acts are frequently used in verbal communication, the interpretation of them is of great importance in order to meet the demands of the development of students' communicative competence. This paper, therefore, intends to present Searle' s indirect speech acts and explore the way how indirect speech acts are interpreted in accordance with two influential theories. It consists of four parts. Part one gives a general introduction to the notion of speech acts theory. Part two makes an elaboration upon the conception of indirect speech act theory proposed by Searle and his supplement and development of illocutionary acts. Part three deals with the interpretation of indirect speech acts. Part four draws implication from the previous study and also serves as the conclusion of the dissertation.

  9. Knocking down the expression of adenylate cyclase-associated protein 1 inhibits the proliferation and migration of breast cancer cells.

    Yu, Xia-Fei; Ni, Qi-Chao; Chen, Jin-Peng; Xu, Jun-Fei; Jiang, Ying; Yang, Shu-Yun; Ma, Jing; Gu, Xiao-Ling; Wang, Hua; Wang, Ying-Ying

    2014-04-01

    Adenylate cyclase-associated protein 1 (CAP1) is a conserved protein that was found to be up-regulated in breast cancer and related to the migration of breast cancer. We verified its roles in breast cancer specimens and cell lines. In our results, 71 of 100 specimens of breast cancer showed high levels of CAP1 by immunohistochemistry. Associated with statistical analysis, we saw that CAP1 was related to the grade of breast cancer. In MDA-MB-231, the expression of CAP1 was the highest and by knocking down the expression of CAP1 in MDA-MB-231, its ability for proliferating and migrating apparently decreased and induced changes in morphology, which were related to the arrangement of F-actin. Therefore, CAP1 might be a potential molecular targeted therapy for surgery and immune treatment.

  10. Intergenerational and striatal CAG repeat instability in Huntington's disease knock-in mice involve different DNA repair genes.

    Dragileva, Ella; Hendricks, Audrey; Teed, Allison; Gillis, Tammy; Lopez, Edith T; Friedberg, Errol C; Kucherlapati, Raju; Edelmann, Winfried; Lunetta, Kathryn L; MacDonald, Marcy E; Wheeler, Vanessa C

    2009-01-01

    Modifying the length of the Huntington's disease (HD) CAG repeat, the major determinant of age of disease onset, is an attractive therapeutic approach. To explore this we are investigating mechanisms of intergenerational and somatic HD CAG repeat instability. Here, we have crossed HD CAG knock-in mice onto backgrounds deficient in mismatch repair genes, Msh3 and Msh6, to discern the effects on CAG repeat size and disease pathogenesis. We find that different mechanisms predominate in inherited and somatic instability, with Msh6 protecting against intergenerational contractions and Msh3 required both for increasing CAG length and for enhancing an early disease phenotype in striatum. Therefore, attempts to decrease inherited repeat size may entail a full understanding of Msh6 complexes, while attempts to block the age-dependent increases in CAG size in striatal neurons and to slow the disease process will require a full elucidation of Msh3 complexes and their function in CAG repeat instability.

  11. Prolonged starvation causes up-regulation of AQP1 in adipose tissue capillaries of AQP7 knock-out mice

    Skowronski, Mariusz T.; Skowronska, Agnieszka; Rojek, Aleksandra;

    2016-01-01

    study, we aimed to find out whether prolonged starvation influences the AQP1 expression of AQP7 knock-out mice (AQP7 KO) in the WAT. To resolve this hypothesis, immunoperoxidase, immunoblot and immunogold microscopy were used. AQP1 expression was found with the use of immunohistochemistry...... and was confirmed by immunogold microscopy in the vessels of mouse WAT of all studied groups. Semi-quantitative immunoblot and quantitative immunogold microscopy showed a significant increase (by 2.5- to 3-fold) in the abundance of AQP1 protein expression in WAT in the 72 h starved AQP7 KO mice as compared to AQP7......+/+ (p mice. The present data suggest that an interaction of different AQP isoforms is required...

  12. Spectral confocal imaging of fluorescently tagged nicotinic receptors in knock-in mice with chronic nicotine administration.

    Renda, Anthony; Nashmi, Raad

    2012-02-10

    Ligand-gated ion channels in the central nervous system (CNS) are implicated in numerous conditions with serious medical and social consequences. For instance, addiction to nicotine via tobacco smoking is a leading cause of premature death worldwide (World Health Organization) and is likely caused by an alteration of ion channel distribution in the brain. Chronic nicotine exposure in both rodents and humans results in increased numbers of nicotinic acetylcholine receptors (nAChRs) in brain tissue. Similarly, alterations in the glutamatergic GluN1 or GluA1 channels have been implicated in triggering sensitization to other addictive drugs such as cocaine, amphetamines and opiates. Consequently, the ability to map and quantify distribution and expression patterns of specific ion channels is critically important to understanding the mechanisms of addiction. The study of brain region-specific effects of individual drugs was advanced by the advent of techniques such as radioactive ligands. However, the low spatial resolution of radioactive ligand binding prevents the ability to quantify ligand-gated ion channels in specific subtypes of neurons. Genetically encoded fluorescent reporters, such as green fluorescent protein (GFP) and its many color variants, have revolutionized the field of biology. By genetically tagging a fluorescent reporter to an endogenous protein one can visualize proteins in vivo. One advantage of fluorescently tagging proteins with a probe is the elimination of antibody use, which have issues of nonspecificity and accessibility to the target protein. We have used this strategy to fluorescently label nAChRs, which enabled the study of receptor assembly using Förster Resonance Energy Transfer (FRET) in transfected cultured cells. More recently, we have used the knock-in approach to engineer mice with yellow fluorescent protein tagged α4 nAChR subunits (α4YFP), enabling precise quantification of the receptor ex vivo at submicrometer resolution in CNS

  13. Promoting Prevention Through the Affordable Care Act: Workplace Wellness

    Anderko, Laura; Roffenbender, Jason S.; Goetzel, Ron Z.; Millard, Francois; Wildenhaus, Kevin; DeSantis, Charles; Novelli, William

    2012-01-01

    Public health in the United States can be improved by building workplace “cultures of health” that support healthy lifestyles. The Affordable Care Act (ACA), which includes the Prevention and Public Health Fund, will support a new focus on prevention and wellness, offering opportunities to strengthen the public’s health through workplace wellness initiatives. This article describes the opportunity the ACA provides to improve worker wellness.

  14. Genetic background modifies nuclear mutant huntingtin accumulation and HD CAG repeat instability in Huntington's disease knock-in mice.

    Lloret, Alejandro; Dragileva, Ella; Teed, Allison; Espinola, Janice; Fossale, Elisa; Gillis, Tammy; Lopez, Edith; Myers, Richard H; MacDonald, Marcy E; Wheeler, Vanessa C

    2006-06-15

    Genetically precise models of Huntington's disease (HD), Hdh CAG knock-in mice, are powerful systems in which phenotypes associated with expanded HD CAG repeats are studied. To dissect the genetic pathways that underlie such phenotypes, we have generated Hdh(Q111) knock-in mouse lines that are congenic for C57BL/6, FVB/N and 129Sv inbred genetic backgrounds and investigated four Hdh(Q111) phenotypes in these three genetic backgrounds: the intergenerational instability of the HD CAG repeat and the striatal-specific somatic HD CAG repeat expansion, nuclear mutant huntingtin accumulation and intranuclear inclusion formation. Our results reveal increased intergenerational and somatic instability of the HD CAG repeat in C57BL/6 and FVB/N backgrounds compared with the 129Sv background. The accumulation of nuclear mutant huntingtin and the formation of intranuclear inclusions were fastest in the C57BL/6 background, slowest in the 129Sv background and intermediate in the FVB/N background. Inbred strain-specific differences were independent of constitutive HD CAG repeat size and did not correlate with Hdh mRNA levels. These data provide evidence for genetic modifiers of both intergenerational HD CAG repeat instability and striatal-specific phenotypes. Different relative contributions of C57BL/6 and 129Sv genetic backgrounds to the onset of nuclear mutant huntingtin and somatic HD CAG repeat expansion predict that the initiation of each of these two phenotypes is modified by different genes. Our findings set the stage for defining disease-related genetic pathways that will ultimately provide insight into disease mechanism.

  15. Knock-down of hypoxia-induced carbonic anhydrases IX and XII radiosensitizes tumor cells by increasing intracellular acidosis

    Jérôme eDoyen

    2013-01-01

    Full Text Available The relationship between acidosis within the tumor microenvironment and radioresistance of hypoxic tumor cells remains unclear. Previously we reported that hypoxia-induced carbonic anhydrases CAIX and CAXII constitute a robust pHi-regulating system that confers a survival advantage on hypoxic human colon carcinoma LS174Tr cells in acidic microenvironments. Here we investigate the role of acidosis, CAIX and CAXII knock-down in combination with ionizing radiation. Fibroblasts cells (-/+ CAIX and LS174Tr cells (inducible knock-down for ca9/ca12 were analyzed for cell cycle phase distribution and survival after irradiation in extracellular pHo manipulations and hypoxia (1% O2 exposure. Radiotherapy was used to target ca9/ca12-silenced LS174Tr tumors grown in nude mice. We found that diminishing the pHi-regulating capacity of fibroblasts through inhibition of NHE-1 sensitize cells to radiation-induced cell death. Secondly, the pHi-regulating function of CAIX plays a key protective role in irradiated fibroblasts in an acidic environment as accompanied by a reduced number of cells in the radiosensitive phases of the cell cycle. Thirdly, we demonstrate that irradiation of LS174Tr spheroids, silenced for either ca9 or both ca9/ca12, showed a respective 50% and 75% increase in cell death as a result of a decrease in cell number in the radioresistant S phase and a disruption of CA-mediated pHi regulation. Finally, LS174Tr tumor progression was strongly decreased when ca9/ca12 silencing was combined with irradiation in vivo. These findings highlight the combinatory use of radiotherapy with targeting of the pHi-regulating carbonic anhydrases as an anti-cancer strategy.

  16. Absence of progeria-like disease phenotypes in knock-in mice expressing a non-farnesylated version of progerin.

    Yang, Shao H; Chang, Sandy Y; Ren, Shuxun; Wang, Yibin; Andres, Douglas A; Spielmann, H Peter; Fong, Loren G; Young, Stephen G

    2011-02-01

    Hutchinson-Gilford progeria syndrome (HGPS) is caused by a mutant prelamin A, progerin, that terminates with a farnesylcysteine. HGPS knock-in mice (Lmna(HG/+)) develop severe progeria-like disease phenotypes. These phenotypes can be ameliorated with a protein farnesyltransferase inhibitor (FTI), suggesting that progerin's farnesyl lipid is important for disease pathogenesis and raising the possibility that FTIs could be useful for treating humans with HGPS. Subsequent studies showed that mice expressing non-farnesylated progerin (Lmna(nHG/+) mice, in which progerin's carboxyl-terminal -CSIM motif was changed to -SSIM) also develop severe progeria, raising doubts about whether any treatment targeting protein prenylation would be particularly effective. We suspected that those doubts might be premature and hypothesized that the persistent disease in Lmna(nHG/+) mice could be an unanticipated consequence of the cysteine-to-serine substitution that was used to eliminate farnesylation. To test this hypothesis, we generated a second knock-in allele yielding non-farnesylated progerin (Lmna(csmHG)) in which the carboxyl-terminal -CSIM motif was changed to -CSM. We then compared disease phenotypes in mice harboring the Lmna(nHG) or Lmna(csmHG) allele. As expected, Lmna(nHG/+) and Lmna(nHG/nHG) mice developed severe progeria-like disease phenotypes, including osteolytic lesions and rib fractures, osteoporosis, slow growth and reduced survival. In contrast, Lmna(csmHG/+) and Lmna(csmHG/csmHG) mice exhibited no bone disease and displayed entirely normal body weights and survival. The frequencies of misshapen cell nuclei were lower in Lmna(csmHG/+) and Lmna(csmHG/csmHG) fibroblasts. These studies show that the ability of non-farnesylated progerin to elicit disease depends on the carboxyl-terminal mutation used to eliminate protein prenylation.

  17. Career opportunities in clinical engineering.

    Morse, W A

    1992-01-01

    The varied career opportunities open to clinical engineers are described in this paper. Many of these opportunities are within the medical device industry in research, development, manufacturing design, regulatory activities, production, operations, sales, marketing, service, and management. Additional opportunities are available in hospitals, with the Veterans Administration, or working as an entrepreneur or a consultant. Each of these careers requires specific training and skills, and they all require a fundamental scientific knowledge of physical principles and mathematics. Research and management, however, require different educational preparation. The research emphasis should be on theoretical principles and creativity; the management emphasis should be on financial and labor problems. In all clinical engineering careers, the individual is a problem solver.

  18. The Man and the Opportunity

    Orison; Swett; Marden; 詹比发

    2003-01-01

    选注者言:人生不得志者,往往将自己的失意归咎于命运之不公、机会之不肯眷顾!本文从一个全新的视角,向人们揭示机会的本质:Opportunities!Every lifeis full of them.成事纵然在天,谋事还须在人。让我们把此句当作座右铭:Golden opportunities are nothing to laziness,but industry makes the commonestchances golden.

  19. TEACHER TALK AND LEARNER OPPORTUNITY

    LanWeidong

    2004-01-01

    Adopting the position that maximizing learner involvement is conducive to second language acquisition, this paper aims to explore the relationship between teacher talk and learner opportunities in language classrooms in senior schools through classroom observation techniques. Four excellent high school teachers from Zhejiang province in China are involved in this research. The results reveal that such features as minimal teacher talking time, referential questions, extended wait time,discoursal feedback can increase potential of learning opportunities through classroom interaction in language classrooms in high schools.

  20. Fluorescent protein tagging of endogenous protein in brain neurons using CRISPR/Cas9-mediated knock-in and in utero electroporation techniques

    Uemura, Takeshi; Mori, Takuma; Kurihara, Taiga; Kawase, Shiori; Koike, Rie; Satoga, Michiru; Cao, Xueshan; Li, Xue; Yanagawa, Toru; Sakurai, Takayuki; Shindo, Takayuki; Tabuchi, Katsuhiko

    2016-01-01

    Genome editing is a powerful technique for studying gene functions. CRISPR/Cas9-mediated gene knock-in has recently been applied to various cells and organisms. Here, we successfully knocked in an EGFP coding sequence at the site immediately after the first ATG codon of the β-actin gene in neurons in the brain by the combined use of the CRISPR/Cas9 system and in utero electroporation technique, resulting in the expression of the EGFP-tagged β-actin protein in cortical layer 2/3 pyramidal neurons. We detected EGFP fluorescence signals in the soma and neurites of EGFP knock-in neurons. These signals were particularly abundant in the head of dendritic spines, corresponding to the localization of the endogenous β-actin protein. EGFP knock-in neurons showed no detectable changes in spine density and basic electrophysiological properties. In contrast, exogenously overexpressed EGFP-β-actin showed increased spine density and EPSC frequency, and changed resting membrane potential. Thus, our technique provides a potential tool to elucidate the localization of various endogenous proteins in neurons by epitope tagging without altering neuronal and synaptic functions. This technique can be also useful for introducing a specific mutation into genes to study the function of proteins and genomic elements in brain neurons. PMID:27782168

  1. Homologous Recombination-Independent Large Gene Cassette Knock-in in CHO Cells Using TALEN and MMEJ-Directed Donor Plasmids

    Tetsushi Sakuma

    2015-10-01

    Full Text Available Gene knock-in techniques have rapidly evolved in recent years, along with the development and maturation of genome editing technology using programmable nucleases. We recently reported a novel strategy for microhomology-mediated end-joining-dependent integration of donor DNA by using TALEN or CRISPR/Cas9 and optimized targeting vectors, named PITCh (Precise Integration into Target Chromosome vectors. Here we describe TALEN and PITCh vector-mediated integration of long gene cassettes, including a single-chain Fv-Fc (scFv-Fc gene, in Chinese hamster ovary (CHO cells, with comparison of targeting and cloning efficiency among several donor design and culture conditions. We achieved 9.6-kb whole plasmid integration and 7.6-kb backbone-free integration into a defined genomic locus in CHO cells. Furthermore, we confirmed the reasonable productivity of recombinant scFv-Fc protein of the knock-in cells. Using our protocol, the knock-in cell clones could be obtained by a single transfection and a single limiting dilution using a 96-well plate, without constructing targeting vectors containing long homology arms. Thus, the study described herein provides a highly practical strategy for gene knock-in of large DNA in CHO cells, which accelerates high-throughput generation of cell lines stably producing any desired biopharmaceuticals, including huge antibody proteins.

  2. Anticoagulant effect of dietary fish oil in hyperlipidemia. A study of hepatic gene expression in APOE2 knock-in mice

    K. Vanschoonbeek (Kristof); K. Wouters (Kristiaan); P.E.J. van der Meijden (Paola); P.J. van Gorp (Patrick); M.A.H. Feijge (Marion); M. Herfs (Marjolein); L.J. Schurgers; M.A. Hofker (Marten); M.P.M. de Maat (Moniek); J.W.M. Heemskerk (Johan)

    2008-01-01

    textabstractObjective - In hyperlipidemia, dietary fish oil containing n-3 polyunsaturated fatty acids (PUFA) provokes plasma triacylglycerol lowering and hypocoagulant activity. Using APOE2 knock-in mice, the relation of these fish-oil effects with altered gene expression was investigated. Methods

  3. A neuroanatomical and physiological study of the non-image forming visual system of the cone-rod homeobox gene (Crx) knock out mouse

    Rovsing, Louise; Rath, Martin F; Lund-Andersen, Casper

    2010-01-01

    The anatomy and physiology of the non-image forming visual system was investigated in a visually blind cone-rod homeobox gene (Crx) knock-out mouse (Crx(-)(/)(-)), which lacks the outer segments of the photoreceptors. We show that the suprachiasmatic nuclei (SCN) in the Crx(-/-) mouse exhibit...

  4. ACT Verbal Prep Course

    Standridge, Nathan

    2012-01-01

    Comprehensive Prep for ACT Verbal. Every year, students pay 1,000 and more to test prep companies to prepare for the verbal sections of the ACT. Now you can get the same preparation in a book. The verbal sections are not easy. There is no quick fix that will allow you to "beat" the ACT, but it is very learnable. If you study hard and master the techniques in this book, your score will improve-significantly. The ACT cannot be "beaten." But it can be mastered-through hard work, analytical thought, and by training yourself to think like a test writer. Many of the exercises in this book are design

  5. Nikola Tesla Educational Opportunity School.

    Design Cost Data, 2001

    2001-01-01

    Describes the architectural design, costs, general description, and square footage data for the Nikola Tesla Educational Opportunity School in Colorado Springs, Colorado. A floor plan and photos are included along with a list of manufacturers and suppliers used for the project. (GR)

  6. Postdoctoral Opportunities and Career Options

    Manka, R. H.

    2001-05-01

    Following the completion of a Ph.D. degree, in the sciences a postdoctoral appointment has traditionally been a key step in career development to expand the student's background and broaden their perspective. The postdoctoral appointment often is almost a requirement to obtain some positions in academia and government laboratories. In addition, postdoctoral positions in industry are becoming more common and offer an opportunity to explore a field without making a long-term commitment. We describe the nature of a postdoctoral appointment and discuss the advantages and disadvantages of the recent Ph.D. taking a postdoctoral position. We comment on the role such positions play in university, government and the corporate research. Finally, we describe some of the national postdoctoral opportunities that exist including large programs offered by the National Research Council through Federal laboratories including those of NASA, NOAA, EPA, and the Department of Defense. Exciting new interdisciplinary opportunities such as fellowships at the NASA Astrobiology Institute are summarized, as are international opportunities such as the von Humboldt fellowships in Germany.

  7. Graduate Opportunities for Black Students.

    Paynter, Julie, Ed.

    This document catalogues graduate opportunities specifically for black students in 1969-70 at 42 universities, 96 additional graduate departments (social sciences, natural sciences, mathematics, and humanities), and 111 additional professional schools (particularly social work, education, law, medicine, theology, business, and library science).…

  8. Investment opportunities with YPFB capitalization

    Escobar, F. [Yacimientos Petroliferos Fiscales Bolivianos, La Paz (Bolivia)

    1996-10-01

    Investment opportunities with Yacimientos Petroliferos Fiscales Bolivianos (LPFB) in La Paz, Bolivia, were discussed, especially as they may be affected by the new Hydrocarbon Law No. 1689, whose main objective is to encourage investments in Bolivia and to increase production capacity through investors` incorporation. Some of the areas of potential importance examined included reserve development, transportation, upstream consulting, and hydrocarbon development.

  9. Using Activity Theory to Understand Entrepreneurial Opportunity

    Holt, Robin

    2008-01-01

    Entrepreneurship is often described as the ability to recognize and exploit opportunities. Identifying opportunities is intentional and idiosyncratic insofar as they are recognized as opportunities is a novel and conscious event (otherwise the entrepreneur would be doing nothing new). Yet opportunities also have to be recognized by others as ones…

  10. Marine Mammal Protection Act

    National Oceanic and Atmospheric Administration, Department of Commerce — The Marine Mammal Protection Act (MMPA or Act) prohibits, with certain exceptions, the "take" of marine mammals in U.S. waters and by U.S. citizens on the high seas,...

  11. The Apocryphal Acts Of Andrew

    Bremmer, Jan N.

    2000-01-01

    Following the first three volumes of the new series on the Acts of John (1995), the Acts of Paul and Thecla (1996) and the Acts of Peter (1998), this new volume is devoted to the Acts of Andrew. After a study of the relationship between the Acts of Andrew and the Acts of Andrew and Matthias, the maj

  12. Recent Opportunity Microscopic Imager Results

    Herkenhoff, K. E.; Arvidson, R. E.; Jolliff, B. L.; Yingst, R.; Team, A.

    2013-12-01

    Opportunity arrived at exposures of Endeavour crater rim rocks in August 2011, on a hill dubbed 'Cape York.' These rocks have been the goal of exploration by Opportunity for the past few years because spectral evidence for phyllosilicates was observed at this location in orbital remote sensing data. As Opportunity circum¬navigated Cape York, the Microscopic Imager (MI) was used to examine the fine-scale textures of various soils and rocky outcrops. As reported previously, Opportunity discovered multiple bright linear features along the western periphery of Cape York that have been interpreted as veins of Ca sulfate deposited in fractures within the bedrock of Cape York. Opportunity then explored the northern and eastern sides of Cape York, including the area around 'Matijevic Hill' that shows evidence for phyllosilicates in CRISM data acquired from the Mars Reconnaissance Orbiter. One of the first outcrops examined near Matijevic Hill, dubbed 'Kirkwood,' is dominated by millimeter-size spherules. Unlike the hematite-rich concretions observed by Opportunity on Meridiani Planum, the aggregated 'newberries' in the Kirkwood exposure display internal structure and resistant rims. Compositionally, the spherule-rich rock is very similar to a nearby spherule-poor outcrop dubbed 'Whitewater Lake.' Thus these spherules have a more basalt-like composition compared to the hematite-rich concretions of the Burns Formation. The origin of the Kirkwood outcrop is uncertain, but the setting on the rim of the 22-km diameter Endeavour crater suggests that perhaps impact melting was involved in lapilli formation, possibly followed by mobilization and sorting in the ejecta blanket. Alternatively, the newberries may be diagenetic iron oxide concretions that are less well cemented than the 'blueberries' of the younger sulfate-rich Burns Formation. The Whitewater Lake outcrops contain the phyllosilicate phases observed from orbit, and are the oldest materials yet investigated by

  13. Etude expérimentale du cliquetis à haut régime Experimental Study of Hight-Speed Knocking

    Guibet J. C.

    2006-11-01

    Full Text Available La première partie de cette étude a consisté à observer et à tenter d'interpréter l'action des conditions de fonctionnement et des paramètres de réglage du moteur sur la tendance au cliquetis à haut régime. On a montré ensuite que les différentes familles chimiques d'hydrocarbures qui constituent les carburants classiques présentent chacune un comportement bien distinct en fonction de la richesse, de la pression et de la température d'admission. On a également étudié l'influence de la teneur en plomb du carburant et du type d'alkyle de plomb employé. Quelques expériences ont été effectuées afin de déterminer l'incidence d'une réduction de un point de taux de compression sur l'exigence en octane à haut régime et sur l'action des caractéristiques de composition du carburant. Enfin, en déterminant le pourcentage de cycles soumis au cliquetis pour différentes avances à l'allumage, il a été possible de fournir quelques indications permettant de mieux caractériser l'intensité du phénomène. The first part of this study consists in observing and trying to interpret the effect of operating conditions and engine tuning parameters on the tendency for high-speed knocking to appear. The different chemical families of the hydrocarbons making up conventional fuels are shown to each have a quite different behavior depending on the fuel-air equivalency ratio and the admission pressure and temperature. The influence of the lead content in the fuel and of the type of lead alkyl used is also studied. Some experiments were performed to determine the influence of a one-point reduction in the compression ratio on the high-speed octane requirement and on the effect of fuel composition properties. Lastly, by determing the percentage of cycles accompanied by knocking at different spark advances, some indications were found for better characterizing the intensity of the phenomenon.

  14. Lentivirus-ABCG1 instillation reduces lipid accumulation and improves lung compliance in GM-CSF knock-out mice

    Malur, Anagha; Huizar, Isham [Program in Lung Cell Biology and Translational Research, Division of Pulmonary, Critical Care and Sleep Medicine, East Carolina University, Greenville, NC (United States); Wells, Greg [Department of Microbiology and Immunology, East Carolina University, Greenville, NC (United States); Barna, Barbara P. [Program in Lung Cell Biology and Translational Research, Division of Pulmonary, Critical Care and Sleep Medicine, East Carolina University, Greenville, NC (United States); Malur, Achut G. [Department of Microbiology and Immunology, East Carolina University, Greenville, NC (United States); Thomassen, Mary Jane, E-mail: thomassenm@ecu.edu [Program in Lung Cell Biology and Translational Research, Division of Pulmonary, Critical Care and Sleep Medicine, East Carolina University, Greenville, NC (United States); Department of Microbiology and Immunology, East Carolina University, Greenville, NC (United States)

    2011-11-18

    Highlights: Black-Right-Pointing-Pointer Lentivirus-ABCG1 reduces lipid accumulation in lungs of GM-CSF knock-out mice. Black-Right-Pointing-Pointer Up-regulation of ABCG1 improves lung function. Black-Right-Pointing-Pointer Upregulation of ABCG1 improves surfactant metabolism. -- Abstract: We have shown decreased expression of the nuclear transcription factor, peroxisome proliferator-activated receptor-gamma (PPAR{gamma}) and the PPAR{gamma}-regulated ATP-binding cassette transporter G1 (ABCG1) in alveolar macrophages from patients with pulmonary alveolar proteinosis (PAP). PAP patients also exhibit neutralizing antibodies to granulocyte-macrophage colony stimulating factor (GM-CSF), an upregulator of PPAR{gamma}. In association with functional GM-CSF deficiency, PAP lung is characterized by surfactant-filled alveolar spaces and lipid-filled alveolar macrophages. Similar pathology characterizes GM-CSF knock-out (KO) mice. We reported previously that intratracheal instillation of a lentivirus (lenti)-PPAR{gamma} plasmid into GM-CSF KO animals elevated ABCG1 and reduced alveolar macrophage lipid accumulation. Here, we hypothesized that instillation of lenti-ABCG1 might be sufficient to decrease lipid accumulation and improve pulmonary function in GM-CSF KO mice. Animals received intratracheal instillation of lenti-ABCG1 or control lenti-enhanced Green Fluorescent Protein (eGFP) plasmids and alveolar macrophages were harvested 10 days later. Alveolar macrophage transduction efficiency was 79% as shown by lenti-eGFP fluorescence. Quantitative PCR analyses indicated a threefold (p = 0.0005) increase in ABCG1 expression with no change of PPAR{gamma} or ABCA1 in alveolar macrophages of lenti-ABCG1 treated mice. ABCG1 was unchanged in control lenti-eGFP and PBS-instilled groups. Oil Red O staining detected reduced intracellular neutral lipid in alveolar macrophages from lenti-ABCG1 treated mice. Extracellular cholesterol and phospholipids were also decreased as shown by

  15. From knock-out phenotype to three-dimensional structure of a promising antibiotic target from Streptococcus pneumoniae.

    Con Dogovski

    Full Text Available Given the rise in drug-resistant Streptococcus pneumoniae, there is an urgent need to discover new antimicrobials targeting this pathogen and an equally urgent need to characterize new drug targets. A promising antibiotic target is dihydrodipicolinate synthase (DHDPS, which catalyzes the rate-limiting step in lysine biosynthesis. In this study, we firstly show by gene knock out studies that S. pneumoniae (sp lacking the DHDPS gene is unable to grow unless supplemented with lysine-rich media. We subsequently set out to characterize the structure, function and stability of the enzyme drug target. Our studies show that sp-DHDPS is folded and active with a k(cat = 22 s(-1, K(M(PYR = 2.55 ± 0.05 mM and K(M(ASA = 0.044 ± 0.003 mM. Thermal denaturation experiments demonstrate sp-DHDPS exhibits an apparent melting temperature (T(M(app of 72 °C, which is significantly greater than Escherichia coli DHDPS (Ec-DHDPS (T(M(app = 59 °C. Sedimentation studies show that sp-DHDPS exists in a dimer-tetramer equilibrium with a K(D(4→2 = 1.7 nM, which is considerably tighter than its E. coli ortholog (K(D(4→2 = 76 nM. To further characterize the structure of the enzyme and probe its enhanced stability, we solved the high resolution (1.9 Å crystal structure of sp-DHDPS (PDB ID 3VFL. The enzyme is tetrameric in the crystal state, consistent with biophysical measurements in solution. Although the sp-DHDPS and Ec-DHDPS active sites are almost identical, the tetramerization interface of the s. pneumoniae enzyme is significantly different in composition and has greater buried surface area (800 Å(2 compared to its E. coli counterpart (500 Å(2. This larger interface area is consistent with our solution studies demonstrating that sp-DHDPS is considerably more thermally and thermodynamically stable than Ec-DHDPS. Our study describe for the first time the knock-out phenotype, solution properties, stability and crystal structure of DHDPS from S. pneumoniae, a

  16. Knock down of Whitefly Gut Gene Expression and Mortality by Orally Delivered Gut Gene-Specific dsRNAs

    Ali, Muhammad Yousaf; Ashraf, Muhammad Aleem; Mansoor, Shahid; Shahid, Ahmad Ali; Brown, Judith K.

    2017-01-01

    Control of the whitefly Bemisia tabaci (Genn.) agricultural pest and plant virus vector relies on the use of chemical insecticides. RNA-interference (RNAi) is a homology-dependent innate immune response in eukaryotes, including insects, which results in degradation of the corresponding transcript following its recognition by a double-stranded RNA (dsRNA) that shares 100% sequence homology. In this study, six whitefly ‘gut’ genes were selected from an in silico-annotated transcriptome library constructed from the whitefly alimentary canal or ‘gut’ of the B biotype of B. tabaci, and tested for knock down efficacy, post-ingestion of dsRNAs that share 100% sequence homology to each respective gene target. Candidate genes were: Acetylcholine receptor subunit α, Alpha glucosidase 1, Aquaporin 1, Heat shock protein 70, Trehalase1, and Trehalose transporter1. The efficacy of RNAi knock down was further tested in a gene-specific functional bioassay, and mortality was recorded in 24 hr intervals, six days, post-treatment. Based on qPCR analysis, all six genes tested showed significantly reduced gene expression. Moderate-to-high whitefly mortality was associated with the down-regulation of osmoregulation, sugar metabolism and sugar transport-associated genes, demonstrating that whitefly survivability was linked with RNAi results. Silenced Acetylcholine receptor subunit α and Heat shock protein 70 genes showed an initial low whitefly mortality, however, following insecticide or high temperature treatments, respectively, significantly increased knockdown efficacy and death was observed, indicating enhanced post-knockdown sensitivity perhaps related to systemic silencing. The oral delivery of gut-specific dsRNAs, when combined with qPCR analysis of gene expression and a corresponding gene-specific bioassay that relates knockdown and mortality, offers a viable approach for functional genomics analysis and the discovery of prospective dsRNA biopesticide targets. The

  17. Eand P opportunities in Brazil

    Castilho, Marcelo [National Petroleum Agency of Brasil (Brazil)

    2011-07-01

    Brazil is one of the world's largest economies and the country also has significant heavy oil reserves. This report from the National Petroleum Agency of Brazil aims at presenting the situation of the oil and gas sector in Brazil in terms of resources, production, regulatory framework and opportunities for the future. Brazil has numerous sedimentary basins at its disposal, most of them being prospected by both national and foreign companies from all over the world. Brazil has over 14 billion barrels of proven reserves, its production is 2,1 MMBbl/d and heavy oil represents almost 40% of that production. The National Petroleum Agency of Brazil is responsible for the implementation of oil sector policy with the aims of maintaining self-sufficiency, implementing good practices in terms of health and safety, and increasing local content. This paper pointed out that Brazil has an important opportunity to enhance its energy sector through the development of heavy oil.

  18. UTBB FDSOI: Evolution and opportunities

    Monfray, Stephane; Skotnicki, Thomas

    2016-11-01

    As today's 28 nm FDSOI (Fully Depleted Silicon On Insulator) technology is at the industrialization level, this paper aims to summarize the key advantages allowed by the thin BOX (Buried Oxide) of the FDSOI, through the technology evolution but also new opportunities, among logic applications and extending the possibilities offered by the platform. We will summarize how the advantages provided by the thin BOX have been first explored and developed, and how the back biasing techniques are the key to the outstanding performances provided by the FDSOI at low voltage. Then, as the FDSOI technology is also a solution to develop innovative platforms and applications, we will detail some opportunities. In particular, we will present monolithic 3D integration, ultra-low power devices for IoT (Internet of Things) and ultra-sensitive sensors.

  19. Opportunity Structures for Selective Exposure

    Skovsgaard, Morten; Shehata, Adam; Strömbäck, Jesper

    2016-01-01

    is to investigate the two types of selective exposure in a country—Sweden—where the opportunity structures for selective exposure differ from the American context. This study investigates both types of selective exposure in relation to televised party-leader interviews. Based on panel survey data, the findings show...... interest. Evidence for both has been found primarily in an American context, while there is less research on European countries. This is problematic, as the opportunity structures for different forms of selectivity vary across media environments. Against this background, the purpose of this study...... that selective exposure based on political interest is substantially more important than selective exposure based on ideological preferences in explaining exposure to party-leader interviews. To substantiate this finding, the results are replicated with partisan learning as the dependent variable....

  20. Investment opportunities as real options

    Adnan Rovčanin

    2005-06-01

    Full Text Available Opportunity (optional approach to capital investment appraisal represents, completely new theoretical and methodological framework for investment analysis. Compared to traditional, discount cash flow (DCF model of analysis, the optional approach provides opportunity for valuation and managing flexibility, i.e. possibility of approaching (amending the previous decisions in compliance with market changes. Risk and uncertainty are inevitably following the capital investment. Therefore, the importance of optional approach to investments is also that it provides possible better “treatment” of risks in the investment analysis, and also more rational allocation of resources, accordingly. This approach should be of more interest to the Countries in transition, considering the limited financial sources as well as risk and uncertainty are emphasized.

  1. Brexit: potential opportunities, potential risks.

    2017-01-21

    ▪ Identifying opportunities and risks that might arise from the UK's exit from the European Union▪ Managing mental health issues and building resilient teams▪ Supporting efforts to eliminate rabiesThese were among matters discussed by the BVA Council at its meeting on December 7, 2016. The BVA President, Gudrun Ravetz, chaired the meeting, which was held at the BVA's headquarters in Mansfield Street, London.

  2. Immigrant Capital and Entrepreneurial Opportunities

    Malavika Sundararajan

    2016-01-01

    Full Text Available Objective: The main objective of this study is to define and operationalize the concept of immigrant capital, a key factor that differentiates immigrant from host country entrepreneurs in how they recognize and start new ventures. Research Design & Methods: A detailed analysis of contemporary immigrant entrepreneurship and opportunity recognition literature was carried out. Using grounded theory, we synthesized the outcomes from the analysis of eight Canadian and U.S. case studies of successful immigrant entrepreneurs with the key findings from the literature to define and develop a model of immigrant capital. Findings: Based on our grounded theory development process we show that the concept of immigrant capital as a distillate of human, cultural, economic and social capital that goes beyond expected opportunity recognition (OR drivers like prior knowledge and prior experience to differentiate and enhance the immigrant entrepreneur’s ability to recognize business opportunities compared to host country entrepreneurs. We found immigrant capital to be a consequence of being boundary spanners in host and home country networks. Implications & Recommendations: Understanding a unique resource like immigrant capital, will help immigrant as well as host country entrepreneurs further develop their opportunity recognition ability by bridging gaps and fulfilling the needs for both, immigrant and host country consumers. Contribution & Value Added: The main contribution is the theoretical development, identification and definition of the immigrant capital model and propositions that will articulate the factors that lead to the conceptualization and operationalization of immigrant capital. Furthermore, the immigrant capital model can serve host country entrepreneurs to develop cross-cultural networks and jump-start entrepreneurial activities in their home countries as well as learn how to expand their operations into global markets.

  3. US maglev: Status and opportunities

    Coffey, H.T.

    1992-01-01

    Recognizing the development of maglev systems in Germany and Japan, and the growing congestion, air pollution and energy consumption resulting from our current transportation system, the United States, in 1990, embarked on a program to evaluate the potential usefulness of these systems in the US. In this paper, the utility of maglev systems in alleviating some of these problems, progress in the current program, and opportunities for participation by the superconductivity and cryogenic communities are discussed.

  4. US maglev: Status and opportunities

    Coffey, H.T.

    1992-09-01

    Recognizing the development of maglev systems in Germany and Japan, and the growing congestion, air pollution and energy consumption resulting from our current transportation system, the United States, in 1990, embarked on a program to evaluate the potential usefulness of these systems in the US. In this paper, the utility of maglev systems in alleviating some of these problems, progress in the current program, and opportunities for participation by the superconductivity and cryogenic communities are discussed.

  5. Office of Equal Opportunity Programs

    Chin, Jennifer L.

    2004-01-01

    The NASA Glenn Office of Equal Opportunity Programs works to provide quality service for all programs and/or to assist the Center in becoming a model workplace. During the summer of 2004, I worked with Deborah Cotleur along with other staff members to create and modify customer satisfaction surveys. This office aims to assist in developing a model workplace by providing functions as a change agent to the center by serving as an advisor to management to ensure equity throughout the Center. In addition, the office serves as a mediator for the Center in addressing issues and concerns. Lastly, the office provides assistance to employees to enable attainment of personal and organizational goals. The Office of Equal Opportunities is a staff office which reports and provides advice to the Center Director and Executive Leadership, implements laws, regulations, and presidential executive orders, and provides center wide leadership and assistance to NASA GRC employees. Some of the major responsibilities of the office include working with the discrimination complaints program, special emphasis programs (advisory groups), management support, monitoring and evaluation, contract compliance, and community outreach. During my internship in this office, my main objective was to create four customer satisfaction surveys based on EO retreats, EO observances, EO advisory boards, and EO mediation/counseling. I created these surveys after conducting research on past events and surveys as well as similar survey research created and conducted by other NASA centers, program for EO Advisory group members, leadership training sessions for supervisors, preventing sexual harassment training sessions, and observance events. I also conducted research on the style and format from feedback surveys from the Marshall Equal Opportunity website, the Goddard website, and the main NASA website. Using the material from the Office of Equal Opportunity Programs at Glenn Research Center along with my

  6. Reminder - Equal Opportunities Advisory Panel

    HR Department

    2007-01-01

    At its meeting on 7 December 2006, the Standing Concertation Committee also took note of the nomination of a fourth new member of the Panel: Wisla Carena. The present composition of the Panel (appointed ad personam) is now as follows: Tiziano Camporesi (Chairperson), Wisla Carena, Pierre Charrue, Sue Foffano, Josi Schinzel (Equal Opportunities Officer), Markus Nordberg, Christine Petit-Jean-Genaz and Elena Wildner. Human Resources Department Tel. 74480

  7. Decadal opportunities for space architects

    Sherwood, Brent

    2012-12-01

    A significant challenge for the new field of space architecture is the dearth of project opportunities. Yet every year more young professionals express interest to enter the field. This paper derives projections that bound the number, type, and range of global development opportunities that may be reasonably expected over the next few decades for human space flight (HSF) systems so those interested in the field can benchmark their goals. Four categories of HSF activity are described: human Exploration of solar system bodies; human Servicing of space-based assets; large-scale development of space Resources; and Breakout of self-sustaining human societies into the solar system. A progressive sequence of capabilities for each category starts with its earliest feasible missions and leads toward its full expression. The four sequences are compared in scale, distance from Earth, and readiness. Scenarios hybridize the most synergistic features from the four sequences for comparison to status quo, government-funded HSF program plans. Finally qualitative, decadal, order-of-magnitude estimates are derived for system development needs, and hence opportunities for space architects. Government investment towards human planetary exploration is the weakest generator of space architecture work. Conversely, the strongest generator is a combination of three market drivers: (1) commercial passenger travel in low Earth orbit; (2) in parallel, government extension of HSF capability to GEO; both followed by (3) scale-up demonstration of end-to-end solar power satellites in GEO. The rich end of this scale affords space architecture opportunities which are more diverse, complex, large-scale, and sociologically challenging than traditional exploration vehicle cabins and habitats.

  8. A ‘Smart’ Opportunity

    Breitenbauch, Henrik Ø.; Giegerich, Bastian

    2012-01-01

    cooperation, however, leads industry to think about cooperation mostly in terms of delays and market-distorting principles. With this backward-looking mindset, industry risks missing a crucial growth potential, a market that will only exist because of Smart Defense. Across the Atlantic, industry should seize...... this opportunity as eagerly as it would any good business development prospect. Simply put, the Smart Defense framework will offer a way to sell products that would not otherwise be sold....

  9. Engineering ethics challenges and opportunities

    Bowen, W Richard

    2014-01-01

    Engineering Ethics: Challenges and Opportunities aims to set a new agenda for the engineering profession by developing a key challenge: can the great technical innovation of engineering be matched by a corresponding innovation in the acceptance and expression of ethical responsibility?  Central features of this stimulating text include:   ·         An analysis of engineering as a technical and ethical practice providing great opportunities for promoting the wellbeing and agency of individuals and communities. ·         Elucidation of the ethical opportunities of engineering in three key areas:             - Engineering for Peace, emphasising practical amelioration of the root causes of    conflict rather than military solutions.             - Engineering for Health, focusing on close collaboration with healthcare professionals      for both the promotion and restoration of health.             - Engineering for Development, providing effective solution...

  10. Opportunities in Reform: Bioethics and Mental Health Ethics.

    Williams, Arthur Robin

    2016-05-01

    Last year marks the first year of implementation for both the Patient Protection and Affordable Care Act and the Mental Health Parity and Addiction Equity Act in the United States. As a result, healthcare reform is moving in the direction of integrating care for physical and mental illness, nudging clinicians to consider medical and psychiatric comorbidity as the expectation rather than the exception. Understanding the intersections of physical and mental illness with autonomy and self-determination in a system realigning its values so fundamentally therefore becomes a top priority for clinicians. Yet Bioethics has missed opportunities to help guide clinicians through one of medicine's most ethically rich and challenging fields. Bioethics' distancing from mental illness is perhaps best explained by two overarching themes: 1) An intrinsic opposition between approaches to personhood rooted in Bioethics' early efforts to protect the competent individual from abuses in the research setting; and 2) Structural forces, such as deinstitutionalization, the Patient Rights Movement, and managed care. These two themes help explain Bioethics' relationship to mental health ethics and may also guide opportunities for rapprochement. The potential role for Bioethics may have the greatest implications for international human rights if bioethicists can re-energize an understanding of autonomy as not only free from abusive intrusions but also with rights to treatment and other fundamental necessities for restoring freedom of choice and self-determination. Bioethics thus has a great opportunity amid healthcare reform to strengthen the important role of the virtuous and humanistic care provider.

  11. Rescue of cardiomyopathy through U7snRNA-mediated exon skipping in Mybpc3-targeted knock-in mice.

    Gedicke-Hornung, Christina; Behrens-Gawlik, Verena; Reischmann, Silke; Geertz, Birgit; Stimpel, Doreen; Weinberger, Florian; Schlossarek, Saskia; Précigout, Guillaume; Braren, Ingke; Eschenhagen, Thomas; Mearini, Giulia; Lorain, Stéphanie; Voit, Thomas; Dreyfus, Patrick A; Garcia, Luis; Carrier, Lucie

    2013-07-01

    Exon skipping mediated by antisense oligoribonucleotides (AON) is a promising therapeutic approach for genetic disorders, but has not yet been evaluated for cardiac diseases. We investigated the feasibility and efficacy of viral-mediated AON transfer in a Mybpc3-targeted knock-in (KI) mouse model of hypertrophic cardiomyopathy (HCM). KI mice carry a homozygous G>A transition in exon 6, which results in three different aberrant mRNAs. We identified an alternative variant (Var-4) deleted of exons 5-6 in wild-type and KI mice. To enhance its expression and suppress aberrant mRNAs we designed AON-5 and AON-6 that mask splicing enhancer motifs in exons 5 and 6. AONs were inserted into modified U7 small nuclear RNA and packaged in adeno-associated virus (AAV-U7-AON-5+6). Transduction of cardiac myocytes or systemic administration of AAV-U7-AON-5+6 increased Var-4 mRNA/protein levels and reduced aberrant mRNAs. Injection of newborn KI mice abolished cardiac dysfunction and prevented left ventricular hypertrophy. Although the therapeutic effect was transient and therefore requires optimization to be maintained over an extended period, this proof-of-concept study paves the way towards a causal therapy of HCM.

  12. Predicting the names of the best teams after the knock-out phase of a cricket series.

    Lemmer, Hermanus Hofmeyr

    2014-01-01

    Cricket players' performances can best be judged after a large number of matches had been played. For test or one-day international (ODI) players, career data are normally used to calculate performance measures. These are normally good indicators of future performances, although various factors influence the performance of a player in a specific match. It is often necessary to judge players' performances based on a small number of scores, e.g. to identify the best players after a short series of matches. The challenge then is to use the best available criteria in order to assess performances as accurately and fairly as possible. In the present study the results of the knock-out phase of an International Cricket Council (ICC) World Cup ODI Series are used to predict the names of the best teams by means of a suitably formulated logistic regression model. Despite using very sparse data, the methods used are reasonably successful. It is also shown that if the same technique is applied to career ratings, very good results are obtained.

  13. The Phospholipase D2 Knock Out Mouse Has Ectopic Purkinje Cells and Suffers from Early Adult-Onset Anosmia

    Zhang, Qifeng; Smethurst, Elizabeth; Segonds-Pichon, Anne; Schrewe, Heinrich; Wakelam, Michael J. O.

    2016-01-01

    Phospholipase D2 (PLD2) is an enzyme that produces phosphatidic acid (PA), a lipid messenger molecule involved in a number of cellular events including, through its membrane curvature properties, endocytosis. The PLD2 knock out (PLD2KO) mouse has been previously reported to be protected from insult in a model of Alzheimer's disease. We have further analysed a PLD2KO mouse using mass spectrophotometry of its lipids and found significant differences in PA species throughout its brain. We have examined the expression pattern of PLD2 which allowed us to define which region of the brain to analyse for defect, notably PLD2 was not detected in glial-rich regions. The expression pattern lead us to specifically examine the mitral cells of olfactory bulbs, the Cornus Amonis (CA) regions of the hippocampus and the Purkinje cells of the cerebellum. We find that the change to longer PA species correlates with subtle architectural defect in the cerebellum, exemplified by ectopic Purkinje cells and an adult-onset deficit of olfaction. These observations draw parallels to defects in the reelin heterozygote as well as the effect of high fat diet on olfaction. PMID:27658289

  14. Longitudinal analysis of the behavioural phenotype in Hdh(CAG)150 Huntington's disease knock-in mice.

    Brooks, Simon; Higgs, Gemma; Jones, Lesley; Dunnett, Stephen B

    2012-06-01

    In people with Huntington's disease, an expanded CAG repeat sequence on the HTT gene confers a toxic gain function resulting in a progressive and fatal neurodegeneration. The Hdh((CAG)Q150) Huntington's disease mouse line is a knock-in model of the disease that carries ∼150 CAG repeats on the normal mouse Htt locus. To determine that these mice are a useful model of the disease, they were assessed longitudinally for motor and cognitive deficits relevant to the human disease state. Each test was conducted bi-monthly across the lifespan of the animal. The results indicate that the Hdh(Q150/Q150) mice were impaired on each of the measures used, with deficits appearing on a 3-stage water maze test at 4 months of age and on prepulse inhibition at 6 months of age, both of which were prior to the manifestation of motor abnormalities. Grip strength, as measured by the inverted cage lid test, was reduced in the Hdh(Q150/Q150) mice from 10 months of age, when the male mice also exhibited weight loss relative to their wildtype littermates. On the accelerating rotarod, deficits in the carrier mice did not appear until they were 21 months old. Our results demonstrate that the Hdh((CAG)150) is a valid model of HD that displays early and progressive cognitive deficits that precede the onset of motor abnormalities.

  15. Generation of a Tlx1(CreER-Venus) knock-in mouse strain for the study of spleen development.

    Nakahara, Ryo; Kawai, Yasuhiro; Oda, Akihisa; Nishimura, Miyuki; Murakami, Akikazu; Azuma, Takachika; Kaifu, Tomonori; Goitsuka, Ryo

    2014-11-01

    The spleen is a lymphoid organ that serves as a unique niche for immune reactions, extramedullary hematopoiesis, and the removal of aged erythrocytes from the circulation. While much is known about the immunological functions of the spleen, the mechanisms governing the development and organization of its stromal microenvironment remain poorly understood. Here we report the generation and analysis of a Tlx1(Cre) (ER) (-Venus) knock-in mouse strain engineered to simultaneously express tamoxifen-inducible CreER(T2) and Venus fluorescent protein under the control of regulatory elements of the Tlx1 gene, which encodes a transcription factor essential for spleen development. We demonstrated that Venus as well as CreER expression recapitulates endogenous Tlx1 transcription within the spleen microenvironment. When Tlx1(Cre) (ER) (-Venus) mice were crossed with the Cre-inducible reporter strain, Tlx1-expressing cells as well as their descendants were specifically labeled following tamoxifen administration. We also showed by cell lineage tracing that asplenia caused by Tlx1 deficiency is attributable to altered contribution of mesenchymal cells in the spleen anlage to the pancreatic mesenchyme. Thus, Tlx1(Cre) (ER) (-Venus) mice represent a new tool for lineage tracing and conditional gene manipulation of spleen mesenchymal cells, essential approaches for understanding the molecular mechanisms of spleen development.

  16. Pantothenate kinase-associated neurodegeneration: altered mitochondria membrane potential and defective respiration in Pank2 knock-out mouse model.

    Brunetti, Dario; Dusi, Sabrina; Morbin, Michela; Uggetti, Andrea; Moda, Fabio; D'Amato, Ilaria; Giordano, Carla; d'Amati, Giulia; Cozzi, Anna; Levi, Sonia; Hayflick, Susan; Tiranti, Valeria

    2012-12-15

    Neurodegeneration with brain iron accumulation (NBIA) comprises a group of neurodegenerative disorders characterized by high brain content of iron and presence of axonal spheroids. Mutations in the PANK2 gene, which encodes pantothenate kinase 2, underlie an autosomal recessive inborn error of coenzyme A metabolism, called pantothenate kinase-associated neurodegeneration (PKAN). PKAN is characterized by dystonia, dysarthria, rigidity and pigmentary retinal degeneration. The pathogenesis of this disorder is poorly understood and, although PANK2 is a mitochondrial protein, perturbations in mitochondrial bioenergetics have not been reported. A knock-out (KO) mouse model of PKAN exhibits retinal degeneration and azoospermia, but lacks any neurological phenotype. The absence of a clinical phenotype has partially been explained by the different cellular localization of the human and murine PANK2 proteins. Here we demonstrate that the mouse Pank2 protein localizes to mitochondria, similar to its human orthologue. Moreover, we show that Pank2-defective neurons derived from KO mice have an altered mitochondrial membrane potential, a defect further corroborated by the observations of swollen mitochondria at the ultra-structural level and by the presence of defective respiration.

  17. Comparison of immune response in Pacific white shrimp, Litopenaeus vannamei, after knock down of Toll and IMD gene in vivo.

    Liu, Yongjie; Song, Lei; Sun, Yuhang; Liu, Tao; Hou, Fujun; Liu, Xiaolin

    2016-07-01

    The Toll and immune deficiency (IMD) pathways are essential for inducing immune related genes during invasion of pathogens. In the present study, transcripts of eight pathway-related genes in Litopenaeus vannamei, including Toll, IMD, Pelle, IAP1, TRAF6, ALF, Crustin and Penaeidin3 were analyzed to further understand the potential relationship between Toll and IMD pathway. The high transcription levels of TRAF6, Pelle, Toll, IMD and IAP1 in selected tissues indicates their functional roles in Toll and IMD pathways. The increased mRNA expression of Toll and IMD detected in the early stage might suggest the inducible role of Toll and IMD upon bacterial infection. Moreover, the continuous increase of IMD and the high level of Pelle and TRAF6 in Vibrio anguillarum challenged group indicated that Gram-negative bacterium can activate both the Toll and IMD signaling pathway. Silencing of Toll by a dsRNA-mediated RNAi strongly increased the transcripts of IMD, Pelle, TRAF6, IAP1 and Akirin, knocking down of IMD also markedly increased the transcripts of Toll, Pelle, IAP1 and Akirin. Furthermore, ALF expression was significantly increased in response to V. anguillarum and Micrococcus lysodeikticus challenge, while the transcripts of Crustin and Pen3 in hemocytes were significantly reduced in V. anguillarum group, but rose significantly following M. lysodeikticus infection. In summary, we speculate that Toll and IMD pathway are not independent in shrimp, but linked to defense against bacterial infection.

  18. Generation and evaluation of Myostatin knock-out rabbits and goats using CRISPR/Cas9 system.

    Guo, Rihong; Wan, Yongjie; Xu, Dan; Cui, Libin; Deng, Mingtian; Zhang, Guomin; Jia, Ruoxin; Zhou, Wenjun; Wang, Zhen; Deng, Kaiping; Huang, Mingrui; Wang, Feng; Zhang, Yanli

    2016-07-15

    Myostatin (Mstn) is a conserved negative regulator of skeletal muscle mass in mammals. However, whether precise disruption of Mstn in livestock can be achieved and safely used to improve meat productivity has not been proven. We applied CRISPR/Cas9 system to generate Mstn knock-out (KO) rabbits and goats and then analyzed the changes in their phenotypes to answer this question. We efficiently generated 24 Mstn KO rabbits out of 32 newborn infants after embryo injection with two sgRNAs targeting rabbit Mstn, and found that the Mstn KO rabbits exhibited increased birthweight and a significantly increase in the weight ratios of the quadriceps and biceps muscles to the whole body. Mstn KO also caused high probability of enlarged tongue phenomenon and severe health problems such as stillbirth and early stage death. Using the same method, one out of four goats was generated with edition at Mstn locus. The early stage growth rate of this goat outperformed the control goats. In conclusion, we efficiently generated Mstn KO rabbits and goats using CRISPR/Cas9 technology. However, Mstn KO causes severe health problems and may also have the same effects on other species. This safety issue must be studied further before applied to animal reproduction processes.

  19. Reconstructing gene regulatory networks from knock-out data using Gaussian Noise Model and Pearson Correlation Coefficient.

    Mohamed Salleh, Faridah Hani; Arif, Shereena Mohd; Zainudin, Suhaila; Firdaus-Raih, Mohd

    2015-12-01

    A gene regulatory network (GRN) is a large and complex network consisting of interacting elements that, over time, affect each other's state. The dynamics of complex gene regulatory processes are difficult to understand using intuitive approaches alone. To overcome this problem, we propose an algorithm for inferring the regulatory interactions from knock-out data using a Gaussian model combines with Pearson Correlation Coefficient (PCC). There are several problems relating to GRN construction that have been outlined in this paper. We demonstrated the ability of our proposed method to (1) predict the presence of regulatory interactions between genes, (2) their directionality and (3) their states (activation or suppression). The algorithm was applied to network sizes of 10 and 50 genes from DREAM3 datasets and network sizes of 10 from DREAM4 datasets. The predicted networks were evaluated based on AUROC and AUPR. We discovered that high false positive values were generated by our GRN prediction methods because the indirect regulations have been wrongly predicted as true relationships. We achieved satisfactory results as the majority of sub-networks achieved AUROC values above 0.5.

  20. ReacKnock: identifying reaction deletion strategies for microbial strain optimization based on genome-scale metabolic network.

    Zixiang Xu

    Full Text Available Gene knockout has been used as a common strategy to improve microbial strains for producing chemicals. Several algorithms are available to predict the target reactions to be deleted. Most of them apply mixed integer bi-level linear programming (MIBLP based on metabolic networks, and use duality theory to transform bi-level optimization problem of large-scale MIBLP to single-level programming. However, the validity of the transformation was not proved. Solution of MIBLP depends on the structure of inner problem. If the inner problem is continuous, Karush-Kuhn-Tucker (KKT method can be used to reformulate the MIBLP to a single-level one. We adopt KKT technique in our algorithm ReacKnock to attack the intractable problem of the solution of MIBLP, demonstrated with the genome-scale metabolic network model of E. coli for producing various chemicals such as succinate, ethanol, threonine and etc. Compared to the previous methods, our algorithm is fast, stable and reliable to find the optimal solutions for all the chemical products tested, and able to provide all the alternative deletion strategies which lead to the same industrial objective.

  1. Selective chemokine receptor usage by central nervous system myeloid cells in CCR2-red fluorescent protein knock-in mice.

    Noah Saederup

    Full Text Available BACKGROUND: Monocyte subpopulations distinguished by differential expression of chemokine receptors CCR2 and CX3CR1 are difficult to track in vivo, partly due to lack of CCR2 reagents. METHODOLOGY/PRINCIPAL FINDINGS: We created CCR2-red fluorescent protein (RFP knock-in mice and crossed them with CX3CR1-GFP mice to investigate monocyte subset trafficking. In mice with experimental autoimmune encephalomyelitis, CCR2 was critical for efficient intrathecal accumulation and localization of Ly6C(hi/CCR2(hi monocytes. Surprisingly, neutrophils, not Ly6C(lo monocytes, largely replaced Ly6C(hi cells in the central nervous system of these mice. CCR2-RFP expression allowed the first unequivocal distinction between infiltrating monocytes/macrophages from resident microglia. CONCLUSION/SIGNIFICANCE: These results refine the concept of monocyte subsets, provide mechanistic insight about monocyte entry into the central nervous system, and present a novel model for imaging and quantifying inflammatory myeloid populations.

  2. A knock-in Npm1 mutation in mice results in myeloproliferation and implies a perturbation in hematopoietic microenvironment.

    Shiu-Huey Chou

    Full Text Available Somatic Nucleophosmin (NPM1 mutation frequently occurs in acute myeloid leukemia (AML, but its role in leukemogenesis remains unclear. This study reports the first "conventional" knock-in mouse model of Npm1 mutation, which was achieved by inserting TCTG after nucleotide c.857 (c.854_857dupTCTG to mimic human mutation without any "humanized" sequence. The resultant mutant peptide differed slightly different from that in humans but exhibited cytoplasmic pulling force. Homozygous (Npm1(c+/c+ mice showed embryonic lethality before day E8.5, wheras heterozygous (Npm1(wt/c+ mice appeared healthy at birth and were fertile. Approximately 36% of Npm1(wt/c+ mice developed myeloproliferative disease (MPD with extramedullary hematopoiesis. Those Npm1(wt/c+ mice that did not develop MPD nevertheless gradually developed monocytosis and showed increased numbers of marrow myeloid precursors. This second group of Npm1(wt/c+ mice also showed compromised cobblestone area formation, suggesting pathology in the hematopoietic niche. Microarray experiments and bioinformatic analysis on mice myeloid precursor cells and 227 human samples revealed the expression of CXCR4/CXCL12-related genes was significantly suppressed in mutant cells from both mice and humans. Thus, our mouse model demonstrated that Npm1 mutation can result in MPD, but is insufficient for leukemogenesis. Perturbation of hematopoietic niche in mutant hematopoietic stem cells (implied by underrepresentation of CXCR4/CXCL12-related genes may be important in the pathogenesis of NPM1 mutations.

  3. Knock-down of IL-1Ra in obese mice decreases liver inflammation and improves insulin sensitivity.

    Niclas Franck

    Full Text Available Interleukin 1 Receptor antagonist (IL-1Ra is highly elevated in obesity and is widely recognized as an anti-inflammatory cytokine. While the anti-inflammatory role of IL-1Ra in the pancreas is well established, the role of IL-1Ra in other insulin target tissues and the contribution of systemic IL-1Ra levels to the development of insulin resistance remains to be defined. Using antisense knock down of IL-1Ra in vivo, we show that normalization of IL-1Ra improved insulin sensitivity due to decreased inflammation in the liver and improved hepatic insulin sensitivity and these effects were independent of changes in body weight. A similar effect was observed in IL1-R1 KO mice, suggesting that at high concentrations of IL-1Ra typically observed in obesity, IL-1Ra can contribute to the development of insulin resistance in a mechanism independent of IL-1Ra binding to IL-1R1. These results demonstrate that normalization of plasma IL-1Ra concentration improves insulin sensitivity in diet- induced obese mice.

  4. Hyperfunction of muscarinic receptor maintains long-term memory in 5-HT4 receptor knock-out mice.

    Luis Segu

    Full Text Available Patients suffering from dementia of Alzheimer's type express less serotonin 4 receptors (5-HTR(4, but whether an absence of these receptors modifies learning and memory is unexplored. In the spatial version of the Morris water maze, we show that 5-HTR(4 knock-out (KO and wild-type (WT mice performed similarly for spatial learning, short- and long-term retention. Since 5-HTR(4 control mnesic abilities, we tested whether cholinergic system had circumvented the absence of 5-HTR(4. Inactivating muscarinic receptor with scopolamine, at an ineffective dose (0.8 mg/kg to alter memory in WT mice, decreased long-term but not short-term memory of 5-HTR(4 KO mice. Other changes included decreases in the activity of choline acetyltransferase (ChAT, the required enzyme for acetylcholine synthesis, in the septum and the dorsal hippocampus in 5-HTR(4 KO under baseline conditions. Training- and scopolamine-induced increase and decrease, respectively in ChAT activity in the septum in WT mice were not detected in the 5-HTR(4 KO animals. Findings suggest that adaptive changes in cholinergic systems may circumvent the absence of 5-HTR(4 to maintain long-term memory under baseline conditions. In contrast, despite adaptive mechanisms, the absence of 5-HTR(4 aggravates scopolamine-induced memory impairments. The mechanisms whereby 5-HTR(4 mediate a tonic influence on ChAT activity and muscarinic receptors remain to be determined.

  5. Spatial and temporal lineage analysis of a Pitx3-driven Cre-recombinase knock-in mouse model.

    Marten P Smidt

    Full Text Available Development and function of mesodiencephalic dopaminergic (mdDA neurons has received a lot of scientific interest since these neurons are critically involved in neurological diseases as Parkinson and psychiatric diseases as schizophrenia, depression and attention deficit hyperactivity disorder (ADHD. The understanding of the molecular processes that lead to normal development and function of mdDA neurons has provided insight in the pathology and provided critical information on new treatment paradigms. In order to be able to study specific genetic ablation in mdDA neurons a new tools was developed that drives Cre-recombinase under the control of the Pitx3 locus. The Pitx3 gene is well known for its specific expression in mdDA neurons and is present at the onset of terminal differentiation. Analysis of newly generated Pitx3-Cre knock-in mice shows that Cre expression, measured through the activation of eYfp by removal of a "Stop" signal (LoxP-Stop-LoxP-eYfp reporter mouse, is present at the onset of terminal differentiation and mimics closely the native Pitx3 expression domain. In conclusion, we present here a new Cre-driver mouse model to be used in the restricted ablation of interesting genes in mdDA neurons in order to improve our understanding of the underlying molecular programming.

  6. Spatial and Temporal Lineage Analysis of a Pitx3-Driven Cre-Recombinase Knock-In Mouse Model

    Smidt, Marten P.; von Oerthel, Lars; Hoekstra, Elisa J.; Schellevis, Raymond D.; Hoekman, Marco F. M.

    2012-01-01

    Development and function of mesodiencephalic dopaminergic (mdDA) neurons has received a lot of scientific interest since these neurons are critically involved in neurological diseases as Parkinson and psychiatric diseases as schizophrenia, depression and attention deficit hyperactivity disorder (ADHD). The understanding of the molecular processes that lead to normal development and function of mdDA neurons has provided insight in the pathology and provided critical information on new treatment paradigms. In order to be able to study specific genetic ablation in mdDA neurons a new tools was developed that drives Cre-recombinase under the control of the Pitx3 locus. The Pitx3 gene is well known for its specific expression in mdDA neurons and is present at the onset of terminal differentiation. Analysis of newly generated Pitx3-Cre knock-in mice shows that Cre expression, measured through the activation of eYfp by removal of a “Stop” signal (LoxP-Stop-LoxP-eYfp reporter mouse), is present at the onset of terminal differentiation and mimics closely the native Pitx3 expression domain. In conclusion, we present here a new Cre-driver mouse model to be used in the restricted ablation of interesting genes in mdDA neurons in order to improve our understanding of the underlying molecular programming. PMID:22870339

  7. Acting Antarctica: science on stage

    Ciceri, Piera; Tizzoni, Paola; Pierro, Luigia

    2016-04-01

    Key-words: Polar science, Earth science, Theatre, Hands on activities The legendary Antarctic Expedition of sir E. Shackleton and his crew of 27 aboard the Endurance (1914/16) trapped in the Antarctic ice has become the starting point to learn about Polar Science and Climate Change. While the students were involved into this incredible adventure by the astonishing images of the Australian photographer Frank Hurley (who joined the crew), they discovered the world in which this story happened. Students were then involved in hands-on activities and role plays and have become the writers of the play "Uomini a scienza ai confini del mondo". They act the story of Shackelton's expedition and they tell at the same time to the audience about ice pack, ice cores and their role in understanding the past of the climate, physical and geographical characteristic of polar regions, thermal phenomena related to adaptations of polar animals, solar radiation at different latitude, day/night duration. The theater was the place to "stage" some scientific experiments and to explain the current research carried out in polar regions and their importance in climate change studies and to stress some similarities between Antarctica and space. The project was carried out from teachers of science, letters and geography and was born in collaboration with the "Piccolo Teatro di Milano" and the association "Science Under 18" with the support of a professional actor and director and was played for other schools at "EXPO 2015" in Milano (Italy). In our opinion drama activities improve reading comprehension, and both verbal and non-verbal communication skills. To be able to write and to act, students need a deep understanding of contents. Arts, including theatre, are a good key to involve emotionally students. To have an audience different from their own teachers and classmates offers a real task and the opportunity to play and let grow real skills.

  8. Compelling Research Opportunities using Isotopes

    None

    2009-04-23

    Isotopes are vital to the science and technology base of the US economy. Isotopes, both stable and radioactive, are essential tools in the growing science, technology, engineering, and health enterprises of the 21st century. The scientific discoveries and associated advances made as a result of the availability of isotopes today span widely from medicine to biology, physics, chemistry, and a broad range of applications in environmental and material sciences. Isotope issues have become crucial aspects of homeland security. Isotopes are utilized in new resource development, in energy from bio-fuels, petrochemical and nuclear fuels, in drug discovery, health care therapies and diagnostics, in nutrition, in agriculture, and in many other areas. The development and production of isotope products unavailable or difficult to get commercially have been most recently the responsibility of the Department of Energy's Nuclear Energy program. The President's FY09 Budget request proposed the transfer of the Isotope Production program to the Department of Energy's Office of Science in Nuclear Physics and to rename it the National Isotope Production and Application program (NIPA). The transfer has now taken place with the signing of the 2009 appropriations bill. In preparation for this, the Nuclear Science Advisory Committee (NSAC) was requested to establish a standing subcommittee, the NSAC Isotope Subcommittee (NSACI), to advise the DOE Office of Nuclear Physics. The request came in the form of two charges: one, on setting research priorities in the short term for the most compelling opportunities from the vast array of disciplines that develop and use isotopes and two, on making a long term strategic plan for the NIPA program. This is the final report to address charge 1. NSACI membership is comprised of experts from the diverse research communities, industry, production, and homeland security. NSACI discussed research opportunities divided into three areas: (1

  9. Clean Water Act

    National Oceanic and Atmospheric Administration, Department of Commerce — The Clean Water Act (CWA) establishes the basic structure for regulating discharges of pollutants into U.S. waters and regulating quality standards for surface...

  10. Affordable Care Act (ACA)

    Social Security Administration — The Affordable Care Act (ACA) is a federal statute enacted with a goal of increasing the quality and affordability of health insurance. Through a web service, CMS...

  11. Acts of Research

    Nelund, Sidsel

    with an awareness of larger political, economic, geographical and art-related aspects. The concept of ‘acts of research’ is suggested as a way to understand knowledge production as a creative act in which research carried out in relation to a specific material challenges and resists the protocols of conventional...... described as knowledge producers and exhibitions and art works as instances of knowledge production. Acts of Research: Knowledge Production in Contemporary Arts between Knowledge Economy and Critical Practices analyses this development. The academic discussion of knowledge production in the arts has taken...... place mostly in seminars and articles, in which knowledge is often discussed as an intrinsic quality of the artwork. Acts of Research, however, is devoted to studying the rise of knowledge production in contemporary art from the perspective of artistic, curatorial and educational research...

  12. Endangered Species Act

    National Oceanic and Atmospheric Administration, Department of Commerce — The purpose of the Endangered Species Act (ESA) is to protect and recover imperiled species and the ecosystems upon which they depend. The U.S. Fish and Wildlife...

  13. Energy Policy Act

    National Oceanic and Atmospheric Administration, Department of Commerce — The Energy Policy Act (EPA) addresses energy production in the United States, including: (1) energy efficiency; (2) renewable energy; (3) oil and gas; (4) coal; (5)...

  14. National Environmental Policy Act

    National Oceanic and Atmospheric Administration, Department of Commerce — The National Environmental Policy Act (NEPA) was the first major environmental law in the United States and established national environmental policies for the...

  15. Abandoned Shipwreck Act

    National Oceanic and Atmospheric Administration, Department of Commerce — The Abandoned Shipwreck Act of 1987 (ASA) affirms the authority of state governments to claim ownership to, protect, and manage abandoned shipwrecks on state...

  16. Marine Pollution Prevention Act

    National Oceanic and Atmospheric Administration, Department of Commerce — The Marine Pollution Prevention Act of 2008 implements the International Convention for the Prevention of Pollution from Ships, including related Protocols (MARPOL)...

  17. ACT250 Districts

    Vermont Center for Geographic Information — The ACT 250 Districts layer is part of a larger dataset that contains administrative boundaries for Vermont's Agency of Natural Resources. The dataset includes...

  18. AlphaACT

    2014-07-20

    CBR can be found in the world around us (e.g., a doctor’s diagnosis based on a prior patient case, a lawyer preparing arguments based on legal ... metaphors in decision research. Judgment & Decision Making, 3(3), 195-204. Payne, J., Bettman, J., & Johnson, E. (1993). The Adaptive Decision Maker...alphaact. com 64 AlphaACT HAZMAT User Guide 8.3 Changing Measurement Units AlphaACT HAZMAT lets you show distances in either metric or English

  19. The Role of Different Opportunities in the Activation and Use of the Business Opportunity Prototype

    Costa, Silvia F.; Ehrenhard, Michel L.; Caetano, Antonio; Santos, Susana C.

    2016-01-01

    This study analyses how the different nature of business opportunities affects the way potential entrepreneurs recognize a business opportunity prototypical features. Although scholars have examined the reasons why some individuals, but not others, identify business opportunities, little is known ab

  20. Generation of an Rx-tTA: TetOp-Cre knock-in mouse line for doxycycline regulated Cre activity in the Rx expression domain.

    Timothy F Plageman

    Full Text Available Genetic deletion of mouse genes has played a crucial role in our understanding of embryonic eye development. Transgenic, tissue specific Cre recombinase expression in various eye structures has facilitated these experiments. However, an early expressing, temporally-regulated, optic vesicle-specific Cre line has not been available. In this report, we detail the generation and analysis of a knock-in, inducible Cre line designed to drive recombination specifically within the Rx expression domain. Crossing this line with a reporter line demonstrates that recombination can be mediated within the early optic vesicle and throughout retinal development. Recombination can also be mediated in the Rx-expressing, ventral diencephalon and future posterior pituitary gland. Furthermore, it was demonstrated that dietary doxycycline could effectively modulate Cre activity. This line has the potential to facilitate conditional knock-out experimentation to study early retina and/or posterior pituitary development.

  1. Shape and structure of N=Z 64Ge; Electromagnetic transition rates from the application of the Recoil Distance Method to knock-out reaction

    Starosta, K; Dunomes, A; Adrich, P; Amthor, A M; Baumann, T; Bazin, D; Bowen, M; Brown, B A; Chester, A; Gade, A; Galaviz, D; Glasmacher, T; Ginter, T; Hausmann, M; Horoi, M; Jolie, J; Melon, B; Miller, D; Moeller, V; Norris, R P; Pissulla, T; Portillo, M; Rother, W; Shimbara, Y; Stolz, A; Vaman, C; Voss, P; Weisshaar, D; Zelevinsky, V

    2007-01-01

    Transition rate measurements are reported for the first and the second 2+ states in N=Z 64Ge. The experimental results are in excellent agreement with large-scale Shell Model calculations applying the recently developed GXPF1A interactions. Theoretical analysis suggests that 64Ge is a collective gamma-soft anharmonic vibrator. The measurement was done using the Recoil Distance Method (RDM) and a unique combination of state-of-the-art instruments at the National Superconducting Cyclotron Laboratory (NSCL). States of interest were populated via an intermediate-energy single-neutron knock-out reaction. RDM studies of knock-out and fragmentation reaction products hold the promise of reaching far from stability and providing lifetime information for excited states in a wide range of nuclei.

  2. A Human t-PA Mutant cDNA Cassette Knocked in the Murine fgfr-4 Locus Targeting for Mammary Gland Expression

    Fu-Yu LIN; Hong-Xing CHEN; Xuan CHENG; Xiao YANG; Ji-Xian DENG; Pei-Tang HUANG

    2004-01-01

    The expression of foreign gene in transgenic animals produced by pronuclear microinjection is often confounded by the position effects caused by not only the nature of chromosomal integration site but also the number and arrangement of multiple transgene copies. Gene targeting provides a new way to overcome these inhibitions by introducing single-copy transgene into a chosen site. The choice of a good chromosomal site will favor transgene expression in a predictable fashion. In this study, we tested a new site (fgfr-4) for foreign gene integration and expression. A t-PA mutant (t-PAm) expression cassette under bovine αs1-casein regulatory sequences was efficiently knocked-infgfr-4 site through homologous recombination. The t-PAm was expressed in the milk of all targeted mice. Our experiment indicates that the fgfr-4 may be a candidate site for knocking foreign gene to make transgenic animals.

  3. Vaccination with recombinant adenoviruses expressing Ebola virus glycoprotein elicits protection in the interferon alpha/beta receptor knock-out mouse.

    O'Brien, Lyn M; Stokes, Margaret G; Lonsdale, Stephen G; Maslowski, David R; Smither, Sophie J; Lever, Mark S; Laws, Thomas R; Perkins, Stuart D

    2014-03-01

    The resistance of adult immunocompetent mice to infection with ebolaviruses has led to the development of alternative small animal models that utilise immunodeficient mice, for example the interferon α/β receptor knock-out mouse (IFNR(-/-)). IFNR(-/-) mice have been shown to be susceptible to infection with ebolaviruses by multiple routes but it is not known if this murine model is suitable for testing therapeutics that rely on the generation of an immune response for efficacy. We have tested recombinant adenovirus vectors for their ability to protect IFNR(-/-) mice from challenge with Ebola virus and have analysed the humoral response generated after immunisation. The recombinant vaccines elicited good levels of protection in the knock-out mouse and the antibody response in IFNR(-/-) mice was similar to that observed in vaccinated wild-type mice. These results indicate that the IFNR(-/-) mouse is a relevant small animal model for studying ebolavirus-specific therapeutics.

  4. Investigating of the Knocking Out Properties of Moulding Sands with New Inorganic Binders Used for Castings of Non-ferrous Metal Alloys in Comparison with the Previously Used

    I. Izdebska-Szanda

    2012-12-01

    Full Text Available The article presents the results of investigations, which make a fragment of the broad-scale studies carried out as a part of the projectPOIG.01.01.02-00-015/09 “Advanced materials and technologies”.One of the objectives of the introduction of new inorganic binders is to provide a good knocking out properties of moulding sands, whilemaintaining an appropriate level of strength properties.Therefore, a logical continuation of the previous studies were carried out the tests knocking out properties of moulding sands with newinorganic binders, including making moulds, pouring them by the chosen of non-ferrous metal alloys, knoking-out, and determining theknocking out work.The results of the study were related to the research results obtained by applying the moulding sand performed by existing technology.

  5. Clinical leadership development and education for nurses: prospects and opportunities

    Joseph ML

    2015-07-01

    Full Text Available M Lindell Joseph, Diane L Huber College of Nursing, The University of Iowa, Iowa City, IA, USA Abstract: With the implementation of the Affordable Care Act, elevated roles for nurses of care coordinator, clinical nurse leader, and advanced practice registered nurse have come to the forefront. Because change occurs so fast, matching development and education to job requirements is a challenging forecasting endeavor. The purpose of this article is to envision clinical leadership development and education opportunities for three emerging roles. The adoption of a common framework for intentional leadership development is proposed for clinical leadership development across the continuum of care. Solutions of innovation and interdependency are framed as core concepts that serve as an opportunity to better inform clinical leadership development and education. Additionally, strategies are proposed to advance knowledge, skills, and abilities for crucial implementation of improvements and new solutions at the point of care. Keywords: clinical leadership, nursing leadership, CNL, care coordination, innovation, interdependency

  6. Overcoming Obstacles: Opportunities of academically talented women in Iran

    Shahla Alborzi, Ph.D

    2008-03-01

    Full Text Available The aim of the present research was to study the lifetime obstacles and opportunities of academically successful women working at Iran universities. Successful female academics in Iran are concerned about the social and personal barriers to pursuing successful careers in academia. These women continually work to overcome these barriers in an ongoing process called overcoming obstacles. This basic social process has five stages: perceiving inequality, conflicting, dissolving, empowering and acting purposefully. Throughout the process, these women have first become aware of gender inequities and then worked towards overcoming them using self-motivation properties and support from external sources such as family, mentors and colleagues. This substantive theory, though rooted in a specific country with a strong male dominated social structure, is applicable to all societies as they continue to work towards equitable access to high-level career opportunities.

  7. A unique funding opportunity for public health in Texas.

    Schlenker, Thomas; Huber, Carol A

    2015-01-01

    In addition to the Affordable Care Act, states are more frequently turning to Medicaid waivers to achieve the "Triple Aim" goals of improving the experience of care, improving population health, and reducing per capita costs. These demonstration waivers provide opportunities to test innovative ways to finance and deliver care. Texas is currently implementing a waiver known as the Transformation and Quality Improvement Program. Its inclusion of public health agencies is a unique approach to a system typically limited to traditional providers. San Antonio Metropolitan Health District is one public health agency taking advantage of this new funding opportunity to implement 6 new or expanded programs targeting health issues of highest priority in this south Texas region. This article discusses the use of Medicaid waivers and the advantages and challenges of public health agency participation.

  8. 16 CFR 1101.26 - Circumstances when the Commission does not provide notice and opportunity to comment.

    2010-01-01

    ... 16 Commercial Practices 2 2010-01-01 2010-01-01 false Circumstances when the Commission does not provide notice and opportunity to comment. 1101.26 Section 1101.26 Commercial Practices CONSUMER PRODUCT SAFETY COMMISSION CONSUMER PRODUCT SAFETY ACT REGULATIONS INFORMATION DISCLOSURE UNDER SECTION 6(b) OF THE CONSUMER PRODUCT SAFETY ACT...

  9. 76 FR 73985 - Redelegation of Administrative Authority for Title VI of the Civil Rights Act of 1964

    2011-11-29

    ... URBAN DEVELOPMENT Redelegation of Administrative Authority for Title VI of the Civil Rights Act of 1964... Opportunity (FHEO) supersedes all redelegations of authority under Title VI of the Civil Rights Act of 1964... pertaining to civil rights statutes. Included in that consolidated delegation is, all authority to act as...

  10. A knock-in model of human epilepsy in Drosophila reveals a novel cellular mechanism associated with heat-induced seizure

    Sun, Lei; Gilligan, Jeff; Staber, Cynthia; Schutte, Ryan J.; Nguyen, Vivian; O'Dowd, Diane K.; Reenan, Robert

    2012-01-01

    Over 40 missense mutations in the human SCN1A sodium channel gene are linked to an epilepsy syndrome termed genetic epilepsy with febrile seizures plus (GEFS+). Inheritance of GEFS+ is dominant but the underlying cellular mechanisms remain poorly understood. Here we report knock-in of a GEFS+ SCN1A mutation (K1270T) into the Drosophila sodium channel gene, para, causes a semi-dominant temperature-induced seizure phenotype. Electrophysiological studies of GABAergic interneurons in the brains o...

  11. Knock-Limited Performance of Triptane and 28-R Fuel Blends as Affected by Changes in Compression Ratio and in Engine Operating Variables

    Brun, Rinaldo J.; Feder, Melvin S.; Fisher, William F.

    1947-01-01

    A knock-limited performance investigation was conducted on blends of triptane and 28-P fuel with a 12-cylinder, V-type, liquid-cooled aircraft engine of 1710-cubic-inch displacement at three compression ratios: 6.65, 7.93, and 9.68. At each compression ratio, the effect of changes in temperature of the inlet air to the auxiliary-stage supercharger and in fuel-air ratio were investigated at engine speeds of 2280 and. 3000 rpm. The results show that knock-limited engine performance, as improved by the use of triptane, allowed operation at both take-off and cruising power at a compression ratio of 9.68. At an inlet-air temperature of 60 deg F, an engine speed of 3000 rpm ; and a fuel-air ratio of 0,095 (approximately take-off conditions), a knock-limited engine output of 1500 brake horsepower was possible with 100-percent 28-R fuel at a compression ratio of 6.65; 20-percent triptane was required for the same power output at a compression ratio of 7.93, and 75 percent at a compression ratio of 9.68 allowed an output of 1480 brake horsepower. Knock-limited power output was more sensitive to changes in fuel-air ratio as the engine speed was increased from 2280 to 3000 rpm, as the compression ratio is raised from 6.65 to 9.68, or as the inlet-air temperature is raised from 0 deg to 120 deg F.

  12. Expression and Dendritic Trafficking of BDNF-6 Splice Variant are Impaired in Knock-In Mice Carrying Human BDNF Val66Met Polymorphism

    Mallei, A.; Baj, G.; Ieraci, A.; Corna, S.; Musazzi, L.; Lee, F S; Tongiorgi, E.; Popoli, M.

    2015-01-01

    Background: The human Val66Met polymorphism in brain-derived neurotrophic factor (BDNF), a key factor in neuroplasticity, synaptic function, and cognition, has been implicated in the pathophysiology of neuropsychiatric and neurodegenerative disorders. BDNF is encoded by multiple transcripts with distinct regulation and localization, but the impact of the Val66Met polymorphism on BDNF regulation remains unclear. Methods: In BDNF Val66Met knock-in mice, which recapitulate the phenotypic hallmar...

  13. Energy Development Opportunities for Wyoming

    Larry Demick

    2012-11-01

    The Wyoming Business Council, representing the state’s interests, is participating in a collaborative evaluation of energy development opportunities with the NGNP Industry Alliance (an industry consortium), the University of Wyoming, and the US Department of Energy’s Idaho National Laboratory. Three important energy-related goals are being pursued by the State of Wyoming: Ensuring continued reliable and affordable sources of energy for Wyoming’s industries and people Restructuring the coal economy in Wyoming Restructuring the natural gas economy in Wyoming

  14. Educational Homogamy: Preferences or Opportunities?

    Nielsen, Helena Skyt; Svarer, Michael

    Individuals match on length and type of education. We investigate whether thesystematic relationship between educations of partners is explained by opportuni-ties (e.g. low search frictions) or preferences (e.g. complementarities in householdproduction or portfolio optimization). We find that half...... of the systematic sortingon education is due to low search frictions in marriage markets of the educationalinstitutions. The other half is attributed to complementarities in household pro-duction, since income properties of the joint income process show no influence on partner selection....

  15. Strengths, weaknesses, opportunities and threats

    Bull, J. W.; Jobstvogt, N.; Böhnke-Henrichs, A.;

    2016-01-01

    environmental awareness. Threats include resistance to change, and difficulty with interdisciplinary collaboration. Consideration of SWOT themes suggested five strategic areas for developing and implementing ES.The ES concept could improve decision-making related to natural resource use, and interpretation...... facilitate interdisciplinary research, ensuring decision-making that supports sustainable development........ Such an assessment could form the basis for improving ES thinking, further embedding it into environmental decisions and management.The Young Ecosystem Services Specialists (YESS) completed a Strengths-Weaknesses-Opportunities-Threats (SWOT) analysis of ES through YESS member surveys. Strengths include the approach...

  16. Examining Opportunity-to-Learn and Success in High School Mathematics Performance in California under NCLB

    Gavrilovic, Daniel Miodrag

    2013-01-01

    The No Child Left Behind Act of 2001 has put many schools under a lot of pressure to meet its high demands. In this quantitative study, the effects that the NCLB act has had on students' opportunity to learn (OTL) and Subject Level Success (SS) from 2004 to 2012 in 9th, 10th, and 11th grade math coursework (Algebra 1, Geometry, Algebra 2, and…

  17. Reverse genetics in the tide pool: knock-down of target gene expression via RNA interference in the copepod Tigriopus californicus.

    Barreto, Felipe S; Schoville, Sean D; Burton, Ronald S

    2015-07-01

    Reverse genetic tools are essential for characterizing phenotypes of novel genes and testing functional hypotheses generated from next-generation sequencing studies. RNA interference (RNAi) has been a widely used technique for describing or quantifying physiological, developmental or behavioural roles of target genes by suppressing their expression. The marine intertidal copepod Tigriopus californicus has become an emerging model for evolutionary and physiological studies, but this species is not amenable to most genetic manipulation approaches. As crustaceans are susceptible to RNAi-mediated gene knock-down, we developed a simple method for delivery of gene-specific double-stranded RNA that results in significant suppression of target gene transcription levels. The protocol was examined on five genes of interest, and for each, at least 50% knock-down in expression was achieved. While knock-down levels did not reach 100% in any trial, a well-controlled experiment with one heat-shock gene showed unambiguously that such partial gene suppression may cause dramatic changes in phenotype. Copepods with suppressed expression of heat-shock protein beta 1 (hspb1) exhibited dramatically decreased tolerance to high temperatures, validating the importance of this gene during thermal stress, as proposed by a previous study. The application of this RNAi protocol in T. californicus will be invaluable for examining the role of genes putatively involved in reproductive isolation, mitochondrial function and local adaptation.

  18. Longitudinal behavioral, cross-sectional transcriptional and histopathological characterization of a knock-in mouse model of Huntington's disease with 140 CAG repeats.

    Rising, Aaron C; Xu, Jia; Carlson, Aaron; Napoli, Vincent V; Denovan-Wright, Eileen M; Mandel, Ronald J

    2011-04-01

    The discovery of the gene mutation responsible for Huntington's disease (HD), huntingtin, in 1993 allowed for a better understanding of the pathology of and enabled the development of animal models. HD is caused by the expansion of a polyglutamine repeat region in the N-terminal of the huntingtin protein. Here we examine the behavioral, transcriptional, histopathological and anatomical characteristics of a knock-in HD mouse model with a 140 polyglutamine expansion in the huntingtin protein. This CAG 140 model contains a portion of the human exon 1 with 140 CAG repeats knocked into the mouse huntingtin gene. We have longitudinally examined the rearing behavior, accelerating rotarod, constant speed rotarod and gait for age-matched heterozygote, homozygote and non-transgenic mice and have found a significant difference in the afflicted mice. However, while there were significant differences between the non-transgenic and the knock-in mice, these behaviors were not progressive. As in HD, we show that the CAG 140 mice also have a significant decrease in striatally enriched mRNA transcripts. In addition, striatal neuronal intranuclear inclusion density increases with age. Lastly these CAG 140 mice show slight cortical thinning compared to non-transgenic mice, similarly to the cortical thinning recently reported in HD.

  19. The influence of high-octane fuel blends on the performance of a two-stroke SI engine with knock-limited-compression ratio

    Poola, Ramesh B.; Bhasker, T.; Nagalingam, B.; Gopalakrishnan, K. V.

    The use of alcohol-gasoline blends enables the favorable features of alcohols to be utilized in spark ignition (SI) engines while avoiding the shortcomings of their application as straight fuels. Eucalyptus and orange oils possess high octane values and are also good potential alternative fuels for SI engines. The high octane value of these fuels can enhance the octane value of the fuel when it is blended with low-octane gasoline. In the present work, 20 percent by volume of orange oil, eucalyptus oil, methanol and ethanol were blended separately with gasoline, and the performance, combustion and exhaust emission characteristics were evaluated at two different compression ratios. The phase separation problems arising from the alcohol-gasoline blends were minimized by adding eucalyptus oil as a cosolvent. Test results indicate that the compression ratio can be raised from 7.4 to 9 without any detrimental effect, due to the higher octane rating of the fuel blends. Knock-limited maximum brake output also increases due to extension of the knock limit. The knock limit is extended by methanol-eucalyptus-ethanol-orange oil blends, in descending order.

  20. A combination method for simulation of secondary knock-on atoms of boron carbide induced by neutron irradiation in SPRR-300

    Wu, Jian-Chun; Feng, Qi-Jie; Liu, Xian-Kun; Zhan, Chang-Yong; Zou, Yu; Liu, Yao-Guang

    2016-02-01

    A multiscale sequence of simulation should be used to predict properties of materials under irradiation. Binary collision theory and molecular dynamics (MDs) method are commonly used to characterize the displacement cascades induced by neutrons in a material. In order to reduce the clock time spent for the MD simulation of damages induced by high-energy primary knock-on atoms (PKAs), the damage zones were split into sub-cascade according to the sub-cascade formation criteria. Two well-known codes, Geant4 and TRIM, were used to simulate high-energy PKA-induced cascades in B4C and then produce the secondary knock-on atom (SKA) energy spectrum. It has been found that both high-energy primary knock-on B and C atoms move a long range in the boron carbide. These atoms produce sub-cascades at the tip of trajectory. The energy received by most of the SKAs is <10 keV, which can be used as input to reduce the clock time spent for MD simulation.

  1. VCP associated inclusion body myopathy and paget disease of bone knock-in mouse model exhibits tissue pathology typical of human disease.

    Mallikarjun Badadani

    Full Text Available Dominant mutations in the valosin containing protein (VCP gene cause inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia (IBMPFD. We have generated a knock-in mouse model with the common R155H mutation. Mice demonstrate progressive muscle weakness starting approximately at the age of 6 months. Histology of mutant muscle showed progressive vacuolization of myofibrils and centrally located nuclei, and immunostaining shows progressive cytoplasmic accumulation of TDP-43 and ubiquitin-positive inclusion bodies in quadriceps myofibrils and brain. Increased LC3-II staining of muscle sections representing increased number of autophagosomes suggested impaired autophagy. Increased apoptosis was demonstrated by elevated caspase-3 activity and increased TUNEL-positive nuclei. X-ray microtomography (uCT images show radiolucency of distal femurs and proximal tibiae in knock-in mice and uCT morphometrics shows decreased trabecular pattern and increased cortical wall thickness. Bone histology and bone marrow derived macrophage cultures in these mice revealed increased osteoclastogenesis observed by TRAP staining suggestive of Paget bone disease. The VCP(R155H/+ knock-in mice replicate the muscle, bone and brain pathology of inclusion body myopathy, thus representing a useful model for preclinical studies.

  2. A combination method for simulation of secondary knock-on atoms of boron carbide induced by neutron irradiation in SPRR-300

    Wu, Jian-Chun [Key Laboratory of Radiation Physics and Technology of Education Ministry of China, Institute of Nuclear Science and Technology, Sichuan University, Chengdu, Sichuan 610064 (China); Feng, Qi-Jie; Liu, Xian-Kun [Institute of Nuclear Physics and Chemistry, China Academy of Engineering Physics, Mianyang, Sichuan 621900 (China); Zhan, Chang-Yong [Key Laboratory of Radiation Physics and Technology of Education Ministry of China, Institute of Nuclear Science and Technology, Sichuan University, Chengdu, Sichuan 610064 (China); Zou, Yu, E-mail: zouyu@scu.edu.cn [Key Laboratory of Radiation Physics and Technology of Education Ministry of China, Institute of Nuclear Science and Technology, Sichuan University, Chengdu, Sichuan 610064 (China); Liu, Yao-Guang [Institute of Nuclear Physics and Chemistry, China Academy of Engineering Physics, Mianyang, Sichuan 621900 (China)

    2016-02-01

    A multiscale sequence of simulation should be used to predict properties of materials under irradiation. Binary collision theory and molecular dynamics (MDs) method are commonly used to characterize the displacement cascades induced by neutrons in a material. In order to reduce the clock time spent for the MD simulation of damages induced by high-energy primary knock-on atoms (PKAs), the damage zones were split into sub-cascade according to the sub-cascade formation criteria. Two well-known codes, Geant4 and TRIM, were used to simulate high-energy PKA-induced cascades in B{sub 4}C and then produce the secondary knock-on atom (SKA) energy spectrum. It has been found that both high-energy primary knock-on B and C atoms move a long range in the boron carbide. These atoms produce sub-cascades at the tip of trajectory. The energy received by most of the SKAs is <10 keV, which can be used as input to reduce the clock time spent for MD simulation.

  3. 12 CFR 563.201 - Corporate opportunity.

    2010-01-01

    ...-OPERATIONS Reporting and Bonding § 563.201 Corporate opportunity. (a) If you are a director or officer of a... 12 Banks and Banking 5 2010-01-01 2010-01-01 false Corporate opportunity. 563.201 Section 563.201... duty to a savings association, you must not take advantage of corporate opportunities belonging to...

  4. Contractile abnormalities and altered drug response in engineered heart tissue from Mybpc3-targeted knock-in mice.

    Stöhr, Andrea; Friedrich, Felix W; Flenner, Frederik; Geertz, Birgit; Eder, Alexandra; Schaaf, Sebastian; Hirt, Marc N; Uebeler, June; Schlossarek, Saskia; Carrier, Lucie; Hansen, Arne; Eschenhagen, Thomas

    2013-10-01

    Myosin-binding protein C (Mybpc3)-targeted knock-in mice (KI) recapitulate typical aspects of human hypertrophic cardiomyopathy. We evaluated whether these functional alterations can be reproduced in engineered heart tissue (EHT) and yield novel mechanistic information on the function of cMyBP-C. EHTs were generated from cardiac cells of neonatal KI, heterozygous (HET) or wild-type controls (WT) and developed without apparent morphological differences. KI had 70% and HET 20% lower total cMyBP-C levels than WT, accompanied by elevated fetal gene expression. Under standard culture conditions and spontaneous beating, KI EHTs showed more frequent burst beating than WT and occasional tetanic contractions (14/96). Under electrical stimulation (6Hz, 37°C) KI EHTs exhibited shorter contraction and relaxation times and a twofold higher sensitivity to external [Ca(2+)]. Accordingly, the sensitivity to verapamil was 4-fold lower and the response to isoprenaline or the Ca(2+) sensitizer EMD 57033 2- to 4-fold smaller. The loss of EMD effect was verified in 6-week-old KI mice in vivo. HET EHTs were apparently normal under basal conditions, but showed similarly altered contractile responses to [Ca(2+)], verapamil, isoprenaline and EMD. In contrast, drug-induced changes in intracellular Ca(2+) transients (Fura-2) were essentially normal. In conclusion, the present findings in auxotonically contracting EHTs support the idea that cMyBP-C's normal role is to suppress force generation at low intracellular Ca(2+) and stabilize the power-stroke step of the cross bridge cycle. Pharmacological testing in EHT unmasked a disease phenotype in HET. The altered drug response may be clinically relevant.

  5. Adrenergic stress reveals septal hypertrophy and proteasome impairment in heterozygous Mybpc3-targeted knock-in mice.

    Schlossarek, Saskia; Schuermann, Friederike; Geertz, Birgit; Mearini, Giulia; Eschenhagen, Thomas; Carrier, Lucie

    2012-05-01

    Hypertrophic cardiomyopathy (HCM) is characterized by asymmetric septal hypertrophy and is often caused by mutations in MYBPC3 gene encoding cardiac myosin-binding protein C. In contrast to humans, who are already affected at the heterozygous state, mouse models develop the phenotype mainly at the homozygous state. Evidence from cell culture work suggested that altered proteasome function contributes to the pathogenesis of HCM. Here we tested in two heterozygous Mybpc3-targeted mouse models whether adrenergic stress unmasks a specific cardiac phenotype and proteasome dysfunction. The first model carries a human Mybpc3 mutation (Het-KI), the second is a heterozygous Mybpc3 knock-out (Het-KO). Both models were compared to wild-type (WT) mice. Mice were treated with a combination of isoprenaline and phenylephrine (ISO/PE) or NaCl for 1 week. Whereas ISO/PE induced left ventricular hypertrophy (LVH) with increased posterior wall thickness to a similar extent in all groups, it increased septum thickness only in Het-KI and Het-KO. ISO/PE did not affect the proteasomal chymotrypsin-like activity or β5-subunit protein level in Het-KO or wild-type mice (WT). In contrast, both parameters were markedly lower in Het-KI and negatively correlated with the degree of LVH in Het-KI only. In conclusion, adrenergic stress revealed septal hypertrophy in both heterozygous mouse models of HCM, but proteasome dysfunction only in Het-KI mice, which carry a mutant allele and closely mimic human HCM. This supports the hypothesis that proteasome impairment contributes to the pathophysiology of HCM.

  6. Knock-in reporter mice demonstrate that DNA repair by non-homologous end joining declines with age.

    Amita Vaidya

    2014-07-01

    Full Text Available Accumulation of genome rearrangements is a characteristic of aged tissues. Since genome rearrangements result from faulty repair of DNA double strand breaks (DSBs, we hypothesized that DNA DSB repair becomes less efficient with age. The Non-Homologous End Joining (NHEJ pathway repairs a majority of DSBs in vertebrates. To examine age-associated changes in NHEJ, we have generated an R26NHEJ mouse model in which a GFP-based NHEJ reporter cassette is knocked-in to the ROSA26 locus. In this model, NHEJ repair of DSBs generated by the site-specific endonuclease, I-SceI, reconstitutes a functional GFP gene. In this system NHEJ efficiency can be compared across tissues of the same mouse and in mice of different age. Using R26NHEJ mice, we found that NHEJ efficiency was higher in the skin, lung, and kidney fibroblasts, and lower in the heart fibroblasts and brain astrocytes. Furthermore, we observed that NHEJ efficiency declined with age. In the 24-month old animals compared to the 5-month old animals, NHEJ efficiency declined 1.8 to 3.8-fold, depending on the tissue, with the strongest decline observed in the skin fibroblasts. The sequence analysis of 300 independent NHEJ repair events showed that, regardless of age, mice utilize microhomology sequences at a significantly higher frequency than expected by chance. Furthermore, the frequency of microhomology-mediated end joining (MMEJ events increased in the heart and lung fibroblasts of old mice, suggesting that NHEJ becomes more mutagenic with age. In summary, our study provides a versatile mouse model for the analysis of NHEJ in a wide range of tissues and demonstrates that DNA repair by NHEJ declines with age in mice, which could provide a mechanism for age-related genomic instability and increased cancer incidence with age.

  7. Knock-In Reporter Mice Demonstrate that DNA Repair by Non-homologous End Joining Declines with Age

    Vaidya, Amita; Mao, Zhiyong; Tian, Xiao; Spencer, Brianna; Seluanov, Andrei; Gorbunova, Vera

    2014-01-01

    Accumulation of genome rearrangements is a characteristic of aged tissues. Since genome rearrangements result from faulty repair of DNA double strand breaks (DSBs), we hypothesized that DNA DSB repair becomes less efficient with age. The Non-Homologous End Joining (NHEJ) pathway repairs a majority of DSBs in vertebrates. To examine age-associated changes in NHEJ, we have generated an R26NHEJ mouse model in which a GFP-based NHEJ reporter cassette is knocked-in to the ROSA26 locus. In this model, NHEJ repair of DSBs generated by the site-specific endonuclease, I-SceI, reconstitutes a functional GFP gene. In this system NHEJ efficiency can be compared across tissues of the same mouse and in mice of different age. Using R26NHEJ mice, we found that NHEJ efficiency was higher in the skin, lung, and kidney fibroblasts, and lower in the heart fibroblasts and brain astrocytes. Furthermore, we observed that NHEJ efficiency declined with age. In the 24-month old animals compared to the 5-month old animals, NHEJ efficiency declined 1.8 to 3.8-fold, depending on the tissue, with the strongest decline observed in the skin fibroblasts. The sequence analysis of 300 independent NHEJ repair events showed that, regardless of age, mice utilize microhomology sequences at a significantly higher frequency than expected by chance. Furthermore, the frequency of microhomology-mediated end joining (MMEJ) events increased in the heart and lung fibroblasts of old mice, suggesting that NHEJ becomes more mutagenic with age. In summary, our study provides a versatile mouse model for the analysis of NHEJ in a wide range of tissues and demonstrates that DNA repair by NHEJ declines with age in mice, which could provide a mechanism for age-related genomic instability and increased cancer incidence with age. PMID:25033455

  8. Orexin/hypocretin and histamine: distinct roles in the control of wakefulness demonstrated using knock-out mouse models.

    Anaclet, Christelle; Parmentier, Régis; Ouk, Koliane; Guidon, Gérard; Buda, Colette; Sastre, Jean-Pierre; Akaoka, Hidéo; Sergeeva, Olga A; Yanagisawa, Masashi; Ohtsu, Hiroshi; Franco, Patricia; Haas, Helmut L; Lin, Jian-Sheng

    2009-11-18

    To determine the respective role played by orexin/hypocretin and histamine (HA) neurons in maintaining wakefulness (W), we characterized the behavioral and sleep-wake phenotypes of orexin (Ox) knock-out (-/-) mice and compared them with those of histidine-decarboxylase (HDC, HA-synthesizing enzyme)-/- mice. While both mouse strains displayed sleep fragmentation and increased paradoxical sleep (PS), they presented a number of marked differences: (1) the PS increase in HDC(-/-) mice was seen during lightness, whereas that in Ox(-/-) mice occurred during darkness; (2) contrary to HDC(-/-), Ox(-/-) mice had no W deficiency around lights-off, nor an abnormal EEG and responded to a new environment with increased W; (3) only Ox(-/-), but not HDC(-/-) mice, displayed narcolepsy and deficient W when faced with motor challenge. Thus, when placed on a wheel, wild-type (WT), but not littermate Ox(-/-) mice, voluntarily spent their time in turning it and as a result, remained highly awake; this was accompanied by dense c-fos expression in many areas of their brains, including Ox neurons in the dorsolateral hypothalamus. The W and motor deficiency of Ox(-/-) mice was due to the absence of Ox because intraventricular dosing of orexin-A restored their W amount and motor performance whereas SB-334867 (Ox1-receptor antagonist, i.p.) impaired W and locomotion of WT mice during the test. These data indicate that Ox, but not HA, promotes W through enhanced locomotion and suggest that HA and Ox neurons exert a distinct, but complementary and synergistic control of W: the neuropeptide being more involved in its behavioral aspects, whereas the amine is mainly responsible for its qualitative cognitive aspects and cortical EEG activation.

  9. Disruption of seven hypothetical aryl alcohol dehydrogenase genes from Saccharomyces cerevisiae and construction of a multiple knock-out strain.

    Delneri, D; Gardner, D C; Bruschi, C V; Oliver, S G

    1999-11-01

    By in silicio analysis, we have discovered that there are seven open reading frames (ORFs) in Saccharomyces cerevisiae whose protein products show a high degree of amino acid sequence similarity to the aryl alcohol dehydrogenase (AAD) of the lignin-degrading fungus Phanerochaete chrysosporium. Yeast cultures grown to stationary phase display a significant aryl alcohol dehydrogenase activity by degrading aromatic aldehydes to the corresponding alcohols. To study the biochemical and the biological role of each of the AAD genes, a series of mutant strains carrying deletion of one or more of the AAD-coding sequences was constructed by PCR-mediated gene replacement, using the readily selectable marker kanMX. The correct targeting of the PCR-generated disruption cassette into the genomic locus was verified by analytical PCR and by pulse-field gel electrophoresis (PFGE) followed by Southern blot analysis. Double, triple and quadruple mutant strains were obtained by classical genetic methods, while the construction of the quintuple, sextuple and septuple mutants was achieved by using the marker URA3 from Kluyveromyces lactis, HIS3 from Schizosaccharomyces pombe and TRP1 from S. cerevisiae. None of the knock-out strains revealed any mutant phenotype when tested for the degradation of aromatic aldehydes using both spectrophotometry and high performance liquid chromatography (HPLC). Specific tests for changes in the ergosterol and phospholipids profiles did not reveal any mutant phenotype and mating and sporulation efficiencies were not affected in the septuple deletant. Compared to the wild-type strain, the septuple deletant showed an increased resistance to the anisaldehyde, but there is a possibility that the nutritional markers used for gene replacement are causing this effect.

  10. T cell responses in mammalian diaphanous-related formin mDia1 knock-out mice.

    Eisenmann, Kathryn M; West, Richard A; Hildebrand, Dagmar; Kitchen, Susan M; Peng, Jun; Sigler, Robert; Zhang, Jinyi; Siminovitch, Katherine A; Alberts, Arthur S

    2007-08-24

    Activated T cells rapidly assemble filamentous (F-) actin networks in response to ligation of the T cell receptor or upon interaction with adhesive stimuli in order to facilitate cell migration and the formation of the immune synapse. Branched filament assembly is crucial for this process and is dependent upon activation of the Arp2/3 complex by the actin nucleation-promoting factor Wiskott-Aldrich Syndrome protein (WASp). Genetic disruption of the WAS gene has been linked to hematopoietic malignancies and various cytopenias. Although the contributions of WASp and Arp2/3 to T cell responses are fairly well characterized, the role of the mammalian Diaphanous (mDia)-related formins, which both nucleate and processively elongate non-branched F-actin, has not been demonstrated. Here, we report the effects on T cell development and function following the knock out of the murine Drf1 gene encoding the canonical formin p140mDia1. Drf1(-/-) mice develop lymphopenia characterized by diminished T cell populations in lymphoid tissues. Consistent with a role for p140mDia1 in the regulation of the actin cytoskeleton, isolated Drf1(-/-) splenic T cells adhered poorly to extracellular matrix proteins and migration in response to chemotactic stimuli was completely abrogated. Both integrin and chemokine receptor expression was unaffected by Drf1(-/-) targeting. In response to proliferative stimuli, both thymic and splenic Drf1(-/-) T cells failed to proliferate; ERK1/2 activation was also diminished in activated Drf1(-/-) T cells. These data suggest a central role for p140mDia1 in vivo in dynamic cytoskeletal remodeling events driving normal T cell responses.

  11. Bone marrow transplantation improves autoinflammation and inflammatory bone loss in SH3BP2 knock-in cherubism mice.

    Yoshitaka, Teruhito; Kittaka, Mizuho; Ishida, Shu; Mizuno, Noriyoshi; Mukai, Tomoyuki; Ueki, Yasuyoshi

    2015-02-01

    Cherubism (OMIM#118400) is a genetic disorder in children characterized by excessive jawbone destruction with proliferation of fibro-osseous lesions containing a large number of osteoclasts. Mutations in the SH3-domain binding protein 2 (SH3BP2) are responsible for cherubism. Analysis of the knock-in (KI) mouse model of cherubism showed that homozygous cherubism mice (Sh3bp2(KI/KI)) spontaneously develop systemic autoinflammation and inflammatory bone loss and that cherubism is a TNF-α-dependent hematopoietic disorder. In this study, we investigated whether bone marrow transplantation (BMT) is effective for the treatment of inflammation and bone loss in Sh3bp2(KI/KI) mice. Bone marrow (BM) cells from wild-type (Sh3bp2(+/+)) mice were transplanted to 6-week-old Sh3bp2(KI/KI) mice with developing inflammation and to 10-week-old Sh3bp2(KI/KI) mice with established inflammation. Six-week-old Sh3bp2(KI/KI) mice transplanted with Sh3bp2(+/+) BM cells exhibited improved body weight loss, facial swelling, and survival rate. Inflammatory lesions in the liver and lung as well as bone loss in calvaria and mandibula were ameliorated at 10weeks after BMT compared to Sh3bp2(KI/KI) mice transplanted with Sh3bp2(KI/KI) BM cells. Elevation of serum TNF-α levels was not detected after BMT. BMT was effective for up to 20weeks in 6-week-old Sh3bp2(KI/KI) mice transplanted with Sh3bp2(+/+) BM cells. BMT also ameliorated the inflammation and bone loss in 10-week-old Sh3bp2(KI/KI) mice. Thus our study demonstrates that BMT improves the inflammation and bone loss in cherubism mice. BMT may be effective for the treatment of cherubism patients.

  12. New Lmna knock-in mice provide a molecular mechanism for the 'segmental aging' in Hutchinson-Gilford progeria syndrome.

    Jung, Hea-Jin; Tu, Yiping; Yang, Shao H; Tatar, Angelica; Nobumori, Chika; Wu, Daniel; Young, Stephen G; Fong, Loren G

    2014-03-15

    Lamins A and C (products of the LMNA gene) are found in roughly equal amounts in peripheral tissues, but the brain produces mainly lamin C and little lamin A. In HeLa cells and fibroblasts, the expression of prelamin A (the precursor to lamin A) can be reduced by miR-9, but the relevance of those cell culture studies to lamin A regulation in the brain was unclear. To address this issue, we created two new Lmna knock-in alleles, one (Lmna(PLAO-5NT)) with a 5-bp mutation in a predicted miR-9 binding site in prelamin A's 3' UTR, and a second (Lmna(PLAO-UTR)) in which prelamin A's 3' UTR was replaced with lamin C's 3' UTR. Neither allele had significant effects on lamin A levels in peripheral tissues; however, both substantially increased prelamin A transcript levels and lamin A protein levels in the cerebral cortex and the cerebellum. The increase in lamin A expression in the brain was more pronounced with the Lmna(PLAO-UTR) allele than with the Lmna(PLAO-5NT) allele. With both alleles, the increased expression of prelamin A transcripts and lamin A protein was greater in the cerebral cortex than in the cerebellum. Our studies demonstrate the in vivo importance of prelamin A's 3' UTR and its miR-9 binding site in regulating lamin A expression in the brain. The reduced expression of prelamin A in the brain likely explains why children with Hutchinson-Gilford progeria syndrome (a progeroid syndrome caused by a mutant form of prelamin A) are spared from neurodegenerative disease.

  13. Multiphysics simulations: challenges and opportunities.

    Keyes, D.; McInnes, L. C.; Woodward, C.; Gropp, W.; Myra, E.; Pernice, M. (Mathematics and Computer Science); (KAUST and Columbia Univ.); (Lawrence Livermore National Laboratory); (Univ. of Illinois at Urbana-Champaign); (Univ. of Mich.); (Idaho National Lab.)

    2012-11-29

    This report is an outcome of the workshop Multiphysics Simulations: Challenges and Opportunities, sponsored by the Institute of Computing in Science (ICiS). Additional information about the workshop, including relevant reading and presentations on multiphysics issues in applications, algorithms, and software, is available via https://sites.google.com/site/icismultiphysics2011/. We consider multiphysics applications from algorithmic and architectural perspectives, where 'algorithmic' includes both mathematical analysis and computational complexity and 'architectural' includes both software and hardware environments. Many diverse multiphysics applications can be reduced, en route to their computational simulation, to a common algebraic coupling paradigm. Mathematical analysis of multiphysics coupling in this form is not always practical for realistic applications, but model problems representative of applications discussed herein can provide insight. A variety of software frameworks for multiphysics applications have been constructed and refined within disciplinary communities and executed on leading-edge computer systems. We examine several of these, expose some commonalities among them, and attempt to extrapolate best practices to future systems. From our study, we summarize challenges and forecast opportunities. We also initiate a modest suite of test problems encompassing features present in many applications.

  14. Arctic resources : a mechatronics opportunity

    McKean, M.; Baiden, G. [Penguin Automated Systems Inc., Naughton, ON (Canada)

    2008-07-01

    This paper discussed the telerobotic mechatronics opportunities that exist to access mineral resources in the Arctic. The Mining Automation Project (MAP) determined that telerobotics could contribute to productivity gains while providing increased worker safety. The socio-economic benefits of advanced mechatronics for Arctic resource development are particularly attractive due to reduced infrastructure needs; operating costs; and environmental impacts. A preliminary analysis of mining transportation options by the authors revealed that there is a case for in-situ resource utilization (ISRU) for oil and gas processing to address resource development. The ISRU options build on concepts developed to support space exploration and were proposed to reduce or modify transportation loads to allow more sustainable and efficient Arctic resource development. Many benefits in terms of efficiency could be achieved by combining demonstrated mechatronics with ISRU because of the constrained transportation infrastructure in the Arctic. In the context of harsh environment operations, mechatronics may provide an opportunity for undersea resource facilities. 15 refs., 6 figs.

  15. Examining equity of opportunities for learning mathematics through positioning theory

    Tait-McCutcheon, Sandi L.; Loveridge, Judith

    2016-06-01

    This exploratory study examined how two teachers from two New Zealand primary schools introduced and taught the same mathematics lesson to their lowest ability group of year 2 and 3 students. Emphasis was given to analysing the positioning of the teacher and students and the developing storylines and social acts from that positioning. Different positionings by teachers of themselves and their students led to inequitable opportunities for active and collaborative participation in the mathematics. The differences in pedagogy revealed through the use of positioning theory suggest that the way teachers positioned themselves and their students was more influential than the resources they were teaching with.

  16. The ACTS multibeam antenna

    Regier, Frank A.

    1992-01-01

    The Advanced Communications Technology Satellite (ACTS) to be launched in 1993 is briefly introduced. Its multibeam antenna, consisting of electrically similar 30 GHz receive and 20 GHz transmit offset Cassegrain systems, both utilizing orthogonal polarizations, is described. Dual polarization is achieved by using one feed assembly for each polarization in conjunction with nested front and back subreflectors, the gridded front subreflector acting as a window for one polarization and a reflector for the other. The antennas produce spot beams with approximately 0.3 degree beamwidth and gains of approximately 50 dbi. High surface accuracy and high edge taper produce low sidelobe levels and high cross-polarization isolation. A brief description is given of several Ka-band components fabricated for ACTS. These include multiflare antenna feedhorns, beam-forming networks utilizing latching ferrite waveguide switches, a 30 GHz HEMT low-noise amplifier and a 20 GHz TWT power amplifier.

  17. The ACTS multibeam antenna

    Regier, Frank A.

    1992-06-01

    The Advanced Communications Technology Satellite (ACTS) to be launched in 1993 is briefly introduced. Its multibeam antenna, consisting of electrically similar 30 GHz receive and 20 GHz transmit offset Cassegrain systems, both utilizing orthogonal polarizations, is described. Dual polarization is achieved by using one feed assembly for each polarization in conjunction with nested front and back subreflectors, the gridded front subreflector acting as a window for one polarization and a reflector for the other. The antennas produce spot beams with approximately 0.3 degree beamwidth and gains of approximately 50 dbi. High surface accuracy and high edge taper produce low sidelobe levels and high cross-polarization isolation. A brief description is given of several Ka-band components fabricated for ACTS. These include multiflare antenna feedhorns, beam-forming networks utilizing latching ferrite waveguide switches, a 30 GHz HEMT low-noise amplifier and a 20 GHz TWT power amplifier.

  18. CONSIDERATIONS UPON ASSIMILATED ADMINISTRATIVE ACTS

    2011-01-01

    Although the classic administrative courts know as object the acts against classic administrative acts, it should not be lost sight of the assimilated administrative acts, which also may be subject to acts in this litigation. Taking in consideration this category of acts, this study will examine the documents falling into this category and the impact that such acts have on public authorities. Given the significant increase of administrative cases that have as object assimilated administrative...

  19. Opportunities for green growth; Vihreaen kasvun mahdollisuudet

    Antikainen, R.; Mickwitz, P.; Seppaelae, J. [and others

    2013-03-15

    The report seeks an answer to the question as to the kind of policy decisions (steps) by which preconditions for green growth may be created in Finland. The proposed steps are based on a review of earlier research and studies relating to Finland's key consumption and production systems (food, housing, transport and energy) and to certain path finding countries in terms of the green economy (the Netherlands, Germany, Sweden, Brazil). In addition, the report examines various models by which systemic change towards a green economy may be supported. The report also highlights successful examples of green business activity and measures to promote green growth. Green Growth is defined as low-carbon, resource-efficient economic growth based on safeguarding the functional capacity of ecosystems while promoting wellbeing and social justice. Green growth is considered to have significant worldwide potential, which is currently evident particularly in the rapid growth of cleantech demand. Successful future actors will be more material- and energy-efficient than their competitors, and they will be able to provide services and products flexibly for a low-carbon society. There are opportunities for green growth in all sectors of society. Green growth may consist of an entirely new kind of business activity and create new companies, but there are also opportunities in our traditional energy- and resource-intensive industries. Companies have a key role in growth, but realising green growth also requires changes in consumption. Central, regional and local government will act as facilitators in creating the preconditions for green growth. The report presents a number of policy measures and processes by which Finland can support green growth. Proposals for steps towards green growth include: (A.) Creating preconditions for green growth through a joint vision and political commitment. (B.) Stimulating companies' green growth potential and boosting green demand. (C

  20. Exploration Science Opportunities for Students within Higher Education

    Bailey, Brad; Minafra, Joseph; Schmidt, Gregory

    2016-10-01

    The NASA Solar System Exploration Research Virtual Institute (SSERVI) is a virtual institute focused on exploration science related to near-term human exploration targets, training the next generation of lunar scientists, and education and public outreach. As part of the SSERVI mission, we act as a hub for opportunities that engage the public through education and outreach efforts in addition to forming new interdisciplinary, scientific collaborations.SSERVI provides opportunities for students to bridge the scientific and generational gap currently existing in the planetary exploration field. This bridge is essential to the continued international success of scientific, as well as human and robotic, exploration.The decline in funding opportunities after the termination of the Apollo missions to the Moon in the early 1970's produced a large gap in both the scientific knowledge and experience of the original lunar Apollo researchers and the resurgent group of young lunar/NEA researchers that have emerged within the last 15 years. One of SSERVI's many goals is to bridge this gap through the many networking and scientific connections made between young researchers and established planetary principle investigators. To this end, SSERVI has supported the establishment of NextGen Lunar Scientists and Engineers group (NGLSE), a group of students and early-career professionals designed to build experience and provide networking opportunities to its members. SSERVI has also created the LunarGradCon, a scientific conference dedicated solely to graduate and undergraduate students working in the lunar field. Additionally, SSERVI produces monthly seminars and bi-yearly virtual workshops that introduce students to the wide variety of exploration science being performed in today's research labs. SSERVI also brokers opportunities for domestic and international student exchange between collaborating laboratories as well as internships at our member institutions. SSERVI provides a

  1. ST–ACTS

    Gidofalvi, Gyozo; Pedersen, Torben Bach

    2006-01-01

    various geo–statistical data sources and intuitive principles, models the so far neglected aspects. ST–ACTS considers that (1) objects (representing mobile users) move from one spatio–temporal location to another with the objective of performing a certain activity at the latter location; (2) not all users...

  2. Acting like a Pro

    Walker, Marlon A.

    2012-01-01

    The Saturday morning acting class in the Pearson Hall auditorium at Miles College boasts the school's highest attendance all year. The teacher, actress Robin Givens, was a lure few students--and others from surrounding areas--could resist. Some came to learn about their prospective field from a professional. Others were there for pointers to…

  3. Acts of Research

    Nelund, Sidsel

    described as knowledge producers and exhibitions and art works as instances of knowledge production. Acts of Research: Knowledge Production in Contemporary Arts between Knowledge Economy and Critical Practices analyses this development. The academic discussion of knowledge production in the arts has taken...

  4. Photovoltaic research opportunities. Final report

    Macaleer, B.; Bowers, J.; Hurlburt, B.

    1985-11-19

    The purpose of this study is to identify opportunities for photovoltaic (PV) research projects to capitalize on related but non-PV research. The study is performed under the assumption that a considerable body of ongoing semiconductor research in non-PV areas could be of value to its PV Program and the PV community in general. Research related to III-V compounds, thin films, and crystalline silicon materials is included. Research that is known to be PV-related or sponsored by DOE was excluded from consideration. The study resulted in 11 recommendations (research areas) and a subset of 58 specific research projects. In addition, over 75 non-PV research managers in the semiconductor field are identified as potential sources of ideas which could benefit photovoltaics.

  5. Opportunities From the Digital Revolution

    Louise Corti

    2016-11-01

    Full Text Available In the 1990s, the term “online” research emerged as a new and vibrant suite of methods, focused on exploitation of sources not collected by traditional social science methods. Today, at least one part of the research life cycle is likely to be carried out “online,” from data collection through to publishing. In this article, we seek to understand emergent modes of doing and reporting qualitative research “online.” With a greater freedom now to term oneself a “researcher,” what opportunities and problems do working with online data sources bring? We explore implications of emerging requirements to submit supporting data for social science journal articles and question whether these demands might disrupt the very nature of and identity of qualitative research. Finally, we examine more recent forms of publishing and communicating research that support outputs where data play an integral role in elucidating context and enhancing the reading experience.

  6. Challenges and opportunities in presbycusis.

    Parham, Kourosh; McKinnon, Brian J; Eibling, David; Gates, George A

    2011-04-01

    The population aged 65 years and older is increasing at a faster rate than the total population, with predictions that by 2030, 20% of the population will be 65 years or older. In 2006, between 35% and 50% of those aged 65 years or older reportedly had presbycusis, a sensory impairment that contributes to social isolation and loss of autonomy and is associated with anxiety, depression, and cognitive decline. To address these concerns, the Geriatric Committee of the American Academy of Otolaryngology, in conjunction with the Hearing Committee, focused on 3 challenges and opportunities in the management of presbycusis: (1) the financial burden of caring for patients with presbycusis in the face of increasing costs and declining reimbursements; (2) future treatment options arising from improved understanding of the molecular mechanisms underlying presbycusis, and (3) recognition of central presbycusis as a condition commonly superimposed on peripheral age-related hearing loss whose diagnosis and management can improve outcomes.

  7. Physics Opportunities with Meson Beams

    Briscoe, William J; Haberzettl, Helmut; Manley, D Mark; Naruki, Megumi; Strakovsky, Igor I; Swanson, Eric S

    2015-01-01

    Over the past two decades, meson photo- and electro-production data of unprecedented quality and quantity have been measured at electromagnetic facilities worldwide. By contrast, the meson-beam data for the same hadronic final states are mostly outdated and largely of poor quality, or even nonexistent, and thus provide inadequate input to help interpret, analyze, and exploit the full potential of the new electromagnetic data. To reap the full benefit of the high-precision electromagnetic data, new high-statistics data from measurements with meson beams, with good angle and energy coverage for a wide range of reactions, are critically needed to advance our knowledge in baryon and meson spectroscopy and other related areas of hadron physics. To address this situation, a state of-the-art meson-beam facility needs to be constructed. The present paper summarizes unresolved issues in hadron physics and outlines the vast opportunities and advances that only become possible with such a facility.

  8. Multiphysics simulations: Challenges and opportunities

    Keyes, David E.

    2013-02-01

    We consider multiphysics applications from algorithmic and architectural perspectives, where "algorithmic" includes both mathematical analysis and computational complexity, and "architectural" includes both software and hardware environments. Many diverse multiphysics applications can be reduced, en route to their computational simulation, to a common algebraic coupling paradigm. Mathematical analysis of multiphysics coupling in this form is not always practical for realistic applications, but model problems representative of applications discussed herein can provide insight. A variety of software frameworks for multiphysics applications have been constructed and refined within disciplinary communities and executed on leading-edge computer systems. We examine several of these, expose some commonalities among them, and attempt to extrapolate best practices to future systems. From our study, we summarize challenges and forecast opportunities. © The Author(s) 2012.

  9. CORIDORS: DEVELOPMENT OPPORTUNITY OF SERBIA

    Laketa Marko

    2011-12-01

    Full Text Available Long-term vision of the Republic of Serbia is for it to be: territorially determined and regionally balanced, of sustainable economic growth and competitive, socially coherent and stable, infrastructurally equipped and accessible in terms of transportation, of preserved and protected natural and cultural heritage, high-quality living environment and functionally integrated into environment. High-quality transportation infrastructure is one of the main conditions of linking and integration into a broader environment. The aim of this paper is to show, based on the identification of the effects expected (internal and external, that Corridors 7 and 10, as logistics resources, are a development opportunity of Serbia and that its realization will multiply contribute to the achievement of long-term development goals of Serbia.

  10. Biomass Business Opportunities Viet Nam

    Zwebe, D. [SNV Netherlands Development Organisation, Ha Noi (Viet Nam)

    2012-03-15

    The goal of this survey is to provide a more specific and integral perspective in which niches, relevant policy development by the Vietnamese government, legislation and sustainability criteria are clearly addressed to benefit both the Dutch Private sector as well as to stimulate Dutch-Vietnamese cooperation and support the Vietnamese government in its search for tangible options to develop the desired enabling environment for a sustainable biomass/biofuel market. The following activities are defined to be executed to reach the goal of the project: Biomass availability in Vietnam (Chapter 2); Government of Vietnam and Energy (Chapter 3); The opportunities and barriers to enter the market in Vietnam (Chapter 4 and 5); Stakeholder analysis of the bio-energy sector (Chapter 6); and Recommendations (Chapter 7)

  11. Angiogenesis and Its Therapeutic Opportunities

    So Young Yoo

    2013-01-01

    Full Text Available Angiogenesis plays critical roles in human physiology that range from reproduction and fetal growth to wound healing and tissue repair. The sophisticated multistep process is tightly regulated in a spatial and temporal manner by “on-off switch signals” between angiogenic factors, extracellular matrix components, and endothelial cells. Uncontrolled angiogenesis may lead to several angiogenic disorders, including vascular insufficiency (myocardial or critical limb ischemia and vascular overgrowth (hemangiomas, vascularized tumors, and retinopathies. Thus, numerous therapeutic opportunities can be envisaged through the successful understanding and subsequent manipulation of angiogenesis. Here, we review the clinical implications of angiogenesis and discuss pro- and antiangiogenic agents that offer potential therapy for cancer and other angiogenic diseases.

  12. Physics opportunities with meson beams

    Briscoe, William J.; Doering, Michael; Haberzettl, Helmut; Strakovsky, Igor I. [The George Washington University, Washington, DC (United States); Manley, D.M. [Kent State University, Kent, OH (United States); Naruki, Megumi [Kyoto University, Kyoto (Japan); Swanson, Eric S. [University of Pittsburgh, Pittsburgh, PA (United States)

    2015-10-15

    Over the past two decades, meson photo- and electroproduction data of unprecedented quality and quantity have been measured at electromagnetic facilities worldwide. By contrast, the meson-beam data for the same hadronic final states are mostly outdated and largely of poor quality, or even non-existent, and thus provide inadequate input to help interpret, analyze, and exploit the full potential of the new electromagnetic data. To reap the full benefit of the high-precision electromagnetic data, new high-statistics data from measurements with meson beams, with good angle and energy coverage for a wide range of reactions, are critically needed to advance our knowledge in baryon and meson spectroscopy and other related areas of hadron physics. To address this situation, a state-of-the-art meson-beam facility needs to be constructed. The present paper summarizes unresolved issues in hadron physics and outlines the vast opportunities and advances that only become possible with such a facility. (orig.)

  13. Multiphysics Simulations: Challenges and Opportunities

    Keyes, David; McInnes, Lois C.; Woodward, Carol; Gropp, William; Myra, Eric; Pernice, Michael; Bell, John; Brown, Jed; Clo, Alain; Connors, Jeffrey; Constantinescu, Emil; Estep, Don; Evans, Kate; Farhat, Charbel; Hakim, Ammar; Hammond, Glenn E.; Hansen, Glen; Hill, Judith; Isaac, Tobin; Jiao, Xiangmin; Jordan, Kirk; Kaushik, Dinesh; Kaxiras, Efthimios; Koniges, Alice; Lee, Ki Hwan; Lott, Aaron; Lu, Qiming; Magerlein, John; Maxwell, Reed M.; McCourt, Michael; Mehl, Miriam; Pawlowski, Roger; Randles, Amanda; Reynolds, Daniel; Riviere, Beatrice; Rude, Ulrich; Scheibe, Timothy D.; Shadid, John; Sheehan, Brendan; Shephard, Mark; Siegel, Andrew; Smith, Barry; Tang, Xianzhu; Wilson, Cian; Wohlmuth, Barbara

    2013-02-12

    We consider multiphysics applications from algorithmic and architectural perspectives, where ‘‘algorithmic’’ includes both mathematical analysis and computational complexity, and ‘‘architectural’’ includes both software and hardware environments. Many diverse multiphysics applications can be reduced, en route to their computational simulation, to a common algebraic coupling paradigm. Mathematical analysis of multiphysics coupling in this form is not always practical for realistic applications, but model problems representative of applications discussed herein can provide insight. A variety of software frameworks for multiphysics applications have been constructed and refined within disciplinary communities and executed on leading-edge computer systems. We examine several of these, expose some commonalities among them, and attempt to extrapolate best practices to future systems. From our study, we summarize challenges and forecast opportunities.

  14. Opportunity structures for selective exposure

    Skovsgaard, Morten; Shehata, Adam; Strömbäck, Jesper

    2016-01-01

    Abstract The transition from low-choice to high-choice media environments has raised new concerns about selective exposure. In this context, two types of selective media exposure are relevant. One is selectivity based on political ideological preferences, the other selectivity based on political...... interest. Evidence for both has been found primarily in an American context, while there is less research on European countries. This is problematic, as the opportunity structures for different forms of selectivity vary across media environments. Against this background, the purpose of this study...... that selective exposure based on political interest is substantially more important than selective exposure based on ideological preferences in explaining exposure to party-leader interviews. To substantiate this finding, the results are replicated with partisan learning as the dependent variable....

  15. Plastics recycling: challenges and opportunities.

    Hopewell, Jefferson; Dvorak, Robert; Kosior, Edward

    2009-07-27

    Plastics are inexpensive, lightweight and durable materials, which can readily be moulded into a variety of products that find use in a wide range of applications. As a consequence, the production of plastics has increased markedly over the last 60 years. However, current levels of their usage and disposal generate several environmental problems. Around 4 per cent of world oil and gas production, a non-renewable resource, is used as feedstock for plastics and a further 3-4% is expended to provide energy for their manufacture. A major portion of plastic produced each year is used to make disposable items of packaging or other short-lived products that are discarded within a year of manufacture. These two observations alone indicate that our current use of plastics is not sustainable. In addition, because of the durability of the polymers involved, substantial quantities of discarded end-of-life plastics are accumulating as debris in landfills and in natural habitats worldwide. Recycling is one of the most important actions currently available to reduce these impacts and represents one of the most dynamic areas in the plastics industry today. Recycling provides opportunities to reduce oil usage, carbon dioxide emissions and the quantities of waste requiring disposal. Here, we briefly set recycling into context against other waste-reduction strategies, namely reduction in material use through downgauging or product reuse, the use of alternative biodegradable materials and energy recovery as fuel. While plastics have been recycled since the 1970s, the quantities that are recycled vary geographically, according to plastic type and application. Recycling of packaging materials has seen rapid expansion over the last decades in a number of countries. Advances in technologies and systems for the collection, sorting and reprocessing of recyclable plastics are creating new opportunities for recycling, and with the combined actions of the public, industry and governments it

  16. The Interpretation and Effective Implementation of the Stevenson-Wydler Technology Innovation Act of 1996

    Heard, Pamala D.

    1996-01-01

    The purpose of this research is to develop a plan that gives schools the opportunity to acquire knowledge of the Stevenson-Wydler Technology Innovation Act. The law suggests that federal agencies give surplus equipment to educational entities. It would then become the school's choice to take advantage of the opportunity. The purpose of this proposal is to develop an ongoing partnership with schools around the United States. Its attempt is to inform schools about the law and organize a plan that will allow schools to take advantage of this opportunity. It would inform teachers about available resources and expose their students to educational opportunities.

  17. 76 FR 11285 - Notice of Funding Opportunity and Solicitation for Grant Applications (SGA) for Serving Juvenile...

    2011-03-01

    ... Workforce Investment Act of 1998 is described in further detail on ETA's Web site at http://www.doleta.gov... Opportunity Number: SGA/DFA PY 10-09. SUMMARY: Through this notice, the Department of Labor's Employment and Training Administration (ETA) announces the availability of approximately $17 million in grant...

  18. 76 FR 6634 - Notice of Funding Opportunity and Solicitation for Grant Applications (SGA) for Civic Justice...

    2011-02-07

    ... Justice Corps projects funded through this grant announcement will provide young offenders the opportunity... (SGA) for Civic Justice Corps Grants Serving Juvenile Offenders AGENCY: Employment and Training... Workforce Investment Act for Civic Justice Corps Grants to serve juvenile offenders ages 18 to 24 who...

  19. The theory act

    Wæver, Ole

    2015-01-01

    such as social equality or solidarity and equal opportunities for genders, all of which would not be conceivable in a ‘state of nature’ ethology. To acknowledge in theory and investigate such power is at the same time to foster it and defend it against the risk of regression into forms of social life based......Austin gives us insights into the capacity of mankind for creating shared environments through language, not as a matter of transmitting anything from one head to the other or of causally influencing each other’s mental states, but as a matter of establishing situations and roles and attributing...

  20. The theory act

    Wæver, Ole

    2015-01-01

    local statuses to participants. Herein lies the power of human civilization as opposed to ‘state of nature’; the power which alone makes it possible, on occasion, for someone weak and without weapons to be listened to and even obeyed, the power which makes it possible to conceive and pursue things...... such as social equality or solidarity and equal opportunities for genders, all of which would not be conceivable in a ‘state of nature’ ethology. To acknowledge in theory and investigate such power is at the same time to foster it and defend it against the risk of regression into forms of social life based...

  1. Efficient Generation of Myostatin Knock-Out Sheep Using CRISPR/Cas9 Technology and Microinjection into Zygotes.

    M Crispo

    Full Text Available While CRISPR/Cas9 technology has proven to be a valuable system to generate gene-targeted modified animals in several species, this tool has been scarcely reported in farm animals. Myostatin is encoded by MSTN gene involved in the inhibition of muscle differentiation and growth. We determined the efficiency of the CRISPR/Cas9 system to edit MSTN in sheep and generate knock-out (KO animals with the aim to promote muscle development and body growth. We generated CRISPR/Cas9 mRNAs specific for ovine MSTN and microinjected them into the cytoplasm of ovine zygotes. When embryo development of CRISPR/Cas9 microinjected zygotes (n = 216 was compared with buffer injected embryos (n = 183 and non microinjected embryos (n = 173, cleavage rate was lower for both microinjected groups (P<0.05 and neither was affected by CRISPR/Cas9 content in the injected medium. Embryo development to blastocyst was not affected by microinjection and was similar among the experimental groups. From 20 embryos analyzed by Sanger sequencing, ten were mutant (heterozygous or mosaic; 50% efficiency. To obtain live MSTN KO lambs, 53 blastocysts produced after zygote CRISPR/Cas9 microinjection were transferred to 29 recipient females resulting in 65.5% (19/29 of pregnant ewes and 41.5% (22/53 of newborns. From 22 born lambs analyzed by T7EI and Sanger sequencing, ten showed indel mutations at MSTN gene. Eight showed mutations in both alleles and five of them were homozygous for indels generating out-of frame mutations that resulted in premature stop codons. Western blot analysis of homozygous KO founders confirmed the absence of myostatin, showing heavier body weight than wild type counterparts. In conclusion, our results demonstrate that CRISPR/Cas9 system was a very efficient tool to generate gene KO sheep. This technology is quick and easy to perform and less expensive than previous techniques, and can be applied to obtain genetically modified animal models of interest for

  2. Distribution of knock-down resistance mutations in Anopheles gambiae molecular forms in west and west-central Africa

    Caccone Adalgisa

    2008-04-01

    Full Text Available Abstract Background Knock-down resistance (kdr to DDT and pyrethroids in the major Afrotropical vector species, Anopheles gambiae sensu stricto, is associated with two alternative point mutations at amino acid position 1014 of the voltage-gated sodium channel gene, resulting in either a leucine-phenylalanine (L1014F, or a leucine-serine (L1014S substitution. In An. gambiae S-form populations, the former mutation appears to be widespread in west Africa and has been recently reported from Uganda, while the latter, originally recorded in Kenya, has been recently found in Gabon, Cameroon and Equatorial Guinea. In M-form populations surveyed to date, only the L1014F mutation has been found, although less widespread and at lower frequencies than in sympatric S-form populations. Methods Anopheles gambiae M- and S-form specimens from 19 sites from 11 west and west-central African countries were identified to molecular form and genotyped at the kdr locus either by Hot Oligonucleotide Ligation Assay (HOLA or allele-specific PCR (AS-PCR. Results The kdr genotype was determined for about 1,000 An. gambiae specimens. The L1014F allele was found at frequencies ranging from 6% to 100% in all S-form samples (N = 628, with the exception of two samples from Angola, where it was absent, and coexisted with the L1014S allele in samples from Cameroon, Gabon and north-western Angola. The L1014F allele was present in M-form samples (N = 354 from Benin, Nigeria, and Cameroon, where both M- and S-forms were sympatric. Conclusion The results represent the most comprehensive effort to analyse the overall distribution of the L1014F and L1014S mutations in An. gambiae molecular forms, and will serve as baseline data for resistance monitoring. The overall picture shows that the emergence and spread of kdr alleles in An. gambiae is a dynamic process and that there is marked intra- and inter-form heterogeneity in resistance allele frequencies. Further studies are needed to

  3. A simplified high-throughput method for pyrethroid knock-down resistance (kdr detection in Anopheles gambiae

    Walker Edward D

    2005-03-01

    Full Text Available Abstract Background A single base pair mutation in the sodium channel confers knock-down resistance to pyrethroids in many insect species. Its occurrence in Anopheles mosquitoes may have important implications for malaria vector control especially considering the current trend for large scale pyrethroid-treated bednet programmes. Screening Anopheles gambiae populations for the kdr mutation has become one of the mainstays of programmes that monitor the development of insecticide resistance. The screening is commonly performed using a multiplex Polymerase Chain Reaction (PCR which, since it is reliant on a single nucleotide polymorphism, can be unreliable. Here we present a reliable and potentially high throughput method for screening An. gambiae for the kdr mutation. Methods A Hot Ligation Oligonucleotide Assay (HOLA was developed to detect both the East and West African kdr alleles in the homozygous and heterozygous states, and was optimized for use in low-tech developing world laboratories. Results from the HOLA were compared to results from the multiplex PCR for field and laboratory mosquito specimens to provide verification of the robustness and sensitivity of the technique. Results and Discussion The HOLA assay, developed for detection of the kdr mutation, gives a bright blue colouration for a positive result whilst negative reactions remain colourless. The results are apparent within a few minutes of adding the final substrate and can be scored by eye. Heterozygotes are scored when a sample gives a positive reaction to the susceptible probe and the kdr probe. The technique uses only basic laboratory equipment and skills and can be carried out by anyone familiar with the Enzyme-linked immunosorbent assay (ELISA technique. A comparison to the multiplex PCR method showed that the HOLA assay was more reliable, and scoring of the plates was less ambiguous. Conclusion The method is capable of detecting both the East and West African kdr alleles

  4. Knock and Drill Technique: A Simple Tips for the Instrumentation in Complex Craniovertebral Junction Anomalies without using Fluoroscopy

    Srivastava, Arun; Sardhara, Jayesh; Behari, Sanjay; Pavaman, Sindgikar; Joseph, Jeena; Das, Kuntal; Mehrotra, Anant; Jaiswal, Awadhesh K.; Bhaishora, Kamlesh

    2017-01-01

    Context: Existence of complex variable bony and vertebral artery (VA) anomalies at craniovertebral junction (CVJ) in subset of complex CVJ anomalies demands individualized instrumentation policy and placing screws in each bone requires strategic preoperative planning and intraoperative skills. Aim: To evaluate the clinical accuracy of knock and drill (K and D) technique for the screw placement in complex CVJ anomalies. Settings and Design: Prospective study and operative technical note. Materials and Methods: Totally 36 consecutive patients (16 - pediatrics, 20 - adult patients) of complex CVJ: Complete/partial occipitalized C1 vertebra; at least one hypoplastic (C1/C2) articular mass, rotational component, and variations in the third part of VA were included in this study. Preoperative detail computed tomography (CT) CT CVJ with three-dimensional reconstruction was done for the assessment of CVJ anatomy and facet joint orientation. The accuracy of novel technique was assessed with postoperative CT to evaluate cortical breach in between 5th and 7th postoperative day in all the patients. All patients were underwent clinico-radiological evaluation at 6-month follow-up. Results: Totally 144 screws were placed using K and D technique (pediatric group - 64 screws, adult patients - 80 screws). Total of 12 screws were placed in C1 lateral mass in both age group without any bony cortical breach and complication. Sixteen C2 pedicle screws and 12 C2 pars screw in pediatrics and 18 C2 pedicle screws in adult patients were placed without any bony breach or VA injury. Out of thirty subaxial lateral mass screws in pediatric group, the bony breach was encountered with one screw (3.3%). Total of 38 C2 pars screws was placed in adult group in which bony breach along with VA injury was encounter with 1screw (2.6%). Conclusion: A simple technique of K and D for placing a screw increases the accuracy and spectrum of bony purchase and has the potential to reduce the complication in

  5. Expression of wild-type Rp1 protein in Rp1 knock-in mice rescues the retinal degeneration phenotype.

    Qin Liu

    Full Text Available Mutations in the retinitis pigmentosa 1 (RP1 gene are a common cause of autosomal dominant retinitis pigmentosa (adRP, and have also been found to cause autosomal recessive RP (arRP in a few families. The 33 dominant mutations and 6 recessive RP1 mutations identified to date are all nonsense or frameshift mutations, and almost exclusively (38 out of 39 are located in the 4(th and final exon of RP1. To better understand the underlying disease mechanisms of and help develop therapeutic strategies for RP1 disease, we performed a series of human genetic and animal studies using gene targeted and transgenic mice. Here we report that a frameshift mutation in the 3(rd exon of RP1 (c.686delC; p.P229QfsX35 found in a patient with recessive RP1 disease causes RP in the homozygous state, whereas the heterozygous carriers are unaffected, confirming that haploinsufficiency is not the causative mechanism for RP1 disease. We then generated Rp1 knock-in mice with a nonsense Q662X mutation in exon 4, as well as Rp1 transgenic mice carrying a wild-type BAC Rp1 transgene. The Rp1-Q662X allele produces a truncated Rp1 protein, and homozygous Rp1-Q662X mice experience a progressive photoreceptor degeneration characterized disorganization of photoreceptor outer segments. This phenotype could be prevented by expression of a normal amount of Rp1 protein from the BAC transgene without removal of the mutant Rp1-Q662X protein. Over-expression of Rp1 protein in additional BAC Rp1 transgenic lines resulted in retinal degeneration. These findings suggest that the truncated Rp1-Q662X protein does not exert a toxic gain-of-function effect. These results also imply that in principle gene augmentation therapy could be beneficial for both recessive and dominant RP1 patients, but the levels of RP1 protein delivered for therapy will have to be carefully controlled.

  6. Identification of genes differentially expressed in myogenin knock-down bovine muscle satellite cells during differentiation through RNA sequencing analysis.

    Eun Ju Lee

    Full Text Available BACKGROUND: The expression of myogenic regulatory factors (MRFs consisting of MyoD, Myf5, myogenin (MyoG and MRF4 characterizes various phases of skeletal muscle development including myoblast proliferation, cell-cycle exit, cell fusion and the maturation of myotubes to form myofibers. Although it is well known that the function of MyoG cannot be compensated for other MRFs, the molecular mechanism by which MyoG controls muscle cell differentiation is still unclear. Therefore, in this study, RNA-Seq technology was applied to profile changes in gene expression in response to MyoG knock-down (MyoGkd in primary bovine muscle satellite cells (MSCs. RESULTS: About 61-64% of the reads of over 42 million total reads were mapped to more than 13,000 genes in the reference bovine genome. RNA-Seq analysis identified 8,469 unique genes that were differentially expressed in MyoGkd. Among these genes, 230 were up-regulated and 224 were down-regulated by at least four-fold. DAVID Functional Annotation Cluster (FAC and pathway analysis of all up- and down-regulated genes identified overrepresentation for cell cycle and division, DNA replication, mitosis, organelle lumen, nucleoplasm and cytosol, phosphate metabolic process, phosphoprotein phosphatase activity, cytoskeleton and cell morphogenesis, signifying the functional implication of these processes and pathways during skeletal muscle development. The RNA-Seq data was validated by real time RT-PCR analysis for eight out of ten genes as well as five marker genes investigated. CONCLUSIONS: This study is the first RNA-Seq based gene expression analysis of MyoGkd undertaken in primary bovine MSCs. Computational analysis of the differentially expressed genes has identified the significance of genes such as SAP30-like (SAP30L, Protein lyl-1 (LYL1, various matrix metalloproteinases, and several glycogenes in myogenesis. The results of the present study widen our knowledge of the molecular basis of skeletal muscle

  7. Emerging Issues and Opportunities in Health Information Technology.

    Nardi, Elizabeth A; Lentz, Lisa Korin; Winckworth-Prejsnar, Katherine; Abernethy, Amy P; Carlson, Robert W

    2016-10-01

    When used effectively, health information technology (HIT) can transform clinical care and contribute to new research discoveries. Despite advances in HIT and increased electronic health record adoption, many challenges to optimal use, interoperability, and data sharing exist. Data standardization across systems is limited, and scanned medical note documents result in unstructured data that make reporting on quality measures for reimbursement burdensome. Different policies and initiatives, including the Health Information Technology for Economic and Clinical Health Act, the Medicare Access and CHIP Reauthorization Act, and the National Cancer Moonshot initiative, among others, all recognize the impact that HIT can have on cancer care. Given the growing role HIT plays in health care, it is vital to have effective and efficient HIT systems that can exchange information, collect credible data that is analyzable at the point of care, and improves the patient-provider relationship. In June 2016, NCCN hosted the Emerging Issues and Opportunities in Health Information Technology Policy Summit. The summit addressed challenges, issues, and opportunities in HIT as they relate to cancer care. Keynote presentations and panelists discussed moving beyond Meaningful Use, HIT readiness to support and report on quality care, the role of HIT in precision medicine, the role of HIT in the National Cancer Moonshot initiative, and leveraging HIT to improve quality of clinical care.

  8. RECOGNISING SPEECH ACTS

    Phyllis Kaburise

    2012-09-01

    Full Text Available Speech Act Theory (SAT, a theory in pragmatics, is an attempt to describe what happens during linguistic interactions. Inherent within SAT is the idea that language forms and intentions are relatively formulaic and that there is a direct correspondence between sentence forms (for example, in terms of structure and lexicon and the function or meaning of an utterance. The contention offered in this paper is that when such a correspondence does not exist, as in indirect speech utterances, this creates challenges for English second language speakers and may result in miscommunication. This arises because indirect speech acts allow speakers to employ various pragmatic devices such as inference, implicature, presuppositions and context clues to transmit their messages. Such devices, operating within the non-literal level of language competence, may pose challenges for ESL learners.

  9. The Act of Walking

    Vestergaard, Maria Quvang Harck; Olesen, Mette; Helmer, Pernille Falborg

    2014-01-01

    individuals in Denmark conduct and experience walking, and the ‘rationalities’ (Giddens 1984) that lie behind their choice of mobility. It provides insight into how different lifestyles perceive and act walking in their everyday life. Kaufmann (2002) describes how the individual mobility is influenced......’ of mobility (Jensen 2013:111) such as the urban environment, and the infrastructures. Walking has indeed also a ‘software dimension’ as an embodied performance that trigger the human senses (Jensen 2013) and which is closely related to the habitus and identity of the individual (Halprin 1963). The individual...... by individual strategies, values, perceptions and habits, and how appropriation of mobility is constructed through the internalization of standards and values. The act of walking could thus be understood as the result of dynamic internal negotiation of individual, everyday mobility strategies (Lassen 2005...

  10. Opportunities of Continuing Adult Education

    Lidija Ušeckienė

    2011-04-01

    Full Text Available After becoming the member state of the European Union, Lithuania undertook all the obligations of a member state. One of them is the implementation of The Lisbon Strategy aiming at the worlds most dynamic and competitive knowledge– based economy by 2010. Under the strategy, a stronger economy will drive job creation, sustainable development, and social inclusion. These changes demand the modernisation of education systems in the E U states, Lithuania among them. To achieve this objective, political forces came to an agreement on the future of Lithuanian education. In 2003 The Seimas of the Republic of Lithuania approved of National Education Strategy 2003–2012. This strategy is special not only because it is based on the experiences of the reform, addresses current and future world’s challenges and opportunities, maintains links with other strategic national reforms, but also emphasises efforts to ensure quality lifelong education for Lithuanian population and striving to become a partner in modern knowledge-based economy. Therefore, an extensive discussion on lifelong education strategies on individual and institution levels in all spheres of social and personal life has started in the E U and Lithuania. Nowadays lifelong learning is not just one aspect of education and training; it gradually is becoming the most important principle in the continuum of complex learning contexts. Such vision must be implemented this decade. The object of the research: the preconditions for the development of continuing adult education. The aim of the research: to examine the peculiarities of the preconditions for the development of continuing adult education in Pakruojis region. The methods of the research: analysis of references and documents on education; an anonymous survey in written form (a questionnaire; statistical analysis of data. The sample. The research was conducted in Pakruojis region in January-April, 2006. 300 respondents of different age

  11. CRISIS LEADERSHIP - AN ORGANIZATIONAL OPPORTUNITY

    James E. Prewitt

    2011-09-01

    Full Text Available Reactive leadership and crisis management have been synonymous for years. This flows from the belief that crisis is unpredictable and unexpected, which is simply not true. Crisis has its genesis in the values, beliefs, culture, or behavior of an organization which become incongruent with the milieu in which the organization operates. A leader, who is able to read the signals of looming crisis and understands how to harness the exigency brought on by the situation, can diminish the potential dangers and take full advantage of the resulting opportunities. This paper presents a generic crisis lifecycle as a representation of overall crisis. Since a crisis can be broken down into three unique phases, crisis lifecycles can be understood and utilized for the benefit of the organization. In the first phase of the lifecycle, the organization finds itself mired in a static phase which equates to a comfort zone. In this first phase leaders struggle when they attempt to introduce change or learning due to the organizations preference to avoid conflict and maintain stasis. When a crisis engulfs an organization then the stasis that envelops the organization evaporates and gives rise to the second phase or the disaster phase. The disaster phase often threatens the very existence of the organization. When the organization successfully eliminates the immediate organizational threat, the organization is able to enter the adjustive phase of the crisis lifecycle. In this third phase, the leader has the undivided attention of the organization and the underlying urgency to solve the issues that led to the crisis in the first place. Regrettably, many leaders don’t take advantage of this golden opportunity and push the organization back toward the status-quo which ensures that the crisis will return in force. The study of crisis leadership has become more important since the dawn of the new millennium because leaders in all areas face differing degrees of crisis in

  12. Toxic Substances Control Act

    1992-05-15

    This Reference Book contains a current copy of the Toxic Substances Control Act and those regulations that implement the statute and appear to be most relevant to DOE activities. The document is provided to DOE and contractor staff for informational purposes only and should not be interpreted as legal guidance. Questions concerning this Reference Book may be directed to Mark Petts, EH-231 (202/586-2609).

  13. A multidisciplinary conceptualization of conservation opportunity.

    Moon, Katie; Adams, Vanessa M; Januchowski-Hartley, Stephanie R; Polyakov, Maksym; Mills, Morena; Biggs, Duan; Knight, Andrew T; Game, Edward T; Raymond, Christopher M

    2014-12-01

    An opportunity represents an advantageous combination of circumstances that allows goals to be achieved. We reviewed the nature of opportunity and how it manifests in different subsystems (e.g., biophysical, social, political, economic) as conceptualized in other bodies of literature, including behavior, adoption, entrepreneur, public policy, and resilience literature. We then developed a multidisciplinary conceptualization of conservation opportunity. We identified 3 types of conservation opportunity: potential, actors remove barriers to problem solving by identifying the capabilities within the system that can be manipulated to create support for conservation action; traction, actors identify windows of opportunity that arise from exogenous shocks, events, or changes that remove barriers to solving problems; and existing, everything is in place for conservation action (i.e., no barriers exist) and an actor takes advantage of the existing circumstances to solve problems. Different leverage points characterize each type of opportunity. Thus, unique stages of opportunity identification or creation and exploitation exist: characterizing the system and defining problems; identifying potential solutions; assessing the feasibility of solutions; identifying or creating opportunities; and taking advantage of opportunities. These stages can be undertaken independently or as part of a situational analysis and typically comprise the first stage, but they can also be conducted iteratively throughout a conservation planning process. Four types of entrepreneur can be identified (business, policy, social, and conservation), each possessing attributes that enable them to identify or create opportunities and take advantage of them. We examined how different types of conservation opportunity manifest in a social-ecological system (the Great Barrier Reef) and how they can be taken advantage of. Our multidisciplinary conceptualization of conservation opportunity strengthens and

  14. Tuberculosis diagnostics: Challenges and opportunities

    Vijay Nema

    2012-01-01

    Full Text Available Tuberculosis (TB has been a disease affecting almost all parts of the world since ages. Lot many efforts came in the past for improving diagnosis and treatment. Also, an effective vaccine has been sought after for long. With the emergence of resistant strains of Mycobacterium tuberculosis, the causal organisms of tuberculosis, and complexities emerging due to other associated infections and disease conditions, there is a desperate need for further research input in the field. Be it the better medication and care or better resistance management, proper diagnostics holds the key to success. It has been observed that a high burden of the disease was accompanied by resource limitations and poor research set-up. The scenario remained like this for several decades. With the refreshed vision of resourceful countries and funding agencies, funding is being provided in many areas of research in tuberculosis diagnosis and treatment. This review has been written with an aim to bring forth the limitations of available methods in the field of diagnostics and making researchers aware about the changing scenario with better funding opportunities and support. The author visualizes an enthusiasm from all over the world for the development of better modalities and urges scientists to join the struggle at this very perfect time to take the challenge and come forward with innovations in this field.

  15. Research opportunities in photochemical sciences

    NONE

    1996-07-01

    The workshop entitled {open_quotes}Research Opportunities in Photochemical Sciences{close_quotes} was initiated by the U.S. Department of Energy (DOE), Office of Energy Research (ER), Office of Basic Energy Sciences (BES), Division of Chemical Sciences. The National Renewable Energy Laboratory (NREL) in Golden, Colorado was requested by ER to host the workshop. It was held February 5-8, 1996 at the Estes Park Conference Center, Estes Park, CO, and attended by about 115 leading scientists and engineers from the U.S., Japan, and Europe; program managers for the DOE ER and Energy Efficiency and Renewable Energy (EERE) programs also attended. The purpose of the workshop was to bridge the communication gap between the practioneers and supporters of basic research in photochemical science and the practioneers and supporters of applied research and development in technologies related to photochemical science. For the purposes of the workshop the definition of the term {open_quotes}photochemical science{close_quotes} was broadened to include homogeneous photochemistry, heterogeneous photochemistry, photoelectrochemistry, photocatalysis, photobiology (for example, the light-driven processes of biological photosynthesis and proton pumping), artificial photosynthesis, solid state photochemistry, and solar photochemistry. The technologies under development through DOE support that are most closely related to photochemical science, as defined above, are the renewable energy technologies of photovoltaics, biofuels, hydrogen energy, carbon dioxide reduction and utilization, and photocatalysis for environmental cleanup of water and air. Individual papers were processed separately for the United states Department of Energy databases.

  16. Obesogenic environment – intervention opportunities

    Mauro Fisberg

    2016-06-01

    Full Text Available ABSTRACT Objectives: To evaluate environmental obesogenic-related factors, such as physical activity in neighborhoods and schools, nutritional behavior, and intervention programs. Sources: Critical analysis of literature with personal point of view from infant obesity experts and political advisors for public intervention. Data synthesis: Although obesity is a public health problem affecting several age groups, it is among children and adolescents that it plays a more important role, due to treatment complexity, high likelihood of persistence into adulthood, and association with other non- transmissible diseases while still in early age. Environment is a main component of the genesis and outcomes in the near future or long term. Modification of intake with high-density food, meal skipping, and high intake of saturated fat, sugar, and salt, associated to high levels of sedentarism are main causes of obesity. Conclusion: Intervention opportunities are related to modifications in political, environmental, and individual settings. School and physical activities in the educational environment are intertwined with nutrition intervention in continuous education. A critical review of some different scenarios in Latin American countries is presented.

  17. Market opportunity in computational proteomics.

    Razvi, Enal

    2002-03-01

    The current exuberance on the potential of proteomics as a means to deploy the wealth of the human genome is expected to last into the coming years. Unlike the genome, a finite entity with a fixed number of base pairs of the genetic material, the proteome is "plastic", changing throughout growth and development and environmental stresses, as well as in pathological situations. Our proteomes change over time, and therefore there is no one proteome; the proteome is for practical purposes an infinite entity. It is therefore crucial to build systems that are capable of manipulating the information content that is the proteome, thence the need for computational proteomics as a discipline. In this Market View article, we present the industry landscape that is emerging in the computational proteomics space. This space is still in its infancy and for the most part undefined; therefore we seek to present the market opportunity in informatics in the drug discovery space and then extend that to an examination of industry trends in proteomics. Thus, the gestalt is a set of predictions as to the evolution of the landscape in computational proteomics over the coming years.

  18. Engineering opportunities in cancer immunotherapy.

    Jeanbart, Laura; Swartz, Melody A

    2015-11-24

    Immunotherapy has great potential to treat cancer and prevent future relapse by activating the immune system to recognize and kill cancer cells. A variety of strategies are continuing to evolve in the laboratory and in the clinic, including therapeutic noncellular (vector-based or subunit) cancer vaccines, dendritic cell vaccines, engineered T cells, and immune checkpoint blockade. Despite their promise, much more research is needed to understand how and why certain cancers fail to respond to immunotherapy and to predict which therapeutic strategies, or combinations thereof, are most appropriate for each patient. Underlying these challenges are technological needs, including methods to rapidly and thoroughly characterize the immune microenvironment of tumors, predictive tools to screen potential therapies in patient-specific ways, and sensitive, information-rich assays that allow patient monitoring of immune responses, tumor regression, and tumor dissemination during and after therapy. The newly emerging field of immunoengineering is addressing some of these challenges, and there is ample opportunity for engineers to contribute their approaches and tools to further facilitate the clinical translation of immunotherapy. Here we highlight recent technological advances in the diagnosis, therapy, and monitoring of cancer in the context of immunotherapy, as well as ongoing challenges.

  19. OPPORTUNITIES TO PRODUCE HEALTHIER BEEF

    G. HOLLÓ

    2013-12-01

    Full Text Available In this study the opportunities for enhancing the beneficial fatty acid in beef was examined. The effect of diet (extensive vs. intensive diet, forage to concentrate ratio, feeding concentrates rich in n-3 fatty acids and the breed (old: Hungarian Grey, dual purpose: Hungarian Simmental, dairy: Hungarian Holstein-Friesian was investigated on the fatty acid composition of beef. Findings reveal that the extensive diet with linseed supplemented concentrate influenced the n-6/n-3 ratio and the CLA content of longissimus muscle more advantageous concerning human nutrition. The meat from Hungarian Grey (HG contained more CLA and less n-6 fatty acids than that of Holstein-Friesian bulls. The different forage to concentrate ratio with/without linseed supplementation did not significantly affect the performance and slaughter traits in Hungarian Simmental (HS young bulls. The wider forage to linseed concentrate ratio caused slightly higher dressing percentage, meat and fat proportion and lower bone in carcass. The effect of muscle type on chemical composition of muscles is more significant than that of the diet. SFA and MUFA were affected by muscle type, n-3 fatty acids and n-6/n-3 fatty acid ratio of the diet. The level of cis-9 trans-11 CLA (mg/100 g was influenced by muscle type, but not by diet.

  20. The Opportunity Cost of Capital

    Ayman Chit PhD

    2015-04-01

    Full Text Available The opportunity cost of the capital invested in pharmaceutical research and development (R&D to bring a new drug to market makes up as much as half the total cost. However, the literature on the cost of pharmaceutical R&D is mixed on how, exactly, one should calculate this “hidden” cost. Some authors attempt to adopt models from the field of finance, whereas other prominent authors dismiss this practice as biased, arguing that it artificially inflates the R&D cost to justify higher prices for pharmaceuticals. In this article, we examine the arguments made by both sides of the debate and then explain the cost of capital concept and describe in detail how this value is calculated. Given the significant contribution of the cost of capital to the overall cost of new drug R&D, a clear understanding of the concept is critical for policy makers, investors, and those involved directly in the R&D.

  1. Concurrent sourcing and external supplier opportunism

    Mols, Niels Peter

    When a firm simultaneously makes and buys the same components then the firm uses concurrent sourcing. This paper presents an agency model for explaining how and when concurrent sourcing reduces the likelihood of external supplier opportunism. In the proposed model, the external supplier’s expected...... costs of opportunism are determined as a product of four factors. The four factors are: likelihood of discovering supplier opportunism, buyer’s internalized quantity as reaction to supplier opportunism, asset specificity of external supplier’s investments, and multiplicator effects. Each...

  2. Knock Resistance and Fine Particle Emissions for Several Biomass-Derived Oxygenates in a Direct-Injection Spark-Ignition Engine

    Ratcliff, Matthew A.; Burton, Jonathan; Sindler, Petr; Christensen, Earl; Fouts, Lisa; Chupka, Gina M.; McCormick, Robert L.

    2016-04-01

    Several high octane number oxygenates that could be derived from biomass were blended with gasoline and examined for performance properties and their impact on knock resistance and fine particle emissions in a single cylinder direct-injection spark-ignition engine. The oxygenates included ethanol, isobutanol, anisole, 4-methylanisole, 2-phenylethanol, 2,5-dimethyl furan, and 2,4-xylenol. These were blended into a summertime blendstock for oxygenate blending at levels ranging from 10 to 50 percent by volume. The base gasoline, its blends with p-xylene and p-cymene, and high-octane racing gasoline were tested as controls. Relevant gasoline properties including research octane number (RON), motor octane number, distillation curve, and vapor pressure were measured. Detailed hydrocarbon analysis was used to estimate heat of vaporization and particulate matter index (PMI). Experiments were conducted to measure knock-limited spark advance and particulate matter (PM) emissions. The results show a range of knock resistances that correlate well with RON. Molecules with relatively low boiling point and high vapor pressure had little effect on PM emissions. In contrast, the aromatic oxygenates caused significant increases in PM emissions (factors of 2 to 5) relative to the base gasoline. Thus, any effect of their oxygen atom on increasing local air-fuel ratio was outweighed by their low vapor pressure and high double-bond equivalent values. For most fuels and oxygenate blend components, PMI was a good predictor of PM emissions. However, the high boiling point, low vapor pressure oxygenates 2-phenylethanol and 2,4-xylenol produced lower PM emissions than predicted by PMI. This was likely because they did not fully evaporate and combust, and instead were swept into the lube oil.

  3. Increased myofilament Ca2+ sensitivity and diastolic dysfunction as early consequences of Mybpc3 mutation in heterozygous knock-in mice.

    Fraysse, Bodvaël; Weinberger, Florian; Bardswell, Sonya C; Cuello, Friederike; Vignier, Nicolas; Geertz, Birgit; Starbatty, Jutta; Krämer, Elisabeth; Coirault, Catherine; Eschenhagen, Thomas; Kentish, Jonathan C; Avkiran, Metin; Carrier, Lucie

    2012-06-01

    Hypertrophic cardiomyopathy (HCM) is frequently caused by mutations in MYBPC3 encoding cardiac myosin-binding protein C (cMyBP-C). The mechanisms leading from gene mutations to the HCM phenotype remain incompletely understood, partially because current mouse models of HCM do not faithfully reflect the human situation and early hypertrophy confounds the interpretation of functional alterations. The goal of this study was to evaluate whether myofilament Ca(2+) sensitization and diastolic dysfunction are associated or precede the development of left ventricular hypertrophy (LVH) in HCM. We evaluated the function of skinned and intact cardiac myocytes, as well as the intact heart in a recently developed Mybpc3-targeted knock-in mouse model carrying a point mutation frequently associated with HCM. Compared to wild-type, 10-week old homozygous knock-in mice exhibited i) higher myofilament Ca(2+) sensitivity in skinned ventricular trabeculae, ii) lower diastolic sarcomere length, and faster Ca(2+) transient decay in intact myocytes, and iii) LVH, reduced fractional shortening, lower E/A and E'/A', and higher E/E' ratios by echocardiography and Doppler analysis, suggesting systolic and diastolic dysfunction. In contrast, heterozygous knock-in mice, which mimic the human HCM situation, did not exhibit LVH or systolic dysfunction, but exhibited higher myofilament Ca(2+) sensitivity, faster Ca(2+) transient decay, and diastolic dysfunction. These data demonstrate that myofilament Ca(2+) sensitization and diastolic dysfunction are early phenotypic consequences of Mybpc3 mutations independent of LVH. The accelerated Ca(2+) transients point to compensatory mechanisms directed towards normalization of relaxation. We propose that HCM is a model for diastolic heart failure and this mouse model could be valuable in studying mechanisms and treatment modalities.

  4. Cytotoxic Effects during Knock Out of Multiple Porcine Endogenous Retrovirus (PERV Sequences in the Pig Genome by Zinc Finger Nucleases (ZFN.

    Marwan Semaan

    Full Text Available Xenotransplantation has been proposed as a solution to the shortage of suitable human donors for transplantation and pigs are currently favoured as donor animals. However, xenotransplantation may be associated with the transmission of zoonotic microorganisms. Whereas most porcine microorganisms representing a risk for the human recipient may be eliminated by designated pathogen free breeding, multiple copies of porcine endogenous retroviruses (PERVs are integrated in the genome of all pigs and cannot be eliminated this way. PERVs are released as infectious particles and infect human cells. The zinc finger nuclease (ZFN technology allows knocking out specifically cellular genes, however it was not yet used to eliminate multiple integrated proviral sequences with a strong conservation in the target sequence. To reduce the risk of horizontal PERV transmission and to knock out as many as possible proviruses, for the first time the powerful tool of the ZFN technology was used. ZFN were designed to bind specifically to sequences conserved in all known replication-competent proviruses. Expression and transport of the ZFN into the nucleus was shown by Western blot analysis, co-localisation analysis, PLA and FRET. Survival of transfected cells was analysed using fluorescent ZFN and cell counting. After transfection a strong expression of the ZFN proteins and a co-localisation of the expressed ZFN proteins were shown. However, expression of the ZFN was found to be extremely toxic for the transfected cells. The induced cytotoxicity was likely due to the specific cutting of the high copy number of the PERV proviruses, which is also commonly observed when ZFN with low specificity cleave numerous off-target sites in a genome. This is the first attempt to knock out multiple, nearly identical, genes in a cellular genome using ZFN. The attempt failed, and other strategies should be used to prevent PERV transmission.

  5. Comparative proteomic analysis of silkworm fat body after knocking out fibroin heavy chain gene: a novel insight into cross-talk between tissues.

    Chen, Quanmei; Ma, Zhengang; Wang, Xin; Li, Zhiqing; Zhang, Yan; Ma, Sanyuan; Zhao, Ping; Xia, Qingyou

    2015-09-01

    Cross-talk between tissues plays key roles in development of organisms; however, there are few researches on cross-talk between tissues in insects. Our previous studies showed that the pupal body weight was elevated after knocking out the fibroin heavy chain gene (BmFib-H), whereas the gene specifically expressed in silk glands of silkworm. Hence, the mutant is a good material for studying the cross-talk between tissues. It is considered that the fat body of silkworm during larval stage is used to store nutrients for pupal development. Herein, comparative proteomic of fat body on the 5th day of fifth instar was performed between BmFib-H gene knock-out Bombyx mori line (FGKO) and its wide-type Dazao. These results revealed that a single gene knock-out in silk gland triggered large-scale metabolic pathways changes in fat body. The levels of proteins involved in glycolysis/gluconeogenesis, pentose phosphate pathway, and glycine-serine biosynthetic pathway were down-regulated in the FGKO fat body. In contrast, the abundances of many proteins participating in protein synthesis, including ribosomal proteins, eukaryotic translation initiation factor, and elongation factor, were up-regulated. Moreover, the concentrations of glycogen and proteins in the FGKO fat body were greatly increased. These findings provided a novel insight into the cross-talk between silk gland and fat body in silkworm, and the presence of cross-talk between silk gland and fat body could regulate the redistribution of nutrients in the FGKO fat body leading to the increase of the pupal weight.

  6. Knock-Limited Performance of Triptane and Xylidines Blended with 28-R Aviation Fuel at High Compression Ratios and Maximum-Economy Spark Setting

    Held, Louis F.; Pritchard, Ernest I.

    1946-01-01

    An investigation was conducted to evaluate the possibilities of utilizing the high-performance characteristics of triptane and xylidines blended with 28-R fuel in order to increase fuel economy by the use of high compression ratios and maximum-economy spark setting. Full-scale single-cylinder knock tests were run with 20 deg B.T.C. and maximum-economy spark settings at compression ratios of 6.9, 8.0, and 10.0, and with two inlet-air temperatures. The fuels tested consisted of triptane, four triptane and one xylidines blend with 28-R, and 28-R fuel alone. Indicated specific fuel consumption at lean mixtures was decreased approximately 17 percent at a compression ratio of 10.0 and maximum-economy spark setting, as compared to that obtained with a compression ratio of 6.9 and normal spark setting. When compression ratio was increased from 6.9 to 10.0 at an inlet-air temperature of 150 F, normal spark setting, and a fuel-air ratio of 0.065, 55-percent triptane was required with 28-R fuel to maintain the knock-limited brake power level obtained with 28-R fuel at a compression ratio of 6.9. Brake specific fuel consumption was decreased 17.5 percent at a compression ratio of 10.0 relative to that obtained at a compression ratio of 6.9. Approximately similar results were noted at an inlet-air temperature of 250 F. For concentrations up through at least 20 percent, triptane can be more efficiently used at normal than at maximum-economy spark setting to maintain a constant knock-limited power output over the range of compression ratios tested.

  7. A Study on the Korea Database Industry Promotion Act Legislation

    Bae, Seoung-Hun

    2013-09-01

    Full Text Available The Database Industry Promotion Act was proposed at the National Assembly plenary session on July 26, 2012 and since then it has been in the process of enactment in consultation with all the governmental departments concerned. The recent trend of economic globalization and smart device innovation suggests a new opportunity and challenges for all industries. The database industry is also facing a new phase in an era of smart innovation. Korea is in a moment of opportunity to take an innovative approach to promoting the database industry. Korea should set up a national policy to promote the database industry for citizens, government, and research institutions, as well as enterprises. Above all, the Database Industry Promotion Act could play a great role in promoting the social infrastructure to enhance the capacity of small and medium-sized enterprises. This article discusses the background of the development of the Database Industry Promotion Act and its legislative processes in order to clarify its legal characteristics, including the meaning of the act. In addition, this article explains individual items related to the overall structure of the Database Industry Promotion Act. Finally, this article reviews the economic effects of the database industry for now and the future.

  8. Formation of polyglutamine inclusions in a wide range of non-CNS tissues in the HdhQ150 knock-in mouse model of Huntington's disease.

    Hilary Moffitt

    Full Text Available BACKGROUND: Huntington's disease (HD is an inherited progressive neurodegenerative disorder caused by a CAG repeat expansion in the ubiquitously expressed HD gene resulting in an abnormally long polyglutamine repeat in the huntingtin protein. Polyglutamine inclusions are a hallmark of the neuropathology of HD. We have previously shown that inclusion pathology is also present in the peripheral tissues of the R6/2 mouse model of HD which expresses a small N-terminal fragment of mutant huntingtin. To determine whether this peripheral pathology is a consequence of the aberrant expression of this N-terminal fragment, we extend this analysis to the genetically precise knock-in mouse model of HD, HdhQ150, which expresses mutant mouse huntingtin. METHODOLOGY/PRINCIPAL FINDINGS: We have previously standardized the CAG repeat size and strain background of the R6/2 and HdhQ150 knock-in mouse models and found that they develop a comparable and widespread neuropathology. To determine whether HdhQ150 knock-in mice also develop peripheral inclusion pathology, homozygous Hdh(Q150/Q150 mice were perfusion fixed at 22 months of age, and tissues were processed for histology and immunohistochemistry with the anti-huntingtin antibody S830. The peripheral inclusion pathology was almost identical to that found in R6/2 mice at 12 weeks of age with minor differences in inclusion abundance. CONCLUSIONS/SIGNIFICANCE: The highly comparable peripheral inclusion pathology that is present in both the R6/2 and HdhQ150 knock-in models of HD indicates that the presence of peripheral inclusions in R6/2 mice is not a consequence of the aberrant expression of an N-terminal huntingtin protein. It remains to be determined whether peripheral inclusions are a pathological feature of the human disease. Both mouse models carry CAG repeats that cause childhood disease in humans, and therefore, inclusion pathology may be a feature of the childhood rather than the adult forms of HD. It is

  9. Retigabine, a Kv7.2/Kv7.3-Channel Opener, Attenuates Drug-Induced Seizures in Knock-In Mice Harboring Kcnq2 Mutations.

    Ihara, Yukiko; Tomonoh, Yuko; Deshimaru, Masanobu; Zhang, Bo; Uchida, Taku; Ishii, Atsushi; Hirose, Shinichi

    2016-01-01

    The hetero-tetrameric voltage-gated potassium channel Kv7.2/Kv7.3, which is encoded by KCNQ2 and KCNQ3, plays an important role in limiting network excitability in the neonatal brain. Kv7.2/Kv7.3 dysfunction resulting from KCNQ2 mutations predominantly causes self-limited or benign epilepsy in neonates, but also causes early onset epileptic encephalopathy. Retigabine (RTG), a Kv7.2/ Kv7.3-channel opener, seems to be a rational antiepileptic drug for epilepsies caused by KCNQ2 mutations. We therefore evaluated the effects of RTG on seizures in two strains of knock-in mice harboring different Kcnq2 mutations, in comparison to the effects of phenobarbital (PB), which is the first-line antiepileptic drug for seizures in neonates. The subjects were heterozygous knock-in mice (Kcnq2Y284C/+ and Kcnq2A306T/+) bearing the Y284C or A306T Kcnq2 mutation, respectively, and their wild-type (WT) littermates, at 63-100 days of age. Seizures induced by intraperitoneal injection of kainic acid (KA, 12mg/kg) were recorded using a video-electroencephalography (EEG) monitoring system. Effects of RTG on KA-induced seizures of both strains of knock-in mice were assessed using seizure scores from a modified Racine's scale and compared with those of PB. The number and total duration of spike bursts on EEG and behaviors monitored by video recording were also used to evaluate the effects of RTG and PB. Both Kcnq2Y284C/+ and Kcnq2A306T/+ mice showed significantly more KA-induced seizures than WT mice. RTG significantly attenuated KA-induced seizure activities in both Kcnq2Y284C/+ and Kcnq2A306T/+ mice, and more markedly than PB. This is the first reported evidence of RTG ameliorating KA-induced seizures in knock-in mice bearing mutations of Kcnq2, with more marked effects than those observed with PB. RTG or other Kv7.2-channel openers may be considered as first-line antiepileptic treatments for epilepsies resulting from KCNQ2 mutations.

  10. Retigabine, a Kv7.2/Kv7.3-Channel Opener, Attenuates Drug-Induced Seizures in Knock-In Mice Harboring Kcnq2 Mutations.

    Yukiko Ihara

    Full Text Available The hetero-tetrameric voltage-gated potassium channel Kv7.2/Kv7.3, which is encoded by KCNQ2 and KCNQ3, plays an important role in limiting network excitability in the neonatal brain. Kv7.2/Kv7.3 dysfunction resulting from KCNQ2 mutations predominantly causes self-limited or benign epilepsy in neonates, but also causes early onset epileptic encephalopathy. Retigabine (RTG, a Kv7.2/ Kv7.3-channel opener, seems to be a rational antiepileptic drug for epilepsies caused by KCNQ2 mutations. We therefore evaluated the effects of RTG on seizures in two strains of knock-in mice harboring different Kcnq2 mutations, in comparison to the effects of phenobarbital (PB, which is the first-line antiepileptic drug for seizures in neonates. The subjects were heterozygous knock-in mice (Kcnq2Y284C/+ and Kcnq2A306T/+ bearing the Y284C or A306T Kcnq2 mutation, respectively, and their wild-type (WT littermates, at 63-100 days of age. Seizures induced by intraperitoneal injection of kainic acid (KA, 12mg/kg were recorded using a video-electroencephalography (EEG monitoring system. Effects of RTG on KA-induced seizures of both strains of knock-in mice were assessed using seizure scores from a modified Racine's scale and compared with those of PB. The number and total duration of spike bursts on EEG and behaviors monitored by video recording were also used to evaluate the effects of RTG and PB. Both Kcnq2Y284C/+ and Kcnq2A306T/+ mice showed significantly more KA-induced seizures than WT mice. RTG significantly attenuated KA-induced seizure activities in both Kcnq2Y284C/+ and Kcnq2A306T/+ mice, and more markedly than PB. This is the first reported evidence of RTG ameliorating KA-induced seizures in knock-in mice bearing mutations of Kcnq2, with more marked effects than those observed with PB. RTG or other Kv7.2-channel openers may be considered as first-line antiepileptic treatments for epilepsies resulting from KCNQ2 mutations.

  11. Nuclear domain ‘knock-in’ screen for the evaluation and identification of small molecule enhancers of CRISPR-based genome editing

    Pinder, Jordan; Salsman, Jayme; Dellaire, Graham

    2015-01-01

    CRISPR is a genome-editing platform that makes use of the bacterially-derived endonuclease Cas9 to introduce DNA double-strand breaks at precise locations in the genome using complementary guide RNAs. We developed a nuclear domain knock-in screen, whereby the insertion of a gene encoding the green fluorescent protein variant Clover is inserted by Cas9-mediated homology directed repair (HDR) within the first exon of genes that are required for the structural integrity of subnuclear domains suc...

  12. The Skeletal Response to Estrogen is Impaired in Female but not in Male Steroid Receptor Coactivator (SRC)-1 Knock Out Mice

    Mödder, U. I.; Sanyal, A.; Xu, J; O’Malley, B.W.; Spelsberg, T C; Khosla, S.

    2007-01-01

    Estrogen (E) is critical for the maintenance of bone mass in both female and male mice and steroid receptor coactivator (SRC)-1 has been shown to be important for mediating E effects on bone, at least in female mice. In the present study, we defined the skeletal phenotype of male SRC-1 knock out (KO) mice and compared it with their female littermates. Further, to determine the role of SRC-1 in mediating effects of E on bone in male mice, we examined the skeletal effects of gonadectomy (gnx) w...

  13. Williamson Act - The California Land Conservation Act of 1965

    California Department of Resources — The California Land Conservation Act of 1965 - commonly referred to as the Williamson Act - is the State's primary program for the conservation of private land in...

  14. Forecast of Contracting and Subcontracting Opportunities, Fiscal year 1995

    1995-02-01

    Welcome to the US Department of Energy`s Forecast of Contracting and Subcontracting Opportunities. This forecast, which is published pursuant to Public Low 100--656, ``Business Opportunity Development Reform Act of 1988,`` is intended to inform small business concerns, including those owned and controlled by socially and economically disadvantaged individuals, and women-owned small business concerns, of the anticipated fiscal year 1995 contracting and subcontracting opportunities with the Department of Energy and its management and operating contractors and environmental restoration and waste management contractors. This document will provide the small business contractor with advance notice of the Department`s procurement plans as they pertain to small, small disadvantaged and women-owned small business concerns.Opportunities contained in the forecast support the mission of the Department, to serve as advocate for the notion`s energy production, regulation, demonstration, conservation, reserve maintenance, nuclear weapons and defense research, development and testing, when it is a national priority. The Department`s responsibilities include long-term, high-risk research and development of energy technology, the marketing of Federal power, and maintenance of a central energy data collection and analysis program. A key mission for the Department is to identify and reduce risks, as well as manage waste at more than 100 sites in 34 states and territories, where nuclear energy or weapons research and production resulted in radioactive, hazardous, and mixed waste contamination. Each fiscal year, the Department establishes contracting goals to increase contracts to small business concerns and meet our mission objectives.

  15. Missed opportunities in child healthcare

    Linda Jonker

    2014-01-01

    Full Text Available Background: Various policies in health, such as Integrated Management of Childhood Illnesses, were introduced to enhance integrated service delivery in child healthcare. During clinical practice the researcher observed that integrated services may not be rendered.Objectives: This article describes the experiences of mothers that utilised comprehensive child health services in the Cape Metropolitan area of South Africa. Services included treatment for diseases; preventative interventions such as immunisation; and promotive interventions, such as improvement in nutrition and promotion of breastfeeding.Method: A qualitative, descriptive phenomenological approach was applied to explore the experiences and perceptions of mothers and/or carers utilising child healthcare services. Thirty percent of the clinics were selected purposively from the total population. A convenience purposive non-probability sampling method was applied to select 17 mothers who met the criteria and gave written consent. Interviews were conducted and recorded digitally using an interview guide. The data analysis was done using Tesch’s eight step model.Results: Findings of the study indicated varied experiences. Not all mothers received information about the Road to Health book or card. According to the mothers, integrated child healthcare services were not practised. The consequences were missed opportunities in immunisation, provision of vitamin A, absence of growth monitoring, feeding assessment and provision of nutritional advice.Conclusion: There is a need for simple interventions such as oral rehydration, early recognition and treatment of diseases, immunisation, growth monitoring and appropriate nutrition advice. These services were not offered diligently. Such interventions could contribute to reducing the incidence of child morbidity and mortality.

  16. GWAS 2011: Opportunities and challenges

    Jian-Jun Liu; Xue-Jun Zhang

    2011-01-01

    The wide adoption of genome-wide association study (GWAS) has dramatically changed the landscape of the genetic studies of human diseases.Banking on the study design that employs large and multiple-independent samples,linkage disequilibrium (LD) -based systematic genome-wide interrogation,and vigorous statistical standard for declaring genetic association,GWAS has greatly advanced the genetic studies of human disease by successfully identifying over 4 thousands of genetic susceptibility SNPs or loci for 210 diseases/traits in human.Besides its unrivaled scientific achievements,GWAS has also transformed the communities of human genetics by stimulating unprecedented broad and large-scale collaboration and data sharing across different groups and countries,which has enabled some mega genetic studies where dozens or hundreds of thousands of samples were investigated through mete-analysis,providing enormous statistical power for discovering genetic variants,even the ones with very moderate effect on disease phenotype or physiological trait.While the success of GWAS has been widely recognized,there are many concerns on GWAS that are being passionately debated.In particular,there ate heated discussions on why only a limited proportion,quiet often a small proportion,of genetic heritability can be explained by the GWAS findings,and whether and how the GWAS findings have really advanced the biological investigation and understanding of disease mechanisms.Concerning these shortcomings of GWAS,many have genuinely questioned the perspective of translating the GWAS findings into clinical practice.To provide a platform to discuss the progresses and shortcomings of GWAS,a nature conference,titled “GWAS 2011:Opportunities and Challenges”,was organized through the collaboration between the Nature Genetics and Anhui Medical University,which was held in Hefei,China on May 19-21,2011.

  17. Virtual Acts of Balance!

    Madsen, Anders Koed

    2013-01-01

    improve 'knowledge-democracy' in different ways. The paper denotes such portals 'virtual technologies of knowledge management' and it uses the documental data as a window to analyze and discuss the infrastructural choices of such portals. The analysis is grounded in theories related to 'Social....... It is especially emphasized how technical web-ontologies implicitly carries with them deeper philosophical ontologies about phanomena such as 'politic', 'scientific intentionality' and 'freedom'. The compromise between these technical influences and the social intentions is described as a 'virtual act of balance...

  18. Teaching Speech Acts

    Teaching Speech Acts

    2007-01-01

    Full Text Available In this paper I argue that pragmatic ability must become part of what we teach in the classroom if we are to realize the goals of communicative competence for our students. I review the research on pragmatics, especially those articles that point to the effectiveness of teaching pragmatics in an explicit manner, and those that posit methods for teaching. I also note two areas of scholarship that address classroom needs—the use of authentic data and appropriate assessment tools. The essay concludes with a summary of my own experience teaching speech acts in an advanced-level Portuguese class.

  19. Superfund Reauthorization 1994: DoD’s Opportunity to Clean Up Its Hazardous Waste Act

    1994-04-01

    House Comm. on Government Operations, 101st Cong., 1st Sess. 3 (1989) (testimony of Richard L. Hembra , Director, Environmental Protection Issues...Public Works and Transportation, 102d Cong., 2d Sess. 701 (1992) (statement of Richard Hembra , Director, Environmental Protection Issues, Resources

  20. 78 FR 42942 - Clean Water Act Class II: Proposed Administrative Settlement, Penalty Assessment and Opportunity...

    2013-07-18

    ... emergency response commission (SERC), and the fire department with jurisdiction over these facilities. In..., SERC, and the fire department with jurisdiction over these facilities. Under EPCRA Section 325, 42 U.S... RCRA, 42 U.S.C. 6922, and the regulations found at 40 CFR 273.13--.15 (universal waste requirements...

  1. 78 FR 76212 - Patient Protection and Affordable Care Act; Maximizing January 1, 2014 Coverage Opportunities

    2013-12-17

    ... purposes of the RFA, small entities include small businesses, nonprofit organizations, and small government... meeting the size standards of the Small Business Administration (SBA); (2) a not-for-profit organization... than 50,000. States and individuals are not included in the definition of ``small entity.'' CMS uses...

  2. 77 FR 58129 - Clean Water Act Class II: Proposed Administrative Settlement, Penalty Assessment and Opportunity...

    2012-09-19

    .... Urbandale 4157 109th St Urbandale IA 5. Evansville 4510 O'Hara Dr Evansville IN 6. St. Rose 160 James Dr St. Rose LA 7. Southborough 155 Northborough Dr Southborough MA 8. Albany 2 Kross Key Dr Albany NY 9. New..., operator, or person in charge of a vessel, onshore facility, or offshore facility from which oil...

  3. 78 FR 36749 - Determination Under the African Growth and Opportunity Act

    2013-06-19

    ... determined that certain textile and apparel goods from Benin shall be treated as ``folklore articles'' and..., including handloomed, handmade, or folklore articles of a beneficiary country that are certified as such by..., folklore articles, or ethnic printed fabrics. See 66 FR 7271, 7271-72 (January 22, 2001) and 70 FR...

  4. 75 FR 40774 - Determination Under the African Growth and Opportunity Act

    2010-07-14

    ... determined that certain textile and apparel goods from Burkina Faso shall be treated as ``folklore articles... sub-Saharan African countries, including handloomed, handmade, or folklore articles of a beneficiary... treated as being handloomed, handmade, folklore articles, or ethnic printed fabrics. See 66 FR 7271,...

  5. On Risks and Opportunities in Financial Markets

    S.D. Lansdorp (Simon)

    2012-01-01

    textabstractInvesting in financial securities inevitably involves risks on the one hand and opportunities on the other hand. This thesis bundles four different studies on risks and/or opportunities in financial markets. In one study, we examine the cross-sectional explanatory power of different risk

  6. 75 FR 10464 - Broadband Technology Opportunities Program

    2010-03-08

    ... National Telecommunications and Information Administration RIN 0660-ZA28 Broadband Technology Opportunities... Technology Opportunities Program (BTOP) is extended until 5:00 p.m. Eastern Daylight Time (EDT) on March 26... Sustainable Broadband Adoption (SBA) projects. DATES: All applications for funding CCI projects must...

  7. Vegetables Business Opportunities in Ghana: 2014

    Saavedra Gonzalez, Y.R.; Dijkxhoorn, Y.; Elings, A.; Glover-Tay, J.; Koomen, I.; Maden, van der E.C.L.J.; Nkansah, G.; Obeng, P.

    2014-01-01

    This report addresses the current performance, overall business climate of the vegetable sector and tries to come up with a number of business opportunities. These include business opportunities for high-quality exports, greenhouse technology, and healthy food for the domestic market. It equally adv

  8. Opportunity Texas[TM]: Learn. Earn. Save.

    Center for Public Policy Priorities, 2010

    2010-01-01

    Texas faces numerous challenges but also has abundant opportunities to build the middle class and increase prosperity. Unfortunately, too many Texans are on the sideline, lacking access to opportunities to learn, earn, and save to secure a more prosperous future for themselves and their families. To create jobs, increase income, and promote…

  9. Preventive maintenance at opportunities of restricted duration

    R. Dekker (Rommert); E. Smeitink

    1994-01-01

    textabstractThis article deals with the problem of setting priorities for the execution of maintenance packages at randomly occurring opportunities. These opportunities are of restricted duration, implying that only a limited number of packages can be executed. The main idea proposed is to set up a

  10. Opportunists and opportunities: the 2010 SHEA Lecture.

    Henderson, David K

    2010-11-01

    My experience as a hospital epidemiologist at the National Institutes of Health Clinical Center has underscored the importance of aggressively managing infection with opportunistic pathogens and of taking advantage of opportunities as they arise (most often as crises). I review selected aspects of my career and use these as examples of the opportunists and opportunities now facing healthcare epidemiology.

  11. Vocational Education and Equality of Opportunity.

    Horowitz, Benjamin; Feinberg, Walter

    1990-01-01

    Examines the concepts of equality of opportunity and equality of educational opportunity and their relationship to vocational education. Traces the history of vocational education. Delineates the distinction between training and education as enumerated in Aristotelian philosophy. Discusses the role vocational education can play in the educative…

  12. Putting Opportunism in the Back Seat

    Foss, Nicolai; Weber, Libby

    2013-01-01

    TCE and its applications in management research put more emphasis on opportunism than on bounded rationality. By augmenting the bounded rationality assumption to include interpretive limitations, we show that there are sources of costly conflict that are not rooted in opportunism. Moreover, we show...

  13. Challenges and Opportunities for Libraries in Pakistan

    Shafiq UR, Rehman; Pervaiz, Ahmad

    2007-01-01

    Abstract: This paper, based on review of literature, observation, and informal conversations, discusses various challenges regarding finance, collection development, ICTs, human resources, library education, library association and research & development faced by library profession in Pakistan. The opportunities to meet these challenges have also been explored. Keywords: Library challenges and opportunities (Pakistan); Librarianship (Pakistan); Library issues; Library profession in Pa...

  14. Marketing Opportunities in the Digital World.

    Kiani, G. Reza

    1998-01-01

    Addresses the opportunities offered by the Web to marketers. Considers the Web as a two-way communication model in which four different communication states can take place. Suggests the necessity of new concepts and models for marketers to manage their Web sites, and presents opportunities supporting the marketers' objectives in the new…

  15. Crisis/Opportunity: 2011 WICHE Workplan

    Western Interstate Commission for Higher Education, 2010

    2010-01-01

    Public higher education has faced a crisis of massive proportions in the first decade of this millennium. Nevertheless, for higher education, this year represents a turning point and, yes, an opportunity. The opportunity, then, for the West is one that generations of Americans are familiar with: to do more with less. Dealing with scarcity--whether…

  16. 47 CFR 73.1941 - Equal opportunities.

    2010-10-01

    ... 47 Telecommunication 4 2010-10-01 2010-10-01 false Equal opportunities. 73.1941 Section 73.1941... Rules Applicable to All Broadcast Stations § 73.1941 Equal opportunities. (a) General requirements...-spot coverage of bona fide news events (including, but not limited to political conventions...

  17. Affordable Care Act and Women

    ... Outcomes Research Trust Fund (PCORTF) Poverty Poverty Guidelines Poverty Analysis Teen Pregnancy Prevention Homelessness MACRA Publications Data and Tools Evaluation Database The Affordable Care Act and Women 03/20/2012 Home The Affordable Care Act ...

  18. 78 FR 73466 - Privacy Act

    2013-12-06

    ... CORPORATION 22 CFR Part 707 Privacy Act AGENCY: Overseas Private Investment Corporation. ACTION: Notice of... (``OPIC'') Privacy Act (``PA'') regulations by making substantive and administrative changes. These... procedure, Privacy. For the reasons stated in the preamble the Overseas Private Investment...

  19. Social problems as sources of opportunity – antecedents of social entrepreneurship opportunities

    Agnieszka Żur

    2016-02-01

    Full Text Available Objective: Based on extensive literature review, this paper aims to establish if, why and how, in given environmental and market contexts, social entrepreneurship (SE opportunities are discovered and exploited. It positions social problems as sources of entrepreneurial opportunity. The article presents an integrated process-based view of SE opportunity antecedents and concludes with a dynamic model of SE opportunity. Research Design & Methods: To fulfil its goal, the paper establishes opportunity as unit of research and explores the dynamics of opportunity recognition. To identify the components of SE opportunity through a process-based view, the study follows the steps of critical literature review method. The literature review follows with logical reasoning and inference, which results in the formulation of a model proposition of social entrepreneurship opportunity. Findings: The paper presents a holistic perspective on opportunity antecedents in SE context and introduces social problems, information, social awareness and entrepreneurial mindset  as fundamental components of social entrepreneurship opportunity equation. Implications & Recommendations: It is necessary to remember for policy makers, investors and partners involved within the social sector, that social problems can be the source of entrepreneurial opportunity. Training, assisting and engaging socially aware entrepreneurs is a promising line of development for all communities. Contribution & Value Added: The major contribution of this study lies in extending the existing body of social entrepreneurship research by providing a new perspective, placing social problem as opportunity in the centre of the discussion.

  20. Opportunity for Whom?: Political Opportunity and Critical Events in Canadian Aboriginal Mobilization, 1951-2000

    Ramos, Howard

    2008-01-01

    Many social movement researchers question the usefulness of political opportunity as a concept. However, others argue that it can be refined by disaggregating different opportunities for actors and outcomes to understand the underlying mechanisms that influence each. This research extends this analysis by asking "political opportunity for…

  1. Opportunities for Funding at NSF

    Kafafi, Zakya H.

    2009-03-01

    Materials science, inter- and multi-disciplinary in nature, provides the bridge to many areas of fundamental and applied sciences such as biology, chemistry, physics, mathematics, computer sciences, and engineering. Strong links that may exist between materials science and other disciplines, such as biology or chemistry or physics, very often lead to novel applications and enable technologies of great benefit to our society. The Division of Materials Research (DMR) invested 274.0 M in FY 2008 and is estimated to invest 324.6 M in FY 2009 funding research and education as well as enabling tools & instrumentation for individual investigators, groups, centers, and national facilities. DMR programs cover a wide spectrum of materials research and education ranging from condensed matter and materials physics, solid-state and materials chemistry, multifunctional, hybrid, electronic, photonic, metallic, ceramic, polymeric, bio-materials, composites and nanostructures to list a few. New modes of funding, research opportunities and directions, such as the recent SOLAR solicitation, will be described. This Solar Energy Initiative launched jointly by three divisions, namely Chemistry, Materials Research and Mathematical Science is aimed at supporting truly interdisciplinary efforts that address the scientific challenges of highly efficient harvesting, conversion, and storage of solar energy. The goal of this new program is to create a new modality of linking the mathematical with the chemical and materials sciences to develop transformative paradigms based on the integrated expertise and synergy from three disciplinary communities. DMR is also seeking new ways to transform materials science and education, and make it more attractive as a career for bright, young women & men. A description will be given of several workshops held this year and planned for next year with this purpose in mind. Outreach programs that emphasize how the innovations resulting from materials research

  2. A broad phenotypic screen identifies novel phenotypes driven by a single mutant allele in Huntington's disease CAG knock-in mice.

    Sabine M Hölter

    Full Text Available Huntington's disease (HD is an autosomal dominant neurodegenerative disorder caused by the expansion of a CAG trinucleotide repeat in the HTT gene encoding huntingtin. The disease has an insidious course, typically progressing over 10-15 years until death. Currently there is no effective disease-modifying therapy. To better understand the HD pathogenic process we have developed genetic HTT CAG knock-in mouse models that accurately recapitulate the HD mutation in man. Here, we describe results of a broad, standardized phenotypic screen in 10-46 week old heterozygous HdhQ111 knock-in mice, probing a wide range of physiological systems. The results of this screen revealed a number of behavioral abnormalities in HdhQ111/+ mice that include hypoactivity, decreased anxiety, motor learning and coordination deficits, and impaired olfactory discrimination. The screen also provided evidence supporting subtle cardiovascular, lung, and plasma metabolite alterations. Importantly, our results reveal that a single mutant HTT allele in the mouse is sufficient to elicit multiple phenotypic abnormalities, consistent with a dominant disease process in patients. These data provide a starting point for further investigation of several organ systems in HD, for the dissection of underlying pathogenic mechanisms and for the identification of reliable phenotypic endpoints for therapeutic testing.

  3. A broad phenotypic screen identifies novel phenotypes driven by a single mutant allele in Huntington's disease CAG knock-in mice.

    Hölter, Sabine M; Stromberg, Mary; Kovalenko, Marina; Garrett, Lillian; Glasl, Lisa; Lopez, Edith; Guide, Jolene; Götz, Alexander; Hans, Wolfgang; Becker, Lore; Rathkolb, Birgit; Rozman, Jan; Schrewed, Anja; Klingenspor, Martin; Klopstock, Thomas; Schulz, Holger; Wolf, Eckhard; Wursta, Wolfgang; Gillis, Tammy; Wakimoto, Hiroko; Seidman, Jonathan; MacDonald, Marcy E; Cotman, Susan; Gailus-Durner, Valérie; Fuchs, Helmut; de Angelis, Martin Hrabě; Lee, Jong-Min; Wheeler, Vanessa C

    2013-01-01

    Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by the expansion of a CAG trinucleotide repeat in the HTT gene encoding huntingtin. The disease has an insidious course, typically progressing over 10-15 years until death. Currently there is no effective disease-modifying therapy. To better understand the HD pathogenic process we have developed genetic HTT CAG knock-in mouse models that accurately recapitulate the HD mutation in man. Here, we describe results of a broad, standardized phenotypic screen in 10-46 week old heterozygous HdhQ111 knock-in mice, probing a wide range of physiological systems. The results of this screen revealed a number of behavioral abnormalities in HdhQ111/+ mice that include hypoactivity, decreased anxiety, motor learning and coordination deficits, and impaired olfactory discrimination. The screen also provided evidence supporting subtle cardiovascular, lung, and plasma metabolite alterations. Importantly, our results reveal that a single mutant HTT allele in the mouse is sufficient to elicit multiple phenotypic abnormalities, consistent with a dominant disease process in patients. These data provide a starting point for further investigation of several organ systems in HD, for the dissection of underlying pathogenic mechanisms and for the identification of reliable phenotypic endpoints for therapeutic testing.

  4. High resolution magnetic resonance imaging for characterization of the neuroligin-3 knock-in mouse model associated with autism spectrum disorder.

    Manoj Kumar

    Full Text Available Autism spectrum disorders (ASD comprise an etiologically heterogeneous set of neurodevelopmental disorders. Neuroligin-3 (NL-3 is a cell adhesion protein that mediates synapse development and has been implicated in ASD. We performed ex-vivo high resolution magnetic resonance imaging (MRI, including diffusion tensor imaging (DTI and behavioral (social approach and zero maze tests at 3 different time points (30, 50 and 70 days-of-age on NL-3 and wild-type littermates to assess developmental brain abnormalities in NL-3 mice. MRI data were segmented in 39 different gray and white matter regions. Volumetric measurements, along with DTI indices from these segmented regions were also performed. After controlling for age and gender, the NL-3 knock-in animals demonstrated significantly reduced sociability and lower anxiety-related behavior in comparison to their wild type littermates. Significantly reduced volume of several white and gray matter regions in the NL-3 knock-in mice were also observed after considering age, gender and time point as covariates. These findings suggest that structural changes in the brain of NL-3 mice are induced by the mutation in the NL-3 gene. No significant differences in DTI indices were observed, which suggests that the NL-3 mutation may not have a profound effect on water diffusion as detected by DTI. The volumetric and DTI studies aid in understanding the biology of disrupting function on an ASD risk model and may assist in the development of imaging biomarkers for ASD.

  5. Improvement of constraint-based flux estimation during L-phenylalanine production with Escherichia coli using targeted knock-out mutants.

    Weiner, Michael; Tröndle, Julia; Albermann, Christoph; Sprenger, Georg A; Weuster-Botz, Dirk

    2014-07-01

    Fed-batch production of the aromatic amino acid L-phenylalanine was studied with recombinant Escherichia coli strains on a 15 L-scale using glycerol as carbon source. Flux Variability Analysis (FVA) was applied for intracellular flux estimation to obtain an insight into intracellular flux distribution during L-phenylalanine production. Variability analysis revealed great flux uncertainties in the central carbon metabolism, especially concerning malate consumption. Due to these results two recombinant strains were genetically engineered differing in the ability of malate degradation and anaplerotic reactions (E. coli FUS4.11 ΔmaeA pF81kan and E. coli FUS4.11 ΔmaeA ΔmaeB pF81kan). Applying these malic enzyme knock-out mutants in the standardized L-phenylalanine production process resulted in almost identical process performances (e.g., L-phenylalanine concentration, production rate and byproduct formation). This clearly highlighted great redundancies in central metabolism in E. coli. Uncertainties of intracellular flux estimations by constraint-based analyses during fed-batch production of L-phenylalanine were drastically reduced by application of the malic enzyme knock-out mutants.

  6. Designing and Cloning Molecular Constructs to Knock Out N-Acetylglucosamine Phosphatidylinositol De-N-Acetylase (GPI12 Gene in Leishmania major (MRHO/IR/75/ER

    Pooya GHASEMI NEJAD ALMANI

    2016-12-01

    Full Text Available Background: Leishmaniasis represents a major public health concern in tropical and sub-tropical countries. At present, there is no efficacious vaccine against the disease and new control methods are needed. One way to access this important goal is to knock out genes of specific macromolecules to evaluate the effect of deletion on the growth, multiplication, pathogenesis and immunity of the parasite. The aim of this study was to design and clone molecular constructs to knock out N-acetylglucosamine phosphatidylinositol de-N-acetylase (GPI12 gene in Leishmania major.Methods: For designing and making molecular constructs, we used pLEXSY-neo2 and pLEXSY-hyg2 vectors. The molecular constructs were cloned in E. coli strain Top10. The molecular constructs were transfected by electroporation into L. major in two stages.Results: The molecular constructs were confirmed by Colony PCR and sequencing. The recombinant strains were isolated by selective antibiotics, after which they were confirmed by PCR, Southern and Western blots.Conclusion: Recombinant parasites were created and examined for subsequent study. With the use of molecular constructs, it was possible to remove and study gene GPI12 and to achieve a live recombinant Leishmania parasite that maintained the original form of the antigenic parasites. This achievement can be used as an experimental model for vaccine development studies. Further investigations are essential to check this model in a suitable host.

  7. Knock-down of HEXA and HEXB genes correlate with the absence of the immunostimulatory function of HSC-derived dendritic cells.

    Tiribuzi, Roberto; D'Angelo, Francesco; Berardi, Anna C; Martino, Sabata; Orlacchio, Aldo

    2012-01-01

    In an attempt to investigate whether the genetic defect in the HEXA and HEXB genes (which causes the absence of the lysosomal β-N-acetyl-hexosaminidase), are related to the wide inflammation in GM2 gangliosidoses (Tay-Sachs and Sandhoff disease), we have chosen the dendritic cells (DCs) as a study model. Using the RNA interference approach, we generated an in vitro model of HEXs knock-down immunogenic DCs (i-DCs) from CD34(+)-haemopoietic stem cells (CD34(+)-HSCs), thus mimicking the Tay-Sachs (HEXA-/-) and Sandhoff (HEXB-/-) cells. We showed that the absence of β-N-acetyl-hexosaminidase activity does not alter the differentiation of i-DCs from HSCs, but it is critical for the activation of CD4(+)T cells because knock-down of HEXA or HEXB gene causes a loss of function of i-DCs. Notably, the silencing of the HEXA gene had a stronger immune inhibitory effect, thereby indicating a major involvement of β-N-acetyl-hexosaminidase A isoenzyme within this mechanism.

  8. Nuclear domain 'knock-in' screen for the evaluation and identification of small molecule enhancers of CRISPR-based genome editing.

    Pinder, Jordan; Salsman, Jayme; Dellaire, Graham

    2015-10-30

    CRISPR is a genome-editing platform that makes use of the bacterially-derived endonuclease Cas9 to introduce DNA double-strand breaks at precise locations in the genome using complementary guide RNAs. We developed a nuclear domain knock-in screen, whereby the insertion of a gene encoding the green fluorescent protein variant Clover is inserted by Cas9-mediated homology directed repair (HDR) within the first exon of genes that are required for the structural integrity of subnuclear domains such as the nuclear lamina and promyelocytic leukemia nuclear bodies (PML NBs). Using this approach, we compared strategies for enhancing CRISPR-mediated HDR, focusing on known genes and small molecules that impact non-homologous end joining (NHEJ) and homologous recombination (HR). Ultimately, we identified the small molecule RS-1 as a potent enhancer of CRISPR-based genome editing, enhancing HDR 3- to 6-fold depending on the locus and transfection method. We also characterized U2OS human osteosarcoma cells expressing Clover-tagged PML and demonstrate that this strategy generates cell lines with PML NBs that are structurally and functionally similar to bodies in the parental cell line. Thus, the nuclear domain knock-in screen that we describe provides a simple means of rapidly evaluating methods and small molecules that have the potential to enhance Cas9-mediated HDR.

  9. FCC and the Sunshine Act.

    Weiss, Kenneth

    The Sunshine Act, designed to encourage open meetings to increase public understanding of the governmental decision-making process, went into effect in March 1977. A total of 50 agencies, including the Federal Communications Commission (FCC), are subject to the provisions of the Sunshine Act. The act lists 10 exemptions, any of which can result in…

  10. A series of N-terminal epitope tagged Hdh knock-in alleles expressing normal and mutant huntingtin: their application to understanding the effect of increasing the length of normal huntingtin’s polyglutamine stretch on CAG140 mouse model pathogenesis

    Zheng Shuqiu

    2012-08-01

    Full Text Available Abstract Background Huntington’s disease (HD is an autosomal dominant neurodegenerative disease that is caused by the expansion of a polyglutamine (polyQ stretch within Huntingtin (htt, the protein product of the HD gene. Although studies in vitro have suggested that the mutant htt can act in a potentially dominant negative fashion by sequestering wild-type htt into insoluble protein aggregates, the role of the length of the normal htt polyQ stretch, and the adjacent proline-rich region (PRR in modulating HD mouse model pathogenesis is currently unknown. Results We describe the generation and characterization of a series of knock-in HD mouse models that express versions of the mouse HD gene (Hdh encoding N-terminal hemaglutinin (HA or 3xFlag epitope tagged full-length htt with different polyQ lengths (HA7Q-, 3xFlag7Q-, 3xFlag20Q-, and 3xFlag140Q-htt and substitution of the adjacent mouse PRR with the human PRR (3xFlag20Q- and 3xFlag140Q-htt. Using co-immunoprecipitation and immunohistochemistry analyses, we detect no significant interaction between soluble full-length normal 7Q- htt and mutant (140Q htt, but we do observe N-terminal fragments of epitope-tagged normal htt in mutant htt aggregates. When the sequences encoding normal mouse htt’s polyQ stretch and PRR are replaced with non-pathogenic human sequence in mice also expressing 140Q-htt, aggregation foci within the striatum, and the mean size of htt inclusions are increased, along with an increase in striatal lipofuscin and gliosis. Conclusion In mice, soluble full-length normal and mutant htt are predominantly monomeric. In heterozygous knock-in HD mouse models, substituting the normal mouse polyQ and PRR with normal human sequence can exacerbate some neuropathological phenotypes.

  11. A Balancing Act?

    Gerstlberger, Wolfgang; Stampe, Ian; Knudsen, Mette Præst

    the 2009 European Manufacturing Survey for the Danish sub-sample including 335 manufacturing firms. Through factor analysis, the paper confirms three main focus areas of new product development in relation to production facilities: efficiency considerations, market attention and greening of innovation....... Logistic regression analysis demonstrates that while market attention is important for new product development, green aspects of innovation and efficiency considerations for innovation are important for the energy efficiency of the production companies. Combining these models highlights that energy...... efficiency moderates the effect of market attention on new product development. The paper therefore concludes that product innovation and energy efficiency is a balancing act, focusing on one will have detrimental effects on the other! These findings point to the conclusion that researchers and practitioners...

  12. Environmental Threats to Security, Stability, and U.S. Interests in Southern Africa: Opportunity Knocks - Time for a Comprehensive Region Defense Environmental International Cooperation and Environmental Security Assistance Strategy

    2009-01-01

    the satisfaction of all stakeholders”).9 The 2000 Mozambique floods, for instance, originated in cross-border shared basins where poor disaster...analysis of ecological , socio-economic, and demographic factors the Council identified southern Africa as a potential climate change hotspot where...top 10 worldwide for victims killed or affected per 100,000 inhabitants: Malawi 37,376; Zambia 10,666; Mozambique 7,461.16 Mozambique has also been

  13. Computer Aided Modelling – Opportunities and Challenges

    Cameron, Ian; Gani, Rafiqul

    2011-01-01

    -based solutions to significant problems? The important issues of workflow and data flow are discussed together with fit-for-purpose model development. As well, the lack of tools around multiscale modelling provides opportunities for the development of efficient tools to address such challenges. The ability......This chapter considers the opportunities that are present in developing, extending and applying aspects of computer-aided modelling principles and practice. What are the best tasks to be done by modellers and what needs the application of CAPE tools? How do we efficiently develop model...... and opportunities are discussed for such systems....

  14. 77 FR 58111 - Notice of Submission for OMB Review; Office of Postsecondary Education; Higher Education Act (HEA...

    2012-09-19

    ... Notice of Submission for OMB Review; Office of Postsecondary Education; Higher Education Act (HEA) Title II Report Cards on State Teacher Credentialing and Preparation SUMMARY: The Higher Education Opportunity Act of 2008 (HEOA) calls for annual reports from states and institutions of higher education...

  15. Flight Opportunities: Space Technology Mission Directorate

    Van Dijk, Alexander

    2016-01-01

    Flight Opportunities enables maturation of new space technologies by funding access to commercially available space-relevant test environments. The program also supports capability development in the commercial suborbital and orbital small satellite launcher markets.

  16. USAJOBS Job Opportunity Announcements (JOA) SOAP API

    Office of Personnel Management — The purpose of the SOAP based API is to provide the full Federal Job Opportunity Announcement (JOA) content to the consumer. It is anticipated that this API will be...

  17. Water Technology Innovation: Ten Market Opportunities

    The Water Technology Innovation Blueprint offers an overview of market opportunities that include conserving and recovering energy, recovering nutrients, improving water infrastructure, reducing costs for water monitoring, and improving water quality.

  18. Sport Opportunities for Athletes with Disabilities.

    Journal of Physical Education, Recreation & Dance, 1984

    1984-01-01

    This series outlines sport opportunities for athletes with disabilities. Included are articles discussing sports for athletes with cerebral palsy, deaf athletes, blind athletes, wheelchair bound athletes, amputee athletes, as well as a discussion of the Special Olympics. (JMK)

  19. USAJOBS Job Opportunity Announcements (JOA) REST API

    Office of Personnel Management — This REST-based API is designed to support lightweight Federal Job Opportunity Announcement (JOA) content consumption by consumers. It is anticipated that this API...

  20. Technological opportunities and paths of development

    Plichta, Kirsten

    1993-01-01

    rational they tend to choose opportunities for incremental improvements in their products and production techniques rather than developing radical new products and techniques. 4) Persistent differences between firms in an industry with regard to their products and process technologies are an outcome......Executive summary: 1) The technological development of firms in an industry is influenced by the opportunities for improving product and process, their ability to identify such opportunities and their ability to appropriate the benefit of the development effort. 2) Firms' historically developed...... technological knowledge, their production, development and other routines as well prior investments in products and production equipment play an important role with regard to the technological opportunities that firms' identify and select for development. 3) Because history matters and because firms are bounded...

  1. Making Money from Exploiting Schumpeterian Opportunities: John Sanguinetti and the Electronic Design Automation Industry

    Arthur Low

    2012-05-01

    Full Text Available Accounts of the effect that John Sanguinetti’s two companies had on the market for integrated circuit design languages were used to gain insights on how to profit from the exploitation of Schumpeterian opportunities. This article will be of interest to entrepreneurs who expect to profit from exploiting opportunities that disrupt the status quo. To write this article, the author reviewed the literature on Schumpeterian and Kirznerian opportunities and examined the writings of and about Sanguinetti and his companies, blogs written by industry insiders, and articles in industry trade journals. Sanguinetti’s first company introduced a new technology and his second company introduced a new business strategy and a new technology. Both of Sanguinetti's companies undermined the capital investments of the established incumbents and created new value for customers. The article provides three main insights. First, deep knowledge and experience in the customer domain enable an entrepreneur to recognize and act to profit from a Schumpeterian opportunity. Second, to profit from a Schumpeterian opportunity the entrepreneur needs to combine technology and business model components in a way that adds significant value to customers. Third, large amounts of venture capital may or may not be required to exploit Schumpeterian opportunities.

  2. Ubiquitin ligase RNF123 mediates degradation of heterochromatin protein 1α and β in lamin A/C knock-down cells.

    Pankaj Chaturvedi

    Full Text Available BACKGROUND: The nuclear lamina is a key determinant of nuclear architecture, integrity and functionality in metazoan nuclei. Mutations in the human lamin A gene lead to highly debilitating genetic diseases termed as laminopathies. Expression of lamin A mutations or reduction in levels of endogenous A-type lamins leads to nuclear defects such as abnormal nuclear morphology and disorganization of heterochromatin. This is accompanied by increased proteasomal degradation of certain nuclear proteins such as emerin, nesprin-1α, retinoblastoma protein and heterochromatin protein 1 (HP1. However, the pathways of proteasomal degradation have not been well characterized. METHODOLOGY/PRINCIPAL FINDINGS: To investigate the mechanisms underlying the degradation of HP1 proteins upon lamin misexpression, we analyzed the effects of shRNA-mediated knock-down of lamins A and C in HeLa cells. Cells with reduced levels of expression of lamins A and C exhibited proteasomal degradation of HP1α and HP1β but not HP1γ. Since specific ubiquitin ligases are upregulated in lamin A/C knock-down cells, further studies were carried out with one of these ligases, RNF123, which has a putative HP1-binding motif. Ectopic expression of GFP-tagged RNF123 directly resulted in degradation of HP1α and HP1β. Mutational analysis showed that the canonical HP1-binding pentapeptide motif PXVXL in the N-terminus of RNF123 was required for binding to HP1 proteins and targeting them for degradation. The role of endogenous RNF123 in the degradation of HP1 isoforms was confirmed by RNF123 RNAi experiments. Furthermore, FRAP analysis suggested that HP1β was displaced from chromatin in laminopathic cells. CONCLUSIONS/SIGNIFICANCE: Our data support a role for RNF123 ubiquitin ligase in the degradation of HP1α and HP1β upon lamin A/C knock-down. Hence lamin misexpression can cause degradation of mislocalized proteins involved in key nuclear processes by induction of specific components of

  3. Regenerative Medicine-Opportunities and Challenges

    Zhengguo Wang

    2006-01-01

    In this paper, the definitions and contents of regenerative medicine, including tissue engineering, cell therapy, cytokine therapy and microecologic cure, were presented. And then, the prospects and difficulties for clinical application of these therapies were further mentioned. It indicated that the regenerative medicine came to a new era with full of opportunities and challenges. To face and seize this evanescent opportunity is worthy of detailed discussions.

  4. Telecommunications: Opportunities in the emerging technologies

    Schultheis, R.W. [Mission Telecommunications Group, Charlottesville, VA (United States)

    1994-12-31

    A series of slides present opportunities for Utility Telecommunications. The following aspects are covered: (1) Technology in a period of revolution; (2) Technology Management by the Energy Utility, (3) Contemporary Telecommunication Network Architectures, (4) Opportunity Management, (5) Strategic Planning for Profits and Growth, (6) Energy Industry in a period of challenge. Management topics and applications are presented in a matrix for generation, transmission, distribution, customer service and new business revenue growth subjects.

  5. Opportunities for Biorenewables in Oil Refineries

    Marker, T.L.

    2005-12-19

    Abstract: The purpose of this study was to evaluate the potential for using biorenewable feedstocks in oil refineries. Economic analyses were conducted, with support from process modeling and proof of principle experiments, to assess a variety of potential processes and configurations. The study considered two primary alternatives: the production of biodiesel and green diesel from vegetable oils and greases and opportunities for utilization of pyrolysis oil. The study identified a number of promising opportunities for biorenewables in existing or new refining operations.

  6. Industrial Development Opportunity & Trend of Chinese Medicine

    Wang YiTao

    2001-01-01

    @@ While having a great development opportunity, CM faces a great marketing competition when entering to WTO. An important change will take place in CM technology, industry as well as overseas and domestic marketing. The domestic CM industry and marketing tend to be "internationalized” while the foreign herbal and traditional drugs tend to be "CM”. This article aims to explore the opportunity, trend and future of CM by analyzing the present status of CM technology, industry and marketing.

  7. Industrial Development Opportunity & Trend of Chinese Medicine

    Wang; YiTao

    2001-01-01

    While having a great development opportunity, CM faces a great marketing competition when entering to WTO. An important change will take place in CM technology, industry as well as overseas and domestic marketing. The domestic CM industry and marketing tend to be "internationalized” while the foreign herbal and traditional drugs tend to be "CM”. This article aims to explore the opportunity, trend and future of CM by analyzing the present status of CM technology, industry and marketing.  ……

  8. Double acting bit holder

    Morrell, Roger J.; Larson, David A.; Ruzzi, Peter L.

    1994-01-01

    A double acting bit holder that permits bits held in it to be resharpened during cutting action to increase energy efficiency by reducing the amount of small chips produced. The holder consist of: a stationary base portion capable of being fixed to a cutter head of an excavation machine and having an integral extension therefrom with a bore hole therethrough to accommodate a pin shaft; a movable portion coextensive with the base having a pin shaft integrally extending therefrom that is insertable in the bore hole of the base member to permit the moveable portion to rotate about the axis of the pin shaft; a recess in the movable portion of the holder to accommodate a shank of a bit; and a biased spring disposed in adjoining openings in the base and moveable portions of the holder to permit the moveable portion to pivot around the pin shaft during cutting action of a bit fixed in a turret to allow front, mid and back positions of the bit during cutting to lessen creation of small chip amounts and resharpen the bit during excavation use.

  9. An Act of Colonization

    Rasmussen, Anders Bo

    When Gideon Welles, U.S. Secretary of the Navy, sat down to write his diary entry on September 26, 1862, his thoughts turned once more to colonization. President Lincoln was an ardent proponent of colonization, “the government-promoted settlement of black Americans in Africa or some other location......” and based on the recurring cabinet discussions, Welles understood that “Great Britain, Denmark and perhaps other powers would take them [the black population].” Since at least 1860, Denmark had encouraged the American government to send the “quite uncivilized (…) Africans liberated” from slave ships to St...... and the United States signed an act on July 19, 1862, wherein the U.S. Navy agreed to unload “all negroes, mulattoes, or persons of color, delivered from on board vessels seized in the prosecution of the slave trade.” Yet, despite the two countries’ mutual interests in employing “laborers of African Extraction...

  10. CRISPR/Cas9 allows efficient and complete knock-in of a destabilization domain-tagged essential protein in a human cell line, allowing rapid knockdown of protein function.

    Arnold Park

    Full Text Available Although modulation of protein levels is an important tool for study of protein function, it is difficult or impossible to knockdown or knockout genes that are critical for cell growth or viability. For such genes, a conditional knockdown approach would be valuable. The FKBP protein-based destabilization domain (DD-tagging approach, which confers instability to the tagged protein in the absence of the compound Shield-1, has been shown to provide rapid control of protein levels determined by Shield-1 concentration. Although a strategy to knock-in DD-tagged protein at the endogenous loci has been employed in certain parasite studies, partly due to the relative ease of knock-in as a result of their mostly haploid lifecycles, this strategy has not been demonstrated in diploid or hyperploid mammalian cells due to the relative difficulty of achieving complete knock-in in all alleles. The recent advent of CRISPR/Cas9 homing endonuclease-mediated targeted genome cleavage has been shown to allow highly efficient homologous recombination at the targeted locus. We therefore assessed the feasibility of using CRISPR/Cas9 to achieve complete knock-in to DD-tag the essential gene Treacher Collins-Franceschetti syndrome 1 (TCOF1 in human 293T cells. Using a double antibiotic selection strategy to select clones with at least two knock-in alleles, we obtained numerous complete knock-in clones within three weeks of initial transfection. DD-TCOF1 expression in the knock-in cells was Shield-1 concentration-dependent, and removal of Shield-1 resulted in destabilization of DD-TCOF1 over the course of hours. We further confirmed that the tagged TCOF1 retained the nucleolar localization of the wild-type untagged protein, and that destabilization of DD-TCOF1 resulted in impaired cell growth, as expected for a gene implicated in ribosome biogenesis. CRISPR/Cas9-mediated homologous recombination to completely knock-in a DD tag likely represents a generalizable and

  11. A knock-in model of human epilepsy in Drosophila reveals a novel cellular mechanism associated with heat-induced seizure.

    Sun, Lei; Gilligan, Jeff; Staber, Cynthia; Schutte, Ryan J; Nguyen, Vivian; O'Dowd, Diane K; Reenan, Robert

    2012-10-10

    Over 40 missense mutations in the human SCN1A sodium channel gene are linked to an epilepsy syndrome termed genetic epilepsy with febrile seizures plus (GEFS+). Inheritance of GEFS+ is dominant, but the underlying cellular mechanisms remain poorly understood. Here we report that knock-in of a GEFS+ SCN1A mutation (K1270T) into the Drosophila sodium channel gene, para, causes a semidominant temperature-induced seizure phenotype. Electrophysiological studies of GABAergic interneurons in the brains of adult GEFS+ flies reveal a novel cellular mechanism underlying heat-induced seizures: the deactivation threshold for persistent sodium currents reversibly shifts to a more negative voltage when the temperature is elevated. This leads to sustained depolarizations in GABAergic neurons and reduced inhibitory activity in the central nervous system. Furthermore, our data indicate a natural temperature-dependent shift in sodium current deactivation (exacerbated by mutation) may contribute to febrile seizures in GEFS+ and perhaps normal individuals.

  12. Mice carrying a knock-in mutation of Aicda resulting in a defect in somatic hypermutation have impaired gut homeostasis and compromised mucosal defense.

    Wei, Min; Shinkura, Reiko; Doi, Yasuko; Maruya, Mikako; Fagarasan, Sidonia; Honjo, Tasuku

    2011-03-01

    To elucidate the specific role of somatic hypermutation (SHM) in mucosal immunity, we generated mice carrying a knock-in point mutation in Aicda, which encodes activation-induced cytidine deaminase (AID), an enzyme essential to SHM and class-switch recombination (CSR). These mutant AID(G23S) mice had much less SHM but had normal amounts of immunoglobulin in both serum and intestinal secretions. AID(G23S) mice developed hyperplasia of germinal center B cells in gut-associated lymphoid tissues, accompanied by expansion of microflora in the small intestine. Moreover, AID(G23S) mice had more translocation of Yersinia enterocolitica into mesenteric lymph nodes and were more susceptible than wild-type mice to oral challenge with cholera toxin. Together our results indicate that SHM is critical in maintaining intestinal homeostasis and efficient mucosal defense.

  13. Overexpression or knock-down of runt-related transcription factor 1 affects BCR-ABL-induced proliferation and migration in vitro and leukemogenesis in vivo in mice

    YANG Li-jun; YU Wei-dong; DU Jun-bao; CHAO Shuang; CHEN Min-xia; ZHAO He-hua; GUO Jing-zhu

    2009-01-01

    Background Runt-related transcription factor 1 (Runx1) plays a crucial role in hematogenesis and its dysfunction may contribute to leukemogenesis. However, it is not clear whether or not abnormal expression of Runx1 will induce leukemia and how the change of Runx1 expression level could affect BCR-ABL-induced leukemogenesis. In the present study, we aimed to analyze if abnormal expression of Runx1 in BaF3 cells alone would induce leukemogenesis. And we also wanted to know if abnormal expression of Runx1 in leukemic cells would affect leukemogenesis. Furthermore, we investigated whether overexpression or knock-down of Runx1 in BaF3 cells would induce leukemogenesis.Methods Plasmids containing full-length Runx1 cDNA were transduced into BaF3 cells and BaF3-P185wt cells (BCR-ABL transformed BaF3 cells) by electroporation. Plasmids containing a short hairpin RNA of Runx1 were transduced into BaF3 cells and BaF3-P185wt cells by electroporation. Runx1 expression level was quantified by Western blotting and quantitative real-time PCR. The effects of overexpression or knock-down of Runx1 on proliferation, apoptosis and migration of cells were detected in vitro. Then, using MSCV-P185wt-FGFP as a control, we transplanted MSCV-P185wt-Runx1 cells or MSCV-P185wt-shRNA cells into Balb/c mice through tail vein and observed tumorgenesis of the different phenotypes.Results In vitro analysis revealed that overexpression of Runx1 in P185wt cells could inhibit cell proliferation and slow down cell migration; while knock-down of Runx1 could promote cell proliferation and speed up cell migration. In vivo analysis indicated that mice transplanted with MSCV-P185wt-Runx1 survived longer than controls. In contrast, mice transplanted with MSCV-P185wt-shRNA survived shorter than the control group. Gross pathological analysis revealed that the MSCV-P185wt-Runx1 group had less severe splenomegaly and hepatomegaly compared to the control group, and the MSCV-P185wt-shRNA group had more severe

  14. Advanced Communications Technology Satellite (ACTS)

    Olmstead, Dean A.; Schertler, Ronald J.

    The benefits that will be offered by the NASA-sponsored communication spacecraft ACTS which is scheduled for launch in 1992 are described together with examples of demonstrations on proposed data, video, and voice applications supported by the advanced ACTS technologies. Compared to existing satellite service, the ACTS will provide lower cost, better service, greater convenience, and improved service reliability of telecommunications to customers around the world. In addition, the pioneering ACTS technology will provide many capabilities qualitatively different from those of current satellite systems, such as on-demand assignment, frequency reuse, and the flexible targeting of spot beams directly to the very-small-aperture terminals at customer premises.

  15. [Euthanasia and medical act].

    2011-05-01

    Right to life -as the prohibition of intentionally and arbitrarily taking life, even with authorization of the concerned one- is an internationally recognized right. In many countries, debate regarding euthanasia is more centered in its convenience, social acceptability and how it is regulated, than in its substantial legitimacy. Some argue that euthanasia should be included as part of clinical practice of health professionals, grounded on individual's autonomy claims-everyone having the liberty to choose how to live and how to die. Against this, others sustain that life has a higher value than autonomy, exercising autonomy without respecting the right to life would become a serious moral and social problem. Likewise, euthanasia supporters some-times claim a 'right to live with dignity', which must be understood as a personal obligation, referred more to the ethical than to the strictly legal sphere. In countries where it is already legalized, euthanasia practice has extended to cases where it is not the patient who requests this but the family or some healthcare professional, or even the legal system-when they think that the patient is living in a condition which is not worthy to live. Generalization of euthanasia possibly will end in affecting those who need more care, such as elder, chronically ill or dying people, damaging severely personal basic rights. Nature, purpose and tradition of medicine rule out the practice of euthanasia, which ought not be considered a medical act or legitimately compulsory for physicians. Today's medicine counts with effective treatments for pain and suffering, such as palliative care, including sedative therapy, which best preserves persons dignity and keeps safe the ethos of the medical profession.

  16. 75 FR 63703 - Privacy Act of 1974; Privacy Act Regulation

    2010-10-18

    ... Federal Register, 73 FR 25594, May 7, 2008. The proposed amendments: (1) Waived all copying fees in..., 73 FR 54595, September 22, 2008, certain portions of BGFRS-37 (Electronic Applications) may be exempt... CFR Part 261a Privacy Act of 1974; Privacy Act Regulation AGENCY: Board of Governors of the...

  17. Calcilytic Ameliorates Abnormalities of Mutant Calcium-Sensing Receptor (CaSR) Knock-In Mice Mimicking Autosomal Dominant Hypocalcemia (ADH).

    Dong, Bingzi; Endo, Itsuro; Ohnishi, Yukiyo; Kondo, Takeshi; Hasegawa, Tomoka; Amizuka, Norio; Kiyonari, Hiroshi; Shioi, Go; Abe, Masahiro; Fukumoto, Seiji; Matsumoto, Toshio

    2015-11-01

    Activating mutations of calcium-sensing receptor (CaSR) cause autosomal dominant hypocalcemia (ADH). ADH patients develop hypocalcemia, hyperphosphatemia, and hypercalciuria, similar to the clinical features of hypoparathyroidism. The current treatment of ADH is similar to the other forms of hypoparathyroidism, using active vitamin D3 or parathyroid hormone (PTH). However, these treatments aggravate hypercalciuria and renal calcification. Thus, new therapeutic strategies for ADH are needed. Calcilytics are allosteric antagonists of CaSR, and may be effective for the treatment of ADH caused by activating mutations of CaSR. In order to examine the effect of calcilytic JTT-305/MK-5442 on CaSR harboring activating mutations in the extracellular and transmembrane domains in vitro, we first transfected a mutated CaSR gene into HEK cells. JTT-305/MK-5442 suppressed the hypersensitivity to extracellular Ca(2+) of HEK cells transfected with the CaSR gene with activating mutations in the extracellular and transmembrane domains. We then selected two activating mutations locating in the extracellular (C129S) and transmembrane (A843E) domains, and generated two strains of CaSR knock-in mice to build an ADH mouse model. Both mutant mice mimicked almost all the clinical features of human ADH. JTT-305/MK-5442 treatment in vivo increased urinary cAMP excretion, improved serum and urinary calcium and phosphate levels by stimulating endogenous PTH secretion, and prevented renal calcification. In contrast, PTH(1-34) treatment normalized serum calcium and phosphate but could not reduce hypercalciuria or renal calcification. CaSR knock-in mice exhibited low bone turnover due to the deficiency of PTH, and JTT-305/MK-5442 as well as PTH(1-34) increased bone turnover and bone mineral density (BMD) in these mice. These results demonstrate that calcilytics can reverse almost all the phenotypes of ADH including hypercalciuria and renal calcification, and suggest that calcilytics can become a

  18. Towards in vivo mutation analysis: knock-out of specific chlorophylls bound to the light-harvesting complexes of Arabidopsis thaliana - the case of CP24 (Lhcb6).

    Passarini, Francesca; Xu, Pengqi; Caffarri, Stefano; Hille, Jacques; Croce, Roberta

    2014-09-01

    In the last ten years, a large series of studies have targeted antenna complexes of plants (Lhc) with the aim of understanding the mechanisms of light harvesting and photoprotection. Combining spectroscopy, modeling and mutation analyses, the role of individual pigments in these processes has been highlighted in vitro. In plants, however, these proteins are associated with multiple complexes of the photosystems and function within this framework. In this work, we have envisaged a way to bridge the gap between in vitro and in vivo studies by knocking out in vivo pigments that have been proposed to play an important role in excitation energy transfer between the complexes or in photoprotection. We have complemented a CP24 knock-out mutant of Arabidopsis thaliana with the CP24 (Lhcb6) gene carrying a His-tag and with a mutated version lacking the ligand for chlorophyll 612, a specific pigment that in vitro experiments have indicated as the lowest energy site of the complex. Both complexes efficiently integrated into the thylakoid membrane and assembled into the PSII supercomplexes, indicating that the His-tag does not impair the organization in vivo. The presence of the His-tag allowed the purification of CP24-WT and of CP24-612 mutant in their native states. It is shown that CP24-WT coordinates 10 chlorophylls and 2 carotenoid molecules and has properties identical to those of the reconstituted complex, demonstrating that the complex self-assembled in vitro assumes the same folding as in the plant. The absence of the ligand for chlorophyll 612 leads to the loss of one Chl a and of lutein, again as in vitro, indicating the feasibility of the method. This article is part of a special issue entitled: photosynthesis research for sustainability: keys to produce clean energy.

  19. Genetic knock-down of HDAC3 does not modify disease-related phenotypes in a mouse model of Huntington's disease.

    Lara Moumné

    Full Text Available Huntington's disease (HD is an autosomal dominant progressive neurodegenerative disorder caused by an expansion of a CAG/polyglutamine repeat for which there are no disease modifying treatments. In recent years, transcriptional dysregulation has emerged as a pathogenic process that appears early in disease progression and has been recapitulated across multiple HD models. Altered histone acetylation has been proposed to underlie this transcriptional dysregulation and histone deacetylase (HDAC inhibitors, such as suberoylanilide hydroxamic acid (SAHA, have been shown to improve polyglutamine-dependent phenotypes in numerous HD models. However potent pan-HDAC inhibitors such as SAHA display toxic side-effects. To better understand the mechanism underlying this potential therapeutic benefit and to dissociate the beneficial and toxic effects of SAHA, we set out to identify the specific HDAC(s involved in this process. For this purpose, we are exploring the effect of the genetic reduction of specific HDACs on HD-related phenotypes in the R6/2 mouse model of HD. The study presented here focuses on HDAC3, which, as a class I HDAC, is one of the preferred targets of SAHA and is directly involved in histone deacetylation. To evaluate a potential benefit of Hdac3 genetic reduction in R6/2, we generated a mouse carrying a critical deletion in the Hdac3 gene. We confirmed that the complete knock-out of Hdac3 is embryonic lethal. To test the effects of HDAC3 inhibition, we used Hdac3(+/- heterozygotes to reduce nuclear HDAC3 levels in R6/2 mice. We found that Hdac3 knock-down does not ameliorate physiological or behavioural phenotypes and has no effect on molecular changes including dysregulated transcripts. We conclude that HDAC3 should not be considered as the major mediator of the beneficial effect induced by SAHA and other HDAC inhibitors in HD.

  20. Knock-down of transcript abundance of a family of Kunitz proteinase inhibitor genes in white clover (Trifolium repens) reveals a redundancy and diversity of gene function.

    Islam, Afsana; Leung, Susanna; Burgess, Elisabeth P J; Laing, William A; Richardson, Kim A; Hofmann, Rainer W; Dijkwel, Paul P; McManus, Michael T

    2015-12-01

    The transcriptional regulation of four phylogenetically distinct members of a family of Kunitz proteinase inhibitor (KPI) genes isolated from white clover (Trifolium repens; designated Tr-KPI1, Tr-KPI2, Tr-KPI4 and Tr-KPI5) has been investigated to determine their wider functional role. The four genes displayed differential transcription during seed germination, and in different tissues of the mature plant, and transcription was also ontogenetically regulated. Heterologous over-expression of Tr-KPI1, Tr-KPI2, Tr-KPI4 and Tr-KPI5 in Nicotiana tabacum retarded larval growth of the herbivore Spodoptera litura, and an increase in the transcription of the pathogenesis-related genes PR1 and PR4 was observed in the Tr-KPI1 and Tr-KPI4 over-expressing lines. RNA interference (RNAi) knock-down lines in white clover displayed significantly altered vegetative growth phenotypes with inhibition of shoot growth and a stimulation of root growth, while knock-down of Tr-KPI1, Tr-KPI2 and Tr-KPI5 transcript abundance also retarded larval growth of S. litura. Examination of these RNAi lines revealed constitutive stress-associated phenotypes as well as altered transcription of cellular signalling genes. These results reveal a functional redundancy across members of the KPI gene family. Further, the regulation of transcription of at least one member of the family, Tr-KPI2, may occupy a central role in the maintenance of a cellular homeostasis.

  1. Variable laterality of corticospinal tract axons that regenerate after spinal cord injury as a result of PTEN deletion or knock-down.

    Willenberg, Rafer; Zukor, Katherine; Liu, Kai; He, Zhigang; Steward, Oswald

    2016-09-01

    Corticospinal tract (CST) axons from one hemisphere normally extend and terminate predominantly in the contralateral spinal cord. We previously showed that deleting the gene phosphatase and tensin homolog (PTEN) in the sensorimotor cortex enables CST axons to regenerate after spinal cord injury and that some regenerating axons extend along the "wrong" side. Here, we characterize the degree of specificity of regrowth in terms of laterality. PTEN was selectively deleted via cortical adeno-associated virus (AAV)-Cre injections in neonatal PTEN-floxed mice. As adults, mice received dorsal hemisection injuries at T12 or complete crush injuries at T9. CST axons from one hemisphere were traced by unilateral biotinylated dextran amine (BDA) injections in PTEN-deleted mice with spinal cord injury and in noninjured PTEN-floxed mice that had not received AAV-Cre. In noninjured mice, 97.9 ± 0.7% of BDA-labeled axons in white matter and 88.5 ± 1.0% of BDA-labeled axons in gray matter were contralateral to the cortex of origin. In contrast, laterality of CST axons that extended past a lesion due to PTEN deletion varied across animals. In some cases, regenerated axons extended predominantly on the ipsilateral side; in other cases, axons extended predominantly contralaterally, and in others, axons were similar in numbers on both sides. Similar results were seen in analyses of cases from previous studies using short hairpin (sh)RNA-mediated PTEN knock-down. These results indicate that CST axons that extend past a lesion due to PTEN deletion or knock-down do not maintain the contralateral rule of the noninjured CST, highlighting one aspect of how the resultant circuitry from regenerating axons may differ from that of the uninjured CST. J. Comp. Neurol. 524:2654-2676, 2016. © 2016 Wiley Periodicals, Inc.

  2. A new humanized ataxin-3 knock-in mouse model combines the genetic features, pathogenesis of neurons and glia and late disease onset of SCA3/MJD.

    Switonski, Pawel M; Szlachcic, Wojciech J; Krzyzosiak, Wlodzimierz J; Figiel, Maciej

    2015-01-01

    Spinocerebellar ataxia type 3 (SCA3/MJD) is a neurodegenerative disease triggered by the expansion of CAG repeats in the ATXN3 gene. Here, we report the generation of the first humanized ataxin-3 knock-in mouse model (Ki91), which provides insights into the neuronal and glial pathology of SCA3/MJD. First, mutant ataxin-3 accumulated in cell nuclei across the Ki91 brain, showing diffused immunostaining and forming intranuclear inclusions. The humanized allele revealed expansion and contraction of CAG repeats in intergenerational transmissions. CAG mutation also exhibited age-dependent tissue-specific expansion, which was most prominent in the cerebellum, pons and testes of Ki91 animals. Moreover, Ki91 mice displayed neuroinflammatory processes, showing astrogliosis in the cerebellar white matter and the substantia nigra that paralleled the transcriptional deregulation of Serpina3n, a molecular sign of neurodegeneration and brain damage. Simultaneously, the cerebellar Purkinje cells in Ki91 mice showed neurodegeneration, a pronounced decrease in Calbindin D-28k immunoreactivity and a mild decrease in cell number, thereby modeling the degeneration of the cerebellum observed in SCA3. Moreover, these molecular and cellular neuropathologies were accompanied by late behavioral deficits in motor coordination observed in rotarod and static rod tests in heterozygous Ki91 animals. In summary, we created an ataxin-3 knock-in mouse model that combines the molecular and behavioral disease phenotypes with the genetic features of SCA3. This model will be very useful for studying the pathogenesis and responses to therapy of SCA3/MJD and other polyQ disorders.

  3. The de-ubiquitinating enzyme ataxin-3 does not modulate disease progression in a knock-in mouse model of Huntington disease.

    Zeng, Li; Tallaksen-Greene, Sara J; Wang, Bo; Albin, Roger L; Paulson, Henry L

    2013-01-01

    Ataxin-3 is a deubiquitinating enzyme (DUB) that participates in ubiquitin-dependent protein quality control pathways and, based on studies in model systems, may be neuroprotective against toxic polyglutamine proteins such as the Huntington's disease (HD) protein, huntingtin (htt). HD is one of at least nine polyglutamine neurodegenerative diseases in which disease-causing proteins accumulate in ubiquitin-positive inclusions within neurons. In studies crossing mice null for ataxin-3 to an established HD knock-in mouse model (HdhQ200), we tested whether loss of ataxin-3 alters disease progression, perhaps by impairing the clearance of mutant htt or the ubiquitination of inclusions. While loss of ataxin-3 mildly exacerbated age-dependent motor deficits, it did not alter inclusion formation, ubiquitination of inclusions or levels of mutant or normal htt. Ataxin-3, itself a polyglutamine-containing protein with multiple ubiquitin binding domains, was not observed to localize to htt inclusions. Changes in neurotransmitter receptor binding known to occur in HD knock-in mice also were not altered by the loss of ataxin-3, although we unexpectedly observed increased GABAA receptor binding in the striatum of HdhQ200 mice, which has not previously been noted. Finally, we confirmed that CNS levels of hsp70 are decreased in HD mice as has been reported in other HD mouse models, regardless of the presence or absence of ataxin-3. We conclude that while ataxin-3 may participate in protein quality control pathways, it does not critically regulate the handling of mutant htt or contribute to major features of disease pathogenesis in HD.

  4. Impaired Cytogenetic Damage Repair and Cell Cycle Regulation in Response to Ionizing Radiation in Human Fibroblast Cells with Individual Knock-down of 25 Genes

    Zhang, Ye; Rohde, Larry; Emami, Kamal; Hammond, Dianne; Casey, Rachael; Mehta, Satish; Jeevarajan, Antony; Pierson, Duane; Wu, Honglu

    2008-01-01

    Changes of gene expression profile are one of the most important biological responses in living cells after ionizing radiation (IR) exposure. Although some studies have demonstrated that genes with upregulated expression induced by IR may play important roles in DNA damage sensing, cell cycle checkpoint and chromosomal repair, the relationship between the regulation of gene expression by IR and its impact on cytogenetic responses to ionizing radiation has not been systematically studied. In our present study, the expression of 25 genes selected based on their transcriptional changes in response to IR or from their known DNA repair roles were individually knocked down by siRNA transfection in human fibroblast cells. Chromosome aberrations (CA) and micronuclei (MN) formation were measured as the cytogenetic endpoints. Our results showed that the yield of MN and/or CA formation were significantly increased by suppressed expression of 5 genes that included Ku70 in the DSB repair pathway; XPA in the NER pathway; RPA1 in the MMR pathway; RAD17 and RBBP8 in cell cycle control. Knocked-down expression of 4 genes including MRE11A, RAD51 in the DSB pathway, and SESN1 and SUMO1 showed significant inhibition of cell cycle progression, possibly because of severe impairment of DNA damage repair. Furthermore, loss of XPA, p21 and MLH1 expression resulted in both enhanced cell cycle progression and significantly higher yield of cytogenetic damage, indicating the involvement of these gene products in both cell cycle control and DNA damage repair. Of these 11 genes that affected the cytogenetic response, 9 were up-regulated in the cells exposed to gamma radiation, suggesting that genes transcriptionally modulated by IR were critical to regulating the biological consequences after IR. Failure to express these IR-responsive genes, such as by gene mutation, could seriously change the outcome of the post IR scenario and lead to carcinogenesis.

  5. RNAi knock-down of LHCBM1, 2 and 3 increases photosynthetic H2 production efficiency of the green alga Chlamydomonas reinhardtii.

    Melanie Oey

    Full Text Available Single cell green algae (microalgae are rapidly emerging as a platform for the production of sustainable fuels. Solar-driven H2 production from H2O theoretically provides the highest-efficiency route to fuel production in microalgae. This is because the H2-producing hydrogenase (HYDA is directly coupled to the photosynthetic electron transport chain, thereby eliminating downstream energetic losses associated with the synthesis of carbohydrate and oils (feedstocks for methane, ethanol and oil-based fuels. Here we report the simultaneous knock-down of three light-harvesting complex proteins (LHCMB1, 2 and 3 in the high H2-producing Chlamydomonas reinhardtii mutant Stm6Glc4 using an RNAi triple knock-down strategy. The resultant Stm6Glc4L01 mutant exhibited a light green phenotype, reduced expression of LHCBM1 (20.6% ±0.27%, LHCBM2 (81.2% ±0.037% and LHCBM3 (41.4% ±0.05% compared to 100% control levels, and improved light to H2 (180% and biomass (165% conversion efficiencies. The improved H2 production efficiency was achieved at increased solar flux densities (450 instead of ∼100 µE m(-2 s(-1 and high cell densities which are best suited for microalgae production as light is ideally the limiting factor. Our data suggests that the overall improved photon-to-H2 conversion efficiency is due to: 1 reduced loss of absorbed energy by non-photochemical quenching (fluorescence and heat losses near the photobioreactor surface; 2 improved light distribution in the reactor; 3 reduced photoinhibition; 4 early onset of HYDA expression and 5 reduction of O2-induced inhibition of HYDA. The Stm6Glc4L01 phenotype therefore provides important insights for the development of high-efficiency photobiological H2 production systems.

  6. 78 FR 65608 - Information Collection; Outreach Opportunity Questionnaire

    2013-11-01

    ... Forest Service Information Collection; Outreach Opportunity Questionnaire AGENCY: Forest Service, USDA... with revision of a currently approved information collection, Outreach Opportunity Questionnaire. DATES... INFORMATION: Title: Outreach Opportunity Questionnaire. OMB Number: 0596-0207. Expiration Date of...

  7. 75 FR 30364 - Information Collection; Outreach Opportunity Questionnaire

    2010-06-01

    ...; ] DEPARTMENT OF AGRICULTURE Forest Service Information Collection; Outreach Opportunity Questionnaire AGENCY... Opportunity Questionnaire. DATES: Comments must be received in writing on or before August 2, 2010 to be... Friday. SUPPLEMENTARY INFORMATION: Title: Outreach Opportunity Questionnaire. OMB Number:...

  8. Is globalisation good for Sub-Saharan Africa? Threats and Opportunities

    Njau Ntuli, Anthony

    2004-01-01

    This paper reviews the effects globalisation has on the economic prosperity of sub-Saharan Africa, on a global information economy context, and in particular, the threats that globalisation has brought about as well as, the opportunities that are likely to emerge because of it. The fundamental shift in the nature of the global economy backed up by viable strategies, acting within the realities of globalisation and information economy open-up new windows for latecomers, and enables them conver...

  9. Sustainable Fashion Business Strategies : Opportunities for circular economy in the textile industry

    Kemppainen, Jenni

    2016-01-01

    The theme of the thesis arose from an interest in recycling and increasing circular economy pilot projects especially in the textile industry. Besides traditional flea markets and auctions, business operations with bigger volume that further circular economy have started to grow now. The aim of the thesis was to study the opportunities for circular economy in the textile industry. The new waste management act which comes into force in 2016 forces waste management to burn most of the texti...

  10. Overview of energy-conservation research opportunities

    Hopp, W.J.; Hauser, S.G.; Hane, G.J.; Gurwell, W.E.; Bird, S.P.; Cliff, W.C.; Williford, R.E.; Williams, T.A.; Ashton, W.B.

    1981-12-01

    This document is a study of research opportunities that are important to developing advanced technologies for efficient energy use. The study's purpose is to describe a wide array of attractive technical areas from which specific research and development programs could be implemented. Research areas are presented for potential application in each of the major end-use sectors. The study develops and applies a systematic approach to identifying and screening applied energy conservation research opportunities. To broadly cover the energy end-use sectors, this study develops useful information relating to the areas where federally-funded applied research will most likely play an important role in promoting energy conservation. This study is not designed to produce a detailed agenda of specific recommended research activities. The general information presented allows uniform comparisons of disparate research areas and as such provides the basis for formulating a cost-effective, comprehensive federal-applied energy conservation research strategy. Chapter 2 discusses the various methodologies that have been used in the past to identify research opportunities and details the approach used here. In Chapters 3, 4, and 5 the methodology is applied to the buildings, transportation, and industrial end-use sectors and the opportunities for applied research in these sectors are discussed.Chapter 6 synthesizes the results of the previous three chapters to give a comprehensive picture of applied energy conservation research opportunities across all end-use sectors and presents the conclusions to the report.

  11. Cultural Differences in Opportunity Cost Consideration

    Zhang, Ning; Ji, Li-Jun; Li, Ye

    2017-01-01

    Two studies were conducted to investigate cultural differences in opportunity cost consideration between Chinese and Euro-Canadians. Opportunity cost is defined as the cost of a benefit that must be forgone in order to pursue a better alternative (Becker et al., 1974). In both studies, participants read about hypothetical purchase scenarios, and then decided whether they would buy a certain product. Opportunity cost consideration was measured in two ways: (1) participants' thoughts pertaining to other (nonfocal) products while making decisions; (2) participants' decisions not to buy a focal product (Study 1) or a more expensive product (Study 2). Across both indexes, we found that after controlling for individual difference variables and amount of pocket money, Chinese participants in China considered financial opportunity cost more than Euro-Canadians in Study 1. Similar results were observed in Study 2 when comparing Chinese in Canada with Euro-Canadians However, the cultural effect on opportunity cost consideration was confounded by family income in Study 2. Implications for resource management, limitations of the current research and directions for future research are discussed. PMID:28184202

  12. Partner Market Opportunities and Relationship Stability

    Ingmar Rapp

    2015-10-01

    Full Text Available Although partner market opportunities are generally considered to be important for relationship stability, they have never been measured accurately. In order to be able to test the anticipated effects of partner market opportunities, this study conceptualises them as individual opportunities for contact and interaction in concrete social contexts, like the neighbourhood, the workplace, leisure activities, etc. Using data from the German Marriage Market Survey, we first examine the impact of individual partner market opportunities on the risk of separation. Second, we examine to what extend the most frequently studied determinants of divorce and separation depend on partner market opportunities. Our results show that the number of opposite sex contacts increases the probability of separation. Sharing the same contacts with one’s partner decreases the risk of separation. Our results indicate further that reducing opposite sex contacts in the course of the relationship is partly responsible for the higher stability of longer-lasting relationships. Having a migration background is associated with fewer opposite sex contacts. This means that having a migration background would be more destabilising if these individuals did not have less opposite sex contacts than individuals without a migration background. In contrast, joint home ownership, church attendance, higher education and residing in western Germany would generally be more stabilising if these factors were not connected with more opposite sex contacts.

  13. Retrieval opportunities while multitasking improve name recall.

    Helder, Elizabeth; Shaughnessy, John J

    2008-11-01

    In two experiments we tested whether providing retrieval opportunities while people were multitasking would improve memory for names. College students (n=195) in Experiment 1 did addition problems and intermittently were "introduced" to 12 face-name pairs to learn. For half the names students were given three within-list retrieval opportunities. Name recall (cued with the faces) was tested either immediately or after 24 hours. Retrieval opportunities improved name recall with both immediate and delayed tests. Experiment 2 more closely resembled the multitasking required in a real-life social situation. College students (n=98) viewed a videotape and were asked to learn the names of 12 dormitory residents who were introduced during an ongoing conversation. Retrieval opportunities were provided for 8 of the 12 residents by having them appear three additional times in the video without repeating their names. Retrieval opportunities improved name recall, but the effect was much smaller than in Experiment 1. The present research demonstrates that distributed retrieval can be effective when people are multitasking including when the multitasking involves a conversation.

  14. Cultural Differences in Opportunity Cost Consideration.

    Zhang, Ning; Ji, Li-Jun; Li, Ye

    2017-01-01

    Two studies were conducted to investigate cultural differences in opportunity cost consideration between Chinese and Euro-Canadians. Opportunity cost is defined as the cost of a benefit that must be forgone in order to pursue a better alternative (Becker et al., 1974). In both studies, participants read about hypothetical purchase scenarios, and then decided whether they would buy a certain product. Opportunity cost consideration was measured in two ways: (1) participants' thoughts pertaining to other (nonfocal) products while making decisions; (2) participants' decisions not to buy a focal product (Study 1) or a more expensive product (Study 2). Across both indexes, we found that after controlling for individual difference variables and amount of pocket money, Chinese participants in China considered financial opportunity cost more than Euro-Canadians in Study 1. Similar results were observed in Study 2 when comparing Chinese in Canada with Euro-Canadians However, the cultural effect on opportunity cost consideration was confounded by family income in Study 2. Implications for resource management, limitations of the current research and directions for future research are discussed.

  15. 76 FR 59073 - Privacy Act

    2011-09-23

    ...: Consistent with the Privacy Act (PA), the Central Intelligence Agency (CIA) has undertaken and completed a... clearly reflect the current CIA organizational structure and policies and practices, and to eliminate... Act (PA), the CIA has undertaken and completed a review of its public PA regulations. As a result...

  16. Acting to let someone die.

    McGee, Andrew

    2015-02-01

    This paper examines the recent prominent view in medical ethics that withdrawing life-sustaining treatment (LST) is an act of killing. I trace this view to the rejection of the traditional claim that withdrawing LST is an omission rather than an act. Although that traditional claim is not as problematic as this recent prominent view suggests, my main claim is that even if we accepted that withdrawing LST should be classified as an act rather than as an omission, it could still be classified as letting die rather than killing. Even though omissions are contrasted with acts, letting die need not be, for one can let die by means of acts. The remainder of the paper is devoted to establishing this claim and addresses certain objections to it.

  17. Science Policy: A World of Opportunities

    Mazza, Anne-Marie

    2017-01-01

    Opportunities are everywhere for scientists to engage in public policy, whether they stay at the bench or decide to move directly into the policy arena. In its 19th year, the National Academies of Sciences, Engineering, and Medicine's Christine Mirzayan Science and Technology Policy Graduate Fellowship Program provides early career individuals with the opportunity to spend 12 weeks at the Academies in Washington, DC learning about science and technology policy and the role that scientists and engineers play in advising the nation. Fellows leave the program prepared to engage in policy whether in DC, at the international level, or at the state and local level back at their home institutions. This discussion will explore these opportunities and highlight some of the positions pursued by Mirzayan alumni.

  18. Unveiling information on opportunity costs in REDD

    Delacote, Philip; Palmer, Charles; Bakkegaard, Riyong Kim;

    2014-01-01

    objectives in REDD-affected communities, having full information makes no difference to overall welfare as rents remain with agents. The amount of deforestation avoided will at least be as high as under asymmetric information. These results are illustrated with data collected on opportunity costs in Amazonas......Improving information about individual opportunity costs of deforestation agents has the potential to increase the efficiency of REDD when it takes the form of a payment for environmental services scheme. However, objectives pursued in REDD projects may vary across policy makers. Within...... a theoretical framework, this paper explores the impacts of different policy objectives under two opportunity cost settings: asymmetric and full information. For a policy maker aiming to maximize net income from REDD, having full information may not increase the amount of forest conserved but could lead...

  19. An Opportunity to Learn US History: What NAEP Data Suggest Regarding the Opportunity Gap

    Heafner, Tina L.; Fitchett, Paul G.

    2015-01-01

    The purpose of this study is to determine the degree to which Opportunity to Learn (OTL), is associated with students' achievement in US History. Opportunity to Learn stems from the basic premise that there is an important relationship between the quality and frequency of classroom instruction and students' levels of academic success. The authors…

  20. Opportunity identification competence : explaining individual and exploring team opportunity identification by employees

    Baggen, Yvette

    2017-01-01

    Opportunities and their identification are of significant importance for competitiveness in today’s complex and turbulent business environment because they serve as a key influencing factor for new value-creation. Opportunity identification (OI) is interesting not only from the perspective of

  1. The Indian National Food Security Act, 2013: a commentary.

    Varadharajan, Kiruba Sankar; Thomas, Tinku; Kurpad, Anura

    2014-06-01

    The National Food Security Act (NFSA) 2013, passed recently by the Indian Parliament, aims to ensure food security in India, chiefly by providing cereals at subsidized prices through the Targeted Public Distribution System (TPDS) for about two-thirds of households. The predominant line of criticism of the NFSA has been the costs of such an ambitious rights-based approach in the context of decelerating economic growth and growing fiscal deficits. We argue that the food subsidy has been increasing through the last few decades and is set to climb even higher with this act but that the incremental costs, at about 0.2% of gross domestic product, are not as high as claimed. Further, recent evidence of increasing utilization of the TPDS and decreasing corruption add credence to the act's premise that significant income transfers to poor households can be achieved, thereby promoting food security as well as dietary diversity. Several concerns remain to be addressed in the design and implementation of the act, including its proposed coverage, a cereal-centric approach, the identification of beneficiaries, and its adaptability at the state level. If these are resolved effectively, the act can prove to be a significant step forward in India's long-drawn-out battle against undernutrition and food insecurity. Finally, the NFSA also provides a fresh opportunity to reform and strengthen the TPDS, which has been an integral component of India's strategy to achieve food security at the national level.

  2. Future Propulsion Opportunities for Commuter Airplanes

    Strack, W. C.

    1982-01-01

    Commuter airplane propulsion opportunities are summarized. Consideration is given to advanced technology conventional turboprop engines, advanced propellers, and several unconventional alternatives: regenerative turboprops, rotaries, and diesels. Advanced versions of conventional turboprops (including propellers) offer 15-20 percent savings in fuel and 10-15 percent in DOC compared to the new crop of 1500-2000 SHP engines currently in development. Unconventional engines could boost the fuel savings to 30-40 percent. The conclusion is that several important opportunities exist and, therefore, powerplant technology need not plateau.

  3. Research Funding Opportunities for Early Career Scientists

    Wiener, Richard

    2009-10-01

    This talk will describe opportunities for early career faculty members in the physical sciences to obtain funding for scientific research and educational projects. I will discuss programs offered by Research Corporation for Science Advancement, a private nonprofit foundation, which include opportunities for scientists at primarily undergraduate institutions and at research universities. I will emphasize strategies for successful grant writing. The target audience is early career academic scientists in Astronomy, Physics, and related fields, as well as graduate students and postdoctoral researchers considering careers in these academic disciplines.

  4. Research opportunities to advance solar energy utilization.

    Lewis, Nathan S

    2016-01-22

    Major developments, as well as remaining challenges and the associated research opportunities, are evaluated for three technologically distinct approaches to solar energy utilization: solar electricity, solar thermal, and solar fuels technologies. Much progress has been made, but research opportunities are still present for all approaches. Both evolutionary and revolutionary technology development, involving foundational research, applied research, learning by doing, demonstration projects, and deployment at scale will be needed to continue this technology-innovation ecosystem. Most of the approaches still offer the potential to provide much higher efficiencies, much lower costs, improved scalability, and new functionality, relative to the embodiments of solar energy-conversion systems that have been developed to date.

  5. Identifying PHM market and network opportunities.

    Grube, Mark E; Krishnaswamy, Anand; Poziemski, John; York, Robert W

    2015-11-01

    Two key processes for healthcare organizations seeking to assume a financially sustainable role in population health management (PHM), after laying the groundwork for the effort, are to identify potential PHM market opportunities and determine the scope of the PHM network. Key variables organizations should consider with respect to market opportunities include the patient population, the overall insurance/employer market, and available types of insurance products. Regarding the network's scope, organizations should consider both traditional strategic criteria for a viable network and at least five additional criteria: network essentiality and PHM care continuum, network adequacy, service distribution right-sizing, network growth strategy, and organizational agility.

  6. Nanotechnology in biorobotics: opportunities and challenges

    Ricotti, Leonardo, E-mail: l.ricotti@sssup.it; Menciassi, Arianna [Scuola Superiore Sant’Anna, The BioRobotics Institute (Italy)

    2015-02-15

    Nanotechnology recently opened a series of unexpected technological opportunities that drove the emergence of novel scientific and technological fields, which have the potential to dramatically change the lives of millions of citizens. Some of these opportunities have been already caught by researchers working in the different fields related to biorobotics, while other exciting possibilities still lie on the horizon. This article highlights how nanotechnology applications recently impacted the development of advanced solutions for actuation and sensing and the achievement of microrobots, nanorobots, and non-conventional larger robotic systems. The open challenges are described, together with the most promising research avenues involving nanotechnology.

  7. Genome editing for crop improvement: Challenges and opportunities.

    Abdallah, Naglaa A; Prakash, Channapatna S; McHughen, Alan G

    2015-01-01

    Genome or gene editing includes several new techniques to help scientists precisely modify genome sequences. The techniques also enables us to alter the regulation of gene expression patterns in a pre-determined region and facilitates novel insights into the functional genomics of an organism. Emergence of genome editing has brought considerable excitement especially among agricultural scientists because of its simplicity, precision and power as it offers new opportunities to develop improved crop varieties with clear-cut addition of valuable traits or removal of undesirable traits. Research is underway to improve crop varieties with higher yields, strengthen stress tolerance, disease and pest resistance, decrease input costs, and increase nutritional value. Genome editing encompasses a wide variety of tools using either a site-specific recombinase (SSR) or a site-specific nuclease (SSN) system. Both systems require recognition of a known sequence. The SSN system generates single or double strand DNA breaks and activates endogenous DNA repair pathways. SSR technology, such as Cre/loxP and Flp/FRT mediated systems, are able to knockdown or knock-in genes in the genome of eukaryotes, depending on the orientation of the specific sites (loxP, FLP, etc.) flanking the target site. There are 4 main classes of SSN developed to cleave genomic sequences, mega-nucleases (homing endonuclease), zinc finger nucleases (ZFNs), transcriptional activator-like effector nucleases (TALENs), and the CRISPR/Cas nuclease system (clustered regularly interspaced short palindromic repeat/CRISPR-associated protein). The recombinase mediated genome engineering depends on recombinase (sub-) family and target-site and induces high frequencies of homologous recombination. Improving crops with gene editing provides a range of options: by altering only a few nucleotides from billions found in the genomes of living cells, altering the full allele or by inserting a new gene in a targeted region of

  8. 76 FR 20354 - Notice of Intent To Award Supplemental Affordable Care Act Funding

    2011-04-12

    ...-1001, ``APHL--CDC Partnership for Quality Laboratory Practice'' cooperative agreement. AGENCY: Centers... published version of Funding Opportunity CDC-RFA-HM10-1001. Award Information: Type of Award: Cooperative... President signed into law the Affordable Care Act (ACA), Public Law 111-148. ACA is designed to improve...

  9. 75 FR 79352 - Arbitration Panel Decision Under the Randolph-Sheppard Act

    2010-12-20

    ... (Complainant) alleged violations by the Oregon Commission for the Blind, the State licensing agency (SLA... ] the SLA improperly administered the Randolph-Sheppard Vending Facility Program in violation of the Act... SLA denied him an opportunity to manage vending machines at the Chemeketa Community College...

  10. 76 FR 6604 - Arbitration Panel Decision Under the Randolph-Sheppard Act

    2011-02-07

    ... agency (SLA), under the Act and implementing regulations in 34 CFR part 395. Specifically, Complainant alleged that the SLA improperly administered the Ohio Randolph-Sheppard Vending Facility Program in... further alleged that the SLA's selection committee denied him an opportunity to manage Vending...

  11. 76 FR 73989 - Redelegation of Administrative Authority Under Section 504 of the Rehabilitation Act of 1973

    2011-11-29

    ... URBAN DEVELOPMENT Redelegation of Administrative Authority Under Section 504 of the Rehabilitation Act...: Notice of redelegation of authority. SUMMARY: In this notice, the Assistant Secretary for Fair Housing and Equal Opportunity (FHEO) supersedes all prior redelegations of authority made within the Office...

  12. Inclusive Education and the "No Child Left Behind Act": Resisting Entrenchment

    Hulgin, Kathleen Maria; Drake, Bob M.

    2011-01-01

    This article examines inclusive education in view of the current US policy climate. The "No Child Left Behind Act" provides the opportunity to examine dominant social forces and the underlying theories of mechanism and positivism that run counter to a constructivist approach to inclusive education. The incompatibility of these theories…

  13. 7 CFR 160.95 - Proceedings prior to reporting violations of the act.

    2010-01-01

    ... violation of the act should be reported to the United States Department of Justice for appropriate action... receipt of such notice why the alleged violation should not be reported to the Department of Justice. The person so notified may within the period stated apply for an opportunity to present his views in...

  14. Identifying opportunities in online-communities

    Hienerth, C.; Lettl, Christopher

    how this phenomenon - as manifested in user communities - can be used to derive deeper insights into the prominent phases of opportunity identification, evaluation and exploitation. We also outline how user communities create new avenues for empirical research on these early entrepreneurial processes...

  15. Teaching science students to identify entrepreneurial opportunities

    Nab, J.

    2015-01-01

    This dissertation describes a research project on teaching science students to identify entrepreneurial opportunities, which is a core competence for entrepreneurs that should be emphasized in education. This research consists of four studies. The first case study aims at finding design strategies f

  16. Transhumanism: projections of opportunities, risks and dangers

    Kindras, Natasha

    2013-01-01

    The experience of recent decades reveals a special changeability of various aspects of human existence. The nomadic movement in space «trans» is especially typical. Modern philosophical thought for these processes uses the term «transhumanism». The paper considers scientifically oriented outlook of transhumanism, analyzes the opportunities, risks and dangers of biotechnological transformation of human into posthuman.

  17. Undergraduate Research Mentoring: Obstacles and Opportunities

    Johnson, W. Brad; Behling, Laura L.; Miller, Paul; Vandermaas-Peeler, Maureen

    2015-01-01

    Researchers and policy-makers in higher education increasingly espouse the view that undergraduate students should have the opportunity to learn about scholarship and research in the context of faculty-mentored research experiences. There is mounting consensus that mentored undergraduate research should be standard pedagogical practice in all…

  18. Information exposure, opportunity evaluation and entrepreneurial action

    Autio, E.; Dahlander, L.; Frederiksen, Lars

    2013-01-01

    We study how an individual's exposure to external information regulates the evaluation of entrepreneurial opportunities and entrepreneurial action. Combining data from interviews, a survey, and a comprehensive web log of an online user community spanning eight years, we find that technical inform...

  19. Advancing Sustainable Surface Engineering: Challenges & Future Opportunities

    2014-11-01

    Energy costs – Inefficient processes – Supply chain risk • Reduced Liability – Environmental and occupational • Increased Availability...2013 Noblis, Inc. Advancing Sustainable Surface Engineering: Challenges & Future Opportunities Dr. Jeffrey Marqusee Chief Scientist...control number. 1. REPORT DATE NOV 2014 2. REPORT TYPE 3. DATES COVERED 00-00-2014 to 00-00-2014 4. TITLE AND SUBTITLE Advancing Sustainable

  20. Farmers’ perception of opportunities for farm development

    Methorst, Ron

    2016-01-01

    Differences in the perception of opportunities for farm development is researched in this thesis in relation to differences in the embedding of the farm in the socio-material context. This study contributes to a Sociology of Entrepreneurship in focusing on the decision-maker specific aspects using t

  1. Opportunities for pharmaceutical care with critical pathways.

    Koch, K E

    1995-01-01

    Critical pathways are multidisciplinary tools designed to improve patient care and efficiency. Almost every path requires some type of pharmacotherapeutic intervention, from selection of surgical prophylaxis to management of anticoagulation. Pharmacists should become involved with the critical pathway process because it offers an excellent opportunity to incorporate pharmaceutical care and to meet Joint Commission on Accreditation of Healthcare Organization compliance criteria.

  2. Pitfalls and opportunities for environmental marketers.

    Gillespie, R J

    1992-01-01

    Issues such as global warming, ozone depletion, insufficient landfill capacity, and excess packaging are foremost on the minds of consumers. Companies face a myriad of environmental challenges, but they also recognize the opportunities to be gained by implementing responsible marketing action plans.

  3. Opportunity Theory and Agricultural Crime Victimization

    Mears, Daniel P.; Scott, Michelle L.; Bhati, Avinash S.

    2007-01-01

    A growing body of research lends support to opportunity theory and its variants, but has yet to focus systematically on a number of specific offenses and contexts. Typically, the more crimes and contexts to which a theory applies, the broader its scope and range, respectively, and thus generalizability. In this paper, we focus on agricultural…

  4. Assessing the Opportunity to Learn Mathematics

    Harskamp, E.; Suhre, C.

    1994-01-01

    Research on education often faces the problem of measurement of the opportunity to learn. This is also the case with mathematics education. Researchers may choose either a retrospective measurement approach (e.g., a questionnaire) or an immediate recording approach (e.g.,logbooks). In the present st

  5. Learning paths and OER: trends and opportunities

    Janssen, José; Berlanga, Adriana; Koper, Rob

    2013-01-01

    Janssen, J., Berlanga, A. J., & Koper, R. (2013). Learning paths and OER: trends and opportunities. In R. Jacobi, H. Jelgerhuis, & N. van der Woert (Eds.), Trendreport Open Educational Resources 2013 (pp. 76-80). Utrecht: SURF Foundation - Special Interest Group Open Educational Resources SURF. Fina

  6. Hotels Gear up for Olympic Opportunities

    WANGPEI

    2005-01-01

    The 2008 Olympic games is a great opportunity for China to present itself on the world stage. As the host city, Beijing is preparing to extend the best hospitality it can to the many expected guests from all around the world.

  7. Nurse executives: new roles, new opportunities.

    Kleinman, C S

    1999-01-01

    As women have been nursing since the earliest days of recorded civilization, so nurses have been associated with health care since the earliest days of recorded medical history. Gender and function have been inextricably woven in ways that created a struggle for success within a male-dominated industry. Nurses, as women, have been undervalued as, until recently, their role in health care has been similarly undervalued. Changing realities in the health care environment have created an opportunity for women's unique skills and talents to be revalued in a way that offers new opportunities for nurses. Teamwork, global thinking, multitasking, creativity, and flexibility are characteristics that have assumed new importance in the marketplace. Nursing leaders possess these attributes, along with a strong clinical foundation that is integrated with knowledge of sound business principles. This combination now positions nurse executives to reach the highest levels of heath care administration. Critical to this achievement is the professional credibility obtained through education at the master's degree level in health care and nursing administration programs that provide the essential tools for professional success. New opportunities for nurse executives afford educators in health care and nursing administration similar opportunities to develop and market programs to this large group of health care professionals who are seeking graduate education in increasing numbers.

  8. Challenges and Opportunities in Teaching Mathematics

    Goos, Merrilyn

    2016-01-01

    At the special conference celebrating the 50th anniversary of the Australian Association of Mathematics Teachers (AAMT), the author was asked to speak about the challenges and opportunities in teaching mathematics as a stimulus for discussion of AAMT's "future directions". With an open invitation to be a little provocative, the author…

  9. Knowledge as the Source of Opportunity

    Erikson, Truls; Korsgaard, Steffen

    2016-01-01

    In this paper, we show how Davidson's theory of knowledge can be used to elaborate the objective, intersubjective and subjective components of knowledge. Departing from Hayek's core insights about the dispersion of knowledge in society, we reiterate that opportunities involve subjective knowledge...

  10. Community Languages in Europe : Challenges and Opportunities

    McPake, J.; Martyniuk, W.; Aarts, R.; Broeder, Peter; Latomaa, Sirkku; Mijares, Laura; Tinsley, Teresa

    2004-01-01

    This paper reviews issues affecting school students’ learning of community languages across Europe, with the aim of identifying both challenges and opportunities inherent in the current context. Language education pol icy has become more inclusive of late, addressing the full range of languages rath

  11. The Window of locational opportunity-concept

    Boschma, Ron

    1996-01-01

    This article aims to set out a theoretical concept, i.e. the Window of Locational Opportunity concept, which accounts for notions like indeterminacy, human agency and historical accidents when explaining the spatial pattern of newly emerging industries. We will state that their spatial formation doe

  12. Environmental Management in Bolivia : Innovations and Opportunities

    2013-01-01

    Pollution management is at the top of the development agenda of Bolivia, and this program helps address it in a cross-sectoral manner. In the context of the implementation of the program environmental management in Bolivia: innovations and opportunities which was conducted from September 2010 until October 2012, the World Bank has implemented a technical assistance program and supported a ...

  13. Linguistic Opportunism and English in Moldova.

    Ciscel, Matthew H.

    2002-01-01

    Investigates the role of English in Moldova. Building on Phillipson's concept of linguistic imperialism and Kachru's three concentric circles of world Englishes, proposes a weak form of linguistic dominance based on the notion of opportunism. The model is supported by data from a recent study of language attitudes and language use in Moldova. Data…

  14. Unveiling information on opportunity costs in REDD

    Delacote, Philip; Palmer, Charles; Bakkegaard, Riyong Kim;

    2014-01-01

    Improving information about individual opportunity costs of deforestation agents has the potential to increase the efficiency of REDD when it takes the form of a payment for environmental services scheme. However, objectives pursued in REDD projects may vary across policy makers. Within a theoret...

  15. Employment Opportunities in Agribusiness. A Report.

    Dempsey, Richard E.

    This report, which was written during a project to develop a better understanding of which occupations may relate to agribusiness and to identify employment opportunities in agribusiness, is designed to assist state occupational information coordinating committees and state employment security agencies in developing special reports/lists of…

  16. Learning Motivation: The Role of Opportunity

    McCaslin, Mary

    2008-01-01

    Background/Context: Student motivation typically has been studied as it relates to extrinsic (e.g., reinforcement) and intrinsic (e.g., choice) sources of influence. Our observation of Grades 3-5 classrooms engaged in Comprehensive School Reform (CSR), however, unexpectedly indicated that opportunities for both rewards and choice were scarce. This…

  17. Views on personal networks and business opportunities

    Windekilde, Iwona Maria; Roswall, Rune

    2009-01-01

    The EU project MAGNET-Beyond has examined the business opportunities regarding Personal Networks (PN) for the typical value network stakeholders. In the current communication markets, companies deliver services to customers in cooperation with other market players profiting on different business...

  18. Biofuels and Fisheries: Risks and Opportunities .

    A rapidly developing biofuels industry in the U.S. and around the globe poses novel environmental challenges and opportunities, with implications for teh health and sustainability of fisheries. Changes in land uses and agricultural practices for production of biofuel feedstocks ...

  19. Materials Education: Opportunities over a Lifetime

    Anderson, Iver E.; Schwartz, Lyle H.; Faber, Katherine T.; Cargill III, G. Slade; Houston, Betsy

    2003-10-28

    A report, in the form of abbreviated notes, of the 17th Biennial Conference on National Materials Policy ''Materials Education: Opportunities over a Lifetime'' held May 20-21, 2002 in College Park, MD, sponsored by the Federation of Materials Societies and the University Materials Council.

  20. Nanosized metal clusters : Challenges and opportunities

    De Hosson, JTM; Palasantzas, G; Vystavel, T; Koch, S

    2004-01-01

    This article presents challenges and opportunities to control the microstructure in nanostructured coatings using a nanocluster source. The cluster size distribution is monodisperse and the kinetic energy of the clusters during deposition can be varied. Interestingly, the clusters are grown in extre