Science.gov

Sample records for policy deliverable d3

  1. QUEST2: Sysdtem architecture deliverable set

    SciTech Connect

    Braaten, F.D.

    1995-02-27

    This document contains the system architecture and related documents which were developed during the Preliminary Analysis/System Architecture phase of the Quality, Environmental, Safety T-racking System redesign (QUEST2) project. Each discreet document in this deliverable set applies to a analytic effort supporting the architectural model of QUEST2. The P+ methodology cites a list of P+ documents normally included in a ``typical`` system architecture. Some of these were deferred to the release development phase of the project. The documents included in this deliverable set represent the system architecture itself. Related to that architecture are some decision support documents which provided needed information for management reviews that occurred during April. Consequently, the deliverables in this set were logically grouped and provided to support customer requirements. The remaining System Architecture Phase deliverables will be provided as a ``Supporting Documents`` deliverable set for the first release.

  2. Heat deliverability of homogeneous geothermal reservoirs

    SciTech Connect

    Iglesias, Eduardo R.; Moya, Sara L.

    1991-01-01

    For the last two decades, the petroleum industry has been successfully using simple inflow performance relationships (IPR's) to predict oil deliverability. In contrast, the geothermal industry lacked a simple and reliable method to estimate geothermal wells' heat deliverability. To address this gap in the standard geothermal-reservoir-assessment arsenal, we developed generalized dimensionless geothermal inflow performance relationships (GIPR's). These ''reference curves'' may be regarded as an approximate general solution of the equations describing the practically important case of radial 2-phase inflow. Based on this approximate solution, we outline a straightforward approach to estimate the reservoir contribution to geothermal wells heat and mass deliverability for 2-phase reservoirs. This approach is far less costly and in most cases as reliable as numerically modeling the reservoir, which is the alternative for 2-phase inflow.

  3. "Deliverance": The Anatomy of a Challenge.

    ERIC Educational Resources Information Center

    Mitoraj, Suzanne O.

    2000-01-01

    Describes how an English department and a school district responded to a parental challenge to the use of James Dickey's novel "Deliverance" in a senior English class. Offers a 2-month chronology of events, beginning with a letter of complaint to the principal, continuing through responses, meetings, media coverage, and the meeting and…

  4. Adaptive interpretation of gas well deliverability tests

    NASA Astrophysics Data System (ADS)

    Sergeev, V. L.; Thac Hoai Phuong, Nguyen; Strelnikova, A. B.

    2016-09-01

    The paper considers topical issues of improving accuracy of data obtained from gas well deliverability tests, decreasing the number of test stages and well test time, and reducing gas emissions. The aim of the research is to develop the method of adaptive interpretation of gas well deliverability tests with resulting IPR curve conducted in gas wells with steady-state filtration, which allows obtaining and taking into account additional a priori data on the formation pressure and flow coefficients, setting the number of test stages adequate for efficient well testing and reducing test time. The present research is based on the previous theoretical and practical findings in the spheres of gas well deliverability tests, systems analysis, system identification, function optimization and linear algebra. To test the method, the authors used the field data of deliverability tests run in the Urengoy gas and condensate field, Tyumen Oblast. The authors suggest the method of adaptive interpretation of gas well deliverability tests with resulting IPR curve, which is based on the law for gas filtration with variables dependent on the number of test stage and account of additional a priori data. The suggested method allows defining the estimates of the formation pressure and flow coefficients, optimal in terms of preassigned measures of quality, and setting the adequate number of test stages in the course of well testing. The case study of IPR curve data processing has indicated that adaptive interpretation provides more accurate estimates on the formation pressure and flow coefficients, as well as reduces the number of test stages.

  5. Oilwell deliverability monitoring: A case history

    SciTech Connect

    Thrasher, T.S.; Fetkovich, E.J.; Scott, S.L.

    1994-12-31

    This paper presents a case history study that demonstrates a method to monitor wellhead deliverability performance for flowing oil wells in a manner similar to gas wells. Separator test data measured for production allocation are used along with the material balance relationship and multiphase flow analysis to develop a wellhead backpressure curve for flowing oil wells. An equivalent wellhead static pressure for flowing oil wells is described and shown to be a function of reservoir depletion and multiphase flow rate. Determination of the equivalent wellhead static pressure extends the understanding of wellhead backpressure analysis for both flowing oil and flowing gas wells.

  6. Students with Disabilities in Juvenile Justice Programs: Directions for Federal Support. Policy Forum. Proceedings Document (Alexandria, Virginia, October 26-27, 1998). Final Report, Deliverable-Task 2-3.1a.

    ERIC Educational Resources Information Center

    National Association of State Directors of Special Education, Alexandria, VA.

    This proceedings discusses the role for federal policy in achieving the best possible short and long-term educational results for youth with disabilities in juvenile justice programs. Participants identified the 11 issues regarding students with disabilities in juvenile justice programs and developed a set of recommendations as to how the federal…

  7. Audit of departmental receipt of final deliverables for grant awards

    SciTech Connect

    1997-12-04

    To help meet legislatively mandated and programmatic mission requirements, the Department of Energy (DOE) awards grants to colleges and universities, state and local governments, individuals, small businesses, and non-profit corporations. As of July 15, 1996, the DOE was responsible for administering over 7,400 grants with purposes ranging from basic research to weatherizing homes. The Government`s share of these grants was about $8 billion. The objective of this audit was to determine whether the DOE received final deliverables, detailing grantee accomplishments and expenditure of funds, in accordance with Federal and Departmental policies and procedures. The Code of Federal Regulations requires that grants benefit the general public. This is demonstrated through technical and/or financial reports that each grantee is usually required to deliver. These reports describe the final results of the grant effort. In spite of this requirement, many grantees did not provide final technical and/or financial reports. For example, at the five procurement offices audited, it is projected that the Department had not received final deliverables on 718 inactive grants valued at about $232 million. In other cases, officials inappropriately extended performance periods so that the grant instrument would continue to be classified as active. This non-reporting occurred because the Department did not effectively implement existing procedures or establish other monitoring procedures that ensured grantees fulfilled their grant obligations. Specifically, the Department did not establish procedures to withhold payment if a grantee failed to comply with grant terms and conditions. In addition, the Department did not defer additional awards to grantees that had not met the tenons and conditions of prior grants and inappropriately extended grant performance periods for excessive periods of time. Further, Departmental personnel waived reporting requirements in order to close out grant awards.

  8. Oilwell deliverability monitoring: A case history

    SciTech Connect

    Thrasher, T.S.; Fetkovich, E.J.; Scott, S.L.

    1995-11-01

    This paper presents a case history study that demonstrates a method to monitor wellhead-deliverability performance for flowing oil wells in a manner similar to gas wells. Separator test data measured for production allocation are used along with the material-balance relationship and multiphase-flow analysis to develop a wellhead backpressure curve for flowing oil wells. An equivalent wellhead static pressure for flowing oil wells is described and shown to be a function of reservoir depletion and multiphase-flow rate. Determination of the equivalent wellhead static pressure extends the understanding of wellhead backpressure analysis for both flowing oil and gas wells. A case history example demonstrating the application of the methods described in the paper is developed with the separator test data from Point Arguello field wells. The resulting wellhead backpressure curves clearly defined individual well deliverability and proved to be valuable diagnostic tools to monitor well performance and to quantify production potential. The authors show that the procedures developed in this paper are directly equivalent to procedures applied to conventional gaswell wellhead backpressure analysis commonly used in the industry to monitor gaswell performance. By monitoring flowing oilwell performance with the methods described in this paper, operators can address the challenge of maintaining well productivity and field production plateau.

  9. QUEST2: Release 1: Project plan deliverable set

    SciTech Connect

    Braaten, F.D.

    1995-02-10

    This Project Management Plan combines the project management deliverables from the P+ methodology which are applicable to Release 1 of the QUEST2 work. This consolidation reflects discussions with WHC QA regarding an appropriate method for ensuring that P+ deliverables fulfill the intent of WHC-CM-3-10 and QR-19.

  10. 49 CFR 22.25 - Lender deliverables and delivery schedule.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 1 2010-10-01 2010-10-01 false Lender deliverables and delivery schedule. 22.25 Section 22.25 Transportation Office of the Secretary of Transportation SHORT-TERM LENDING PROGRAM (STLP) Participating Lenders § 22.25 Lender deliverables and delivery schedule. All Participating Lenders must adhere...

  11. Molecular Science: Network-Deliverable Curricula

    NASA Astrophysics Data System (ADS)

    Russell, Arlene; Chapman, Orville; Wegner, Patrick

    1998-05-01

    The Molecular Science systemic reform project, which has just begun its third year, is developing network-deliverable curricula for the first two years of Chemistry.1 The goals of the project are to prepare students who have a deep understanding of chemistry concepts and principles, have learned collaboration skills, can use the modern-technology tools of the chemist, and can write about chemistry. In addition, the project is integrating technology and telecommunications into the instructional process and shifting the instruction from lecture to active student learning. Faculty from six institutions (Crossroads School, East Los Angeles College, Pasadena City College, Mt. San Antonio College, California State University, Fullerton [CSUF], and the University of California, Los Angeles [UCLA]) form the core of the project. This cross-section represents the common and shared responsibility that exists for teaching the first two years of chemistry and the diversity of students in the nation.

  12. Intersecting D 3 -D3 ' -brane system at finite temperature

    NASA Astrophysics Data System (ADS)

    Cottrell, William; Hanson, James; Hashimoto, Akikazu; Loveridge, Andrew; Pettengill, Duncan

    2017-02-01

    We analyze the dynamics of the intersecting D 3 -D3 ' -brane system overlapping in 1 +1 dimensions, in a holographic treatment where N D3 branes are manifested as anti-de Sitter Schwartzschild geometry, and the D3 ' brane is treated as a probe. We extract the thermodynamic equation of state from the set of embedding solutions, and analyze the stability at the perturbative and the nonperturbative level. We review a systematic procedure to resolve local instabilities and multivaluedness in the equations of state based on classic ideas of convexity in the microcanonical ensemble. We then identify a runaway behavior which was not noticed previously for this system.

  13. Influences Determining European Coal Seam Gas Deliverability

    NASA Astrophysics Data System (ADS)

    Clark, G.

    2009-04-01

    Technically the coal basins of Europe have generated significant Gas In Place figures that has historically generated investor's interest in the development of this potential coal seam gas (CSG) resource. In the early 1980's, a wave of international, principally American, companies arrived, established themselves, drilled and then left with a poor record of success and disappointed investors. Recently a second wave of investment started after 2002, with the smaller companies leading the charge but have the lesson been learned from the past failures? To select a CSG investment project the common European approach has been to: 1. Find an old mining region; 2. Look to see if it had a coal mine methane gas problem; 3. Look for the non-mined coal seams; and 4. Peg the land. This method is perhaps the reason why the history of CSG exploration in Europe is such a disappointment as generally the coal mining regions of Europe do not have commercial CSG reservoir attributes. As a result, investors and governments have lost confidence that CSG will be a commercial success in Europe. New European specific principles for the determination of commercial CSG prospects have had to be delineated that allow for the selection of coal basins that have a strong technical case for deliverability. This will result in the return of investor confidence.

  14. Strategic planning for information management: what are the deliverables?

    PubMed Central

    Olsen, A. J.; Stead, W. W.

    1995-01-01

    This paper describes the deliverables framework developed by Vanderbilt University Medical Center (VUMC) in its IAIMS planning process. The key deliverables include: visions for the future; mission, goals, and objectives for the information management function; critical functions for IAIMS; categorized projects; priority recommendations; and a straw man project sequence reflecting dependencies. The paper also discusses how the plan will be used and how it interacts with direction-setting for the Medical Center. PMID:8563398

  15. 16 CFR Appendix D3 to Part 305 - Water Heaters-Oil

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... DISCLOSURES REGARDING ENERGY CONSUMPTION AND WATER USE OF CERTAIN HOME APPLIANCES AND OTHER PRODUCTS REQUIRED UNDER THE ENERGY POLICY AND CONSERVATION ACT (âAPPLIANCE LABELING RULEâ) Pt. 305, App. D3 Appendix D3 to...

  16. Hopf bifurcation with D 3 × D 3-symmetry

    NASA Astrophysics Data System (ADS)

    Dangelmayr, Gerhard; Güttinger, Werner; Wegelin, Michael

    1993-07-01

    A generic Hopf bifurcation involving an eight dimensional center eigenspace is considered for systems possessing a D 3 × D 3-symmetry. This kind of Hopf bifurcation can occur in systems of three interacting groups of oscillators, where each group itself is composed of three individual oscillators. The terminology “micro” and “Macro” is introduced here to denote symmetry operations acting on individual oscillators and on the whole groups, respectively. The normal form for the Hopf bifurcation admits 11 distinct periodic solutions with maximal isotropy subgroups. These are classified and their branching-types and stabilities are determined in terms of the cubic and relevant quintic coefficients of the normal form. The symmetry properties of these solutions when only certain Macro variables in the oscillator groups are observed are discussed in the context of the remaining symmetry. Furthermore, the relation of the normal form to the corresponding one for a single D 3-symmetry is established by restricting the system to four dimensional fixed point subspaces associated with submaximal isotropy subgroups. Based on this information the possibility of quasiperiodic solutions and of a particular class of heteroclinic cycles is discussed.

  17. The D3 Middleware Architecture

    NASA Technical Reports Server (NTRS)

    Walton, Joan; Filman, Robert E.; Korsmeyer, David J.; Lee, Diana D.; Mak, Ron; Patel, Tarang

    2002-01-01

    DARWIN is a NASA developed, Internet-based system for enabling aerospace researchers to securely and remotely access and collaborate on the analysis of aerospace vehicle design data, primarily the results of wind-tunnel testing and numeric (e.g., computational fluid-dynamics) model executions. DARWIN captures, stores and indexes data; manages derived knowledge (such as visualizations across multiple datasets); and provides an environment for designers to collaborate in the analysis of test results. DARWIN is an interesting application because it supports high-volumes of data. integrates multiple modalities of data display (e.g., images and data visualizations), and provides non-trivial access control mechanisms. DARWIN enables collaboration by allowing not only sharing visualizations of data, but also commentary about and views of data. Here we provide an overview of the architecture of D3, the third generation of DARWIN. Earlier versions of DARWIN were characterized by browser-based interfaces and a hodge-podge of server technologies: CGI scripts, applets, PERL, and so forth. But browsers proved difficult to control, and a proliferation of computational mechanisms proved inefficient and difficult to maintain. D3 substitutes a pure-Java approach for that medley: A Java client communicates (though RMI over HTTPS) with a Java-based application server. Code on the server accesses information from JDBC databases, distributed LDAP security services, and a collaborative information system. D3 is a three tier-architecture, but unlike 'E-commerce' applications, the data usage pattern suggests different strategies than traditional Enterprise Java Beans - we need to move volumes of related data together, considerable processing happens on the client, and the 'business logic' on the server-side is primarily data integration and collaboration. With D3, we are extending DARWIN to handle other data domains and to be a distributed system, where a single login allows a user

  18. The D3 Middleware Architecture

    NASA Technical Reports Server (NTRS)

    Walton, Joan; Filman, Robert E.; Korsmeyer, David J.; Lee, Diana D.; Mak, Ron; Patel, Tarang

    2002-01-01

    DARWIN is a NASA developed, Internet-based system for enabling aerospace researchers to securely and remotely access and collaborate on the analysis of aerospace vehicle design data, primarily the results of wind-tunnel testing and numeric (e.g., computational fluid-dynamics) model executions. DARWIN captures, stores and indexes data; manages derived knowledge (such as visualizations across multiple datasets); and provides an environment for designers to collaborate in the analysis of test results. DARWIN is an interesting application because it supports high-volumes of data. integrates multiple modalities of data display (e.g., images and data visualizations), and provides non-trivial access control mechanisms. DARWIN enables collaboration by allowing not only sharing visualizations of data, but also commentary about and views of data. Here we provide an overview of the architecture of D3, the third generation of DARWIN. Earlier versions of DARWIN were characterized by browser-based interfaces and a hodge-podge of server technologies: CGI scripts, applets, PERL, and so forth. But browsers proved difficult to control, and a proliferation of computational mechanisms proved inefficient and difficult to maintain. D3 substitutes a pure-Java approach for that medley: A Java client communicates (though RMI over HTTPS) with a Java-based application server. Code on the server accesses information from JDBC databases, distributed LDAP security services, and a collaborative information system. D3 is a three tier-architecture, but unlike 'E-commerce' applications, the data usage pattern suggests different strategies than traditional Enterprise Java Beans - we need to move volumes of related data together, considerable processing happens on the client, and the 'business logic' on the server-side is primarily data integration and collaboration. With D3, we are extending DARWIN to handle other data domains and to be a distributed system, where a single login allows a user

  19. 48 CFR 452.247-71 - Marking Deliverables.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 48 Federal Acquisition Regulations System 4 2011-10-01 2011-10-01 false Marking Deliverables. 452.247-71 Section 452.247-71 Federal Acquisition Regulations System DEPARTMENT OF AGRICULTURE CLAUSES AND FORMS SOLICITATION PROVISIONS AND CONTRACT CLAUSES Texts of Provisions and Clauses 452.247-71...

  20. Implications of Disruption to Natural Gas Deliverability

    SciTech Connect

    Science Applications International

    2008-09-30

    This project was sponsored by Department of Energy/Office of Electricity Delivery and Energy Reliability and managed by the National Energy Technology Laboratory. The primary purpose of the project was to analyze the capability of the natural gas production, transmission and supply systems to continue to provide service in the event of a major disruption in capacity of one or more natural gas transmission pipelines. The project was specifically designed to detail the ability of natural gas market to absorb facility losses and efficiently reallocate gas supplies during a significant pipeline capacity disruption in terms that allowed federal and state agencies and interests to develop effective policies and action plans to prioritize natural gas deliveries from a regional and national perspective. The analyses for each regional study were based on four primary considerations: (1) operating conditions (pipeline capacity, storage capacity, local production, power dispatch decision making and end user options); (2) weather; (3) magnitude and location of the disruption; and, (4) normal versus emergency situation. The detailed information contained in the region reports as generated from this project are Unclassified Controlled Information; and as such are subject to disclosure in accordance with the Freedom of Information Act. Therefore, this report defines the regions that were analyzed and the basic methodologies and assumptions used to completing the analysis.

  1. 7 CFR 15d.3 - Compliance.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 7 Agriculture 1 2013-01-01 2013-01-01 false Compliance. 15d.3 Section 15d.3 Agriculture Office of the Secretary of Agriculture NONDISCRIMINATION IN PROGRAMS OR ACTIVITIES CONDUCTED BY THE UNITED STATES DEPARTMENT OF AGRICULTURE § 15d.3 Compliance. The Director of the Office of Civil Rights...

  2. 7 CFR 15d.3 - Compliance.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 1 2010-01-01 2010-01-01 false Compliance. 15d.3 Section 15d.3 Agriculture Office of the Secretary of Agriculture NONDISCRIMINATION IN PROGRAMS OR ACTIVITIES CONDUCTED BY THE UNITED STATES DEPARTMENT OF AGRICULTURE § 15d.3 Compliance. The Director of the Office of Civil Rights...

  3. The chemistry of D3-trishomocubane

    NASA Astrophysics Data System (ADS)

    Levandovsky, I. A.; Sharapa, D. I.; Cherenkova, O. A.; Gaidai, A. V.; Shubina, T. E.

    2010-12-01

    Data on the chemistry of D3-trishomocubane and its derivatives are described systematically. Different versions of construction of D3-trishomocubane cage are presented. The methods of synthesis of mono-, di- and poly-substituted D3-trishomocubanes and their heteroanalogues as well as their properties are considered. Data on biological activity of homocubanes are generalized.

  4. 20 CFR 638.300 - Eligibility for funds and eligible deliverers.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... LABOR JOB CORPS PROGRAM UNDER TITLE IV-B OF THE JOB TRAINING PARTNERSHIP ACT Funding, Site Selection... made available by the Secretary to eligible deliverers for the operation of centers and for the provision of Job Corps operational support services. (b) Eligible deliverers for the operation of centers...

  5. 20 CFR 638.300 - Eligibility for funds and eligible deliverers.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 20 Employees' Benefits 3 2010-04-01 2010-04-01 false Eligibility for funds and eligible deliverers. 638.300 Section 638.300 Employees' Benefits EMPLOYMENT AND TRAINING ADMINISTRATION, DEPARTMENT OF..., and Facilities Management § 638.300 Eligibility for funds and eligible deliverers. (a) Funds shall...

  6. Project deliverables - a waste of time or a chance for knowledge transfer and dissemination?

    NASA Astrophysics Data System (ADS)

    Walter, Sylvia

    2016-04-01

    Deliverables are a common tool to measure a distinct output of a project. They should be meaningful in terms of the project's objectives and are normally constituted by e.g. a written report or document, a developed tool or software, an organized training or conference. They can be scientific or technical. The number of deliverables must be reasonable and commensurate to the project and its content. Deliverables as contractual obligations are often time consuming and often seen as a waste of "research" time, as one more administrative task without any use. However, deliverables are needed to verify the progress of a project and to convince the sponsor that the project is going in the right direction and the money well-invested. The presentation will deal with the question on how to use a deliverable in a profitable way for the project and what are the possibilities of use.

  7. Deliverable navigation for multicriteria step and shoot IMRT treatment planning

    NASA Astrophysics Data System (ADS)

    Craft, David; Richter, Christian

    2013-01-01

    We consider Pareto surface based multi-criteria optimization for step and shoot IMRT planning. By analyzing two navigation algorithms, we show both theoretically and in practice that the number of plans needed to form convex combinations of plans during navigation can be kept small (much less than the theoretical maximum number needed in general, which is equal to the number of objectives for on-surface Pareto navigation). Therefore a workable approach for directly deliverable navigation in this setting is to segment the underlying Pareto surface plans and then enforce the mild restriction that only a small number of these plans are active at any time during plan navigation, thus limiting the total number of segments used in the final plan.

  8. Deliverability on the interstate natural gas pipeline system

    SciTech Connect

    1998-05-01

    Deliverability on the Interstate Natural Gas Pipeline System examines the capability of the national pipeline grid to transport natural gas to various US markets. The report quantifies the capacity levels and utilization rates of major interstate pipeline companies in 1996 and the changes since 1990, as well as changes in markets and end-use consumption patterns. It also discusses the effects of proposed capacity expansions on capacity levels. The report consists of five chapters, several appendices, and a glossary. Chapter 1 discusses some of the operational and regulatory features of the US interstate pipeline system and how they affect overall system design, system utilization, and capacity expansions. Chapter 2 looks at how the exploration, development, and production of natural gas within North America is linked to the national pipeline grid. Chapter 3 examines the capability of the interstate natural gas pipeline network to link production areas to market areas, on the basis of capacity and usage levels along 10 corridors. The chapter also examines capacity expansions that have occurred since 1990 along each corridor and the potential impact of proposed new capacity. Chapter 4 discusses the last step in the transportation chain, that is, deliverability to the ultimate end user. Flow patterns into and out of each market region are discussed, as well as the movement of natural gas between States in each region. Chapter 5 examines how shippers reserve interstate pipeline capacity in the current transportation marketplace and how pipeline companies are handling the secondary market for short-term unused capacity. Four appendices provide supporting data and additional detail on the methodology used to estimate capacity. 32 figs., 15 tabs.

  9. Vitamin D3 in fat tissue

    PubMed Central

    Blum, Miriam; Dolnikowski, Gregory; Seyoum, Elias; Harris, Susan S.; Booth, Sarah L.; Peterson, James; Saltzman, Edward

    2010-01-01

    The literature describing vitamin D content of fat tissue is extremely limited. We conducted a pilot study that measured the concentrations of vitamin D3 in the fat tissue and serum of obese adults. These measurements were performed using a new liquid chromatography mass spectrometry (LC/MS) method. The objectives of this study were: to measure and report the vitamin D3 concentration in serum and subcutaneous fat samples from obese individuals and to examine the association of vitamin D3 in fat with vitamin D3 in serum. This cross-sectional study was conducted in 17 obese men and women who were scheduled to undergo gastric bypass surgery. The mean vitamin D3 concentration in subjects’ subcutaneous fat tissue samples was 102.8 ± 42.0 nmol/kg. The mean vitamin D3 concentration in serum was 7.78 ± 3.99 nmol/l. Vitamin D3 concentrations of fat tissue and serum were positively correlated (r = 0.68, P = 0.003). Consistent with previous findings in obese subjects, subjects in this study had suboptimal vitamin D status as demonstrated by a mean 25-hydroxyvitamin D concentration of 43.3 ± 15.4 nmol/l. In conclusion, fat tissue vitamin D3 can be measured by LC/MS and is detectable in obese subjects with suboptimal vitamin D status. Compatible with the long-standing concept that fat tissue is a storage site for vitamin D, fat tissue and serum vitamin D3 concentrations were positively correlated. PMID:18338271

  10. Dimensional reduction for D3-brane moduli

    NASA Astrophysics Data System (ADS)

    Cownden, Brad; Frey, Andrew R.; Marsh, M. C. David; Underwood, Bret

    2016-12-01

    Warped string compactifications are central to many attempts to stabilize moduli and connect string theory with cosmology and particle phenomenology. We present a first-principles derivation of the low-energy 4D effective theory from dimensional reduction of a D3-brane in a warped Calabi-Yau compactification of type IIB string theory with imaginary self-dual 3-form flux, including effects of D3-brane motion beyond the probe approximation, and find the metric on the moduli space of brane positions, the universal volume modulus, and axions descending from the 4-form potential. As D3-branes may be considered as carrying either electric or magnetic charges for the self-dual 5-form field strength, we present calculations in both duality frames. Our results are consistent with, but extend significantly, earlier results on the low-energy effective theory arising from D3-branes in string compactifications.

  11. Vitamin D3 Mediated Tumor Regression.

    DTIC Science & Technology

    1998-07-01

    1,25(OH)2D3 and its synthetic analog EB 1089 induce characteristic features of apoptosis in MCF-7 cells in vitro. To determine whether vitamin D3...after five weeks. The reduced growth of tumors from EB 1089 treated mice was associated with characteristic apoptotic morphology. After five weeks of...treatment with EB 1089 , MCF-7 tumors exhibited a six-fold increase in DNA fragmentation and a two-fold reduction in proliferation relative to control

  12. Record of principal work activities/deliverables. Final technical report, September 28, 1984--September 27, 1989

    SciTech Connect

    Not Available

    1989-09-01

    Over the five year period of performance, thirteen task assignments were issued by the DOE to ARINC Research. During the two year base period seven tasks were assigned. Two task assignments were issued for each of the three consecutive one year option periods. Associated with all task assignments were multiple subtasks, some of which required significant effort. These subtasks are appropriately cited in this report under their respective task assignments as principal work activities or deliverables. The technical and management support provided to the DOE under this contract focused on two general areas: (1) appraisal activities and (2) non-appraisal activities. Support to appraisals included planning, document review, developing lines-of-inquiry, interviewing, data collection, report writing, and follow-up. Such work was executed both on-site at the DOE facility under review and off-site. Non-appraisal support was varied and included such areas as document review, data base development, technical assessments. statistical analysis, policy analysis, reliability engineering, and workshop and conference planning and execution.

  13. Possibilities for a valorisation of geomorphologic research deliverables

    NASA Astrophysics Data System (ADS)

    Geilhausen, M.; Götz, J.; Otto, J.-C.; Schrott, L.

    2009-04-01

    Many geomorphological studies focus on fundamental research questions in large parts, although there are lots of applied fields like landslide hazard assessment or water framework directive. As fundamental research is a common property, their outcomes should be more "open" and accessible to the public. This means that scientists have to find new ways presenting their results and outcomes besides publishing in scientific journals. This paper shows possibilities for a valorisation of geomorphologic research deliverables using print as well as digital media. Geotrails explain remarkable and exciting landscape features using information boards and become more and more popular and important for tourism in many parts of the world. With the growing interest in environmental change and outdoor activities, print media like field guides reach an increasing number of people. Field guides and Geotrails can be coupled in order to arise awareness about geomorphological landforms and to deliver more specific information on the site beyond the information given on the boards in the field. As field guides are designed for the general public they can be used for educational purposes as well. Today, this information can also be found in the internet offering virtual trips through landscapes using dynamic maps. Here, server side GIS technologies (WebGIS) using standardised interfaces provide new possibilities to show geomorphic data to the public and to share them with the scientific community. Furthermore, data formats like XML or KML are powerful tools for data exchange and can be used in interactive data viewers like Google Earth. We will present the Geotrail "Geomorphologischer Lehrpfad am Fuße der Zugspitze. Das Reintal - Eine Wanderung durch Raum und Zeit" (Bavarian Alps, Germany). Additionally, three geomorphologic WebGIS applications (Geomorphologic map Turtmanntal, Permafrostmap of Austria, Geomorphologic maps of Germany) will exemplify how geomorphologic information and

  14. FY2004 Progress Summary and FY2005 Program Plan Statement of Work and Deliverables

    SciTech Connect

    Meier, W; Bibeau, C

    2006-01-23

    FY2004 progress summary and FY2005 program plan statement of work and deliverables for development of high average power diode-pumped solid state lasers, and complementary technologies for applications in energy and defense.

  15. QUEST2: Release 1, SA/Release 1 supporting documents deliverable set

    SciTech Connect

    Braaten, F.D.

    1995-02-27

    This document contains deliverables which reflect the last of the System Architecture phase analysis for the Quality, Environmental, Safety Tracking System redesign (QUEST2) project. These deliverables are focused on the final insights required to start functional design of the first QUEST2 release. They include the data definitions, conversion rules, standards for design and user interface, performance criteria, and rules to be followed during the prototyping activity described in the Project Management Plan.

  16. D = 3 unification of curious supergravities

    NASA Astrophysics Data System (ADS)

    Duff, M. J.; Ferrara, S.; Marrani, A.

    2017-01-01

    We consider the dimensional reduction to D = 3 of four maximal-rank super-gravities which preserve minimal supersymmetry in D = 11, 7, 5 and 4. Such " curious" theories were investigated some time ago, and the four-dimensional one corresponds to an N=1 supergravity with 7 chiral multiplets spanning the seven-disk manifold. Recently, this latter theory provided cosmological models for α-attractors, which are based on the disk geometry with possible restrictions on the parameter α. A unified picture emerges in D = 3, where the Ehlers group of General Relativity merges with the S-, T- and U-dualities of the D = 4 parent theories.

  17. 42 CFR 52d.3 - Eligibility.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL CANCER INSTITUTE CLINICAL CANCER EDUCATION PROGRAM § 52d.3 Eligibility. To be eligible for a grant under this part, an applicant..., affiliated teaching hospital, or specialized cancer institute; and (b) Located in a State, the District of...

  18. 42 CFR 52d.3 - Eligibility.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL CANCER INSTITUTE CLINICAL CANCER EDUCATION PROGRAM § 52d.3 Eligibility. To be eligible for a grant under this part, an applicant..., affiliated teaching hospital, or specialized cancer institute; and (b) Located in a State, the District of...

  19. 42 CFR 52d.3 - Eligibility.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL CANCER INSTITUTE CLINICAL CANCER EDUCATION PROGRAM § 52d.3 Eligibility. To be eligible for a grant under this part, an applicant..., affiliated teaching hospital, or specialized cancer institute; and (b) Located in a State, the District of...

  20. 42 CFR 52d.3 - Eligibility.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL CANCER INSTITUTE CLINICAL CANCER EDUCATION PROGRAM § 52d.3 Eligibility. To be eligible for a grant under this part, an applicant..., affiliated teaching hospital, or specialized cancer institute; and (b) Located in a State, the District of...

  1. 42 CFR 52d.3 - Eligibility.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL CANCER INSTITUTE CLINICAL CANCER EDUCATION PROGRAM § 52d.3 Eligibility. To be eligible for a grant under this part, an applicant..., affiliated teaching hospital, or specialized cancer institute; and (b) Located in a State, the District of...

  2. Primary Human Osteoblasts in Response to 25-Hydroxyvitamin D3, 1,25-Dihydroxyvitamin D3 and 24R,25-Dihydroxyvitamin D3

    PubMed Central

    van der Meijden, Karen; Lips, Paul; van Driel, Marjolein; Heijboer, Annemieke C.; Schulten, Engelbert A. J. M.; den Heijer, Martin; Bravenboer, Nathalie

    2014-01-01

    The most biologically active metabolite 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) has well known direct effects on osteoblast growth and differentiation in vitro. The precursor 25-hydroxyvitamin D3 (25(OH)D3) can affect osteoblast function via conversion to 1,25(OH)2D3, however, it is largely unknown whether 25(OH)D3 can affect primary osteoblast function on its own. Furthermore, 25(OH)D3 is not only converted to 1,25(OH)2D3, but also to 24R,25-dihydroxyvitamin D3 (24R,25(OH)2D3) which may have bioactivity as well. Therefore we used a primary human osteoblast model to examine whether 25(OH)D3 itself can affect osteoblast function using CYP27B1 silencing and to investigate whether 24R,25(OH)2D3 can affect osteoblast function. We showed that primary human osteoblasts responded to both 25(OH)D3 and 1,25(OH)2D3 by reducing their proliferation and enhancing their differentiation by the increase of alkaline phosphatase, osteocalcin and osteopontin expression. Osteoblasts expressed CYP27B1 and CYP24 and synthesized 1,25(OH)2D3 and 24R,25(OH)2D3 dose-dependently. Silencing of CYP27B1 resulted in a decline of 1,25(OH)2D3 synthesis, but we observed no significant differences in mRNA levels of differentiation markers in CYP27B1-silenced cells compared to control cells after treatment with 25(OH)D3. We demonstrated that 24R,25(OH)2D3 increased mRNA levels of alkaline phosphatase, osteocalcin and osteopontin. In addition, 24R,25(OH)2D3 strongly increased CYP24 mRNA. In conclusion, the vitamin D metabolites 25(OH)D3, 1,25(OH)2D3 and 24R,25(OH)2D3 can affect osteoblast differentiation directly or indirectly. We showed that primary human osteoblasts not only respond to 1,25(OH)2D3, but also to 24R,25(OH)2D3 by enhancing osteoblast differentiation. This suggests that 25(OH)D3 can affect osteoblast differentiation via conversion to the active metabolite 1,25(OH)2D3, but also via conversion to 24R,25(OH)2D3. Whether 25(OH)D3 has direct actions on osteoblast function needs further

  3. 2D/3D switchable displays

    NASA Astrophysics Data System (ADS)

    Dekker, T.; de Zwart, S. T.; Willemsen, O. H.; Hiddink, M. G. H.; IJzerman, W. L.

    2006-02-01

    A prerequisite for a wide market acceptance of 3D displays is the ability to switch between 3D and full resolution 2D. In this paper we present a robust and cost effective concept for an auto-stereoscopic switchable 2D/3D display. The display is based on an LCD panel, equipped with switchable LC-filled lenticular lenses. We will discuss 3D image quality, with the focus on display uniformity. We show that slanting the lenticulars in combination with a good lens design can minimize non-uniformities in our 20" 2D/3D monitors. Furthermore, we introduce fractional viewing systems as a very robust concept to further improve uniformity in the case slanting the lenticulars and optimizing the lens design are not sufficient. We will discuss measurements and numerical simulations of the key optical characteristics of this display. Finally, we discuss 2D image quality, the switching characteristics and the residual lens effect.

  4. \\overline{D3} induced geometric inflation

    NASA Astrophysics Data System (ADS)

    Kallosh, Renata; Linde, Andrei; Roest, Diederik; Yamada, Yusuke

    2017-07-01

    Effective supergravity inflationary models induced by anti-D3 brane interaction with the moduli fields in the bulk geometry have a geometric description. The Kähler function carries the complete geometric information on the theory. The non-vanishing bisectional curvature plays an important role in the construction. The new geometric formalism, with the nilpotent superfield representing the anti-D3 brane, allows a powerful generalization of the existing inflationary models based on supergravity. They can easily incorporate arbitrary values of the Hubble parameter, cosmological constant and gravitino mass. We illustrate it by providing generalized versions of polynomial chaotic inflation, T- and E-models of α-attractor type, disk merger. We also describe a multi-stage cosmological attractor regime, which we call cascade inflation.

  5. The Comstar D/3 gain degradation experiment

    NASA Technical Reports Server (NTRS)

    Lee, T. C.; Hodge, D. B.

    1981-01-01

    The results of gain degradation measurements using the Comstar D/3 19.04 GHz beacon are reported. This experiment utilized 0.6 and 5 m aperture antennas aligned along the same propagation path to examine propagation effects which are related to the antenna aperture size. Sample data for clear air, scintillation in clear air, and precipitation fading are presented. Distributions of the received signal levels and variances for both antennas are also presented.

  6. Adaptive interpretation of gas well deliverability tests with generating data of the IPR curve

    NASA Astrophysics Data System (ADS)

    Sergeev, V. L.; Phuong, Nguyen T. H.; Krainov, A. I.

    2017-01-01

    The paper considers topical issues of improving accuracy of estimated parameters given by data obtained from gas well deliverability tests, decreasing test time, and reducing gas emissions into the atmosphere. The aim of the research is to develop the method of adaptive interpretation of gas well deliverability tests with a resulting IPR curve and using a technique of generating data, which allows taking into account additional a priori information, improving accuracy of determining formation pressure and flow coefficients, reducing test time. The present research is based on the previous theoretical and practical findings in the spheres of gas well deliverability tests, systems analysis, system identification, function optimization and linear algebra. To test the method, the authors used the field data of deliverability tests of two wells, run in the Urengoy gas and condensate field, Tyumen Oblast. The authors suggest the method of adaptive interpretation of gas well deliverability tests with the resulting IPR curve and the possibility of generating data of bottomhole pressure and a flow rate at different test stages. The suggested method allows defining the estimates of the formation pressure and flow coefficients, optimal in terms of preassigned measures of quality, and setting the adequate number of test stages in the course of well testing. The case study of IPR curve data processing has indicated that adaptive interpretation provides more accurate estimates on the formation pressure and flow coefficients, as well as reduces the number of test stages.

  7. Landscape-scale learning: from lectures to professional deliverables

    NASA Astrophysics Data System (ADS)

    Follain, S.; Devaux, N.; Colin, F.

    2009-04-01

    Earth Science ingenieers (Master degree) need to be trained in multidisciplinary approaches but also to learn how to combine theoretical and practical knowledge. Nevertheless we notice it is not always easy to combine in a same lecture, theoretical and practical issues. In order to build bridges between these instructions we propose to student a new teaching unit: "Sustainability Diagnosis". Its originalities are i) to be couple to an other (theoretical) teaching unit dealing with landscape-scale learning ii) to be performed under a project mode and iii) to provide deliverables ordered by professional users, e.g. farmers, catchment managers. The landscape-scale learning is a classical learning period with lectures provided by specialists in various disciplines e.g. Soil Science, Hydrology, Agronomy, which focus on a common spatial scale, the landscape. It explicitly develops knowledge on energy and matter transfers between landscape components and explains potential effects of human-induced disturbances on both landscape and fluxes evolution. The deliverables for the farmer (chosen professional user) concern issues on his crop system sustainability. It requires a diagnosis in one hand on soil use and management potentialities and in another hand on environmental externalities (soil and water conservation) induced by the cropping system. The communication will present the work done by 14 students during this new teaching unit (Sustainability Diagnosis) of two weeks. This first attempt expertized a one square kilometer area located in Saint-Chinian vineyard region (South of France). This production area with guarantee of origin (AOC) has productivity constraints linked to landscape properties which directly impact farmer decisions. In the same time it has been shown that vineyard crop system induces water pollution by pesticides and increases soil degradation; in a sustainability perspective, these environmental impacts need to be reduced. The learning period was

  8. In Silico Discovery of High Deliverable Capacity Metal-Organic Frameworks

    NASA Astrophysics Data System (ADS)

    Bao, Yi; Martin, Richard; Simon, Cory; Haranczyk, Maciej; Smit, Berend; Deem, Michael; Michael W. Deem Team; Maciej Haranczyk Team; Berend Smit Team

    2015-03-01

    Metal organic frameworks (MOFs) are actively being explored as potential adsorbed natural gas storage materials for small vehicles. Experimental exploration of potential materials is limited by the throughput of synthetic chemistry. We here describe a computational methodology to complement and guide these experimental efforts. The method uses known chemical transformations in silico to identify MOFs with high methane deliverable capacity. The procedure explicitly considers synthesizability with geometric requirements on organic linkers. We efficiently search the composition and conformation space of organic linkers for nine MOF networks, finding 48 materials with higher predicted deliverable capacity (at 65 bar storage, 5.8 bar depletion, and 298 K) than MOF-5 in four of the nine networks. The best material has a predicted deliverable capacity 8% higher than that of MOF-5. US Department of Energy.

  9. Mars Reconnaissance Orbiter, Ground Data System, Receivables and Deliverables (REC/DELs)

    NASA Technical Reports Server (NTRS)

    Carlton, Magdi

    2006-01-01

    This paper presents one JPL element manager's approach to describe a complex Ground Data System (GDS) with its receivables and deliverables (REC/DEL). The Mars Reconnaissance Orbiter (MRO) Ground Data System is the integrated set of ground software, hardware, facilities and networks that support mission operation. REC/DEL is a powerful tool for specifying hierarchy of commitments among systems and teams. Receivable of a system is a deliverable of another system. Focusing on tangible products enables the manager to objectively measure progress in a schedule. The Jet Propulsion Laboratory mandates the use of REC/DEL for flight projects. Tutorial and training is provided for managers to create an integrated REC/DEL database using automated systems. Project schedules are based on REC/DELs. This paper is not focusing on the mechanics of REC/DEL database creation, but it provides a guideline how one systematically creates categories of deliverables and receivables for ground data system components...

  10. Mars Reconnaissance Orbiter, Ground Data System, Receivables and Deliverables (REC/DELs)

    NASA Technical Reports Server (NTRS)

    Carlton, Magdi

    2006-01-01

    This paper presents one JPL element manager's approach to describe a complex Ground Data System (GDS) with its receivables and deliverables (REC/DEL). The Mars Reconnaissance Orbiter (MRO) Ground Data System is the integrated set of ground software, hardware, facilities and networks that support mission operation. REC/DEL is a powerful tool for specifying hierarchy of commitments among systems and teams. Receivable of a system is a deliverable of another system. Focusing on tangible products enables the manager to objectively measure progress in a schedule. Jet Propulsion Laboratory mandates the use of REC/DEL for flight projects. Tutorial and training is provided for managers to create integrated REC/DEL database using automated systems. Project schedules are based on REC/DELs. This paper is not focusing on the mechanics of REC/DEL database creation, but it provides a guideline how one systematically creates categories of deliverables and receivables for ground data system components.

  11. Mars Reconnaissance Orbiter, Ground Data System, Receivables and Deliverables (REC/DELs)

    NASA Technical Reports Server (NTRS)

    Carlton, Magdi

    2006-01-01

    This paper presents one JPL element manager's approach to describe a complex Ground Data System (GDS) with its receivables and deliverables (REC/DEL). The Mars Reconnaissance Orbiter (MRO) Ground Data System is the integrated set of ground software, hardware, facilities and networks that support mission operation. REC/DEL is a powerful tool for specifying hierarchy of commitments among systems and teams. Receivable of a system is a deliverable of another system. Focusing on tangible products enables the manager to objectively measure progress in a schedule. The Jet Propulsion Laboratory mandates the use of REC/DEL for flight projects. Tutorial and training is provided for managers to create an integrated REC/DEL database using automated systems. Project schedules are based on REC/DELs. This paper is not focusing on the mechanics of REC/DEL database creation, but it provides a guideline how one systematically creates categories of deliverables and receivables for ground data system components...

  12. Mars Reconnaissance Orbiter, Ground Data System, Receivables and Deliverables (REC/DELs)

    NASA Technical Reports Server (NTRS)

    Carlton, Magdi

    2006-01-01

    This paper presents one JPL element manager's approach to describe a complex Ground Data System (GDS) with its receivables and deliverables (REC/DEL). The Mars Reconnaissance Orbiter (MRO) Ground Data System is the integrated set of ground software, hardware, facilities and networks that support mission operation. REC/DEL is a powerful tool for specifying hierarchy of commitments among systems and teams. Receivable of a system is a deliverable of another system. Focusing on tangible products enables the manager to objectively measure progress in a schedule. Jet Propulsion Laboratory mandates the use of REC/DEL for flight projects. Tutorial and training is provided for managers to create integrated REC/DEL database using automated systems. Project schedules are based on REC/DELs. This paper is not focusing on the mechanics of REC/DEL database creation, but it provides a guideline how one systematically creates categories of deliverables and receivables for ground data system components.

  13. Computational Design of Metal-Organic Frameworks with High Methane Deliverable Capacity

    NASA Astrophysics Data System (ADS)

    Bao, Yi; Martin, Richard; Simon, Cory; Haranczyk, Maciej; Smit, Berend; Deem, Michael; Deem Team; Haranczyk Team; Smit Team

    Metal-organic frameworks (MOFs) are a rapidly emerging class of nanoporous materials with largely tunable chemistry and diverse applications in gas storage, gas purification, catalysis, etc. Intensive efforts are being made to develop new MOFs with desirable properties both experimentally and computationally in the past decades. To guide experimental synthesis with limited throughput, we develop a computational methodology to explore MOFs with high methane deliverable capacity. This de novo design procedure applies known chemical reactions, considers synthesizability and geometric requirements of organic linkers, and evolves a population of MOFs with desirable property efficiently. We identify about 500 MOFs with higher deliverable capacity than MOF-5 in 10 networks. We also investigate the relationship between deliverable capacity and internal surface area of MOFs. This methodology can be extended to MOFs with multiple types of linkers and multiple SBUs. DE-FG02- 12ER16362.

  14. Fluorometric assay of 25-hydroxyvitamin D3 and 24R,25-dihydroxyvitamin D3 in plasma.

    PubMed

    Shimizu, M; Gao, Y; Aso, T; Nakatsu, K; Yamada, S

    1992-08-01

    The first practical fluorometric assay of plasma 25-hydroxyvitamin D3 (25-OH-D3) and 24R,25-dihydroxyvitamin D3 (24,25-(OH)2D3) is described. The method uses a highly fluorescent dienophile, 4-[2-(6,7-dimethoxy-4-methyl-3-oxo-3,4-dihydroquinoxalyl)ethyl]-1, 2,4- triazoline-3,5-dione (DMEQ-TAD), to fluorescence-label vitamin D. Vitamin D metabolites were roughly purified with a short cartridge column followed by HPLC, labeled with DMEQ-TAD, and the product was analyzed on HPLC. In the assay of 25-OH-D3 the new fluorometric method was compared with the HPLC-uv method and was confirmed to be as accurate and reliable (CV, 4-5%) as the HPLC-uv method. Plasma 24,25-(OH)2D3 was accurately assayed by the HPLC-FL method, where the standard addition method was successfully used to calculate the overall recovery.

  15. Automated D/3 to Visio Analog Diagrams

    SciTech Connect

    Posey, Stephen B.

    2000-08-10

    ADVAD1 reads an ASCII file containing the D/3 DCS MDL input for analog points for a D/3 continuous database. It uses the information in the files to create a series of Visio files representing the structure of each analog chain, one drawing per Visio file. The actual drawing function is performed by Visio (requires Visio version 4.5+). The user can configure the program to select which fields in the database are shown on the diagram and how the information is to be presented. This gives a visual representation of the structure of the analog chains, showing selected fields in a consistent manner. Updating documentation can be done easily and the automated approach eliminates human error in the cadding process. The program can also create the drawings far faster than a human operator is capable, able to create approximately 270 typical diagrams in about 8 minutes on a Pentium II 400 MHz PC. The program allows for multiple option sets to be saved to provide different settings (i.e., different fields, different field presentations, and /or different diagram layouts) for various scenarios or facilities on one workstation. Option sets may be exported from the Windows registry to allow duplication of settings on another workstation.

  16. 21 CFR 172.380 - Vitamin D3.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Vitamin D3. 172.380 Section 172.380 Food and Drugs... Dietary and Nutritional Additives § 172.380 Vitamin D3. Vitamin D3 may be used safely in foods as a... prescribed conditions: (a) Vitamin D3, also known as cholecalciferol, is the chemical...

  17. 21 CFR 172.380 - Vitamin D3.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Vitamin D3. 172.380 Section 172.380 Food and Drugs... Dietary and Nutritional Additives § 172.380 Vitamin D3. Vitamin D3 may be used safely in foods as a... prescribed conditions: (a) Vitamin D3, also known as cholecalciferol, is the chemical...

  18. 21 CFR 172.380 - Vitamin D3.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 3 2012-04-01 2012-04-01 false Vitamin D3. 172.380 Section 172.380 Food and Drugs... Dietary and Nutritional Additives § 172.380 Vitamin D3. Vitamin D3 may be used safely in foods as a... prescribed conditions: (a) Vitamin D3, also known as cholecalciferol, is the chemical...

  19. 21 CFR 172.380 - Vitamin D 3;.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 3 2013-04-01 2013-04-01 false Vitamin D 3;. 172.380 Section 172.380 Food and... Dietary and Nutritional Additives § 172.380 Vitamin D 3;. Vitamin D3 may be used safely in foods as a... prescribed conditions: (a) Vitamin D3, also known as cholecalciferol, is the chemical...

  20. A 3d-3d appetizer

    NASA Astrophysics Data System (ADS)

    Pei, Du; Ye, Ke

    2016-11-01

    We test the 3d-3d correspondence for theories that are labeled by Lens spaces. We find a full agreement between the index of the 3d N=2 "Lens space theory" T [ L( p, 1)] and the partition function of complex Chern-Simons theory on L( p, 1). In particular, for p = 1, we show how the familiar S 3 partition function of Chern-Simons theory arises from the index of a free theory. For large p, we find that the index of T[ L( p, 1)] becomes a constant independent of p. In addition, we study T[ L( p, 1)] on the squashed three-sphere S b 3 . This enables us to see clearly, at the level of partition function, to what extent G ℂ complex Chern-Simons theory can be thought of as two copies of Chern-Simons theory with compact gauge group G.

  1. Conversion of 25-hydroxyvitamin D3 to 1,25-dihydroxyvitamin D3 and 24,25-dihydroxyvitamin D3 in renal slices from the rat

    SciTech Connect

    Armbrecht, H.J.; Zenser, T.V.; Davis, B.B.

    1981-07-01

    Isolated renal cortical slices were used to study the conversion of 25-hydroxyvitamin D3 to 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) and 24,25-dihydroxyvitamin D3 (24,25)(OH2)D3) by the rat kidney. Production of 1,25-(OH)2D3 and 24,25-(OH)2D3 was linear with time (30-90 min) and tissue weight (40-250 mg). Production of 1,25-(OH)2D3 was greatest (134 +/- 17 pg/mg tissue.h) in animals fed a low calcium, vitamin D-deficient diet. The greatest 24,25-(OH)2D3 production (106 +/- 17 pg/mg tissue.h) was seen in animals fed a high calcium, vitamin D-replete diet, 1,25-(OH)2D3 production was reduced to 23% of maximum by the addition of 1.2% calcium or 0.8% strontium to the vitamin D-deficient, low calcium diet. Production of 1,25-(OH)2D3 and 24,25-(OH)2D3 was greatly reduced in renal cortical slices that had been heated before incubation. Slices of renal medulla produced only small amounts of 1,25-(OH)2D3 compared to slices of renal cortex. These studies provide direct evidence for the production of 1,25-(OH)2D3 and 24,25-(OH)2D3 by the mammalian renal cortex. They also demonstrate that this production may be modulated by dietary calcium, strontium, and vitamin D.

  2. Effect of 24,25-dihydroxyvitamin D3 on 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) metabolism in vitamin D-deficient rats infused with 1,25-(OH)2D3

    SciTech Connect

    Yamato, H.; Matsumoto, T.; Fukumoto, S.; Ikeda, K.; Ishizuka, S.; Ogata, E.

    1989-01-01

    Previous studies revealed that administration of 24,25-dihydroxyvitamin D3 (24,25-(OH)2D3) to calcium (Ca)-deficient rats causes a dose-dependent reduction in markedly elevated serum 1,25-(OH)2D3 level. Although the results suggested that the metabolism of 1,25-(OH)2D3 was accelerated by 24,25-(OH)2D3, those experiments could not define whether the enhanced metabolism of 1,25-(OH)2D3 played a role in the reduction in the serum 1,25-(OH)2D3 level. In the present study, in order to address this issue more specifically, serum 1,25-(OH)2D3 was maintained solely by exogenous administration through miniosmotic pumps of 1,25-(OH)2D3 into vitamin D-deficient rats. Thus, by measuring the serum 1,25-(OH)2D3 concentration, the effect of 24,25-(OH)2D3 on the MCR of 1,25-(OH)2D3 could be examined. Administration of 24,25-(OH)2D3 caused a dose-dependent enhancement in the MCR of 1,25-(OH)2D3, and 1 microgram/100 g rat.day 24,25-(OH)2D3, which elevated serum 24,25-(OH)2D3 to 8.6 +/- 1.3 ng/ml, significantly increased MCR and suppressed serum levels of 1,25-(OH)2D3. The effect of 24,25-(OH)2D3 on 1,25-(OH)2D3 metabolism developed with a rapid time course, and the recovery of iv injected (1 beta-3H)1,25-(OH)2D3 in blood was significantly reduced within 1 h. In addition, there was an increase in radioactivity in the water-soluble fraction of serum as well as in urine, suggesting that 1,25-(OH)2D3 is rapidly degraded to a water-soluble metabolite(s). Furthermore, the reduction in serum 1,25-(OH)2D3 was associated with a reduction in both serum and urinary Ca levels. Because the conversion of (3H)24,25-(OH)2D3 to (3H)1,24,25-(OH)2D3 or other metabolites was minimal in these rats, 24,25-(OH)2D3 appears to act without being converted into other metabolites. These results demonstrate that 24,25-(OH)2D3 rapidly stimulates the metabolism of 1,25-(OH)2D3 and reduces its serum level.

  3. 20 CFR 638.812 - State and local taxation of Job Corps deliverers.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 20 Employees' Benefits 3 2012-04-01 2012-04-01 false State and local taxation of Job Corps... LABOR JOB CORPS PROGRAM UNDER TITLE IV-B OF THE JOB TRAINING PARTNERSHIP ACT Administrative Provisions § 638.812 State and local taxation of Job Corps deliverers. The Act provides that transactions conducted...

  4. 20 CFR 638.812 - State and local taxation of Job Corps deliverers.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 20 Employees' Benefits 3 2010-04-01 2010-04-01 false State and local taxation of Job Corps... LABOR JOB CORPS PROGRAM UNDER TITLE IV-B OF THE JOB TRAINING PARTNERSHIP ACT Administrative Provisions § 638.812 State and local taxation of Job Corps deliverers. The Act provides that transactions conducted...

  5. 20 CFR 638.812 - State and local taxation of Job Corps deliverers.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 20 Employees' Benefits 3 2011-04-01 2011-04-01 false State and local taxation of Job Corps deliverers. 638.812 Section 638.812 Employees' Benefits EMPLOYMENT AND TRAINING ADMINISTRATION, DEPARTMENT OF LABOR JOB CORPS PROGRAM UNDER TITLE IV-B OF THE JOB TRAINING PARTNERSHIP ACT Administrative Provisions § 638.812 State and local taxation of...

  6. Application of new and novel fracture stimulation technologies to enhance the deliverability of gas storage wells

    SciTech Connect

    1995-04-01

    Based on the information presented in this report, our conclusions regarding the potential for new and novel fracture stimulation technologies to enhance the deliverability of gas storage wells are as follows: New and improved gas storage well revitalization methods have the potential to save industry on the order of $20-25 million per year by mitigating deliverability decline and reducing the need for costly infill wells Fracturing technologies have the potential to fill this role, however operators have historically been reluctant to utilize this approach due to concerns with reservoir seal integrity. With advanced treatment design tools and methods, however, this risk can be minimized. Of the three major fracturing classifications, namely hydraulic, pulse and explosive, two are believed to hold potential to gas storage applications (hydraulic and pulse). Five particular fracturing technologies, namely tip-screenout fracturing, fracturing with liquid carbon dioxide, and fracturing with gaseous nitrogen, which are each hydraulic methods, and propellant and nitrogen pulse fracturing, which are both pulse methods, are believed to hold potential for gas storage applications and will possibly be tested as part of this project. Field evidence suggests that, while traditional well remediation methods such as blowing/washing, mechanical cleaning, etc. do improve well deliverability, wells are still left damaged afterwards, suggesting that considerable room for further deliverability enhancement exists. Limited recent trials of hydraulic fracturing imply that this approach does in fact provide superior deliverability results, but further RD&D work is needed to fully evaluate and demonstrate the benefits and safe application of this as well as other fracture stimulation technologies.

  7. Synchronized patterns in hierarchical networks of neuronal oscillators with D3 × D3 symmetry

    NASA Astrophysics Data System (ADS)

    Wegelin, Michael; Oppenländer, Jörg; Tomes, Jörg; Güttinger, Werner; Dangelmayr, Gerhard

    1998-10-01

    The spatiotemporal patterns generated by systems of nine coupled nonlinear oscillators which are equivariant under the permutation symmetry group D3 × D3 are determined. This system can be interpreted as a hierarchically organized network composed of three interacting systems each of which consists of three coupled oscillators. We determine generic synchronized oscillation patterns and transitions between these analytically, by numerical simulations, and experimentally with an electronic analog-network. In the theoretical analysis the representative nonlinear ordinary differential equations are reduced to the normal form equations for coupled Hopf bifurcations in an eight-dimensional center eigenspace, whose generic states have been classified previously. The results are applied to a specific model system in which the network is formed by a class of oscillators, each composed of two asymmetrically coupled Hopfield neurons. Experiments performed on an analog-electronic network of such nonlinear oscillators show that most of the states predicted by the theory of the Hopf bifurcation with D3 × D3- symmetry appear in a stable way. We find a great variety of periodic and quasiperiodic oscillation patterns of maximal and submaximal symmetry which can be classified in a two-level pattern hierarchy. In addition to these states we find in simulations homoclinic cycles within the same isotropy class as well as heteroclinic switchings between such cycles.

  8. A 3d-3d appetizer

    DOE PAGES

    Pei, Du; Ye, Ke

    2016-11-02

    Here, we test the 3d-3d correspondence for theories that are labeled by Lens spaces. We find a full agreement between the index of the 3d N=2 “Lens space theory” T [L(p, 1)] and the partition function of complex Chern-Simons theory on L(p, 1). In particular, for p = 1, we show how the familiar S3 partition function of Chern-Simons theory arises from the index of a free theory. For large p, we find that the index of T[L(p, 1)] becomes a constant independent of p. In addition, we study T[L(p, 1)] on the squashed three-sphere Sb3. This enables us tomore » see clearly, at the level of partition function, to what extent GC complex Chern-Simons theory can be thought of as two copies of Chern-Simons theory with compact gauge group G.« less

  9. A 3d-3d appetizer

    SciTech Connect

    Pei, Du; Ye, Ke

    2016-11-02

    Here, we test the 3d-3d correspondence for theories that are labeled by Lens spaces. We find a full agreement between the index of the 3d N=2 “Lens space theory” T [L(p, 1)] and the partition function of complex Chern-Simons theory on L(p, 1). In particular, for p = 1, we show how the familiar S3 partition function of Chern-Simons theory arises from the index of a free theory. For large p, we find that the index of T[L(p, 1)] becomes a constant independent of p. In addition, we study T[L(p, 1)] on the squashed three-sphere Sb3. This enables us to see clearly, at the level of partition function, to what extent GC complex Chern-Simons theory can be thought of as two copies of Chern-Simons theory with compact gauge group G.

  10. 20-Hydroxyvitamin D3, a Product of Vitamin D3 Hydroxylation by Cytochrome P450scc, Stimulates Keratinocyte Differentiation

    PubMed Central

    Zbytek, Blazej; Janjetovic, Zorica; Tuckey, Robert C.; Zmijewski, Michal A.; Sweatman, Trevor W.; Jones, Emily; Nguyen, Minh N.; Slominski, Andrzej T.

    2008-01-01

    It has been shown that mammalian cytochrome P450scc can metabolize vitamin D3 to 20-hydroxyvitamin D3 (20(OH)D3) and 20,22(OH)2D3. To define the biological significance of this pathway, we tested the effects of 20(OH)D3 on the differentiation program of keratinocytes and on the expression of enzymes engaged in vitamin D3 metabolism. Immortalized HaCaT and adult human epidermal keratinocytes were used as a model and the effects of 20(OH)D3 were compared with those of 25(OH)D3 and 1,25(OH)2D3. 20(OH)D3 inhibited proliferation and caused G2/M arrest. 20(OH)D3 stimulated involucrin and inhibited cytokeratin 14 expression. The potency of 20(OH)D3 was comparable to that of 1,25(OH)2D3. 20(OH)D3 decreased the expression of cytochrome P450 enzyme (CYP)27A1 and CYP27B1, however, having only slight effect on CYP24. The effect of 20(OH)D3 was dependent on the vitamin D receptor (VDR). As shown by electrophoretic mobility shift assay, 20(OH)D3 stimulated the binding of nuclear proteins to the VDRE. Transfection of cells with VDR-specific siRNA decreased 20(OH)D3-stimulated transcriptional activity of the VDRE promoter and the expression of involucrin and CYP24 mRNA. Therefore, the above studies identify 20(OH)D3 as a biologically active secosteroid that induces keratinocyte differentiation. These data imply that the previously unreported pathway of vitamin D3 metabolism by P450scc may have wider biological implications depending, for example, on the extent of adrenal gland or cutaneous metabolism. PMID:18368131

  11. 1,25-dihydroxyvitamin D3: a novel immunoregulatory hormone.

    PubMed

    Tsoukas, C D; Provvedini, D M; Manolagas, S C

    1984-06-29

    The hormonal form of vitamin D3, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], at picomolar concentrations, inhibited the growth-promoting lymphokine interleukin-2, which is produced by human T lymphocytes activated in vitro by the mitogen phytohemagglutinin. Other metabolites of vitamin D3 were less effective than 1,25(OH)2D3 in suppressing interleukin-2; their order of potency corresponded to their respective affinity for the 1,25(OH)2D3 receptor, suggesting that the effect on interleukin-2 was mediated by this specific receptor. The proliferation of mitogen-activated lymphocytes was also inhibited by 1,25(OH)2D3. This effect of the hormone became more pronounced at later stages of the culture. These findings demonstrate that 1,25(OH)2D3 is an immunoregulatory hormone.

  12. High Affinity Dopamine D3 Receptor (D3R)-Selective Antagonists Attenuate Heroin Self-Administration in Wild-Type but not D3R Knockout Mice

    PubMed Central

    2015-01-01

    The dopamine D3 receptor (D3R) is a promising target for the development of pharmacotherapeutics to treat substance use disorders. Several D3R-selective antagonists are effective in animal models of drug abuse, especially in models of relapse. Nevertheless, poor bioavailability, metabolic instability, and/or predicted toxicity have impeded success in translating these drug candidates to clinical use. Herein, we report a series of D3R-selective 4-phenylpiperazines with improved metabolic stability. A subset of these compounds was evaluated for D3R functional efficacy and off-target binding at selected 5-HT receptor subtypes, where significant overlap in SAR with D3R has been observed. Several high affinity D3R antagonists, including compounds 16 (Ki = 0.12 nM) and 32 (Ki = 0.35 nM), showed improved metabolic stability compared to the parent compound, PG648 (6). Notably, 16 and the classic D3R antagonist SB277011A (2) were effective in reducing self-administration of heroin in wild-type but not D3R knockout mice. PMID:26203768

  13. 21 CFR 172.380 - Vitamin D 3.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 3 2014-04-01 2014-04-01 false Vitamin D 3. 172.380 Section 172.380 Food and....380 Vitamin D 3. Vitamin D3 may be used safely in foods as a nutrient supplement defined under § 170.3(o)(20) of this chapter in accordance with the following prescribed conditions: (a) Vitamin D3,...

  14. 21 CFR 582.5953 - Vitamin D3.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Vitamin D3. 582.5953 Section 582.5953 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS... 1 § 582.5953 Vitamin D3. (a) Product. Vitamin D3. (b) Conditions of use. This substance is...

  15. 21 CFR 582.5953 - Vitamin D3.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Vitamin D3. 582.5953 Section 582.5953 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS... 1 § 582.5953 Vitamin D3. (a) Product. Vitamin D3. (b) Conditions of use. This substance is...

  16. 21 CFR 582.5953 - Vitamin D3.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Vitamin D3. 582.5953 Section 582.5953 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS... 1 § 582.5953 Vitamin D3. (a) Product. Vitamin D3. (b) Conditions of use. This substance is...

  17. 21 CFR 582.5953 - Vitamin D 3.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Vitamin D 3. 582.5953 Section 582.5953 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS... 1 § 582.5953 Vitamin D 3. (a) Product. Vitamin D3. (b) Conditions of use. This substance...

  18. 21 CFR 582.5953 - Vitamin D 3.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Vitamin D 3. 582.5953 Section 582.5953 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS... 1 § 582.5953 Vitamin D 3. (a) Product. Vitamin D3. (b) Conditions of use. This substance...

  19. Conformational analysis of vitamin D 3 derivatives by molecular mechanics . Part II. 1α,25-dihydroxyvitamin D 3 and analogues

    NASA Astrophysics Data System (ADS)

    Mosquera, Ricardo A.; Rios, Miguel A.; Tovar, Clara A.; Maestro, Miguel

    1989-10-01

    The conformational analysis of vitamin D 3 derivatives, including the biologically active form 1α,25-dihydroxyvitamin D 3 (III) and several synthetic analogues: b-deoxy-1α,25-dihydroxyvitamin D 3 (IV), 3-deoxy-3α-methyl-1α,25-dihydroxyvitamin D 3 (V), 3-deoxy-3β-methyl-1α,25-dihydroxyvitamin D 3 (VI), and 3-deoxy-3,3-dimethyl-1α,25-dihydroxyvitamin D 3 (VII), has been carried out employing Allinger's molecular mechanics method. The results obtained for conformational equilibrium populations are found to be in good agreement with those provided by NMR studies. Comparison of the active form of vitamin D 3 (1α,25-dihydroxyvitamin D 3) with the other species reveals no important geometrical differences.

  20. Metabolism and pharmacokinetics of 24,25-dihydroxyvitamin D3 in the vitamin D3-replete rat

    SciTech Connect

    Jarnagin, K.; Zeng, S.Y.; Phelps, M.; DeLuca, H.F.

    1985-11-05

    The time course of in vivo metabolism of 24,25-dihydroxyvitamin D3 in rats has been examined. Several tissues were surveyed in an effort to discover new metabolites of 24,25-dihydroxyvitamin D3 and to estimate the concentrations of previously identified metabolites. Rapidly growing male rats were dosed with 24,25-dihydroxyvitamin D3 orally until plasma concentrations of 24,25-dihydroxyvitamin D3 were at steady state. 24,25-Dihydroxyvitamin (3-TH)D3 was then administered. At 10 min and 1, 6, 15, 24, 96, and 192 h after dosing, the animals were killed, and plasma, liver, intestine, and bones were analyzed with a newly developed gradient straight-phase high performance liquid chromatography system. The high performance liquid chromatography system is capable of base-line resolution of most of the major vitamin D metabolites. 24,25-Dihydroxyvitamin D3 clearance from plasma, liver, and kidney but not intestine followed a two-compartment model. 24,25-Dihydroxyvitamin D3 disappeared from plasma with a half-life of 0.55 h (fast phase) and 73.8 h (slow phase). Only two lipid-soluble metabolites of 24,25-dihydroxyvitamin D3 were detected: 24-oxo-25-hydroxyvitamin D3 and 1,24,25-trihydroxyvitamin D3. These compounds circulate at very low concentrations in the plasma (50 pg/ml of plasma).

  1. Vitamin D3 and 25-Hydroxyvitamin D3 Content of Retail White Fish and Eggs in Australia

    PubMed Central

    Dunlop, Eleanor; Cunningham, Judy; Sherriff, Jill L.; Lucas, Robyn M.; Greenfield, Heather; Arcot, Jayashree; Strobel, Norbert; Black, Lucinda J.

    2017-01-01

    Dietary vitamin D may compensate for inadequate sun exposure; however, there have been few investigations into the vitamin D content of Australian foods. We measured vitamin D3 and 25-hydroxyvitamin D3 (25(OH)D3) in four species of white fish (barramundi, basa, hoki and king dory), and chicken eggs (cage and free-range), purchased from five Australian cities. Samples included local, imported and wild-caught fish, and eggs of varying size from producers with a range of hen stocking densities. Raw and cooked samples were analysed using high performance liquid chromatography with photodiode array. Limits of reporting were 0.2 and 0.1 μg/100 g for vitamin D3 and 25(OH)D3, respectively. The vitamin D3 content of cooked white fish ranged from <0.1 to 2.3 μg/100 g, and the 25(OH)D3 content ranged from 0.3 to 0.7 μg/100 g. The vitamin D3 content of cooked cage eggs ranged from 0.4 to 0.8 μg/100 g, and the 25(OH)D3 content ranged from 0.4 to 1.2 μg/100 g. The vitamin D3 content of cooked free-range eggs ranged from 0.3 to 2.2 μg/100 g, and the 25(OH)D3 content ranged from 0.5 to 0.8 μg/100 g. If, as has been suggested, 25(OH)D3 has five times greater bioactivity than vitamin D3, one cooked serve (100 g) of white fish, and one cooked serve of cage or free-range eggs (120 g) may provide 50% or 100%, respectively, of the current guidelines for the adequate intake of vitamin D (5 µg) for Australians aged 1–50 years. PMID:28640196

  2. Structure of the Human Dopamine D3 Receptor in Complex with a D2/D3 Selective Antagonist

    SciTech Connect

    Chien, Ellen Y.T.; Liu, Wei; Zhao, Qiang; Katritch, Vsevolod; Han, Gye Won; Hanson, Michael A.; Shi, Lei; Newman, Amy Hauck; Javitch, Jonathan A.; Cherezov, Vadim; Stevens, Raymond C.

    2010-11-30

    Dopamine modulates movement, cognition, and emotion through activation of dopamine G protein-coupled receptors in the brain. The crystal structure of the human dopamine D3 receptor (D3R) in complex with the small molecule D2R/D3R-specific antagonist eticlopride reveals important features of the ligand binding pocket and extracellular loops. On the intracellular side of the receptor, a locked conformation of the ionic lock and two distinctly different conformations of intracellular loop 2 are observed. Docking of R-22, a D3R-selective antagonist, reveals an extracellular extension of the eticlopride binding site that comprises a second binding pocket for the aryl amide of R-22, which differs between the highly homologous D2R and D3R. This difference provides direction to the design of D3R-selective agents for treating drug abuse and other neuropsychiatric indications.

  3. HoxD3 accelerates wound healing in diabetic mice

    SciTech Connect

    Hansen, Scott L.; Myers, Connie A.; Charboneau, Aubri; Young, David M.; and Boudreau, Nancy

    2003-12-01

    Poorly healing diabetic wounds are characterized by diminished collagen production and impaired angiogenesis. HoxD3, a homeobox transcription factor that promotes angiogenesis and collagen synthesis, is up-regulated during normal wound repair whereas its expression is diminished in poorly healing wounds of the genetically diabetic (db/db) mouse. To determine whether restoring expression of HoxD3 would accelerate diabetic wound healing, we devised a novel method of gene transfer, which incorporates HoxD3 plasmid DNA into a methylcellulose film that is placed on wounds created on db/db mice. The HoxD3 transgene was expressed in endothelial cells, fibroblasts, and keratinocytes of the wounds for up to 10 days. More importantly, a single application of HoxD3 to db/db mice resulted in a statistically significant acceleration of wound closure compared to control-treated wounds. Furthermore, we also observed that the HoxD3-mediated improvement in diabetic wound repair was accompanied by increases in mRNA expression of the HoxD3 target genes, Col1A1 and beta 3-integrin leading to enhanced angiogenesis and collagen deposition in the wounds. Although HoxD3-treated wounds also show improved re-epithelialization as compared to control db/db wounds, this effect was not due to direct stimulation of keratinocyte migration by HoxD3. Finally, we show that despite the dramatic increase in collagen synthesis and deposition in HoxD3-treated wounds, these wounds showed normal remodeling and we found no evidence of abnormal wound healing. These results indicate that HoxD3 may provide a means to directly improve collagen deposition, angiogenesis and closure in poorly healing diabetic wounds.

  4. Impact of a single oral dose of 100,000 IU vitamin D3 on profiles of serum 25(OH)D3 and its metabolites 24,25(OH)2D3, 3-epi-25(OH)D3, and 1,25(OH)2D3 in adults with vitamin D insufficiency.

    PubMed

    Saleh, Lanja; Tang, Jonathan; Gawinecka, Joanna; Boesch, Lukas; Fraser, William D; von Eckardstein, Arnold; Nowak, Albina

    2017-03-22

    We investigate the effect of a high dose of vitamin D3 on circulating concentrations of 25(OH)D3 and its metabolites 24,25(OH)2D3, 3-epi-25(OH)D3, and 1,25(OH)2D3 in healthy individuals with self-perceived fatigue and vitamin D insufficiency [25(OH)D3<50 nmol/L]. One hundred and seven study participants (age 20-50 years) were randomized to receive a single 100,000 IU dose of vitamin D3 (n=52) or placebo (n=55). Vitamin D metabolite concentrations in serum were measured before, and 4 weeks after, supplementation. Overall, 52% of participants receiving vitamin D3 attained a serum 25(OH)D3 level >75 nmol/L. Among individuals who received vitamin D3, there were significant increases in serum concentrations of 25(OH)D3 and its metabolites 24,25(OH)2D3, 3-epi-25(OH)D3, and 1,25(OH)2D3 at 4 weeks; however, inter-individual variability in these changes was substantial. Positive correlations between serum 25(OH)D3 and 24,25(OH)2D3 and 3-epi-25(OH)D3, and a significant negative correlation between serum 1,25(OH)2D3 and 3-epi-25(OH)D3, were found 4 weeks after supplementation. The 24,25(OH)2D3/25(OH)D3 and 24,25(OH)2D3/1,25(OH)2D3 ratios were significantly increased, compared with baseline, in participants receiving vitamin D3. Baseline 25(OH)D3 concentration was the only factor predictive of the change in 25(OH)D3 after supplementation. Administration of a single high dose of vitamin D3 leads to a significant increase in concentrations of 25(OH)D3, 24,25(OH)2D3, 3-epi-25(OH)D3 and 1,25(OH)2D3; induction of the catabolic pathway predominates over the production of 1,25(OH)2D3. Due to the high inter-individual variation in the 25(OH)D3 response to supplementation, any given dose of vitamin D is unlikely to achieve optimal vitamin D status in all treated individuals.

  5. 21 CFR 584.725 - 25-Hydroxyvitamin D3.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... of use. This substance is generally recognized as safe as a source of vitamin D3 activity in feed or... 21 Food and Drugs 6 2011-04-01 2011-04-01 false 25-Hydroxyvitamin D3. 584.725 Section 584.725 Food... DRINKING WATER OF ANIMALS Listing of Specific Substances Affirmed as GRAS § 584.725 25-Hydroxyvitamin...

  6. 21 CFR 584.725 - 25-Hydroxyvitamin D3.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... of use. This substance is generally recognized as safe as a source of vitamin D3 activity in feed or... 21 Food and Drugs 6 2010-04-01 2010-04-01 false 25-Hydroxyvitamin D3. 584.725 Section 584.725 Food... DRINKING WATER OF ANIMALS Listing of Specific Substances Affirmed as GRAS § 584.725 25-Hydroxyvitamin...

  7. Continuous-flow synthesis of vitamin D3.

    PubMed

    Fuse, Shinichiro; Tanabe, Nobutake; Yoshida, Masahito; Yoshida, Hayato; Doi, Takayuki; Takahashi, Takashi

    2010-12-14

    A highly efficient, two-stage, continuous-flow synthesis of vitamin D(3) from provitamin D(3) was achieved. The developed method afforded the desired product in high yield (HPLC-UV: 60%, isolated: 32%) and required neither intermediate purification nor high-dilution conditions.

  8. Superconductivity in noncentrosymmetric A g2P d3S

    NASA Astrophysics Data System (ADS)

    Yoshida, H.; Okabe, H.; Matsushita, Y.; Isobe, M.; Takayama-Muromachi, E.

    2017-05-01

    We have successfully synthesized the single crystal of A g2P d3S , which exhibits superconductivity with the transition temperature of Tc=2.25 K . A g2P d3S crystallizes in the space group P 4132 with the filled β -Mn structure, which has no inversion symmetry. The value of the Ginzburg-Landau parameter κGL indicates that A g2P d3S is a type-II superconductor. Δ C (Tc) /γnTc=1.50 and 2 Δ /kBTc=3.48 from the heat-capacity analyses indicate that A g2P d3S is a weak-coupling Bardeen-Cooper-Schrieffer (BCS) superconductor with an isotropic superconducting gap. On the other hand, the violation of the Werthamer-Helfand-Hohenberg curve in the H -T phase diagram implies A g2P d3S is not a typical BCS superconductor.

  9. Shuttle orbiter Ku-band radar/communications system design evaluation. Deliverable test equipment evaluation

    NASA Technical Reports Server (NTRS)

    Maronde, R. G.

    1980-01-01

    The Ku-band test equipment, known as the Deliverable System Test equipment (DSTE), is reviewed and evaluated. The DSTE is semiautomated and computer programs were generated for 14 communication mode tests and 17 radar mode tests. The 31 test modules provide a good cross section of tests with which to exercise the Ku-band system; however, it is very limited when being used to verify Ku-band system performance. More detailed test descriptions are needed, and a major area of concern is the DSTE sell-off procedure which is inadequate.

  10. Shuttle orbiter Ku-band radar/communications system design evaluation. Deliverable test equipment evaluation

    NASA Astrophysics Data System (ADS)

    Maronde, R. G.

    1980-07-01

    The Ku-band test equipment, known as the Deliverable System Test equipment (DSTE), is reviewed and evaluated. The DSTE is semiautomated and computer programs were generated for 14 communication mode tests and 17 radar mode tests. The 31 test modules provide a good cross section of tests with which to exercise the Ku-band system; however, it is very limited when being used to verify Ku-band system performance. More detailed test descriptions are needed, and a major area of concern is the DSTE sell-off procedure which is inadequate.

  11. 1,25-Vitamin D3 Deficiency Induces Albuminuria.

    PubMed

    Sonneveld, Ramon; Hoenderop, Joost G J; Stavenuiter, Andrea W D; Ferrantelli, Evelina; Baltissen, Marijke P A; Dijkman, Henry B; Florquin, Sandrine; Rops, Angelique L; Wetzels, Jack F M; Berden, Jo H M; van der Vlag, Johan; Nijenhuis, Tom

    2016-04-01

    Vitamin D plays an important role in renal (patho)physiology. Patients with glomerular diseases have an injured renal filtration barrier, leading to proteinuria and reduced renal function. An impaired renal function also leads to 1,25-vitamin D3 deficiency as a result of reduced renal 1α-hydroxylase activity. Vitamin D treatment to reduce proteinuria remains controversial, although there is an inverse correlation between vitamin D levels and proteinuria. Herein, we showed that 1,25-vitamin D3-deficient 25-hydroxy-vitamin-D3-1α-hydroxylase knockout mice and 1,25-vitamin D3-deficient rats develop podocyte injury and renal dysfunction. Glomerular injury was characterized by proteinuria and partial podocyte foot process effacement. Expression of nephrin, podocin, desmin, and transient receptor potential channel C6 in the podocyte was significantly altered in 1,25-vitamin D3-deficient animals. Supplementation with 1,25-vitamin D3 or 1,25-vitamin D2 prevented podocyte effacement or reversed glomerular and tubulointerstitial damage in 1,25-vitamin D3-deficient animals, thereby preserving and restoring renal function, respectively. The effect of 1,25-vitamin D3 deficiency and 1,25-vitamin D3 and 1,25-vitamin D2 repletion on proteinuria could not be explained by hypocalcemia, changes in parathyroid hormone, or fibroblast growth factor 23. This study demonstrates that 1,25-vitamin D3 deficiency directly leads to renal injury in rodents. Translated to human subjects, this would underline the need for early vitamin D supplementation in patients with glomerular disease and chronic renal insufficiency, which might inhibit or potentially reverse renal injury.

  12. Current drug treatments targeting dopamine D3 receptor.

    PubMed

    Leggio, Gian Marco; Bucolo, Claudio; Platania, Chiara Bianca Maria; Salomone, Salvatore; Drago, Filippo

    2016-09-01

    Dopamine receptors (DR) have been extensively studied, but only in recent years they became object of investigation to elucidate the specific role of different subtypes (D1R, D2R, D3R, D4R, D5R) in neural transmission and circuitry. D1-like receptors (D1R and D5R) and D2-like receptors (D2R, D2R and D4R) differ in signal transduction, binding profile, localization in the central nervous system and physiological effects. D3R is involved in a number of pathological conditions, including schizophrenia, Parkinson's disease, addiction, anxiety, depression and glaucoma. Development of selective D3R ligands has been so far challenging, due to the high sequence identity and homology shared by D2R and D3R. As a consequence, despite a rational design of selective DR ligands has been carried out, none of currently available medicines selectively target a given D2-like receptor subtype. The availability of the D3R ligand [(11)C]-(+)-PHNO for positron emission tomography studies in animal models as well as in humans, allows researchers to estimate the expression of D3R in vivo; displacement of [(11)C]-(+)-PHNO binding by concurrent drug treatments is used to estimate the in vivo occupancy of D3R. Here we provide an overview of studies indicating D3R as a target for pharmacological therapy, and a review of market approved drugs endowed with significant affinity at D3R that are used to treat disorders where D3R plays a relevant role.

  13. Vitamin D3 analogs stimulate hair growth in nude mice.

    PubMed

    Vegesna, Vijaya; O'Kelly, James; Uskokovic, Milan; Said, Jonathan; Lemp, Nathan; Saitoh, Takayuki; Ikezoe, Takayuki; Binderup, Lise; Koeffler, H Phillip

    2002-11-01

    The active form of vitamin D3 can regulate epidermal keratinization by inducing terminal differentiation; and mice lacking the vitamin D receptor display defects leading to postnatal alopecia. These observations implicate the vitamin D3 pathway in regulation of hair growth. We tested the ability of 1,25 dihydroxyvitamin D3 and its synthetic analogs to stimulate hair growth in biege/nude/xid (BNX) nu/nu (nude) mice exhibiting congenital alopecia. Nude mice were treated with different vitamin D3 analogs at doses that we had previously found to be the highest dose without inducing toxicity (hypercalcemia). The mice were monitored for hair growth and were scored according to a defined scale. Skin samples were taken for histological observation of hair follicles and for extraction of RNA and protein. Vitamin D3 analogs dramatically stimulated the hair growth of nude mice, although parental 1,25 dihydroxyvitamin D3 had no effect. Hair growth occurred in a cyclical pattern, accompanied by formation of normal hair follicles and increased expression of certain keratins (Ha7, Ha8, and Hb3). Vitamin D3 analogs seem to act on keratinocytes to initiate hair follicle cycling and stimulate hair growth in mice that otherwise do not grow hair.

  14. LANL12-RS-107J PYTHON Radiography Analysis Tool (PyRAT). Mid-Year Deliverable Report for FY15

    SciTech Connect

    Temple, Brian Allen; Armstrong, Jerawan Chudoung

    2015-04-14

    This document is a mid-year report on a deliverable for the PYTHON Radiography Analysis Tool (PyRAT) for project LANL12-RS-107J in FY15. The deliverable is deliverable number 2 in the work package and is titled “Add the ability to read in more types of image file formats in PyRAT”. Right now PyRAT can only read in uncompressed TIF files (tiff files). It is planned to expand the file formats that can be read by PyRAT, making it easier to use in more situations. A summary of the file formats added include jpeg, jpg, png and formatted ASCII files.

  15. Cost savings deliverables and criteria for the OST technology decision process

    SciTech Connect

    McCown, A.

    1997-04-01

    This document has been prepared to assist focus area (FA) technical and management teams in understanding the cost savings deliverables associated with a technology system during its research and development (R and D) phases. It discusses the usefulness of cost analysis in the decision-making process, and asserts that the level of confidence and data quality of a cost analysis is proportional to the maturity of the technology system`s development life cycle. Suggestions of specific investment criteria or cost savings metrics that a FA might levy on individual research projects are made but the final form of these elements should be stipulated by the FA management based on their rationale for a successful technology development project. Also, cost savings deliverables for a single FA will be more detailed than those for management of the Office of Science and Technology (OST). For example, OST management may want an analysis of the overall return on investment for each FA, while the FA program manager may want this analysis and the return on investment metrics for each technology research activity the FA supports.

  16. SU-E-T-597: Influence of Smoothing Parameters on Dynamic IMRT Plan Quality and Deliverability.

    PubMed

    Manigandan, D; Sharma, S; Gandhi, A; Subramani, V; Sharma, D; Kumar, P; Julka, P; Rath, G

    2012-06-01

    To study the impact of different smoothing parameters on IMRT plan quality and deliverabilityMethods: Five previously treated patients of carcinoma cervix were chosen. Planning target volume (PTV) and organ at risk (OAR) i.e. bladder and rectum were contoured. In each case, five different dynamic IMRT plans with 6MV photon beam were created in eclipse TPS for Varian 2300C/D linear accelerator. During optimization, dose volume constraints and priorities were kept constant and smoothing parameters were varied as follows: 10/5, 40/30 (TPS default value), 80/60, 100/80 and 200/150 in x/y direction. Total dose was 5040cGy in 28 fractions and prescribed at 95% isodose. Plan quality was analyzed by means of coverage index (CI=PTV covered by prescription dose/PTV), OAR mean doses and total monitor units (MUs) required to deliver a plan. In each case, deliverability of treatment plans were verified with I'matriXX ion-chamber array and compared with TPS dose-plane using gamma index of 3% dose difference and 3mm distance to agreement criteria. The CI values were 0.9435±0.032, 0.9418±0.034, 0.9380±0.041, 0.9330±0.047 and 0.8681±0.072 for 10/5, 40/30, 80/60, 100/80 and 200/150 in x/y direction. PTV dose maximum decreases with the increase of smoothing parameters and values were 5724.38±106.08 5723.30±131.60, 5708.44±1 16.74, 5697.92±116.82 and 5587.50±189.50cGy. The bladder mean doses were 4027.46±630.40, 3821.62±420.62, 3819.58±427.08, 3813.42±435.02 and 3814.78±438.0cGy. Rectum mean doses were 3839.88±466.02, 3835.52±473.18, 3837.52±472.88, 3839.10±471.20 and 3918.94±469.76cGy. Similarly, Total MUs were 1588±205, 1573±214, 1513±274, 1456±335 and 1219±68. Gamma pass rate increases with the increase of smoothing parameters and values were 99.16±0.21%, 99.07±0.19%, 99.24±0.28%, 99.29±0.29% and 99.75±0.15%. When smoothing parameters decreased below TPS default value, plan quality increases, but deliverability decreases. If smoothing parameters

  17. Assessment Report Sandia National Laboratories Fuel Cycle Technologies Quality Assurance Evaluation of FY15 SNL FCT M2 Milestone Deliverables

    SciTech Connect

    Appel, Gordon John

    2016-05-01

    Sandia National Laboratories (SNL) Fuel Cycle Technologies (FCT) program activities are conducted in accordance with FCT Quality Assurance Program Document (FCT-QAPD) requirements. The FCT-QAPD interfaces with SNL approved Quality Assurance Program Description (SNL-QAPD) as explained in the Sandia National Laboratories QA Program Interface Document for FCT Activities (Interface Document). This plan describes SNL's FY16 assessment of SNL's FY15 FCT M2 milestone deliverable's compliance with program QA requirements, including SNL R&A requirements. The assessment is intended to confirm that SNL's FY15 milestone deliverables contain the appropriate authenticated review documentation and that there is a copy marked with SNL R&A numbers.

  18. Mechanochemical synthesis and crystal structure of alpha'-AlD3 and alpha-AlD3.

    PubMed

    Brinks, Hendrik W; Istad-Lem, Andreas; Hauback, Bjørn C

    2006-12-28

    AlD3 AlD3 was synthesized by ball milling of 3LiAlD4 + AlCl3. Planetary ball milling at room temperature resulted in a mixture of AlD3 (alpha and alpha') and Al in addition to LiCl, whereas cryomilling at 77 K resulted in only AlD3 and LiCl. The AlD3 obtained was a mixture of about 2/3alpha and 1/3alpha'. Alpha' was determined by powder neutron diffraction to take the beta-AlF3 structure with space group Cmcm and a = 6.470(3), b = 11.117(5), and c = 6.562(2) A. It is built up of corner-sharing AlD6 octahedra in an open structure with hexagonal holes of radius 3.9 A. Alpha' slowly decomposes during storage at 40 degrees C. Alpha-AlD3 is also described by a corner-sharing AlD6 network but in a more dense ReO3-type arrangement. Both AlD3 modifications have slightly shorter Al-D distances compared to Na3AlD6, Na2LiAlD6, and K2NaAlH6.

  19. Phagocytic cells metabolize 25-hydroxyvitamin D3 in vitro.

    PubMed Central

    Cohen, M S; Gray, T K

    1984-01-01

    Phagocytic cells are widely distributed in tissues known to be important in the metabolism of vitamin D. Incubation of human polymorphonuclear leukocytes and monocytes and resident rat peritoneal macrophages with 3H-labeled 25-hydroxyvitamin D3 leads to the formation of three radioactive peaks. Peak I is most consistent with a lactone derivative of 25-hydroxyvitamin D3, and peak II has been identified as putative 24,25-dihydroxyvitamin D3. Peak III is a novel metabolite of 25-hydroxyvitamin D3 unlike any of the synthetic standards available in our laboratories. Human neutrophils converted more substrate than did the other phagocytes examined. The stimulation of neutrophils by opsonized zymosan or phorbol myristate acetate led to a 4-fold increase in synthesis of the metabolites. These results suggest that vitamin D metabolism by phagocytic cells may play a role in the microenvironmental events that surround bony metabolism and calcium homeostasis. PMID:6322179

  20. Analysis of Human Dopamine D3 Receptor Quaternary Structure*

    PubMed Central

    Marsango, Sara; Caltabiano, Gianluigi; Pou, Chantevy; Varela Liste, María José; Milligan, Graeme

    2015-01-01

    The dopamine D3 receptor is a class A, rhodopsin-like G protein-coupled receptor that can form dimers and/or higher order oligomers. However, the molecular basis for production of these complexes is not well defined. Using combinations of molecular modeling, site-directed mutagenesis, and homogenous time-resolved FRET, the interfaces that allow dopamine D3 receptor monomers to interact were defined and used to describe likely quaternary arrangements of the receptor. These were then compared with published crystal structures of dimeric β1-adrenoreceptor, μ-opioid, and CXCR4 receptors. The data indicate important contributions of residues from within each of transmembrane domains I, II, IV, V, VI, and VII as well as the intracellular helix VIII in the formation of D3-D3 receptor interfaces within homo-oligomers and are consistent with the D3 receptor adopting a β1-adrenoreceptor-like quaternary arrangement. Specifically, results suggest that D3 protomers can interact with each other via at least two distinct interfaces: the first one comprising residues from transmembrane domains I and II along with those from helix VIII and a second one involving transmembrane domains IV and V. Moreover, rather than existing only as distinct dimeric species, the results are consistent with the D3 receptor also assuming a quaternary structure in which two transmembrane domain I-II-helix VIII dimers interact to form a ”rhombic” tetramer via an interface involving residues from transmembrane domains VI and VII. In addition, the results also provide insights into the potential contribution of molecules of cholesterol to the overall organization and potential stability of the D3 receptor and possibly other GPCR quaternary structures. PMID:25931118

  1. Serum level of vitamin D3 in cutaneous melanoma

    PubMed Central

    de Oliveira, Renato Santos; de Oliveira, Daniel Arcuschin; Martinho, Vitor Augusto Melão; Antoneli, Célia Beatriz Gianotti; Marcussi, Ludmilla Altino de Lima; Ferreira, Carlos Eduardo dos Santos

    2014-01-01

    Objective To compare the level of vitamin D3 in cutaneous melanoma patients, with or without disease activity, with reference values and with patients from a general hospital. Methods The serum levels of vitamin D3 were measured in cutaneous melanoma patients, aged 20 to 88 years, both genders, from January 2010 to December 2013. The samples from the general group were processed at Hospital Israelita Albert Einstein (control group). Data analysis was performed using the Statistics software. Results A total of 100 patients were studied, 54 of them men, with mean age of 54.67 years, and 95 Caucasian. Out of these 100 patients, 17 had active disease. The average levels of vitamin D3 in the melanoma patients were lower than the level considered sufficient, but above the average of the control group. Both groups (with or without active disease) of patients showed a similar distribution of vitamin D3 deficiency. Conclusion Vitamin D3 levels in melanoma patients were higher than those of general patients and lower than the reference level. If the reference values are appropriate, a large part of the population had insufficient levels of vitamin D, including those with melanoma, or else, this standard needs to be reevaluated. No difference in vitamin D3 levels was found among melanoma patients with or without active disease. More comprehensive research is needed to assess the relation between vitamin D and melanoma. PMID:25628199

  2. Vitamin D3: a helpful immuno-modulator

    PubMed Central

    Di Rosa, Michelino; Malaguarnera, Michele; Nicoletti, Ferdinando; Malaguarnera, Lucia

    2011-01-01

    The active metabolite of vitamin D, 1α, 25-dihydroxyvitamin D3 [1,25(OH)2D3], is involved in calcium and phosphate metabolism and exerts a large number of biological effects. Vitamin D3 inhibits parathyroid hormone secretion, adaptive immunity and cell proliferation, and at the same time promotes insulin secretion, innate immunity and stimulates cellular differentiation. The role of vitamin D3 in immunoregulation has led to the concept of a dual function as both as an important secosteroid hormone for the regulation of body calcium homeostasis and as an essential organic compound that has been shown to have a crucial effect on the immune responses. Altered levels of vitamin D3 have been associated, by recent observational studies, with a higher susceptibility of immune-mediated disorders and inflammatory diseases. This review reports the new developments with specific reference to the metabolic and signalling mechanisms associated with the complex immune-regulatory effects of vitamin D3 on immune cells. PMID:21896008

  3. A Quantitative Study into the Information Technology Project Portfolio Practice: The Impact on Information Technology Project Deliverables

    ERIC Educational Resources Information Center

    Yu, Wei

    2013-01-01

    This dissertation applied the quantitative approach to the data gathered from online survey questionnaires regarding the three objects: Information Technology (IT) Portfolio Management, IT-Business Alignment, and IT Project Deliverables. By studying this data, this dissertation uncovered the underlying relationships that exist between the…

  4. A Quantitative Study into the Information Technology Project Portfolio Practice: The Impact on Information Technology Project Deliverables

    ERIC Educational Resources Information Center

    Yu, Wei

    2013-01-01

    This dissertation applied the quantitative approach to the data gathered from online survey questionnaires regarding the three objects: Information Technology (IT) Portfolio Management, IT-Business Alignment, and IT Project Deliverables. By studying this data, this dissertation uncovered the underlying relationships that exist between the…

  5. From Field Work to Deliverables. Experiences on the Tin House Courtyard Documentation

    NASA Astrophysics Data System (ADS)

    Bello Caballero, L.; Mezzino, D.; Federman, A.; Santana Quintero, M.

    2017-08-01

    The Tin House Courtyard is a property of the National Capital Commission (NCC) in Ottawa, Canada. The site is located within the `Mile of History', a historical route running from Parliament Hill to the Governor General's residence. Currently, existing assets are under intervention works that include several preservation and renewal actions. Within the broader project, one of the tasks before construction works started was the documentation of the set of facades. The Carleton Immersive Media Studio (CIMS) at Carleton University in Ottawa was commissioned by NCC to conduct the recording of the area. This paper describes the process undertaken from field work to the final deliverable to the client, as well as the issues faced in between. Nowadays, up to date surveying technologies have revolutionized the methodologies for cultural heritage documentation. In this regard, the recording strategy employed encompassed the use of photogrammetry, laser scanner, total station, as well as different pre and post processing software in order to generate the desired outcomes.

  6. Predicting deliverability of volumetric-modulated arc therapy (VMAT) plans using aperture complexity analysis.

    PubMed

    Younge, Kelly C; Roberts, Don; Janes, Lindsay A; Anderson, Carlos; Moran, Jean M; Matuszak, Martha M

    2016-07-08

    The purpose of this study was to evaluate the ability of an aperture complexity metric for volumetric-modulated arc therapy (VMAT) plans to predict plan delivery accuracy. We developed a complexity analysis tool as a plug-in script to Varian's Eclipse treatment planning system. This script reports the modulation of plans, arcs, and individual control points for VMAT plans using a previously developed complexity metric. The calculated complexities are compared to that of 649 VMAT plans previously treated at our institution from 2013 to mid-2015. We used the VMAT quality assurance (QA) results from the 649 treated plans, plus 62 plans that failed pretreatment QA, to validate the ability of the complexity metric to predict plan deliverability. We used a receiver operating characteristic (ROC) analysis to determine an appropriate complexity threshold value above which a plan should be considered for reoptimization before it moves further through our planning workflow. The average complexity metric for the 649 treated plans analyzed with the script was 0.132 mm-1 with a standard deviation of 0.036 mm-1. We found that when using a threshold complexity value of 0.180 mm-1, the true positive rate for correctly identifying plans that failed QA was 44%, and the false-positive rate was 7%. Used clinically with this threshold, the script can identify overly modulated plans and thus prevent a significant portion of QA failures. Reducing VMAT plan complexity has a number of important clinical benefits, including improving plan deliverability and reducing treatment time. Use of the complexity metric during both the planning and QA processes can reduce the number of QA failures and improve the quality of VMAT plans used for treatment. © 2016 The Authors

  7. Improving the driving practices of pizza deliverers: Response generalization and moderating effects of driving history

    PubMed Central

    Ludwig, Timothy D.; Geller, E. Scott

    1991-01-01

    A practical intervention program, targeting the safety belt use of pizza deliverers at two stores, increased significantly the use of both safety belts (143% above baseline) and turn signals (25% above baseline). Control subjects (i.e., pizza deliverers at a third no-intervention store and patrons driving to the pizza stores) showed no changes in belt or turn signal use over the course of 7-month study. The intervention program was staggered across two pizza stores and consisted of a group meeting wherein employees discussed the value of safety belts, received feedback regarding their low safety belt use, offered suggestions for increasing their belt use, and made a personal commitment to buckle up by signing buckle-up promise cards. Subsequently, employee-designed buckle-up reminder signs were placed in the pizza stores. By linking license plate numbers to individual driving records, we examined certain aspects of driving history as moderators of pre- and postintervention belt use. Although baseline belt use was significantly lower for drivers with one or more driving demerits or accidents in the previous 5 years, after the intervention these risk groups increased their belt use significantly and at the same rate as drivers with no demerits or accidents. Whereas baseline belt use was similar for younger (under 25) and older (25 or older) drivers, younger drivers were markedly more influenced by the intervention than were older drivers. Individual variation in belt use during baseline, intervention, and follow-up phases indicated that some drivers require more effective and costly intervention programs to motivate their safe driving practices. PMID:16795743

  8. Improving the driving practices of pizza deliverers: Response generalization and moderating effects of driving history.

    PubMed

    Ludwig, T D; Geller, E S

    1991-01-01

    A practical intervention program, targeting the safety belt use of pizza deliverers at two stores, increased significantly the use of both safety belts (143% above baseline) and turn signals (25% above baseline). Control subjects (i.e., pizza deliverers at a third no-intervention store and patrons driving to the pizza stores) showed no changes in belt or turn signal use over the course of 7-month study. The intervention program was staggered across two pizza stores and consisted of a group meeting wherein employees discussed the value of safety belts, received feedback regarding their low safety belt use, offered suggestions for increasing their belt use, and made a personal commitment to buckle up by signing buckle-up promise cards. Subsequently, employee-designed buckle-up reminder signs were placed in the pizza stores. By linking license plate numbers to individual driving records, we examined certain aspects of driving history as moderators of pre- and postintervention belt use. Although baseline belt use was significantly lower for drivers with one or more driving demerits or accidents in the previous 5 years, after the intervention these risk groups increased their belt use significantly and at the same rate as drivers with no demerits or accidents. Whereas baseline belt use was similar for younger (under 25) and older (25 or older) drivers, younger drivers were markedly more influenced by the intervention than were older drivers. Individual variation in belt use during baseline, intervention, and follow-up phases indicated that some drivers require more effective and costly intervention programs to motivate their safe driving practices.

  9. Genetic algorithm based deliverable segments optimization for static intensity-modulated radiotherapy.

    PubMed

    Li, Yongjie; Yao, Jonathan; Yao, Dezhong

    2003-10-21

    The static delivery technique (also called step-and-shoot technique) has been widely used in intensity-modulated radiotherapy (IMRT) because of the simple delivery and easy quality assurance. Conventional static IMRT consists of two steps: first to calculate the intensity-modulated beam profiles using an inverse planning algorithm, and then to translate these profiles into a series of uniform segments using a leaf-sequencing tool. In order to simplify the procedure and shorten the treatment time of the static mode, an efficient technique, called genetic algorithm based deliverable segments optimization (GADSO), is developed in our work, which combines these two steps into one. Taking the pre-defined beams and the total number of segments per treatment as input, the number of segments for each beam, the segment shapes and weights are determined automatically. A group of interim modulated beam profiles quickly calculated using a conjugate gradient (CG) method are used to determine the segment number for each beam and to initialize segment shapes. A modified genetic algorithm based on a two-dimensional binary coding scheme is used to optimize the segment shapes, and a CG method is used to optimize the segment weights. The physical characters of a multileaf collimator, such as the leaves interdigitation limitation and leaves maximum over-travel distance, are incorporated into the optimization. The algorithm is applied to some examples and the results demonstrate that GADSO is able to produce highly conformal dose distributions using 20-30 deliverable segments per treatment within a clinically acceptable computation time.

  10. Predicting deliverability of volumetric-modulated arc therapy (VMAT) plans using aperture complexity analysis.

    PubMed

    Younge, Kelly C; Roberts, Don; Janes, Lindsay A; Anderson, Carlos; Moran, Jean M; Matuszak, Martha M

    2016-07-01

    The purpose of this study was to evaluate the ability of an aperture complexity metric for volumetric-modulated arc therapy (VMAT) plans to predict plan delivery accuracy. We developed a complexity analysis tool as a plug-in script to Varian's Eclipse treatment planning system. This script reports the modulation of plans, arcs, and individual control points for VMAT plans using a previously developed complexity metric. The calculated complexities are compared to that of 649 VMAT plans previously treated at our institution from 2013 to mid-2015. We used the VMAT quality assurance (QA) results from the 649 treated plans, plus 62 plans that failed pretreatment QA, to validate the ability of the complexity metric to predict plan deliverability. We used a receiver operating characteristic (ROC) analysis to determine an appropriate complexity threshold value above which a plan should be considered for reoptimization before it moves further through our planning workflow. The average complexity metric for the 649 treated plans analyzed with the script was 0.132 mm-1 with a standard deviation of 0.036 mm-1. We found that when using a threshold complexity value of 0.180 mm-1, the true positive rate for correctly identifying plans that failed QA was 44%, and the false-positive rate was 7%. Used clinically with this threshold, the script can identify overly modulated plans and thus prevent a significant portion of QA failures. Reducing VMAT plan complexity has a number of important clinical benefits, including improving plan deliverability and reducing treatment time. Use of the complexity metric during both the planning and QA processes can reduce the number of QA failures and improve the quality of VMAT plans used for treatment. PACS number(s): 87.55.de, 87.55.Qr, 87.56.jk. © 2016 The Authors.

  11. Incorporating deliverable monitor unit constraints into spot intensity optimization in intensity-modulated proton therapy treatment planning

    NASA Astrophysics Data System (ADS)

    Cao, Wenhua; Lim, Gino; Li, Xiaoqiang; Li, Yupeng; Zhu, X. Ronald; Zhang, Xiaodong

    2013-08-01

    The purpose of this study is to investigate the feasibility and impact of incorporating deliverable monitor unit (MU) constraints into spot intensity optimization (SIO) in intensity-modulated proton therapy (IMPT) treatment planning. The current treatment planning system (TPS) for IMPT disregards deliverable MU constraints in the SIO routine. It performs a post-processing procedure on an optimized plan to enforce deliverable MU values that are required by the spot scanning proton delivery system. This procedure can create a significant dose distribution deviation between the optimized and post-processed deliverable plans, especially when small spot spacings are used. In this study, we introduce a two-stage linear programming approach to optimize spot intensities and constrain deliverable MU values simultaneously, i.e., a deliverable SIO (DSIO) model. Thus, the post-processing procedure is eliminated and the associated optimized plan deterioration can be avoided. Four prostate cancer cases at our institution were selected for study and two parallel opposed beam angles were planned for all cases. A quadratic programming based model without MU constraints, i.e., a conventional SIO (CSIO) model, was also implemented to emulate commercial TPS. Plans optimized by both the DSIO and CSIO models were evaluated for five different settings of spot spacing from 3 to 7 mm. For all spot spacings, the DSIO-optimized plans yielded better uniformity for the target dose coverage and critical structure sparing than did the CSIO-optimized plans. With reduced spot spacings, more significant improvements in target dose uniformity and critical structure sparing were observed in the DSIO than in the CSIO-optimized plans. Additionally, better sparing of the rectum and bladder was achieved when reduced spacings were used for the DSIO-optimized plans. The proposed DSIO approach ensures the deliverability of optimized IMPT plans that take into account MU constraints. This eliminates the post

  12. D3-Brane Model Building and the Supertrace Rule.

    PubMed

    Bena, Iosif; Graña, Mariana; Kuperstein, Stanislav; Ntokos, Praxitelis; Petrini, Michela

    2016-04-08

    A common way to obtain standard-model-like Lagrangians in string theory is to place D3-branes inside flux compactifications. The bosonic and fermionic masses and couplings of the resulting gauge theory are determined by the ten-dimensional metric and the fluxes, respectively, and the breaking of supersymmetry is soft. However, not any soft-supersymmetry-breaking Lagrangian can be obtained this way since the string theory equations of motion impose certain relations between the soft couplings. We show that for D3-branes in background fluxes, these relations imply that the sums of the squares of the boson and of the fermion masses are equal and that, furthermore, one- and two-loop quantum corrections do not spoil this equality. This makes the use of D3-branes for constructing computationally controllable models for physics beyond the standard model problematic.

  13. Vitamin D3 and calcidiol are not equipotent.

    PubMed

    Navarro-Valverde, Cristina; Sosa-Henríquez, Manuel; Alhambra-Expósito, Maria Rosa; Quesada-Gómez, José Manuel

    2016-11-01

    Despite the discussion on the optimal threshold of 25-hydroxyvitamin D serum level continues, there is now consensus on the fact that post-menopausal and elderly populations have inadequate Vitamin D serum levels worldwide. The adjustment of these levels is necessary to improve both bone and general health, as it is to optimize bone response to antiresortive treatments. It is recommended, as endorsed by international clinical guides, to use Vitamin D3, the physiological form of Vitamin D, in a dose range between 600-2000IU. It should be administered on a daily basis or on its weekly or monthly equivalents. In Spain, the use of calcidiol (25(OH)D3) at the same dose than Vitamin D3 is the most extended prescription, notwithstanding the available evidence stating that they are not equipotent. This may lead to over-dosage. In order to provide evidence on this circumstance, a convenience study was performed. Four groups of ten post-menopausal osteoporotic women each (average age 67), deficient in Vitamin D ((25(OH)D 37.5±10 nmol/L)) were enrolled. Each group followed a different treatment regimen: (G1) vitamin D3 20μg/day [800IU/day]; (G2) 25 (OH)D3 20μg/day; (G3) 25(OH)D3 266μg/week and (G4) 25(OH)D3 0.266mg every two weeks. 25(OH)D levels were measured for each group at 0, 6 and 12 months, with the following results: G1 (40.5±4.7;80.0±2; 86.2±23.7), G2 (37,2±4.2; 161±21.7;188.0±24.0), G3 (38±3.7;213.5±80.0; 233.0±81.2), G4 (39.5±4;164.5±41,7;210.5±22.2). These data reveal that both metabolites are not equipotent. Calcidiol is faster and 3-6 times more potent to obtain serum levels of 25(OH)D in the medium to long term. This circumstance must be assessed and included in the therapeutic prescription guides for Osteoporosis, since it should be of concern when planning and prescribing treatments to normalize serum levels of 25(OH)D3 and avoid potential adverse impacts. Copyright © 2016. Published by Elsevier Ltd.

  14. Ghost-free, finite, fourth-order D = 3 gravity.

    PubMed

    Deser, S

    2009-09-04

    Canonical analysis of a recently proposed linear + quadratic curvature gravity model in D = 3 establishes its pure, irreducibly fourth derivative, quadratic curvature limit as both ghost-free and power-counting UV finite, thereby maximally violating standard folklore. This limit is representative of a generic class whose kinetic terms are conformally invariant in any dimension, but it is unique in simultaneously avoiding the transverse-traceless graviton ghosts plaguing D > 3 quadratic actions as well as double pole propagators in its other variables. While the two-term model is also unitary, its additional mode's second-derivative nature forfeits finiteness.

  15. Simultaneous Quantification of 25-Hydroxyvitamin D3 and 24,25-Dihydroxyvitamin D3 in Rats Shows Strong Correlations between Serum and Brain Tissue Levels.

    PubMed

    Xue, Ying; He, Xin; Li, Huan-De; Deng, Yang; Yan, Miao; Cai, Hua-Lin; Tang, Mi-Mi; Dang, Rui-Li; Jiang, Pei

    2015-01-01

    While vitamin D3 is recognized as a neuroactive steroid affecting both brain development and function, efficient analytical method in determining vitamin D3 metabolites in the brain tissue is still lacking, and the relationship of vitamin D3 status between serum and brain remains elusive. Therefore, we developed a novel analysis method by using high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) to simultaneously quantify the concentrations of 25-hydroxyvitamin D3 (25(OH)D3) and 24,25-dihydroxyvitamin D3 (24,25(OH)2D3) in the serum and brain of rats fed with different dose of vitamin D3. We further investigated whether variations of serum vitamin D3 metabolites could affect vitamin D3 metabolite levels in the brain. Serum and brain tissue were analyzed by HPLC-MS/MS with electrospray ionization following derivatization with 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD). The method is highly sensitive, specific, and accurate to quantify 25(OH)D3 and 24,25(OH)2D3 in animal brain tissue. Vitamin D3 metabolites in brain tissue were significantly lower in rats fed with a vitamin D deficiency diet than in rats fed with high vitamin D3 diet. There was also a strong correlation of vitamin D3 metabolites in serum and brain. These results indicate that vitamin D3 status in serum affects bioavailability of vitamin D3 metabolites in the brain.

  16. Simultaneous Quantification of 25-Hydroxyvitamin D3 and 24,25-Dihydroxyvitamin D3 in Rats Shows Strong Correlations between Serum and Brain Tissue Levels

    PubMed Central

    Xue, Ying; He, Xin; Li, Huan-De; Deng, Yang; Yan, Miao; Cai, Hua-Lin; Tang, Mi-Mi; Dang, Rui-Li; Jiang, Pei

    2015-01-01

    While vitamin D3 is recognized as a neuroactive steroid affecting both brain development and function, efficient analytical method in determining vitamin D3 metabolites in the brain tissue is still lacking, and the relationship of vitamin D3 status between serum and brain remains elusive. Therefore, we developed a novel analysis method by using high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) to simultaneously quantify the concentrations of 25-hydroxyvitamin D3 (25(OH)D3) and 24,25-dihydroxyvitamin D3 (24,25(OH)2D3) in the serum and brain of rats fed with different dose of vitamin D3. We further investigated whether variations of serum vitamin D3 metabolites could affect vitamin D3 metabolite levels in the brain. Serum and brain tissue were analyzed by HPLC-MS/MS with electrospray ionization following derivatization with 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD). The method is highly sensitive, specific, and accurate to quantify 25(OH)D3 and 24,25(OH)2D3 in animal brain tissue. Vitamin D3 metabolites in brain tissue were significantly lower in rats fed with a vitamin D deficiency diet than in rats fed with high vitamin D3 diet. There was also a strong correlation of vitamin D3 metabolites in serum and brain. These results indicate that vitamin D3 status in serum affects bioavailability of vitamin D3 metabolites in the brain. PMID:26713090

  17. Quantum Electrodynamics in d=3 from the ε Expansion.

    PubMed

    Di Pietro, Lorenzo; Komargodski, Zohar; Shamir, Itamar; Stamou, Emmanuel

    2016-04-01

    We study quantum electrodynamics in d=3 coupled to N_{f} flavors of fermions. The theory flows to an IR fixed point for N_{f} larger than some critical number N_{f}^{c}. For N_{f}≤N_{f}^{c}, chiral-symmetry breaking is believed to take place. In analogy with the Wilson-Fisher description of the critical O(N) models in d=3, we make use of the existence of a fixed point in d=4-2ε to study the three-dimensional conformal theory. We compute, in perturbation theory, the IR dimensions of fermion bilinear and quadrilinear operators. For small N_{f}, a quadrilinear operator can become relevant in the IR and destabilize the fixed point. Therefore, the epsilon expansion can be used to estimate N_{f}^{c}. An interesting novelty compared to the O(N) models is that the theory in d=3 has an enhanced symmetry due to the structure of 3D spinors. We identify the operators in d=4-2ε that correspond to the additional conserved currents at d=3 and compute their infrared dimensions.

  18. 21 CFR 584.725 - 25-Hydroxyvitamin D3.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... of use. This substance is generally recognized as safe as a source of vitamin D3 activity in feed or...) Not more than 1 percent of any individual sterol. (iii) Not more than 5 percent water. (iv) Not more... expiration date on all premix labeling. (iv) A statement on all premix labeling (feed and drinking water...

  19. 21 CFR 584.725 - 25-Hydroxyvitamin D3.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... of use. This substance is generally recognized as safe as a source of vitamin D3 activity in feed or...) Not more than 1 percent of any individual sterol. (iii) Not more than 5 percent water. (iv) Not more... expiration date on all premix labeling. (iv) A statement on all premix labeling (feed and drinking water...

  20. 21 CFR 584.725 - 25-Hydroxyvitamin D3.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... of use. This substance is generally recognized as safe as a source of vitamin D3 activity in feed or...) Not more than 1 percent of any individual sterol. (iii) Not more than 5 percent water. (iv) Not more... expiration date on all premix labeling. (iv) A statement on all premix labeling (feed and drinking water...

  1. D3-D power supply, design, and development

    NASA Astrophysics Data System (ADS)

    Nerem, A.

    1995-02-01

    An overview of the D3-D power supply system with information details concerning the configuration, power ratings, acquisition costs, and cost scaling relevant to the design of ITER and other tokamaks is presented. The power supplies for the D3-D tokamak were installed and commissioned during the late 1970's and the beginning of the 1980's. Several upgrades have been implemented during the last two years to solve increasing reliability problems encountered as the equipment aged, to provide enhanced operational flexibilities, and to enable operation at the higher power levels needed to provide experimental data relevant to the ITER and TPX design activities. These upgrades ranged from redesign of the power supply control systems to the replacement of vacuum circuit breakers which had become unreliable in service. A new interlock and protection system has also been implemented using the latest programmable logic controllers (PLC) and computer technology. These upgrades have been highly successful and are described to provide insight to many issues in the specification of high power converters. Power supply models used in the design of the D3-D Plasma Control System are also described along with model verification test data. These models are being used in the development of a new advanced plasma control system for the D3-D tokamak. Recent operational experience and results are presented.

  2. Converting Basic D3 Charts into Reusable Style Templates.

    PubMed

    Harper, Jonathan; Agrawala, Maneesh

    2017-02-07

    We present a technique for converting a basic D3 chart into a reusable style template. Then, given a new data source we can apply the style template to generate a chart that depicts the new data, but in the style of the template. To construct the style template we first deconstruct the input D3 chart to recover its underlying structure: the data, the marks and the mappings that describe how the marks encode the data. We then rank the perceptual effectiveness of the deconstructed mappings. To apply the resulting style template to a new data source we first obtain importance ranks for each new data field. We then adjust the template mappings to depict the source data by matching the most important data fields to the most perceptually effective mappings. We show how the style templates can be applied to source data in the form of either a data table or another D3 chart. While our implementation focuses on generating templates for basic chart types (e.g. variants of bar charts, line charts, dot plots, scatterplots, etc.), these are the most commonly used chart types today. Users can easily find such basic D3 charts on the Web, turn them into templates, and immediately see how their own data would look in the visual style (e.g. colors, shapes, fonts, etc.) of the templates. We demonstrate the effectiveness of our approach by applying a diverse set of style templates to a variety of source datasets.

  3. The use of vitamin D3 to improve beef tenderness.

    PubMed

    Montgomery, J L; Parrish, F C; Beitz, D C; Horst, R L; Huff-Lonergan, E J; Trenkle, A H

    2000-10-01

    An experiment was designed to test the hypothesis that short-term oral administration of dietary vitamin D3 to beef cattle before slaughter would increase beef tenderness through greater calcium-activated calpain activity in postmortem aged skeletal muscle. Thirty continental crossbred steers were allotted randomly to three treatment groups housed in one pen. One group served as a control; two other groups were administered boluses with either 5 x 10(6) or 7.5 x 10(6) IU of vitamin D3 daily for 9 d. Cattle were slaughtered 1 d later. The longissimus lumborum was excised from each carcass 72 h postmortem and steaks removed at 3, 7, 14, and 21 d postmortem. The semimembranosus muscle (top round) was excised from each carcass 72 h postmortem and steaks removed at 7, 14, and 21 d postmortem. Blood plasma calcium concentration of cattle treated with 5 or 7.5 x 10(6) IU of vitamin D3 was higher (P < .05) than that of controls. Strip loin and top loin steaks from cattle fed supplemental doses of vitamin D3 had lower (P < .05) Warner-Bratzler (W-B) shear values at 14 d postmortem but were not significantly different from controls at 3, 7, or 21 d (strip loins) or 7 or 21 d (top rounds). No significant difference in strip loin steak tenderness was observed by sensory panel at 14 d postmortem (P < .17) between steaks from control and vitamin D3-treated steers. At 14 d postmortem, strip loin and top round steaks from cattle fed 5 x 10(6) IU of vitamin D3, but not from those given 7.5 x 10(6) IU, showed more proteolysis (P < .05) than did steaks from control cattle, based on Western blotting analysis. Therefore, the use of supplemental dietary vitamin D3 given daily for 9 d before slaughter did improve tenderness (lower W-B shear values) of 14-d postmortem aged beef. Increased proteolysis seems to be the mechanism of tenderization.

  4. Unrecognized vitamin D3 deficiency is common in Parkinson disease

    PubMed Central

    Ding, Hongliu; Dhima, Kaltra; Lockhart, Kaitlin C.; Locascio, Joseph J.; Hoesing, Ashley N.; Duong, Karen; Trisini-Lipsanopoulos, Ana; Hayes, Michael T.; Sohur, U. Shivraj; Wills, Anne-Marie; Mollenhauer, Brit; Flaherty, Alice W.; Hung, Albert Y.; Mejia, Nicte; Khurana, Vikram; Gomperts, Stephen N.; Selkoe, Dennis J.; Schwarzschild, Michael A.; Schlossmacher, Michael G.; Hyman, Bradley T.; Sudarsky, Lewis R.; Growdon, John H.

    2013-01-01

    Objective: To conclusively test for a specific association between the biological marker 25-hydroxy-vitamin D3, a transcriptionally active hormone produced in human skin and liver, and the prevalence and severity of Parkinson disease (PD). Methods: We used liquid chromatography/tandem mass spectrometry to establish an association specifically between deficiency of 25-hydroxy-vitamin D3 and PD in a cross-sectional and longitudinal case-control study of 388 patients (mean Hoehn and Yahr stage of 2.1 ± 0.6) and 283 control subjects free of neurologic disease nested in the Harvard Biomarker Study. Results: Plasma levels of 25-hydroxy-vitamin D3 were associated with PD in both univariate and multivariate analyses with p values = 0.0034 and 0.047, respectively. Total 25-hydroxy-vitamin D levels, the traditional composite measure of endogenous and exogenous vitamin D, were deficient in 17.6% of patients with PD compared with 9.3% of controls. Low 25-hydroxy-vitamin D3 as well as total 25-hydroxy-vitamin D levels were correlated with higher total Unified Parkinson’s Disease Rating Scale scores at baseline and during follow-up. Conclusions: Our study reveals an association between 25-hydroxy-vitamin D3 and PD and suggests that thousands of patients with PD in North America alone may be vitamin D–deficient. This finding has immediate relevance for individual patients at risk of falls as well as public health, and warrants further investigation into the mechanism underlying this association. PMID:24068787

  5. Genetic diversity of genotype D3 in acute hepatitis B.

    PubMed

    Alestig, Erik; Söderström, Ann; Norkrans, Gunnar; Lindh, Magnus

    2013-07-01

    Acute hepatitis B related to injection drug use is often caused by HBV-D3, a subgenotype that probably was introduced in Western Europe in the 1960s. The aim of this study was to describe genetic change over time in injection drug use-related HBV-D3 in one geographic area. Fourteen complete genomes and partial genomic regions of 17 HBV strains of subgenotype D3 causing acute (n = 30) or chronic (n = 1) hepatitis B at different time points between 1975 and 2009 were investigated. The 14 complete genomes clustered in phylogenetic trees on a sub-branch of HBV-D3 along with a few published sequences with high bootstrap values. In contrast, the phylogenetic tree topology based on nucleotides coding for surface antigen or core was uncertain with bootstrap values below 70% or lower. Variation of nucleotides coding for amino acids 125, 136, and 143 in the a determinant of HBsAg was however linked to complete genome phylogeny, indicating that these codons might be useful as markers for clades. The results show that knowledge about circulating strains is critical for the interpretation of molecular epidemiology investigations. The low degree of genetic change over time of HBV-D3 in the studied groups suggests that outbreaks of acute hepatitis B in injection drug users might originate from a limited number of individuals with chronic infection. Classification based on core or S region phylogeny obtained poor support from bootstrap values, but the presence of clade-specific amino acid substitutions suggests that the S region may be useful for subgenomic molecular epidemiology of HBV.

  6. 48 CFR 1552.211-79 - Compliance with EPA policies for information resources management.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ..., and technology. Examples of these services include but are not limited to the following: (1) The... majority of the Agency's IRM policies, standards, and procedures. (c) Section 508 requirements (accessibility). Contract deliverables are required to be compliant with Section 508 requirements...

  7. TU-C-17A-06: Evaluating IMRT Plan Deliverability Via PTV Shape and MLC Motion

    SciTech Connect

    McGurk, R; Smith, VA; Price, M

    2014-06-15

    Purpose: For step-and-shoot intensity-modulated radiation therapy (IMRT) plans, the dosimetry and deliverability can be affected by the number and shape of the segments used. Thus, plan deliverability is likely related to target volume and shape. We investigated whether the sphericity of target volumes and the previously proposed Modulation Complexity Score (MCS) could be used together to improve the detection of IMRT fields that failed quality assurance (QA). Methods: 526 and 353 IMRT fields from 32 prostate and 28 head-and-neck (H'N) patients, respectively, were analyzed. MCS was used to quantify the complexity of multi-leaf collimator shapes and motion patterns for each field. Sphericity was calculated using the surface area and volume of each patient’s planning target volume (PTV). Logistic regression models with MCS-alone or MCS and sphericity terms were fit to PlanUNC IMRT pass/fail results (5% dose difference, 4mm distance-to-agreement criteria) using SAS 9.3 (Cary, NC). Model concordance, discordance and area under the curve (AUC) were used to quantify model accuracy. Results: Mean (±1 standard deviation) MCS for prostate and H'N were 0.58(±0.15) and 0.40 (±0.14), respectively. Mean sphericity scores were 0.75(±0.05) for prostate and 0.63 (±0.12) for H'N. Both metrics were significantly different between treatment locations (p<0.01, Wilcoxon Rank Sum Test) indicating greater complexity in shape and variations for H'N PTVs. For prostate, concordance, discordance and AUC using MCS alone were 80.8%, 18.7% and 0.811. Including sphericity in the model improved these to 81.7%, 17.7% and 0.820. For H'N, the original concordance, discordance and AUC were of 72.9%, 26.9% and 0.729. Including sphericity into the model improved these metrics to 76.5%, 23.2% and 0.729. Conclusion: Sphericity provides a quantitative measure of PTV shape. While improvement in IMRT QA failure detection was modest for both prostate and H'N plans, including sphericity in the model

  8. On the origin of mRNA encoding the truncated dopamine D3-type receptor D3nf and detection of D3nf-like immunoreactivity in human brain.

    PubMed

    Liu, K; Bergson, C; Levenson, R; Schmauss, C

    1994-11-18

    A truncated dopamine D3-receptor-like mRNA, named D3nf, predicts a protein that differs from the D3-receptor only in the carboxyl terminus. However, such a protein has lost the predicted membrane topology typically found for G protein-coupled receptors. Results presented here show that D3nf mRNA arises from the D3-encoded primary transcript via alternative splicing. This splicing, however, appears to involve cleavage of an unusual 3' splice site. Therefore, we tested the possibility that D3nf mRNA results from a splicing error. If this were the case, D3nf mRNA would be expected to be present in the cytoplasm only at very low amounts, and it would not be expected to be translated into protein. However, the relative abundance of cytoplasmic D3/D3nf mRNA in human cortical tissues was found to be similar. Furthermore, we raised polyclonal antisera against the predicted carboxyl-terminal peptide sequence of D3nf that reacts specifically with a protein expressed in stably D3nf mRNA-expressing COS 7 cells. The use of this antiserum also revealed the presence of a approximately 68 kDa D3nf-like immunoreactive protein in human brain, suggesting that the atypically processed D3nf mRNA is translated.

  9. A liposomal model that mimics the cutaneous production of vitamin D3. Studies of the mechanism of the membrane-enhanced thermal isomerization of previtamin D3 to vitamin D3

    NASA Technical Reports Server (NTRS)

    Tian, X. Q.; Holick, M. F.

    1999-01-01

    We reported previously that the rate of previtamin D3 (preD3) <==> vitamin D3 isomerization was enhanced by about 10 times in the skin compared with that in organic solvents. To elucidate the mechanism by which the rate of this reaction is enhanced in the skin, we developed a liposomal model that mimicked the enhanced isomerization of preD3 to vitamin D3 that was described in human skin. Using this model we studied the effect of changing the polarity of preD3 as well as changing the chain length and the degree of saturation of liposomal phospholipids on the kinetics of preD3 <==> vitamin D3 isomerization. We found that a decrease in the hydrophilic interaction of the preD3 with liposomal phospholipids by an esterification of the 3beta-hydroxy of preD3 (previtamin D3-3beta-acetate) reduced the rate of the isomerization by 67%. The addition of a hydroxyl on C-25 of the hydrophobic side chain (25-hydroxyprevitamin D3), which decreased the hydrophobic interaction of preD3 with the phospholipids, reduced the rate by 87%. In contrast, in an isotropic n-hexane solution, there was little difference among the rates of the conversion of preD3, its 3beta-acetate, and 25-hydroxy derivatives to their corresponding vitamin D3 compounds. We also determined rate constants (k) of preD3 <==> vitamin D3 isomerization in liposomes containing phosphatidylcholines with different carbon chain lengths. The rates of the reaction were found to be enhanced as the number of carbons (Cn) in the hydrocarbon chain of the phospholipids increased from 10 to 18. In conclusion, these results support our hypothesis that amphipathic interactions between preD3 and membrane phospholipids stabilize preD3 in its "cholesterol like" cZc-conformer, the only conformer of preD3 that can convert to vitamin D3. The stronger these interactions were, the more preD3 was likely in its cZc conformation at any moment and the faster was the rate of its conversion to vitamin D3.

  10. A D-3He IEC power unit for space applications

    NASA Astrophysics Data System (ADS)

    Miley, G. H.

    1999-01-01

    There is an urgent need for small power units for on-board and landing site power for space travel. The conceptual design of a 1-MWe Inertial Electrostatic Confinement (IEC) fusion unit burning D-3He fuel is considered here for such applications. The IEC is attractive for space power-its non-Maxwellian beam-beam character is well-suited for D-3He operation, small size units with a high specific power density are conceivable. Small scale IEC experiments have produced encouraging results and are used here as the basis for extrapolation to the space power unit. However, critical scale-up experiments are essential to verify the feasibility of the concept.

  11. The field theory of intersecting D3-branes

    NASA Astrophysics Data System (ADS)

    Mintun, Eric; Polchinski, Joseph; Sun, Sichun

    2015-08-01

    We examine the defect gauge theory on two perpendicular D3-branes with a 1+1 dimensional intersection, consisting of U(1) fields on the D3-branes and charged hypermultiplets on the intersection. We argue that this gauge theory must have a magnetically charged soliton corresponding to the D-string stretched between the branes. We show that the hypermultiplets actually source magnetic as well as electric fields. The magnetic charges are confined if the hypermultiplet action is canonical, but considerations of periodicity of the hypermultiplet space in string theory imply a nontrivial Gibbons-Hawking metric, and we show that there is then the expected magnetic kink solution. The hypermultiplet metric has a singularity, which we argue must be resolved by embedding in the full string theory. Another interesting feature is that the classical field equations have logarithmic divergences at the intersection, which lead to a classical renormalization group flow in the action.

  12. Constrained superfields on metastable anti-D3-branes

    NASA Astrophysics Data System (ADS)

    Aalsma, Lars; van der Schaar, Jan Pieter; Vercnocke, Bert

    2017-05-01

    We study the effect of brane polarization on the supersymmetry transformations of probe anti-D3-branes at the tip of a Klebanov-Strassler throat geometry. As is well known, the probe branes can polarize into NS5-branes and decay to a supersymmetric state by brane-flux annihilation. The effective potential has a metastable minimum as long as the number of anti-D3-branes is small compared to the number of flux quanta. We study the reduced four-dimensional effective NS5-brane theory and show that in the metastable minimum supersymmetry is non-linearly realized to leading order, as expected for spontaneously broken supersymmetry. However, a strict decoupling limit of the higher order corrections in terms of a standard nilpotent superfield does not seem to exist. We comment on the possible implications of these results for more general low-energy effective descriptions of inflation or de Sitter vacua.

  13. Fast wave current drive antenna performance on D3-D

    NASA Astrophysics Data System (ADS)

    Mayberry, M. J.; Pinsker, R. I.; Petty, C. C.; Chiu, S. C.; Jackson, G. L.; Lippmann, S. I.; Prater, R.; Porkolab, M.

    1991-10-01

    Fast wave current drive (FWCD) experiments at 60 MHz are being performed on the D3-D tokamak for the first time in high electron temperature, high (beta) target plasmas. A four-element phased-array antenna is used to launch a directional wave spectrum with the peak n(sub parallel) value (approximately = 7) optimized for strong single-pass electron absorption due to electron Landau damping. For this experiment, high power FW injection (2 MW) must be accomplished without voltage breakdown in the transmission lines or antenna, and without significant impurity influx. In addition, there is the technological challenge of impedance matching a four-element antenna while maintaining equal currents and the correct phasing (90 degrees) in each of the straps for a directional spectrum. We describe the performance of the D3-D FWCD antenna during initial FW electron heating and current drive experiments in terms of these requirements.

  14. Holographic Schwinger effect with a moving D3-brane

    NASA Astrophysics Data System (ADS)

    Zhang, Zi-qiang; Hou, De-fu; Chen, Gang

    2017-03-01

    We study the Schwinger effect with a moving D3-brane in a N=4 SYM plasma with the aid of AdS/CFT correspondence. We discuss the test particle pair moving transverse and parallel to the plasma wind, respectively. It is found that for both cases the presence of velocity tends to increase the Schwinger effect. In addition, the velocity has a stronger influence on the Schwinger effect when the pair moves transverse to the plasma wind rather than parallel.

  15. A simultaneous 2D/3D autostereo workstation

    NASA Astrophysics Data System (ADS)

    Chau, Dennis; McGinnis, Bradley; Talandis, Jonas; Leigh, Jason; Peterka, Tom; Knoll, Aaron; Sumer, Aslihan; Papka, Michael; Jellinek, Julius

    2012-03-01

    We present a novel immersive workstation environment that scientists can use for 3D data exploration and as their everyday 2D computer monitor. Our implementation is based on an autostereoscopic dynamic parallax barrier 2D/3D display, interactive input devices, and a software infrastructure that allows client/server software modules to couple the workstation to scientists' visualization applications. This paper describes the hardware construction and calibration, software components, and a demonstration of our system in nanoscale materials science exploration.

  16. Nonperturbative gluon and ghost propagators in d = 3

    SciTech Connect

    Papavassiliou, Joannis

    2011-05-23

    We study the nonperturbative gluon and ghost propagators in d = 3 Yang-Mills, using the Schwinger-Dyson equations of the pinch technique. The use of the Schwinger mechanism leads to the dynamical generation of a gluon mass, which, in turn, gives rise to an infrared finite gluon propagator and ghost dressing function. The propagators obtained are in very good agreement with the results of SU(2) lattice simulations.

  17. Multiple D3-Instantons and Mock Modular Forms I

    NASA Astrophysics Data System (ADS)

    Alexandrov, Sergei; Banerjee, Sibasish; Manschot, Jan; Pioline, Boris

    2017-07-01

    We study D3-instanton corrections to the hypermultiplet moduli space in type IIB string theory compactified on a Calabi-Yau threefold. In a previous work, consistency of D3-instantons with S-duality was established at first order in the instanton expansion, using the modular properties of the M5-brane elliptic genus. We extend this analysis to the two-instanton level, where wall-crossing phenomena start playing a role. We focus on the contact potential, an analogue of the Kähler potential which must transform as a modular form under S-duality. We show that it can be expressed in terms of a suitable modification of the partition function of D4-D2-D0 BPS black holes, constructed out of the generating function of MSW invariants (the latter coincide with Donaldson-Thomas invariants in a particular chamber). Modular invariance of the contact potential then requires that, in the case where the D3-brane wraps a reducible divisor, the generating function of MSW invariants must transform as a vector-valued mock modular form, with a specific modular completion built from the MSW invariants of the constituents. Physically, this gives a powerful constraint on the degeneracies of BPS black holes. Mathematically, our result gives a universal prediction for the modular properties of Donaldson-Thomas invariants of pure two-dimensional sheaves.

  18. Rotation invariance principles in 2D/3D registration

    NASA Astrophysics Data System (ADS)

    Birkfellner, Wolfgang; Wirth, Joachim; Burgstaller, Wolfgang; Baumann, Bernard; Staedele, Harald; Hammer, Beat; Gellrich, Niels C.; Jacob, Augustinus L.; Regazzoni, Pietro; Messmer, Peter

    2003-05-01

    2D/3D patient-to-computed tomography (CT) registration is a method to determine a transformation that maps two coordinate systems by comparing a projection image rendered from CT to a real projection image. Applications include exact patient positioning in radiation therapy, calibration of surgical robots, and pose estimation in computer-aided surgery. One of the problems associated with 2D/3D registration is the fast that finding a registration includes sovling a minimization problem in six degrees-of-freedom in motion. This results in considerable time expenses since for each iteration step at least one volume rendering has to be computed. We show that by choosing an appropriate world coordinate system and by applying a 2D/2D registration method in each iteration step, the number of iterations can be grossly reduced from n6 to n5. Here, n is the number of discrete variations aroudn a given coordinate. Depending on the configuration of the optimization algorithm, this reduces the total number of iterations necessary to at least 1/3 of its original value. The method was implemented and extensively tested on simulated x-ray images of a pelvis. We conclude that this hardware-indepenent optimization of 2D/3D registration is a step towards increasing the acceptance of this promising method for a wide number of clinical applications.

  19. Multiple D3-Instantons and Mock Modular Forms I

    NASA Astrophysics Data System (ADS)

    Alexandrov, Sergei; Banerjee, Sibasish; Manschot, Jan; Pioline, Boris

    2016-11-01

    We study D3-instanton corrections to the hypermultiplet moduli space in type IIB string theory compactified on a Calabi-Yau threefold. In a previous work, consistency of D3-instantons with S-duality was established at first order in the instanton expansion, using the modular properties of the M5-brane elliptic genus. We extend this analysis to the two-instanton level, where wall-crossing phenomena start playing a role. We focus on the contact potential, an analogue of the Kähler potential which must transform as a modular form under S-duality. We show that it can be expressed in terms of a suitable modification of the partition function of D4-D2-D0 BPS black holes, constructed out of the generating function of MSW invariants (the latter coincide with Donaldson-Thomas invariants in a particular chamber). Modular invariance of the contact potential then requires that, in the case where the D3-brane wraps a reducible divisor, the generating function of MSW invariants must transform as a vector-valued mock modular form, with a specific modular completion built from the MSW invariants of the constituents. Physically, this gives a powerful constraint on the degeneracies of BPS black holes. Mathematically, our result gives a universal prediction for the modular properties of Donaldson-Thomas invariants of pure two-dimensional sheaves.

  20. How 3-D, 3-C seismic characterized a carbonate reservoir

    SciTech Connect

    Arestad, J.F.; Mattocks, B.W.; Davis, T.L.; Benson, R.D.

    1995-04-01

    The Reservoir Characterization Project (RCP) at the Colorado School of Mines has pioneered research into 3-D, 3-C (multicomponent) reflection seismology for nearly a decade utilizing both P-wave and S-wave sources. Multicomponent-seismic surveys provide significantly more information about petroleum reservoirs than compressional-wave surveys. Initial 3-D, 3-C surveys acquired by RCP were targeted at characterizing naturally fractured reservoirs. The current phase of the project is oriented towards utilizing shear waves to discriminate lithologic and diagenetic changes within stratigraphic reservoirs where compressional-seismic data has not be effective. The Joffre field, Nisku reservoir, is the site of RCP`s ongoing multidisciplinary research effort in Western Canada. The research team is directed by Colorado School of Mines faculty with graduate team members from geology, geophysics and petroleum engineering departments. While this study is still in progress, some key findings and directions of this research are reported here. The following topics will be discussed: Joffre field 3-D, 3-C survey; compressional wave 3-D technique; shear-wave 3-D technique; converted-wave 3-D technique; reservoir characterization, and future directions.

  1. Extension of the D3 dispersion coefficient model

    NASA Astrophysics Data System (ADS)

    Caldeweyher, Eike; Bannwarth, Christoph; Grimme, Stefan

    2017-07-01

    A new model, termed D4, for the efficient computation of molecular dipole-dipole dispersion coefficients is presented. As in the related, well established D3 scheme, these are obtained as a sum of atom-in-molecule dispersion coefficients over atom pairs. Both models make use of dynamic polarizabilities obtained from first-principles time-dependent density functional theory calculations for atoms in different chemical environments employing fractional atomic coordination numbers for interpolation. Different from the D3 model, the coefficients are obtained on-the-fly by numerical Casimir-Polder integration of the dynamic, atomic polarizabilities α (iω ). Most importantly, electronic density information is now incorporated via atomic partial charges computed at a semi-empirical quantum mechanical tight-binding level, which is used to scale the polarizabilities. Extended statistical measures show that errors for dispersion coefficients with the proposed D4 method are significantly lower than with D3 and other, computationally more involved schemes. Alongside, accurate isotropic charge and hybridization dependent, atom-in-molecule static polarizabilities are obtained with an unprecedented efficiency. Damping function parameters are provided for three standard density functionals, i.e., TPSS, PBE0, and B3LYP, allowing evaluation of the new DFT-D4 model for common non-covalent interaction energy benchmark sets.

  2. Tuning ethylene gas adsorption via metal node modulation: Cu-MOF-74 for a high ethylene deliverable capacity.

    PubMed

    Liao, Yijun; Zhang, Lin; Weston, Mitchell H; Morris, William; Hupp, Joseph T; Farha, Omar K

    2017-08-17

    M-MOF-74s were examined for potential applications in ethylene abatement and/or storage/delivery. Due to labile binding resulting from a Jahn-Teller distortion, Cu-MOF-74 exhibits a gradual initial uptake that, in turn, translates into the highest deliverable capacity among the MOFs examined (3.6 mmol g(-1)). In contrast, Co-MOF-74 is the most promising candidate for ethylene abatement due to the sharp uptake at low pressure.

  3. Silver deposited carboxymethyl chitosan-grafted magnetic nanoparticles as dual action deliverable antimicrobial materials.

    PubMed

    Vo, Duc-Thang; Sabrina, Sabrina; Lee, Cheng-Kang

    2017-04-01

    Carboxymethyl chitosan (CMCS) was known to have a much better antimicrobial activity than chitosan due to the increased cationic -NH3(+) groups resulted from the intra- and intermolecular interactions between the carboxyl and amino groups. CMCS was grafted onto the surface of silica coated magnetic nanoparticles (MNPs) to obtain magnetically retrievable and deliverable antimicrobial nanoparticles (MNPs@CMCS). The presence of carboxylate groups in CMCS not only enhanced antimicrobial activity but also enabled Ag ions chelating ability to induce the in situ formation of Ag nanoparticles (AgNPs). The deposition of AgNPs on the surface of MNPs@CMCS could significantly increase its antimicrobial activity against planktonic cells due to the dual action of CMCS and AgNPs. Due to its high magnetism, the as-prepared MNPs@CMCS-Ag could be efficiently delivered into an existing biofilm under the guidance of an applied magnetic field. Without direct contact, the Ag ions and/or radical oxygen species (ROS) released from the deposited Ag nanoparticles could effectively kill the bacteria embedded in the extracellular polymeric substances (EPS) matrix of biofilm.

  4. Vitamin D3 for uncontrolled childhood asthma: A pilot study.

    PubMed

    Kerley, Conor P; Hutchinson, Katrina; Cormican, Liam; Faul, John; Greally, Peter; Coghlan, David; Elnazir, Basil

    2016-06-01

    Observational and mechanistic data suggest a role for vitamin D in childhood asthma. However, subsequent interventional trials have been inconsistent. We aimed to assess the effect of 15 weeks of vitamin D3 supplementation compared with placebo (PL) in Irish children with asthma. We conducted a double-blind, randomized, PL-controlled trial of vitamin D supplementation (2000 IU/day) in 44 urban, Caucasian children at high latitude. Assessments were completed at baseline and after 15 weeks of supplementation. Outcome measures were lung function, subjective asthma control and biochemical parameters of total vitamin D, allergy, immunity, airway inflammation, and systemic inflammation. Finally, parents/guardians completed a weekly diary during the trial. There was no significant difference in baseline 25(OH)D levels, but there was a significant increase in median 25(OH)D in the vitamin D3 group (57.5-105 nmol/l) compared with the PL group (52.5-57.5 nmol/l) (p < 0.0001). There was no significant difference between groups regarding subjective asthma control. Compared with PL, there was a significant decrease in school days missed due to asthma (1 vs. 5 days, p = 0.04) and alkaline phosphatase (-3.4 vs. +16; p = 0.037) in the vitamin D3 group, but there were no beneficial effects regarding several other secondary end-points. However, there were non-significant, advantageous changes in the PL group compared with the vitamin D3 group in subjective asthma control and lung function, particularly percentage of predicted forced expiratory volume in 1 s (+2.5 vs. -4; p = 0.06). Vitamin D3 supplementation led to a significant increase in serum 25(OH)D and decreased school days missed (p = 0.04), but no other advantageous changes in asthma parameters compared with PL. The potential adverse effect of vitamin D deficiency on growth and the potential negative effect of high serum 25(OH)D on pulmonary function warrant further investigation. © 2016 John Wiley & Sons A/S. Published by

  5. 25(OH)D status: Effect of D3 supplement

    PubMed Central

    Luebbers, P. E.

    2017-01-01

    Summary Background Excess adipose tissue may lead to sequestrating of vitamin D, making it less available for use in the body. Objective This study determined if overweight or obese individuals (BMI > 25 kg m−2) had insufficient (<30 ng mL−1) levels of 25‐hydroxyvitamin D [25(OH)D] and, if so, would serum levels respond to exogenous supplementation. Methods Sixty‐three women who were overweight/obese (BMI = 31.07 ± 5.00 kg m−2) were randomly assigned in a double‐blind manner to receive 5,000 IU of vitamin D3 (D3) (n = 31) or a placebo (PL) (n = 32) daily. Serum 25(OH)D concentrations were measured by finger‐stick analyses at baseline and after 8 weeks of supplementation. Data were analyzed by using a 2 × 2 (group × time) repeated measure multivariate analysis of variance to determine group differences for pre‐values and post‐values (p < 0.05). Results On day one of the study, both D3 and PL groups had insufficient levels of vitamin D (mean ± SD) 24.03 ± 9.78 ng mL−1 and 23.62 ± 9.77 ng mL−1, respectively. After 8 weeks of supplementation, the D3 group 25(OH)D level rose to a mean of 43.57 ± 10.87 ng mL−1 (p < 0.001) versus the PL group whose 25(OH)D level remained statistically unchanged 24.31 ± 8.84 ng mL−1. Women who were overweight/obese had insufficient vitamin D levels prior to supplementation. Conclusions Following supplementation with 5,000 IU of vitamin D3, all subjects' 25(OH)D levels rose to a sufficient level (≥30 ng mL−1). The findings of this study concur with the Institute of Medicine and Endocrine Society recommendations in that two to three times the daily requirement of vitamin D is required to improve serum vitamin D levels in individuals who are overweight or obese. PMID:28392936

  6. Case study: Hydraulic fracturing with cross-linked gels in the Oriskany formation to improve gas storage deliverability

    SciTech Connect

    Stiles, E.K.; Reese, R.R.

    1995-12-31

    During the summer and fall of 1994, CNG Transmission Corporation fracture-stimulated thirty (30) gas storage wells with a cross-linked gel fluid system. The work was done to increase late season field deliverability. Individual well tests taken to date have shown that, on average, per-well deliverability has increased by a factor of five. The text that follows will detail the engineering and geologic aspects, procedures, results, and analysis of the project. A discussion of the strategic placement of the storage fields involved will be presented, along with a review of FERC Order 636 and it`s impact on the current gas storage business mechanics. Overviews are presented on the geology, reservoir properties, and characteristics of the storage fields involved in the project. General well design and well completion configuration are discussed. Fracturing/refracturing candidate selection criteria are presented. Basic fracturing design criteria are discussed including: fluid parameters, geometry, proppant selection, and concentration. Discussions of observations and minor changes in treatment designs which occurred between the different fields are discussed. The treatments are summarized and compared on a pre and post fracturing deliverability test analysis. Explanations are offered for wells with exceptional results, as well as marginally successful treatments.

  7. Recombination of H(3+) and D(3+) ions with electrons

    NASA Technical Reports Server (NTRS)

    Johnsen, R.; Gougousi, T.; Golde, M. F.

    1994-01-01

    Flowing-afterglow measurements in decaying H3(+) or D3(+) plasmas suggest that de-ionization does not occur by simple binary recombination of a single ion species. We find that vibrational excitation of the ions fails to provide an explanation for the effect, contrary to an earlier suggestion. Instead, we suggest that collisional stabilization of H3** Rydberg molecules by ambient electrons introduces an additional dependence on electron density. The proposed mechanism would permit plasma de-ionization to occur without the need for dissociative recombination by the mechanism of potential-surface crossings.

  8. D3-D5 theories with unquenched flavors

    NASA Astrophysics Data System (ADS)

    Conde, Eduardo; Lin, Hai; Penín, José Manuel; Ramallo, Alfonso V.; Zoakos, Dimitrios

    2017-01-01

    We construct the string duals of the defect theories generated when Nf flavor D5-branes intersect Nc color D3-branes along a 2 + 1 dimensional subspace. We work in the Veneziano limit in which Nc and Nf are large and Nf /Nc is fixed. By smearing the D5-branes, we find supergravity solutions that take into account the backreaction of the flavor branes and preserve two supercharges. When the flavors are massless the resulting metric displays an anisotropic Lifshitz-like scale invariance. The case of massive quarks is also considered.

  9. Effects of vitamin D3 supplementation and UVb exposure on the growth and plasma concentration of vitamin D3 metabolites in juvenile bearded dragons (Pogona vitticeps).

    PubMed

    Oonincx, D G A B; Stevens, Y; van den Borne, J J G C; van Leeuwen, J P T M; Hendriks, W H

    2010-06-01

    The effectiveness of dietary vitamin D3 and UVb exposure on plasma vitamin D metabolites in growing bearded dragons (Pogona vitticeps) was studied. A total of 84 (40 males and 44 females) newly hatched bearded dragons were allocated to six levels of oral vitamin D3 supplementation (0 to 400%) or six UVb exposure times (2 to 12 h). At 3 and 6 months of age, blood samples were obtained from each animal and analysed for 25(OH)D3 and 1,25(OH)2D3. At 3 months of age, plasma concentrations of 25(OH)D3 did not increase with increasing vitamin D3 supplementation unlike the 1,25(OH)2D3. At 6 months of age, plasma concentrations of both 25(OH)D(3) and 1,25(OH)2D3 increased with increasing vitamin D(3) supplementation. Plasma concentrations in UVb-exposed animals were 18 times higher for 25(OH)D3 (178.4+/-9.0 vs. 9.9+/-1.3 nmol/L) and 5.3 times higher for 1,25(OH)2D3 (1.205+/-0.100 vs. 0.229+/-0.025 nmol/L) than in vitamin D(3) supplemented animals at 6 months of age. This study shows that 2h of UVb exposure enables adequate physiological concentrations of plasma vitamin D metabolites to be maintained in growing bearded dragons. Oral supplementation of vitamin D(3) is ineffective in raising plasma concentrations of 25(OH)D3 and 1,25(OH)2D3 to concentrations observed in UVb-exposed animals.

  10. Search for muon catalyzed d 3He-fusion

    NASA Astrophysics Data System (ADS)

    Maev, E. M.; Balin, D. V.; Case, T.; Crowe, K. M.; Del Rosso, A.; Ganzha, V. A.; Hartmann, F. J.; Kozlov, S. M.; Lauss, B.; Maev, O. E.; Mühlbauer, M.; Mulhauser, F.; Petitjean, C.; Petrov, G. E.; Sadetsky, S. M.; Schapkin, G. N.; Schott, W.; Semenchuk, G. G.; Smirenin, Yu. V.; Soroka, M. A.; Vasiliev, A. A.; Vorobyov, A. A.; Voropaev, N. I.; Zmeskal, J.

    1999-06-01

    We report on the results of an experiment aimed at observing muon-catalyzed d 3He-fusion with a setup previously used for studies of the muon-catalyzed dd-fusion. The basic element of the setup is a high pressure ionization chamber operating as an active target. In this experiment the chamber was filled with an HD + 3He (5.6%) gas mixture at 13.2 bar pressure and 50 K temperature. These conditions were chosen as optimal for formation of the 3Heμd-molecules with a low level of background from the d-μ-d fusion. The chamber was exposed to the negative muon beam at PSI. During a 3-week data-taking period, 9.7 × 108 muon stops have been selected. The analysis of the data was able to determine a new upper limit for the d 3He-fusion rate in the 3Heμd-molecule (λf≤ 6× 104 s-1), which is more than three orders of magnitude lower than the previously existed limit.

  11. Experimental Search for μd 3He Fusion

    NASA Astrophysics Data System (ADS)

    Knowles, P. E.; Boreiko, V. M.; Bystritsky, V. M.; Filipowicz, M.; Huot, O.; Mulhauser, F.; Pavlov, V. N.; Penkov, F. M.; Petitjean, C.; Popov, N. P.; Sandukovsky, V. G.; Schaller, L. A.; Schneuwly, H.; Stolupin, V. A.; Woźniak, J.

    2001-12-01

    The vast majority of muon catalyzed fusion research has been concerned with muonic molecules of hydrogen isotopes only, since the dynamics of higher-Z muonic atoms in general preclude the formation of molecular systems. In the specific case of hydrogen helium mixtures, bound muonic molecular states can exist, and thus it is possible to search for the reaction μd 3He xrightarrow{{tilde λ f}} μ+α(3.66 MeV)+p(14.64 MeV). Until recently, the theoretical predictions for the nuclear fusion rate in the μd 3He molecule, {tilde λ } f , ranged over one order of magnitude, from 105 to 106 per second. An experimental upper limit has been measured for {tilde λ } f in HD + 3He giving a value (<6×104 s-1 [1]). We report on the analysis of an experiment in D2 + 3He which has shown a signal coming either from the muon catalyzed reaction, or from the fusion in flight of 3He's formed from dμd fusion.

  12. AdS spacetimes from wrapped D3-branes

    NASA Astrophysics Data System (ADS)

    Gauntlett, Jerome P.; MacConamhna, Oisín A. P.

    2007-12-01

    We derive a geometrical characterization of a large class of AdS3 and AdS2 supersymmetric spacetimes in type IIB supergravity with non-vanishing five-form flux using G-structures. These are obtained as special cases of a class of supersymmetric spacetimes with an {{\\bb R}}^{1,1} or {{\\bb R}} (time) factor that are associated with D3 branes wrapping calibrated two or three cycles, respectively, in manifolds with SU(2), SU(3), SU(4) and G2 holonomy. We show how two explicit AdS solutions, previously constructed in gauged supergravity, satisfy our more general G-structure conditions. For each explicit solution, we also derive a special holonomy metric which, although singular, has an appropriate calibrated cycle. After analytic continuation, some of the classes of AdS spacetimes give rise to known classes of BPS bubble solutions with {{\\bb R}}\\times {\\it SO}(4)\\times {\\it SO}(4), {{\\bb R}}\\times {\\it SO}(4)\\times U(1) and {{\\bb R}}\\times {\\it SO}(4) symmetry. These have 1/2, 1/4 and 1/8 supersymmetry, respectively. We present a new class of 1/8 BPS geometries with {{\\bb R}}\\times {\\it SU}(2) symmetry, obtained by analytic continuation of the class of AdS spacetimes associated with D3-brane wrapped on associative three cycles.

  13. A fast scanning probe for D3-D

    NASA Astrophysics Data System (ADS)

    Watkins, J. G.; Salmonson, J.; Doerner, R.; Lehmer, R.; Moyer, R.; Schmitz, L.; Hill, D. N.

    A fast reciprocating probe was developed for D3-D which can penetrate the separatrix during H - mode with up to 5MW of NBI heating. The probe was designed to carry various sensor tips into the scrape-off layer at a velocity of 3 m/sec and dwell motionless for a programmed period of time. The driving force is provided by a pneumatic cylinder charged with helium to facilitate greater mass flow. The first series of experiments were done using a Langmuir probe head with 5 graphite tips to measure radial profiles of n(sub e), T(sub e), phi(sub f), (n tilde)(sub e), and (phi tilde)(sub f). The amplitude and phase of the fluctuating quantities are measured by using specially constructed vacuum compatible 5 kV coaxial transmission lines which allow us to extend the measurements into the MHz range. TTZ ceramic bearings and fast stroke bellows were also specially designed for the D3-D probe. Initial measurements will be presented.

  14. Simultaneous measurement of plasma vitamin D3 metabolites including 4β,25-dihydroxyvitamin D3 using liquid chromatography-tandem mass spectrometry

    PubMed Central

    Wang, Zhican; Senn, Tauri; Kalhorn, Tom; Zheng, Xi Emily; Zheng, Songmao; Davis, Connie L.; Hebert, Mary F.; Lin, Yvonne S.; Thummel, Kenneth E.

    2011-01-01

    Simultaneous and accurate measurement of circulating vitamin D metabolites is critical to studies of the metabolic regulation of vitamin D and its impact on health and disease. To that end, we developed a specific LC-MS/MS method that permits the quantification of major circulating vitamin D3 metabolites in human plasma. Plasma samples were subjected to a protein precipitation, liquid-liquid extraction and Diels-Alder derivatization procedure prior to LC-MS/MS analysis. Importantly, in all human plasma samples tested, we identified a significant dihydroxyvitamin D3 peak that could potentially interfere with the determination of 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3] concentrations. This interfering metabolite has been identified as 4β,25-dihydroxyvitamin D3 [4β,25(OH)2D3] and was found at concentrations comparable to 1α,25(OH)2D3. Quantification of 1α,25(OH)2D3 in plasma required complete chromatographic separation of 1α,25(OH)2D3 from 4β,25(OH)2D3. An assay incorporating this feature was used to simultaneously determine the plasma concentrations of 25OHD3, 24R,25(OH)2D3, 1α,25(OH)2D3, and 4β,25(OH)2D3 in healthy individuals. The LC-MS/MS method developed and described here, could result in considerable improvement in the quantification of 1α,25(OH)2D3, as well as monitoring the newly identified circulating metabolite, 4β,25(OH)2D3. PMID:21784054

  15. Interactive initialization of 2D/3D rigid registration

    SciTech Connect

    Gong, Ren Hui; Güler, Özgür; Kürklüoglu, Mustafa; Lovejoy, John; Yaniv, Ziv

    2013-12-15

    Purpose: Registration is one of the key technical components in an image-guided navigation system. A large number of 2D/3D registration algorithms have been previously proposed, but have not been able to transition into clinical practice. The authors identify the primary reason for the lack of adoption with the prerequisite for a sufficiently accurate initial transformation, mean target registration error of about 10 mm or less. In this paper, the authors present two interactive initialization approaches that provide the desired accuracy for x-ray/MR and x-ray/CT registration in the operating room setting. Methods: The authors have developed two interactive registration methods based on visual alignment of a preoperative image, MR, or CT to intraoperative x-rays. In the first approach, the operator uses a gesture based interface to align a volume rendering of the preoperative image to multiple x-rays. The second approach uses a tracked tool available as part of a navigation system. Preoperatively, a virtual replica of the tool is positioned next to the anatomical structures visible in the volumetric data. Intraoperatively, the physical tool is positioned in a similar manner and subsequently used to align a volume rendering to the x-ray images using an augmented reality (AR) approach. Both methods were assessed using three publicly available reference data sets for 2D/3D registration evaluation. Results: In the authors' experiments, the authors show that for x-ray/MR registration, the gesture based method resulted in a mean target registration error (mTRE) of 9.3 ± 5.0 mm with an average interaction time of 146.3 ± 73.0 s, and the AR-based method had mTREs of 7.2 ± 3.2 mm with interaction times of 44 ± 32 s. For x-ray/CT registration, the gesture based method resulted in a mTRE of 7.4 ± 5.0 mm with an average interaction time of 132.1 ± 66.4 s, and the AR-based method had mTREs of 8.3 ± 5.0 mm with interaction times of 58 ± 52 s. Conclusions: Based on the

  16. 2D-3D transition of gold cluster anions resolved

    NASA Astrophysics Data System (ADS)

    Johansson, Mikael P.; Lechtken, Anne; Schooss, Detlef; Kappes, Manfred M.; Furche, Filipp

    2008-05-01

    Small gold cluster anions Aun- are known for their unusual two-dimensional (2D) structures, giving rise to properties very different from those of bulk gold. Previous experiments and calculations disagree about the number of gold atoms nc where the transition to 3D structures occurs. We combine trapped ion electron diffraction and state of the art electronic structure calculations to resolve this puzzle and establish nc=12 . It is shown that theoretical studies using traditional generalized gradient functionals are heavily biased towards 2D structures. For a correct prediction of the 2D-3D crossover point it is crucial to use density functionals yielding accurate jellium surface energies, such as the Tao-Perdew-Staroverov-Scuseria (TPSS) functional or the Perdew-Burke-Ernzerhof functional modified for solids (PBEsol). Further, spin-orbit effects have to be included, and large, flexible basis sets employed. This combined theoretical-experimental approach is promising for larger gold and other metal clusters.

  17. Neutral beam injection in a D 3He FRC reactor

    NASA Astrophysics Data System (ADS)

    Ferrari, Hugo; Farengo, Ricardo

    2007-06-01

    The use of neutral beam injection (NBI) to sustain a fraction of the plasma current in a field reversed configuration (FRC) reactor operating with the D-3He reaction is studied. A Monte Carlo code already used to study NBI in medium size FRCs is employed (Lifschitz A F, Farengo R and Arista N R 2002 Nucl. Fusion 42 863, Lifschitz A F, Farengo R and Arista N R 2002 Plasma Phys. Control. Fusion 44 1979, Lifschitz A F, Farengo R and Hoffman A L 2004 Nucl. Fusion 44 1015) and the plasma parameters are similar to those proposed in the ARTEMIS (Momota H, Ishida A, Kohzaki Y, Miley G, Ohi S, Ohnishi M, Sato K, Steinhauer L, Tomita Y and Tuszewki M 1992 Fusion Technol. 21 2307) conceptual reactor design. A simple analysis shows that the driven current cannot reach the values quoted in the ARTEMIS project and a procedure to search for plasma parameters that result in higher efficiencies is presented.

  18. Direct energy conversion system for D(3)-He fusion

    NASA Astrophysics Data System (ADS)

    Tomita, Y.; Shu, L. Y.; Momota, H.

    1993-11-01

    A novel and highly efficient direct energy conversion system is proposed for utilizing D(3)-He fueled fusion. In order to convert kinetic energy of ions, we applied a pair of direct energy conversion systems each of which has a cusp-type DEC and a traveling wave DEC (TWDEC). In a cusp-type DEC, electrons are separated from the escaping ions at the first line-cusp and the energy of thermal ion components is converted at the second cusp DEC. The fusion protons go through the cusp-type DEC and arrive at the TWDEC, which principle is similar to 'LINAC'. The energy of fusion protons is recovered to electricity with an efficiency of more than 70%. These DEC's bring about the high efficient fusion plant.

  19. Fully automated 2D-3D registration and verification.

    PubMed

    Varnavas, Andreas; Carrell, Tom; Penney, Graeme

    2015-12-01

    Clinical application of 2D-3D registration technology often requires a significant amount of human interaction during initialisation and result verification. This is one of the main barriers to more widespread clinical use of this technology. We propose novel techniques for automated initial pose estimation of the 3D data and verification of the registration result, and show how these techniques can be combined to enable fully automated 2D-3D registration, particularly in the case of a vertebra based system. The initialisation method is based on preoperative computation of 2D templates over a wide range of 3D poses. These templates are used to apply the Generalised Hough Transform to the intraoperative 2D image and the sought 3D pose is selected with the combined use of the generated accumulator arrays and a Gradient Difference Similarity Measure. On the verification side, two algorithms are proposed: one using normalised features based on the similarity value and the other based on the pose agreement between multiple vertebra based registrations. The proposed methods are employed here for CT to fluoroscopy registration and are trained and tested with data from 31 clinical procedures with 417 low dose, i.e. low quality, high noise interventional fluoroscopy images. When similarity value based verification is used, the fully automated system achieves a 95.73% correct registration rate, whereas a no registration result is produced for the remaining 4.27% of cases (i.e. incorrect registration rate is 0%). The system also automatically detects input images outside its operating range.

  20. 24R,25-dihydroxyvitamin D3 [24R,25(OH)2D3] controls growth plate development by inhibiting apoptosis in the reserve zone and stimulating response to 1alpha,25(OH)2D3 in hypertrophic cells.

    PubMed

    Boyan, B D; Hurst-Kennedy, J; Denison, T A; Schwartz, Z

    2010-07-01

    Previously we showed that costochondral growth plate resting zone (RC) chondrocytes response primarily to 24R,25(OH)2D3 whereas prehypertrophic and hypertrophic (GC) cells respond to 1alpha,25(OH)2D3. 24R,25(OH)2D3 increases RC cell proliferation and inhibits activity of matrix processing enzymes, suggesting it stabilizes cells in the reserve zone, possibly by inhibiting the matrix degradation characteristic of apoptotic hypertrophic GC cells. To test this, apoptosis was induced in rat RC cells by treatment with exogenous inorganic phosphate (Pi). 24R,25(OH)2D3 blocked apoptotic effects in a dose-dependent manner. Similarly, apoptosis was induced in ATDC5 cell cultures and 24R,25(OH)2D3 blocked this effect. Further studies indicated that 24R,25(OH)2D3 acts via at least two independent pathways. 24R,25(OH)2D3 increases LPA receptor-1 (LPA R1) expression and production of lysophosphatidic acid (LPA), and subsequent LPA R1/3-dependent signaling, thereby decreasing p53 abundance. LPA also increases the Bcl-2/Bax ratio. In addition, 24R,25(OH)2D3 acts by increasing PKC activity. 24R,25(OH)2D3 stimulates 1-hydroxylase activity, resulting in increased levels of 1,25(OH)2D3, and it increases levels of phospholipase A2 activating protein, which is required for rapid 1alpha,25(OH)2D3-dependent activation of PKC in GC cells. These results suggest that 24R,25(OH)2D3 modulates growth plate development by controlling the rate and extent of RC chondrocyte transition to a GC chondrocyte phenotype.

  1. 25-Hydroxyvitamin D3 induces osteogenic differentiation of human mesenchymal stem cells

    PubMed Central

    Lou, Yan-Ru; Toh, Tai Chong; Tee, Yee Han; Yu, Hanry

    2017-01-01

    25-Hydroxyvitamin D3 [25(OH)D3] has recently been found to be an active hormone. Its biological actions are demonstrated in various cell types. 25(OH)D3 deficiency results in failure in bone formation and skeletal deformation. Here, we investigated the effect of 25(OH)D3 on osteogenic differentiation of human mesenchymal stem cells (hMSCs). We also studied the effect of 1α,25-dihydroxyvitamin D3 [1α,25-(OH)2D3], a metabolite of 25(OH)D3. One of the vitamin D responsive genes, 25(OH)D3-24-hydroxylase (cytochrome P450 family 24 subfamily A member 1) mRNA expression is up-regulated by 25(OH)D3 at 250–500 nM and by 1α,25-(OH)2D3 at 1–10 nM. 25(OH)D3 and 1α,25-(OH)2D3 at a time-dependent manner alter cell morphology towards osteoblast-associated characteristics. The osteogenic markers, alkaline phosphatase, secreted phosphoprotein 1 (osteopontin), and bone gamma-carboxyglutamate protein (osteocalcin) are increased by 25(OH)D3 and 1α,25-(OH)2D3 in a dose-dependent manner. Finally, mineralisation is significantly increased by 25(OH)D3 but not by 1α,25-(OH)2D3. Moreover, we found that hMSCs express very low level of 25(OH)D3-1α-hydroxylase (cytochrome P450 family 27 subfamily B member 1), and there is no detectable 1α,25-(OH)2D3 product. Taken together, our findings provide evidence that 25(OH)D3 at 250–500 nM can induce osteogenic differentiation and that 25(OH)D3 has great potential for cell-based bone tissue engineering. PMID:28211493

  2. IEC-^3He Breeder for D-^3He Satellite Systems.

    NASA Astrophysics Data System (ADS)

    Chacon, L.; Miley, G. H.

    1996-11-01

    D-^3He fusion minimizes neutrons and maximizes charged fusion products, enabling increased energy recovery efficiency by direct conversion. However, scarce ^3He terrestrial resources have deterred R&D on this alternative. Here, we explore ^3He production through Inertial Electrostatic Confinement^1 (IEC) D-breeders, which supply ^3He to FRC D-^3He satellite reactors.^2 Favorable features for the IEC breeder include simplicity, low cost, easy extraction of fusion products, and compatibility with direct conversion. The breeder-satellite system energy balance is analyzed taking the net energy gain of the overall system, Q_N, as the figure of merit. Breeding is applicable for systems where the satellite Q-value, Q_S, > the breeder Q-value, Q_B. For improved performance, i.e., for high Q_N, QS >= QB >> 1 is needed; however, lower QB values (typical of the IEC) are permissible and still offer sufficient Q_N. An economic study determined breeding produces ^3He at a cost comparable to lunar ^3He, already shown to lead to competitive power.^3 The cost of electricity (COE) for the breeder-satellite complex was compared with the ARTEMIS COE,^4 using lunar ^3He fuel: assuming one satellite (1000 MWe)/breeder (170 MWe), the ratio of the breeding system COE to the lunar mining base COE is ~ 1.2. However, economic breeding is driven by large IEC breeder powers, i.e., increased ^3He breeding rates. Thus, the COE ratio approaches unity with two or three satellites/breeder, requiring increased breeder size and power (340 MWe for 2 satellites, 510 MWe for 3 satellites). Such systems potentially provide a ``bridge'' to a future lunar ^3He economy. 1. G.H. Miley et al., Dense Z-pinches, AIP Conf. 299, AIP Press, 675-689 (1994). 2. G.H. Miley, Nucl. Instrum. Methods, A271, 197-202 (1988). 3. L.J. Wittenberg et al., Fusion Technol., 10, 167-178 (1986). 4. H. Momota et al., Fusion Technol., 21, 2307-2323 (1992).

  3. Effects of 1,25(OH)2D3 and 25(OH)D3 on C2C12 Myoblast Proliferation, Differentiation, and Myotube Hypertrophy

    PubMed Central

    van der Meijden, K.; Bravenboer, N.; Dirks, N.F.; Heijboer, A.C.; den Heijer, M.; de Wit, G.M.J.; Offringa, C.; Lips, P.

    2016-01-01

    An adequate vitamin D status is essential to optimize muscle strength. However, whether vitamin D directly reduces muscle fiber atrophy or stimulates muscle fiber hypertrophy remains subject of debate. A mechanism that may affect the role of vitamin D in the regulation of muscle fiber size is the local conversion of 25(OH)D to 1,25(OH)2D by 1α‐hydroxylase. Therefore, we investigated in a murine C2C12 myoblast culture whether both 1,25(OH)2D3 and 25(OH)D3 affect myoblast proliferation, differentiation, and myotube size and whether these cells are able to metabolize 25(OH)D3 and 1,25(OH)2D3. We show that myoblasts not only responded to 1,25(OH)2D3, but also to the precursor 25(OH)D3 by increasing their VDR mRNA expression and reducing their proliferation. In differentiating myoblasts and myotubes 1,25(OH)2D3 as well as 25(OH)D3 stimulated VDR mRNA expression and in myotubes 1,25(OH)2D3 also stimulated MHC mRNA expression. However, this occurred without notable effects on myotube size. Moreover, no effects on the Akt/mTOR signaling pathway as well as MyoD and myogenin mRNA levels were observed. Interestingly, both myoblasts and myotubes expressed CYP27B1 and CYP24 mRNA which are required for vitamin D3 metabolism. Although 1α‐hydroxylase activity could not be shown in myotubes, after treatment with 1,25(OH)2D3 or 25(OH)D3 myotubes showed strongly elevated CYP24 mRNA levels compared to untreated cells. Moreover, myotubes were able to convert 25(OH)D3 to 24R,25(OH)2D3 which may play a role in myoblast proliferation and differentiation. These data suggest that skeletal muscle is not only a direct target for vitamin D3 metabolites, but is also able to metabolize 25(OH)D3 and 1,25(OH)2D3. J. Cell. Physiol. 231: 2517–2528, 2016. © 2016 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc. PMID:27018098

  4. Effects of 1,25(OH)2 D3 and 25(OH)D3 on C2C12 Myoblast Proliferation, Differentiation, and Myotube Hypertrophy.

    PubMed

    van der Meijden, K; Bravenboer, N; Dirks, N F; Heijboer, A C; den Heijer, M; de Wit, G M J; Offringa, C; Lips, P; Jaspers, R T

    2016-11-01

    An adequate vitamin D status is essential to optimize muscle strength. However, whether vitamin D directly reduces muscle fiber atrophy or stimulates muscle fiber hypertrophy remains subject of debate. A mechanism that may affect the role of vitamin D in the regulation of muscle fiber size is the local conversion of 25(OH)D to 1,25(OH)2 D by 1α-hydroxylase. Therefore, we investigated in a murine C2C12 myoblast culture whether both 1,25(OH)2 D3 and 25(OH)D3 affect myoblast proliferation, differentiation, and myotube size and whether these cells are able to metabolize 25(OH)D3 and 1,25(OH)2 D3 . We show that myoblasts not only responded to 1,25(OH)2 D3 , but also to the precursor 25(OH)D3 by increasing their VDR mRNA expression and reducing their proliferation. In differentiating myoblasts and myotubes 1,25(OH)2 D3 as well as 25(OH)D3 stimulated VDR mRNA expression and in myotubes 1,25(OH)2 D3 also stimulated MHC mRNA expression. However, this occurred without notable effects on myotube size. Moreover, no effects on the Akt/mTOR signaling pathway as well as MyoD and myogenin mRNA levels were observed. Interestingly, both myoblasts and myotubes expressed CYP27B1 and CYP24 mRNA which are required for vitamin D3 metabolism. Although 1α-hydroxylase activity could not be shown in myotubes, after treatment with 1,25(OH)2 D3 or 25(OH)D3 myotubes showed strongly elevated CYP24 mRNA levels compared to untreated cells. Moreover, myotubes were able to convert 25(OH)D3 to 24R,25(OH)2 D3 which may play a role in myoblast proliferation and differentiation. These data suggest that skeletal muscle is not only a direct target for vitamin D3 metabolites, but is also able to metabolize 25(OH)D3 and 1,25(OH)2 D3 . J. Cell. Physiol. 231: 2517-2528, 2016. © 2016 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc. © 2016 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc.

  5. Highly Selective Dopamine D3 Receptor (D3R) Antagonists and Partial Agonists Based on Eticlopride and the D3R Crystal Structure: New Leads for Opioid Dependence Treatment.

    PubMed

    Kumar, Vivek; Bonifazi, Alessandro; Ellenberger, Michael P; Keck, Thomas M; Pommier, Elie; Rais, Rana; Slusher, Barbara S; Gardner, Eliot; You, Zhi-Bing; Xi, Zheng-Xiong; Newman, Amy Hauck

    2016-08-25

    The recent and precipitous increase in opioid analgesic abuse and overdose has inspired investigation of the dopamine D3 receptor (D3R) as a target for therapeutic intervention. Metabolic instability or predicted toxicity has precluded successful translation of previously reported D3R-selective antagonists to clinical use for cocaine abuse. Herein, we report a series of novel and D3R crystal structure-guided 4-phenylpiperazines with exceptionally high D3R affinities and/or selectivities with varying efficacies. Lead compound 19 was selected based on its in vitro profile: D3R Ki = 6.84 nM, 1700-fold D3R versus D2R binding selectivity, and its metabolic stability in mouse microsomes. Compound 19 inhibited oxycodone-induced hyperlocomotion in mice and reduced oxycodone-induced locomotor sensitization. In addition, pretreatment with 19 also dose-dependently inhibited the acquisition of oxycodone-induced conditioned place preference (CPP) in rats. These findings support the D3R as a target for opioid dependence treatment and compound 19 as a new lead molecule for development.

  6. Projection-slice theorem based 2D-3D registration

    NASA Astrophysics Data System (ADS)

    van der Bom, M. J.; Pluim, J. P. W.; Homan, R.; Timmer, J.; Bartels, L. W.

    2007-03-01

    In X-ray guided procedures, the surgeon or interventionalist is dependent on his or her knowledge of the patient's specific anatomy and the projection images acquired during the procedure by a rotational X-ray source. Unfortunately, these X-ray projections fail to give information on the patient's anatomy in the dimension along the projection axis. It would be very profitable to provide the surgeon or interventionalist with a 3D insight of the patient's anatomy that is directly linked to the X-ray images acquired during the procedure. In this paper we present a new robust 2D-3D registration method based on the Projection-Slice Theorem. This theorem gives us a relation between the pre-operative 3D data set and the interventional projection images. Registration is performed by minimizing a translation invariant similarity measure that is applied to the Fourier transforms of the images. The method was tested by performing multiple exhaustive searches on phantom data of the Circle of Willis and on a post-mortem human skull. Validation was performed visually by comparing the test projections to the ones that corresponded to the minimal value of the similarity measure. The Projection-Slice Theorem Based method was shown to be very effective and robust, and provides capture ranges up to 62 degrees. Experiments have shown that the method is capable of retrieving similar results when translations are applied to the projection images.

  7. Association study of dopamine D3 receptor gene and schizophrenia

    SciTech Connect

    Kennedy, J.L.; Billett, E.A.; Macciardi, F.M.

    1995-12-18

    Several groups have reported an association between schizophrenia and the MscI polymorphism in the first exon of the dopamine D3 receptor gene (DRD3). We studied this polymorphism using a North American sample (117 patients plus 188 controls) and an Italian sample (97 patients plus 64 controls). In the first part of the study, we compared allele frequencies of schizophrenia patients and unmatched controls and observed a significant difference in the total sample (P = 0.01). The second part of the study involved a case control approach in which each schizophrenia patient was matched to a control of the same sex, and of similar age and ethnic background. The DRD3 allele frequencies of patients and controls revealed no significant difference between the two groups in the Italian (N = 53) or the North American (N = 54) matched populations; however, when these two matched samples were combined, a significant difference was observed (P = 0.026). Our results suggest that the MscI polymorphism may be associated with schizophrenia in the populations studied. 32 refs., 2 tabs.

  8. Ammonia Induces Autophagy through Dopamine Receptor D3 and MTOR.

    PubMed

    Li, Zhiyuan; Ji, Xinmiao; Wang, Wenchao; Liu, Juanjuan; Liang, Xiaofei; Wu, Hong; Liu, Jing; Eggert, Ulrike S; Liu, Qingsong; Zhang, Xin

    2016-01-01

    Hyperammonemia is frequently seen in tumor microenvironments as well as in liver diseases where it can lead to severe brain damage or death. Ammonia induces autophagy, a mechanism that tumor cells may use to protect themselves from external stresses. However, how cells sense ammonia has been unclear. Here we show that culture medium alone containing Glutamine can generate milimolar of ammonia at 37 degrees in the absence of cells. In addition, we reveal that ammonia acts through the G protein-coupled receptor DRD3 (Dopamine receptor D3) to induce autophagy. At the same time, ammonia induces DRD3 degradation, which involves PIK3C3/VPS34-dependent pathways. Ammonia inhibits MTOR (mechanistic target of Rapamycin) activity and localization in cells, which is mediated by DRD3. Therefore, ammonia has dual roles in autophagy: one to induce autophagy through DRD3 and MTOR, the other to increase autophagosomal pH to inhibit autophagic flux. Our study not only adds a new sensing and output pathway for DRD3 that bridges ammonia sensing and autophagy induction, but also provides potential mechanisms for the clinical consequences of hyperammonemia in brain damage, neurodegenerative diseases and tumors.

  9. Ammonia Induces Autophagy through Dopamine Receptor D3 and MTOR

    PubMed Central

    Li, Zhiyuan; Ji, Xinmiao; Wang, Wenchao; Liu, Juanjuan; Liang, Xiaofei; Wu, Hong; Liu, Jing; Eggert, Ulrike S.; Liu, Qingsong

    2016-01-01

    Hyperammonemia is frequently seen in tumor microenvironments as well as in liver diseases where it can lead to severe brain damage or death. Ammonia induces autophagy, a mechanism that tumor cells may use to protect themselves from external stresses. However, how cells sense ammonia has been unclear. Here we show that culture medium alone containing Glutamine can generate milimolar of ammonia at 37 degrees in the absence of cells. In addition, we reveal that ammonia acts through the G protein-coupled receptor DRD3 (Dopamine receptor D3) to induce autophagy. At the same time, ammonia induces DRD3 degradation, which involves PIK3C3/VPS34-dependent pathways. Ammonia inhibits MTOR (mechanistic target of Rapamycin) activity and localization in cells, which is mediated by DRD3. Therefore, ammonia has dual roles in autophagy: one to induce autophagy through DRD3 and MTOR, the other to increase autophagosomal pH to inhibit autophagic flux. Our study not only adds a new sensing and output pathway for DRD3 that bridges ammonia sensing and autophagy induction, but also provides potential mechanisms for the clinical consequences of hyperammonemia in brain damage, neurodegenerative diseases and tumors. PMID:27077655

  10. 2D/3D registration algorithm for lung brachytherapy

    SciTech Connect

    Zvonarev, P. S.; Farrell, T. J.; Hunter, R.; Wierzbicki, M.; Hayward, J. E.; Sur, R. K.

    2013-02-15

    Purpose: A 2D/3D registration algorithm is proposed for registering orthogonal x-ray images with a diagnostic CT volume for high dose rate (HDR) lung brachytherapy. Methods: The algorithm utilizes a rigid registration model based on a pixel/voxel intensity matching approach. To achieve accurate registration, a robust similarity measure combining normalized mutual information, image gradient, and intensity difference was developed. The algorithm was validated using a simple body and anthropomorphic phantoms. Transfer catheters were placed inside the phantoms to simulate the unique image features observed during treatment. The algorithm sensitivity to various degrees of initial misregistration and to the presence of foreign objects, such as ECG leads, was evaluated. Results: The mean registration error was 2.2 and 1.9 mm for the simple body and anthropomorphic phantoms, respectively. The error was comparable to the interoperator catheter digitization error of 1.6 mm. Preliminary analysis of data acquired from four patients indicated a mean registration error of 4.2 mm. Conclusions: Results obtained using the proposed algorithm are clinically acceptable especially considering the complications normally encountered when imaging during lung HDR brachytherapy.

  11. Efficacy of Vitamin D3 Supplementation on Osseointegration of Implants.

    PubMed

    Javed, Fawad; Malmstrom, Hans; Kellesarian, Sergio Varela; Al-Kheraif, Abdulaziz A; Vohra, Fahim; Romanos, Georgios E

    2016-04-01

    The aim was to systematically review the efficacy of vitamin D3 (VD3) supplementation on the osseointegration of implants. The addressed focused question was "does VD3 supplementation affect osseointegration around implants?" Indexed databases were searched from 1969 up to and including March 2015 using various key words including: "Bone to implant contact"; "implant"; "vitamin D"; and "osseointegration." Letters to the editor, case reports/case series, reviews, and articles published in languages other than English were excluded. The pattern of the present systematic review was customized to primarily summarize the pertinent data. Six experimental studies (4 in rodents and 2 in rabbits) were included. Number of titanium implants placed ranged between 28 and 100 implants. Results from 5 studies showed that VD3 supplementation enhanced new bone formation and/or bone to implant contact (BIC) around implants. One study showed no significant difference in BIC and new bone formation around VD3 coated and noncoated implants. One study reported that insulin therapy with adjunct VD3 supplementation enhances new bone formation around implants in diabetic rats than when insulin replacement therapy is used alone. Efficacy of VD3 supplementation on osseointegration of implants remains controversial and requires further investigations.

  12. D3-instantons, mock theta series and twistors

    NASA Astrophysics Data System (ADS)

    Alexandrov, Sergei; Manschot, Jan; Pioline, Boris

    2013-04-01

    The D-instanton corrected hypermultiplet moduli space of type II string theory compactified on a Calabi-Yau threefold is known in the type IIA picture to be determined in terms of the generalized Donaldson-Thomas invariants, through a twistorial construction. At the same time, in the mirror type IIB picture, and in the limit where only D3-D1-D(-1)-instanton corrections are retained, it should carry an isometric action of the S-duality group SL(2, {Z} ). We prove that this is the case in the one-instanton approximation, by constructing a holomorphic action of SL(2, {Z} ) on the linearized twistor space. Using the modular invariance of the D4-D2-D0 black hole partition function, we show that the standard Darboux coordinates in twistor space have modular anomalies controlled by period integrals of a Siegel-Narain theta series, which can be canceled by a contact transformation generated by a holomorphic mock theta series.

  13. Total synthesis of biologically active 20S-hydroxyvitamin D3

    PubMed Central

    Wang, Qinghui; Lin, Zongtao; Kim, Tae-Kang; Slominski, Andrzej T.; Miller, Duane D.; Li, Wei

    2015-01-01

    A total synthetic strategy of 20S-hydroxyvitamin D3 [20S-(OH)D3] involving modified synthesis of key intermediates 7 and 12, Grignard reaction to stereoseletively generate 20S-OH and Wittig-Horner coupling to establish D3 framework, was completed in 16 steps with an overall yield of 0.4 %. The synthetic 20S-(OH)D3 activated vitamin D receptor (VDR) and initiated the expression of downstream genes. In addition, 20S-(OH)D3 showed similar inhibitory potency as calcitriol [1,25(OH)2D3] on proliferation of melanoma cells. PMID:26433048

  14. Activity of various hydroxylated vitamin D3 analogs for improving phosphorus utilisation in chicks receiving diets adequate in vitamin D3.

    PubMed

    Biehl, R R; Baker, D H; Deluca, H F

    1998-07-01

    1. Young chicks were used to evaluate the efficacy of 2 new vitamin D3 analogs relative to 1 alpha-hydroxycholecalciferol (1 alpha-OH D3) for their ability to improve the bioavailability of phytate-bound phosphorus (P) when added to P-deficient maize-soyabean meal diets that were superadequate in cholecalciferol. 2. Both 20-epi-19-nor-1,25-(OH)2 D3 and 20-epi-19-nor-1 alpha-OH D3 were observed to have phytate-P releasing activity, as measured by bone ash responses. 3. However, the bioactivity of the 2 new analogs differed when compared with 1 alpha-OH D3. The 20-epi-19-nor-1 alpha-OH D3 analog had a lower (P < 0.05) phytate-P releasing activity (45%) than either 1 alpha-OH D3 of 20-epi-19-nor-1,25-(OH)2 D3, which did not differ. 4. A dietary concentration of 10 to 15 micrograms/kg 1 alpha-OH D3 was found to optimize phytate-P utilisation in 2-week-old chicks.

  15. Vitamin D deficiency as a public health issue: using vitamin D2 or vitamin D3 in future fortification strategies.

    PubMed

    Wilson, Louise R; Tripkovic, Laura; Hart, Kathryn H; Lanham-New, Susan A

    2017-03-28

    The role of vitamin D in supporting the growth and maintenance of the skeleton is robust; with recent research also suggesting a beneficial link between vitamin D and other non-skeletal health outcomes, including immune function, cardiovascular health and cancer. Despite this, vitamin D deficiency remains a global public health issue, with a renewed focus in the UK following the publication of Public Health England's new Dietary Vitamin D Requirements. Natural sources of vitamin D (dietary and UVB exposure) are limited, and thus mechanisms are needed to allow individuals to achieve the new dietary recommendations. Mandatory or voluntary vitamin D food fortification may be one of the mechanisms to increase dietary vitamin D intakes and subsequently improve vitamin D status. However, for the food industry and public to make informed decisions, clarity is needed as to whether vitamins D2 and D3 are equally effective at raising total 25-hydroxyvitamin D (25(OH)D) concentrations as the evidence thus far is inconsistent. This review summarises the evidence to date behind the comparative efficacy of vitamins D2 and D3 at raising 25(OH)D concentrations, and the potential role of vitamin D food fortification as a public health policy to support attainment of dietary recommendations in the UK. The comparative efficacy of vitamins D2 and D3 has been investigated in several intervention trials, with most indicating that vitamin D3 is more effective at raising 25(OH)D concentrations. However, flaws in study designs (predominantly under powering) mean there remains a need for a large, robust randomised-controlled trial to provide conclusive evidence, which the future publication of the D2-D3 Study should provide (BBSRC DRINC funded: BB/I006192/1). This review also highlights outstanding questions and gaps in the research that need to be addressed to ensure the most efficacious and safe vitamin D food fortification practices are put in place. This further research, alongside cost

  16. Effect of vitamin D3 on self-perceived fatigue

    PubMed Central

    Nowak, Albina; Boesch, Lukas; Andres, Erik; Battegay, Edouard; Hornemann, Thorsten; Schmid, Christoph; Bischoff-Ferrari, Heike A.; Suter, Paolo M.; Krayenbuehl, Pierre-Alexandre

    2016-01-01

    Abstract Background: Vitamin D deficiency is frequent and has been associated with fatigue in uncontrolled trials. Methods: This is the first double-blind placebo-controlled clinical trial to investigate the efficacy of per os vitamin D3 (cholecalciferol) in treating fatigue among otherwise healthy persons with low serum 25-hydroxyvitamin D (25(OH)D) levels. We enrolled 120 individuals (mean age 29 ± 6 years, 53% women) presenting with fatigue and vitamin D deficiency (serum 25(OH)D < 20 μg/L). Participants were randomized to a single oral dose of 100,000 units of vitamin D or placebo. The primary endpoint was intra-individual change in the fatigue assessment scale (FAS) at 4 weeks after treatment. Result: The mean age of the participants was 29 ± 6 years, 53% were women. Mean FAS decreased significantly more in the vitamin D group (−3.3 ± 5.3; 95% confidence interval [CI] for change −14.1 to 4.1) compared with placebo (−0.8 ± 5.3; 95% CI for change −9.0 to 8.7); (P = 0.01). Amelioration of fatigue was reported more frequently in vitamin D than in placebo group (42 [72%] vs. 31 [50%]; P = 0.01; odds ratio [OR] 2.63, 95% CI for OR 1.23–5.62). Among all participants, improvement in fatigue score correlated with the rise in 25(OH)D level (R = −0.22, P = 0.02). Conclusion: Vitamin D treatment significantly improved fatigue in otherwise healthy persons with vitamin D deficiency. This study was registered at the www.ClinicalTrials.gov Protocol ID NCT02022475. PMID:28033244

  17. Interactive client side data visualization with d3.js

    NASA Astrophysics Data System (ADS)

    Rodzianko, A.; Versteeg, R.; Johnson, D. V.; Soltanian, M. R.; Versteeg, O. J.; Girouard, M.

    2015-12-01

    Geoscience data associated with near surface research and operational sites is increasingly voluminous and heterogeneous (both in terms of providers and data types - e.g. geochemical, hydrological, geophysical, modeling data, of varying spatiotemporal characteristics). Such data allows scientists to investigate fundamental hydrological and geochemical processes relevant to agriculture, water resources and climate change. For scientists to easily share, model and interpret such data requires novel tools with capabilities for interactive data visualization. Under sponsorship of the US Department of Energy, Subsurface Insights is developing the Predictive Assimilative Framework (PAF): a cloud based subsurface monitoring platform which can manage, process and visualize large heterogeneous datasets. Over the last year we transitioned our visualization method from a server side approach (in which images and animations were generated using Jfreechart and Visit) to a client side one that utilizes the D3 Javascript library. Datasets are retrieved using web service calls to the server, returned as JSON objects and visualized within the browser. Users can interactively explore primary and secondary datasets from various field locations. Our current capabilities include interactive data contouring and heterogeneous time series data visualization. While this approach is very powerful and not necessarily unique, special attention needs to be paid to latency and responsiveness issues as well as to issues as cross browser code compatibility so that users have an identical, fluid and frustration-free experience across different computational platforms. We gratefully acknowledge support from the US Department of Energy under SBIR Award DOE DE-SC0009732, the use of data from the Lawrence Berkeley National Laboratory (LBNL) Sustainable Systems SFA Rifle field site and collaboration with LBNL SFA scientists.

  18. Brazilian Valuation of EQ-5D-3L Health States: Results from a Saturation Study.

    PubMed

    Santos, Marisa; Cintra, Monica A C T; Monteiro, Andrea L; Santos, Braulio; Gusmão-Filho, Fernando; Andrade, Mônica Viegas; Noronha, Kenya; Cruz, Luciane N; Camey, Suzi; Tura, Bernardo; Kind, Paul

    2016-02-01

    Most EQ-5D-3L valuation studies include the same sample of health states that was used in the protocol of the original UK Measurement and Valuation of Health (MVH) study. Thus far, no studies using a time tradeoff utility elicitation method have been carried out using all 243 EQ-5D health states. Because the values and preferences regarding health outcomes differ among countries, it is essential to have country-specific data to enable local high-level decisions regarding resource allocation. This study developed a country-specific set of values for EQ-5D-3L health states. A multicentric study was conducted in 4 Brazilian areas. A probabilistic sample of the general population, aged 18 to 64 y, stratified by age and gender, was surveyed. The interview followed a revised version of the MVH protocol, in which all 243 health states were valued. Each respondent ranked and valued 7 health states using the TTO in a home interview. Data were collected from 9148 subjects. The best-fitting regression model was an individual-level mixed-effects model without any interaction terms. The dimensions "Mobility" and "Usual Activities" were associated with higher losses in health state utility value. The "Anxiety/Depression" dimension was the domain that contributed to lower losses in health state utility value. This study generated significant insight into the Brazilian population's health preferences that can be applied to health technology assessment and economic analyses in Brazil. This information represents an important new tool that can be used in Brazilian health policy creation and evaluation. © The Author(s) 2015.

  19. Serum Concentrations of 1,25-Dihydroxyvitamin D2 and 1,25-Dihydroxyvitamin D3 in Response to Vitamin D2 and Vitamin D3 Supplementation

    PubMed Central

    Biancuzzo, Rachael M.; Clarke, Nigel; Reitz, Richard E.; Travison, Thomas G.

    2013-01-01

    Objective: The purpose of this study was to determine 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and 1,25-dihydroxyvitamin D2 [1,25(OH)2D2] levels in healthy adults consuming 1000 IU vitamin D2 or vitamin D3 per day for 11 weeks. Subjects and Design: Blood from 34 healthy male and female adults, aged 18 to 79 years, from a placebo-controlled, double-blind study who received a placebo, 1000 IU vitamin D3, or 1000 IU vitamin D2 daily for 11 weeks at end of winter was analyzed. Serum levels of 25-hydroxyvitamin D2, 25-hydroxyvitamin D3, 1,25(OH)2D2, and 1,25(OH)2D3 were determined by liquid chromatography–tandem mass spectroscopy. Results: Of the adults, 82% were vitamin D insufficient (serum 25-hydroxyvitamin D [25(OH)D <30 ng/mL]) at the start of the study. Administration of vitamin D2 and vitamin D3 induced similar increases in total 25(OH)D as well as in 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3, respectively. Compared with placebo and adjusting for baseline levels, 1000 IU daily of vitamin D2 was associated with a mean increase of 7.4 pg/mL (95% confidence interval, 4.4–10.3) in 1,25(OH)2D2, which was accompanied by a mean decrease of 9.9 pg/mL (−15.8 to −4.0) in 1,25(OH)2D3. No such differences accompanied administration of 1000 IU daily of vitamin D3. Conclusion: Vitamin D2 and vitamin D3 were effective in raising and maintaining total serum concentrations of 25(OH)D. Ingestion of vitamin D2 also resulted in an increase in serum concentrations of 1,25(OH)2D2. This increase was accompanied by a comparable decrease in serum concentrations of 1,25(OH)2D3; therefore, the total 1,25-dihydroxyvitamin D [1,25(OH)2D] concentrations did not significantly change after 11 weeks compared with baseline levels. Ingestion of vitamin D3 did not alter serum concentrations of 1,25(OH)2D3 or total 1,25(OH)2D. Therefore, ingestion of 1000 IU vitamin D2 or vitamin D3 for 11 weeks was effective in raising total serum concentrations of 25(OH)D as well as sustaining serum

  20. Serum concentrations of 1,25-dihydroxyvitamin D2 and 1,25-dihydroxyvitamin D3 in response to vitamin D2 and vitamin D3 supplementation.

    PubMed

    Biancuzzo, Rachael M; Clarke, Nigel; Reitz, Richard E; Travison, Thomas G; Holick, Michael F

    2013-03-01

    The purpose of this study was to determine 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and 1,25-dihydroxyvitamin D2 [1,25(OH)2D2] levels in healthy adults consuming 1000 IU vitamin D2 or vitamin D3 per day for 11 weeks. Blood from 34 healthy male and female adults, aged 18 to 79 years, from a placebo-controlled, double-blind study who received a placebo, 1000 IU vitamin D3, or 1000 IU vitamin D2 daily for 11 weeks at end of winter was analyzed. Serum levels of 25-hydroxyvitamin D2, 25-hydroxyvitamin D3, 1,25(OH)2D2, and 1,25(OH)2D3 were determined by liquid chromatography-tandem mass spectroscopy. Of the adults, 82% were vitamin D insufficient (serum 25-hydroxyvitamin D [25(OH)D <30 ng/mL]) at the start of the study. Administration of vitamin D2 and vitamin D3 induced similar increases in total 25(OH)D as well as in 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3, respectively. Compared with placebo and adjusting for baseline levels, 1000 IU daily of vitamin D2 was associated with a mean increase of 7.4 pg/mL (95% confidence interval, 4.4-10.3) in 1,25(OH)2D2, which was accompanied by a mean decrease of 9.9 pg/mL (-15.8 to -4.0) in 1,25(OH)2D3. No such differences accompanied administration of 1000 IU daily of vitamin D3. Vitamin D2 and vitamin D3 were effective in raising and maintaining total serum concentrations of 25(OH)D. Ingestion of vitamin D2 also resulted in an increase in serum concentrations of 1,25(OH)2D2. This increase was accompanied by a comparable decrease in serum concentrations of 1,25(OH)2D3; therefore, the total 1,25-dihydroxyvitamin D [1,25(OH)2D] concentrations did not significantly change after 11 weeks compared with baseline levels. Ingestion of vitamin D3 did not alter serum concentrations of 1,25(OH)2D3 or total 1,25(OH)2D. Therefore, ingestion of 1000 IU vitamin D2 or vitamin D3 for 11 weeks was effective in raising total serum concentrations of 25(OH)D as well as sustaining serum concentrations of total 1,25(OH)2D.

  1. Hooked on the D3 receptor: CaMKII's new addiction.

    PubMed

    Hell, Johannes W

    2009-02-12

    The dopaminergic D3 receptor (D3R) is emerging as an antagonist of sensitized behavior induced by addictive drugs such as cocaine. New work by Wang and coworkers in this issue of Neuron now identifies CaMKII as an important negative regulator of the D3R. CaMKII relieves the D3R-mediated inhibition on sensitized behavior to foster drug-seeking behavior.

  2. 42 CFR 51d.3 - Who is eligible for an award under this subpart?

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false Who is eligible for an award under this subpart? 51d.3 Section 51d.3 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS MENTAL HEALTH AND SUBSTANCE ABUSE EMERGENCY RESPONSE PROCEDURES § 51d.3 Who is eligible for...

  3. 42 CFR 51d.3 - Who is eligible for an award under this subpart?

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false Who is eligible for an award under this subpart? 51d.3 Section 51d.3 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS MENTAL HEALTH AND SUBSTANCE ABUSE EMERGENCY RESPONSE PROCEDURES § 51d.3 Who is eligible for...

  4. 42 CFR 51d.3 - Who is eligible for an award under this subpart?

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false Who is eligible for an award under this subpart? 51d.3 Section 51d.3 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS MENTAL HEALTH AND SUBSTANCE ABUSE EMERGENCY RESPONSE PROCEDURES § 51d.3 Who is eligible for...

  5. 42 CFR 51d.3 - Who is eligible for an award under this subpart?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Who is eligible for an award under this subpart? 51d.3 Section 51d.3 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS MENTAL HEALTH AND SUBSTANCE ABUSE EMERGENCY RESPONSE PROCEDURES § 51d.3 Who is eligible for...

  6. 42 CFR 51d.3 - Who is eligible for an award under this subpart?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false Who is eligible for an award under this subpart? 51d.3 Section 51d.3 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS MENTAL HEALTH AND SUBSTANCE ABUSE EMERGENCY RESPONSE PROCEDURES § 51d.3 Who is eligible for...

  7. Green Tea Polyphenols and Vitamin D3 Protect Bone Microarchitecture in Female Rats with Chronic Inflammation

    USDA-ARS?s Scientific Manuscript database

    Our recent study showed that green tea polyphenols (GTP) in conjunction with 1-a-OH¬vit-D3 (vitD3) treatment mitigates lipopolysaccharide (LPS)-induced bone mineral density loss in female rats. This study was undertaken to further explore the mechanism and bone microarchitecture of GTP plus vitD3 in...

  8. 22 CFR 40.301 - Waiver for ineligible nonimmigrants under INA 212(d)(3)(A).

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 212(d)(3)(A). 40.301 Section 40.301 Foreign Relations DEPARTMENT OF STATE VISAS REGULATIONS PERTAINING... Ground of Ineligibility § 40.301 Waiver for ineligible nonimmigrants under INA 212(d)(3)(A). (a) Report... Homeland Security pursuant to the provisions of INA 212(d)(3)(A) in the case of an alien who...

  9. SU-E-T-199: How Number of Control Points Influences the Dynamic IMRT Plan Quality and Deliverability

    SciTech Connect

    Sharma, S; Manigandan, D; Chander, S; Subramani, V; Julka, P; Rath, G

    2014-06-01

    Purpose: To study the influence of number of control points on plan quality and deliverability. Methods: Five previously treated patients of carcinoma of rectum were selected. Planning target volume (PTV) and organs at risk (OARs) i.e. bladder and bowel were contoured. Dynamic IMRT plans (6MV, 7-fields, 45Gy/25 fractions and prescribed at 95% isodose) were created in Eclipse (Varian medical system, Palo Alto, CA) treatment planning system (TPS) for Varian CL2300C/D linear-accelerator. Base plan was calculated with 166 control points, variable mode (Eclipse Default). For generating other plans, all parameters were kept constant, only number of control points (Fixed mode) was varied as follows: 100, 166 and 200. Then, plan quality was analyzed in terms of maximum and mean dose received by the PTV and OARs. For plan deliverability, TPS calculated fluence was verified with I’matriXX (IBA Dosimetry, Germany) array and compared with TPS dose-plane using gamma index criteria of 3% dose difference and 3mm distance to agreement (DTA). Total number of monitor units (MU) required to deliver a plan was also noted. Results: The maximum variation for the PTV maximum with respect to eclipse default control point (166) was 0.28% (0.14Gy). Similarly, PTV mean varied only up to 0.22 %( 0.11Gy). Bladder maximum and bladder mean varied up to 0.51% (0.24Gy) and 0.16% (0.06Gy). The variation for the bowel maximum and bowel mean was also only 0.39% (0.19Gy) and 0.33% (0.04Gy). Total MU was within 0.32 % (4MU). Average gamma pass rate using different control points for five patients are 98.75±0.33%, 99.37±0.09%, 99.29±0.12%, 98.14±0.13% and 99.25±0.14% respectively. Conclusion: Slight variation (<1%) in PTV and OARs maximum and mean doses was observed with varying number of control points. Monitor unit was also not varied much. Reducing number of control points did not showed any comprise in plan deliverability in terms of gamma index pass rate.

  10. YQA14: a novel dopamine D3 receptor antagonist that inhibits cocaine self-administration in rats and mice, but not in D3 receptor-knockout mice

    PubMed Central

    Song, Rui; Yang, Ri-Fang; Wu, Ning; Su, Rui-Bin; Li, Jin; Peng, Xiao-Qing; Li, Xia; Gaál, József; Xi, Zheng-Xiong; Gardner, Eliot L.

    2017-01-01

    The dopamine (DA) D3 receptor is posited to be importantly involved in drug reward and addiction, and D3 receptor antagonists have shown extraordinary promise as potential anti-addiction pharmacotherapeutic agents in animal models of drug addiction. SB-277011A is the best characterized D3 receptor antagonist in such models. However, the potential use of SB-277011A in humans is precluded by pharmacokinetic and toxicity problems. We here report a novel D3 receptor antagonist YQA14 that shows similar pharmacological properties as SB-277011A. In vitro receptor binding assays suggest that YQA14 has two binding sites on human cloned D3 receptors with Ki-High (0.68 × 10−4 nM) and Ki-Low (2.11 nM), and displays > 150-fold selectivity for D3 over D2 receptors and > 1000-fold selectivity for D3 over other DA receptors. Systemic administration of YQA14 (6.25–25 mg/kg) or SB-277011A (12.5–25 mg/kg) significantly and dose-dependently reduced intravenous cocaine self-administration under both low fixed-ratio and progressive-ratio reinforcement conditions in rats, while failing to alter oral sucrose self-administration and locomotor activity, suggesting a selective inhibition of drug reward. However, when the drug dose was increased to 50 mg/kg, YQA14 and SB-277011A significantly inhibited basal and cocaine-enhanced locomotion in rats. Finally, both D3 antagonists dose-dependently inhibited intravenous cocaine self-administration in wild-type mice, but not in D3 receptor-knockout mice, suggesting that their action is mediated by D3 receptor blockade. These findings suggest that YQA14 has a similar anti-addiction profile as SB-277011A, and deserves further study and development. PMID:21507153

  11. Sunlight regulates the cutaneous production of vitamin D3 by causing its photodegradation.

    PubMed

    Webb, A R; DeCosta, B R; Holick, M F

    1989-05-01

    Exposure to sunlight initiates the formation of vitamin D3 in skin as the UV B radiation in the solar spectrum causes the photoconversion of 7-dehydrocholesterol to previtamin D3. A heat-induced isomerization then converts previtamin D3 to vitamin D3 over a period of days. A number of irradiation products of vitamin D3 are known to form upon irradiation with high intensity UV radiation, but the effect of subsequent exposures to sunlight on the vitamin D3 formed in skin is not known. To investigate this phenomenon, human skin containing vitamin D3 was exposed to sunlight in Boston. A model system of [3H]vitamin D3 in methanol was also used to study the effects of sunlight on vitamin D3 throughout the year. Vitamin D3 proved to be exquisitely sensitive to sunlight, and once formed in the skin, exposure to sunlight resulted in its rapid photodegradation to a variety of photoproducts, including 5,6-transvitamin D3, suprasterol I, and suprasterol II.

  12. Metabolism of 25-hydroxyvitamin D3 by cultured pulmonary alveolar macrophages in sarcoidosis.

    PubMed Central

    Adams, J S; Sharma, O P; Gacad, M A; Singer, F R

    1983-01-01

    Metabolism of [3H]25-hydroxyvitamin D3(25-OH-D3) was studied in primary cultures of pulmonary alveolar macrophages (PAM) from seven patients with sarcoidosis and two patients with idiopathic pulmonary fibrosis. Production of a [3H]1,25-dihydroxyvitamin D3 (1,25-[OH]2-D3)-like metabolite of [3H]25-OH-D3 was detected in lipid extracts of cells from five patients with sarcoidosis. Synthesis of this compound in vitro was limited to viable PAM and was greatest in cells derived from a patient with hypercalcemia and an elevated serum concentration of 1,25-dihydroxyvitamin D. The tritiated PAM metabolite coeluted with authentic 1,25-(OH)2-D3 in three different solvent systems on straight-phase high performance liquid chromatography (HPLC) and demonstrated binding to extracted receptor for 1,25-(OH)2-D3, which was identical to that of commercially available [3H]1,25-(OH)2-D3 of comparable specific activity. Incubation of PAM with high concentrations of 25-OH-D3 resulted in production of an unlabeled metabolite that co-chromatographed with the 3H-PAM metabolite on HPLC and that was bound with high affinity by both the specific receptor for 1,25-(OH)2-D3 and antiserum to 1,25-(OH)2-D3. PMID:6688814

  13. Comparative effects of 1,25-dihydroxyvitamin D3 and EB 1089 on mouse renal and intestinal 25-hydroxyvitamin D3-24-hydroxylase.

    PubMed

    Roy, S; Martel, J; Tenenhouse, H S

    1995-12-01

    EB 1089 is a vitamin D analog that is less potent than 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in its calcemic action but more potent in its antiproliferative action. We characterized the interaction of 1,25(OH)2D3 and EB 1089 with renal 25-hydroxyvitamin D3-24-hydroxylase (24-hydroxylase), the first enzyme in the C-24 oxidation pathway, and compared the effects of 1,25(OH)2D3 and EB 1089 on induction of 24-hydroxylase mRNA in mouse kidney and intestine. 1,25(OH)2D3 and EB 1089 were competitive inhibitors of 24-hydroxylase activity. However, the Ki for 1,25(OH)2D3 (5.2 +/- 2.5 nM) was significantly lower than that for EB 1089 (286 +/- 59 nM). In the kidney, the time course and extent of 24-hydroxylase mRNA induction, relative to 18S rRNA, was similar for 1,25(OH)2D3 and EB 1089 with a peak response at approximately equal to 6 h that was sustained for at least 16 h. In the intestine, however, induction of 24-hydroxylase mRNA, relative to 18S rRNA, was approximately 50% lower for EB 1089 than for 1,25(OH)2D3 at 3 h (p < 0.05) and 6 h (p < 0.05) while at 16 h 24-hydroxylase mRNA was no longer detectable. Moreover, while both 1,25(OH)2D3 and EB 10898 elicited a similar dose-dependent induction of 24-hydroxylase mRNA in the kidney (EC50 = 0.4 +/- 0.13 and 0.3 +/- 0.08 ng/g for EB 1089 and 1,25(OH)2D3, respectively), the EC50 for EB 1089 (6.6 +/- 1.7 ng/g) was significantly higher than that for 1,25(OH)2D3 (0.9 +/- 0.32 ng/g) in the intestine (p < 0.01). EB 1089 was also less effective than 1,25(OH)2D3 in the induction of intestinal but not renal calbindin-D9k mRNA. To determine the mechanism for tissue-specific differences in potency, we determined the binding affinity of 1,25(OH)2D3 and EB 1089 for the vitamin D receptor. In the kidney, Kd values for 1,25(OH)2D3 (0.40 +/- 0.95 nM) and EB 1089 (0.48 +/- 0.04 nM) were not different. However, in the intestine, the Kd for EB 1089 (1.43 +/- 0.19 nM) was significantly higher than that for 1,25(OH)2D3 (0.85 +/- 0.06 nM; p < 0

  14. Photoactivable analogs for labeling 25-hydroxyvitamin D3 serum binding protein and for 1,25-dihydroxyvitamin D3 intestinal receptor protein

    NASA Technical Reports Server (NTRS)

    Kutner, A.; Link, R. P.; Schnoes, H. K.; DeLuca, H. F.

    1986-01-01

    3-Azidobenzoates and 3-azidonitrobenzoates of 25-hydroxyvitamin D3 as well as 3-deoxy-3-azido-25-hydroxyvitamin D3 and 3-deoxy-3-azido-1,25-dihydroxyvitamin D3 were prepared as photoaffinity labels for vitamin D serum binding protein and 1,25-dihydroxyvitamin D3 intestinal receptor protein. The compounds prepared were easily activated by short- or long-wavelength uv light, as monitored by uv and ir spectrometry. The efficacy of the compounds to compete with 25-hydroxyvitamin D3 or 1,25-dihydroxyvitamin D3 for the binding site of serum binding protein and receptor, respectively, was studied to evaluate the vitamin D label with the highest affinity for the protein. The presence of an azidobenzoate or azidonitrobenzoate substituent at the C-3 position of 25-OH-D3 significantly decreased (10(4)- to 10(6)-fold) the binding activity. However, the labels containing the azido substituent attached directly to the vitamin D skeleton at the C-3 position showed a high affinity, only 20- to 150-fold lower than that of the parent compounds with their respective proteins. Therefore, 3-deoxy-3-azidovitamins present potential ligands for photolabeling of vitamin D proteins and for studying the structures of the protein active sites.

  15. Photoactivable analogs for labeling 25-hydroxyvitamin D3 serum binding protein and for 1,25-dihydroxyvitamin D3 intestinal receptor protein

    NASA Technical Reports Server (NTRS)

    Kutner, A.; Link, R. P.; Schnoes, H. K.; DeLuca, H. F.

    1986-01-01

    3-Azidobenzoates and 3-azidonitrobenzoates of 25-hydroxyvitamin D3 as well as 3-deoxy-3-azido-25-hydroxyvitamin D3 and 3-deoxy-3-azido-1,25-dihydroxyvitamin D3 were prepared as photoaffinity labels for vitamin D serum binding protein and 1,25-dihydroxyvitamin D3 intestinal receptor protein. The compounds prepared were easily activated by short- or long-wavelength uv light, as monitored by uv and ir spectrometry. The efficacy of the compounds to compete with 25-hydroxyvitamin D3 or 1,25-dihydroxyvitamin D3 for the binding site of serum binding protein and receptor, respectively, was studied to evaluate the vitamin D label with the highest affinity for the protein. The presence of an azidobenzoate or azidonitrobenzoate substituent at the C-3 position of 25-OH-D3 significantly decreased (10(4)- to 10(6)-fold) the binding activity. However, the labels containing the azido substituent attached directly to the vitamin D skeleton at the C-3 position showed a high affinity, only 20- to 150-fold lower than that of the parent compounds with their respective proteins. Therefore, 3-deoxy-3-azidovitamins present potential ligands for photolabeling of vitamin D proteins and for studying the structures of the protein active sites.

  16. SU-F-BRB-07: A Plan Comparison Tool to Ensure Robustness and Deliverability in Online-Adaptive Radiotherapy

    SciTech Connect

    Hill, P; Labby, Z; Bayliss, R A; Geurts, M; Bayouth, J

    2015-06-15

    Purpose: To develop a plan comparison tool that will ensure robustness and deliverability through analysis of baseline and online-adaptive radiotherapy plans using similarity metrics. Methods: The ViewRay MRIdian treatment planning system allows export of a plan file that contains plan and delivery information. A software tool was developed to read and compare two plans, providing information and metrics to assess their similarity. In addition to performing direct comparisons (e.g. demographics, ROI volumes, number of segments, total beam-on time), the tool computes and presents histograms of derived metrics (e.g. step-and-shoot segment field sizes, segment average leaf gaps). Such metrics were investigated for their ability to predict that an online-adapted plan reasonably similar to a baseline plan where deliverability has already been established. Results: In the realm of online-adaptive planning, comparing ROI volumes offers a sanity check to verify observations found during contouring. Beyond ROI analysis, it has been found that simply editing contours and re-optimizing to adapt treatment can produce a delivery that is substantially different than the baseline plan (e.g. number of segments increased by 31%), with no changes in optimization parameters and only minor changes in anatomy. Currently the tool can quickly identify large omissions or deviations from baseline expectations. As our online-adaptive patient population increases, we will continue to develop and refine quantitative acceptance criteria for adapted plans and relate them historical delivery QA measurements. Conclusion: The plan comparison tool is in clinical use and reports a wide range of comparison metrics, illustrating key differences between two plans. This independent check is accomplished in seconds and can be performed in parallel to other tasks in the online-adaptive workflow. Current use prevents large planning or delivery errors from occurring, and ongoing refinements will lead to

  17. Pharmacokinetics and effects of demographic factors on blood 25(OH)D3 levels after a single orally administered high dose of vitamin D3

    PubMed Central

    Chen, Pei-zhan; Li, Mian; Duan, Xiao-hua; Jia, Jing-ying; Li, Jing-quan; Chu, Rui-ai; Yu, Chen; Han, Jun-hua; Wang, Hui

    2016-01-01

    Aim: To examine the biological consequences and demographic factors that might affect the pharmacokinetics of vitamin D3 after a single high dose intervention in a young Chinese population with vitamin D insufficiency status. Methods: A total of 28 young subjects (25 to 35 years old) with vitamin D insufficiency status [serum 25(OH)D <30 ng/mL] was recruited in Shanghai, China. The subjects were orally administered a single high dose of vitamin D3 (300 000 IU). Baseline characteristics and blood samples were collected at d 0, 1, 2, 3, 7, 28, 56, 84 and 112 after the intervention. The blood biomarker levels were determined with standardized methods. Results: The intervention markedly increased the blood 25(OH)D3 levels within the first five days (mean Tmax=5.1±2.1 d) and sustained an optimal circulating level of 25(OH)D3 (≥30 ng/mL) for 56 d. After the intervention, body weight and baseline 25(OH)D3 levels were significantly correlated with circulating 25(OH)D3 levels. No adverse events and no consistently significant changes in serum calcium, creatinine, glucose, parathyroid hormone, vitamin D binding protein, or the urinary calcium/reatinine ratio were observed. However, there was a significant increase in phosphorus after the vitamin D3 intervention. Total cholesterol and triglyceride levels were decreased at the end of the trial. Conclusion: The pharmacokinetics of vitamin D after intervention were influenced by baseline 25(OH)D3 levels and the body weight of the subjects. The results suggest that a single high oral vitamin D3 intervention is safe and efficient for improving the vitamin D status of young Chinese people with vitamin D insufficiency. PMID:27569392

  18. Pharmacokinetics and effects of demographic factors on blood 25(OH)D3 levels after a single orally administered high dose of vitamin D3.

    PubMed

    Chen, Pei-Zhan; Li, Mian; Duan, Xiao-Hua; Jia, Jing-Ying; Li, Jing-Quan; Chu, Rui-Ai; Yu, Chen; Han, Jun-Hua; Wang, Hui

    2016-11-01

    To examine the biological consequences and demographic factors that might affect the pharmacokinetics of vitamin D3 after a single high dose intervention in a young Chinese population with vitamin D insufficiency status. A total of 28 young subjects (25 to 35 years old) with vitamin D insufficiency status [serum 25(OH)D <30 ng/mL] was recruited in Shanghai, China. The subjects were orally administered a single high dose of vitamin D3 (300 000 IU). Baseline characteristics and blood samples were collected at d 0, 1, 2, 3, 7, 28, 56, 84 and 112 after the intervention. The blood biomarker levels were determined with standardized methods. The intervention markedly increased the blood 25(OH)D3 levels within the first five days (mean Tmax=5.1±2.1 d) and sustained an optimal circulating level of 25(OH)D3 (≥30 ng/mL) for 56 d. After the intervention, body weight and baseline 25(OH)D3 levels were significantly correlated with circulating 25(OH)D3 levels. No adverse events and no consistently significant changes in serum calcium, creatinine, glucose, parathyroid hormone, vitamin D binding protein, or the urinary calcium/reatinine ratio were observed. However, there was a significant increase in phosphorus after the vitamin D3 intervention. Total cholesterol and triglyceride levels were decreased at the end of the trial. The pharmacokinetics of vitamin D after intervention were influenced by baseline 25(OH)D3 levels and the body weight of the subjects. The results suggest that a single high oral vitamin D3 intervention is safe and efficient for improving the vitamin D status of young Chinese people with vitamin D insufficiency.

  19. Selective Overexpression of Dopamine D3 Receptors in the Striatum Disrupts Motivation but not Cognition

    PubMed Central

    Simpson, Eleanor H.; Winiger, Vanessa; Biezonski, Dominik K.; Haq, Iram; Kandel, Eric R.; Kellendonk, Christoph

    2014-01-01

    Background Evidence indicating an increase in dopamine D2 receptor (D2R) density and occupancy in patients with schizophrenia comes from positron emission tomography studies using ligands that bind both D2Rs and dopamine D3 receptors (D3Rs), questioning the role of D3Rs in the pathophysiology of the disease. Dopamine D3 receptor positron emission tomography ligands have recently been developed and antagonists with preferential affinity for D3R versus D2R are undergoing clinical evaluation. To determine if an increase in D3Rs in the striatum could produce phenotypes relevant to schizophrenia, we generated a transgenic model of striatal D3R overexpression. Methods A bi-transgenic system was used to generate mice with increased D3Rs selectively in the striatum. Mice with overexpression of D3R were subjected to an extensive battery of behavioral tests, including several relevant to schizophrenia. Ligand binding and quantitative reverse transcription polymerase chain reaction methods were used to quantify the effect of D3R overexpression on dopamine D1 receptors (D1Rs) in the striatum. Results Mice with overexpression of D3R show no abnormalities in basic behavioral functions or cognitive tests but do display a deficit in incentive motivation. This was associated with a reduction in striatal D1R ligand binding, driven by a downregulation at the level of transcription. Both motivation and D1R expression were rescued by switching off the transgene in adulthood. Conclusions Overexpression of D3Rs in the striatum of mice does not elicit cognitive deficits but disrupts motivation, suggesting that changes in D3Rs may be involved in the negative symptoms of schizophrenia. These data imply that it will be important to evaluate the effects of D3R antagonists on motivational symptoms, which are not improved by currently available antipsychotic medications. PMID:24387821

  20. The cutaneous photosynthesis of previtamin D3: a unique photoendocrine system

    SciTech Connect

    Holick, M.F.

    1981-07-01

    The skin has been recognized as the site for the sun-mediated photosynthesis of vitamin D3; until recently, however, very little was known about either the sequence of events leading to the formation of vitamin D3 in human skin or the factors that regulate the synthesis of this hormone. It is now established that, during exposure to sunlight, the cutaneous reservoir of 7-dehydrocholesterol (principally in the stratum Malpighii) converts to previtamin D3. Once this thermally labile previtamin is formed, it undergoes a temperature-dependent isomerization to vitamin D3 over a period of 3 days. The plasma vitamin-D binding protein preferentially translocates vitamin D3 from the skin into the circulation. During prolonged exposure to the sun, the accumulation of previtamin D3 is limited to about 10 to 15% of the original 7-dehydrocholesterol content because the previtamin photoisomerizes to 2 biologically inert photoproducts, lumisterol3 and tachysterol3. Increases in either latitude or the melanin concentration in the skin diminish the epidermal synthesis of previtamin D3. A single total body exposure to 3 minimal erythemal doses of ultraviolet radiation increased the vitamin-D3 levels in the serum 25-hydroxyvitamin-D levels after 7 days. The unique mechanism for the cutaneous synthesis, storage, and steady release of vitamin D3 into the circulation prompted an investigation into the potential therapeutic benefits of using the skin as the site for the synthesis and absorption of vitamin-D3 metabolites.

  1. UV-Stressed Daphnia pulex Increase Fitness through Uptake of Vitamin D3

    PubMed Central

    Walling, Kelly; Wilbert, Steven A.; Catlin, Diane M.; Monaghan, Cailin E.; Hlynchuk, Sofiya; Meehl, Pamela G.; Resch, Lauren N.; Carrera, J. Valerie; Bowles, Stephanie M.; Clark, Michael D.

    2015-01-01

    Ultraviolet radiation is known to be highly variable in aquatic ecosystems. It has been suggested that UV-exposed organisms may demonstrate enough phenotypic plasticity to maintain the relative fitness of natural populations. Our long-term objective is to determine the potential photoprotective effect of vitamin D3 on Daphnia pulex exposed to acute or chronic UV radiation. Herein we report our initial findings in this endeavor. D. pulex survival and reproduction (fitness) was monitored for 5 d as a proof of concept study. Significantly higher fitness was observed in the D. pulex with D3 than those without (most extreme effects observed were 0% survival in the absence of D3 and 100% with 10 ppm D3). Vitamin D3 was isolated from the culture media, the algal food (Pseudokirchneriella), and the D. pulex and quantified using high performance liquid chromatography (HPLC). Vitamin D3 was fluorescently labeled using a phenothiazinium dye and added to cultures of D. pulex. Images demonstrating the uptake of D3 into the tissues and carapace of the D. pulex were acquired. Our initial findings suggest a positive role for D3 in ecosystems as both UV-stressed algae and Daphnia sequester D3, and D. pulex demonstrate increased fitness in the presence of D3. PMID:26147286

  2. Blonanserin extensively occupies rat dopamine D3 receptors at antipsychotic dose range.

    PubMed

    Baba, Satoko; Enomoto, Takeshi; Horisawa, Tomoko; Hashimoto, Takashi; Ono, Michiko

    2015-03-01

    Antagonism of the dopamine D3 receptor has been hypothesized to be beneficial for schizophrenia cognitive deficits, negative symptoms and extrapyramidal symptoms. However, recent animal and human studies have shown that most antipsychotics do not occupy D3 receptors in vivo, despite their considerable binding affinity for this receptor in vitro. In the present study, we investigated the D3 receptor binding of blonanserin, a dopamine D2/D3 and serotonin 5-HT2A receptors antagonist, in vitro and in vivo. Blonanserin showed the most potent binding affinity for human D3 receptors among the tested atypical antipsychotics (risperidone, olanzapine and aripiprazole). Our GTPγS-binding assay demonstrated that blonanserin acts as a potent full antagonist for human D3 receptors. All test-drugs exhibited antipsychotic-like efficacy in methamphetamine-induced hyperactivity in rats. Treatment with blonanserin at its effective dose blocked the binding of [(3)H]-(+)-PHNO, a D2/D3 receptor radiotracer, both in the D2 receptor-rich region (striatum) and the D3 receptor-rich region (cerebellum lobes 9 and 10). On the other hand, the occupancies of other test-drugs for D3 receptors were relatively low. In conclusion, we have shown that blonanserin, but not other tested antipsychotics, extensively occupies D3 receptors in vivo in rats. Copyright © 2015 Japanese Pharmacological Society. Production and hosting by Elsevier B.V. All rights reserved.

  3. Degradation of vitamin D3 in a stressed formulation: the identification of esters of vitamin D3 formed by a transesterification with triglycerides.

    PubMed

    Ballard, John M; Zhu, Limin; Nelson, Eric D; Seburg, Randal A

    2007-01-04

    Four unknown degradants in the LC-UV profile of a stressed experimental tablet formulation that contains vitamin D3 have been identified by a combination of Ag+-cationization electrospray ionization (ESI) LC/MS and atmospheric pressure chemical ionization (APCI) LC/MS/MS. The peaks elute in the method chromatography in two pairs of two peaks. The first pair of peaks has m/z 511 while the second pair has m/z 539. The major, first peak of each set of peaks corresponds to the octanoate and decanoate ester of vitamin D3, respectively. These are formed by a transesterification with the two major fatty acid components (octanoate and decanoate) of the triglycerides present in the formulation. The formation of two degradation products with each fatty acid is due to the presence of both vitamin D3 (major component) and the isomeric pre-vitamin D3 (minor component) in the stressed formulation.

  4. Role of the 1,25D3-MARRS receptor in the 1,25(OH)2D3-stimulated uptake of calcium and phosphate in intestinal cells.

    PubMed

    Nemere, Ilka; Garbi, Natalio; Hammerling, Günter; Hintze, Korry J

    2012-08-01

    We have used mice with a targeted knockout (KO) of the 1,25D(3)-MARRS receptor (ERp57/PDIA3) in intestine to study rapid responses to 1,25-dihydroxyvitamin D(3) [1,25D(3)] with regards to calcium or phosphate uptake. Western analyses indicated the presence of the 1,25D(3)-MARRS receptor in littermate (LM) mice, but not KO mice. Saturation analyses for [(3)H]1,25D(3) binding revealed comparable affinities for the hormone in lysates from female and male LM, but a reduced B(max) in females. Binding in lysates from KO mice was absent or severely reduced. Enterocytes from KO mice failed to respond to hormone with regard to either ion uptake, while cells from LM mice exhibited an increase in uptake. For calcium uptake, the protein kinase (PK) A pathway mediated the response to 1,25D(3). Enterocytes from LM mice responded to 1,25D(3) with enhanced PKA activity, while cells from KO mice did not, although both cell types responded to forskolin. Calcium transport in LM mice in vivo was greater than in KO mice. Cells from LM and KO mice had cell surface VDR; however, anti-VDR antibodies had no effect on ion uptake. Unlike chicks, the PKC pathway was not involved in phosphate uptake. As in chicks and rats, intestinal cells from adult male mice lost the ability to respond to 1,25D(3) with enhanced phosphate uptake, whereas in female mice, uptake in cells from adults was greater than that observed in young mice. Finally, when we tested phosphate uptake in vivo, we found that young female mice had a much greater rate of transport than young male mice. Copyright © 2012 Elsevier Inc. All rights reserved.

  5. Ribozyme knockdown functionally links a 1,25(OH)2D3 membrane binding protein (1,25D3-MARRS) and phosphate uptake in intestinal cells

    PubMed Central

    Nemere, I.; Farach-Carson, M. C.; Rohe, B.; Sterling, T. M.; Norman, A. W.; Boyan, B. D.; Safford, S. E.

    2004-01-01

    We used a ribozyme loss-of-function approach to demonstrate that the protein product of a cDNA encoding a multifunctional membrane-associated protein binds the seco-steroid 1,25(OH)2D3 and transduces its stimulatory effects on phosphate uptake. These results are paralleled by studies in which the ability of the hormone to stimulate phosphate uptake in isolated chick intestinal epithelial cells is abolished by preincubation with Ab099 directed against the amino terminus of the protein. We now report the complete sequence of the cloned chicken cDNA for the 1,25D3-MARRS (membrane-associated, rapid-response steroid-binding) protein and reveal it to be identical to the multifunctional protein ERp57. Functional studies showed that active ribozyme, but not a scrambled control, decreased specific membrane-associated 1,25(OH)2D3 binding, but did not affect binding to the nuclear receptor for 1,25(OH)2D3. Seco-steroid-dependent stimulation of protein kinase C activity was diminished as 1,25D3-MARRS protein levels were reduced in the presence of the ribozyme, as judged by Western blot analyses. Phosphate uptake in isolated cells is an index of intestinal phosphate transport that occurs during growth and maturation. Whereas cells and perfused duodena robustly responded to 1,25(OH)2D3 in preparations from young birds, older animals no longer responded with stimulated phosphate uptake or transport. The age-related decline was accompanied by a decrease in 1,25D3-MARRS mRNA that was apparent up to 1 year of age. Together, these studies functionally link phosphate transport in the chick duodenum with the 1,25D3-MARRS protein and point to a previously uncharacterized role for this multifunctional protein class. PMID:15123837

  6. The influence of latitude on the concentration of vitamin D3 and 25-hydroxy-vitamin D3 in Australian red meat.

    PubMed

    Liu, Jerry; Greenfield, Heather; Strobel, Norbert; Fraser, David R

    2013-10-01

    There is little information on the vitamin D content of Australian red meat or on the possible influence of latitude on this content. To determine the content of vitamin D3 and 25-hydroxy-vitamin D3 (25OHD3), lamb and beef were analysed from 34° S with LC-IT-MS. To investigate the possible influence of latitude on vitamin D in meat, the lean meat and fat from five cuts of beef were analysed from 17° S and 41° S. Lamb contained 0.10μg vitamin D3/100g and 0.20μg 25OHD3/100g lean meat, while beef contained 0.12μg vitamin D3 and 0.27μg 25OHD3/100g (lean meat). Latitude had no effect on the vitamin D3 (P=0.21) or 25OHD3 (P=0.29) content of lean beef, but fat from cattle in the 17° S latitude group contained significantly higher (P<0.01) concentrations of vitamin D3 than fat from the 41° S group of cattle.

  7. Vitamin D(3) synthesis in the entire skin surface of dairy cows despite hair coverage.

    PubMed

    Hymøller, L; Jensen, S K

    2010-05-01

    How hair-coated animals such as dairy cows synthesize endogenous vitamin D(3) during exposure to summer sunlight has been unclear since vitamin D(3) and its relation to sunlight was discovered. The fur of fur-bearing animals is thought to be comparable to clothing in humans, which prevents vitamin D(3) synthesis in the skin during exposure to sunlight. Different scenarios have been suggested but never tested in cows; for example, that vitamin D(3) is synthesized from sebum on the hair and ingested by cows during grooming or that body areas such as the udder and muzzle that have scant hair exclusively produce the vitamin. To test different scenarios, 16 Danish Holstein dairy cows were subjected to 4 degrees of coverage of their bodies with fabric that prevented vitamin D(3) synthesis in the covered skin areas. The treatments were horse blanket (cows fitted with horse blankets), udder cover (cows fitted with udder covers, horse blanket+udder cover (cows fitted with both horse blankets and udder covers), and natural (cows without any coverage fitted). The cows were let out to pasture daily between 1000 and 1500h for 4 wk in July and August 2009. Blood samples were collected 15 times during the study and analyzed for content of 25-hydroxyvitamin D(3) [25(OH)D(3)] indicative of the animals' vitamin D(3) status. Results showed that uncovered cows had a higher 25(OH)D(3) concentration in plasma after 28 d of access to sunlight compared with covered cows and that the plasma concentration of 25(OH)D(3) was strongly inversely correlated to the body surface area covered. These results are consistent with findings in humans, wherein the vitamin D(3) status of different individuals was inversely proportional to the amount of clothing worn during exposure to artificial sunlight. Hence, it appears that human clothing and cow hair are not comparable with respect to prevention of vitamin D(3) synthesis and that cows, like humans, synthesize vitamin D(3) evenly over their body

  8. Dopamine D3 receptor dysfunction prevents anti-nociceptive effects of morphine in the spinal cord.

    PubMed

    Brewer, Kori L; Baran, Christine A; Whitfield, Brian R; Jensen, A Marley; Clemens, Stefan

    2014-01-01

    Dopamine (DA) modulates spinal reflexes, including nociceptive reflexes, in part via the D3 receptor subtype. We have previously shown that mice lacking the functional D3 receptor (D3KO) exhibit decreased paw withdrawal latencies from painful thermal stimuli. Altering the DA system in the CNS, including D1 and D3 receptor systems, reduces the ability of opioids to provide analgesia. Here, we tested if the increased pain sensitivity in D3KO might result from a modified μ-opioid receptor (MOR) function at the spinal cord level. As D1 and D3 receptor subtypes have competing cellular effects and can form heterodimers, we tested if the changes in MOR function may be mediated in D3KO through the functionally intact D1 receptor system. We assessed thermal paw withdrawal latencies in D3KO and wild type (WT) mice before and after systemic treatment with morphine, determined MOR and phosphorylated MOR (p-MOR) protein expression levels in lumbar spinal cords, and tested the functional effects of DA and MOR receptor agonists in the isolated spinal cord. In vivo, a single morphine administration (2 mg/kg) increased withdrawal latencies in WT but not D3KO, and these differential effects were mimicked in vitro, where morphine modulated spinal reflex amplitudes (SRAs) in WT but not D3KO. Total MOR protein expression levels were similar between WT and D3KO, but the ratio of pMOR/total MOR was higher in D3KO. Blocking D3 receptors in the isolated WT cord precluded morphine's inhibitory effects observed under control conditions. Lastly, we observed an increase in D1 receptor protein expression in the lumbar spinal cord of D3KO. Our data suggest that the D3 receptor modulates the MOR system in the spinal cord, and that a dysfunction of the D3 receptor can induce a morphine-resistant state. We propose that the D3KO mouse may serve as a model to study the onset of morphine resistance at the spinal cord level, the primary processing site of the nociceptive pathway.

  9. Vitamin D3 induces autophagy in human monocytes/macrophages via cathelicidin.

    PubMed

    Yuk, Jae-Min; Shin, Dong-Min; Lee, Hye-Mi; Yang, Chul-Su; Jin, Hyo Sun; Kim, Kwang-Kyu; Lee, Zee-Won; Lee, Sang-Hee; Kim, Jin-Man; Jo, Eun-Kyeong

    2009-09-17

    Autophagy and vitamin D3-mediated innate immunity have been shown to confer protection against infection with intracellular Mycobacterium tuberculosis. Here, we show that these two antimycobacterial defenses are physiologically linked via a regulatory function of human cathelicidin (hCAP-18/LL-37), a member of the cathelicidin family of antimicrobial proteins. We show that 1,25-dihydroxyvitamin D3 (1,25D3), the active form of vitamin D, induced autophagy in human monocytes via cathelicidin, which activated transcription of the autophagy-related genes Beclin-1 and Atg5. 1,25D3 also induced the colocalization of mycobacterial phagosomes with autophagosomes in human macrophages in a cathelicidin-dependent manner. Furthermore, the antimycobacterial activity in human macrophages mediated by physiological levels of 1,25D3 required autophagy and cathelicidin. These results indicate that human cathelicidin, a protein that has direct antimicrobial activity, also serves as a mediator of vitamin D3-induced autophagy.

  10. Vitamin D3 for the Treatment of Epilepsy: Basic Mechanisms, Animal Models, and Clinical Trials

    PubMed Central

    Pendo, Kevin; DeGiorgio, Christopher M.

    2016-01-01

    There is increasing evidence supporting dietary and alternative therapies for epilepsy, including the ketogenic diet, modified Atkins diet, and omega-3 fatty acids. Vitamin D3 is actively under investigation as a potential intervention for epilepsy. Vitamin D3 is fat-soluble steroid, which shows promise in animal models of epilepsy. Basic research has shed light on the possible mechanisms by which Vitamin D3 may reduce seizures, and animal data support the efficacy of Vitamin D3 in rat and mouse models of epilepsy. Very little clinical data exist to support the treatment of human epilepsy with Vitamin D3, but positive findings from preliminary clinical trials warrant larger Phase I and II clinical trials in order to more rigorously determine the potential therapeutic value of Vitamin D3 as a treatment for human epilepsy. PMID:28008324

  11. Vitamin D3 pretreatment alleviates renal oxidative stress in lipopolysaccharide-induced acute kidney injury.

    PubMed

    Xu, Shen; Chen, Yuan-Hua; Tan, Zhu-Xia; Xie, Dong-Dong; Zhang, Cheng; Xia, Mi-Zhen; Wang, Hua; Zhao, Hui; Xu, De-Xiang; Yu, De-Xin

    2015-08-01

    Increasing evidence demonstrates that reactive oxygen species plays important roles in sepsis-induced acute kidney injury. This study investigated the effects of VitD3 pretreatment on renal oxidative stress in sepsis-induced acute kidney injury. Mice were intraperitoneally injected with lipopolysaccharide (LPS, 2.0mg/kg) to establish an animal model of sepsis-induced acute kidney injury. In VitD3+LPS group, mice were orally pretreated with three doses of VitD3 (25 μg/kg) at 1, 24 and 48 h before LPS injection. As expected, oral pretreatment with three daily recommended doses of VitD3 markedly elevated serum 25(OH)D concentration and efficiently activated renal VDR signaling. Interestingly, LPS-induced renal GSH depletion and lipid peroxidation were markedly alleviated in VitD3-pretreated mice. LPS-induced serum and renal nitric oxide (NO) production was obviously suppressed by VitD3 pretreatment. In addition, LPS-induced renal protein nitration, as determined by 3-nitrotyrosine residue, was obviously attenuated by VitD3 pretreatment. Further analysis showed that LPS-induced up-regulation of renal inducible nitric oxide synthase (inos) was repressed in VitD3-pretreated mice. LPS-induced up-regulation of renal p47phox and gp91phox, two NADPH oxidase subunits, were normalized by VitD3 pretreatment. In addition, LPS-induced down-regulation of renal superoxide dismutase (sod) 1 and sod2, two antioxidant enzyme genes, was reversed in VitD3-pretreated mice. Finally, LPS-induced tubular epithelial cell apoptosis, as determined by TUNEL, was alleviated by VitD3 pretreatment. Taken together, these results suggest that VitD3 pretreatment alleviates LPS-induced renal oxidative stress through regulating oxidant and antioxidant enzyme genes. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. The role of central dopamine D3 receptors in drug addiction: a review of pharmacological evidence

    PubMed Central

    Heidbreder, Christian A.; Gardner, Eliot L.; Xi, Zheng-Xiong; Thanos, Panayotis K.; Mugnaini, Manolo; Hagan, Jim J.; Ashby, Charles R.

    2013-01-01

    The cDNA for the dopamine D3 receptor was isolated and characterized in 1990. Subsequent studies have indicated that D3 receptors, as well as D3 receptor mRNA, are primarily localized in limbic regions in mammals. This finding led to the postulate that D3 receptors may be involved in drug dependence and addiction. However, this hypothesis has been difficult to test due to the lack of compounds with high selectivity for central D3 receptors. The interpretation of results from studies using mixed D2/D3 agonists and/or antagonists is problematic because these agents have low selectivity for D3 over D2 receptors and it is likely that their actions are primarily related to D2 receptor antagonism and possibly interaction with other neurotransmitter receptors. Currently, with the synthesis and characterization of new highly selective D3 receptor antagonists such as SB-277011-A this difficulty has been surmounted. The purpose of the present article is to review, for the first time, the effects of various putative D3 receptor selective compounds in animal models of drug dependence and addiction. The results obtained with highly selective D3 receptor antagonists such as SB-277011-A, SB-414796, and NGB-2904 indicate that central D3 receptors may play an important role in drug-induced reward, drug-taking, and cue-, drug-, and stress-induced reinstatement of drug-seeking behavior. Provided these results can be extrapolated to human drug addicts, they suggest that selective DA D3 receptor antagonists may prove effective as potential pharmacotherapeutic agents to manage drug dependence and addiction. PMID:15960988

  13. Pharmacological targeting of dopamine D3 receptors: Possible clinical applications of selective drugs.

    PubMed

    Pich, Emilio Merlo; Collo, Ginetta

    2015-09-01

    Dopamine D3 receptors have been pharmacologically engaged in humans since the development of the first antipsychotics and ergot-derivative dopamine (DA) agonists, even without knowing it. These agents were generally non-selective, developed primarily to target D2 receptors. In the last 10 years the understanding of the clinical implication of D3 receptors has been progressing also due to the identification of D3 gene polymorphisms, the use of more selective PET ligands such as [(11)C]-(+)-PHNO and the learning regarding the clinical use of the D3-preferential D2/D3 agonists ropinirole and pramipexole. A new specific neuroplasticity role of D3 receptor regarding dendrite arborisation outgrowth in dopaminergic neurons was also proposed to support, at least in part, the slowing of disease observed in subjects with Parkinson׳s Disease treated with DA agonists. Similar mechanisms could be at the basis of the antidepressant-like effects observed with DA agonists when co-administered with standard of care. Severe adverse event occurring with the use of anti-parkinsonian DA agonists in predisposed subjects, i.e., impulse control disorders, are now suggested to be putatively related to overactive D3 receptors. Not surprisingly, blockade of D3 receptors was proposed as treatment for addictive disorders, a goal that could be potentially achieved by repositioning buspirone, an anxiolytic drug with D3-preferential antagonistic features, or with novel selective D3 antagonists or partial agonists currently in development for schizophrenia. At the moment ABT-925 is the only selective D3 antagonist tested in schizophrenic patients in Phase II, showing an intriguing cognitive enhancing effects supported by preclinical data. Finally, exploratory pharmacogenetic analysis suggested that ABT-925 could be effective in a subpopulation of patients with a polymorphism on the D3 receptor, opening to a possible personalised medicine approach.

  14. 1,25(OH)2 D3 attenuates hepatic steatosis by inducing autophagy in mice.

    PubMed

    Li, Renlong; Guo, Enshuang; Yang, Jiankun; Li, Anyi; Yang, Yan; Liu, Shenpei; Liu, Anding; Jiang, Xiaojing

    2017-03-01

    1,25(OH)2 D3 has been reported to attenuate liver steatosis; however, its exact mechanism of action remains poorly understood. This study aimed to determine whether 1,25(OH)2 D3 can attenuate hepatic steatosis by inducing autophagy. Male C57BL/6 mice fed a high-fat diet (HFD) were injected with 1,25(OH)2 D3 for 4 weeks. These mice were given 3-methyladenine (3-MA) to inhibit autophagy. HepG2 cells were preincubated with a free fatty acid (FFA) and then treated with 1,25(OH)2 D3 . Vitamin D receptor (VDR) shRNA and autophagy-related 16-like 1 (ATG16L1) siRNA were used for VDR knockdown or ATG16L1 silencing, respectively. 1,25(OH)2 D3 diminished HFD-induced liver damage and steatosis, changes accompanied by autophagy and ATG16L1 expression upregulation. Inhibition of 1,25(OH)2 D3 -induced autophagy mediated by 3-MA blocked the protective effects of 1,25(OH)2 D3 on hepatic steatosis. Additionally, 1,25(OH)2 D3 -induced autophagy appeared to play a role in anti-inflammation and lipid metabolism modulation in the liver. In HepG2 cells, 1,25(OH)2 D3 reduced lipid accumulation and increased autophagy and ATG16L1 expression; however, this effect was abrogated after VDR knockdown. The protective effects of 1,25(OH)2 D3 -mediated autophagy against lipid accumulation were abolished by 3-MA. Furthermore, siRNA-mediated ATG16L1 knockdown prevented 1,25(OH)2 D3 -induced autophagy, resulting in increased fat accumulation. The data suggest that 1,25(OH)2 D3 may ameliorate hepatic steatosis by inducing autophagy by upregulating ATG16L1. © 2017 The Obesity Society.

  15. Evaluation of DFT-D3 dispersion corrections for various structural benchmark sets

    NASA Astrophysics Data System (ADS)

    Schröder, Heiner; Hühnert, Jens; Schwabe, Tobias

    2017-01-01

    We present an evaluation of our newly developed density functional theory (DFT)-D3 dispersion correction D3(CSO) in comparison to its predecessor D3(BJ) for geometry optimizations. Therefore, various benchmark sets covering bond lengths, rotational constants, and center of mass distances of supramolecular complexes have been chosen. Overall both corrections give accurate structures and show no systematic differences. Additionally, we present an optimized algorithm for the computation of the DFT-D3 gradient, which reduces the formal scaling of the gradient calculation from O (N3) to O (N2) .

  16. Subapical localization of the dopamine D3 receptor in proximal tubules of the rat kidney.

    PubMed

    Nürnberger, Asja; Räbiger, Marcus; Mack, Andreas; Diaz, Jorge; Sokoloff, Pierre; Mühlbauer, Bernd; Luippold, Gerd

    2004-12-01

    The dopamine D3 receptor (D3R), intensively studied in neuroscience, also plays an important role in the regulation of renal and cardiovascular function. In contrast to functional findings, less information is available on its localization in the kidney. Neither RT-PCR studies nor radioligand binding assays are suitable to selectively determine the distribution of renal D3R at the level of cellular or even subcellular structures. We studied the renal D3R distribution in Sprague-Dawley rats by a polyclonal antiserum directed against an epitope in the third intracytoplasmic loop. D3R immunoreactivity was detected by indirect immunofluorescence and confocal laser scanning microscopy. D3R staining was confined to the renal cortex and occurred in proximal convoluted tubules near or in direct connection with the urinary pole of the glomeruli. The fluorescent spots were restricted to the subapical portion of the proximal tubular cells. Double staining with the F-actin marker phalloidin revealed a localization of the D3R below the brush border region. However, staining by anti-beta1/beta2-adaptins, recognizing clathrin-coated compartments, did not correspond to the distribution of the D3R signal. This is the first description of a D3R accumulation in a cytoplasmic pool in the kidney, probably corresponding to a recycling mechanism or storage compartment.

  17. Characterization of D-3-hydroxybutyrylcarnitine (ketocarnitine): an identified ketosis-induced metabolite.

    PubMed

    Soeters, Maarten R; Serlie, Mireille J; Sauerwein, Hans P; Duran, Marinus; Ruiter, Jos P; Kulik, Willem; Ackermans, Mariëtte T; Minkler, Paul E; Hoppel, Charles L; Wanders, Ronald J A; Houten, Sander M

    2012-07-01

    Hydroxybutyrylcarnitine (HB-carnitine) is a metabolite that has been associated with insulin resistance and type 2 diabetes mellitus. It is currently unknown whether HB-carnitine can be produced from D-3-hydroxybutyrate (D-3HB), a ketone body; but its formation from L-3-HB-CoA, a fatty acid β-oxidation intermediate, is well established. We aimed to assess which stereoisomers of 3-HB-carnitine are present in vivo. Ketosis and increased fatty acid oxidation were induced in 12 lean healthy men by a 38-hour fasting period. The D-3HB kinetics (stable isotope technique) and stereoisomers of muscle 3-HB-carnitine (high-performance liquid chromatography/ultra-performance liquid chromatography-tandem mass spectrometry) were measured. Muscle D-3HB-carnitine content was much higher compared with L-3HB-carnitine. In addition, muscle D-3HB-carnitine correlated significantly with D-3-HB production. Following the finding that a ketone body can be converted into a carnitine ester in vivo, we show in vitro that D-3-HB can be converted into HB-carnitine (ketocarnitine) via an acyl-CoA synthetase reaction in several tissues including human muscle. During fasting, HB-carnitine in muscle is derived mainly from the ketone body D-3HB. The role of D-3HB-carnitine synthesis in metabolism remains to be elucidated.

  18. 1,25-dihydroxyvitamin D3 enhances milk antibody titers to Escherichia coli J5 vaccine.

    PubMed

    Reinhardt, T A; Stabel, J R; Goff, J P

    1999-09-01

    Recent evidence in cattle and mice has suggested that 1,25-dihydroxyvitamin D3 may stimulate T-lymphocyte differentiation pathways responsible for humoral immunity. The use of 1,25-dihydroxyvitamin D3 as an adjuvant for an Escherichia coli J5 vaccine was tested. Ten midlactation cows received J5 vaccine and were revaccinated 6 wk after the first vaccine administration. Five of these cows were given 200 micrograms of 1,25-dihydroxyvitamin D3, in addition to the primary vaccination, and they received an additional 200 micrograms of 1,25-dihydroxyvitamin D3 1 wk after the primary vaccination. No 1,25-dihydroxyvitamin D3 was administered with the wk 6 J5 vaccine booster. Milk immunoglobin (Ig)M, IgG, and IgA antibodies to E. coli J5 were significantly increased in cows receiving 1,25-dihydroxyvitamin D3 + E. coli J5 vaccine compared with cows that received only E. coli J5 vaccine. Serum IgG and IgG1 antibodies to E. coli J5 were also significantly enhanced by 1,25-dihydroxyvitamin D3 treatment compared with cows receiving vaccine alone. In contrast, serum IgG2 titers tended to decline in cows receiving 1,25-dihydroxyvitamin D3. Taken together, these data suggest that 1,25-dihydroxyvitamin D3 has potential usefulness in boosting humoral responses to vaccines such as J5 and may further enhance the protective qualities of vaccines.

  19. Dopamine D3 receptor status modulates sexual dimorphism in voluntary wheel running behavior in mice.

    PubMed

    Klinker, Florian; Ko Hnemann, Kathrin; Paulus, Walter; Liebetanz, David

    2017-08-30

    Sexual dimorphism has been described in various aspects of physiological and pathophysiological processes involving dopaminergic signaling. This might account for the different disease characteristics in men and women in e.g. Parkinson's disease or ADHD. A better understanding might contribute to the future individualization of therapy. We examined spontaneous wheel running activity of male and female mice, homo- and heterozygote for dopamine D3 receptor deficiency (D3R -/- and D3R+/-), and compared them to wild type controls. We found higher wheel running activity in female mice than in their male littermates. D3-/- mice, irrespective of sex, were also hyperactive compared to both D3+/- and wild type animals. Hyperactivity of D3-/- female mice was pronounced during the first days of wheel running but then decreased while their male counterparts continued to be hyperactive. Physical activity was menstrual cycle-dependent. Activity fluctuations were also seen in D3 receptor knockout mice and are therefore presumably independent of D3 receptor activation. Our data underscore the complex interaction of dopaminergic signaling and gonadal hormones that leads to specific running behavior. Furthermore, we detected sex- and D3 receptor status-specific reactions during novel exposure to the running wheel. These findings suggest the need for adapting dopaminergic therapies to individual factors such as sex or even menstrual cycle to optimize therapeutic success. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. VitD3-loaded solid lipid nanoparticles: stability, cytotoxicity and cytokine levels.

    PubMed

    Demirbilek, Murat; Laçin Türkoglu, Nelisa; Aktürk, Selçuk; Akça, Cem

    2017-08-01

    Vitamin D3 (VitD3) has several beneficial effects on many metabolic pathways such as immunity system, bone development. The aim of the study, encapsulation of VitD3 with solid lipids, determine encapsulation efficiency and biocompatibility of nanoparticles. Therefore, VitD3-loaded solid lipid nanoparticles (SLNPs) were developed by optimising ratios of VitD3, stearic acid, beeswax and sodium dodecyl sulphate (SDS). Thermal stability, degradation profile, crystallinity rate, encapsulation efficiency and release profile of SLNPs were determined. Cytotoxicity of SLNPs on HaCaT, L929 and HUVEC cells were investigated. Negatively charged and VitD3-loaded nanoparticles with diameters between 30 and 60 nm were obtained. SLNPs containing up to 5.1 mg VitD3 per 10 mg powder samples were obtained. Cell proliferations were stimulated after exposure with VitD3-loaded SLNPs. Besides, inflammatory response after exposure to VitD3-loaded SLNPs was evaluated via determining IL10 and TNF-alpha levels on THP-1 cells. According to the results, no inflammatory response was observed.

  1. The potential role of dopamine D3 receptor neurotransmission in cognition

    PubMed Central

    Nakajima, Shinichiro; Gerretsen, Philip; Takeuchi, Hiroyoshi; Caravaggio, Fernando; Chow, Tiffany; Le Foll, Bernard; Mulsant, Benoit; Pollock, Bruce; Graff-Guerrero, Ariel

    2013-01-01

    Currently available treatments have limited pro-cognitive effects for neuropsychiatric disorders, such as schizophrenia, Parkinson’s disease and Alzheimer’s disease. The primary objective of this work is to review the literature on the role of dopamine D3 receptors in cognition, and propose dopamine D3 receptor antagonists as possible cognitive enhancers for neuropsychiatric disorders. A literature search was performed to identify animal and human studies on D3 receptors and cognition using PubMed, MEDLINE and EMBASE. The search terms included “dopamine D3 receptor” and “cognition”. The literature search identified 164 articles. The results revealed: (1) D3 receptors are associated with cognitive functioning in both healthy individuals and those with neuropsychiatric disorders; (2) D3 receptor blockade appears to enhance while D3 receptor agonism seems to impair cognitive function, including memory, attention, learning, processing speed, social recognition and executive function independent of age; and (3) D3 receptor antagonists may exert their pro-cognitive effect by enhancing the release of acetylcholine in the prefrontal cortex, disinhibiting the activity of dopamine neurons projecting to the nucleus accumbens or prefrontal cortex, or activating CREB signaling in the hippocampus. These findings suggest that D3 receptor blockade may enhance cognitive performance in healthy individuals and treat cognitive dysfunction in individuals with a neuropsychiatric disorder. Clinical trials are needed to confirm these effects. PMID:23791072

  2. Effects of repeated treatment with the dopamine D2/D3 receptor partial agonist aripiprazole on striatal D2/D3 receptor availability in monkeys

    PubMed Central

    Czoty, Paul W.; Gage, H. Donald; Garg, Pradeep K.; Garg, Sudha; Nader, Michael A.

    2013-01-01

    Rationale Chronic treatment with dopamine (DA) receptor agonists and antagonists can differentially affect measures of DA D2/D3 receptor number and function, but the effects of chronic treatment with a partial D2/D3 receptor agonist are not clear. Objective We used a within-subjects design in male cynomolgus monkeys to determine the effects of repeated (17-day) treatment with the D2/D3 receptor partial agonist aripiprazole (ARI; 0.03 mg/kg and 0.1 mg/kg i.m.) on food-reinforced behavior (n=5) and on D2/D3 receptor availability as measured with positron emission tomography (PET; n=9). Methods Five monkeys responded under a fixed-ratio 50 schedule of food reinforcement and D2/D3 receptor availability was measured before and four days after ARI treatment using PET and the D2/D3 receptor-selective radioligand [18F]fluoroclebopride (FCP). Four additional monkeys were studied using [11C]raclopride and treated sequentially with each dose of ARI for 17 days. Results ARI decreased food-maintained responding with minimal evidence of tolerance. Repeated ARI administration increased FCP and raclopride distribution volume ratios (DVRs) in the caudate nucleus and putamen in most monkeys, but decreases were observed in monkeys with the highest baseline DVRs. Conclusions The results indicate that repeated treatment with a low efficacy DA receptor partial agonist produces effects on brain D2/D3 receptor availability that are qualitatively different from those of both high-efficacy receptor agonists and antagonists, and suggest that the observed individual differences in response to ARI treatment may reflect its partial agonist activity. PMID:24077804

  3. SU-F-P-64: The Impact of Plan Complexity Parameters On the Plan Quality and Deliverability of Volumetric Modulated Arc Therapy with Canonical Correlation Analysis

    SciTech Connect

    Jin, X; Yi, J; Xie, C

    2016-06-15

    Purpose: To evaluate the impact of complexity indices on the plan quality and deliverability of volumetric modulated arc therapy (VMAT), and to determine the most significant parameters in the generation of an ideal VMAT plan. Methods: A multi-dimensional exploratory statistical method, canonical correlation analysis (CCA) was adopted to study the correlations between VMAT parameters of complexity, quality and deliverability, as well as their contribution weights with 32 two-arc VMAT nasopharyngeal cancer (NPC) patients and 31 one-arc VMAT prostate cancer patients. Results: The MU per arc (MU/Arc) and MU per control point (MU/CP) of NPC were 337.8±25.2 and 3.7±0.3, respectively, which were significantly lower than those of prostate cancer patients (MU/Arc : 506.9±95.4, MU/CP : 5.6±1.1). The plan complexity indices indicated that two-arc VMAT plans were more complex than one-arc VMAT plans. Plan quality comparison confirmed that one-arc VMAT plans had a high quality than two-arc VMAT plans. CCA results implied that plan complexity parameters were highly correlated with plan quality with the first two canonical correlations of 0.96, 0.88 (both p<0.001) and significantly correlated with deliverability with the first canonical correlation of 0.79 (p<0.001), plan quality and deliverability was also correlated with the first canonical correlation of 0.71 (p=0.02). Complexity parameters of MU/CP, segment area (SA) per CP, percent of MU/CP less 3 and planning target volume (PTV) were weighted heavily in correlation with plan quality and deliveability . Similar results obtained from individual NPC and prostate CCA analysis. Conclusion: Relationship between complexity, quality, and deliverability parameters were investigated with CCA. MU, SA related parameters and PTV volume were found to have strong effect on the plan quality and deliverability. The presented correlation among different quantified parameters could be used to improve the plan quality and the efficiency

  4. How the NDA Provides Transparency and Visibility of the Technical Deliverability of the R and D Programme - 13303

    SciTech Connect

    Seed, Ian; James, Paula; Brownridge, Melanie; McMinn, Mervin

    2013-07-01

    The Nuclear Decommissioning Authority (NDA) was created under the UK Energy Act 2004 to ensure the UK historic civil public sector nuclear legacy sites are decommissioned safely, securely, cost effectively and in ways that protect the environment. The delivery will involve carrying out many unique projects within a high hazard environment requiring the very highest standards in safety, security and environmental management. Unique problems require unique solutions and there is a substantial amount of research and development required for each project. The NDA's R and D strategic objective is to ensure that delivery of the NDA's mission is technically underpinned by sufficient and appropriate research and development. This drives a requirement to provide transparency and visibility of the technical deliverability of the programme through the technical baseline and accompanying research and development requirements. The NDA need to have confidence in the technical deliverability of the Site License Companies (SLCs) plans, provide overall visibility of R and D across the NDA Estate and ensure that appropriate R and D is being carried out in a timely manner. They need to identify where coordinated R and D programmes may be advantageous as a result of common needs, risks and opportunities and ensure key R and D needs across NDA are identified, prioritised and work programmes are costed and scheduled in the Lifetime Plans for individual sites and SLCs. Evidence of the Site License Company's approach and their corresponding technical underpinning programmes is achieved through submission of a number of outputs collectively known as TBuRDs (Technical Baseline and Underpinning Research and Development Requirements). This paper is a summary of the information generated by an independent review of those TBuRDs. It highlights some of the key messages, synergies and common R and D activities across the estate. It demonstrates the value of a consistent approach to collecting R

  5. 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 exert distinct effects on human skeletal muscle function and gene expression

    PubMed Central

    Hassan-Smith, Zaki K.; Jenkinson, Carl; Smith, David J.; Hernandez, Ivan; Morgan, Stuart A.; Crabtree, Nicola J.; Gittoes, Neil J.; Keevil, Brian G.; Stewart, Paul M.

    2017-01-01

    Age-associated decline in muscle function represents a significant public health burden. Vitamin D-deficiency is also prevalent in aging subjects, and has been linked to loss of muscle mass and strength (sarcopenia), but the precise role of specific vitamin D metabolites in determining muscle phenotype and function is still unclear. To address this we quantified serum concentrations of multiple vitamin D metabolites, and assessed the impact of these metabolites on body composition/muscle function parameters, and muscle biopsy gene expression in a retrospective study of a cohort of healthy volunteers. Active serum 1,25-dihydroxyvitamin D3 (1α,25(OH)2D3), but not inactive 25-hydroxyvitamin D3 (25OHD3), correlated positively with measures of lower limb strength including power (rho = 0.42, p = 0.02), velocity (Vmax, rho = 0.40, p = 0.02) and jump height (rho = 0.36, p = 0.04). Lean mass correlated positively with 1α,25(OH)2D3 (rho = 0.47, p = 0.02), in women. Serum 25OHD3 and inactive 24,25-dihydroxyvitamin D3 (24,25(OH)2D3) had an inverse relationship with body fat (rho = -0.30, p = 0.02 and rho = -0.33, p = 0.01, respectively). Serum 25OHD3 and 24,25(OH)2D3 were also correlated with urinary steroid metabolites, suggesting a link with glucocorticoid metabolism. PCR array analysis of 92 muscle genes identified vitamin D receptor (VDR) mRNA in all muscle biopsies, with this expression being negatively correlated with serum 25OHD3, and Vmax, and positively correlated with fat mass. Of the other 91 muscle genes analysed by PCR array, 24 were positively correlated with 25OHD3, but only 4 were correlated with active 1α,25(OH)2D3. These data show that although 25OHD3 has potent actions on muscle gene expression, the circulating concentrations of this metabolite are more closely linked to body fat mass, suggesting that 25OHD3 can influence muscle function via indirect effects on adipose tissue. By contrast, serum 1α,25(OH)2D3 has limited effects on muscle gene expression

  6. Targeted delivery of 1,25-dihydroxyvitamin D3 to colon tissue and identification of a major 1,25-dihydroxyvitamin D3 glycoside from Solanumglaucophyllum plant leaves.

    PubMed

    Zimmerman, Duane R; Koszewski, Nicholas J; Hoy, Derrel A; Goff, Jesse P; Horst, Ronald L

    2015-04-01

    Leaves of the Solanum glaucophyllum (Sg) plant, indigenous to South America, have long been known for their calcinogenic toxicity in ruminant animals. It was determined the leaves contained glycosidic derivatives of 1,25-dihydroxyvitamin D3 (1,25D3) and liberation of the free hormone by rumen bacterial populations elicited a hypercalcemic response. Our interest in the leaves is predicated on the concept that the glycoside forms of 1,25D3 would target release of the active hormone in the lower gut of non-ruminant mammals. This would provide a means of delivering 1,25D3 directly to the colon, where the hormone has been shown to have beneficial effects in models of inflammatory bowel disease (IBD) and colon cancer. We fed mice for 10 days with variable amounts of Sg leaf. Feeding 7-333μg leaf/day produced no changes in plasma Ca(2+) and 1,25D3 concentrations, and only at ≥1000μg leaf/day did these values become significantly elevated compared to controls. Gene expression studies from colon tissue indicated a linear relationship between the amount of leaf consumed and expression of the Cyp24a1 gene. In contrast, Cyp24a1 gene expression in the duodenums and ileums of these mice was unchanged compared to controls. One of the major 1,25D3-glycosides was isolated from leaves following extraction and purification by Sep-Pak cartridges and HPLC fractionation. Ultraviolet absorbance was consistent with modification of the 1-hydroxyl group, and positive ion ESI mass spectrometry indicated a diglycoside of 1,25D3. 2-Dimensional NMR analyses were carried out and established the C1 proton of the A-ring was interacting with a C1' sugar proton, while the C3 proton of the A-ring was linked with a second C1' sugar proton. The structure of the isolated compound is therefore consistent with a β-linked 1,3-diglycoside of 1,25D3. Thus, Sg leaf administered to mice at up to 333 ug/day can elicit colon-specific enhancement of Cyp24a1 gene expression without inducing hypercalcemia, and

  7. Antidepressants differentially related to 1,25-(OH)2 vitamin D3 and 25-(OH) vitamin D3 in late-life depression

    PubMed Central

    Oude Voshaar, R C; Derks, W J; Comijs, H C; Schoevers, R A; de Borst, M H; Marijnissen, R M

    2014-01-01

    A low plasma 25-OH vitamin D3 level is a universal risk factor for a wide range of diseases and has also been implicated in late-life depression. It is currently unknown whether the biologically active form of vitamin D, that is, 1,25-(OH)2 vitamin D3, is also decreased in late-life depression, or whether vitamin D levels correlate with specific depression characteristics. We determined plasma 25-OH vitamin D3, 1,25-(OH)2 vitamin D3 and parathormone levels in 355 depressed older persons and 124 non-depressed comparison subjects (age⩾60 years). Psychopathology was established with the Composite International Diagnostic Interview 2.1, together with potential confounders and depression characteristics (severity, symptom profile, age of onset, recurrence, chronicity and antidepressant drug use). Adjusted for confounders, depressed patients had significantly lower levels of 25-OH vitamin D33 (Cohen's d =0.28 (95% confidence interval: 0.07–0.49), P=0.033) as well as 1,25-(OH)2 vitamin D3 (Cohen's d =0.48 (95% confidence interval: 0.27–0.70), P<0.001) than comparison subjects. Of all depression characteristics tested, only the use of tricyclic antidepressants (TCAs) was significantly correlated with lower 1,25-(OH)2 vitamin D3 levels (Cohen's d =0.86 (95% confidence interval: 0.53–1.19), P<0.001), but not its often measured precursor 25-OH vitamin D3. As vitamin D levels were significantly lower after adjustment for confounders, vitamin D might have an aetiological role in late-life depression. Differences between depressed and non-depressed subjects were largest for the biologically active form of vitamin D. The differential impact of TCAs on 25-OH vitamin D3 and 1,25-(OH)2 vitamin D3 levels suggests modulation of 1-α-hydroxylase and/or 24-hydroxylase, which may in turn have clinical implications for biological ageing mechanisms in late-life depression. PMID:24736799

  8. Reduced sleep duration mediates decreases in striatal D2/D3 receptor availability in cocaine abusers

    PubMed Central

    Wiers, C E; Shumay, E; Cabrera, E; Shokri-Kojori, E; Gladwin, T E; Skarda, E; Cunningham, S I; Kim, S W; Wong, T C; Tomasi, D; Wang, G-J; Volkow, N D

    2016-01-01

    Neuroimaging studies have documented reduced striatal dopamine D2/D3 receptor (D2/D3R) availability in cocaine abusers, which has been associated with impaired prefrontal activity and vulnerability for relapse. However, the mechanism(s) underlying the decreases in D2/D3R remain poorly understood. Recent studies have shown that sleep deprivation is associated with a downregulation of striatal D2/D3R in healthy volunteers. As cocaine abusers have disrupted sleep patterns, here we investigated whether reduced sleep duration mediates the relationship between cocaine abuse and low striatal D2/D3R availability. We used positron emission tomography with [11C]raclopride to measure striatal D2/D3R availability in 24 active cocaine abusers and 21 matched healthy controls, and interviewed them about their daily sleep patterns. Compared with controls, cocaine abusers had shorter sleep duration, went to bed later and reported longer periods of sleep disturbances. In addition, cocaine abusers had reduced striatal D2/D3R availability. Sleep duration predicted striatal D2/D3R availability and statistically mediated the relationship between cocaine abuse and striatal D2/D3R availability. These findings suggest that impaired sleep patterns contribute to the low striatal D2/D3R availability in cocaine abusers. As sleep impairments are similarly observed in other types of substance abusers (for example, alcohol and methamphetamine), this mechanism may also underlie reductions in D2/D3R availability in these groups. The current findings have clinical implications suggesting that interventions to improve sleep patterns in cocaine abusers undergoing detoxification might be beneficial in improving their clinical outcomes. PMID:26954979

  9. Vitamin D(3) is more potent than vitamin D(2) in humans.

    PubMed

    Heaney, Robert P; Recker, Robert R; Grote, James; Horst, Ronald L; Armas, Laura A G

    2011-03-01

    Current unitage for the calciferols suggests that equimolar quantities of vitamins D(2) (D2) and D(3) (D3) are biologically equivalent. Published studies yield mixed results. The aim of the study was to compare the potencies of D2 and D3. The trial used a single-blind, randomized design in 33 healthy adults. Calciferols were dosed at 50,000 IU/wk for 12 wk. Principal outcome variables were area under the curve for incremental total 25-hydroxyvitamin D [25(OH)D] and change in calciferol content of sc fat. Incremental mean (sd) 25(OH)D area under the curve at 12 wk was 1366 ng · d/ml (516) for the D2-treated group and 2136 (606) for the D3 (P < 0.001). Mean (sd) steady-state 25(OH)D increments showed similar differences: 24 ng/ml for D2 (10.3) and 45 ng/ml (16.2) for D3 (P <0.001). Subcutaneous fat content of D2 rose by 50 μg/kg in the D2-treated group, and D3 content rose by 104 μg/kg in the D3-treated group. Total calciferol in fat rose by only 33 ng/kg in the D2-treated, whereas it rose by 104 μg/kg in the D3-treated group. Extrapolating to total body fat D3, storage amounted to just 17% of the administered dose. D3 is approximately 87% more potent in raising and maintaining serum 25(OH)D concentrations and produces 2- to 3-fold greater storage of vitamin D than does equimolar D2. For neither was there evidence of sequestration in fat, as had been postulated for doses in this range. Given its greater potency and lower cost, D3 should be the preferred treatment option when correcting vitamin D deficiency.

  10. Condensin II Subunit dCAP-D3 Restricts Retrotransposon Mobilization in Drosophila Somatic Cells

    PubMed Central

    Schuster, Andrew T.; Sarvepalli, Kavitha; Murphy, Eain A.; Longworth, Michelle S.

    2013-01-01

    Retrotransposon sequences are positioned throughout the genome of almost every eukaryote that has been sequenced. As mobilization of these elements can have detrimental effects on the transcriptional regulation and stability of an organism's genome, most organisms have evolved mechanisms to repress their movement. Here, we identify a novel role for the Drosophila melanogaster Condensin II subunit, dCAP-D3 in preventing the mobilization of retrotransposons located in somatic cell euchromatin. dCAP-D3 regulates transcription of euchromatic gene clusters which contain or are proximal to retrotransposon sequence. ChIP experiments demonstrate that dCAP-D3 binds to these loci and is important for maintaining a repressed chromatin structure within the boundaries of the retrotransposon and for repressing retrotransposon transcription. We show that dCAP-D3 prevents accumulation of double stranded DNA breaks within retrotransposon sequence, and decreased dCAP-D3 levels leads to a precise loss of retrotransposon sequence at some dCAP-D3 regulated gene clusters and a gain of sequence elsewhere in the genome. Homologous chromosomes exhibit high levels of pairing in Drosophila somatic cells, and our FISH analyses demonstrate that retrotransposon-containing euchromatic loci are regions which are actually less paired than euchromatic regions devoid of retrotransposon sequences. Decreased dCAP-D3 expression increases pairing of homologous retrotransposon-containing loci in tissue culture cells. We propose that the combined effects of dCAP-D3 deficiency on double strand break levels, chromatin structure, transcription and pairing at retrotransposon-containing loci may lead to 1) higher levels of homologous recombination between repeats flanking retrotransposons in dCAP-D3 deficient cells and 2) increased retrotransposition. These findings identify a novel role for the anti-pairing activities of dCAP-D3/Condensin II and uncover a new way in which dCAP-D3/Condensin II influences local

  11. Dopamine D3 receptor knockout mice exhibit abnormal nociception in a sex-different manner.

    PubMed

    Liu, Peng; Xing, Bo; Chu, Zheng; Liu, Fei; Lei, Gang; Zhu, Li; Gao, Ya; Chen, Teng; Dang, Yong-Hui

    2016-09-26

    Pain is a complex and subjective experience. Previous studies have shown that mice lacking the dopamine D3 receptor (D3RKO) exhibit hypoalgesia, indicating a role of the D3 receptor in modulation of nociception. Given that there are sex differences in pain perception, there may be differences in responses to nociceptive stimuli between male and female D3RKO mice. In the current study, we examined the role of the D3 receptor in modulating nociception in male and female D3RKO mice. Acute thermal pain was modeled by hot-plate test. This test was performed at different temperatures including 52°C, 55°C, and 58°C. The von Frey hair test was applied to evaluate mechanical pain. And persistent pain produced by peripheral tissue injury and inflammation was modeled by formalin test. In the hot-plate test, compared with wild-type (WT) mice, D3RKO mice generally exhibited longer latencies at each of the three temperatures. Specially, male D3RKO mice showed hypoalgesia compared with male WT mice when the temperature was 55°C, while for the female mice, there was a statistical difference between genotypes when the test condition was 52°C. In the von Frey hair test, both male and female D3RKO mice exhibited hypoalgesia. In the formalin test, the male D3RKO mice displayed a similar nociceptive behavior as their sex-matched WT littermates, whereas significantly depressed late-phase formalin-induced nociceptive behaviors were observed in the female mutants. These findings indicated that the D3 receptor affects nociceptive behaviors in a sex-specific manner and that its absence induces more analgesic behavior in the female knockout mice. © 2016 Wiley Periodicals, Inc.

  12. Role of 1,25-Dihydroxyvitamin D3 in Maintaining Serum Phosphorus and Curing Rickets

    PubMed Central

    Tanaka, Y.; Deluca, H. F.

    1974-01-01

    The intravenous injection of a single dose of 650 pmoles of 1,25-dihydroxyvitamin D3 to rats fed a vitamin D-deficient, low-phosphorus diet caused an elevation of serum phosphorus within 5 hours which reached a maximum in about 10-12 hours. This elevated serum phosphorus returned to deficiency levels 2-3 days later. On the other hand, a single injection of 650 pmoles of 25-hydroxyvitamin D3 produced a significant rise at 12 hours, reached a maximum in 24-36 hours, and was maintained for at least 7 days. The single dose of 1,25-dihydroxyvitamin D3 supported little calcification of bone, whereas the 25-hydroxyvitamin D3 produced marked calcification. Six-hundred and fifty pmoles of 24,25-dihydroxyvitamin D3 increased serum phosphorus only slightly and induced no calcification. When 1,25-dihydroxyvitamin D3 was given each day, a sustained increase in serum phosphorus and marked bone calcification resulted. In contrast to the serum phosphorus responses, intestinal calcium transport remained high 5 days after administration of a single dose of 1,25-dihydroxyvitamin D3. Serum calcium was not changed appreciably by any of the metabolites. Thyroparathyroidectomized rats or rats fed a diet extremely deficient in phosphate still exhibited a marked elevation of serum phosphorus in response to 1,25-dihydroxyvitamin D3. The effect of 1,25-dihydroxyvitamin D3 on serum phosphorus was greatly reduced in nephrectomized rats, suggesting that the serum phosphorus response to 1,25-dihydroxyvitamin D3 may arise from an enhancement of phosphate reabsorption in the renal tubules. It is suggested that 1,25-dihydroxyvitamin D3 cures rickets in rats by increasing the concentration of serum phosphorus rather than by increasing serum calcium concentration and calcium absorption. PMID:4524612

  13. Serum 25–Hydroxyvitamin D3 and Mammography Density among Mexican Women

    PubMed Central

    Amadou, Amina; Biessy, Carine; Rinaldi, Sabina; Fedirko, Veronika; Assi, Nada; Lajous, Martin; Ortiz-Panozo, Eduardo; Yunes, Elsa; Lopez-Ridaura, Ruy; Torres-Mejia, Gabriela; Romieu, Isabelle

    2016-01-01

    Low circulating levels of vitamin D and high mammographic density (MD) have been associated with higher risk of breast cancer. Although some evidence suggested an inverse association between circulating vitamin D and MD, no studies have investigated this association among Mexican women. We examined whether serum 25−hydroxyvitamin D3 [25(OH)D3] levels were associated with MD in a cross-sectional study nested within the large Mexican Teacher's Cohort. This study included 491 premenopausal women with a mean age of 42.9 years. Serum 25(OH)D3 levels were measured by liquid chromatography/tandem mass spectrometry. Linear regression and non-linear adjusted models were used to estimate the association of MD with serum 25(OH)D3. Median serum 25(OH)D3 level was 27.3 (23.3–32.8) (ng/ml). Forty one (8%) women had 25(OH)D3 levels in the deficient range (< 20 ng/ml). Body mass index (BMI) and total physical activity were significantly correlated with 25(OH)D3 (r = −0.109, P = 0.019 and r = 0.095, P = 0.003, respectively). In the multivariable linear regression, no significant association was observed between 25(OH)D3 levels and MD overall. However, in stratified analyses, higher serum 25(OH)D3 levels (≥27.3 ng/ml) were significantly inversely associated with percent MD among women with BMI below the median (β = −0.52, P = 0.047). Although no significant association was observed between serum 25(OH)D3 and percent MD in the overall population, specific subgroups of women may benefit from higher serum 25(OH)D3 levels. PMID:27564705

  14. Vitamin D3 pretreatment regulates renal inflammatory responses during lipopolysaccharide-induced acute kidney injury.

    PubMed

    Xu, Shen; Chen, Yuan-Hua; Tan, Zhu-Xia; Xie, Dong-Dong; Zhang, Cheng; Zhang, Zhi-Hui; Wang, Hua; Zhao, Hui; Yu, De-Xin; Xu, De-Xiang

    2015-12-22

    Vitamin D receptor (VDR) is highly expressed in human and mouse kidneys. Nevertheless, its functions remain obscure. This study investigated the effects of vitamin D3 (VitD3) pretreatment on renal inflammation during lipopolysaccharide (LPS)-induced acute kidney injury. Mice were intraperitoneally injected with LPS. In VitD3 + LPS group, mice were pretreated with VitD3 (25 μg/kg) at 48, 24 and 1 h before LPS injection. As expected, an obvious reduction of renal function and pathological damage was observed in LPS-treated mice. VitD3 pretreatment significantly alleviated LPS-induced reduction of renal function and pathological damage. Moreover, VitD3 pretreatment attenuated LPS-induced renal inflammatory cytokines, chemokines and adhesion molecules. In addition, pretreatment with 1,25(OH)2D3, the active form of VitD3, alleviated LPS-induced up-regulation of inflammatory cytokines and chemokines in human HK-2 cells, a renal tubular epithelial cell line, in a VDR-dependent manner. Further analysis showed that VitD3, which activated renal VDR, specifically repressed LPS-induced nuclear translocation of nuclear factor kappa B (NF-κB) p65 subunit in the renal tubules. LPS, which activated renal NF-κB, reciprocally suppressed renal VDR and its target gene. Moreover, VitD3 reinforced the physical interaction between renal VDR and NF-κB p65 subunit. These results provide a mechanistic explanation for VitD3-mediated anti-inflammatory activity during LPS-induced acute kidney injury.

  15. Condensin II subunit dCAP-D3 restricts retrotransposon mobilization in Drosophila somatic cells.

    PubMed

    Schuster, Andrew T; Sarvepalli, Kavitha; Murphy, Eain A; Longworth, Michelle S

    2013-10-01

    Retrotransposon sequences are positioned throughout the genome of almost every eukaryote that has been sequenced. As mobilization of these elements can have detrimental effects on the transcriptional regulation and stability of an organism's genome, most organisms have evolved mechanisms to repress their movement. Here, we identify a novel role for the Drosophila melanogaster Condensin II subunit, dCAP-D3 in preventing the mobilization of retrotransposons located in somatic cell euchromatin. dCAP-D3 regulates transcription of euchromatic gene clusters which contain or are proximal to retrotransposon sequence. ChIP experiments demonstrate that dCAP-D3 binds to these loci and is important for maintaining a repressed chromatin structure within the boundaries of the retrotransposon and for repressing retrotransposon transcription. We show that dCAP-D3 prevents accumulation of double stranded DNA breaks within retrotransposon sequence, and decreased dCAP-D3 levels leads to a precise loss of retrotransposon sequence at some dCAP-D3 regulated gene clusters and a gain of sequence elsewhere in the genome. Homologous chromosomes exhibit high levels of pairing in Drosophila somatic cells, and our FISH analyses demonstrate that retrotransposon-containing euchromatic loci are regions which are actually less paired than euchromatic regions devoid of retrotransposon sequences. Decreased dCAP-D3 expression increases pairing of homologous retrotransposon-containing loci in tissue culture cells. We propose that the combined effects of dCAP-D3 deficiency on double strand break levels, chromatin structure, transcription and pairing at retrotransposon-containing loci may lead to 1) higher levels of homologous recombination between repeats flanking retrotransposons in dCAP-D3 deficient cells and 2) increased retrotransposition. These findings identify a novel role for the anti-pairing activities of dCAP-D3/Condensin II and uncover a new way in which dCAP-D3/Condensin II influences local

  16. Associations of maternal circulating 25-hydroxyvitamin D3 concentration with pregnancy and birth outcomes.

    PubMed

    Rodriguez, A; García-Esteban, R; Basterretxea, M; Lertxundi, A; Rodríguez-Bernal, C; Iñiguez, C; Rodriguez-Dehli, C; Tardón, A; Espada, M; Sunyer, J; Morales, E

    2015-11-01

    To investigate the association of maternal circulating 25-hydroxyvitamin D3 [25(OH)D3] concentration with pregnancy and birth outcomes. Prospective cohort study. Four geographical areas of Spain, 2003-2008. Of 2382 mother-child pairs participating in the INfancia y Medio Ambiente (INMA) Project. Maternal circulating 25(OH)D3 concentration was measured in pregnancy (mean [SD] 13.5 [2.2] weeks of gestation). We tested associations of maternal 25(OH)D3 concentration with pregnancy and birth outcomes. Gestational diabetes mellitus (GDM), preterm delivery, caesarean section, fetal growth restriction (FGR) and small-for-gestational age (SGA), anthropometric birth outcomes including weight, length and head circumference (HC). Overall, 31.8% and 19.7% of women had vitamin D insufficiency [25(OH)D3 20-29.99 ng/ml] and deficiency [25(OH)D3 < 20 ng/ml], respectively. After adjustment, there was no association between maternal 25(OH)D3 concentration and risk of GDM or preterm delivery. Women with sufficient vitamin D [25(OH)D3 ≥ 30 ng/ml] had a decreased risk of caesarean section by obstructed labour compared with women with vitamin D deficiency [relative risk (RR) = 0.60, 95% CI 0.37, 0.97). Offspring of mothers with higher circulating 25(OH)D3 concentration tended to have smaller HC [coefficient (SE) per doubling concentration of 25(OH)D3, -0.10 (0.05), P = 0.038]. No significant associations were found for other birth outcomes. This study did not find any evidence of an association between vitamin D status in pregnancy and GDM, preterm delivery, FGR, SGA and anthropometric birth outcomes. Results suggest that sufficient circulating vitamin D concentration [25(OH)D3 ≥ 30 ng/ml] in pregnancy may reduce the risk of caesarean section by obstructed labour. © 2014 Royal College of Obstetricians and Gynaecologists.

  17. Clinical and biochemical impact of the d3 growth hormone receptor genotype in acromegaly.

    PubMed

    Mercado, Moisés; González, Baldomero; Sandoval, Carolina; Esquenazi, Yoshua; Mier, Fernando; Vargas, Guadalupe; de los Monteros, Ana Laura Espinosa; Sosa, Ernesto

    2008-09-01

    Lack of exon 3 of the GH receptor (d3-GHR) has been associated with increased responsiveness to GH therapy. By analogy, we hypothesized that patients with acromegaly bearing the d3-GHR genotype may have a more morbid clinical and biochemical picture. Our objective was to determine whether the GHR genotype, by modifying tissue sensitivity to GH, influences the clinical/biochemical expression of acromegaly and its outcome after treatment. The study was conducted at a specialized clinic at a tertiary care hospital. We conducted a prospective genotype investigation and retrospective analysis and correlation with clinical, biochemical, and outcome data from a group of 148 patients. Samples from 175 healthy blood donors were used as controls. GHR genotyping was performed by real-time PCR. We assessed prevalence of the three GHR genotypes (fl/fl, d3/d3, and d3/fl), associations between the genotypes, and baseline as well as post-therapeutic characteristics. Prevalence of the fl/fl, d3/d3, and d3/fl genotypes was 45, 22, and 32%, respectively, similar to what was found in the controls. Baseline characteristics were similar in carriers of the three genotypes. A positive correlation between IGF-I and log GH concentrations was significant only in homo- or heterozygous d3 carriers. Among d3-GHR carriers, diabetes, but no other comorbidities, was more prevalent (odds ratio = 2.02; 95% confidence interval = 0.96-4.2). d3-GHR carriers had significantly higher IGF-I concentrations after treatment. Multiple regression analysis revealed that the homo- or heterozygous lack of exon 3 was the strongest predictor of persistent biochemical activity (odds ratio = 1.29; 95% confidence interval = 0.65-2.58). The absence of exon 3 of the GHR may be associated with a more morbid acromegalic clinical and biochemical picture and a lower chance of achieving IGF-I normalization after therapy.

  18. Induction of CFTR gene expression by 1,25(OH)2 vitamin D3, 25OH vitamin D3, and vitamin D3 in cultured human airway epithelial cells and in mouse airways.

    PubMed

    DiFranco, Kristina M; Mulligan, Jennifer K; Sumal, Aman S; Diamond, Gill

    2017-01-24

    Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which often leads to protein misfolding and no CFTR surface localization. This then leads to chronic airway infections, inflammation, and tissue damage. Although vitamin D has been explored as a therapy to treat CF due to its antimicrobial-inducing and anti-inflammatory properties, the effect of 1,25-dihydroxyvitamin D3 (1α,25(OH)2D3) on CFTR directly has not been studied. We treated cultured healthy and diseased bronchial epithelial cells (BEC) with 10nM 1α,25(OH)2D3 for 6 and 24h and found that 1α,25(OH)2D3 increases both mRNA and protein CFTR levels using RT-qPCR, flow cytometry and fluorescence immunohistochemistry. Treatment of CF cells with 10nM 1α,25(OH)2D3 led to an increase in both total and surface CFTR expression, suggesting 1α,25(OH)2D3 could be used to increase properly localized CFTR in airway cells. To determine if BEC could convert the more clinically relevant cholecalciferol to 25OHD3, cultured non-CF and CF BECs were treated with a range of cholecalciferol concentrations, and 25OHD3 levels were quantified by ELISA. We found that 25OHD3 levels increased in a concentration-dependent manner. Treatment of BEC with 10μM cholecalciferol led to increases in both CYP24A1 and CFTR mRNA levels, even when added to the apical surface of cells grown in an air-liquid interface, suggesting that topical administration of vitamin D could be used therapeutically. To demonstrate this in vivo, we intranasally delivered 1μM 1α,25(OH)2D3 into mice. After 6h, we observed induction of both Cyp24A1 and CFTR expression in the tracheas of treated mice. The major findings of this study are that vitamin D can be converted to the active form when topically administered to the airway, and this could be used to increase CFTR levels in patients with CF. This could potentially be useful as an adjunctive therapy, together with

  19. Brain Regional and Cortical Laminar Effects of Selective D3 Agonists and Antagonists

    PubMed Central

    Choi, Ji-Kyung; Mandeville, Joseph B.; Chen, Y. Iris; Grundt, Peter; Sarkar, Susanta; Newman, Amy Hauck; Jenkins, Bruce G.

    2013-01-01

    Dopamine receptors are divided into two families: D1 including D1 and D5 receptors and D2 including D2, D3 and D4 receptors. The role of dopamine D3 receptors in the brain remains controversial. We found that highly selective D3 antagonists induced positive cerebral blood volume (CBV) changes whereas D3 agonism using 7-OH-DPAT induced negative CBV changes in brain regions including nucleus accumbens, antero-medial striatum, cingulate cortex, thalamus, interpeduncular region and hypothalamus. There was pronounced activation in the hippocampus restricted to the subiculum – the output from the infralimbic cortex and dentate gyrus. At higher doses of D3 agonist, functional changes were differentiated across cortical lamina, with layer V–VI yielding positive CBV changes and layer IV yielding negative CBV changes. These results are consistent with differential D1 and D3 innervation in these layers respectively and provide evidence of D1–D3 receptor interactions. Further, the use of MRI provides a new tool for testing the in vivo selectivity of novel dopaminergic ligands where radiolabels are not available - as in the case of D3 receptors. PMID:20628733

  20. On the breakdown of asymptotic Poincare invariance in D = 3 Einstein gravity

    NASA Technical Reports Server (NTRS)

    Deser, S.

    1985-01-01

    It is shown through a series of calculations that neither momentum nor boosts are definable for finite energy solutions of Einstein gravity in D = 3. The contrast between the effects of Lorentz transformations on the corresponding metrics for D = 3 and D = 4 gravity is demonstrated, and some comparisons with the vector gauge treatment of the problem are offered.

  1. Overestimation of salivary 25-hydroxyvitamin D3 level when using stimulated saliva with gum-chewing.

    PubMed

    Higashi, Tatsuya; Hijikuro, Masayoshi; Yamagata, Kenichiro; Ogawa, Shoujiro

    2013-09-01

    The measurement of 25-hydroxyvitamin D3 [25(OH)D3] in whole saliva can be a noninvasive tool for assessing vitamin D status. Gum-chewing increases salivation and is often used to collect an adequate sample volume of saliva within a shorter time. The aim of this study was to clarify whether the concentration of 25(OH)D3 in whole saliva is influenced by gum-chewing. Stimulated saliva was collected from healthy volunteers chewing a tasteless and flavorless chewing gum after unstimulated saliva was collected without gum-chewing. The salivary 25(OH)D3 and albumin concentrations were measured. The salivary 25(OH)D3 concentration was reproducibly measured when saliva was collected without gum-chewing, whereas the concentration was significantly increased by gum-chewing (p<0.05, paired t-test). One of the causes for the gum-chewing-induced increase in the 25(OH)D3 concentration may be the increased amount of protein-bound 25(OH)D3 in whole saliva. Stimulated saliva by gum-chewing should be used with caution in the measurement of 25(OH)D3. The protein binding rate in plasma is a significant consideration when predicting whether the salivary concentration of a compound is varied by gum-chewing. Copyright © 2013 Elsevier Inc. All rights reserved.

  2. 16 CFR Appendix D3 to Part 305 - Water Heaters-Oil

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 16 Commercial Practices 1 2012-01-01 2012-01-01 false Water Heaters-Oil D3 Appendix D3 to Part 305 Commercial Practices FEDERAL TRADE COMMISSION REGULATIONS UNDER SPECIFIC ACTS OF CONGRESS RULE CONCERNING... Part 305—Water Heaters—Oil Range Information CAPACITY FIRST HOUR RATING Range of Estimated...

  3. Comparison of analysis of vitamin D3 in foods using ultraviolet and mass spectrometric detection

    USDA-ARS?s Scientific Manuscript database

    A method for analysis of vitamin D3 in commonly fortified foods and in fish, which contains endogenous vitamin D3, was developed by combining the best aspects of two official methods. The ethyl ether/petroleum ether extraction procedure from AOAC 992.26 was combined with the chromatographic separat...

  4. Increased vulnerability to cocaine in mice lacking dopamine D3 receptors.

    PubMed

    Song, Rui; Zhang, Hai-Ying; Li, Xia; Bi, Guo-Hua; Gardner, Eliot L; Xi, Zheng-Xiong

    2012-10-23

    Neuroimaging studies using positron emission tomography suggest that reduced dopamine D(2) receptor availability in the neostriatum is associated with increased vulnerability to drug addiction in humans and experimental animals. The role of D(3) receptors (D(3)Rs) in the neurobiology of addiction remains unclear, however. Here we report that D(3)R KO (D(3)(-/-)) mice display enhanced cocaine self-administration and enhanced motivation for cocaine-taking and cocaine-seeking behavior. This increased vulnerability to cocaine is accompanied by decreased dopamine response to cocaine secondary to increased basal levels of extracellular dopamine in the nucleus accumbens, suggesting a compensatory response to decreased cocaine reward in D(3)(-/-) mice. In addition, D(3)(-/-) mice also display up-regulation of dopamine transporters in the striatum, suggesting a neuroadaptative attempt to normalize elevated basal extracellular dopamine. These findings suggest that D(3)R deletion increases vulnerability to cocaine, and that reduced D(3)R availability in the brain may constitute a risk factor for the development of cocaine addiction.

  5. 22 CFR 40.301 - Waiver for ineligible nonimmigrants under INA 212(d)(3)(A).

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ...)(ii), (3)(A)(iii), (3)(C), (3)(E)(i), or (3)(E)(ii). (b) Recommendation to designated DHS officer... 212(d)(3)(A). 40.301 Section 40.301 Foreign Relations DEPARTMENT OF STATE VISAS REGULATIONS PERTAINING... Ground of Ineligibility § 40.301 Waiver for ineligible nonimmigrants under INA 212(d)(3)(A). (a)...

  6. 26 CFR 31.3406(d)-3 - Special 30-day rules for certain reportable payments.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 15 2010-04-01 2010-04-01 false Special 30-day rules for certain reportable payments. 31.3406(d)-3 Section 31.3406(d)-3 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... account. (b) Sale of an instrument for a customer by electronic transmission or by mail. The special...

  7. 16 CFR Appendix D3 to Part 305 - Water Heaters-Oil

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 16 Commercial Practices 1 2013-01-01 2013-01-01 false Water Heaters-Oil D3 Appendix D3 to Part 305... DISCLOSURES REGARDING ENERGY CONSUMPTION AND WATER USE OF CERTAIN HOME APPLIANCES AND OTHER PRODUCTS REQUIRED... Part 305—Water Heaters—Oil Range Information CAPACITY FIRST HOUR RATING Range of Estimated...

  8. Dopamine D(3) receptor deficiency sensitizes mice to iron deficiency-related deficits in motor learning.

    PubMed

    Klinker, F; Hasan, K; Dowling, P; Paulus, W; Liebetanz, D

    2011-07-07

    Iron deficiency is a widespread form of malnutrition and is known to interfere with cognitive performance and development. To elucidate the role of dopamine D3 and iron deficiency (ID) in inducing cognitive deficits, we studied wildtype and D3 knockout mice on normal or iron-deficient diets subjected to a running wheel-based motor skill sequence. Surprisingly, ID alone had no effect on motor learning in this study, whereas combined ID and dopamine D(3) receptor (D3R)-deficiency significantly interfered with the acquisition of motor skills. Reduced D3R function may serve as a predisposing factor towards ID-related effects on motor learning. Copyright © 2011 Elsevier B.V. All rights reserved.

  9. D3D augmented reality imaging system: proof of concept in mammography.

    PubMed

    Douglas, David B; Petricoin, Emanuel F; Liotta, Lance; Wilson, Eugene

    2016-01-01

    The purpose of this article is to present images from simulated breast microcalcifications and assess the pattern of the microcalcifications with a technical development called "depth 3-dimensional (D3D) augmented reality". A computer, head display unit, joystick, D3D augmented reality software, and an in-house script of simulated data of breast microcalcifications in a ductal distribution were used. No patient data was used and no statistical analysis was performed. The D3D augmented reality system demonstrated stereoscopic depth perception by presenting a unique image to each eye, focal point convergence, head position tracking, 3D cursor, and joystick fly-through. The D3D augmented reality imaging system offers image viewing with depth perception and focal point convergence. The D3D augmented reality system should be tested to determine its utility in clinical practice.

  10. D3D augmented reality imaging system: proof of concept in mammography

    PubMed Central

    Douglas, David B; Petricoin, Emanuel F; Liotta, Lance; Wilson, Eugene

    2016-01-01

    Purpose The purpose of this article is to present images from simulated breast microcalcifications and assess the pattern of the microcalcifications with a technical development called “depth 3-dimensional (D3D) augmented reality”. Materials and methods A computer, head display unit, joystick, D3D augmented reality software, and an in-house script of simulated data of breast microcalcifications in a ductal distribution were used. No patient data was used and no statistical analysis was performed. Results The D3D augmented reality system demonstrated stereoscopic depth perception by presenting a unique image to each eye, focal point convergence, head position tracking, 3D cursor, and joystick fly-through. Conclusion The D3D augmented reality imaging system offers image viewing with depth perception and focal point convergence. The D3D augmented reality system should be tested to determine its utility in clinical practice. PMID:27563261

  11. Interactions of 1,25-dihydroxyvitamin D3 and the immune system.

    PubMed

    Manolagas, S C; Provvedini, D M; Tsoukas, C D

    1985-12-01

    A series of recent discoveries indicate that the hormonal form of vitamin D3, namely, 1,25(OH)2D3 plays a role in the regulation of the immune system. Cells of the monocyte/macrophage lineage possess receptors for 1,25(OH)2D3 regardless of their activation stage; cells of the lymphoid lineage also express these receptors but only at certain stages of their differentiation pathway and upon activation. Further, 1,25(OH)2D3 promotes the differentiation of monocyte precursors towards monocyte/macrophages and enhances monocyte function in antigen presentation. In addition 1,25(OH)2D3 is a potent inhibitor of interleukin-2 (IL-2) and suppresses effector functions of both T and B lymphocytes via IL-2-dependent as well as via IL-2-independent mechanisms. The theoretical and clinical implications of these discoveries are discussed.

  12. Adaptive cylindrical lens array for 2D/3D switchable display

    NASA Astrophysics Data System (ADS)

    Zhao, Wu-Xiang; Deng, Huan; Wang, Qiong-Hua

    2017-02-01

    An adaptive Cylindrical Lens Array (ACLA) for a 2D/3D switchable display is demonstrated. The ACLA is based on two transparent liquids of different refractive indexes and an elastic membrane. Driving these two liquids to flow can change the shape of the elastic membrane as well as the focal length. In this design, the gravity effect of liquid can be overcome. An ACLA demo for the 2D/3D switchable display is developed. The experimental result shows that the ACLA demo works as a light splitting and 2D/3D switching component of the 2D/3D switchable display effectively and the 2D/3D switchable display is realized.

  13. Pramipexole Derivatives as Potent and Selective Dopamine D3 Receptor Agonists with Improved Human Microsomal Stability

    PubMed Central

    Jiang, Cheng; Levant, Beth; Li, Xiaoqin; Zhao, Ting; Wen, Bo; Luo, Ruijuan; Sun, Duxin

    2014-01-01

    We report herein the synthesis and evaluation of a series of new pramipexole derivatives as highly potent and selective dopamine-3 (D3) receptor agonists. A number of these new compounds bind to the D3 receptor with subnanomolar affinities and show excellent selectivity (>10,000) for the D3 receptor over the D1 and D2 receptors. Compound 23 for example, binds to the D3 receptor with a Ki value of 0.53 nM and shows a selectivity of >20,000 over the D2 receptor and the D1 receptor in the binding assays using a rat brain preparation. It has excellent stability in human liver microsomes and in vitro functional assays showed it to be a full agonist for the human D3 receptor. PMID:25338762

  14. Regression/Eradication of gliomas in mice by a systemically-deliverable ATF5 dominant-negative peptide

    PubMed Central

    Cates, Charles C.; Arias, Angelo D.; Wong, Lynn S. Nakayama; Lamé, Michael W.; Sidorov, Maxim; Cayanan, Geraldine; Rowland, Douglas J.; Fung, Jennifer; Karpel-Massler, Georg; Siegelin, Markus D.; Greene, Lloyd A.; Angelastro, James M.

    2016-01-01

    Malignant gliomas have poor prognosis and urgently require new therapies. Activating Transcription Factor 5 (ATF5) is highly expressed in gliomas, and interference with its expression/function precipitates targeted glioma cell apoptosis in vitro and in vivo. We designed a novel deliverable truncated-dominant-negative (d/n) form of ATF5 fused to a cell-penetrating domain (Pen-d/n-ATF5-RP) that can be intraperitoneally/subcutaneously administered to mice harboring malignant gliomas generated; (1) by PDGF-B/sh-p53 retroviral transformation of endogenous neural progenitor cells; and (2) by human U87-MG xenografts. In vitro Pen-d/n-ATF5-RP entered into glioma cells and triggered massive apoptosis. In vivo, subcutaneously-administered Pen-d/n-ATF5-RP passed the blood brain barrier, entered normal brain and tumor cells, and then caused rapid selective tumor cell death. MRI verified elimination of retrovirus-induced gliomas within 8-21 days. Histopathology revealed growth-suppression of intracerebral human U87-MG cells xenografts. For endogenous PDGF-B gliomas, there was no recurrence or mortality at 6-12 months versus 66% mortality in controls at 6 months. Necropsy and liver-kidney blood enzyme analysis revealed no adverse effects on brain or other tissues. Our findings thus identify Pen-d/n-ATF5-RP as a potential therapy for malignant gliomas. PMID:26863637

  15. No major effects of vitamin D3 (1,25 dihydroxyvitamin D3) on absorption and pharmacokinetics of folic acid and fexofenadine in healthy volunteers.

    PubMed

    Kullak-Ublick, Gerd A; Gubler, Christoph; Spanaus, Katharina; Ismair, Manfred G; Claro da Silva, Tatiana; Jetter, Alexander

    2016-07-01

    In Caco-2 cells, folate uptake via the proton-coupled folate transporter (PCFT) increases significantly by a 3-day treatment with 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). Additionally, mRNA content and protein expression of the transporter OATP1A2 were increased up to ninefold with 1,25(OH)2D3. We investigated whether these in vitro findings can be confirmed in humans in vivo. Ten healthy volunteers (six women) received 5 mg folic acid orally once before and once together with the last intake of a 10-day course of 0.5 μg 1,25(OH)2D3 orally. One hundred twenty milligrams fexofenadine, an OATP1A2 substrate, was taken in 1 day before the first folic acid intake, and again on the ninth day of 1,25(OH)2D3 intake. Duodenal biopsies were taken for transporter mRNA assessments once before and once on the ninth or tenth day of the vitamin D3 course. Serum folic acid and fexofenadine concentrations were quantified with a chemiluminescence immunoassay and LC-MS/MS, respectively. Pharmacokinetics were compared between periods with standard bioequivalence approaches. While geometric mean folic acid AUC0-2h, which mainly reflects absorption, was 0.403 and 0.414 mg/L·h before and after the vitamin D3 course (geometric mean ratio (GMR), 1.027; 90 % confidence interval (90 % CI), 0.788-1.340), the geometric mean fexofenadine AUC0-2h was 1.932 and 2.761 mg/L·h, respectively (GMR, 1.429; 90 % CI, 0.890-2.294). PCFT- and OATP1A2-mRNA expressions in duodenal biopsies were essentially unchanged. No significant changes in folic acid and fexofenadine absorption were observed after a 10-day course of 1,25(OH)2D3 in humans in vivo. This study underlines the importance of confirming in vitro findings in vivo in humans.

  16. The cytochrome P450scc system opens an alternate pathway of vitamin D3 metabolism.

    PubMed

    Slominski, Andrzej; Semak, Igor; Zjawiony, Jordan; Wortsman, Jacobo; Li, Wei; Szczesniewski, Andre; Tuckey, Robert C

    2005-08-01

    We show that cytochrome P450scc (CYP11A1) in either a reconstituted system or in isolated adrenal mitochondria can metabolize vitamin D3. The major products of the reaction with reconstituted enzyme were 20-hydroxycholecalciferol and 20,22-dihydroxycholecalciferol, with yields of 16 and 4%, respectively, of the original vitamin D3 substrate. Trihydroxycholecalciferol was a minor product, likely arising from further metabolism of dihydroxycholecalciferol. Based on NMR analysis and known properties of P450scc we propose that hydroxylation of vitamin D3 by P450scc occurs sequentially and stereospecifically with initial formation of 20(S)-hydroxyvitamin D3. P450scc did not metabolize 25-hydroxyvitamin D3, indicating that modification of C25 protected it against P450scc action. Adrenal mitochondria also metabolized vitamin D3 yielding 10 hydroxyderivatives, with UV spectra typical of vitamin D triene chromophores. Aminogluthimide inhibition showed that the three major metabolites, but not the others, resulted from P450scc action. It therefore appears that non-P450scc enzymes present in the adrenal cortex to some extent contribute to metabolism of vitamin D3. We conclude that purified P450scc in a reconstituted system or P450scc in adrenal mitochondria can add one hydroxyl group to vitamin D3 with subsequent hydroxylation being observed for reconstituted enzyme but not for adrenal mitochondria. Additional vitamin D3 metabolites arise from the action of other enzymes in adrenal mitochondria. These findings appear to define novel metabolic pathways involving vitamin D3 that remain to be characterized.

  17. The cytochrome P450scc system opens an alternate pathway of vitamin D3 metabolism

    PubMed Central

    Slominski, Andrzej; Semak, Igor; Zjawiony, Jordan; Wortsman, Jacobo; Li, Wei; Szczesniewski, Andre; Tuckey, Robert C.

    2008-01-01

    We show that cytochrome P450scc (CYP11A1) in either a reconstituted system or in isolated adrenal mitochondria can metabolize vitamin D3. The major products of the reaction with reconstituted enzyme were 20-hydroxycholecalciferol and 20,22-dihydroxycholecalciferol, with yields of 16 and 4%, respectively, of the original vitamin D3 substrate. Trihydroxycholecalciferol was a minor product, likely arising from further metabolism of dihydroxycholecalciferol. Based on NMR analysis and known properties of P450scc we propose that hydroxylation of vitamin D3 by P450scc occurs sequentially and stereospecifically with initial formation of 20(S)-hydroxyvitamin D3. P450scc did not metabolize 25-hydroxyvitamin D3, indicating that modification of C25 protected it against P450scc action. Adrenal mitochondria also metabolized vitamin D3 yielding 10 hydroxyderivatives, with UV spectra typical of vitamin D triene chromophores. Aminogluthimide inhibition showed that the three major metabolites, but not the others, resulted from P450scc action. It therefore appears that non-P450scc enzymes present in the adrenal cortex to some extent contribute to metabolism of vitamin D3. We conclude that purified P450scc in a reconstituted system or P450scc in adrenal mitochondria can add one hydroxyl group to vitamin D3 with subsequent hydroxylation being observed for reconstituted enzyme but not for adrenal mitochondria. Additional vitamin D3 metabolites arise from the action of other enzymes in adrenal mitochondria. These findings appear to define novel metabolic pathways involving vitamin D3 that remain to be characterized. PMID:16098191

  18. The vitamin D3 transcriptomic response in skin cells derived from the Atlantic bottlenose dolphin

    PubMed Central

    Ellis, Blake C.; Gattoni-Celli, Sebastiano; Mancia, Annalaura; Kindy, Mark S.

    2012-01-01

    The Atlantic bottlenose dolphin has attracted attention due to the evident impact that environmental stressors have taken on its health. In order to better understand the mechanisms linking environmental health with dolphin health, we have established cell cultures from dolphin skin as in vitro tools for molecular evaluations. The vitamin D3 pathway is one mechanism of interest because of its well established chemopreventative and immunomodulatory properties in terrestrial mammals. On the other hand, little is known of the physiological role of this molecule in aquatic animals. 1,25-dihydroxyvitamin D3 (1,25D3), the bioactive and hormonal form of vitamin D3, exerts its biological function by binding to the vitamin D receptor (VDR), a ligand-activated regulator of gene transcription. Therefore, we investigated the transcriptomic changes induced by 1,25D3 administration in dolphin skin cells. Identification of specific genes activated by 1,25D3 has provided clues to the physiological function of the vitamin D3 pathway in the dolphin. We found that exposure of the cells to 1,25D3 upregulated transactivation of a vitamin D-sensitive promoter. cDNA microarray analysis, using a novel dolphin array, identified specific gene targets within this pathway, and real-time PCR (qPCR) confirmed the enhanced expression of select genes of interest. These transcriptional changes correlated with an increase in VDR levels. This is the first report of the presence and activation of the vitamin D3 pathway in a marine mammal, and our experimental results demonstrate a number of similarities to terrestrial animals. Conservation of this pathway in the Atlantic bottlenose dolphin is consistent with the importance of nonclassic functions of vitamin D3, such as its role in innate immunity, similar to what has been demonstrated in other mammals. PMID:19454332

  19. Dopamine D3 receptor ligands for drug addiction treatment: update on recent findings.

    PubMed

    Le Foll, Bernard; Collo, Ginetta; Rabiner, Eugenii A; Boileau, Isabelle; Merlo Pich, Emilio; Sokoloff, Pierre

    2014-01-01

    The dopamine D3 receptor is located in the limbic area and apparently mediates selective effects on motivation to take drugs and drug-seeking behaviors, so that there has been considerable interest on the possible use of D3 receptor ligands to treat drug addiction. However, only recently selective tools allowing studying this receptor have been developed. This chapter presents an overview of findings that were presented at a symposium on the conference Dopamine 2013 in Sardinia in May 2013. Novel neurobiological findings indicate that drugs of abuse can lead to significant structural plasticity in rodent brain and that this is dependent on the availability of functional dopamine D3 autoreceptor, whose activation increased phosphorylation in the ERK pathway and in the Akt/mTORC1 pathway indicating the parallel engagement of a series of intracellular signaling pathways all involved in cell growth and survival. Preclinical findings using animal models of drug-seeking behaviors confirm that D3 antagonists have a promising profile to treat drug addiction across drugs of abuse type. Imaging the D3 is now feasible in human subjects. Notably, the development of (+)-4-propyl-9-hydroxynaphthoxazine ligand used in positron emission tomography (PET) studies in humans allows to measure D3 and D2 receptors based on the area of the brain under study. This PET ligand has been used to confirm up-regulation of D3 sites in psychostimulant users and to reveal that tobacco smoking produces elevation of dopamine at the level of D3 sites. There are now novel antagonists being developed, but also old drugs such as buspirone, that are available to test the D3 hypothesis in humans. The first results of clinical investigations are now being provided. Overall, those recent findings support further exploration of D3 ligands to treat drug addiction.

  20. Total body skeletal muscle mass: estimation by creatine (methyl-d3) dilution in humans

    PubMed Central

    Walker, Ann C.; O'Connor-Semmes, Robin L.; Leonard, Michael S.; Miller, Ram R.; Stimpson, Stephen A.; Turner, Scott M.; Ravussin, Eric; Cefalu, William T.; Hellerstein, Marc K.; Evans, William J.

    2014-01-01

    Current methods for clinical estimation of total body skeletal muscle mass have significant limitations. We tested the hypothesis that creatine (methyl-d3) dilution (D3-creatine) measured by enrichment of urine D3-creatinine reveals total body creatine pool size, providing an accurate estimate of total body skeletal muscle mass. Healthy subjects with different muscle masses [n = 35: 20 men (19–30 yr, 70–84 yr), 15 postmenopausal women (51–62 yr, 70–84 yr)] were housed for 5 days. Optimal tracer dose was explored with single oral doses of 30, 60, or 100 mg D3-creatine given on day 1. Serial plasma samples were collected for D3-creatine pharmacokinetics. All urine was collected through day 5. Creatine and creatinine (deuterated and unlabeled) were measured by liquid chromatography mass spectrometry. Total body creatine pool size and muscle mass were calculated from D3-creatinine enrichment in urine. Muscle mass was also measured by magnetic resonance imaging (MRI), dual-energy x-ray absorptiometry (DXA), and traditional 24-h urine creatinine. D3-creatine was rapidly absorbed and cleared with variable urinary excretion. Isotopic steady-state of D3-creatinine enrichment in the urine was achieved by 30.7 ± 11.2 h. Mean steady-state enrichment in urine provided muscle mass estimates that correlated well with MRI estimates for all subjects (r = 0.868, P < 0.0001), with less bias compared with lean body mass assessment by DXA, which overestimated muscle mass compared with MRI. The dilution of an oral D3-creatine dose determined by urine D3-creatinine enrichment provides an estimate of total body muscle mass strongly correlated with estimates from serial MRI with less bias than total lean body mass assessment by DXA. PMID:24764133

  1. Total body skeletal muscle mass: estimation by creatine (methyl-d3) dilution in humans.

    PubMed

    Clark, Richard V; Walker, Ann C; O'Connor-Semmes, Robin L; Leonard, Michael S; Miller, Ram R; Stimpson, Stephen A; Turner, Scott M; Ravussin, Eric; Cefalu, William T; Hellerstein, Marc K; Evans, William J

    2014-06-15

    Current methods for clinical estimation of total body skeletal muscle mass have significant limitations. We tested the hypothesis that creatine (methyl-d3) dilution (D3-creatine) measured by enrichment of urine D3-creatinine reveals total body creatine pool size, providing an accurate estimate of total body skeletal muscle mass. Healthy subjects with different muscle masses [n = 35: 20 men (19-30 yr, 70-84 yr), 15 postmenopausal women (51-62 yr, 70-84 yr)] were housed for 5 days. Optimal tracer dose was explored with single oral doses of 30, 60, or 100 mg D3-creatine given on day 1. Serial plasma samples were collected for D3-creatine pharmacokinetics. All urine was collected through day 5. Creatine and creatinine (deuterated and unlabeled) were measured by liquid chromatography mass spectrometry. Total body creatine pool size and muscle mass were calculated from D3-creatinine enrichment in urine. Muscle mass was also measured by magnetic resonance imaging (MRI), dual-energy x-ray absorptiometry (DXA), and traditional 24-h urine creatinine. D3-creatine was rapidly absorbed and cleared with variable urinary excretion. Isotopic steady-state of D3-creatinine enrichment in the urine was achieved by 30.7 ± 11.2 h. Mean steady-state enrichment in urine provided muscle mass estimates that correlated well with MRI estimates for all subjects (r = 0.868, P < 0.0001), with less bias compared with lean body mass assessment by DXA, which overestimated muscle mass compared with MRI. The dilution of an oral D3-creatine dose determined by urine D3-creatinine enrichment provides an estimate of total body muscle mass strongly correlated with estimates from serial MRI with less bias than total lean body mass assessment by DXA. Copyright © 2014 the American Physiological Society.

  2. Decreased Conversion of 25-hydroxyvitamin D3 to 24,25-dihydroxyvitamin D3 Following Cholecalciferol Therapy in Patients with CKD

    PubMed Central

    Zhang, Shiqin; Friedman, Peter A.; Nolin, Thomas D.

    2014-01-01

    Background and objectives Elevated concentrations of fibroblast growth factor 23 (FGF23) are postulated to promote 25-hydroxyvitamin D (25[OH]D) insufficiency in CKD by stimulating 24-hydroxylation of this metabolite, leading to its subsequent degradation; however, prospective human studies testing this relationship are lacking. Design, setting, participants, & measurements An open-label prospective study was conducted from October 2010 through July 2012 to compare the effect of 8 weeks of oral cholecalciferol therapy (50,000 IU twice weekly) on the production of 24,25(OH)2D3 in vitamin D–insufficient patients with CKD (n=15) and controls with normal kidney function (n=15). Vitamin D metabolites were comprehensively profiled at baseline and after treatment, along with FGF23 and other mineral metabolism parameters. Results Vitamin D3 and 25(OH)D3 concentrations increased equivalently in the CKD and control groups following cholecalciferol treatment (median D3 change, 8.6 ng/ml [interquartile range, 3.9–25.6 ng/ml] for controls versus 12.6 ng/ml [6.9–41.2 ng/ml] for CKD [P=0.15]; 25(OH)D3 change, 39.2 ng/ml [30.9–47.2 ng/ml] for controls versus 39.9 ng/ml [31.5–44.1 ng/ml] for CKD [P=0.58]). Likewise, the absolute increase in 1α,25(OH)2D3 was similar between CKD participants and controls (change, 111.2 pg/ml [64.3–141.6 pg/ml] for controls versus 101.1 pg/ml [74.2–123.1 pg/ml] for CKD; P=0.38). Baseline and post-treatment 24,25(OH)2D3 concentrations were lower in the CKD group; moreover, the absolute increase in 24,25(OH)2D3 after therapy was markedly smaller in patients with CKD (change, 2.8 ng/ml [2.3–3.5 ng/ml] for controls versus 1.2 ng/ml [0.6–1.9 ng/ml] for patients with CKD; P<0.001). Furthermore, higher baseline FGF23 concentrations were associated with smaller increments in 24,25(OH)2D3 for individuals with CKD; this association was negated after adjustment for eGFR by multivariate analysis. Conclusions Patients with CKD exhibit an altered

  3. 25 (OH) D3 levels, incidence and recurrence of different clinical forms of BPPV.

    PubMed

    Maslovara, Sinisa; Butkovic Soldo, Silva; Sestak, Anamarija; Milinkovic, Katarina; Rogic-Namacinski, Jasna; Soldo, Anamarija

    2017-06-11

    Benign Paroxysmal Positional Vertigo (BPPV) is the most common cause of dizziness in the general population. It is a condition with potential impact of reduced levels of vitamin D on its recurrent attacks. The aim of this study was to measure the serum levels of 25-hydroxyvitamin D3 (25-OH D3) in patients with BPPV and determine whether there is a difference in the serum levels of vitamin D3 between patients with and without recurrence, as well as between the different clinical forms of BPPV. The study included 40 patients who came to the regular medical examination, diagnosed with PC-BPPV based on the positive Dix-Hallpike's test. All patients underwent Epley manoeuvre after the diagnosis. Patients were classified according to current guidelines for levels of vitamin D3 in the serum in three groups: the deficiency, insufficiency and adequate level. The average serum level of 25-OH D3 among respondents was 20.78ng/mL, indicating a lack or insufficiency of the aforementioned 25-OH D3. According to the levels of 25-OH D3, most patients suffer from deficiency (47.5%). 7 (17.5%) respondents had adequate blood level of 25-OH D3, and 14 (35%) respondents suffer from insufficiency. A significant difference was not found in the serum level of 25-OH D3 between patients with and without BPPV recurrence. There was a significant difference in the serum levels of 25-OH D3 in comparison to the clinical form of the disease. Lower 25-OH D3 values were found in patients with canalithiasis compared to those with cupulolithiasis. There were no significant differences in the vitamin D3 serum level in patients with and without recurrence. The study showed a low level of serum vitamin D3 in most patients, indicating the need for supplemental therapy. Copyright © 2017 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.

  4. 1β,25-Dihydroxyvitamin D3: A new vitamin D metabolite in human serum.

    PubMed

    Pauwels, Steven; Jans, Ivo; Billen, Jaak; Heijboer, Annemieke; Verstuyf, Annemieke; Carmeliet, Geert; Mathieu, Chantal; Maestro, Miguel; Waelkens, Etienne; Evenepoel, Pieter; Bouillon, Roger; Vanderschueren, Dirk; Vermeersch, Pieter

    2017-10-01

    The measurement of 1α,25(OH)2D3 in human serum poses a true challenge as concentrations are very low and structurally similar metabolites can interfere. During optimization of our in-house LC-MSMS method for serum 1α,25(OH)2D3 a previously co-eluting isobaric interference was separated. The isobar was identified as 1β,25(OH)2D3 by comparing retention time and fragmentation spectra to standards (other isobaric dihydroxylated vitamin D3 analogs). 1β,25(OH)2D3 showed specific cluster formation (water), not present in 1α,25(OH)2D3. 1β,25(OH)2D3 was measured in serum of apparently healthy human volunteers (n=20), patients with high serum 25-hydroxyvitamin D [25(OH)D] concentrations (>50ng/mL) (n=33 among which 4 with very high levels (>150ng/mL)) and patients with kidney failure (n=68; 39 stage 1-3, 29 stage 4-5). Pearson's r was calculated for correlations and Mann-Whitney statistic to compare group medians. Median serum 1β,25(OH)2D3 was 11pg/mL in apparently healthy volunteers and increased to 20pg/mL for serum 25(OH)D concentrations above 80ng/mL (n=22) (p<0.0001). 1β,25(OH)2D3 concentrations were significantly correlated to serum 25(OH)D concentrations (r=0.85) for the combined results from healthy volunteers and patient sera (n=53) (p<0.0001). For patients with kidney failure, median serum 1β,25(OH)2D3 was 7pg/mL and not different from the median level in healthy volunteers (p=0.06). The median concentration did not vary with different stages. We present evidence for the widespread presence of 1β,25(OH)2D3, a new vitamin D metabolite, in human serum. The level increases with rising serum 25(OH)D concentrations and is particularly high in patients with very high 25(OH)D levels. We previously demonstrated that 1β,25(OH)2D3 is a poor genomic agonist but a potent non-genomic antagonist of 1α,25(OH)2D3. The clinical implications of the presence of this analog therefore require further exploration. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. Serum levels of 3-epi-25-OH-D3 during hypervitaminosis D in clinical practice.

    PubMed

    Granado-Lorencio, F; Blanco-Navarro, I; Pérez-Sacristán, B; Donoso-Navarro, E; Silvestre-Mardomingo, R

    2012-12-01

    Intoxication from vitamin D supplements has been rarely reported, but nowadays, it occurs more frequently. The presence of the C-3 epimer of 25-hydroxyvitamin D(3) (3-epi-25-OH-D(3)) is highly prevalent in adults, although there is little information regarding its in vivo relevance, if any, especially under pathological conditions. Our aim was to assess the presence of the 3-epi-25-OH-D(3) in serum samples displaying 25-OH-D(3) concentrations indicative of hypervitaminosis D. A total of 58 samples displaying a wide range of concentrations of 25-OH-D(3) (>64-439 ng/ml) by ultrafast liquid chromatography were consecutively recruited and reassessed for the presence of 3-epi-25-OH-D(3) using a second chromatographic system. Data from additional biochemical tests performed as part of the patient evaluation were also recorded. Mean relative contribution of 3-epi-25-OH-D(3) was less than 4%, and concentrations ranged from 2-28.6 ng/ml. Serum levels of the C3 epimer, but not the relative contribution, correlate with serum 25-OH-D(3). Overall, in subjects with 25-OH-D(3) concentrations indicative of hypervitaminosis D, the presence of the C-3 epimer and its levels were apparently unrelated to age, serum markers of renal and liver function, acute-phase reactants, and the presence of hypercalcemia. 3-Epi-25-OH-D(3) did not correlate with PTH, but subjects displaying PTH suppression (<14 pg/ml) showed higher concentrations of 3-epi-25-OH-D(3). The relative contribution of 3-epi-25-D(3) was not significantly altered during hypervitaminosis D, although the absolute levels reached in serum may be biologically relevant. From a clinical viewpoint, although the small size of the group may affect the lack of relationships, the presence of 3-epi-25-OH-D(3) was apparently unrelated to serum markers of renal and liver function, acute-phase reactants, PTH, and the presence of hypercalcemia.

  6. Fortification of cheese with vitamin D3 using dairy protein emulsions as delivery systems.

    PubMed

    Tippetts, M; Martini, S; Brothersen, C; McMahon, D J

    2012-09-01

    Vitamin D is an essential vitamin that is synthesized when the body is exposed to sunlight or after the consumption of fortified foods and supplements. The purpose of this research was to increase the retention of vitamin D(3) in Cheddar cheese by incorporating it as part of an oil-in-water emulsion using a milk protein emulsifier to obtain a fortification level of 280 IU/serving. Four oil-in-water vitamin D emulsions were made using sodium caseinate, calcium caseinate, nonfat dry milk (NDM), or whey protein. These emulsions were used to fortify milk, and the retention of vitamin D(3) in cheese curd in a model cheesemaking system was calculated. A nonemulsified vitamin D(3) oil was used as a control to fortify milk. Significantly more vitamin D(3) was retained in the curd when using the emulsified vitamin D(3) than the nonemulsified vitamin D(3) oil (control). No significant differences were observed in the retention of vitamin D(3) when emulsions were formulated with different emulsifiers. Mean vitamin D(3) retention in the model system cheese curd was 96% when the emulsions were added to either whole or skim milk compared with using the nonemulsified oil, which gave mean retentions of only 71% and 64% when added to whole and skim milk, respectively. A similar improvement in retention was achieved when cheese was made from whole and reduced-fat milk using standard manufacturing procedures on a small scale. When sufficient vitamin D(3) was added to produce cheese containing a target level of approximately 280 IU per 28-g serving, retention was greater when the vitamin D(3) was emulsified with NDM than when using nonemulsified vitamin D(3) oil. Only 58±3% of the nonemulsified vitamin D(3) oil was retained in full-fat Cheddar cheese, whereas 78±8% and 74±1% were retained when using the vitamin D(3) emulsion in full-fat and reduced-fat Cheddar cheese, respectively. Copyright © 2012 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

  7. VizieR Online Data Catalog: H2 d3{Pi}u excitation by elec

    NASA Astrophysics Data System (ADS)

    Liu, X.; Shemansky, D. E.; Yoshii, J.; Johnson, P. V.; Malone, C. P.; Ajello, J. M.

    2016-05-01

    Electron-impact excitation of H2 triplet states plays an imp role in the heating of outer planet upper thermospheres. The d3{Pi}u state is the third ungerade triplet state, and the d3{Pi}u-a3{Sigma}g+ emission is the largest cascade channel for the a3{Sigma}g+ state. Accurate energies of the d3{Pi}u-(v, J) levels are calculated from an ab initio potential energy curve. Radiative lifetimes of the d3{Pi}u(v,J) levels are obtained by an accurate evaluation of the d3{Pi}u-a3{Sigma}g+ transition probabilities. The emission yields are determined from experimental lifetimes and calculated radiative lifetimes and are further verified by comparing experimental and synthetic d3{Pi}u-a3{Sigma}g+ spectra at 20eV impact energy. Spectral analysis revealed that multipolar components beyond the dipolar term are required to model the X1{Sigma}g+-d3{Pi}u excitation, and significant cascade excitation occurs at the d3{Pi}u (v=0,1) levels. Kinetic energy (Ek) distributions of H atoms produced via predissociation of the 3{Pi}u state and the d3{Pi}u-a3{Sigma}g+-b3{Sigma}u+ cascade dissociative emission are obtained. Predissociation of the d3{Pi}u state produces H atoms with an average Ek of 2.3+/-0.4 eV/atom, while the Ekdistribution of the d3{Pi}u-a3{Sigma}g+-b3{Sigma}u+ channel is similar to that of the X1{Sigma}g+-a3{Sigma}g+-b3{Sigma}u+ channel and produces H(1s) atoms with an average Ek of 1.15+/-0.05eV/atom. On average, each H2 excited to the d3{Pi}u state in an H2-dominated atmosphere deposits 3.3+/-0.4eV into the atmosphere, while each H2directly excited to the a3{Sigma}g+ state gives 2.2-2.3eV to the atmosphere. The spectral distribution of the calculated a3{Sigma}g+-b3{Sigma}u+ continuum emission due to the X1{Sigma}g+-d3{Pi}u excitation is significantly different from that of direct a3{Sigma}g+ excitation. (2 data files).

  8. Estimation and fortification of vitamin D3 in pasteurized process cheese.

    PubMed

    Upreti, P; Mistry, V V; Warthesen, J J

    2002-12-01

    The objective of this study was to develop methods for the estimation and fortification of vitamin D3 in pasteurized Process cheese. Vitamin D3 was estimated using alkaline saponification at 70 degrees C for 30 min, followed by extraction with petroleum ether:diethyl ether (90:10 vol/vol) and HPLC. The retention time for vitamin D3 was approximately 9 min. A standard curve with a correlation coefficient of 0.972 was prepared for quantification of vitamin D3 in unknown samples. In the second phase of the study, pasteurized Process cheeses fortified with commercial water- or fat-dispersible forms of vitamin D3 at a level of 100 IU per serving (28 g) were manufactured. There was no loss of vitamin D3 during Process cheese manufacture, and the vitamin was uniformly distributed. No losses of the vitamin occurred during storage of the fortified cheeses over a 9-mo period at 21 to 29 degrees C and 4 to 6 degrees C. There was an approximately 25 to 30% loss of the vitamin when cheeses were heated for 5 min in an oven maintained at 232 degrees C. Added vitamin D3 did not impart any off flavors to the Process cheeses as determined by sensory analysis. There were no differences between the water- and fat-dispersible forms of the vitamin in the parameters measured in fortified cheeses.

  9. Design, Synthesis and Biological Activities of Novel Gemini 20S-Hydroxyvitamin D3 Analogs

    PubMed Central

    LIN, ZONGTAO; MAREPALLY, SRINIVASA R.; KIM, TAE-KANG; JANJETOVIC, ZORICA; OAK, ALLEN SW.; POSTLETHWAITE, ARNOLD E.; MYERS, LINDA K.; TUCKEY, ROBERT C.; SLOMINSKI, ANDRZEJ T.; MILLER, DUANE D.; LI, WEI

    2017-01-01

    Vitamin D3 (D3) can be metabolized by cytochrome P450scc (CYP11A1) into 20S-hydroxyvitamin D3 (20D3) as a major metabolite. This bioactive metabolite has shown strong antiproliferative, antifibrotic, pro-differentiation and anti-inflammatory effects while being non-toxic (non-calcemic) at high concentrations. Since D3 analogs with two symmetric side chains (Gemini analogs) result in potent activation of the vitamin D receptor (VDR), we hypothesized that the chain length and composition of these types of analogs also containing a 20-hydroxyl group would affect their biological activities. In this study, we designed and synthesized a series of Gemini 20D3 analogs. Biological tests showed that some of these analogs are partial VDR activators and can significantly stimulate the expression of mRNA for VDR and VDR-regulated genes including CYP24A1 and transient receptor potential cation channel V6 (TRPV6). These analogs inhibited the proliferation of melanoma cells with potency comparable to that of 1α,25-dihydroxyvitamin D3. Moreover, these analogs reduced the level of interferon γ and up-regulated the expression of leukocyte associated immunoglobulin-like receptor 1 in splenocytes, indicating that they have potent anti-inflammatory activities. There are no clear correlations between the Gemini chain length and their VDR activation or biological activities, consistent with the high flexibility of the ligand-binding pocket of the VDR. PMID:26976974

  10. A Molecular Basis for Selective Antagonist Destabilization of Dopamine D3 Receptor Quaternary Organization.

    PubMed

    Marsango, Sara; Caltabiano, Gianluigi; Jiménez-Rosés, Mireia; Millan, Mark J; Pediani, John D; Ward, Richard J; Milligan, Graeme

    2017-05-18

    The dopamine D3 receptor (D3R) is a molecular target for both first-generation and several recently-developed antipsychotic agents. Following stable expression of this mEGFP-tagged receptor, Spatial Intensity Distribution Analysis indicated that a substantial proportion of the receptor was present within dimeric/oligomeric complexes and that increased expression levels of the receptor favored a greater dimer to monomer ratio. Addition of the antipsychotics, spiperone or haloperidol, resulted in re-organization of D3R quaternary structure to promote monomerization. This action was dependent on ligand concentration and reversed upon drug washout. By contrast, a number of other antagonists with high affinity at the D3R, did not alter the dimer/monomer ratio. Molecular dynamics simulations following docking of each of the ligands into a model of the D3R derived from the available atomic level structure, and comparisons to the receptor in the absence of ligand, were undertaken. They showed that, in contrast to the other antagonists, spiperone and haloperidol respectively increased the atomic distance between reference α carbon atoms of transmembrane domains IV and V and I and II, both of which provide key interfaces for D3R dimerization. These results offer a molecular explanation for the distinctive ability of spiperone and haloperidol to disrupt D3R dimerization.

  11. Neuronal circuitry underlying the impact of D3 receptor ligands in drug addiction.

    PubMed

    Le Foll, Bernard; Di Ciano, Patricia

    2015-09-01

    Since the cloning of the D3 receptor in the early 1990s, there has been a great deal of interest in this receptor as a possible therapeutic target for drug addiction. The development of a D3 ligand suitable for use in humans has remained elusive, so the study of the function of the D3 receptor and its possible therapeutic efficacy has largely been restricted to animals. Pre-clinical studies have established that systemic administration of D3 ligands, particularly antagonists and partial agonists, can alter drug-seeking in animals. Despite over a decade of research, few studies have investigated the effects of intra-cerebral infusion of D3 ligands on drug-seeking. In the present review, these studies are summarized, which have largely focused on stimulus-controlled behaviors. Converging evidence from studies of D3 receptor expression, Fos and pharmacological Magnetic Resonance Imaging (phMRI) is also provided to delineate some of the D3 brain systems involved in drug-seeking and taking. The data so far indicate that different brain systems may be involved in different types of stimulus control as well as drug taking. Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.

  12. Short- and long-range corrected hybrid density functionals with the D3 dispersion corrections

    NASA Astrophysics Data System (ADS)

    Wang, Chih-Wei; Hui, Kerwin; Chai, Jeng-Da

    2016-11-01

    We propose a short- and long-range corrected (SLC) hybrid scheme employing 100% Hartree-Fock exchange at both zero and infinite interelectronic distances, wherein three SLC hybrid density functionals with the D3 dispersion corrections (SLC-LDA-D3, SLC-PBE-D3, and SLC-B97-D3) are developed. SLC-PBE-D3 and SLC-B97-D3 are shown to be accurate for a very diverse range of applications, such as core ionization and excitation energies, thermochemistry, kinetics, noncovalent interactions, dissociation of symmetric radical cations, vertical ionization potentials, vertical electron affinities, fundamental gaps, and valence, Rydberg, and long-range charge-transfer excitation energies. Relative to ωB97X-D, SLC-B97-D3 provides significant improvement for core ionization and excitation energies and noticeable improvement for the self-interaction, asymptote, energy-gap, and charge-transfer problems, while performing similarly for thermochemistry, kinetics, and noncovalent interactions.

  13. Fusion product studies via fast ion D-D and D-3He fusion on JET

    NASA Astrophysics Data System (ADS)

    Sharapov, S. E.; Hellsten, T.; Kiptily, V. G.; Craciunescu, T.; Eriksson, J.; Fitzgerald, M.; Girardo, J.-B.; Goloborod'ko, V.; Hellesen, C.; Hjalmarsson, A.; Johnson, T.; Kazakov, Y.; Koskela, T.; Mantsinen, M.; Monakhov, I.; Nabais, F.; Nocente, M.; Perez von Thun, C.; Rimini, F.; Santala, M.; Schneider, M.; Tardocchi, M.; Tsalas, M.; Yavorskij, V.; Zoita, V.; Contributors, JET

    2016-11-01

    Dedicated fast ion D-D and D-3He fusion experiments were performed on JET with carbon wall (2008) and ITER-like wall (2014) for testing the upgraded neutron and energetic ion diagnostics of fusion products. Energy spectrum of D-D neutrons was the focus of the studies in pure deuterium plasmas. A significant broadening of the energy spectrum of neutrons born in D-D fast fusion was observed, and dependence of the maximum D and D-D neutron energies on plasma density was established. Diagnostics of charged products of aneutronic D-3He fusion reactions, 3.7 MeV alpha-particles similar to those in D-T fusion, and 14.6 MeV protons, were the focus of the studies in D-3He plasmas. Measurements of 16.4 MeV gamma-rays born in the weak secondary branch of D(3He, γ)5Li reaction were used for assessing D-3He fusion power. For achieving high yield of D-D and D-3He reactions at relatively low levels of input heating power, an acceleration of D beam up to the MeV energy range was used employing 3rd harmonic (f=3{{f}CD} ) ICRH technique. These results were compared to the techniques of D beam injection into D-3He mixture, and 3He-minority ICRH in D plasmas.

  14. Identifying Medication Targets for Psychostimulant Addiction: Unraveling the Dopamine D3 Receptor Hypothesis

    PubMed Central

    2016-01-01

    The dopamine D3 receptor (D3R) is a target for developing medications to treat substance use disorders. D3R-selective compounds with high affinity and varying efficacies have been discovered, providing critical research tools for cell-based studies that have been translated to in vivo models of drug abuse. D3R antagonists and partial agonists have shown especially promising results in rodent models of relapse-like behavior, including stress-, drug-, and cue-induced reinstatement of drug seeking. However, to date, translation to human studies has been limited. Herein, we present an overview and illustrate some of the pitfalls and challenges of developing novel D3R-selective compounds toward clinical utility, especially for treatment of cocaine abuse. Future research and development of D3R-selective antagonists and partial agonists for substance abuse remains critically important but will also require further evaluation and development of translational animal models to determine the best time in the addiction cycle to target D3Rs for optimal therapeutic efficacy. PMID:25826710

  15. Evaluation of N-Phenyl Homopiperazine Analogs as Potential Dopamine D3 Receptor Selective Ligands

    PubMed Central

    Li, Aixiao; Mishra, Yogesh; Malik, Maninder; Wang, Qi; Li, Shihong; Taylor, Michelle; Reichert, David E.; Luedtke, Robert R.; Mach, Robert H.

    2013-01-01

    A series of N-(2-methoxyphenyl)homopiperazine analogs was prepared and their affinities for dopamine D2, D3, and D4 receptors were measured using competitive radioligand binding assays. Several ligands exhibited high binding affinity and selectivity for the D3 dopamine receptor compared to the D2 receptor subtype. Compounds 11a, 11b, 11c, 11f, 11j and 11k had Ki values ranging from 0.7–3.9 nM for the D3 receptor with 30- to 170-fold selectivity for the D3 vs. D2 receptor. Calculated log P values (log P = 2.6–3.6) are within the desired range for passive transport across the blood brain barrier. When the binding and the intrinsic efficacy of these phenylhomopiperazines was compared to those of previously published phenylpiperazine analogues, it was found that a) affinity at D2 and D3 dopamine receptors generally decreased, b) the D3 receptor binding selectivity (D2:D3 Ki value ratio) decreased and, c) the intrinsic efficacy, measured using a forskolin-dependent adenylyl cyclase inhibition assay, generally increased. PMID:23618707

  16. Molecular Determinants of Selectivity and Efficacy at the Dopamine D3 Receptor

    PubMed Central

    Newman, Amy Hauck; Beuming, Thijs; Banala, Ashwini K.; Donthamsetti, Prashant; Pongetti, Katherine; LaBounty, Alex; Levy, Benjamin; Cao, Jianjing; Michino, Mayako; Luedtke, Robert R.; Javitch, Jonathan A.; Shi, Lei

    2012-01-01

    The dopamine D3 receptor (D3R) has been implicated in substance abuse and other neuropsychiatric disorders. The high sequence homology between the D3R and D2R, especially within the orthosteric binding site (OBS) that binds dopamine, has made the development of D3R-selective compounds challenging. Here, we deconstruct into pharmacophoric elements a series of D3R-selective substituted-4-phenylpiperazine compounds, and use computational simulations and binding and activation studies to dissect the structural bases for D3R selectivity and efficacy. We find that selectivity arises from divergent interactions within a second binding pocket (SBP) separate from the OBS, whereas efficacy depends on the binding mode in the OBS. Our findings reveal structural features of the receptor that are critical to selectivity and efficacy that can be used to design highly D3R-selective ligands with targeted efficacies. These findings are generalizable to other GPCRs in which the SBP can be targeted by bitopic or allosteric ligands. PMID:22632094

  17. Cariprazine (RGH-188), a dopamine D(3) receptor-preferring, D(3)/D(2) dopamine receptor antagonist-partial agonist antipsychotic candidate: in vitro and neurochemical profile.

    PubMed

    Kiss, Béla; Horváth, Attila; Némethy, Zsolt; Schmidt, Eva; Laszlovszky, István; Bugovics, Gyula; Fazekas, Károly; Hornok, Katalin; Orosz, Szabolcs; Gyertyán, István; Agai-Csongor, Eva; Domány, György; Tihanyi, Károly; Adham, Nika; Szombathelyi, Zsolt

    2010-04-01

    Cariprazine {RGH-188; trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N',N'-dimethylurea hydrochloride}, a novel candidate antipsychotic, demonstrated approximately 10-fold higher affinity for human D(3) versus human D(2L) and human D(2S) receptors (pKi 10.07, 9.16, and 9.31, respectively). It displayed high affinity at human serotonin (5-HT) type 2B receptors (pK(i) 9.24) with pure antagonism. Cariprazine had lower affinity at human and rat hippocampal 5-HT(1A) receptors (pK(i) 8.59 and 8.34, respectively) and demonstrated low intrinsic efficacy. Cariprazine displayed low affinity at human 5-HT(2A) receptors (pK(i) 7.73). Moderate or low affinity for histamine H(1) and 5-HT(2C) receptors (pK(i) 7.63 and 6.87, respectively) suggest cariprazine's reduced propensity for adverse events related to these receptors. Cariprazine demonstrated different functional profiles at dopamine receptors depending on the assay system. It displayed D(2) and D(3) antagonism in [(35)S]GTPgammaS binding assays, but stimulated inositol phosphate (IP) production (pEC(50) 8.50, E(max) 30%) and antagonized (+/-)-quinpirole-induced IP accumulation (pK(b) 9.22) in murine cells expressing human D(2L) receptors. It had partial agonist activity (pEC(50) 8.58, E(max) 71%) by inhibiting cAMP accumulation in Chinese hamster ovary cells expressing human D(3) receptors and potently antagonized R(+)-2-dipropylamino-7-hydroxy-1,2,3,4-tetrahydronaphtalene HBr (7-OH-DPAT)-induced suppression of cAMP formation (pK(b) 9.57). In these functional assays, cariprazine showed similar (D(2)) or higher (D(3)) antagonist-partial agonist affinity and greater (3- to 10-fold) D(3) versus D(2) selectivity compared with aripiprazole. In in vivo turnover and biosynthesis experiments, cariprazine demonstrated D(2)-related partial agonist and antagonist properties, depending on actual dopaminergic tone. The antagonist-partial agonist properties of cariprazine at D(3) and D(2) receptors, with very high

  18. 1,25-Dihydroxyvitamin D3 inhibits lipopolysaccharide-induced immune activation in human endothelial cells

    PubMed Central

    Equils, O; Naiki, Y; Shapiro, A M; Michelsen, K; Lu, D; Adams, J; Jordan, S

    2006-01-01

    In addition to its well-known role in mineral and skeletal homeostasis, 1,25-dihydroxyvitamin D3[1,25-(OH)2, D3] regulates the differentiation, growth and function of a broad range of immune system cells, including monocytes, dendritic cells, T and B lymphocytes. Vascular endothelial cells play a major role in the innate immune activation during infections, sepsis and transplant rejection; however, currently there are no data on the effect of 1,25-(OH)2 D3 on microbial antigen-induced endothelial cell activation. Here we show that 1,25-(OH)2 D3 pretreatment of human microvessel endothelial cells (HMEC) inhibited the enteric Gram-negative bacterial lipopolysaccharide (LPS) activation of transcription factor NF-κB and interleukin (IL)-6, IL-8 and regulated upon activation normal T cell exposed and secreted (RANTES) release. The effect of 1,25-(OH)2 D3 was not due to increased cell death or inhibition of endothelial cell proliferation. 1,25-(OH)2 D3 pretreatment of HMEC did not block MyD88-independent LPS-induced interferon (IFN)-β promoter activation. 1,25-(OH)2 D3 pretreatment of HMEC did not modulate Toll-like receptor 4 (TLR4) or MD-2 expression. These data suggest that 1,25-(OH)2 D3 may play a role in LPS-induced immune activation of endothelial cells during Gram-negative bacterial infections, and a suggest a potential role for 1,25-(OH)2 D3 and its analogues as an adjuvant in the treatment of Gram-negative sepsis. PMID:16367934

  19. Biphasic effect of 1,25-dihydroxyvitamin D3 on primary mouse epidermal keratinocyte proliferation.

    PubMed

    Bollag, W B; Ducote, J; Harmon, C S

    1995-05-01

    1,25-Dihydroxyvitamin D3 [1,25(OH)2D3] has been proposed as a physiologic regulator of keratinocyte growth and differentiation. Utilizing a proliferative serum-free culture system, we have found that a physiologic (picomolar) concentrations this hormone stimulated proliferation of primary mouse epidermal keratinocytes; at higher (nanomolar to micromolar) doses, growth was inhibited by 1,25(OH)2D3. We investigated the nature of the signal transduction mechanism underlying the response to 1,25(OH)2D3 and observed little or no effect of either low or high concentrations of the hormone on cytosolic calcium levels or Fos expression. Furthermore, the protein kinase C inhibitor, Ro 31-7549, had very little effect on the growth inhibition induced by a high dose (1 microM) of 1,25(OH)2D3. This lack of rapid signal transduction events was consistent with the inability of a short (4-hour) exposure to 1,25(OH)2D3 to initiate a complete growth-inhibitory response as measured using [3H]thymidine incorporation. Our results indicate that physiologic concentrations of 1,25(OH)2D3 are required for optimal keratinocyte growth. Furthermore, we found no evidence of rapid effects of 1,25(OH)2D3 and suggest that in mouse epidermal keratinocytes, the response to this hormone is mediated by a slow transduction pathway, such as that activated by the intracellular 1,25(OH)2D3 receptor (VDR).

  20. Differential regulation of cyclins D1 and D3 in hepatocyte proliferation.

    PubMed

    Rickheim, David G; Nelsen, Christopher J; Fassett, John T; Timchenko, Nikolai A; Hansen, Linda K; Albrecht, Jeffrey H

    2002-07-01

    Substantial evidence suggests that cyclin D1 plays a pivotal role in the control of the hepatocyte cell cycle in response to mitogenic stimuli, whereas the closely related protein cyclin D3 has not been extensively evaluated. In the current study, we examined the regulation of cyclins D1 and D3 during hepatocyte proliferation in vivo after 70% partial hepatectomy (PH) and in culture. In contrast to cyclin D1, which was nearly undetectable in quiescent liver and substantially up-regulated after PH, cyclin D3 was constitutively expressed and induced only modestly. In the regenerating liver, the concentration of cyclin D3 was only about 10% of that of cyclin D1. Cyclin D1 formed complexes primarily with cyclin-dependent kinase 4 (cdk4), which were markedly activated in the regenerating liver and readily sequestered the cell cycle inhibitory proteins, p21 and p27. Cyclin D3 bound to both cdk4 and cdk6. Cyclin D3/cdk6 activity was readily detectable in quiescent liver and changed little after PH, and this complex appeared to play a minor role in sequestering p21 and p27. In cultured hepatocytes, epidermal growth factor or insulin had little effect, but the combination of these agents substantially induced cyclin D1 and cell cycle progression. Inhibition of Mek1 or phosphoinositide 3-kinase markedly inhibited cyclin D1 expression and replication. In contrast, cyclin D3 was expressed in the absence of mitogens and was only modestly affected by these manipulations. In addition, growth-inhibitory extracellular matrix conditions inhibited cyclin D1 but not cyclin D3 expression. In conclusion, these results support the concept that cyclin D1 is critically regulated by extracellular stimuli that control proliferation, whereas cyclin D3 is regulated through different pathways and plays a distinct role in the liver.

  1. Heightened Dopaminergic Response to Amphetamine at the D3 Dopamine Receptor in Methamphetamine Users.

    PubMed

    Boileau, Isabelle; Payer, Doris; Rusjan, Pablo M; Houle, Sylvain; Tong, Junchao; McCluskey, Tina; Wilson, Alan A; Kish, Stephen J

    2016-12-01

    Neuroimaging studies in stimulant use (eg, cocaine, methamphetamine) disorders show that diminished dopamine release by dopamine-elevating drugs is a potential marker of relapse and suggest that increasing dopamine at the D2/3 receptors may be therapeutically beneficial. In contrast, recent investigations indicate heightened D3 receptor levels in stimulant users prompting the view that D3 antagonism may help prevent relapse. Here we tested whether a 'blunted' response to amphetamine in methamphetamine (MA) users extends to D3-rich brain areas. Fourteen MA users and 15 healthy controls completed two positron emission tomographic scans with a D3-preferring probe [(11)C]-(+)-PHNO at baseline and after amphetamine (0.4 mg/kg). Relative to healthy controls, MA users had greater decreases in [(11)C]-(+)-PHNO binding (increased dopamine release) after amphetamine in D3-rich substantia nigra (36 vs 20%, p=0.03) and globus pallidus (30 vs 17%, p=0.06), which correlated with self-reported 'drug wanting'. We did not observe a 'blunted' dopamine response to amphetamine in D2-rich striatum; however, drug use severity was negatively associated with amphetamine-induced striatal changes in [(11)C]-(+)-PHNO binding. Our study provides evidence that dopamine transmission in extrastriatal 'D3-areas' is not blunted but rather increased in MA users. Together with our previous finding of elevated D3 receptor level in MA users, the current observation suggests that greater dopaminergic transmission at the D3 dopamine receptor may contribute to motivation to use drugs and argues in favor of D3 antagonism as a possible therapeutic tool to reduce craving and relapse in MA addiction.

  2. Circulating 25-hydroxyvitamin D3 in pregnancy and infant neuropsychological development.

    PubMed

    Morales, Eva; Guxens, Mònica; Llop, Sabrina; Rodríguez-Bernal, Clara L; Tardón, Adonina; Riaño, Isolina; Ibarluzea, Jesús; Lertxundi, Nerea; Espada, Mercedes; Rodriguez, Agueda; Sunyer, Jordi

    2012-10-01

    To investigate whether circulating 25-hydroxyvitamin D(3) [25(OH)D(3)] concentration in pregnancy is associated with neuropsychological development in infants. The Spanish population-based cohort study INfancia y Medio Ambiente Project recruited pregnant women during the first trimester of pregnancy between November 2003 and February 2008. Completed data on 1820 mother-infant pairs were used. Maternal plasma 25(OH)D(3) concentration was measured by high-performance liquid chromatography in pregnancy (mean 13.5 ± 2.1 weeks of gestation). Offspring mental and psychomotor scores were assessed by trained psychologists at age 14 months (range, 11-23) by using the Bayley Scales of Infant Development. β-Coefficients with 95% confidence intervals (CIs) of mental and psychomotor scores associated with continuous or categorical concentrations of maternal plasma 25(OH)D(3) were calculated by using linear regression analysis. The median plasma value of 25(OH)D(3) in pregnancy was 29.6 ng/mL (interquartile range, 21.8-37.3). A positive linear relationship was found between circulating concentrations of maternal 25(OH)D(3) concentrations in pregnancy and mental and psychomotor scores in the offspring. After adjustment for potential confounders, infants of mothers with 25(OH)D(3) concentrations in pregnancy >30 ng/mL showed higher mental score (β = 2.60; 95% CI 0.63-4.56) and higher psychomotor score (β = 2.32; 95% CI 0.36-4.28) in comparison with those of mothers with 25(OH)D(3) concentrations <20 ng/mL. Higher circulating concentration of maternal 25(OH)D(3) in pregnancy was associated with improved mental and psychomotor development in infants.

  3. 25(OH)D3 and Cardiovascular Risk Factors in Female Nonhuman Primates

    PubMed Central

    Jorgensen, Matthew J.; Rudel, Lawrence L.; Nudy, Matthew; Kaplan, Jay R.; Clarkson, Thomas B.; Pajewski, Nicholas M.

    2012-01-01

    Abstract Objective To determine if interindividual differences in plasma concentrations of 25-hydroxyvitamin D3 (25(OH)D3) have pathophysiologic significance, we evaluated a cohort of female monkeys, seeking to identify associations with clinically relevant cardiovascular risk factors, including age, abdominal obesity (waist circumference), and high-density lipoprotein cholesterol (HDL-C). Methods One hundred fifty-five female vervet monkeys (Chlorocebus aethiops sabaeus) aged 3–25 years consumed a typical western diet for 7–8 weeks that provided a woman's equivalent of approximately 1000 IU/day of vitamin D3. Measurements of vitamin D3 and HDL-C concentrations, as well as waist circumference, were obtained. Results Among young monkeys (aged 3–5 years), compared to older monkeys (aged 16–25 years), the mean plasma 25(OH)D3 concentrations were 82.3±3.2 ng/mL and 58.6±2.9 ng/mL (p<0.0001), respectively. Plasma 25(OH)D3 concentrations had a range of 19.6–142.0 ng/mL (mean±standard error [SE] 66.4±1.7 ng/mL). 25(OH)D3 concentrations were inversely associated with age (p<0.0001) and waist circumference (p=0.016) and were positively correlated with HDL-C (p=0.01). However, when statistically controlling for age, none of these relationships remained significant. Conclusions Higher plasma concentrations of 25(OH)D3 were associated with more favorable cardiovascular risk factors, with inverse associations observed between 25(OH)D3 and abdominal obesity, HDL-C, and age. These associations were no longer significant when controlling for age. PMID:22876774

  4. Combined effect of soy isoflavones and vitamin D3 on bone loss in ovariectomized rats.

    PubMed

    Chang, Kee-Lung; Hu, Yu-Chen; Hsieh, Bau-Shan; Cheng, Hsiao-Ling; Hsu, Hen-Wei; Huang, Li-Wen; Su, Shu-Jem

    2013-01-01

    Several studies have shown that soy isoflavones have estrogen-like activities and might constitute an alternative to hormone replacement treatment. The present study investigated the effects of soy isoflavones alone and combined with vitamin D3 on prevention of bone loss. Sprague-Dawley rats were sham-operated (n = 8) or ovariectomized (OVX; n = 40), and then the OVX rats were randomly assigned to five groups that were untreated or treated for 14 wk with vitamin D3, 17β-estradiol, soy isoflavone extract (SIE), or vitamin D3 plus SIE. The effects of the isoflavones and 1α,25(OH)(2)D(3) on cultured osteoblasts and osteoclasts also were investigated. In OVX rats, the bone mineral density and trabecular bone volume loss were improved by 17β-estradiol, SIE, or SIE plus vitamin D3 treatment. SIE treatment was more effective than vitamin D3 or 17β-estradiol in inhibiting increases in serum tumor necrosis factor-α levels and osteoblast osteoprotegerin expression. SIE plus vitamin D3 was more effective in increasing osterix expression than each alone. Bone cell cultures showed that the isoflavones induced preosteoblasts to differentiate into osteoblasts and increased osteoblast mineralization. Isoflavones inhibited preosteoclasts and osteoclast proliferation and decreased osteoclast resorption. The combination of isoflavones plus 1α,25(OH)(2)D(3) showed additive effects on the increase in cell proliferation of cultured preosteoblasts. Treatment with soy isoflavones might be an alternative to hormone replacement therapy in decreasing bone loss from postmenopausal estrogen deficiency. In addition, there are further effects on increasing transcription factor osterix expression and preosteoblast proliferation when these were combined with vitamin D3. Copyright © 2013 Elsevier Inc. All rights reserved.

  5. Dopamine D3 receptor specifically modulates motor and sensory symptoms in iron-deficient mice.

    PubMed

    Dowling, Pascal; Klinker, Florian; Stadelmann, Christine; Hasan, Kenan; Paulus, Walter; Liebetanz, David

    2011-01-05

    Restless legs syndrome (RLS) is a common neurological disorder whose exact pathophysiological mechanism remains unclear despite the successful use of dopaminergic treatment and recent discovery of predisposing genetic factors. As iron deficiency has been associated with RLS for some patients and there is evidence for decreased spinal dopamine D(3)-receptor (D3R) signaling in RLS, we aimed at establishing whether D3R activity and iron deficiency share common pathways within the pathophysiology of RLS sensory and motor symptoms. Using a combined mouse model of iron deficiency and dopamine D(3)-receptor deficiency (D3R-/-), circadian motor symptoms were evaluated by continuous recording of spontaneous wheel running activity. Testing the acute and persistent pain responses with the hot-plate test and formalin test, respectively, assessed sensory symptoms. A 15 week iron-deficient (ID) diet alone increased acute and persistent pain responses as compared to control diet. As compared to C57BL/6 (WT), homozygous D3R-/- mice already exhibited elevated responses to acute and persistent pain stimuli, where the latter was further elevated by concurrent iron deficiency. ID changed the circadian activity pattern toward an increased running wheel usage before the resting period, which resembled the RLS symptom of restlessness before sleep. Interestingly, D3R-/- shifted this effect of iron deficiency to a time point 3-4 h earlier. The results confirm the ability of iron deficiency and D3R-/- to evoke sensory and motor symptoms in mice resembling those observed in RLS patients. Furthermore this study suggests an increase of ID-related sensory symptoms and modification of ID-related motor symptoms by D3R-/-.

  6. Abnormal neurogenesis in the dentate gyrus of adult mice lacking 1,25-dihydroxy vitamin D3 (1,25-(OH)2 D3).

    PubMed

    Zhu, Ying; Zhou, Rong; Yang, Rong; Zhang, Zhuo; Bai, Yinyang; Chang, Fei; Li, Lin; Sokabe, Masahiro; Goltzman, David; Miao, Dengshun; Chen, Ling

    2012-03-01

    In this study, we employed 1α-hydroxylase knockout (1α-(OH)ase(-/-) ) mice to investigate the influence of 1,25-dihydroxy vitamin D(3) (1,25-(OH)(2) D(3) ) deficiency on the adult neurogenesis in the hippocampal dentate gyrus (DG). The numbers of both 24-hr-old BrdU(+) cells and proliferating cell nuclear antigen positive cells in 8-week-old 1α-(OH)ase(-/-) mice increased approximately twofold compared with wild-type littermates. In contrast, the numbers of 7- and 28-day-old BrdU(+) cells in 1α-(OH)ase(-/-) mice decreased by 50% compared with wild-type mice, while the proportion of BrdU(+) /NeuN(+) cells in BrdU(+) population showed no difference between 1α-(OH)ase(-/-) and wild-type mice. Apoptotic cells in the subgranular zone (SGZ) of DG markedly increased in 1α-(OH)ase(-/-) mice. Replenishment of 1,25-(OH)(2) D(3) , but not correction of serum calcium and phosphorus levels, completely prevented changes in the neurogenesis in 1α-(OH)ase(-/-) mice. The absence of 1,25-(OH)(2) D(3) led to an increase in the expression of L-type voltage-gated calcium channel (L-VGCC) and a decrease in the nerve growth factor (NGF) mRNA level. Treatment with the L-VGCC inhibitor nifedipine blocked the increased cell proliferations by 1,25-(OH)(2) D(3) deficiency. Administration of NGF significantly attenuated the loss of newborn neurons in 1α-(OH)ase(-/-) mice. Copyright © 2010 Wiley Periodicals, Inc.

  7. Meteorological Observations and System Performance From the NASA D3R's First 5 Years

    NASA Technical Reports Server (NTRS)

    Chandrasekar, V.; Beauchamp, Robert M.; Vega, Manuel; Chen, Haonan; Kumar, Mohit; Joshil, Shashank; Schwaller, Mathew; Petersen, Walter; Wolff, David

    2017-01-01

    The NASA dual-frequency, dual-polarization, Doppler radar (D3R) was conceived and developed to support ground validation (GV) operations of the Global Precipitation Measurement (GPM) mission. The D3R operates in the same frequencies bands, Ku- and Ka-band, as GPMs dual-frequency precipitation radar enabling direct comparisons of microphysical observations of precipitation. To support the GPM GVmission, D3R substantively participated in four field campaigns in North America with diverse geographic features covering both winter and summer conditions.

  8. [The quantitative determination of vitamin D3 and its metabolites in plasma].

    PubMed

    Kaune, R; Harmeyer, J

    1986-11-01

    A method is described which enables determination of vitamin D3 and its physiologically most important metabolites, i.e. 25-OHD3, 24,25-(OH)2D3, 25,26-(OH)2D3 and 1,25-(OH)2D3 in a plasma sample of about 2 to 4 ml. The whole procedure involves two preparative and one analytical steps: Extraction with methanol/methylene chloride (2:1), chromatographic separation on Lipidex 5000 using a stepwise gradient of n-hexane and chloroform and finally HPLC separation on Zorbax-Sil columns with n-hexane isopropanol mixtures and subsequently reversed phase separation on RP 18-columns and mixtures of methanol and water. Except for 1,25-(OH)2D3 all D compounds were quantified by UV-detection with 1.4 ng of substance being the lowest detectable amount. 1,25-(OH)2D3 was measured by radioimmunoassay. Prior to HPLC analysis the extract was separated into three fractions on Lipidex 5000 which contained 1) vitamin D3, 2) 25-OHD3 and 3) the dihydroxy metabolites. The three fractions were separated by HPLC using different mixtures of isopropanol/n-hexane and methanol/water, respectively. Retention times of the individual D-components longer than 10 min appeared to be essential to separate these compounds from accompanying material. Overall recoveries of the individual metabolites were for vitamin D3 48.9%, for 25-OHD3 54.2%, for 24,25-(OH)2D3 50.9% and for 1,25-(OH)2D3 52.5%. Application of the methods to plasma samples from pigs with pseudovitamin D deficiency rickets, typ I, revealed a reduced concentration of 1,25-(OH)2D3 and 24,25-(OH)2D3 and an elevated level of 25-OHD3 in these animals. The results obtained by this method contributed substantially to a better understanding of the aetiological factors associated with this disease.

  9. Ubiquitination and degradation of the hominoid-specific oncoprotein TBC1D3 is regulated by protein palmitoylation

    SciTech Connect

    Kong, Chen; Lange, Jeffrey J.; Samovski, Dmitri; Su, Xiong; Liu, Jialiu; Sundaresan, Sinju; Stahl, Philip D.

    2013-05-03

    Highlights: •Hominoid-specific oncogene TBC1D3 is targeted to plasma membrane by palmitoylation. •TBC1D3 is palmitoylated on two cysteine residues: 318 and 325. •TBC1D3 palmitoylation governs growth factors-induced TBC1D3 degradation. •Post-translational modifications may regulate oncogenic properties of TBC1D3. -- Abstract: Expression of the hominoid-specific oncoprotein TBC1D3 promotes enhanced cell growth and proliferation by increased activation of signal transduction through several growth factors. Recently we documented the role of CUL7 E3 ligase in growth factors-induced ubiquitination and degradation of TBC1D3. Here we expanded our study to discover additional molecular mechanisms that control TBC1D3 protein turnover. We report that TBC1D3 is palmitoylated on two cysteine residues: 318 and 325. The expression of double palmitoylation mutant TBC1D3:C318/325S resulted in protein mislocalization and enhanced growth factors-induced TBC1D3 degradation. Moreover, ubiquitination of TBC1D3 via CUL7 E3 ligase complex was increased by mutating the palmitoylation sites, suggesting that depalmitoylation of TBC1D3 makes the protein more available for ubiquitination and degradation. The results reported here provide novel insights into the molecular mechanisms that govern TBC1D3 protein degradation. Dysregulation of these mechanisms in vivo could potentially result in aberrant TBC1D3 expression and promote oncogenesis.

  10. Simulation of Porous Medium Hydrogen Storage - Estimation of Storage Capacity and Deliverability for a North German anticlinal Structure

    NASA Astrophysics Data System (ADS)

    Wang, B.; Bauer, S.; Pfeiffer, W. T.

    2015-12-01

    Large scale energy storage will be required to mitigate offsets between electric energy demand and the fluctuating electric energy production from renewable sources like wind farms, if renewables dominate energy supply. Porous formations in the subsurface could provide the large storage capacities required if chemical energy carriers such as hydrogen gas produced during phases of energy surplus are stored. This work assesses the behavior of a porous media hydrogen storage operation through numerical scenario simulation of a synthetic, heterogeneous sandstone formation formed by an anticlinal structure. The structural model is parameterized using data available for the North German Basin as well as data given for formations with similar characteristics. Based on the geological setting at the storage site a total of 15 facies distributions is generated and the hydrological parameters are assigned accordingly. Hydraulic parameters are spatially distributed according to the facies present and include permeability, porosity relative permeability and capillary pressure. The storage is designed to supply energy in times of deficiency on the order of seven days, which represents the typical time span of weather conditions with no wind. It is found that using five injection/extraction wells 21.3 mio sm³ of hydrogen gas can be stored and retrieved to supply 62,688 MWh of energy within 7 days. This requires a ratio of working to cushion gas of 0.59. The retrievable energy within this time represents the demand of about 450000 people. Furthermore it is found that for longer storage times, larger gas volumes have to be used, for higher delivery rates additionally the number of wells has to be increased. The formation investigated here thus seems to offer sufficient capacity and deliverability to be used for a large scale hydrogen gas storage operation.

  11. Determination of vitamin D3 metabolites: state-of-the-art and trends.

    PubMed

    Luque de Castro, M D; Fernández-Romero, J M; Ortiz-Boyer, F; Quesada, J M

    1999-06-01

    The steps involved in the methods for the determination of vitamin D3 metabolites (namely, 25-hydroxyvitamin D3, 1,25-dihydroxyvitamin D3, 24,25-dihydroxyvitamin D3) mainly in clinical samples are critically reviewed. Sample pretreatment (e.g. deproteinization, saponification, liquid liquid and liquid solid extraction, etc.) as a function of both type of sample and detection system, quantitation based on protein saturation and liquid as well as gas chromatography are discussed. The chemical principles on which the methods are based and the derivatization procedures, which facilitate separation and/or detection, are also commented upon. Finally, the future prospects of the research on methods for the determination of these metabolites are outlined.

  12. Novel morpholine scaffolds as selective dopamine (DA) D3 receptor antagonists.

    PubMed

    Micheli, Fabrizio; Cremonesi, Susanna; Semeraro, Teresa; Tarsi, Luca; Tomelleri, Silvia; Cavanni, Paolo; Oliosi, Beatrice; Perdonà, Elisabetta; Sava, Anna; Zonzini, Laura; Feriani, Aldo; Braggio, Simone; Heidbreder, Christian

    2016-02-15

    A new series of morpholine derivatives has been identified as selective DA D3 receptor antagonists; their in vitro profile and pharmacokinetic data are provided. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. FGFR3 and Cyclin D3 as urine biomarkers of bladder cancer recurrence.

    PubMed

    Blanca, Ana; Requena, Maria J; Alvarez, Jose; Cheng, Liang; Montironi, Rodolfo; Raspollini, Maria R; Reymundo, Carlos; Lopez-Beltran, Antonio

    2016-01-01

    To assess the diagnostic performance of FGFR3 and Cyclin D3 urinary protein levels in detecting bladder cancer recurrence. Urine of 321 patients in follow-up for bladder cancer and 150 non-neoplastic urine controls was included. Cytology, cystoscopy and FGFR3 and Cyclin D3 expression by western blot were performed. One hundred ten (34.3%) patients had evidence of tumor recurrence. The sensitivity and specificity of cytology/cystoscopy was 80 and 84%, and for FGFR3/Cyclin D3 was of 73 and 90%. Combined urinary FGFR3/Cyclin D3 expression shows improved detection rates for bladder cancer recurrence with high specificity and sensitivity, and within the same range of detection shown by cystoscopy, therefore supporting its potential use as noninvasive diagnostic biomarker for bladder cancer recurrence.

  14. Anti-tumor effects of 1,25-dihydroxyvitamin D3 and vitamin D analogs.

    PubMed

    van den Bemd, G J; Pols, H A; van Leeuwen, J P

    2000-05-01

    The role of 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) as a regulator of cell growth and differentiation is well recognized. Currently, 1, 25-(OH)2D3 and vitamin D analogs are being evaluated for their therapeutic potential in the treatment of hyperproliferative disorders like cancer. In the present review, we will discuss several processes that might be involved in 1,25-(OH)2D3- and vitamin D analog-mediated suppression of cancer cell growth. The effects on tumor cell proliferation, differentiation, apoptosis, angiogenesis, metastases, and parathyroid hormone-related peptide secretion will be highlighted. In addition, combination therapy with other tumor effec tive drugs will be addressed. Furtermore, we will focus on the potential drawbacks and the possible side effects of vitamin D compounds in the treatment of cancer.

  15. Quantitative analysis of vitamin D3 in a feed using normal phase high pressure liquid chromatography.

    PubMed

    Cohen, H; Lapointe, M

    1979-09-01

    A procedure is described for the separation and quantification of Vitamin D3 from different feeds and premixes. The study was conducted, first using a liquid partition step as a preliminary clean-up after extraction, then chromatography on activated Silica gel 60 before final analysis on a high pressure liquid chromatograph (HPLC) using a LiChrosorb NH2 (10 mu) column and a variable wavelength UV detector set at 264 nm. Total analysis on the HPLC was achieved in fifteen minutes. The detector response curve for an authentic D3 standard was linear using peak areas with a minimum detectable amount being 5 ng. The overall percent recovery of D3 in feeds was 94.4 +/- 2.4%. The minimum detectable amount of D3 in animal feeds was found to be in the region of 2,000 I.U./kg.

  16. 7. VIEW TO NORTH. FROM WEST PLATFORM. SAME AS IL1D3, ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    7. VIEW TO NORTH. FROM WEST PLATFORM. SAME AS IL-1D-3, AFTER TRAIN HAS DEPARTED EAST PLATFORM. - Union Elevated Railroad, Randolph-Wabash Avenue Station, Randolph Street & Wabash Avenue, Chicago, Cook County, IL

  17. Transmutation of \\mathbf{{\\cal N}=2} fractional D3 branes into twisted sector fluxes

    NASA Astrophysics Data System (ADS)

    Cremonesi, Stefano

    2009-08-01

    We study the prototype of fractional D3 branes at non-isolated singularities in gauge/gravity duality at the nonperturbative level. We embed the quantum moduli space of \\mathcal{N}=2 pure SYM, the gauge theory on fractional D3 branes at the A1 singularity, into that of the cascading quiver gauge theory on regular and fractional D3 branes at the same singularity, for which a gravity dual description exists. We deduce a simple analytic expression for the exact twisted sector fields in the type IIB string dual, which encodes the full quantum dynamics of the gauge theory. Nonperturbative effects in the gauge theory translate into the transmutation of fractional D3 branes into twisted sector fluxes.

  18. Tranylcypromine Substituted cis-Hydroxycyclobutylnaphthamides as Potent and Selective Dopamine D3 Receptor Antagonists

    PubMed Central

    2015-01-01

    We report a class of potent and selective dopamine D3 receptor antagonists based upon tranylcypromine. Although tranylcypromine has a low affinity for the rat D3 receptor (Ki = 12.8 μM), our efforts have yielded (1R,2S)-11 (CJ-1882), which has Ki values of 2.7 and 2.8 nM at the rat and human dopamine D3 receptors, respectively, and displays respective selectivities of >10000-fold and 223-fold over the rat and human D2 receptors. Evaluation in a β-arrestin functional assay showed that (1R,2S)-11 is a potent and competitive antagonist at the human D3 receptor. PMID:24848155

  19. Blood mineral, hormone, and osteocalcin responses of multiparous Jersey cows to an oral dose of 25-hydroxyvitamin D3 or vitamin D3 before parturition.

    PubMed

    Taylor, M S; Knowlton, K F; McGilliard, M L; Seymour, W M; Herbein, J H

    2008-06-01

    Twenty-seven multiparous Jersey cows were randomly assigned to receive an oral bolus containing corn starch (control, CON), corn starch plus 15 mg of 25-hydroxyvitamin D(3) (25-OH), or 15 mg of cholecalciferol (D(3)) at 6 d before expected parturition. Cows were maintained in individual box stalls from 20 d before expected parturition and fed a common diet. Jugular blood samples were collected at -14, -13, -5, -4, -3, -2, -1 d before expected calving, at calving, and at 1, 3, 5, 7, 9, 11, 13, 28, 56, and 84 d postcalving. After calving, cows were housed in 1 pen in a free-stall barn and consumed a common diet. Colorimetric assays were used to analyze Ca, P, and Mg concentrations in serum. Serum concentrations of osteocalcin (OC), an indicator of bone formation, serum 25-hydroxyvitamin D(3), and parathyroid hormone (PTH) were determined in samples obtained from d -5 through d 13. The 9 control multiparous cows and 5 untreated primiparous cows were used to evaluate the effect of parity on the variables that were measured. There was no effect of parity on Ca, PTH, or 25-OH concentration. Compared with second-lactation cows and older cows (>2 lactations), first-lactation cows had greater serum OC (22.3, 32.0, and 48.3 ng/mL, respectively), indicating that younger animals were forming more bone. Blood Ca, P, and Mg decreased near the time of calving and then increased over time. Serum 25-hydroxyvitamin D(3) was greater for cows dosed with 25-OH (119.0 ng/mL) compared with those dosed with D(3) (77.5 ng/mL) or CON (69.3 ng/mL). Cows dosed with 25-OH tended to have lower serum PTH concentration, but treatments did not affect serum Ca, P, or Mg. Serum OC was greater in second-lactation cows compared with cows entering their third or fourth lactation but OC was unaffected by treatment. Although results indicated a 60% increase in serum 25-hydroxyvitamin D(3) due to a single oral dose of 25-OH before calving, the amount administered in this study apparently was not

  20. Cyclin D3 expression in primary Ta/T1 bladder cancer.

    PubMed

    Lopez-Beltran, A; Requena, M J; Luque, R J; Alvarez-Kindelan, J; Quintero, A; Blanca, A M; Rodriguez, M E; Siendones, E; Montironi, R

    2006-05-01

    Cyclin D3 deregulation has recently been reported in bladder cancer but its prognostic significance remains uncertain. A cohort of 159 patients with stage Ta or T1 primary bladder tumours was investigated to determine the significance of cyclin D3 expression in association with other G1-S phase regulators of the cell cycle (p53, p21Waf1, p27kip1, cyclin D1), including tumour proliferation (ki67-MIB1); its association with conventional clinicopathological parameters; and the relationship between cyclin D3 and loss of heterozygosity (LOH) at the 9p21 (p16INK4a locus) chromosome region. The end point of the study was progression-free survival. Cyclin D3, other G1-S phase regulators, and tumour proliferation were investigated by immunohistochemistry and measured by the grid-counting method. To validate the immunohistochemical expression, cyclin D3 was additionally assessed by western blotting in selected cases. LOH at the 9p21 chromosome region (marker D9S171) was assessed in 125 cases using an AB Prism 310 genetic analyser and a set of microsatellite fluorescence-labelled primers. Cyclin D3 overexpression was related to larger tumour size (>5 cm; p < 0.0001) and high tumour proliferation (>10%; p = 0.025). Mean cyclin D3 expression increased with 2004 WHO grading categories in stage Ta (p = 0.035, ANOVA) and stage T1 (p = 0.047, t test) tumours. Cyclin D3 was not related to other clinicopathological parameters, G1-S phase modulators, or 9p21 LOH. Cox's multivariate analysis selected cyclin D3 as an independent predictor of progression-free survival (p = 0.0012, relative risk (RR) = 5.2366) together with tumour size (p = 0.0115, RR = 4.4442) and cyclin D1 (p = 0.0065, RR = 3.3023). Cyclin D3 expression had the highest risk ratio. Our results suggest that expression of cyclin D3 is relevant to the progression-free survival of patients with Ta/T1 bladder carcinomas. Copyright 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  1. Tolerance to 1,25 dihydroxyvitamin D3 glycosides from Solanum glaucophyllum by the growing pig.

    PubMed

    Schlegel, P; Guggisberg, D; Gutzwiller, A

    2017-02-16

    Solanum glaucophyllum leaves contain high levels of glycosidically bound 1,25 dihydroxyvitamin D3, the most important vitamin D metabolite. The tolerance to this source was evaluated during six weeks with fifty weaned pigs fed increasing levels (0, 2.5, 5, 10 and 20μg 1,25(OH)2D3/kg diet). The diet contained, per kg, 9.7g Ca, 3.5g digestible P and 2000IU cholecalciferol. Ten additional pigs were fed a diet containing 1000IU cholecalciferol/kg, without 1,25(OH)2D3. Weekly plasma and final kidney, bone and urinary mineral contents, bone density and breaking strength served as indicators for possible adverse effects of the supplement. All animals grew well and remained clinically healthy. The measured parameters remained unchanged when 1000 replaced 2000IU cholecalciferol/kg and when 1,25(OH)2D3 was fed up to 10μg/kg. Twenty μg 1,25(OH)2D3 increased plasma Ca and decreased plasma P from the 2(nd) and the 4(th) experimental week onwards, respectively. Twenty μg 1,25(OH)2D3 increased final plasma Ca and 1,25(OH)2D3 and reduced final plasma P by respectively 19, 56 and 13%. Twenty μg 1,25(OH)2D3 also increased kidney Ca and urinary Ca by 43 and 69%, respectively, reduced bone breaking strength by 12% and tended to decrease bone ash by 3%. To conclude, 2000IU D3 was not beneficial compared to 1000IU cholecalciferol; up to 10μg 1,25(OH)2D3 per kg diet did not lead to observed adverse effects; 20μg 1,25(OH)2D3 altered the homeostatic regulation of Ca and P thus, may lead to first signs of possible adverse effects, such as soft tissue calcification.

  2. Inhibition of interleukin-1 production by 1,25-dihydroxyvitamin D3.

    PubMed

    Tsoukas, C D; Watry, D; Escobar, S S; Provvedini, D M; Dinarello, C A; Hustmyer, F G; Manolagas, S C

    1989-07-01

    The hormonal form of vitamin D, 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3], inhibits the proliferation of T lymphocytes and production of growth-promoting factors (including interleukin-2) (IL2) in CTLL2 murine cells. In this study, we investigated the role of monocytes in this hormone-mediated inhibitory effect, by testing the effects of 1,25-(OH)2D3 on the ability of the mitogenic lectin phytohemagglutinin (PHA) to induce T cell activation in either a monocyte-dependent or phorbol myristate acetate (PMA)-driven (monocyte-independent) system. The results indicate that proliferation of T cells and production of growth-promoting factors are inhibited by 1,25-(OH)2D3 only in the monocyte-dependent system. Preincubation of monocytes with 1,25-(OH)2D3 for various periods of time and subsequent removal of the hormone resulted in inhibition of the PHA-driven proliferation of T cells. Preincubation for 2 h resulted in 20% inhibition, while preincubation for 36 h reduced proliferation to 50% of the control value [no 1,25-(OH)2D3 exposure]. These data suggested that monocytes are important participants in 1,25-(OH)2D3-mediated events. Therefore, we tested the effects of the hormone on the production of IL1, a monocyte-derived product thought to be involved in the induction of IL2 release and the subsequent development of the T cell proliferative response. 1,25-(OH)2D3 inhibited the production of both extracellular and cell-associated immunoreactive IL1 alpha and IL1 beta. Indomethacin, a prostaglandin synthetase inhibitor, did not alter the inhibitory properties of 1,25-(OH)2D3, suggesting that prostaglandins are not responsible for the inhibitory phenomenon. We conclude that part of the ability of 1,25-(OH)2D3 to inhibit T cell proliferation may be due to direct effects on monocytes by down-regulating IL-1 production. However, it is unlikely that the immunoregulatory properties of 1,25-(OH)2D3 on T cells are mediated solely through monocytes, and it is possible that the

  3. Examining the role of dopamine D2 and D3 receptors in Pavlovian conditioned approach behaviors.

    PubMed

    Fraser, Kurt M; Haight, Joshua L; Gardner, Eliot L; Flagel, Shelly B

    2016-05-15

    Elucidating the neurobiological mechanisms underlying individual differences in the extent to which reward cues acquire the ability to act as incentive stimuli may contribute to the development of successful treatments for addiction and related disorders. We used the sign-tracker/goal-tracker animal model to examine the role of dopamine D2 and D3 receptors in the propensity to attribute incentive salience to reward cues. Following Pavlovian training, wherein a discrete lever-cue was paired with food reward, rats were classified as sign- or goal-trackers based on the resultant conditioned response. We examined the effects of D2/D3 agonists, 7-OH-DPAT (0.01-0.32mg/kg) or pramipexole (0.032-0.32mg/kg), the D2/D3 antagonist raclopride (0.1mg/kg), and the selective D3 antagonist, SB-277011A (6 or 24mg/kg), on the expression of sign- and goal-tracking conditioned responses. The lever-cue acquired predictive value and elicited a conditioned response for sign- and goal-trackers, but only for sign-trackers did it also acquire incentive value. Following administration of either 7-OH-DPAT, pramipexole, or raclopride, the performance of the previously acquired conditioned response was attenuated for both sign- and goal-trackers. For sign-trackers, the D2/D3 agonist, 7-OH-DPAT, also attenuated the conditioned reinforcing properties of the lever-cue. The selective D3 antagonist did not affect either conditioned response. Alterations in D2/D3 receptor signaling, but not D3 signaling alone, transiently attenuate a previously acquired Pavlovian conditioned response, regardless of whether the response is a result of incentive motivational processes. These findings suggest activity at the dopamine D2 receptor is critical for a reward cue to maintain either its incentive or predictive qualities. Copyright © 2016 Elsevier B.V. All rights reserved.

  4. Caffeine increases striatal dopamine D2/D3 receptor availability in the human brain.

    PubMed

    Volkow, N D; Wang, G-J; Logan, J; Alexoff, D; Fowler, J S; Thanos, P K; Wong, C; Casado, V; Ferre, S; Tomasi, D

    2015-04-14

    Caffeine, the most widely consumed psychoactive substance in the world, is used to promote wakefulness and enhance alertness. Like other wake-promoting drugs (stimulants and modafinil), caffeine enhances dopamine (DA) signaling in the brain, which it does predominantly by antagonizing adenosine A2A receptors (A2AR). However, it is unclear if caffeine, at the doses consumed by humans, increases DA release or whether it modulates the functions of postsynaptic DA receptors through its interaction with adenosine receptors, which modulate them. We used positron emission tomography and [(11)C]raclopride (DA D2/D3 receptor radioligand sensitive to endogenous DA) to assess if caffeine increased DA release in striatum in 20 healthy controls. Caffeine (300 mg p.o.) significantly increased the availability of D2/D3 receptors in putamen and ventral striatum, but not in caudate, when compared with placebo. In addition, caffeine-induced increases in D2/D3 receptor availability in the ventral striatum were associated with caffeine-induced increases in alertness. Our findings indicate that in the human brain, caffeine, at doses typically consumed, increases the availability of DA D2/D3 receptors, which indicates that caffeine does not increase DA in the striatum for this would have decreased D2/D3 receptor availability. Instead, we interpret our findings to reflect an increase in D2/D3 receptor levels in striatum with caffeine (or changes in affinity). The association between increases in D2/D3 receptor availability in ventral striatum and alertness suggests that caffeine might enhance arousal, in part, by upregulating D2/D3 receptors.

  5. Local Sustained Delivery of 25-Hydroxyvitamin D3 for Production of Antimicrobial Peptides

    PubMed Central

    Jiang, Jiang; Chen, Guojun; Shuler, Franklin D.; Wang, Chi-Hwa; Xie, Jingwei

    2015-01-01

    Purpose This study seeks to develop fiber membranes for local sustained delivery of 25-hydroxyvitamin D3 to induce the expression and secretion of LL-37 at or near the surgical site, which provides a novel therapeutic approach to minimize the risk of infections. Methods 25-hydroxyvitamin D3 loaded poly(L-lactide) (PLA) and poly(ε-caprolactone) (PCL) fibers were produced by electrospinning. The morphology of obtained fibers was characterized using atomic force microscope (AFM) and scanning electron microscope (SEM). 25-hydroxyvitamin D3 releasing kinetics were quantified by enzyme-linked immunosorbent assay (ELISA) kit. The expression of cathelicidin (hCAP 18) and LL-37 was analyzed by immunofluorescence staining and ELISA kit. The antibacterial activity test was conducted by incubating pseudomonas aeruginosa in a monocytes’ lysis solution. Results AFM images suggest that the surface of PCL fibers is smooth, however, the surface of PLA fibers is relatively rough, in particular, after encapsulation of 25-hydroxyvitamin D3. The duration of 25-hydroxyvitamin D3 release can last more than 4 weeks for all the tested samples. Plasma treatment can promote the release rate of 25-hydroxyvitamin D3. Human keratinocytes and monocytes express significantly higher levels of hCAP18/LL-37 after incubation with plasma treated and 25-hydroxyvitamin D3 loaded PCL fibers than the cells incubated with around 10 times amount of free drug. After incubation with this fiber formulation for 5 days LL-37 in the lysis solutions of U937 cells can effectively kill the bacteria. Conclusions plasma treated and 25-hydroxyvitamin D3 loaded PCL fibers induce significantly higher levels of antimicrobial peptide production in human keratinocytes and monocytes without producing cytotoxicity. PMID:25773720

  6. 16 CFR Appendix D3 to Part 305 - Water Heaters-Oil

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 16 Commercial Practices 1 2011-01-01 2011-01-01 false Water Heaters-Oil D3 Appendix D3 to Part 305... Part 305—Water Heaters—Oil Range Information CAPACITY FIRST HOUR RATING Range of Estimated Annual Operating Costs (Dollars/Year) Low High Less than 65 * * 65 to 74 * * 75 to 86 * * 87 to 99 * * 100 to 114...

  7. Caffeine increases striatal dopamine D2/D3 receptor availability in the human brain

    PubMed Central

    Volkow, N D; Wang, G-J; Logan, J; Alexoff, D; Fowler, J S; Thanos, P K; Wong, C; Casado, V; Ferre, S; Tomasi, D

    2015-01-01

    Caffeine, the most widely consumed psychoactive substance in the world, is used to promote wakefulness and enhance alertness. Like other wake-promoting drugs (stimulants and modafinil), caffeine enhances dopamine (DA) signaling in the brain, which it does predominantly by antagonizing adenosine A2A receptors (A2AR). However, it is unclear if caffeine, at the doses consumed by humans, increases DA release or whether it modulates the functions of postsynaptic DA receptors through its interaction with adenosine receptors, which modulate them. We used positron emission tomography and [11C]raclopride (DA D2/D3 receptor radioligand sensitive to endogenous DA) to assess if caffeine increased DA release in striatum in 20 healthy controls. Caffeine (300 mg p.o.) significantly increased the availability of D2/D3 receptors in putamen and ventral striatum, but not in caudate, when compared with placebo. In addition, caffeine-induced increases in D2/D3 receptor availability in the ventral striatum were associated with caffeine-induced increases in alertness. Our findings indicate that in the human brain, caffeine, at doses typically consumed, increases the availability of DA D2/D3 receptors, which indicates that caffeine does not increase DA in the striatum for this would have decreased D2/D3 receptor availability. Instead, we interpret our findings to reflect an increase in D2/D3 receptor levels in striatum with caffeine (or changes in affinity). The association between increases in D2/D3 receptor availability in ventral striatum and alertness suggests that caffeine might enhance arousal, in part, by upregulating D2/D3 receptors. PMID:25871974

  8. Deployment and Performance of the NASA D3R During the GPM OLYMPEx Field Campaign

    NASA Technical Reports Server (NTRS)

    Chandrasekar, V.; Beauchamp, Robert M.; Chen, Haonan; Vega, Manuel; Schwaller, Mathew; Willie, Delbert; Dabrowski, Aaron; Kumar, Mohit; Petersen, Walter; Wolff, David

    2016-01-01

    The NASA D3R was successfully deployed and operated throughout the NASA OLYMPEx field campaign. A differential phase based attenuation correction technique has been implemented for D3R observations. Hydrometeor classification has been demonstrated for five distinct classes using Ku-band observations of both convection and stratiform rain. The stratiform rain hydrometeor classification is compared against LDR observations and shows good agreement in identification of mixed-phase hydrometeors in the melting layer.

  9. Randomized, Blinded Trial of Vitamin D3 for Treating Aromatase Inhibitor-Associated Musculoskeletal Symptoms (AIMSS)

    PubMed Central

    Shapiro, Alice C.; Adlis, Susan A.; Robien, Kim; Kirstein, Mark N.; Liang, Shuang; Richter, Sara A.; Lerner, Rachel E.

    2017-01-01

    Purpose To evaluate the efficacy and safety of vitamin D3 at 4,000 IU/day as a treatment option for aromatase inhibitor-associated musculoskeletal symptoms (AIMSS) when compared with the usual care dose of 600 IU D3. Methods Single site randomized, double-blind, phase 3 clinical trial in women with AIMSS comparing change in symptoms, reproductive hormones and AI pharmacokinetics. Postmenopausal women ≥18 years with stage I-IIIA breast cancer, taking AI and experiencing AIMSS (Breast Cancer Prevention Trial Symptom Scale-Musculoskeletal Subscale ≥1.5 (BCPT-MS)) were admitted. Following randomization, 116 patients had a run-in period of 1 month on 600 IU D3, then began the randomized assignment to either 600 IU D3 (n=56) or 4,000 IU D3 (n=57) daily for 6 months. The primary endpoint was change in AIMSS from baseline (after 1 month run-in) on the BCPT-MS (general musculoskeletal pain; joint pain; muscle stiffness; range for each question: 0=not at all to 4=extremely). Results Groups had no statistically significant differences demographically or clinically. There were no discernable differences between the randomly allocated treatment groups at 6 months in measures of AIMSS, pharmacokinetics of anastrozole and letrozole, serum levels of reproductive hormones, or adverse events. Conclusions We found no significant changes in AIMSS measures between women who took 4000 IU D3 daily compared with 600 IU D3. The 4000 IU D3 did not adversely affect reproductive hormone levels or the steady state pharmacokinetics of anastrozole or letrozole. In both groups, serum 25(OH)D remained in the recommended range for bone health (≥30 ng/mL) and safety (<50 ng/mL). PMID:26868123

  10. On Orbit Performance of the Defense Meteorological Satellite Program (DMSP) 5D3 Spacecraft Power System

    DTIC Science & Technology

    2011-12-30

    AEROSPACE REPORT NO. TR-2011(1550)-2 On Orbit Performance of the Defense Meteorological Satellite Program (DMSP) 5D3 Spacecraft Power System...Laboratory; and Patrick H. Mak, Principal Director, Defense Meteorological Satellite Program . Capt. Victor Thompson was the project officer. This report has...Satellite Program (DMSP) 5D3 Spacecraft Power System 3. DATES COVERED (From - To) 5a. CONTRACT NUMBER FA8802-09-C-0001 5b. GRANT NUMBER 5c. PROGRAM

  11. Caffeine increases striatal dopamine D2/D3 receptor availability in the human brain

    DOE PAGES

    Volkow, N. D.; Wang, G. -J.; Logan, J.; ...

    2015-04-14

    Caffeine, the most widely consumed psychoactive substance in the world, is used to promote wakefulness and enhance alertness. Like other wake-promoting drugs (stimulants and modafinil), caffeine enhances dopamine (DA) signaling in the brain, which it does predominantly by antagonizing adenosine A2A receptors (A2AR). However, it is unclear if caffeine, at the doses consumed by humans, increases DA release or whether it modulates the functions of postsynaptic DA receptors through its interaction with adenosine receptors, which modulate them. We used positron emission tomography and [11C]raclopride (DA D2/D3 receptor radioligand sensitive to endogenous DA) to assess if caffeine increased DA release inmore » striatum in 20 healthy controls. Caffeine (300mg p.o.) significantly increased the availability of D2/D3 receptors in putamen and ventral striatum, but not in caudate, when compared with placebo. In addition, caffeine-induced increases in D2/D3 receptor availability in the ventral striatum were associated with caffeine-induced increases in alertness. Our findings indicate that in the human brain, caffeine, at doses typically consumed, increases the availability of DA D2/D3 receptors, which indicates that caffeine does not increase DA in the striatum for this would have decreased D2/D3 receptor availability. Instead, we interpret our findings to reflect an increase in D2/D3 receptor levels in striatum with caffeine (or changes in affinity). Furthermore, the association between increases in D2/D3 receptor availability in ventral striatum and alertness suggests that caffeine might enhance arousal, in part, by upregulating D2/D3 receptors.« less

  12. Draft Genome Sequence of the Pediocin-Encoding Biopreservative and Biocontrol Strain Pediococcus acidilactici D3

    PubMed Central

    Rajendran, Mahitha; Altermann, Eric

    2013-01-01

    We describe a draft genome sequence for Pediococcus acidilactici strain D3, a component of multistrain commercial cultures with biopreservative and biocontrol properties in food-based applications. Strain D3 encodes at least one antimicrobial peptide, pediocin AMPd3. The AMPd3-encoding operon exhibits high sequence similarity to the archetype pediocin, PA-1, encoded by P. acidilactici PAC 1.0. PMID:23788534

  13. Examining the Role of Dopamine D2 and D3 Receptors in Pavlovian Conditioned Approach Behaviors

    PubMed Central

    Fraser, Kurt M.; Haight, Joshua L.; Gardner, Eliot L.; Flagel, Shelly B.

    2016-01-01

    Elucidating the neurobiological mechanisms underlying individual differences in the extent to which reward cues acquire the ability to act as incentive stimuli may contribute to the development of successful treatments for addiction and related disorders. We used the sign-tracker/goal-tracker animal model to examine the role of dopamine D2 and D3 receptors in the propensity to attribute incentive salience to reward cues. Following Pavlovian training, wherein a discrete lever-cue was paired with food reward, rats were classified as sign- or goal-trackers based on the resultant conditioned response. We examined the effects of D2/D3 agonists, 7-OH-DPAT (0.01–0.32 mg/kg) or pramipexole (0.032–0.32 mg/kg), the D2/D3 antagonist raclopride (0.1 mg/kg), and the selective D3 antagonist, SB-277011A (6 or 24 mg/kg), on the expression of sign- and goal-tracking conditioned responses. The lever-cue acquired predictive value and elicited a conditioned response for sign- and goal-trackers, but only for sign-trackers did it also acquire incentive value. Following administration of either 7-OH-DPAT, pramipexole, or raclopride, the performance of the previously acquired conditioned response was attenuated for both sign- and goal-trackers. For sign-trackers, the D2/D3 agonist, 7-OH-DPAT, also attenuated the conditioned reinforcing properties of the lever-cue. The selective D3 antagonist did not affect either conditioned response. Alterations in D2/D3 receptor signaling, but not D3 signaling alone, transiently attenuate a previously acquired Pavlovian conditioned response, regardless of whether the response is a result of incentive motivational processes. These findings suggest activity at the dopamine D2 receptor is critical for a reward cue to maintain either its incentive or predictive qualities. PMID:26909847

  14. Vitamin D3 attenuates oxidative stress and cognitive deficits in a model of toxic demyelination

    PubMed Central

    Tarbali, Sepideh; Khezri, Shiva

    2016-01-01

    Objective(s): Multiple sclerosis (MS) is a demyelinating disease. The prevalence of MS is highest where environmental supplies of vitamin D are low. Cognitive deficits have been observed in patients with MS. Oxidative damage may contribute to the formation of MS lesions. Considering the involvement of hippocampus in MS, an attempt is made in this study to investigate the effects of vitamin D3 on behavioral process and the oxidative status in the dorsal hippocampus (CA1 area) following the induction of experimental demyelination in rats. Materials and Methods: Animals were divided into six groups. Control group: animals received no surgery and treatment; saline group: animals received normal saline; sham group: animals received 150 μl sesame oil IP; vitamin D3 group: animals received 5 μg/kg vitamin D3 IP; lysophosphatidyl choline (LPC) group (toxic demyelination’s model): animals received LPC by stereotaxic intra-hippocampal injection of 2 μl LPC in CA1 area; Vitamin D3- treated group: animals were treated with vitamin D3 at doses of 5 μg/kg IP for 7 and 21 days post lesion. The spatial memory, biochemical parameters including catalase (CAT) activities and lipid peroxidation levels were investigated. Results: Animals in LPC group had more deficits in spatial memory than the control group in radial arm maze. Vitamin D3 significantly improved spatial memory compared to LPC group. Also, results indicated that vitamin D3 caused a decrease in lipid peroxidation levels and an increase in CAT activities. Conclusion: Current findings suggest that vitamin D3 may have a protective effect on cognitive deficits and oxidative stress in toxic demyelination’s model. PMID:27096068

  15. Overexpression of the dopamine D3 receptor in the rat dorsal striatum induces dyskinetic behaviors.

    PubMed

    Cote, Samantha R; Chitravanshi, Vineet C; Bleickardt, Carina; Sapru, Hreday N; Kuzhikandathil, Eldo V

    2014-04-15

    L-DOPA-induced dyskinesias (LID) are motor side effects associated with treatment of Parkinson's disease (PD). The etiology of LID is not clear; however, studies have shown that the dopamine D3 receptor is upregulated in the basal ganglia of mice, rats and non-human primate models of LID. It is not known if the upregulation of D3 receptor is a cause or result of LID. In this paper we tested the hypothesis that overexpression of the dopamine D3 receptor in dorsal striatum, in the absence of dopamine depletion, will elicit LID. Replication-deficient recombinant adeno-associated virus-2 expressing the D3 receptor or enhanced green fluorescent protein (EGFP) were stereotaxically injected, unilaterally, into the dorsal striatum of adult rats. Post-hoc immunohistochemical analysis revealed that ectopic expression of the D3 receptor was limited to neurons near the injection sites in the dorsal striatum. Following a 3-week recovery period, rats were administered saline, 6 mg/kg L-DOPA, 0.1 mg/kg PD128907 or 10 mg/kg ES609, i.p., and motor behaviors scored. Rats overexpressing the D3 receptor specifically exhibited contralateral axial abnormal involuntary movements (AIMs) following administration of L-DOPA and PD128907 but not saline or the novel agonist ES609. Daily injection of 6 mg/kg L-DOPA to the rats overexpressing the D3 receptor also caused increased vacuous chewing behavior. These results suggest that overexpression of the D3 receptor in the dorsal striatum results in the acute expression of agonist-induced axial AIMs and chronic L-DOPA-induced vacuous chewing behavior. Agonists such as ES609 might provide a novel therapeutic approach to treat dyskinesia. Copyright © 2014 Elsevier B.V. All rights reserved.

  16. Palmitoylation on the carboxyl terminus tail is required for the selective regulation of dopamine D2 versus D3 receptors.

    PubMed

    Zhang, Xiaowei; Le, Hang Thi; Zhang, Xiaohan; Zheng, Mei; Choi, Bo-Gil; Kim, Kyeong-Man

    2016-09-01

    Dopamine D2 receptor (D2R) and D3 receptor (D3R) possess highly conserved amino acid sequences but this study showed that D3R was more extensively palmitoylated than D2R. Based on this finding, the molecular basis of this selective palmitoylation of D3R was determined and the roles of palmitoylation in the regulation of D3R functions were investigated. D3R was palmitoylated on the cysteine residue on its carboxyl terminus tail, the last amino acid residue of D3R, and an exchange of the carboxyl terminus tail between D2R and D3R (D2R-D3C and D3R-D2C) resulted in the switching of the palmitoylation phenotype. When the consensus site for palmitoylation was mutated or the palmitoylation of D3R was inhibited by treatment with 2-bromopalmitate (2BP), a palmitoylation blocker, cell-surface expression, PKC-mediated endocytosis, agonist affinity, and agonist-induced tolerance of D3R were all inhibited. However, these changes were not observed when D3R palmitoylation was inhibited by replacing its carboxyl tail with that of D2R (D3R-D2C) or when the palmitoylation of D2R-D3C was inhibited by treatment with 2BP. Overall, this study shows that D3R is palmitoylated more extensively than D2R even though the carboxyl terminus tails of D2R and D3R are highly homologous, and thus provides a new clue regarding the consensus sequence for palmitoylation. This study also shows that palmitoylation controls various functionalities of D3R only when the receptor is in the intact D3R configuration. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. Purification and properties of D(-)-3-hydroxybutyrate-dimer hydrolase from Zoogloea ramigera I-16-M.

    PubMed

    Tanaka, Y; Saito, T; Fukui, T; Tanio, T; Tomita, K

    1981-08-01

    D(-)-3-Hydroxybutyrate-dimer hydrolase from Zoogloea ramigera I-16-M was purified 7000-fold to electrophoretic homogeneity. The molecular weight of the purified enzyme was 28 000 as determined by Sephadex G-100 gel filtration, and 30 000 as estimated by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate. The isoelectric point was at pH 5.7. The pH optimum for the enzyme reaction was 8.0. The dimer hydrolase was stereospecific for D(-)-3-[D(-)-3-hydroxybutyryloxy]butyric acid (DD-dimer) but also hydrolyzed D(-)-3-[L(+)-3-hydroxybutyryloxy]butyric acid (DL-dimmer) and L(+)-3-[D(-)-3-hydroxybutyryloxy]butyric acid (LD-dimer) at reduced rates. However, the enzyme did not attack L(+)-3-[L(+)-3-hydroxybutyryloxy]butyric acid (LL-dimer) at all. In addition, the purified hydrolase hydrolyzed several oligomeric esters of D(-)-3-hydroxybutyric acid (DDD-dimer, DDDD-tetramer and DDDDD-pentamer) faster than DD-dimer. Time course experiments with these oligomers and analysis of hydrolytic products of DDD-tetramer methyl ester with the hydrolase indicated that the enzyme attached these substrates from the free hydroxyl terminus releasing monomer units one at a time.

  18. Dopamine D3 receptor gene locus: Association with schizophrenia, as well age of onset

    SciTech Connect

    Nimgsonkar, V.L.; Zhang, X.R.; Brar, J.S.

    1994-09-01

    Genetic factors are clearly involved in the etiology of schizophrenia, but their specific nature is unknown. If the genetic etiology is multifactorial or polygenic, the role of specific genes as susceptibility factors can be directly evaluated by examining allelic variation at these loci among cases in comparison with controls. Two studies have independently demonstrated an association of schizophrenia with homozygosity at the dopamine D3 receptor gene (D3RG) locus, using a biallelic polymorphism in the first exon of D3RG. These results are important because D3RG is a favored candidate gene. Three other studies have identified associations among sub-groups of patients, but the majority were negative. The present study involved patients with schizophrenia (DSM-III-R criteria) of Caucasian or African-American ethnicity (n=130). Two groups of controls, matched for ethnicity, were used: adults screened for schizophrenia (n=128) and unselected neonates (n=160). Multivariate analysis revealed an association between allele no. 1 homozygosity and schizophrenia in comparison with adult, but not neonatal controls. The association was most marked among Caucasian patients with a family history of schizophrenia (odds ratio 13.7, C.I. 1.8, 104.3). An association of the D3RG locus with age of onset (AOO) was also noted. The discrepancies in earlier studies may due to variations in control groups, differencies in mean AOO among different cohorts, or ethnic variations in susceptibility attributable to D3RG.

  19. A role for cyclin D3 in the endomitotic cell cycle.

    PubMed Central

    Zimmet, J M; Ladd, D; Jackson, C W; Stenberg, P E; Ravid, K

    1997-01-01

    Platelets, essential for thrombosis and hemostasis, develop from polyploid megakaryocytes which undergo endomitosis. During this cell cycle, cells experience abrogated mitosis and reenter a phase of DNA synthesis, thus leading to endomitosis. In the search for regulators of the endomitotic cell cycle, we have identified cyclin D3 as an important regulatory factor. Of the D-type cyclins, cyclin D3 is present at high levels in megakaryocytes undergoing endomitosis and is markedly upregulated following exposure to the proliferation-, maturation-, and ploidy-promoting factor, Mpl ligand. Transgenic mice in which cyclin D3 is overexpressed in the platelet lineage display a striking increase in endomitosis, similar to changes seen following Mpl ligand administration to normal mice. Electron microscopy analysis revealed that unlike such treated mice, however, D3 transgenic mice show a poor development of demarcation membranes, from which platelets are believed to fragment, and no increase in platelets. Thus, while our model supports a key role for cyclin D3 in the endomitotic cell cycle, it also points to the unique role of Mpl ligand in priming megakaryocytes towards platelet fragmentation. The role of cyclin D3 in promoting endomitosis in other lineages programmed to abrogate mitosis will need further exploration. PMID:9372957

  20. [Has vitamin D(3) dosage improved in Spain? Current levels in a population sample].

    PubMed

    Bernal Pérez, Milagros; Cortés Flores, Giovanna; Giner Soria, Armando; Orden Gonzalo, Isabel; Horno Pérez, Marcial; Benedicto Lorenzo, Isabel

    2010-01-01

    According to current classifications, the metabolite of greatest clinical interest to evaluate vitamin D(3) dosage is 25-hydroxyvitamin D(3) with a reference interval of approximately 10-70ng/ml, although many authors consider values of approximately 40ng/ml or 100nmol/l to be desirable. According to these definitions, three out of four people in Spain would have vitamin D(3) deficiency. The RIA-CT technique was used for diagnosis of 25(OH)D(3) to determine the population status. Subsequently, a case-control study was performed to evaluate the relationship between distinct diseases and vitamin D(3) deficiency. A total of 73.2% of the cases were found to be within the range considered acceptable, according to the present classification. One hundred percent of the control group and healthy menopausal women who did not receive any kind of vitamin supplement had levels of 40 ng/ml or more. Our results indicate that the prior situation of a high prevalence of vitamin D(3) deficiency has improved and that levels are now acceptable in 26.8% of the population, with a mean value of 46.2 ng/ml, considering 10-70 ng/ml as the reference range.

  1. Parkinson's disease treatment may cause impulse-control disorder via dopamine D3 receptors.

    PubMed

    Seeman, Philip

    2015-04-01

    In treating Parkinson's disease with dopaminergic agonists, such as pramipexole, ropinirole, pergolide, rotigotine, apomorphine, or bromocriptine, it has been observed that a significant number of patients develop impulse-control disorders, such as compulsive shopping, pathological gambling, or hypersexuality. Because the dopamine agonists have high affinities for the dopamine D2 and D3 receptors, the drug dissociation constants of these drugs at the functional high-affinity states of these receptors, namely D2High and D3High, were compared. The data show that, compared to the other dopamine agonist drugs, pramipexole has a relatively high selectivity for the dopamine D3 receptor, as compared to D2, suggesting that the D3 receptor may be a primary target for pramipexole. There is a trend showing that the proportion of impulse-control disorders is related to the selectivity for D3 receptors over D2 receptors, with pramipexole having the highest association with, or frequency of, impulse-control disorders. While the number of studies are limited, the proportion of patients with impulse-control disorder in Parkinson patients treated with an add-on agonist were 32% for pramipexole, 25% for ropinirole, 16% for pergolide, 22% for rotigotine, 10% for apomorphine, and 6.8% for bromocriptine. Clinically, temporary replacement of pramipexole by bromocriptine may provide relief or reversal of the impulsive behavior associated with selective D3 stimulation by either pramipexole or ropinirole, while maintaining D2 stimulation needed for the anti-Parkinson action.

  2. 2D/3D-Display Auto-adjustment Switch System.

    PubMed

    Lin, Bor-Shyh; Wu, Pei-Jung; Chen, Chien-Yu

    2017-05-03

    Recently, 2D/3D switchable displays have become the mainstream in 3D display technologies, and people can now watch 3D movies with a naked 2D/3D switchable display at home. However, some studies have indicated that people might encounter visual fatigue after enjoying a 3D film in the theater. Although 2D/3D switchable technologies have been widely developed, 3D display technologies are still lacking in ergonomic and human-care factors such as reducing visual fatigue. This study proposes a novel 2D/3D display auto-adjustment switch system to provide biofeedback functions to reduce users' visual fatigue. In addition, the relationship between the blink rate and the visual fatigue state while watching 3D films was investigated and quantified. In this study, liquid crystal barrier technology was used to develop a 2D/ 3D switchable display, and a wearable EOG acquisition device was also designed to monitor electrooculography signals to estimate the blink rate. Here, the 2D/3D display auto-adjustment criterion of the proposed system was designed according to the change in the visual fatigue state as estimated from the blink rate. Finally, the experimental results show that the proposed system could effectively reduce users' visual fatigue while watching 3D films.

  3. The dopamine D3 receptor: a therapeutic target for the treatment of neuropsychiatric disorders.

    PubMed

    Sokoloff, P; Diaz, J; Le Foll, B; Guillin, O; Leriche, L; Bezard, E; Gross, C

    2006-02-01

    The role of the D(3) receptor has remained largely elusive before the development of selective research tools, such as selective radioligands, antibodies, various highly specific pharmacological agents and knock-out mice. The data collected so far with these tools have removed some of the uncertainties regarding the functions mediated by the D(3) receptor. The D(3) receptor is an autoreceptor that controls the phasic, but not tonic activity of dopamine neurons. The D(3) receptor, via regulation of its expression by the brain-derived neurotrophic factor (BDNF), mediates sensitization to dopamine indirect agonists. This process seems responsible for side-effects of levodopa (dyskinesia) in the treatment of Parkinson's disease (PD), as well as for some aspects of conditioning to drugs of abuse. The D(3) receptor mediates behavioral abnormalities elicited by glutamate/NMDA receptor blockade, which suggests D(3) receptor-selective antagonists as novel antipsychotic drugs. These data allow us to propose novel treatment options in PD, schizophrenia and drug addiction, which are awaiting evaluation in clinical trials.

  4. Synthesis, pharmacological evaluation and molecular modeling studies of triazole containing dopamine D3 receptor ligands.

    PubMed

    Peng, Xin; Wang, Qi; Mishra, Yogesh; Xu, Jinbin; Reichert, David E; Malik, Maninder; Taylor, Michelle; Luedtke, Robert R; Mach, Robert H

    2015-02-01

    A series of 2-methoxyphenyl piperazine analogues containing a triazole ring were synthesized and their in vitro binding affinities at human dopamine D2 and D3 receptors were evaluated. Compounds 5b, 5c, 5d, and 4g, demonstrate high affinity for dopamine D3 receptors and moderate selectivity for the dopamine D3 versus D2 receptor subtypes. To further examine their potential as therapeutic agents, their intrinsic efficacy at both D2 and D3 receptors was determined using a forskolin-dependent adenylyl cyclase inhibition assay. Affinity at dopamine D4 and serotonin 5-HT1A receptors was also determined. In addition, information from previous molecular modeling studies of the binding of a panel of 163 structurally-related benzamide analogues at dopamine D2 and D3 receptors was applied to this series of compounds. The results of the modeling studies were consistent with our previous experimental data. More importantly, the modeling study results explained why the replacement of the amide linkage with the hetero-aromatic ring leads to a reduction in the affinity of these compounds at D3 receptors.

  5. EFFECTS OF SMOKING ON D2/D3 STRIATAL RECEPTOR AVAILABILITY IN ALCOHOLICS AND SOCIAL DRINKERS

    PubMed Central

    Albrecht, Daniel S.; Kareken, David A.; Yoder, Karmen K.

    2013-01-01

    Objective Studies have reported lower striatal D2/D3 receptor availability in both alcoholics and cigarette smokers relative to healthy controls. These substances are commonly co-abused, yet the relationship between comorbid alcohol/tobacco abuse and striatal D2/D3 receptor availability has not been examined. We sought to determine the degree to which dual abuse of alcohol and tobacco is associated with lower D2/D3 receptor availability. Method Eighty-one subjects (34 nontreatment-seeking alcoholic smokers [NTS-S], 21 social-drinking smokers [SD-S], and 26 social-drinking non-smokers [SD-NS]) received baseline [11C]raclopride scans. D2/D3 binding potential (BPND ≡ Bavail/KD) was estimated for ten anatomically defined striatal regions of interest (ROIs). Results Significant group effects were detected in bilateral pre-commissural dorsal putamen, bilateral pre-commissural dorsal caudate; and bilateral post-commissural dorsal putamen. Post-hoc testing revealed that, regardless of drinking status, smokers had lower D2/D3 receptor availability than non-smoking controls. Conclusions Chronic tobacco smokers have lower striatal D2/D3 receptor availability than non-smokers, independent of alcohol use. Additional studies are needed to identify the mechanisms by which chronic tobacco smoking is associated with striatal dopamine receptor availability. PMID:23649848

  6. The Effects of Uric Acid, Serum Vitamin D3, and Their Interaction on Parkinson's Disease Severity

    PubMed Central

    Meamar, Rokhsareh; Shaabani, Pooria; Tabibian, Seyed Reza; Aghaye Ghazvini, Mohammad Reza

    2015-01-01

    Objectives. In current study, the relationships between serum vitamin D3 levels and serum UA concentrations as well as their interaction with severity of PD were evaluated in a sample of Iranian PD patients. Method. In a cross sectional study at the one of the main referral hospitals in central region of Iran, during September to November 2011, 112 patients were recruited. Severity of PD was evaluated sing H&R stages and UPDRS. Results. The Spearman rank correlation coefficient suggests the negative significant association between serum vitamin D3 and UPDRS in patients aged >62 (r = −0.34, P < 0.05). No statistically significant association was observed between the UA levels and severity of PD (represented by H&Y categories) in different levels of serum vitamin D3 not only in total sample but also in separate age and sex groups. The linear regression coefficients suggested positive association between UA and serum vitamin D3 with UPDRSIII scores while negative relationship between UA and serum vitamin D3 interaction with UPDRSIII; however it was only statistically significant in age group ≤62 (P < 0.05). Conclusion. Our study revealed a negative correlation between interaction of serum vitamin D3 and UA with severity of PD; other studies are required to confirm our findings. PMID:25802799

  7. The effects of uric Acid, serum vitamin d3, and their interaction on Parkinson's disease severity.

    PubMed

    Meamar, Rokhsareh; Shaabani, Pooria; Tabibian, Seyed Reza; Aghaye Ghazvini, Mohammad Reza; Feizi, Awat

    2015-01-01

    Objectives. In current study, the relationships between serum vitamin D3 levels and serum UA concentrations as well as their interaction with severity of PD were evaluated in a sample of Iranian PD patients. Method. In a cross sectional study at the one of the main referral hospitals in central region of Iran, during September to November 2011, 112 patients were recruited. Severity of PD was evaluated sing H&R stages and UPDRS. Results. The Spearman rank correlation coefficient suggests the negative significant association between serum vitamin D3 and UPDRS in patients aged >62 (r = -0.34, P < 0.05). No statistically significant association was observed between the UA levels and severity of PD (represented by H&Y categories) in different levels of serum vitamin D3 not only in total sample but also in separate age and sex groups. The linear regression coefficients suggested positive association between UA and serum vitamin D3 with UPDRSIII scores while negative relationship between UA and serum vitamin D3 interaction with UPDRSIII; however it was only statistically significant in age group ≤62 (P < 0.05). Conclusion. Our study revealed a negative correlation between interaction of serum vitamin D3 and UA with severity of PD; other studies are required to confirm our findings.

  8. Evolution of chemical bonding and electron density rearrangements during D(3h) → D(3d) reaction in monolayered TiS2: a QTAIM and ELF study.

    PubMed

    Ryzhikov, Maxim R; Slepkov, Vladimir A; Kozlova, Svetlana G; Gabuda, Svyatoslav P

    2014-08-15

    Monolayered titanium disulfide TiS2, a prospective nanoelectronic material, was previously shown to be subject to an exothermic solid-state D3h -D3d reaction that proceeds via a newly discovered transition state. Here, we study the reaction in detail using topological methods of quantum chemistry (quantum theory of atoms in molecules and electron localization function analysis) and show how electron density and chemical bonding between the atoms change in the course of the reaction. The reaction is shown to undergo a series of topological catastrophes, associated with elementary chemical events such as break and formation of bonds (including the unexpected formation of S-S bonding between sulfur layers), and rearrangement of electron density of outer valence and core shells. Copyright © 2014 Wiley Periodicals, Inc.

  9. Active vitamin D3, 1,25-(OH)2D3, protects against macrovasculopathy in a rat model of type 2 diabetes mellitus.

    PubMed

    Ma, R; Deng, X L; Du, G L; Li, C; Xiao, S; Aibibai, Y; Zhu, J

    2016-06-03

    To investigate the protective effect of the active form of vitamin D3, 1,25-(OH)2D3, on macrovasculopathy in rats with type 2 diabetes mellitus (T2DM), 8-week-old male Sprague-Dawley rats were randomly divided into control group, T2DM group, and treatment group. The T2DM model was established after 6 weeks by administering an intraperitoneal injection of streptozotocin (30 mg/kg). 1,25-(OH)2D3 was administered by gavage to rats in the treatment group, and an equal volume of peanut oil was administered to rats in the T2DM group. Fasting plasma glucose (FPG), triglyceride (TG), total cholesterol (TC), high-density lipoprotein (HDL-C) and low-density lipoprotein (LDL-C) cholesterols were measured in all rats. The morphology of the thoracic aorta was examined, and the expression of tumor necrosis factor alpha (TNF-α), endothelin (ET), endothelial nitric oxide synthase (eNOS), CD54, and CD106 in the thoracic aorta was determined by immunohistochemistry. The expression of FPG, TG, TC, and LDL-C in rats from the T2DM and treatment groups was significantly elevated compared with rats from the control group (P < 0.05). Compared with that in control group, the expression of TNF-α, ET, eNOS, and CD106 was significantly upregulated in the T2DM group and the treatment group, while the expression of CD54 was increased only in the T2DM group (P < 0.05). Moreover, the levels of TNF-α, CD54, and CD106 in rats from the treatment group were lower than those in the T2DM group (P < 0.05). These data suggest that 1,25-(OH)2D3 may protect the macrovessels from injury in T2DM rats by inhibiting the expression of TNF-α, CD54, and CD106.

  10. Regioselective synthesis of isotopically labeled Δ9-tetrahydrocannabinolic acid A (THCA-A-D3) by reaction of Δ9-tetrahydrocannabinol-D3 with magnesium methyl carbonate.

    PubMed

    Roth, Nadine; Wohlfarth, Ariane; Müller, Michael; Auwärter, Volker

    2012-10-10

    For the reliable quantification of Δ9-tetrahydrocannabinolic acid A (THCA-A), the biogenetic precursor of Δ9-tetrahydrocannabinol (THC), in biological matrices by LC-MS/MS and GC-MS(/MS), an isotopically labeled internal standard was synthesized starting from Δ9-tetrahydrocannabinol-D(3) (THC-D(3)). Synthesis strategy was based on a method reported by Mechoulam et al. in 1969 using magnesium methyl carbonate (MMC) as carboxylation reagent for the synthesis of cannabinoid acids. Preliminary experiments with THC to optimize yield of the product (THCA-A) resulted in the synthesis of the positional isomer tetrahydrocannabinolic acid B (THCA-B) as a byproduct. Using the optimized conditions for the desired isomer, THCA-A-D(3) was prepared and isolated with a yield of approx. 10% after two synthesis cycles. Isotope purity was estimated to be >99% by relative abundance of the molecular ions. The synthesized compound proved to be suitable as an internal standard for quantification of THCA-A in serum and hair samples of cannabis consumers.

  11. Associations between blood persistent organic pollutants and 25-hydroxyvitamin D3 in pregnancy.

    PubMed

    Morales, Eva; Gascon, Mireia; Martinez, David; Casas, Maribel; Ballester, Ferran; Rodríguez-Bernal, Clara L; Ibarluzea, Jesus; Marina, Loreto Santa; Espada, Mercedes; Goñi, Fernando; Vizcaino, Esther; Grimalt, Joan O; Sunyer, Jordi

    2013-07-01

    Persistent organic pollutants (POPs) are suggested to contribute to lower vitamin D levels; however, studies in humans are scarce and have never focused on pregnancy, a susceptibility period for vitamin D deficiency. We investigated whether serum levels of POPs were associated with circulating 25-hydroxyvitamin D3 [25(OH)D3] concentration in pregnancy. Cross-sectional associations of serum concentrations of eight POPs with plasma 25(OH)D3 concentration were analyzed in 2031 pregnant women participating in the Spanish population-based cohort INfancia y Medio Ambiente (INMA) Project. Serum concentrations of POPs were measured by gas chromatography and plasma 25(OH)D3 concentration was measured by high-performance liquid chromatography in pregnancy (mean 13.3±1.5weeks of gestation). Multivariable regression models were performed to assess the relationship between blood concentrations of POPs and 25(OH)D3. An inverse linear relationship was found between serum concentration of PCB180 and circulating 25(OH)D3. Multivariate linear regression models showed higher PCB180 levels to be associated with lower 25(OH)D3 concentration: quartile Q4 vs. quartile Q1, coefficient=-1.59, 95% CI -3.27, 0.08, p trend=0.060. A non-monotonic inverse relationship was found between the sum of predominant PCB congeners (PCB 180, 153 and 138) and 25(OH)D3 concentration: coefficient (95% CI) for quartile Q2 vs. Q1 [-0.50 (-1.94, 0.94)], quartile Q3 vs. Q1 [-1.56 (-3.11, -0.02)] and quartile Q4 vs. Q1 [-1.21 (-2.80, 0.38)], p trend=0.081. No significant associations were found between circulating 25(OH)D3 and serum levels of p,p'-DDE, p,p'-DDT, HCB, and ß-HCH. Our results suggest that the background exposure to PCBs may result in lower 25(OH)D3 concentration in pregnant women.

  12. 1,25-Dihydroxyvitamin D(3) Inhibits Podocyte uPAR Expression and Reduces Proteinuria

    PubMed Central

    Liu, Shuangxin; Xie, Shaoting; Yang, Yun; Ma, Juan; Deng, Yujun; Wang, Wenjian; Xu, Lixia; Li, Ruizhao; Zhang, Li; Yu, Chunping; Shi, Wei

    2013-01-01

    Background Accumulating studies have demonstrated that 1,25-Dihydroxyvitamin D(3) (1,25(OH)2D3) reduces proteinuria and protects podocytes from injury. Recently, urokinase receptor (uPAR) and its soluble form have been shown to cause podocyte injury and focal segmental glomerulosclerosis (FSGS). Here, our findings showed that 1,25(OH)2D3 did inhibit podocyte uPAR expression and attenuate proteinuria and podocyte injury. Methodology/Principal Findings In this study, the antiproteinuric effect of 1,25(OH)2D3 was examined in the lipopolysaccharide mice model of transient proteinuria (LPS mice) and in the 5/6 nephrectomy rat FSGS model(NTX rats). uPAR protein expression were tested by flow cytometry, immune cytochemistry and western blot analysis, and uPAR mRNA expression by real-time quantitative PCR in cultured podocytes and kidney glomeruli isolated from mice and rats. Podocyte motility was observed by transwell migration assay and wound healing assay. Podocyte foot processes effacement was identified by transmission electron microscopy. We found that 1,25(OH)2D3 inhibited podocyte uPAR mRNA and protein synthesis in LPS-treated podocytes, LPS mice and NTX rats, along with 1,25(OH)2D3 reducing proteinuria in NTX rats and LPS mice.1,25(OH)2D3 reduced glomerulosclerosis in NTX rats and alleviated podocyte foot processes effacement in LPS mice. Transwell migration assay and wound healing assay showed that LPS-induced podocyte motility, irrespective of random or directed motility, were substantially reduced by 1,25(OH)2D3. Conclusions/Significance Our results demonstrated that 1,25(OH)2D3 inhibited podocyte uPAR expression in vitro and in vivo, which may be an unanticipated off target effect of 1,25(OH)2D3 and explain its antiproteinuric effect in the 5/6 nephrectomy rat FSGS model and the LPS mouse model of transient proteinuria. PMID:23741418

  13. Dopamine D3 Receptor Availability Is Associated with Inflexible Decision Making

    PubMed Central

    Groman, Stephanie M.; Smith, Nathaniel J.; Petrullli, J. Ryan; Massi, Bart; Chen, Lihui; Ropchan, Jim; Huang, Yiyun; Lee, Daeyeol; Morris, Evan D.

    2016-01-01

    Dopamine D2/3 receptor signaling is critical for flexible adaptive behavior; however, it is unclear whether D2, D3, or both receptor subtypes modulate precise signals of feedback and reward history that underlie optimal decision making. Here, PET with the radioligand [11C]-(+)-PHNO was used to quantify individual differences in putative D3 receptor availability in rodents trained on a novel three-choice spatial acquisition and reversal-learning task with probabilistic reinforcement. Binding of [11C]-(+)-PHNO in the midbrain was negatively related to the ability of rats to adapt to changes in rewarded locations, but not to the initial learning. Computational modeling of choice behavior in the reversal phase indicated that [11C]-(+)-PHNO binding in the midbrain was related to the learning rate and sensitivity to positive, but not negative, feedback. Administration of a D3-preferring agonist likewise impaired reversal performance by reducing the learning rate and sensitivity to positive feedback. These results demonstrate a previously unrecognized role for D3 receptors in select aspects of reinforcement learning and suggest that individual variation in midbrain D3 receptors influences flexible behavior. Our combined neuroimaging, behavioral, pharmacological, and computational approach implicates the dopamine D3 receptor in decision-making processes that are altered in psychiatric disorders. SIGNIFICANCE STATEMENT Flexible decision-making behavior is dependent upon dopamine D2/3 signaling in corticostriatal brain regions. However, the role of D3 receptors in adaptive, goal-directed behavior has not been thoroughly investigated. By combining PET imaging with the D3-preferring radioligand [11C]-(+)-PHNO, pharmacology, a novel three-choice probabilistic discrimination and reversal task and computational modeling of behavior in rats, we report that naturally occurring variation in [11C]-(+)-PHNO receptor availability relates to specific aspects of flexible decision making

  14. Dopamine D3 Receptor Availability Is Associated with Inflexible Decision Making.

    PubMed

    Groman, Stephanie M; Smith, Nathaniel J; Petrullli, J Ryan; Massi, Bart; Chen, Lihui; Ropchan, Jim; Huang, Yiyun; Lee, Daeyeol; Morris, Evan D; Taylor, Jane R

    2016-06-22

    Dopamine D2/3 receptor signaling is critical for flexible adaptive behavior; however, it is unclear whether D2, D3, or both receptor subtypes modulate precise signals of feedback and reward history that underlie optimal decision making. Here, PET with the radioligand [(11)C]-(+)-PHNO was used to quantify individual differences in putative D3 receptor availability in rodents trained on a novel three-choice spatial acquisition and reversal-learning task with probabilistic reinforcement. Binding of [(11)C]-(+)-PHNO in the midbrain was negatively related to the ability of rats to adapt to changes in rewarded locations, but not to the initial learning. Computational modeling of choice behavior in the reversal phase indicated that [(11)C]-(+)-PHNO binding in the midbrain was related to the learning rate and sensitivity to positive, but not negative, feedback. Administration of a D3-preferring agonist likewise impaired reversal performance by reducing the learning rate and sensitivity to positive feedback. These results demonstrate a previously unrecognized role for D3 receptors in select aspects of reinforcement learning and suggest that individual variation in midbrain D3 receptors influences flexible behavior. Our combined neuroimaging, behavioral, pharmacological, and computational approach implicates the dopamine D3 receptor in decision-making processes that are altered in psychiatric disorders. Flexible decision-making behavior is dependent upon dopamine D2/3 signaling in corticostriatal brain regions. However, the role of D3 receptors in adaptive, goal-directed behavior has not been thoroughly investigated. By combining PET imaging with the D3-preferring radioligand [(11)C]-(+)-PHNO, pharmacology, a novel three-choice probabilistic discrimination and reversal task and computational modeling of behavior in rats, we report that naturally occurring variation in [(11)C]-(+)-PHNO receptor availability relates to specific aspects of flexible decision making. We confirm

  15. Therapeutic doses of buspirone block D3 receptors in the living primate brain.

    PubMed

    Kim, Sung Won; Fowler, Joanna S; Skolnick, Phil; Muench, Lisa; Kang, Yeona; Shea, Colleen; Logan, Jean; Kim, Dohyun; Carter, Pauline; King, Payton; Alexoff, David; Volkow, Nora D

    2014-08-01

    Dopamine D3 receptor (D3R) antagonists may be effective medications for multiple substance use disorders (SUDs). However, no selective D3R antagonists are currently available for clinical testing. Buspirone, originally characterized as a 5-HT1A partial agonist and used as an anxiolytic, also binds to D3R and D4R with high affinity, with lower affinity to D2R, and interferes with cocaine reward. Here we used PET with [11C]PHNO (D3R-preferring radioligand), [11C]raclopride (D2R/D3R radioligand) and [11C]NNC-112 (D1R radioligand) to measure occupancy of oral and parenteral buspirone in the primate brain. Intramuscular buspirone (0.19 and 0.5 mg/kg) blocked both [11C]PHNO and [11C]raclopride binding to striatum, exhibiting high occupancy (50-85%) at 15 min and rapid wash-out over 2-6 h. In contrast, oral buspirone (3 mg/kg) significantly blocked [11C]PHNO binding in D3-rich regions (globus pallidum and midbrain) at 3 h, but had minimal effects on [11C]raclopride binding (28-37% at 1 h and 10% at 3 h). Buspirone did not block [11C]NNC-112. Our findings provide evidence that i.m. buspirone blocks D3R and D2R, whereas oral buspirone is more selective towards D3R blockade in vivo, consistent with extensive first pass metabolism and supporting the hypothesis that its metabolites (5- and 6'-hydroxybuspirone) merit evaluation for treating SUDs. They also indicate that for oral buspirone to achieve greater than 80% sustained D3R occupancy, as might be needed to treat addiction, higher doses (at least three-fold) than those used to treat anxiety (maximal 60 mg) will be required. Nonetheless, based on previous clinical studies, these doses would be safe and well tolerated.

  16. Vitamin D2 versus vitamin D3 supplementation in hemodialysis patients: a comparative pilot study.

    PubMed

    Daroux, Maïté; Shenouda, Milhad; Bacri, Jean-Louis; Lemaitre, Vincent; Vanhille, Philippe; Bataille, Pierre

    2013-01-01

    In patients with chronic kidney disease, vitamin D insufficiency is highly prevalent. It can be corrected by supplementation with either vitamin D(2) or vitamin D3. Recent studies in patients without impaired kidney function suggest that vitamin D(3) is more efficient than vitamin D(2) in correcting vitamin D insufficiency. However, no direct comparison has been made in hemodialysis (HD) patients. Thirty-nine HD patients with serum 25-hydroxyvitamin D (25(OH)D) levels =20 ng/mL were enrolled in this comparative, prospective pilot study. They were divided into 3 groups and treated over a 3-month period. Each patient received oral doses of 200,000 international units (IU) vitamin D per month according to the following treatment schedule: (i) vitamin D(2) in small fractionated doses at each HD session, 3 times per week (group D2S); (ii) vitamin D(2) once a month (group D2M); or (iii) vitamin D(3) once a month (group D3M). Changes in serum 25(OH)D levels were measured at the end of the study. Posttreatment serum 25(OH)D levels increased significantly in all groups. The mean ± SD serum 25(OH)D value for group D3M patients (40 ± 13 ng/mL) was significantly higher than that for groups D2M (25 ± 9 ng/mL, p<0.01) and D2S patients (25 ± 9 ng/mL, p<0.01). Serum 25(OH)D increased to levels >30 ng/mL in 84% of group D3M patients, but in only 15% and 27% of group D2M and D2S subjects, respectively. Vitamin D(3) is more effective than vitamin D(2) in providing adequate 25(OH)D serum levels in HD patients.

  17. Design, Synthesis and Biological Activities of Novel Gemini 20S-Hydroxyvitamin D3 Analogs.

    PubMed

    Lin, Zongtao; Marepally, Srinivasa R; Kim, Tae-Kang; Janjetovic, Zorica; Oak, Allen Sw; Postlethwaite, Arnold E; Myers, Linda K; Tuckey, Robert C; Slominski, Andrzej T; Miller, Duane D; Li, Wei

    2016-03-01

    Vitamin D3 (D3) can be metabolized by cytochrome P450scc (CYP11A1) into 20S-hydroxyvitamin D3 (20D3) as a major metabolite. This bioactive metabolite has shown strong antiproliferative, antifibrotic, pro-differentiation and anti-inflammatory effects while being non-toxic (non-calcemic) at high concentrations. Since D3 analogs with two symmetric side chains (Gemini analogs) result in potent activation of the vitamin D receptor (VDR), we hypothesized that the chain length and composition of these types of analogs also containing a 20-hydroxyl group would affect their biological activities. In this study, we designed and synthesized a series of Gemini 20D3 analogs. Biological tests showed that some of these analogs are partial VDR activators and can significantly stimulate the expression of mRNA for VDR and VDR-regulated genes including CYP24A1 and transient receptor potential cation channel V6 (TRPV6). These analogs inhibited the proliferation of melanoma cells with potency comparable to that of 1α,25-dihydroxyvitamin D3. Moreover, these analogs reduced the level of interferon γ and up-regulated the expression of leukocyte associated immunoglobulin-like receptor 1 in splenocytes, indicating that they have potent anti-inflammatory activities. There are no clear correlations between the Gemini chain length and their VDR activation or biological activities, consistent with the high flexibility of the ligand-binding pocket of the VDR. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  18. Computational Study and Modified Design of Selective Dopamine D3 Receptor Agonists.

    PubMed

    Duan, Xinli; Zhang, Xin; Xu, Binglin; Wang, Fang; Lei, Ming

    2016-07-01

    Dopamine D3 receptor (D3 R) is considered as a potential target for the treatment of nervous system disorders, such as Parkinson's disease. Current research interests primarily focus on the discovery and design of potent D3 agonists. In this work, we selected 40 D3 R agonists as the research system. Comparative molecular field analysis (CoMFA) of three-dimensional quantitative structure-activity relationship (3D-QSAR), structure-selectivity relationship (3D-QSSR), and molecular docking was performed on D3 receptor agonists to obtain the details at atomic level. The results indicated that both the CoMFA model (r(2) = 0.982, q(2) = 0.503, rpred2 = 0.893, SEE  = 0.057, F = 166.308) for structure-activity and (r(2) = 0.876, q(2) = 0.436, rpred2 = 0.828, F = 52.645) for structure-selectivity have good predictive capabilities. Furthermore, docking studies on three compounds binding to D3 receptor were performed to analyze the binding modes and interactions. The results elucidate that agonists formed hydrogen bond and hydrophobic interactions with key residues. Finally, we designed six molecules under the guidance of 3D-QSAR/QSSR models. The activity and selectivity of designed molecules have been improved, and ADMET properties demonstrate they have low probability of hepatotoxicity (<0.5). These results from 3D-QSAR/QSSR and docking studies have great significance for designing novel dopamine D3 selective agonists in the future. © 2016 John Wiley & Sons A/S.

  19. Solar UV doses of adult Americans and vitamin D3 production

    PubMed Central

    Pope, Stanley J; Grant, William B; Holick, Michael F

    2011-01-01

    Background Sunlight contains UV radiation that affects human health in both detrimental (skin cancers) and beneficial (vitamin D3) ways. An evaluation of the vitamin D status of adult Americans (22–40, 41–59, 60+ yr) show many have deficient or insufficient serum levels of 25-hydroxyvitamin D, indicating they are not getting enough from dietary sources or sunlight. Those findings are in conflict with calculated values from the American Academy of Dermatology who insist people make “ample” vitamin D3 (≥1,000 IU/day) from their “casual,” or everyday, outdoor UV exposures even if they use sunscreens with sun protection factor 15. Objective We investigated this situation using the everyday outdoor UV doses of indoor-working adult Americans (∼7,000) in the north (45°N) and south (35°N) to calculate how much vitamin D3 they produce each season with and without vacationing. Results Only during the summer can skin type II Caucasian adults (21–59 yr) meet their minimum (600 IU/day) vitamin D3 needs from everyday exposures, but only if they do not wear professional clothes or sunscreens (except beach vacations). Method To do vitamin D3 calculations properly, we used action spectrum and geometric conversion factors, not previously incorporated into other calculations. Conclusions Most adult Americans do not go outside enough to meet their minimum or optimum (≥1,200 IU/day) vitamin D3 needs all year. The darker skin types (III–VI) and the oldest people (>59 yr) are at the highest risk for not making enough vitamin D3 during the year from everyday outdoor exposures even with a 2–3 week summer vacation. PMID:22259652

  20. 1,25(OH)2D3 dependent overt hyperactivity phenotype in klotho-hypomorphic mice

    PubMed Central

    Leibrock, Christina B.; Voelkl, Jakob; Kuro-o, Makoto; Lang, Florian; Lang, Undine E

    2016-01-01

    Klotho, a protein mainly expressed in kidney and cerebral choroid plexus, is a powerful regulator of 1,25(OH)2D3 formation. Klotho-deficient mice (kl/kl) suffer from excessive plasma 1,25(OH)2D3-, Ca2+- and phosphate-concentrations, leading to severe soft tissue calcification and accelerated aging. NH4Cl treatment prevents tissue calcification and premature ageing without affecting 1,25(OH)2D3-formation. The present study explored the impact of excessive 1,25(OH)2D3 formation in NH4Cl-treated kl/kl-mice on behavior. To this end kl/kl-mice and wild-type mice were treated with NH4Cl and either control diet or vitamin D deficient diet (LVD). As a result, plasma 1,25(OH)2D3-, Ca2+- and phosphate-concentrations were significantly higher in untreated and in NH4Cl-treated kl/kl-mice than in wild-type mice, a difference abrogated by LVD. In each, open field, dark-light box, and O-maze NH4Cl-treated kl/kl-mice showed significantly higher exploratory behavior than untreated wild-type mice, a difference abrogated by LVD. The time of floating in the forced swimming test was significantly shorter in NH4Cl treated kl/kl-mice compared to untreated wild-type mice and to kl/kl-mice on LVD. In wild-type animals, NH4Cl treatment did not significantly alter 1,25(OH)2D3, calcium and phosphate concentrations or exploratory behavior. In conclusion, the excessive 1,25(OH)2D3 formation in klotho-hypomorphic mice has a profound effect on murine behavior. PMID:27109615

  1. Identification of Human UDP-glucuronosyltransferases Catalyzing Hepatic 1α,25-Dihydroxyvitamin D3 Conjugation

    PubMed Central

    Hashizume, Takanori; Xu, Yang; Mohutsky, Michael A.; Alberts, Jeffrey; Hadden, Chad; Kalhorn, Thomas F.; Isoherranen, Nina; Shuhart, Margaret C.; Thummel, Kenneth E.

    2009-01-01

    The biological effects of 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) are terminated primarily by P450-dependent hydroxylation reactions. However, the hormone is also conjugated in the liver and a metabolite, presumably a glucuronide, undergoes enterohepatic cycling. In this study, the identity of human enzymes capable of catalyzing the 1,25(OH)2D3 glucuronidation reaction was investigated in order to better understand environmental and endogenous factors affecting the disposition and biological effects of vitamin D3. Among twelve different UGT isozymes tested, only UGT1A4 ≫ 2B4 and 2B7 supported the reaction. Two different 1,25(OH)2D3 monoglucuronide metabolites were generated by recombinant UGT1A4 and human liver microsomes. The most abundant product was identified by mass spectral and NMR analyses as the 25-O-glucuronide isomer. The formation of 25-O-glucuronide by UGT1A4 Supersomes and human liver microsomes followed simple hyperbolic kinetics, yielding respective Km and Vmax values of 7.3 and 11.2 μM, and 33.7 ± 1.4 and 32.9 ± 1.9 pmol/min/mg protein. The calculated intrinsic 25-O-glucuronide M1 formation clearance for UGT1A4 was 14-fold higher than the next best isozyme, UGT2B7. There was only limited (4-fold) inter-liver variability in the 25-O-glucuronidation rate, but it was highly correlated with the relative rate of formation of the second, minor metabolite. In addition, formation of both metabolites was inhibited > 80% by the selective UGT1A4 inhibitor, hecogenin. If enterohepatic recycling of 1,25(OH)2D3 represents a significant component of intestinal and systemic 1,25(OH)2D3 disposition, formation of monoglucuronides by hepatic UGT1A4 constitutes an important initial step. PMID:18177842

  2. Cell Cycle-independent Role of Cyclin D3 in Host Restriction of Influenza Virus Infection

    PubMed Central

    Fan, Ying; Mok, Chris Ka-Pun; Chan, Michael Chi Wai; Zhang, Yang; Nal, Béatrice; Kien, François; Bruzzone, Roberto; Sanyal, Sumana

    2017-01-01

    To identify new host factors that modulate the replication of influenza A virus, we performed a yeast two-hybrid screen using the cytoplasmic tail of matrix protein 2 from the highly pathogenic H5N1 strain. The screen revealed a high-score interaction with cyclin D3, a key regulator of cell cycle early G1 phase. M2-cyclin D3 interaction was validated through GST pull-down and recapitulated in influenza A/WSN/33-infected cells. Knockdown of Ccnd3 by small interfering RNA significantly enhanced virus progeny titers in cell culture supernatants. Interestingly, the increase in virus production was due to cyclin D3 deficiency per se and not merely a consequence of cell cycle deregulation. A combined knockdown of Ccnd3 and Rb1, which rescued cell cycle progression into S phase, failed to normalize virus production. Infection by influenza A virus triggered redistribution of cyclin D3 from the nucleus to the cytoplasm, followed by its proteasomal degradation. When overexpressed in HEK 293T cells, cyclin D3 impaired binding of M2 with M1, which is essential for proper assembly of progeny virions, lending further support to its role as a putative restriction factor. Our study describes the identification and characterization of cyclin D3 as a novel interactor of influenza A virus M2 protein. We hypothesize that competitive inhibition of M1-M2 interaction by cyclin D3 impairs infectious virion formation and results in attenuated virus production. In addition, we provide mechanistic insights into the dynamic interplay of influenza virus with the host cell cycle machinery during infection. PMID:28130444

  3. Cell Cycle Independent Role of Cyclin D3 in Host Restriction of Influenza Virus Infection.

    PubMed

    Fan, Ying; Mok, Chris Ka-Pun; Chan, Michael Chi Wai; Zhang, Yang; Nal-Rogier, Béatrice; Kien, François; Bruzzone, Roberto; Sanyal, Sumana

    2017-01-27

    To identify new host factors that modulate the replication of influenza A virus, we performed a yeast two-hybrid screen using the cytoplasmic tail of matrix protein 2 from the highly pathogenic H5N1 strain. The screen revealed a high-score interaction with cyclin D3, a key regulator of cell cycle early G1 phase. M2-cyclin D3 interaction was validated through GST pull-down and recapitulated in influenza A/WSN/33-infected cells. Knockdown of Ccnd3 by small interfering RNA significantly enhanced virus progeny titers in cell culture supernatants. Interestingly, the increase in virus production was due to cyclin D3 deficiency per se, and not merely a consequence of cell cycle deregulation. A combined knockdown of Ccnd3 and Rb1, which rescued cell cycle progression into the S phase, failed to normalize virus production. Infection by IAV triggered redistribution of cyclin D3 from the nucleus to the cytoplasm followed by its proteasomal degradation. When over-expressed in HEK 293T cells cyclin D3 impaired binding of M2 with M1, which is essential for proper assembly of progeny virions, lending further support to its role as a putative restriction factor. Our study describes the identification and characterization of cyclin D3 as a novel interactor of influenza A virus M2 protein. We hypothesize that competitive inhibition of M1-M2 interaction by cyclin D3 impairs infectious virion formation and results in attenuated virus production. In addition, we provide mechanistic insights into the dynamic interplay of influenza virus with the host cell cycle machinery during infection.

  4. Agreement between Patient and Proxy Assessments of Quality of Life among Older Adults with Vascular Cognitive Impairment Using the EQ-5D-3L and ICECAP-O

    PubMed Central

    Davis, Jennifer C.; Hsiung, Ging-Yuek; Bryan, Stirling; Jacova, Claudia; Jacova, Patrizio; Munkacsy, Michelle; Cheung, Winnie; Lee, Philip; Liu-Ambrose, Teresa

    2016-01-01

    Background The assessment of quality of life is critical in ascertaining the benefit of interventions aimed to reduce morbidity among individuals with cognitive impairment. However, the assessment of quality of life is challenging in this population due to the uncertain validity of patient responses as cognitive function declines. Hence, we examined the level of agreement between patient and proxy assessments of health related quality of life (HRQoL) and wellbeing based on the domains that comprise each of these constructs. Methods Analysis of baseline data from 71 community-dwelling older adults with mild Vascular Cognitive Impairment (VCI) who participated in a six-month proof-of-concept single-blinded randomized trial. Level of agreement between patient and caregiver ratings of HRQoL (EQ-5D-3L) and wellbeing (ICECAP-O) were compared using raw agreement (%), intraclass correlation coefficient (ICC) and weighted Cohen’s kappa statistic. Results Self-care (assessed via the EQ-5D-3L) demonstrated almost perfect raw agreement between the patient and caregiver ratings. Three domains (mobility, pain and anxiety) of the EQ-5D-3L demonstrated fair agreement between the patient and caregiver ratings. Two (attachment and control) of the five ICECAP-O domains demonstrated slight agreement. The ICC indicated good agreement for the EQ-5D-3L and poor agreement for the ICECAP-O. Conclusion There is better patient-proxy agreement for the EQ-5D-3L compared with the ICECAP-O among individuals with mild VCI. These findings imply that the ICECAP-O may have limited clinical, research and policy related utility among individuals with mild VCI. Trial Registration ClinicalTrials.gov NCT01027858 PMID:27101402

  5. Effects of community-deliverable exercise on pain and physical function in adults with arthritis and other rheumatic diseases: a meta-analysis.

    PubMed

    Kelley, George A; Kelley, Kristi S; Hootman, Jennifer M; Jones, Dina L

    2011-01-01

    To use the meta-analytic approach to determine the effects of community-deliverable exercise on pain and physical function in adults with arthritis and other rheumatic diseases (AORD). Data sources consisted of 6 electronic databases, cross-referencing from retrieved studies and expert review. Study selection included 1) randomized controlled trials; 2) ≥ 1 exercise intervention group; 3) community-deliverable exercise interventions ≥ 4 weeks in duration; 4) control group; 5) adults ages ≥ 18 years with rheumatoid arthritis, osteoarthritis, fibromyalgia, lupus, gout, or ankylosing spondylitis; 6) published and unpublished studies; 7) studies published in any language between January 1, 1980, and January 1, 2008; and 8) data available for pain and/or physical function. Data abstraction included dual coding by 2 of the authors. Standardized effect sizes (g) and random-effects models were used to pool pain and physical function outcomes. Data were analyzed according to per-protocol and intent-to-treat (ITT) results. The minimally clinically important difference (MCID) and number needed to treat (NNT) were also calculated. Thirty-three studies representing 3,180 men and women (1,857 exercise, 1,323 control) with rheumatoid arthritis, osteoarthritis, and fibromyalgia were included. Statistically significant and clinically important improvements were observed for pain (per-protocol g = -0.37 [95% confidence interval (95% CI) -0.53, -0.21], MCID -18%; ITT g = -0.20 [95% CI -0.33, -0.07], MCID -9%, NNT 9) and physical function (per-protocol g = 0.37 [95% CI 0.21, 0.52], MCID 15%; ITT g = 0.34 [95% CI 0.25, 0.43], MCID 10%, NNT 5). Community-deliverable exercise improves pain and physical function in adults with the types of AORD included in the analysis. Dose-response as well as studies in those with other types of AORD is needed. Copyright © 2011 by the American College of Rheumatology.

  6. Unfolding of the RAP-D3 helical bundle facilitates dissociation of RAP-receptor complexes.

    PubMed

    Estrada, Kristine; Fisher, Carl; Blacklow, Stephen C

    2008-02-12

    The receptor-associated protein (RAP) functions as an escort protein for receptors of the low-density lipoprotein receptor (LDLR) family by preventing premature intracellular binding of ligands and assisting with delivery of mature receptors to the cell surface. The modulation of affinity by pH is believed to play an important role in the escort function of RAP, because RAP binds tightly to proteins of the LDLR family at near-neutral pH early in the secretory pathway where its high affinity precludes premature binding of ligands but then dissociates from bound receptors at the lower pH of the Golgi compartment. The third domain of RAP (RAP-D3), which forms a three-helix bundle, is sufficient to reconstitute the escort activity. Here, we test the hypothesis that low-pH induced unfolding of the RAP-D3 helical bundle facilitates dissociation of RAP-receptor complexes. First, variants of RAP-D3 resistant to low pH-induced unfolding were constructed by replacing interior histidine residues with phenylalanines. In contrast to native RAP-D3, which exhibits an unfolding pKa of 6.3 and a Tm of 42 degrees C, the most hyperstable variant of RAP-D3, in which four histidine residues are replaced with phenylalanine, has an unfolding pKa of 4.8, and a Tm of 58 degrees C. The phenylalanine substitutions in RAP-D3 confer increased stability to pH-induced dissociation of complexes formed between RAP-D3 and a two-repeat fragment of the LDLR (LA3-4). When introduced into full-length RAP, the four mutations that confer hyperstability on RAP-D3 interfere with transport of endogenous LRP-1 to the cell surface in a dominant negative fashion under conditions where expression of normal RAP has no effect on LRP-1 transport. Our studies support a model in which low pH-dependent unfolding of RAP-D3 facilitates dissociation of RAP from the LA repeats of LDLR family proteins in the mildly acidic pH of the Golgi.

  7. Dopamine D3 receptor inhibits the ubiquitin-specific peptidase 48 to promote NHE3 degradation

    PubMed Central

    Armando, Ines; Villar, Van Anthony M.; Jones, John E.; Lee, Hewang; Wang, Xiaoyan; Asico, Laureano D.; Yu, Peiying; Yang, Jian; Escano, Crisanto S.; Pascua-Crusan, Annabelle M.; Felder, Robin A.; Jose, Pedro A.

    2014-01-01

    The dopamine D3 receptor (D3R) is crucial in the regulation of blood pressure and sodium balance, in that Drd3 gene ablation in mice results in hypertension and failure to excrete a dietary salt load. The mechanism responsible for the renal sodium retention in these mice is largely unknown. We now offer and describe a novel mechanism by which D3R decreases sodium transport in the long term by inhibiting the deubiquitinylating activity of ubiquitin-specific peptidase 48 (USP48), thereby promoting Na+-H+ exchanger (NHE)-3 degradation. We found that stimulation with the D3R-specific agonist PD128907 (1 μM, 30 min) promoted the interaction and colocalization among D3R, NHE3, and USP48; inhibited USP48 activity (−35±6%, vs. vehicle), resulting in increased ubiquitinylated NHE3 (+140±10%); and decreased NHE3 expression (−50±9%) in human renal proximal tubule cells (hRPTCs). USP48 silencing decreased NHE3's half-life (USP48 siRNA t1/2=6.1 h vs. vehicle t1/2=12.9 h), whereas overexpression of USP48 increased NHE3 half-life (t1/2=21.8 h), indicating that USP48 protects NHE3 from degradation via deubiquitinylation. USP48 accounted for ∼30% of the total deubiquitinylating activity in these cells. Extending our studies in vivo, we found that pharmacologic blockade of D3R via the D3R-specific antagonist GR103691 (1 μg/kg/min, 4 d) in C57Bl/6J mice increased renal NHE3 expression (+310±15%, vs. vehicle), whereas an innovative kidney-restricted Usp48 silencing via siRNA (3 μg/d, 7 d) increased ubiquitinylated NHE3 (+250±30%, vs. controls), decreased total NHE3 (−23±2%), and lowered blood pressure (−24±2 mm Hg), compared with that in control mice that received either the vehicle or nonsilencing siRNA. Our data demonstrate a crucial role for the dynamic interaction between D3R and USP48 in the regulation of NHE3 expression and function.—Armando, I., Villar, V. A. M., Jones J. E., Lee, H., Wang, X., Asico L. D., Yu, P., Yang, J., Escano, C. S. Jr., Pascua

  8. Tolerance evaluation of overdosed dietary levels of 25-hydroxyvitamin D3 in growing piglets.

    PubMed

    von Rosenberg, S J; Weber, G M; Erhardt, A; Höller, U; Wehr, U A; Rambeck, W A

    2016-04-01

    Forty-eight, cross-bred (GL × LW × P) piglets were used in a 42-day tolerance trial to assess the effects of feeding diets supplemented with vitamin D or increasing levels of 25-hydroxyvitamin D3 (25-OH-D3 ). Six-week-old piglets (24 castrate males, 24 females) were used. Two replicate groups of 6 piglets were randomized by weight and allocated to four dietary treatments. The control group (T1) was supplemented with 50 μg vitamin D3 /kg feed. The experimental groups received 25-OH-D3 at the recommended dose (T2: 50 μg/kg = 1x), at 250 μg/kg (T3: 5x) or at 500 μg/kg (T4: 10x) respectively. Feed intake and daily weight gain were measured weekly, and the animals were examined by a veterinarian daily. After 42 days, body mass, blood, urine, bone and tissue samples were analysed and a pathology examination conducted. Dietary treatments had no significant effect on final body mass or daily weight gain. The 25-OH-D3 plasma concentration in T1 was 17 ± 3 ng/ml (mean ± SD) while the respective values of the experimental groups were significantly increased in T2, T3 and T4. Tissue concentrations of 25-OH-D3 were higher in liver and muscle for T3 and T4 and in skin for T4 than in T1. However, neither gross pathology nor histology, nor blood and urine characteristics, nor bone parameters were affected by dietary treatments. Weight of organs as well as dry matter, ash and calcium content of kidneys remained unaffected by dietary 25-OH-D3 intake. Furthermore, no changes were observed for general indicators of health. The results of this study demonstrated that feeding piglets with 25-OH-D3 at 5 or 10 times the recommended level had no adverse effects on any of the biological parameters measured. It was concluded that 25-OH-D3 can be regarded as a supplement with a very high safety margin when used at the recommended level.

  9. The action spectrum for vitamin D3: initial skin reaction and prolonged exposure.

    PubMed

    van Dijk, Arjan; den Outer, Peter; van Kranen, Henk; Slaper, Harry

    2016-07-06

    Vitamin D3 photosynthesis in the skin is formulated as a set of reaction equations, including side-reactions to lumisterol, tachysterol and toxisterols, and the accompanying reverse reactions, isomerisation of previtamin D3 to vitamin D3 and photodegradation of vitamin D3. The solution of this set is given for the stationary irradiance spectrum. The effective action spectrum for the instantaneous vitamin D3 production changes shape as a function of exposure, and therefore, no single action spectrum can be used. We assessed the action spectrum for unexposed skin and for skin that has been exposed to 7.5 Standard Erythemal Doses (SED). We constructed two new estimates: (1) the RIVM action spectrum, based on absorption spectra, quantum yields and skin transmission spectra, and (2) the modified QUT action spectrum, which is adjusted for self-absorption and skin transmission. For previously unexposed skin, the modified QUT action spectrum gives a qualitatively similar, but larger estimate than the RIVM action spectrum. We have not been able to solve the lack of quantitative agreement between the vitamin D production estimates from the three action spectrum estimates (RIVM, modified QUT and CIE). All new action spectra have stronger emphasis on the short wavelengths than the CIE action spectrum. We showed that, for wavelengths larger than 300 nm, the bandwidth that was used in the experiment that formed the basis of the CIE action spectrum, gives a red-shift of about 1 nm. Generally, with the formation of previtamin D3, the return reaction to provitamin D3 limits the production of vitamin D3. After some exposure, the new action spectrum has negative values for the longer wavelengths in the UVB. For the RIVM action spectrum, this happens after 7.5 SED, for the modified QUT action spectrum already after 1.25 SED, and after 7.5 SED the net production rate is largely cancelled. Thus prolonged exposure of previously unexposed skin saturates vitamin D3 formation. For maximum

  10. Resolvin D3 Is Dysregulated in Arthritis and Reduces Arthritic Inflammation.

    PubMed

    Arnardottir, Hildur H; Dalli, Jesmond; Norling, Lucy V; Colas, Romain A; Perretti, Mauro; Serhan, Charles N

    2016-09-15

    Uncontrolled inflammation is a unifying component of many chronic inflammatory diseases, such as arthritis. Resolvins (Rvs) are a new family from the endogenous specialized proresolving mediators (SPMs) that actively stimulate resolution of inflammation. In this study, using lipid mediator metabololipidomics with murine joints we found a temporal regulation of endogenous SPMs during self-resolving inflammatory arthritis. The SPMs present in self-resolving arthritic joints include the D-series Rvs, for example, RvD1, RvD2, RvD3, and RvD4. Of note, RvD3 levels were reduced in inflamed joints from mice with delayed-resolving arthritis when compared with self-resolving inflammatory arthritis. RvD3 was also reduced in serum from rheumatoid arthritis patients compared with healthy controls. RvD3 administration reduced joint leukocytes as well as paw joint eicosanoids, clinical scores, and edema. Taken together, these findings provide evidence for dysregulated endogenous RvD3 levels in inflamed paw joints and its potent actions in reducing murine arthritis. Copyright © 2016 by The American Association of Immunologists, Inc.

  11. Vitamin D3 supports osteoclastogenesis via functional vitamin D response element of human RANKL gene promoter.

    PubMed

    Kitazawa, Sohei; Kajimoto, Kazuyoshi; Kondo, Takeshi; Kitazawa, Riko

    2003-07-01

    Receptor activator of NF-kappaB ligand (RANKL) has been identified as requisite for osteoclastogenesis. To elucidate the molecular mechanism that conducts its catabolic action on bone, the effect of 1alpha,25 dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)) on osteoclastogenesis and RANKL mRNA expression was examined by coculture, RT-PCR and nuclear run-on studies. By accelerating the transcription rate of the RANKL gene in SaOS2 osteoblastic cells, 1alpha,25(OH)(2)D(3) enhanced in vitro osteoclast formation from peripheral monocytes. Cloning and characterization of the 5'-flanking region of the human RANKL gene revealed that the basic promoter comprises inverted TATA- and CAAT-boxes flanked by RUNX2 binding sites. Both electrophoresis mobility shift assay (EMSA) and transfection studies demonstrated that 1alpha,25(OH)(2)D(3) activated human RANKL promoter through vitamin D responsive elements (VDRE) located at -1584/-1570 by binding VDR and RXRalpha heterodimers in a ligand-dependent manner. The results provide direct evidence that 1alpha,25(OH)(2)D(3) augments osteoclastogenesis by transactivating the human RANKL gene in osteoblastic cells through VDRE.

  12. Determination of cholecalciferol (vitamin D3) in selected foods by liquid chromatography: NMKL collaborative study.

    PubMed

    Staffas, Anders; Nyman, Arne

    2003-01-01

    Results are presented from an NMKL (Nordic Committee on Food Analysis) collaborative study of a method for the determination of cholecalciferol (vitamin D3) in foods. The method is based on the addition of an internal standard (vitamin D2), followed by saponification and extraction with n-heptane. The fraction that contains vitamin D2/D3 is separated by preparative normal-phase liquid chromatography (LC), and the analytes are determined by reversed-phase LC with UV detection at 265 nm. The method was tested by 8 participating laboratories. In this study 6 different matrixes were analyzed for cholecalciferol content: milk, liquid infant formula (gruel), cooking oil, margarine, infant formula, and fish oil. The contents varied from 0.4 to 12 microg/100 g. Three matrixes (milk, gruel, and margarine) were fortified with vitamin D3. In the other matrixes, vitamin D3 was added at 3 different levels at the Swedish National Food Administration. The milk was analyzed as a blind duplicate, whereas the other matrixes were analyzed as split-level pairs. The recoveries from the samples with vitamin D3 added varied from 93 to 102%. The repeatability relative standard deviation (RSDr) values for accepted results varied between 2.2% (fish oil) and 7.4% (cooking oil), whereas the reproducibility relative standard deviation (RSD(R)) values varied between 6.8% (margarine) and 24% (cooking oil).

  13. Calcitonin and vitamin D3 have high therapeutic potential for improving diabetic mandibular growth.

    PubMed

    Abbassy, Mona A; Watari, Ippei; Bakry, Ahmed S; Ono, Takashi; Hassan, Ali H

    2016-03-30

    The goal of this study was to assess the effect of the intermittent combination of an antiresorptive agent (calcitonin) and an anabolic agent (vitamin D3) on treating the detrimental effects of Type 1 diabetes mellitus (DM) on mandibular bone formation and growth. Forty 3-week-old male Wistar rats were divided into four groups: the control group (normal rats), the control C+D group (normal rats injected with calcitonin and vitamin D3), the diabetic C+D group (diabetic rats injected with calcitonin and vitamin D3) and the diabetic group (uncontrolled diabetic rats). An experimental DM condition was induced in the male Wistar rats in the diabetic and diabetic C+D groups using a single dose of 60 mg·kg(-1) body weight of streptozotocin. Calcitonin and vitamin D3 were simultaneously injected in the rats of the control C+D and diabetic C+D groups. All rats were killed after 4 weeks, and the right mandibles were evaluated by micro-computed tomography and histomorphometric analysis. Diabetic rats showed a significant deterioration in bone quality and bone formation (diabetic group). By contrast, with the injection of calcitonin and vitamin D3, both bone parameters and bone formation significantly improved (diabetic C+D group) (P < 0.05). These findings suggest that these two hormones might potentially improve various bone properties.

  14. Safety profile of 1,25-dihydroxyvitamin D3 of herbal origin in broiler chicken.

    PubMed

    Mathis, G; Boland, R; Bachmann, H; Toggenburger, A; Rambeck, W

    2016-12-01

    The safety of supplementing broiler feed with a standardised herbal extract, Solanum Glaucophyllum Standardised Leaves (SGSL) containing glycosylated 1a,25-dihydroxyvitamin D3 (1,25(OH)2D3) and standardised to contain 10 µg/g 1,25(OH)2D3 equivalent, was examined in two studies. In a first study, we examined the potential of SGSL to substitute vitamin D3 (VD3) and the tolerated dose range of SGSL when applied without concomitant VD3 by analyzing performance and blood chemical parameters after 14, 25 and 38 days on diets containing two doses of SGSL (1 and 10 g/kg feed) as source of 1,25(OH)2D3. In the second study, the no adverse effect level of SGSL was determined by analyzing the same parameters after 35 days on diets containing basic VD3 supply and in addition 0.2, 1.0, 2.0 and 4.0 g of SGSL/kg feed. We showed that SGSL was able to substitute VD3 in broilers as far as the performance parameters were concerned. Also, we found that the no adverse effect level is at least 4 g SGSL/kg feed when used with moderate doses of VD3. This is 20 times higher than the upper limit of the commercially recommended dose. We concluded that SGSL is a safe feed additive to use in broiler chicken.

  15. Documenting and harnessing the biological potential of molecules in Distributed Drug Discovery (D3) virtual catalogs.

    PubMed

    Abraham, Milata M; Denton, Ryan E; Harper, Richard W; Scott, William L; O'Donnell, Martin J; Durrant, Jacob D

    2017-04-28

    Virtual molecular catalogs have limited utility if member compounds are (i) difficult to synthesize or (ii) unlikely to have biological activity. The Distributed Drug Discovery (D3) program addresses the synthesis challenge by providing scientists with a free virtual D3 catalog of 73,024 easy-to-synthesize N-acyl unnatural α-amino acids, their methyl esters, and primary amides. The remaining challenge is to document and exploit the bioactivity potential of these compounds. In the current work, a search process is described that retrospectively identifies all virtual D3 compounds classified as bioactive hits in PubChem-cataloged experimental assays. The results provide insight into the broad range of drug-target classes amenable to inhibition and/or agonism by D3-accessible molecules. To encourage computer-aided drug discovery centered on these compounds, a publicly available virtual database of D3 molecules prepared for use with popular computer docking programs is also presented. © 2017 John Wiley & Sons A/S.

  16. Sleep problems and hypothalamic dopamine D3 receptor availability in Parkinson disease.

    PubMed

    Pagano, Gennaro; Molloy, Sophie; Bain, Peter G; Rabiner, Eugenii A; Chaudhuri, K Ray; Brooks, David J; Pavese, Nicola

    2016-12-06

    To investigate the relationship between hypothalamic D3 dopamine receptor availability and severity of sleep problems in Parkinson disease (PD). Twelve patients were assessed with PET and the high-affinity dopamine D3 receptor radioligand [(11)C]-propyl-hexahydro-naphtho-oxazin ([(11)C]-PHNO). Severity of sleep problems was rated with appropriate subitems of the Unified Parkinson's Disease Rating Scale part I (patient questionnaire) and the Epworth Sleepiness Scale. We found that lower dopamine D3 receptor availability measured with [(11)C]-PHNO PET was associated with greater severity of excessive daytime sleepiness but not with problems of falling asleep or insomnia. In our cohort of patients with PD, the occurrence of excessive daytime sleepiness was linked to reductions in hypothalamic dopamine D3 receptor availability. If these preliminary findings are confirmed in larger cohorts of patients with polysomnographic characterization, selective pharmacologic modulation of the dopaminergic D3 system could be used to increase daytime alertness in patients with PD. © 2016 American Academy of Neurology.

  17. Resolvin D3 is dysregulated in arthritis and reduces arthritic inflammation

    PubMed Central

    Arnardottir, Hildur H.; Dalli, Jesmond; Norling, Lucy V.; Colas, Romain A.; Perretti, Mauro; Serhan, Charles N.

    2016-01-01

    Uncontrolled inflammation is a unifying component of many chronic inflammatory diseases, such as arthritis. Resolvins (Rv) are a new family from the endogenous specialized pro-resolving lipid mediators (SPM) that actively stimulate resolution of inflammation. Herein, using lipid mediator (LM) metabololipidomics with murine joints we found a temporal regulation of endogenous SPM during self-resolving inflammatory arthritis. The SPMs present in self-resolving arthritic joints include the D-series resolvins, e.g. Resolvin (Rv) D1, RvD2, RvD3 and RvD4. Of note, RvD3 levels were reduced in inflamed joints from mice with delayed-resolving arthritis when compared to self-resolving inflammatory arthritis. RvD3 was also reduced in serum from rheumatoid arthritis (RA) patients compared to healthy controls. RvD3 administration reduced joint leukocytes as well as paw joint eicosanoids, clinical scores and edema. Together, these findings provide evidence for dysregulated endogenous RvD3 levels in inflamed paw joints and its potent actions in reducing murine arthritis. PMID:27534559

  18. Calcitonin and vitamin D3 have high therapeutic potential for improving diabetic mandibular growth

    PubMed Central

    Abbassy, Mona A; Watari, Ippei; Bakry, Ahmed S; Ono, Takashi; Hassan, Ali H

    2016-01-01

    The goal of this study was to assess the effect of the intermittent combination of an antiresorptive agent (calcitonin) and an anabolic agent (vitamin D3) on treating the detrimental effects of Type 1 diabetes mellitus (DM) on mandibular bone formation and growth. Forty 3-week-old male Wistar rats were divided into four groups: the control group (normal rats), the control C+D group (normal rats injected with calcitonin and vitamin D3), the diabetic C+D group (diabetic rats injected with calcitonin and vitamin D3) and the diabetic group (uncontrolled diabetic rats). An experimental DM condition was induced in the male Wistar rats in the diabetic and diabetic C+D groups using a single dose of 60 mg·kg−1 body weight of streptozotocin. Calcitonin and vitamin D3 were simultaneously injected in the rats of the control C+D and diabetic C+D groups. All rats were killed after 4 weeks, and the right mandibles were evaluated by micro-computed tomography and histomorphometric analysis. Diabetic rats showed a significant deterioration in bone quality and bone formation (diabetic group). By contrast, with the injection of calcitonin and vitamin D3, both bone parameters and bone formation significantly improved (diabetic C+D group) (P < 0.05). These findings suggest that these two hormones might potentially improve various bone properties. PMID:27025264

  19. Constrained superfields from an anti-D3-brane in KKLT

    NASA Astrophysics Data System (ADS)

    Vercnocke, Bert; Wrase, Timm

    2016-08-01

    The KKLT construction of dS vacua [1] relies on an uplift term that arises from an anti-D3-brane. It was argued by Kachru, Pearson and Verlinde [2] that this anti-D3-brane is an excited state in a supersymmetric theory since it can decay to a supersymmetric ground state. Hence the anti-D3-brane breaks supersymmetry spontaneously and one should be able to package all the world-volume fields on the anti-D3-brane into a four dimensional {N} = 1 supersymmetric action. Here we extend previous results and identify the constrained superfields that correspond to all the degrees of freedom on the anti-D3-brane. In particular, we show explicitly that the four 4D worldvolume spinors give rise to constrained chiral multiplets S and Y i , i = 1 , 2 , 3 that satisfy S 2 = SY i = 0. We also conjecture (and provide evidence in a forthcoming publication) that the vector field A μ and the three scalars ϕ i give rise to a field strength multiplet W α and three chiral multiplets H i that satisfy the constraints S{W}_{α }={overline{D}}_{overset{\\cdot }{α }}(S{overline{H}}^i)=0 . This is the first time that such constrained multiplets appear in string theory constructions.

  20. Hypovitaminosis D3, Leukopenia, and Human Serotonin Transporter Polymorphism in Anorexia Nervosa and Bulimia Nervosa.

    PubMed

    Tasegian, Anna; Curcio, Francesco; Dalla Ragione, Laura; Rossetti, Francesca; Cataldi, Samuela; Codini, Michela; Ambesi-Impiombato, Francesco Saverio; Beccari, Tommaso; Albi, Elisabetta

    2016-01-01

    Vitamin D3 has been described to have different extraskeletal roles by acting as parahormone in obesity, diabetes, cancer, cognitive impairment, and dementia and to have important regulatory functions in innate immunity. There are no studies showing extraskeletal changes associated with hypovitaminosis D3 in eating disorders. Methods. We have analyzed the blood of 18 patients affected by anorexia nervosa and bulimia nervosa collected over a 15-month period. We performed a panel of chemical and clinical analyses: the assay of vitamin D3, the immunoblotting of vitamin D receptor and peroxisome proliferator-activated receptor gamma, and the genotyping of 5-hydroxytryptamine transporter linked polymorphic region. Results. We choose 18 patients with a normal blood test profile such as thyroid hormones, hepatic and renal parameters, triglycerides, proteins, vitamin B12, and folic acid. Among these emerged the case of a woman with long-term anorexia nervosa and the case of a woman with long-term bulimia nervosa both complicated by anxiety and depression, severe hypovitaminosis D3, decrease of vitamin D receptor, leukopenia, and 5-hydroxytryptamine transporter linked polymorphic region short allele. Conclusion. The results induce hypothesising that the severe hypovitaminosis D3 might be responsible for the lack of the inflammatory response and the depressive symptoms in patients with long-term eating disorders.

  1. Solar UV doses of young Americans and vitamin D3 production.

    PubMed

    Godar, Dianne Eyvonn; Pope, Stanley James; Grant, William Burgess; Holick, Michael Francis

    2012-01-01

    Sunlight contains ultraviolet B (UVB) radiation (290-315 nm) that affects human health in both detrimental (skin cancers) and beneficial (vitamin D3) ways. Serum 25-hydroxyvitamin D concentrations from young Americans (≤ 19 years) show that many have deficient (< 50 nmol/L, 20 ng/mL) or insufficient (< 75 nmol/L, 30 ng/mL) vitamin D levels, indicating that they are not getting enough sun exposure. Those findings are in conflict with some calculated, published values that suggest people make "ample" vitamin D3 (~ 1,000 IU/day) from their "casual," or everyday, outdoor exposures even if they diligently use sunscreens with sun protection factor (SPF) 15. We estimated how much vitamin D3 young Americans (n = ~ 2,000) produce from their everyday outdoor ultraviolet doses in the North (45°N) and South (35°N) each season of the year with and without vacationing. For these vitamin D3 calculations, we used geometric conversion factors that change planar to whole-body doses, which previous calculations did not incorporate. Our estimates suggest that American children may not be getting adequate outdoor UVB exposures to satisfy their vitamin D3 needs all year, except some Caucasians during the summer if they do not diligently wear sunscreens except during beach vacations. These estimates suggest that most American children may not be going outside enough to meet their minimal (~ 600 IU/day) or optimal (≥ 1,200 IU/day) vitamin D requirements.

  2. Syntheses of 24R,25-dihydroxy-(6,19,19-3H)vitamin D3 and 24R,25-dihydroxy-(6,19,19-2H)vitamin D3

    SciTech Connect

    Yamada, S.; Shimizu, M.; Fukushima, K.; Niimura, K.; Maeda, Y. )

    1989-08-01

    24R,25-Dihydroxy-(6,19,19-3H)vitamin D3 with a specific activity of 54 Ci/mmol and 24R,25-dihydroxy-(6,19,19-2H)vitamin D3 with 2.6 deuterium atoms/mol were synthesized in four steps starting from 24R,25-Dihydroxyvitamin D3 via its sulfur dioxide adduct.

  3. Cubilin dysfunction causes abnormal metabolism of the steroid hormone 25(OH) vitamin D(3).

    PubMed

    Nykjaer, A; Fyfe, J C; Kozyraki, R; Leheste, J R; Jacobsen, C; Nielsen, M S; Verroust, P J; Aminoff, M; de la Chapelle, A; Moestrup, S K; Ray, R; Gliemann, J; Willnow, T E; Christensen, E I

    2001-11-20

    Steroid hormones are central regulators of a variety of biological processes. According to the free hormone hypothesis, steroids enter target cells by passive diffusion. However, recently we demonstrated that 25(OH) vitamin D(3) complexed to its plasma carrier, the vitamin D-binding protein, enters renal proximal tubules by receptor-mediated endocytosis. Knockout mice lacking the endocytic receptor megalin lose 25(OH) vitamin D(3) in the urine and develop bone disease. Here, we report that cubilin, a membrane-associated protein colocalizing with megalin, facilitates the endocytic process by sequestering steroid-carrier complexes on the cellular surface before megalin-mediated internalization of the cubilin-bound ligand. Dogs with an inherited disorder affecting cubilin biosynthesis exhibit abnormal vitamin D metabolism. Similarly, human patients with mutations causing cubilin dysfunction exhibit urinary excretion of 25(OH) vitamin D(3). This observation identifies spontaneous mutations in an endocytic receptor pathway affecting cellular uptake and metabolism of a steroid hormone.

  4. The differentiation and assay of vitamins D2 and D3 by gas–liquid chromatography

    PubMed Central

    Murray, T. K.; Day, K. C.; Kodicek, E.

    1966-01-01

    1. A method is described for the differentiation and determination of as little as 0·2μg. of vitamins D2 and D3 by gas–liquid chromatography. 2. The vitamins are converted by treatment with antimony trichloride into isovitamins D2 and D3, which show single, separate peaks on gas–liquid chromatography, unlike the unmodified vitamins, which give twin peaks due to the formation of pyro and isopyro derivatives. 3. Since isovitamins D2 and D3 remain together in all steps of the procedure except during gas–liquid chromatography, one may be used as an internal standard for the other. 4. The use of an internal standard reduces the importance of loss during sample preparation and increases precision. 5. The application of the method to biological materials is demonstrated. PMID:4287184

  5. Controllable liquid crystal gratings for an adaptive 2D/3D auto-stereoscopic display

    NASA Astrophysics Data System (ADS)

    Zhang, Y. A.; Jin, T.; He, L. C.; Chu, Z. H.; Guo, T. L.; Zhou, X. T.; Lin, Z. X.

    2017-02-01

    2D/3D switchable, viewpoint controllable and 2D/3D localizable auto-stereoscopic displays based on controllable liquid crystal gratings are proposed in this work. Using the dual-layer staggered structure on the top substrate and bottom substrate as driven electrodes within a liquid crystal cell, the ratio between transmitting region and shielding region can be selectively controlled by the corresponding driving circuit, which indicates that 2D/3D switch and 3D video sources with different disparity images can reveal in the same auto-stereoscopic display system. Furthermore, the controlled region in the liquid crystal gratings presents 3D model while other regions maintain 2D model in the same auto-stereoscopic display by the corresponding driving circuit. This work demonstrates that the controllable liquid crystal gratings have potential applications in the field of auto-stereoscopic display.

  6. Intestinal absorption of triglyceride and vitamin D3 in aged and young rats

    SciTech Connect

    Holt, P.R.; Dominguez, A.A.

    1981-12-01

    (3H)Trioleyl glycerol (TO) and (14C)vitamin D3 were perfused intraduodenally for 5 hr in aged (19-21 months) and young adult (4-5 months) Sprague-Dawley rats. The rate of intestinal uptake from the gastrointestinal lumen and transport into the body of these lipids were decreased in the aged animals. Since the distribution of TO lipolytic products in the lumen was unchanged, reduced intestinal uptake rate probably occurred at the mucosal membrane. Furthermore, in the aged rats, the rate of transintestinal transport of both trioleyl glycerol and vitamin D3 was impaired. No evidence for impaired mucosal TO reesterification or for accumulation of vitamin D3 metabolites was found, suggesting that intestinal lipid accumulation resulted from a defect in lipoprotein assembly or in discharge from the mucosal cell. Impaired absorption of lipids may contribute to malnutrition and osteopenia of advancing age.

  7. The Feasibility Of Fusion Reactors Fueled With D-3He And D-D

    NASA Astrophysics Data System (ADS)

    Stott, Peter

    2009-10-01

    In this paper we discuss the feasibility of fusion reactors based on D-3He and D-D fuel mixtures. The low reactivity of the D-3He and D-D fusion reactions and the large energy losses due to bremsstrahlung and synchrotron radiation at high plasma temperatures severely restricts the choice of fuel mixtures that can be brought to ignition. These fuel mixtures are extremely sensitive to impurities and to helium ash retention and they would require reactor conditions (plasma density, temperature, beta and energy confinement time) that are much more demanding than the requirements for D-T. A reactor burning D-3He or D-D would be far beyond the most optimistic extrapolations of known magnetic confinement schemes, it would have problems with sustainable fuel supplies and it would produce substantial numbers of neutrons. Our conclusion is that these fuels cannot be considered as realistic alternatives to D-T.

  8. Core Plasma Characteristics of a Spherical Tokamak D-3He Fusion Reactor

    NASA Astrophysics Data System (ADS)

    Shi, Bingren

    2005-04-01

    The magnetic fusion reactor using the advanced D-3He fuels has the advantage of much less-neutron productions so that the consequent damages to the first wall are less serious. If the establishment of this kind of reactor becomes realistic, the exploration of 3He on the moon will be largely motivated. Based on recent progresses in the spherical torus (ST) research, we have physically designed a D-3He fusion reactor using the extrapolated results from the ST experiments and also the present-day tokamak scaling. It is found that the reactor size significantly depends on the wall reflection coefficient of the synchrotron radiation and of the impurity contaminations. The secondary reaction between D-D that promptly leads to the D-T reaction producing 14 MeV neutrons is also estimated. Comparison of this D-3He ST reactor with the D-T reactor is made.

  9. The chemistry and conformational and biological analysis of vitamin D3, its metabolites and analogues.

    PubMed

    Norman, A W; Johnson, R L; Osborn, T W; Procsal, D A; Carey, S C; Hammond, M L; Mitra, M N; Pirio, M R; Rego, A; Wing, R M; Okamura, W H

    1976-01-01

    The chemical properties, stereochemical relationships and solution conformation, as assessed in part by proton NMR spectroscopy, for vitamin D3, its major metabolites [including 1alpha,25-(OH)2D3, its hormonally active form] and a number of A-ring and side chain analogues are evaluated and discussed in relation to their biological activity. In particular the relative ability of many of these seco-steroids to compete both with 25-OHD3 for its chick serum binding protein and 1alpha,25-(OH)2-D3 for its chick intestinal cytosol-chromatin receptor system was quantitated, in vitro. Further, the relative effectiveness of all these metabolites and analogues to mediate in vivo intestinal calcium absorption and bone calcium mobilization was determined. Collectively these chemical and biological studies constitute a "systems analysis" of the various steroid structural parameters both required and tolerated by the multi-stepped endocrine system associated with the biological actions of vitamin D.

  10. SpreaD3: Interactive Visualization of Spatiotemporal History and Trait Evolutionary Processes.

    PubMed

    Bielejec, Filip; Baele, Guy; Vrancken, Bram; Suchard, Marc A; Rambaut, Andrew; Lemey, Philippe

    2016-08-01

    Model-based phylogenetic reconstructions increasingly consider spatial or phenotypic traits in conjunction with sequence data to study evolutionary processes. Alongside parameter estimation, visualization of ancestral reconstructions represents an integral part of these analyses. Here, we present a complete overhaul of the spatial phylogenetic reconstruction of evolutionary dynamics software, now called SpreaD3 to emphasize the use of data-driven documents, as an analysis and visualization package that primarily complements Bayesian inference in BEAST (http://beast.bio.ed.ac.uk, last accessed 9 May 2016). The integration of JavaScript D3 libraries (www.d3.org, last accessed 9 May 2016) offers novel interactive web-based visualization capacities that are not restricted to spatial traits and extend to any discrete or continuously valued trait for any organism of interest.

  11. RUNX2 Mutation Impairs 1α,25-Dihydroxyvitamin D3 mediated Osteoclastogenesis in Dental Follicle Cells

    PubMed Central

    Wang, X. Z.; Sun, X. Y.; Zhang, C. Y.; Yang, X.; Yan, W. J.; Ge, L. H.; Zheng, S. G.

    2016-01-01

    Cleidocranial dysplasia (CCD), a skeletal disorder characterized by delayed permanent tooth eruption and other dental abnormalities, is caused by heterozygous RUNX2 mutations. As an osteoblast-specific transcription factor, RUNX2 plays a role in bone remodeling, tooth formation and tooth eruption. To investigate the crosstalk between RUNX2 and 1α,25-dihydroxyvitamin D3 (1α,25-(OH)2D3) in human dental follicle cells (hDFCs) during osteoclast formation, we established a co-culture system of hDFCs from CCD patient and healthy donors with peripheral blood mononuclear cells (PBMCs). Expression of the osteoclast-associated genes and the number of TRAP+ cells were reduced in CCD hDFCs, indicating its suppressed osteoclast-inductive ability, which was reflected by the downregulated RANKL/OPG ratio. In addition, 1α,25-(OH)2D3-stimulation elevated the expression of osteoclast-related genes, as well as RANKL mRNA levels and RANKL/OPG ratios in control hDFCs. Conversely, RUNX2 mutation abolished this 1α,25-(OH)2D3-induced RANKL gene activation and osteoclast formation in CCD hDFCs. Therefore, RUNX2 haploinsufficiency impairs dental follicle-induced osteoclast formation capacity through RANKL/OPG signaling, which may be partially responsible for delayed permanent tooth eruption in CCD patients. Furthermore, this abnormality was not rescued by 1α,25-(OH)2D3 application because 1α,25-(OH)2D3-induced RANKL activation in hDFCs is mediated principally via the RUNX2-dependent pathway. PMID:27068678

  12. Impact of vitamin D3 on cardiovascular responses to glucocorticoid excess.

    PubMed

    Ahmed, Mona A

    2013-06-01

    Although the cardiovascular system is not a classical target for 1,25-dihydroxyvitamin D3, both cardiac myocytes and vascular smooth muscle cells respond to this hormone. The present study aimed to elucidate the effect of active vitamin D3 on cardiovascular functions in rats exposed to glucocorticoid excess. Adult male Wistar rats were allocated into three groups: control group, dexamethasone (Dex)-treated group receiving Dex (200 μg/kg) subcutaneously for 12 days, and vitamin D3-Dex-treated group receiving 1,25-(OH)2D3 (100 ng/kg) and Dex (200 μg/kg) subcutaneously for 12 days. Rats were subjected to measurement of systolic (SBP), diastolic (DBP), and mean arterial (MAP) blood pressures and heart rate. Rate pressure product (RPP) was calculated. Rats' isolated hearts were perfused in Langendorff preparation and studied for basal activities (heart rate, peaked developed tension, time to peak tension, half relaxation time, and myocardial flow rate) and their responses to isoproterenol infusion. Blood samples were collected for determination of plasma level of nitrite, nitric oxide surrogate. Dex-treated group showed significant increase in SBP, DBP, MAP, and RPP, as well as cardiac hypertrophy and enhancement of basal cardiac performance evidenced by increased heart rate, rapid and increased contractility, and accelerated lusitropy, together with impaired contractile and myocardial flow rate responsiveness to beta-adrenergic activation and depressed inotropic and coronary vascular reserves. Such alterations were accompanied by low plasma nitrite. These changes were markedly improved by vitamin D3 treatment. In conclusion, vitamin D3 is an efficacious modulator of the deleterious cardiovascular responses induced by glucocorticoid excess, probably via accentuation of nitric oxide.

  13. He I D3 OBSERVATIONS OF THE 1984 MAY 22 M6.3 SOLAR FLARE

    SciTech Connect

    Liu Chang; Xu Yan; Deng Na; Lee, Jeongwoo; Zhang Jifeng; Wang Haimin; Prasad Choudhary, Debi

    2013-09-01

    The He I D3 line has a unique response to a flare impact on the low solar atmosphere and can be a powerful diagnostic tool for energy transport processes. Using images obtained from the recently digitized films of the Big Bear Solar Observatory, we report D3 observations of the M6.3 flare on 1984 May 22, which occurred in an active region with a circular magnetic polarity inversion line (PIL). The impulsive phase of the flare starts with a main elongated source that darkens in D3, inside of which bright emission kernels appear at the time of the initial small peak in hard X-rays (HXRs). These flare cores subsequently evolve into a sharp emission strand lying within the dark halo; this evolution occurs at the same time as the main peak in HXRs, reversing the overall source contrast from -5% to 5%. The radiated energy in D3 during the main peak is estimated to be about 10{sup 30} erg, which is comparable to that carried by nonthermal electrons above 20 keV. Afterward, the flare proceeds along the circular PIL in the counterclockwise direction to form a dark circular ribbon in D3, which apparently mirrors the bright ribbons in H{alpha} and He I 10830 A. All of these ribbons last for over one hour in the late gradual phase. We suggest that the present event resembles the so-called black-light flare that was proposed based on continuum images, and that D3 darkening and brightening features herein may be due to thermal conduction heating and the direct precipitation of high-energy electrons, respectively.

  14. Stability of Vitamin D3 in fortified yoghurt and yoghurt drink (Doogh)

    PubMed Central

    Jafari, Tina; Askari, Gholamreza; Mirlohi, Maryam; Javanmard, Shaghayegh Haghjooy; Faghihimani, Elham; Fallah, Aziz A

    2016-01-01

    Background: Vitamin D deficiency and insufficiency are recognized as a worldwide problem with serious consequences. Fortification of foods with Vitamin D is a certain approach to improve serum Vitamin D status if the stability of vitamin in the foodstuffs was controlled. The purpose of this study was to examine the stability of Vitamin D3 added to low-fat yogurt and yogurt drink “Doogh” during the products shelf-life. Materials and Methods: Two kinds of Vitamin D3, water- and oil-dispersible forms, suitable for food fortification, were compared to find out whether they show different stability in the products. The products were packed in opaque or translucent containers. The content of Vitamin D3 was determined by high performance liquid chromatography method. Results: Vitamin D was not affected by the heat treatment (pasteurization) and other processes (homogenization and fermentation). Both water- and oil-dispersible forms were stable during the shelf-life of yogurt samples packed in opaque containers. The Vitamin D3 content of yogurt fortified with water-dispersible form and packed in translucent containers was not stable during the shelf-life and significantly reduced after 1, 2, and 3 weeks of storage compared to the day 0. The Vitamin D3 content of samples fortified with the oil-dispersible form packed in the same container was only stable after 1-week and significantly reduced after 2 and 3 weeks of storage. The Vitamin D3 content of Doogh packed in the opaque containers remained stable during the shelf-life while it was not stable in the samples packed in translucent containers. Conclusion: The results suggested that both forms of Vitamin D are suitable for fortification, and opaque container is a better choice for packaging of the product. PMID:27110549

  15. Vitamin D3: A Role in Dopamine Circuit Regulation, Diet-Induced Obesity, and Drug Consumption.

    PubMed

    Trinko, Joseph R; Land, Benjamin B; Solecki, Wojciech B; Wickham, Robert J; Tellez, Luis A; Maldonado-Aviles, Jaime; de Araujo, Ivan E; Addy, Nii A; DiLeone, Ralph J

    2016-01-01

    The influence of micronutrients on dopamine systems is not well defined. Using mice, we show a potential role for reduced dietary vitamin D3 (cholecalciferol) in promoting diet-induced obesity (DIO), food intake, and drug consumption while on a high fat diet. To complement these deficiency studies, treatments with exogenous fully active vitamin D3 (calcitriol, 10 µg/kg, i.p.) were performed. Nondeficient mice that were made leptin resistant with a high fat diet displayed reduced food intake and body weight after an acute treatment with exogenous calcitriol. Dopamine neurons in the midbrain and their target neurons in the striatum were found to express vitamin D3 receptor protein. Acute calcitriol treatment led to transcriptional changes of dopamine-related genes in these regions in naive mice, enhanced amphetamine-induced dopamine release in both naive mice and rats, and increased locomotor activity after acute amphetamine treatment (2.5 mg/kg, i.p.). Alternatively, mice that were chronically fed either the reduced D3 high fat or chow diets displayed less activity after acute amphetamine treatment compared with their respective controls. Finally, high fat deficient mice that were trained to orally consume liquid amphetamine (90 mg/L) displayed increased consumption, while nondeficient mice treated with calcitriol showed reduced consumption. Our findings suggest that reduced dietary D3 may be a contributing environmental factor enhancing DIO as well as drug intake while eating a high fat diet. Moreover, these data demonstrate that dopamine circuits are modulated by D3 signaling, and may serve as direct or indirect targets for exogenous calcitriol.

  16. Protective effects of vitamin D3 against d-galactosamine-induced liver injury in rats.

    PubMed

    Colakoglu, Neriman; Kuloglu, Tuncay; Ozan, Enver; Kocaman, Nevin; Dabak, Durrin Ozlem; Parlak, Gozde

    2016-08-01

    In this study, we examined liver damage induced by d-galactosamine (d-GaIN) and the protective effects of vitamin D3 in relation to d-GaIN toxicity. Twenty Wistar albino rats were used in this study. The rats were divided into four groups. Group I rats were used as the control group. Group II rats were given a single intraperitoneal injection of d-GaIN. Group III rats were given a single intraperitoneal injection of d-GaIN, intramuscular vitamin D3 for five days. Group IV rats were given intramuscular vitamin D3 for five days. All of rats were euthanized by cervical decapitation on the fifth day of experiment. Upon completion of the experiment, a midsaggital incision was performed, and the livers of all rats were removed and fixed. The livers were processed to perform TUNEL technique and histochemical staining. During the microscope examination, we observed inflamatory cell infiltration, sinusoidal dilatation, and apoptotic bodies due to d-GaIN exposure. In addition, glycogen content of the group II hepatocytes was significantly decreased. Vitamin D3 treatment provided better structural apperance of the livers in group III. TUNEL positive cells were extremly pervasive in the group II livers. The study found group III TUNEL positive cells at a reduced rate in relation to group II due to vitamin D3 treatment. This findings indicate that d-GaIN causes inflamation in the liver. This inflamation triggers the apoptotic process gradually. Vitamin D3 has potency to decrease the severity of d-GaIN-caused structural liver damage.

  17. Treatment with dexamethasone and vitamin D3 attenuates neuroinflammatory age-related changes in rat hippocampus.

    PubMed

    Moore, Michelle; Piazza, Alessia; Nolan, Yvonne; Lynch, Marina A

    2007-10-01

    Among the changes which occur in the brain with age is an increase in hippocampal concentration of proinflammatory cytokines like interleukin-1beta (IL-1beta) and an increase in IL-1beta-induced signaling. Here we demonstrate that the increase in IL-1beta concentration is accompanied by an increase in expression of IL-1 type I receptor (IL-1RI) and an age-related increase in microglial activation, as shown by increased expression of the cell surface marker, major histocompatibility complex II (MHCII) and increased MHCII staining. The evidence indicates that these age-related changes were abrogated in hippocampus of aged rats treated with dexamethasone and vitamin D3. Similarly, the age-related increases in activation of the stress-activated protein kinase, c-Jun N-terminal kinase (JNK), as well as caspase-3 and PARP were all attenuated in hippocampal tissue prepared from rats that received dexamethasone and vitamin D3. The data indicate that dexamethasone and vitamin D3 ameliorated the age-related increase in IFNgamma and suggest that IFNgamma may be the trigger leading to microglial activation, since it increases MHCII mRNA and IL-1beta release from cultured glia. In parallel with its ability to decrease microglial activation in vivo, we report that treatment of cultured glia with dexamethasone and vitamin D3 blocked the lipopolysaccharide increased MHCII mRNA and IL-1beta concentration, while the IL-1beta-induced increases in activation of JNK and caspase 3 in cultured neurons were also reversed by treatment with dexamethasone and vitamin D3. The data suggest that the antiinflammatory effect of dexamethasone and vitamin D3 derives from their ability to downreguate microglial activation.

  18. Vitamin D3 Supplemental Treatment for Mania in Youth with Bipolar Spectrum Disorders

    PubMed Central

    Sikoglu, Elif M.; Navarro, Ana A. Liso; Starr, Debra; Dvir, Yael; Nwosu, Benjamin Udoka; Czerniak, Suzanne M.; Rogan, Ryan C.; Castro, Martha C.; Edden, Richard A. E.; Frazier, Jean A.

    2015-01-01

    Abstract Objective: We aimed to determine the effect of an open-label 8 week Vitamin D3 supplementation on manic symptoms, anterior cingulate cortex (ACC) glutamate, and γ-aminobutyric acid (GABA) in youth exhibiting symptoms of mania; that is, patients with bipolar spectrum disorders (BSD). We hypothesized that an 8 week Vitamin D3 supplementation would improve symptoms of mania, decrease ACC glutamate, and increase ACC GABA in BSD patients. Single time point metabolite levels were also evaluated in typically developing children (TD). Methods: The BSD group included patients not only diagnosed with BD but also those exhibiting bipolar symptomology, including BD not otherwise specified (BD-NOS) and subthreshold mood ratings (Young Mania Rating Scale [YMRS] ≥8 and Clinical Global Impressions - Severity [CGI-S] ≥3). Inclusion criteria were: male or female participants, 6–17 years old. Sixteen youth with BSD exhibiting manic symptoms and 19 TD were included. BSD patients were asked to a take daily dose (2000 IU) of Vitamin D3 (for 8 weeks) as a supplement. Neuroimaging data were acquired in both groups at baseline, and also for the BSD group at the end of 8 week Vitamin D3 supplementation. Results: Baseline ACC GABA/creatine (Cr) was lower in BSD than in TD (F[1,31]=8.91, p=0.007). Following an 8 week Vitamin D3 supplementation, in BSD patients, there was a significant decrease in YMRS scores (t=−3.66, p=0.002, df=15) and Children's Depression Rating Scale (CDRS) scores (t=−2.93, p=0.01, df=15); and a significant increase in ACC GABA (t=3.18, p=0.007, df=14). Conclusions: Following an 8 week open label trial with Vitamin D3, BSD patients exhibited improvement in their mood symptoms in conjunction with their brain neurochemistry. PMID:26091195

  19. Dopamine D3 Receptor Mediates Preadolescent Stress-Induced Adult Psychiatric Disorders

    PubMed Central

    Seo, Joon H.; Kuzhikandathil, Eldo V.

    2015-01-01

    Several studies have shown that repeated stressful experiences during childhood increases the likelihood of developing depression- and anxiety-related disorders in adulthood; however, the underlying mechanisms are not well understood. We subjected drd3-EGFP and drd3-null mice to daily, two hour restraint stress episodes over a five day period during preadolescence (postnatal day 35 to 39), followed by social isolation. When these mice reached adulthood (post-natal day > 90), we assessed locomotor behavior in a novel environment, and assessed depression-related behavior in the Porsolt Forced Swim test. We also measured the expression and function of dopamine D3 receptor in limbic brain areas such as hippocampus, nucleus accumbens and amygdala in control and stressed drd3-EGFP mice in adulthood. Adult male mice subjected to restraint stress during preadolescence exhibited both anxiety- and depression-related behaviors; however, adult female mice subjected to preadolescent restraint stress exhibited only depression-related behaviors. The development of preadolescent stress-derived psychiatric disorders was blocked by D3 receptor selective antagonist, SB 277011-A, and absent in D3 receptor null mice. Adult male mice that experienced stress during preadolescence exhibited a loss of D3 receptor expression and function in the amygdala but not in hippocampus or nucleus accumbens. In contrast, adult female mice that experienced preadolescent stress exhibited increased D3 receptor expression in the nucleus accumbens but not in amygdala or hippocampus. Our results suggest that the dopamine D3 receptor is centrally involved in the etiology of adult anxiety- and depression-related behaviors that arise from repeated stressful experiences during childhood. PMID:26619275

  20. Antiproliferative action of menadione and 1,25(OH)2D3 on breast cancer cells.

    PubMed

    Marchionatti, Ana M; Picotto, Gabriela; Narvaez, Carmen J; Welsh, Joellen; Tolosa de Talamoni, Nori G

    2009-02-01

    Calcitriol or 1,25(OH)(2)D(3) is a negative growth regulator of MCF-7 breast cancer cells. The growth arrest is due to apoptosis activation, which involves mitochondrial disruption. This effect is blunted in vitamin D resistant cells (MCF-7(DRes) cells). Menadione (MEN), a glutathione (GSH)-depleting compound, may potentiate antitumoral effects of anticancer drugs. The aim of this study was to investigate whether MEN enhances cellular responsiveness of MCF-7 cells to 1,25(OH)(2)D(3). Cells were cultured and treated with different concentrations of 1,25(OH)(2)D(3)+/-MEN or vehicle for 96 h. GSH levels and the activity of antioxidant enzymes were determined by spectrophotometry and ROS production by flow cytometry. Both drugs decreased growth and enhanced ROS in MCF-7 cells, obtaining the maximal effects when 1,25(OH)(2)D(3) was combined with MEN (P<0.01 vs. Control and vs. each compound alone). MCF-7(DRes) cells were not responsive to 1,25(OH)(2)D(3), but the cell proliferation was slightly inhibited by the combined treatment. Calcitriol and MEN separately enhanced antioxidant enzyme activities, but when they were used in combination, the effect was more pronounced (P<0.05 vs. Control and vs. each compound alone). MEN, calcitriol and the combined treatment decreased GSH levels (P<0.05 vs. Control). The data indicate that MEN potentiates the effect of 1,25(OH)(2)D(3) on growth arrest in MCF-7 cells by oxidative stress and increases the activities of antioxidant enzymes, probably as a compensatory mechanism.

  1. 1,25 Dihydroxyvitamin D3 Inhibits TGFβ1-Mediated Primary Human Cardiac Myofibroblast Activation

    PubMed Central

    Meredith, Anna; Boroomand, Seti; Carthy, Jon; Luo, Zongshu; McManus, Bruce

    2015-01-01

    Aims Epidemiological and interventional studies have suggested a protective role for vitamin D in cardiovascular disease, and basic research has implicated vitamin D as a potential inhibitor of fibrosis in a number of organ systems; yet little is known regarding direct effects of vitamin D on human cardiac cells. Given the critical role of fibrotic responses in end stage cardiac disease, we examined the effect of active vitamin D treatment on fibrotic responses in primary human adult ventricular cardiac fibroblasts (HCF-av), and investigated the relationship between circulating vitamin D (25(OH)D3) and cardiac fibrosis in human myocardial samples. Methods and Results Interstitial cardiac fibrosis in end stage HF was evaluated by image analysis of picrosirius red stained myocardial sections. Serum 25(OH)D3 levels were assayed using mass spectrometry. Commercially available HCF-av were treated with transforming growth factor (TGF)β1 to induce activation, in the presence or absence of active vitamin D (1,25(OH)2D3). Functional responses of fibroblasts were analyzed by in vitro collagen gel contraction assay. 1,25(OH)2D3 treatment significantly inhibited TGFβ1-mediated cell contraction, and confocal imaging demonstrated reduced stress fiber formation in the presence of 1,25(OH)2D3. Treatment with 1,25(OH)2D3 reduced alpha-smooth muscle actin expression to control levels and inhibited SMAD2 phosphorylation. Conclusions Our results demonstrate that active vitamin D can prevent TGFβ1-mediated biochemical and functional pro-fibrotic changes in human primary cardiac fibroblasts. An inverse relationship between vitamin D status and cardiac fibrosis in end stage heart failure was observed. Collectively, our data support an inhibitory role for vitamin D in cardiac fibrosis. PMID:26061181

  2. Current perspectives on selective dopamine D3 receptor antagonists as pharmacotherapeutics for addictions and related disorders

    PubMed Central

    Heidbreder, Christian A.; Newman, Amy H.

    2011-01-01

    Repeated exposure to drugs of abuse produces long-term molecular and neurochemical changes that may explain the core features of addiction, such as the compulsive seeking and taking of the drug, as well as the risk of relapse. A growing number of new molecular and cellular targets of addictive drugs have been identified, and rapid advances are being made in relating those targets to specific behavioral phenotypes in animal models of addiction. In this context, the pattern of expression of the dopamine (DA) D3 receptor in the rodent and human brain and changes in this pattern in response to drugs of abuse have contributed primarily to direct research efforts toward the development of selective DA D3 receptor antagonists. Growing preclinical evidence indicates that these compounds may actually regulate the motivation to self-administer drugs and disrupt drug-associated cue-induced craving. This report will be divided into three parts. First, preclinical evidence in support of the efficacy of selective DA D3 receptor antagonists in animal models of drug addiction will be reviewed. The effects of mixed DA D2/D3 receptor antagonists will not be discussed here because most of these compounds have low selectivity at the D3 versus D2 receptor, and their efficacy profile is related primarily to functional antagonism at D2 receptors and possibly interactions with other neurotransmitter systems. Second, major advances in medicinal chemistry for the identification and optimization of selective DA D3 receptor antagonists and partial agonists will be analyzed. Third, translational research from preclinical efficacy studies to so-called proof-of-concept studies for drug addiction indications will be discussed. PMID:20201845

  3. Role of megalin and cubilin in the metabolism of vitamin D(3).

    PubMed

    Kaseda, Ryohei; Hosojima, Michihiro; Sato, Hiroyoshi; Saito, Akihiko

    2011-06-01

    Vitamin D deficiency is associated with various medical conditions including musculoskeletal disorders, infection, metabolic diseases, and cardiovascular disease. Megalin and cubilin, endocytic receptors in proximal tubule cells, are involved in the reabsorption of vitamin D binding protein from glomerular filtrates and the subsequent intracellular conversion of 25-hydroxyvitamin D(3) to biologically active 1α,25-dihydroxyvitamin D(3). Dysfunction of these receptors, which is commonly found in patients with diabetic nephropathy, even at early stages, may explain why vitamin D deficiency is often complicated in these patients. Therapeutic strategies to protect the functions of these receptors from injury could be used to prevent vitamin D deficiency and its related disorders.

  4. Modulation of mouse RANKL gene expression by Runx2 and vitamin D3.

    PubMed

    Kitazawa, Riko; Mori, Kiyoshi; Yamaguchi, Akira; Kondo, Takeshi; Kitazawa, Sohei

    2008-12-01

    The expression of receptor activator of nuclear factor-kappaB ligand (RANKL) is regulated by bone-seeking hormones such as PTH and 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3). Runx2, a master gene for osteoblastic differentiation, also modulates osteoclastogenesis by regulating the RANKL gene. To elucidate the mechanism whereby runx2 and 1,25(OH)2D3 regulate RANKL expression, we studied the function of runx2 on the chromatin structure and on the proximal binding sites using osteoblastic cell lines derived from normal (ST2) and runx2-deficient mice (RD-C6). Although the expression of RANKL in the steady-state was higher in RD-C6 than in ST2, 1,25(OH)2D3-treatment of the cells increased it 20-fold in ST2 but only 1.8-fold in RD-C6. Transient transfection studies with proximal RANKL 2kb promoter, runx2 knock-down in ST2, and forced expression of runx2 in RD-C6 all confirmed that runx2 set the steady-state expression of the RANKL gene at a low level, but exerted a positive effect on enhanced transcriptional activity in response to 1,25(OH)2D3. Also, assessment of the acetylation status of the area spanning 40 kb upstream of the basic promoter in ST2 and RD-C6 by ChIP assay revealed that whereas H3 and H4 histone acetylation was detected even in the steady-state in RD-C6, it was detected only with 1,25(OH)2D3 in ST2. In the steady-state, runx2 may suppress RANKL gene by condensing the chromatin structure; however, it exerts a positive effect on 1,25(OH)2D3-induced RANKL transcription when the proximal runx2 sites are accessible. Thus, RANKL expression in stromal/osteoblastic cells is keenly regulated by 1,25(OH)2D3 which transactivates the gene at two different levels

  5. Nonperturbative gluon and ghost propagators for d=3 Yang-Mills theory

    SciTech Connect

    Aguilar, A. C.; Binosi, D.; Papavassiliou, J.

    2010-06-15

    We study a manifestly gauge-invariant set of Schwinger-Dyson equations to determine the nonperturbative dynamics of the gluon and ghost propagators in d=3 Yang-Mills theory. The use of the well-known Schwinger mechanism, in the Landau gauge leads to the dynamical generation of a mass for the gauge boson (gluon in d=3), which, in turn, gives rise to an infrared finite gluon propagator and ghost dressing function. The propagators obtained from the numerical solution of these nonperturbative equations are in very good agreement with the results of SU(2) lattice simulations.

  6. Discovery of cariprazine (RGH-188): a novel antipsychotic acting on dopamine D3/D2 receptors.

    PubMed

    Agai-Csongor, Eva; Domány, György; Nógrádi, Katalin; Galambos, János; Vágó, István; Keserű, György Miklós; Greiner, István; Laszlovszky, István; Gere, Anikó; Schmidt, Eva; Kiss, Béla; Vastag, Mónika; Tihanyi, Károly; Sághy, Katalin; Laszy, Judit; Gyertyán, István; Zájer-Balázs, Mária; Gémesi, Larisza; Kapás, Margit; Szombathelyi, Zsolt

    2012-05-15

    Medicinal chemistry optimization of an impurity isolated during the scale-up synthesis of a pyridylsulfonamide type dopamine D(3)/D(2) compound (1) led to a series of new piperazine derivatives having affinity to both dopamine D(3) and D(2) receptors. Several members of this group showed excellent pharmacokinetic and pharmacodynamic properties as demonstrated by outstanding activities in different antipsychotic tests. The most promising representative, 2m (cariprazine) had good absorption, excellent brain penetration and advantageous safety profile. Based on its successful clinical development we are looking forward to the NDA filing of cariprazine in 2012. Copyright © 2012 Elsevier Ltd. All rights reserved.

  7. Response of keloid fibroblasts to Vitamin D3 and quercetin treatment - in vitro study.

    PubMed

    Mathangi Ramakrishnan, K; Babu, M; Lakshmi Madhavi, M S

    2015-09-30

    Keloid scars continue to pose a challenge to clinicians as the treatment armamentarium lacks a formidable agent to tackle them. We have undertaken an in vitro study based on the mechanism of action of Vitamin D3 and quercetin on isolated keloid fibroblasts. Dose-dependent action on the reduction of cellular proliferation, collagen synthesis and induction of apoptosis by Vitamin D3 and quercetin are analyzed and probable mechanism of action is elaborated. This study thus opens up newer avenues in tackling keloid scars effectively.

  8. Discriminating Acquisition of 15-MeV Protons from D-3He Fusion Reaction in LHD

    NASA Astrophysics Data System (ADS)

    Watanabe, Tsuguhiro; Miyazawa, Junichi; Yamada, Hiroshi; Murakami, Sadayoshi; Masuzaki, Suguru; Osakabe, Masaki; Isobe, Mitsutaka; Tokitani, Masayuki; Motojima, Osamu

    Discriminating acquisition of 15-MeV protons is possible in LHD D-3He experiments (D+ beam to 3He plasma), due to the nonaxisymmetric structure of the magnetic field and the ultra-high energy of the fusion products. The collisionless orbits of D-3He fusion products are studied numerically in the standard magnetic field configuration of LHD. Three sets of fusion product acquisition systems are installed in LHD and numerical computations show the possibility of discriminating between fusion products and plasma particles. The acquisition rate of 15-MeV protons is expected to be in the range of 12 ˜ 28 %.

  9. Effect of Vitamin D3 on Monocyte Chemoattractant Protein 1 Production in Monocytes and Macrophages

    PubMed Central

    Wang, Yi-Chen; Hsieh, Chong-Chao; Kuo, Hsuan-Fu; Tsai, Ming-Kai; Yang, San-Nan; Kuo, Chang-Hung; Lee, Min-Sheng; Hung, Chih-Hsing

    2014-01-01

    Background Chemokine is important in the initiation and progression of atherosclerosis, the clinically manifest stages of atherosclerosis and acute coronary syndrome. Vitamin D deficiency has been reportedly linked with hypertension and myocardial infarction, as well as other cardiovascular-related diseases, such as congestive heart failure, peripheral vascular disease and atherosclerosis. Monocyte chemoattractant protein 1 (MCP-1) mediates atherosclerosis and other cardiovascular diseases. However, there have been few studies conducted about the role of 1α,25-(OH)2D3 on MCP-1 expression in human monocytes. Methods We investigated the effects of vitamin A, C and 1α,25-(OH)2D3, three common vitamins, to better ascertain MCP-1 expression in human monocyte and also the associated intracellular mechanism. Human monocyte cell line (THP-1 cell) and THP-1 cell-induced macrophage were treated with varying doses of vitamin A, C and 1α,25-(OH)2D3 for 2 hours before LPS stimulation. Supernatants were harvested to measure MCP-1 levels by the enzyme-linked immunosorbent assay (ELISA). The intracellular mechanism about the effects of vitamin A, C and 1α,25-(OH)2D3 on the expression of MCP-1 expression in human monocytes was assessed by western blot. Results We found that Lipopolysaccharides (LPS)-induced MCP-1 production was suppressed by 1α,25-(OH)2D3 in THP-1 cells and THP-1-induced macrophage. Only high concentration of vitamin A and C could reduce LPS-induced MCP-1 production in THP-1-induced macrophage, but not in THP-1 cells. LPS-induced p38 expression in THP-1 cells was suppressed by 1α,25-(OH)2D3. A selective p38 pathway inhibitor SB203580 could also suppress LPS-induced MCP-1 production. However, vitamin D receptor blocking antibody could reverse the suppressive effect of 1α,25-(OH)2D3 on MCP-1 expression. Conclusions These data demonstrate that 1α,25-(OH)2D3 is effective in down-regulating LPS-induced MCP-1. The suppressive effect on MCP-1 may, at least in part

  10. 1,25-Dihydroxyvitamin D3/vitamin D receptor suppresses brown adipocyte differentiation and mitochondrial respiration.

    PubMed

    Ricciardi, Carolyn J; Bae, Jiyoung; Esposito, Debora; Komarnytsky, Slavko; Hu, Pan; Chen, Jiangang; Zhao, Ling

    2015-09-01

    The vitamin D system plays a role in metabolism regulation. 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) suppressed 3T3-L1 white adipocyte differentiation. Vitamin D receptor (VDR) knockout mice showed increased energy expenditure, whereas mice with adipose-specific VDR over-expression showed decreased energy expenditure. Brown adipose tissue (BAT), now known to be present in adult humans, functions in non-shivering thermogenesis by uncoupling ATP synthesis from respiration and plays an important role in energy expenditure. However, the effects of 1,25(OH)2D3/VDR on brown adipocyte differentiation and mitochondrial respiration have not been reported. mRNA expression of VDR and the metabolizing enzymes 1α-hydroxylase (CYP27B1) and 24-hydroxylase (CYP24A1) were examined in BAT of mice models of obesity and during brown adipocyte differentiation. The effects of 1,25(OH)2D3 and VDR over-expression on brown adipocyte differentiation and functional outcomes were evaluated. No significant changes in mRNA of VDR and CYP27B1 were noted in both diet-induced obese (DIO) and ob/ob mice, whereas uncoupling protein 1 mRNA was downregulated in BAT of ob/ob, but not DIO mice when compared to the controls. In contrast, mRNA of VDR, CYP24A1, and CYP27B1 were downregulated during brown adipocyte differentiation in vitro. 1,25(OH)2D3 dose-dependently suppressed brown adipocyte differentiation, accompanied by suppressed isoproterenol-stimulated oxygen consumption rates (OCR), maximal OCR and OCR from proton leak. Consistently, over-expression of VDR also suppressed brown adipocyte differentiation. Further, both 1,25(OH)2D3 and VDR over-expression suppressed PPARγ transactivation in brown preadipocytes. Our results demonstrate the suppressive effects of 1,25(OH)2D3/VDR signaling on brown adipocyte differentiation and mitochondrial respiration. The role of 1,25(OH)2D3/VDR system in regulating BAT development and function in obesity warrant further investigation.

  11. Spectral Characteristics of the He i D3 Line in a Quiescent Prominence Observed by THEMIS

    NASA Astrophysics Data System (ADS)

    Koza, Július; Rybák, Ján; Gömöry, Peter; Kozák, Matúš; López Ariste, Arturo

    2017-08-01

    We analyze the observations of a quiescent prominence acquired by the Téléscope Heliographique pour l'Étude du Magnetisme et des Instabilités Solaires (THEMIS) in the He i 5876 Å (He i D3) multiplet aiming to measure the spectral characteristics of the He i D3 profiles and to find for them an adequate fitting model. The component characteristics of the He i D3 Stokes I profiles are measured by the fitting system by approximating them with a double Gaussian. This model yields an He i D3 component peak intensity ratio of 5.5±0.4, which differs from the value of 8 expected in the optically thin limit. Most of the measured Doppler velocities lie in the interval ± 5 km s-1, with a standard deviation of ± 1.7 km s-1 around the peak value of 0.4 km s-1. The wide distribution of the full-width at half maximum has two maxima at 0.25 Å and 0.30 Å for the He i D3 blue component and two maxima at 0.22 Å and 0.31 Å for the red component. The width ratio of the components is 1.04±0.18. We show that the double-Gaussian model systematically underestimates the blue wing intensities. To solve this problem, we invoke a two-temperature multi-Gaussian model, consisting of two double-Gaussians, which provides a better representation of He i D3 that is free of the wing intensity deficit. This model suggests temperatures of 11.5 kK and 91 kK, respectively, for the cool and the hot component of the target prominence. The cool and hot components of a typical He i D3 profile have component peak intensity ratios of 6.6 and 8, implying a prominence geometrical width of 17 Mm and an optical thickness of 0.3 for the cool component, while the optical thickness of the hot component is negligible. These prominence parameters seem to be realistic, suggesting the physical adequacy of the multi-Gaussian model with important implications for interpreting He i D3 spectropolarimetry by current inversion codes.

  12. Determination of some physiological factors affecting xylanase production from Trichoderma harzianum 1073 D3.

    PubMed

    Seyis, I; Aksoz, N

    2003-01-01

    In this study, different Trichoderma strains were tested and Trichoderma harzianum 1073 D3 was found to be the most potent xylanase producer. Then some cultural parameters, namely, incubation time, substrate concentration, initial culture pH and temperature were optimized in order to increase xylanase production from Trichoderma harzianum 1073 D3. The optimum incubation time was found to be 13 days. It was concluded that 1% xylan concentration is suitable for high xylanase production rate. The optimum temperature and pH were found to be 30 degrees C and 7, respectively. Also, it was determined that agitation during growth was suitable for efficient production.

  13. A Map Between d = 3 and d = 4 Spacetime Dimensional k-strings Using Holography

    NASA Astrophysics Data System (ADS)

    Liu, Xiaolong; Stiffler, Kory

    2009-11-01

    We investigate k-string in d=3 and d=4 spacetime dimensions using holography. Exploiting the similarities between two supergravity backgrounds,Maldacena-Nunez background and Maldacena-Nastase background, we map calculations for k-strings between d = 3 and d = 4 spacetime dimensions. The specific calculations investigated are the usual lowest order tension term for the energy of k-strings and the first order, one loop corrections, the Luscher term. The tension term is proportional to L, the length between quark antiquark pairs and the Luscher term is the typical 1/L Coulombic correction.

  14. CYP24 inhibition preserves 1α,25-dihydroxyvitamin D3 anti-proliferative signaling in lung cancer cells

    PubMed Central

    Zhang, Qiuhong; Kanterewicz, Beatriz; Buch, Shama; Petkovich, Martin; Parise, Robert; Beumer, Jan; Lin, Yan; Diergaarde, Brenda; Hershberger, Pamela A.

    2012-01-01

    Human lung tumors aberrantly express the 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3)-catabolizing enzyme, CYP24. We hypothesized that CYP24 reduces 1,25(OH)2D3-mediated transcription and allows lung cancer cells to escape its growth-inhibitory action. To test this, H292 lung cancer cells and the CYP24-selective inhibitor CTA091 were utilized. In H292 cells, CTA091 reduces 1,25(OH)2D3 catabolism, significantly increases 1,25(OH)2D3-mediated growth inhibition, and increases 1,25(OH)2D3 effects on induced and repressed genesin gene expression profiling studies. Pathway mapping of repressed genes uncovered cell cycle as a predominant 1,25(OH)2D3 target. In H292 cells, 1,25(OH)2D3 significantly decreases cyclin E2 levels and induces G0/G1 arrest. A broader set of cyclins is down-regulated when 1,25(OH)2D3 is combined with CTA091, and cell cycle arrest further increases. Effects of CTA091 on 1,25(OH)2D3 signaling are vitamin D receptor-dependent. These data provide evidence that CYP24 limits 1,25(OH)2D3 anti-proliferative signaling in cancer cells, and suggest that CTA091 may be beneficial in preserving 1,25(OH)2D3 action in lung cancer. PMID:22386975

  15. 24R,25-Dihydroxyvitamin D3 Protects against Articular Cartilage Damage following Anterior Cruciate Ligament Transection in Male Rats

    PubMed Central

    Boyan, Barbara D.; Hyzy, Sharon L.; Pan, Qingfen; Scott, Kayla M.; Coutts, Richard D.; Healey, Robert; Schwartz, Zvi

    2016-01-01

    Osteoarthritis (OA) in humans is associated with low circulating 25-hydroxyvitamin D3 [25(OH)D3]. In vitamin D replete rats, radiolabeled 24R,25-dihydroxyvitamin D3 [24R,25(OH)2D3] accumulates in articular cartilage following injection of [3H]-25(OH)D3. Previously, we showed that 24R,25(OH)2D3 blocks chondrocyte apoptosis via phospholipase D and p53, suggesting a role for 24R,25(OH)2D3 in maintaining cartilage health. We examined the ability of 24R,25(OH)2D3 to prevent degenerative changes in articular cartilage in an OA-like environment and the potential mechanisms involved. In vitro, rat articular chondrocytes were treated with IL-1β with and without 24R,25(OH)2D3 or 1α,25(OH)2D3. 24R,25(OH)2D3 but not 1α,25(OH)2D3 blocked the effects of IL-1β in a dose-dependent manner, and its effect was partially mediated through the TGF-β1 signaling pathway. In vivo, unilateral anterior cruciate ligament transections were performed in immunocompetent rats followed by intra-articular injections of 24R,25(OH)2D3 or vehicle (t = 0, 7, 14, 21 days). Tissues were harvested on day 28. Joints treated with vehicle had changes typical of OA whereas joints treated with 24R,25(OH)2D3 had less articular cartilage damage and levels of inflammatory mediators. These results indicate that 24R,25(OH)2D3 protects against OA, and suggest that it may be a therapeutic approach for preventing trauma-induced osteoarthritis. PMID:27575371

  16. Vitamin E induces regular structure and stability of human insulin, more intense than vitamin D3.

    PubMed

    Soleymani, Hossein; Saboury, Ali A; Moosavi-Movahedi, Ali A; Rahmani, Fatemeh; Maleki, Javad; Yousefinejad, Saeid; Maghami, Parvaneh

    2016-12-01

    Changes in human environment and lifestyle over the last century have caused a dramatic increase in the occurrence of diabetes. Research of past decades illustrated that vitamin D and E have a key role in the improvement of diabetes by reducing oxidative stress, protein glycosylation, insulin resistance and also improving beta cell function. Binding properties and conformational changes of human insulin upon interaction with vitamins D3 and E (α-tocopherol) were investigated by spectroscopy, differential scanning calorimetry (DSC) and molecular dynamic simulation. Tyrosine fluorescence quenching studies indicates changes in the human insulin conformation in the presence of vitamins. Binding constants of vitamins D3 and E for human insulin were determined to be 2.7 and 1.5 (×10(-5)M(-1)) and the corresponding average numbers of binding sites were determined to be 1.3 and 1.2, respectively. Far- and near-UV circular dichroism studies showed that vitamin E can significantly change the secondary and tertiary structures of human insulin via an increase in the content of α-helix structure. Results of DSC showed that both vitamins D3 and E stabilize the structure of human insulin. Molecular dynamic simulation results indicated that vitamin D3 decreases the helical and strand structural contents of human insulin, but vitamin E stabilizes more regular secondary structures such as helical and strand structural contents as shown by experimental results.

  17. Transgenic tobacco plants overexpressing the Nicta; CycD3; 4 gene demonstrate accelerated growth rates.

    PubMed

    Guo, Jia; Wang, Myeong Hyeon

    2008-07-31

    D-type cyclins control the onset of cell division and the response to extracellular signals during the G1 phase. In this study, we transformed a D-type cyclin gene, Nicta;CycD3;4, from Nicotiana tabacum using an Agrobacterium-mediated method. A predicted 1.1 kb cyclin gene was present in all of the transgenic plants, but not in wild-type. Northern analyses showed that the expression level of the Nicta;CycD3;4 gene in all of the transgenic plants was strong when compared to the wild-type plants, suggesting that Nicta;CycD3;4 gene driven by the CaMV 35S promoter was being overexpressed. Our results revealed that transgenic plants overexpressing Nicta;CycD3;4 had an accelerated growth rate when compared to wild-type plants, and that the transgenic plants exhibited a smaller cell size and a decreased cell population in young leaves when compared to wild-type plants.

  18. Comparison of analysis of vitamin D3 in foods using ultraviolet and mass spectrometric detection.

    PubMed

    Byrdwell, William C

    2009-03-25

    A method for analysis of vitamin D(3) in commonly fortified foods and in fish, which contains endogenous vitamin D(3), was developed by combining the best aspects of two official methods. The ethyl ether/petroleum ether extraction procedure from AOAC 992.26 was combined with the chromatographic separation and use of an internal standard (vitamin D(2)) from AOAC 2002.05 to produce a method that was applicable to a variety of food samples. Results for skim milk, orange juice, breakfast cereal, salmon, a diluted USP reference standard (vitamin D(3) in peanut oil), and processed cheese are presented. Results indicated that UV detection was adequate in most cases, but the absence of interfering species must be determined in each food by mass spectrometry. Selected ion monitoring (SIM) atmospheric pressure chemical ionization (APCI) mass spectrometry (MS) was shown to produce statistically indistinguishable results compared to UV detection for the skim milk, orange juice, multigrain cereal, and salmon samples. The processed cheese exhibited interferences that precluded quantification of vitamin D(3) by UV detection, and therefore, only SIM APCI-MS data for that sample were valid.

  19. Dopamine D3 Receptor Antagonists as Potential Therapeutics for the Treatment of Neurological Diseases

    PubMed Central

    Maramai, Samuele; Gemma, Sandra; Brogi, Simone; Campiani, Giuseppe; Butini, Stefania; Stark, Holger; Brindisi, Margherita

    2016-01-01

    D3 receptors represent a major focus of current drug design and development of therapeutics for dopamine-related pathological states. Their close homology with the D2 receptor subtype makes the development of D3 selective antagonists a challenging task. In this review, we explore the relevance and therapeutic utility of D3 antagonists or partial agonists endowed with multireceptor affinity profile in the field of central nervous system disorders such as schizophrenia and drug abuse. In fact, the peculiar distribution and low brain abundance of D3 receptors make them a valuable target for the development of drugs devoid of motor side effects classically elicited by D2 antagonists. Recent research efforts were devoted to the conception of chemical templates possibly endowed with a multi-target profile, especially with regards to other G-protein-coupled receptors (GPCRs). A comprehensive overview of the recent literature in the field is herein provided. In particular, the evolution of the chemical templates has been tracked, according to the growing advancements in both the structural information and the refinement of the key pharmacophoric elements. The receptor/multireceptor affinity and functional profiles for the examined compounds have been covered, together with their most significant pharmacological applications. PMID:27761108

  20. Vitamin D3 suppresses morphological evolution of the cribriform cancerous phenotype.

    PubMed

    Deevi, Ravi K; McClements, Jane; McCloskey, Karen D; Fatehullah, Aliya; Tkocz, Dorota; Javadi, Arman; Higginson, Robyn; Marsh Durban, Victoria; Jansen, Marnix; Clarke, Alan; Loughrey, Maurice B; Campbell, Frederick C

    2016-08-02

    Development of cribriform morphology (CM) heralds malignant change in human colon but lack of mechanistic understanding hampers preventive therapy. This study investigated CM pathobiology in three-dimensional (3D) Caco-2 culture models of colorectal glandular architecture, assessed translational relevance and tested effects of 1,25(OH)2D3,theactive form of vitamin D. CM evolution was driven by oncogenic perturbation of the apical polarity (AP) complex comprising PTEN, CDC42 and PRKCZ (phosphatase and tensin homolog, cell division cycle 42 and protein kinase C zeta). Suppression of AP genes initiated a spatiotemporal cascade of mitotic spindle misorientation, apical membrane misalignment and aberrant epithelial configuration. Collectively, these events promoted "Swiss cheese-like" cribriform morphology (CM) comprising multiple abnormal "back to back" lumens surrounded by atypical stratified epithelium, in 3D colorectal gland models. Intestinal cancer driven purely by PTEN-deficiency in transgenic mice developed CM and in human CRC, CM associated with PTEN and PRKCZ readouts. Treatment of PTEN-deficient 3D cultures with 1,25(OH)2D3 upregulated PTEN, rapidly activated CDC42 and PRKCZ, corrected mitotic spindle alignment and suppressed CM development. Conversely, mutationally-activated KRAS blocked1,25(OH)2D3 rescue of glandular architecture. We conclude that 1,25(OH)2D3 upregulates AP signalling to reverse CM in a KRAS wild type (wt), clinically predictive CRC model system. Vitamin D could be developed as therapy to suppress inception or progression of a subset of colorectal tumors.

  1. The effect of microgravity on 1,25-dihydroxyvitamin d3 signalling in osteoblasts

    NASA Astrophysics Data System (ADS)

    Coenegrachts, Lieve; Stockmans, Ingrid; Segers, Ilse; Bouillon, Roger; Carmeliet, Geert

    2007-09-01

    Microgravity encountered during space flight induces bone loss, as seen in both humans and rats. This type of bone loss is mainly caused by decreased bone formation due to reduced osteoblast proliferation and differentiation. Yet, the molecular alterations induced by microgravity during osteoblast differentiation are still enigmatic. Therefore, the effect of microgravity on the intracellular signalling pathway of 1,25-dihydroxyvita-min D3 was investigated during the Odissea Mission. The ligand 1,25-dihydroxyvitamin D3 interacts with the vitamin D receptor (VDR) and this complex binds to vitamin D response elements (VDRE) in the promoter region of target genes to stimulate or suppress gene transcription. To investigate the interaction of liganded VDR with VDRE, the mouse osteoblastic cell line, MC3T3, was stable transfected with a construct containing multiple VDREs of the rat osteocalcin promoter fused to growth hormone as reporter gene. Treatment of these transfectants with 1,25-dihydroxyvitamin D3 resulted in a time- and dose-dependent release of growth hormone in the culture medium. Space flight cultures responded to 1,25-dihydroxyvitamin D3 treatment with increased growth hormone production that was comparable with the induction observed in ground cultures. No 1g centrifuge was available during the space flight. These data indicate that microgravity for 5 days did not alter the interaction of VDR with the osteocalcin VDRE or the subsequent gene transcription.

  2. Validation for 2D/3D registration I: A new gold standard data set

    PubMed Central

    Pawiro, S. A.; Markelj, P.; Pernuš, F.; Gendrin, C.; Figl, M.; Weber, C.; Kainberger, F.; Nöbauer-Huhmann, I.; Bergmeister, H.; Stock, M.; Georg, D.; Bergmann, H.; Birkfellner, W.

    2011-01-01

    Purpose In this article, the authors propose a new gold standard data set for the validation of two-dimensional/three-dimensional (2D/3D) and 3D/3D image registration algorithms. Methods A gold standard data set was produced using a fresh cadaver pig head with attached fiducial markers. The authors used several imaging modalities common in diagnostic imaging or radiotherapy, which include 64-slice computed tomography (CT), magnetic resonance imaging using Tl, T2, and proton density sequences, and cone beam CT imaging data. Radiographic data were acquired using kilovoltage and megavoltage imaging techniques. The image information reflects both anatomy and reliable fiducial marker information and improves over existing data sets by the level of anatomical detail, image data quality, and soft-tissue content. The markers on the 3D and 2D image data were segmented using analyze 10.0 (AnalyzeDirect, Inc., Kansas City, KN) and an in-house software. Results The projection distance errors and the expected target registration errors over all the image data sets were found to be less than 2.71 and 1.88 mm, respectively. Conclusions The gold standard data set, obtained with state-of-the-art imaging technology, has the potential to improve the validation of 2D/3D and 3D/3D registration algorithms for image guided therapy. PMID:21520860

  3. Validation for 2D/3D registration I: A new gold standard data set

    SciTech Connect

    Pawiro, S. A.; Markelj, P.; Pernus, F.; Gendrin, C.; Figl, M.; Weber, C.; Kainberger, F.; Noebauer-Huhmann, I.; Bergmeister, H.; Stock, M.; Georg, D.; Bergmann, H.; Birkfellner, W.

    2011-03-15

    Purpose: In this article, the authors propose a new gold standard data set for the validation of two-dimensional/three-dimensional (2D/3D) and 3D/3D image registration algorithms. Methods: A gold standard data set was produced using a fresh cadaver pig head with attached fiducial markers. The authors used several imaging modalities common in diagnostic imaging or radiotherapy, which include 64-slice computed tomography (CT), magnetic resonance imaging using Tl, T2, and proton density sequences, and cone beam CT imaging data. Radiographic data were acquired using kilovoltage and megavoltage imaging techniques. The image information reflects both anatomy and reliable fiducial marker information and improves over existing data sets by the level of anatomical detail, image data quality, and soft-tissue content. The markers on the 3D and 2D image data were segmented using ANALYZE 10.0 (AnalyzeDirect, Inc., Kansas City, KN) and an in-house software. Results: The projection distance errors and the expected target registration errors over all the image data sets were found to be less than 2.71 and 1.88 mm, respectively. Conclusions: The gold standard data set, obtained with state-of-the-art imaging technology, has the potential to improve the validation of 2D/3D and 3D/3D registration algorithms for image guided therapy.

  4. Treatment of an intramammary bacterial infection with 25-hydroxyvitamin D3

    USDA-ARS?s Scientific Manuscript database

    Deficiency of serum levels of 25-hydroxyvitamin D3 has been correlated with increased risk of infectious diseases, such as tuberculosis and influenza. A plausible reason for this association is that expression of genes encoding important antimicrobial proteins depends on concentrations of 1,25-dihyd...

  5. 26 CFR 31.3406(d)-3 - Special 30-day rules for certain reportable payments.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 15 2012-04-01 2012-04-01 false Special 30-day rules for certain reportable... COLLECTION OF INCOME TAX AT SOURCE Collection of Income Tax at Source § 31.3406(d)-3 Special 30-day rules for... certification of notified payee underreporting) within 30 days after the establishment or acquisition...

  6. 26 CFR 31.3406(d)-3 - Special 30-day rules for certain reportable payments.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 15 2014-04-01 2014-04-01 false Special 30-day rules for certain reportable... COLLECTION OF INCOME TAX AT SOURCE Collection of Income Tax at Source § 31.3406(d)-3 Special 30-day rules for... certification of notified payee underreporting) within 30 days after the establishment or acquisition...

  7. HB-EGF directs stromal cell polyploidy and decidualization via cyclin D3 during implantation.

    PubMed

    Tan, Yi; Li, Meiling; Cox, Sandra; Davis, Marilyn K; Tawfik, Ossama; Paria, Bibhash C; Das, Sanjoy K

    2004-01-01

    Stromal cell polyploidy is a unique phenomenon that occurs during uterine decidualization following embryo implantation, although the developmental mechanism still remains elusive. The general consensus is that the aberrant expression and altered functional activity of cell cycle regulatory molecules at two particular checkpoints G1 to S and G2 to M in the cell cycle play an important role in the development of cellular polyploidy. Despite the compelling evidence of intrinsic cell cycle alteration, it has been implicated that the development of cellular polyploidy may be controlled by specific actions of extracellular growth regulators. Here we show a novel role for heparin-binding EGF-like growth factor (HB-EGF) in the developmental process of stromal cell polyploidy in mice. HB-EGF, which is one of the earliest known molecular mediators of implantation in mice and humans, promotes stromal cell polyploidy via upregulation of cyclin D3. Adenoviral delivery of antisense cyclin D3 attenuates cyclin D3 expression and abrogates HB-EGF-induced stromal cell polyploidy in vitro and in vivo. Collectively, the results demonstrate that the regulation of stromal cell polyploidy and decidualization induced by HB-EGF depend on cyclin D3 induction.

  8. Ultraviolet radiation and Vitamin D3 in amphibian health, behaviour, diet and conservation.

    PubMed

    Antwis, R E; Browne, R K

    2009-10-01

    Amphibians are currently suffering a period of mass extinction with approximately 20% of species under severe threat and more than 120 species already extinct. In light of this crisis there is an urgency to establish viable ex situ populations and also find the causes of in situ declines. The role of ultraviolet radiation and Vitamin D(3) in amphibian health directly influences both ex situ and in situ populations. Vitamin D(3) can be photosynthesised endogenously via UV-B radiation (UV-B), or acquired through the diet, and then metabolised to calcitriol the biologically active hormonal form. Although, there is a lack of literature concerning Vitamin D(3) requirements and calcitriol synthesis in amphibians, amphibians are likely to have similar Vitamin D(3) requirements and metabolic processes as other vertebrates due to the phylogenetically conservative nature of calcitriol biosynthesis. Deficiencies in calcitriol in amphibians result in nutritional metabolic bone disease (NMBD) and could compromise reproduction and immunity. However, excess biologically active UV radiation has also proven detrimental across all three amphibian life stages and therefore could impact both in situ and ex situ populations. Here we review the role and necessity of UV-B and calcitriol in amphibians and the potential for negative impacts due to excessive exposure to UV radiation. We also identify priorities for research that could provide critical information for maintaining healthy in ex situ and in situ populations of amphibians.

  9. Vitamin D3 supplementation improves insulin sensitivity in subjects with impaired fasting glucose

    PubMed Central

    Nazarian, Shaban; Peter, John V St; Boston, Raymond C; Jones, Sidney A; Mariash, Cary N

    2011-01-01

    Vitamin D has in vitro and in vivo effects on β-cells and insulin sensitivity. Vitamin D deficiency (VDD) has been associated with onset and progression of type 2 diabetes mellitus (DM-2). However, studies involving supplementation of vitamin D in subjects with previously established diabetes have demonstrated inconsistent effects on insulin sensitivity. The aim of this open-label study was to assess the effects of high dose vitamin D3 supplementation on insulin sensitivity in subjects with VDD and impaired fasting glucose. We studied 8 subjects with VDD and pre-diabetes with the modified frequently sampled intravenous glucose tolerance (mFSIGT) test before and after vitamin D supplementation. Vitamin D3 was administered as 10,000 IU daily for 4 weeks. The mFSIGT was analyzed with MinMod Millennnium to obtain estimates of Acute Insulin Response to Glucose (AIRg), Insulin Sensitivity (SI), and Disposition Index (DI). We found that AIRg decreased (p = 0.011) and insulin sensitivity, expressed as SI, increased (p = 0.012) after a intervention with vitamin D. If these findings are repeated in a randomized, double-blind, sudy the results indicate that orally administered high dose vitamin D3 supplementation improves insulin sensitivity in subjects with impaired fasting glucose and suggests that high dose vitamin D3 supplementation might provide an inexpensive public health measure in preventing, or at least delaying, the progression from impaired fasting glucose to diabetes. PMID:22005267

  10. Functional expression and characterization of human D2 and D3 dopamine receptors.

    PubMed

    Potenza, M N; Graminski, G F; Schmauss, C; Lerner, M R

    1994-03-01

    Functional characteristics of human D2 and D3 receptors (DRs) were examined using a new bioassay suited for the study of Gi-protein-coupled receptors (GiRs). The bioassay utilizes pigment granule aggregation within cultured Xenopus laevis melanophores for the quantitative evaluation of ligands as agonists or antagonists upon particular GiRs. Initial feasibility studies were performed by analyzing a melanocyte receptor endogenous to the melanophores. In dose-dependent manners, melatonin inhibited melatonin-stimulating hormone-induced cAMP accumulation and caused pigment aggregation that could be monitored over time. Next, melanophores were transiently transfected with cDNAs coding for the human D2BR (short form) and D3R. Expression of either receptor conferred upon the cells the ability to aggregate their melanosomes in response to selective dopaminergic agonists. The same ligands also inhibited cAMP accumulation within the transfected melanophores, and the agonist-induced pigment aggregation was shown to be sensitive to pertussis toxin. EC50 and IC50 value determinations revealed that agonists activated the D2R and D3R at similar concentrations, while each of the antagonists displaying an effect was more potent upon the D2R. The results reveal functional similarities and differences between the D2R and D3R.

  11. Specific features of provitamin D 3 photoisomerization in a cholesteric liquid crystal

    NASA Astrophysics Data System (ADS)

    Orlova, T. N.; Terenetskaya, I. P.

    2010-04-01

    The method of UV absorption spectroscopy is used to study the influence of the cholesteric pitch on the efficiency of previtamin D (photoisomer of provitamin D 3) cis-trans isomerization in a cholesteric liquid crystal (nematic + optically active dopant + provitamin D 3). It is found that a change in pitch from 14 to 0.364 μm due to an increase in the concentration of an optically active dopant in a wide range (1.6-61 wt %) only slightly reduces the efficiency of the cis-trans isomerization. However, small changes in pitch (0.364-0.368 μm) due to an increase in the provitamin D 3 concentration within the range of 0.07-2.2 wt % significantly increase the efficiency. Reducing in the influence of provitamin D 3 concentration on the cis-trans isomerization efficiency with an increase in mesophase temperature was found in both nematic and cholesteric liquid crystals up to the disappearing of the concentration dependence in the isotropic phase. Altogether, the obtained results indicate the collective character of cis-trans isomerization in liquid crystals due to the ordering of the medium.

  12. Lipopeptide biosurfactant production bacteria Acinetobacter sp. D3-2 and its biodegradation of crude oil.

    PubMed

    Bao, Mutai; Pi, Yongrui; Wang, Lina; Sun, Peiyan; Li, Yiming; Cao, Lixin

    2014-04-01

    In this work, a hydrocarbon-degrading bacterium D3-2 isolated from petroleum contaminated soil samples was investigated for its potential effect in biodegradation of crude oil. The strain was identified as Acinetobacter sp. D3-2 based on morphological, biochemical and phylogenetic analysis. The optimum environmental conditions for growth of the bacteria were determined to be pH 8.0, with a NaCl concentration of 3.0% (w/v) at 30 °C. Acinetobacter sp. D3-2 could utilize various hydrocarbon substrates as the sole carbon and energy source. From this study, we also found that the strain had the ability to produce biosurfactant, with the production of 0.52 g L(-1). The surface tension of the culture broth was decreased from 48.02 to 26.30 mN m(-1). The biosurfactant was determined to contain lipopeptide compounds based on laboratory analyses. By carrying out a crude oil degradation assay in an Erlenmeyer flask experiment and analyzing the hydrocarbon removal rate using gas chromatography, we found that Acinetobacter sp. D3-2 could grow at 30 °C in 3% NaCl solution with a preferable ability to degrade 82% hydrocarbons, showing that bioremediation does occur and plays a profound role during the oil reparation process.

  13. Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease

    PubMed Central

    Grove, Megan L.; Naj, Adam; Vronskaya, Maria; DeStefano, Anita L.; Brody, Jennifer A.; Smith, Albert V.; Amin, Najaf; Sims, Rebecca; Ibrahim-Verbaas, Carla A.; Choi, Seung-Hoan; Lopez, Oscar L.; Beiser, Alexa; Ikram, M. Arfan; Garcia, Melissa E.; Hayward, Caroline; Ripatti, Samuli; Franks, Paul W.; Hallmans, Göran; Rolandsson, Olov; Jansson, Jan-Håkon; Porteous, David J.; Salomaa, Veikko; Eiriksdottir, Gudny; Rice, Kenneth M.; Bellen, Hugo J.; Levy, Daniel; Uitterlinden, Andre G.; Emilsson, Valur; Rotter, Jerome I.; Aspelund, Thor; O’Donnell, Christopher J.; Fitzpatrick, Annette L.; Launer, Lenore J.; Hofman, Albert; Wang, Li-San; Williams, Julie; Schellenberg, Gerard D.; Boerwinkle, Eric; Psaty, Bruce M.; Seshadri, Sudha; Shulman, Joshua M.; Gudnason, Vilmundur; van Duijn, Cornelia M.

    2016-01-01

    We performed an exome-wide association analysis in 1393 late-onset Alzheimer’s disease (LOAD) cases and 8141 controls from the CHARGE consortium. We found that a rare variant (P155L) in TM2D3 was enriched in Icelanders (~0.5% versus <0.05% in other European populations). In 433 LOAD cases and 3903 controls from the Icelandic AGES sub-study, P155L was associated with increased risk and earlier onset of LOAD [odds ratio (95% CI) = 7.5 (3.5–15.9), p = 6.6x10-9]. Mutation in the Drosophila TM2D3 homolog, almondex, causes a phenotype similar to loss of Notch/Presenilin signaling. Human TM2D3 is capable of rescuing these phenotypes, but this activity is abolished by P155L, establishing it as a functionally damaging allele. Our results establish a rare TM2D3 variant in association with LOAD susceptibility, and together with prior work suggests possible links to the β-amyloid cascade. PMID:27764101

  14. 25(OH)D3 Levels Relative to Muscle Strength and Maximum Oxygen Uptake in Athletes

    PubMed Central

    Zagrodna, Aleksandra; Dziubek, Wioletta; Pietraszewski, Bogdan; Ochmann, Bartosz; Słowińska – Lisowska, Małgorzata

    2016-01-01

    Abstract Vitamin D is mainly known for its effects on the bone and calcium metabolism. The discovery of Vitamin D receptors in many extraskeletal cells suggests that it may also play a significant role in other organs and systems. The aim of our study was to assess the relationship between 25(OH)D3 levels, lower limb isokinetic strength and maximum oxygen uptake in well-trained professional football players. We enrolled 43 Polish premier league soccer players. The mean age was 22.7±5.3 years. Our study showed decreased serum 25(OH)D3 levels in 74.4% of the professional players. The results also demonstrated a lack of statistically significant correlation between 25(OH)D3 levels and lower limb muscle strength with the exception of peak torque of the left knee extensors at an angular velocity of 150°/s (r=0.41). No significant correlations were found between hand grip strength and maximum oxygen uptake. Based on our study we concluded that in well-trained professional soccer players, there was no correlation between serum levels of 25(OH)D3 and muscle strength or maximum oxygen uptake. PMID:28149343

  15. Effect of mixed micellar lipid on the absorption of cholesterol and vitamin D3 into lymph

    PubMed Central

    Thompson, Gilbert R.; Ockner, Robert K.; Isselbacher, Kurt J.

    1969-01-01

    The absorption of endogenous cholesterol, labeled with tracer doses of cholesterol 14C or cholesterol-3H and of near physiological doses of vitamin D3-3H was studied in rats with cannulated intestinal lymphatics. The effects of administering mixed micellar solutions of fatty acid, monoglyceride, and bile salt on the absorption of these labeled sterols was determined. It was observed that the specific activity of free cholesterol and the amounts of vitamin D3 appearing in lymph were significantly increased during the intraduodenal administration of mixed micellar solutions of either linoleic or palmitic acid, in contrast to control rats receiving a micellar solution of taurocholate. These increases were related linearly to the lymph triglyceride level. In addition it was observed that when the linoleic acid solution was administered there was a more marked increase in the ratio of the specific activities of free and esterified cholesterol in lymph than with either the palmitic acid or taurocholate solutions. Additional studies in rats with intact lymphatics showed that the uptake of labeled cholesterol and vitamin D3 from the intestinal lumen into the wall was similar whether the sterols were administered in taurocholate or in mixed micellar solution. These findings suggest that mixed micellar lipid increased the rate of appearance of labeled free cholesterol and vitamin D3 in lymph by enhancing their transport out of the intestinal mucosa, rather than by an effect on uptake. PMID:4303790

  16. Biliary excretion of radioactivity after intravenous administration of (3H)25-hydroxyvitamin D3 in man

    SciTech Connect

    Ledger, J.E.; Watson, G.J.; Compston, J.E.

    1986-04-01

    The biliary excretion of radioactivity after intravenous (3H)25-hydroxyvitamin D3 was studied in nine patients with T-tube bile drainage. The mean +/- SD 24-hr radioactivity excretion in T-tube bile expressed as a percentage of the administered dose was 6.7 +/- 2.9%; after correction for incomplete bile collection, the value obtained was 16.0 +/- 11.1%. Chloroform solubility of biliary radioactivity increased from 27.4 +/- 8.9% to 72.9 +/- 10.1% following incubation with beta-glucuronidase. High-performance liquid chromatographic analysis of chloroform extracts of bile revealed that most of the eluted radioactivity was more polar than (3H)25-hydroxyvitamin D3. No free (3H)25-hydroxyvitamin D3 was demonstrated. Thus in man, most of the biliary radioactivity excreted following (3H)25-hydroxyvitamin D3 is in the form of water-soluble compounds, mainly glucuronides. However, our results suggest that glucuronides of metabolites other than 25-OHD3 are predominantly formed.

  17. Effect of spin-polarized D-3He fuel on dense plasma focus for space propulsion

    NASA Astrophysics Data System (ADS)

    Mei-Yu Wang, Choi, Chan K.; Mead, Franklin B.

    1992-01-01

    Spin-polarized D-3He fusion fuel is analyzed to study its effect on the dense plasma focus (DPF) device for space propulsion. The Mather-type plasma focus device is adopted because of the ``axial'' acceleration of the current carrying plasma sheath, like a coaxial plasma gun. The D-3He fuel is chosen based on the neutron-lean fusion reactions with high charged-particle fusion products. Impulsive mode of operation is used with multi-thrusters in order to make higher thrust (F)-to-weight (W) ratio with relatively high value of specific impulse (Isp). Both current (I) scalings with I2 and I8/3 are considered for plasma pinch temperature and capacitor mass. For a 30-day Mars mission, with four thrusters, for example, the typical F/W values ranging from 0.5-0.6 to 0.1-0.2 for I2 and I8/3 scalings, respectively, and the Isp values of above 1600 s are obtained. Parametric studies indicate that the spin-polarized D-3He provides increased values of F/W and Isp over conventional D-3He fuel which was due to the increased fusion power and decreased radiation losses for the spin-polarized case.

  18. Fusion gamma-ray measurements for D-3He experiments at JT-60U

    NASA Astrophysics Data System (ADS)

    Nishitani, T.; Tobita, K.; Kusama, Y.; Shibata, Y.

    2001-01-01

    Fusion gamma rays were measured in D-3He experiments using negative ion-based neutral beam injection (N-NBI) in reverse shear plasmas of the JT-60 tokamak. 3He gas was puffed at plasma initiation and just before N-NB injection. The D-3He reaction produces 3.6 MeV alphas and 14.7 MeV protons, but there is also a small branch which provides 5Li and 16.7 MeV gamma rays. The total D-3He reaction rate can be evaluated from measurement of gamma rays of the 3He (d,γ) 5Li reactions using a 3 in. diam by 3 in. long Bi4Ge3O12 scintillator. The gamma-ray detector was located 17 m below the plasma center and measured the gamma-rays in a vertical line of sight. The detector was mounted inside a heavy collimator with polyethylene and lead shielding. The floor penetration, a 4×8 cm2 hole, was used as a precollimator. Energy calibration of the detector was done with photopeaks for neutron capture gamma rays from the structural materials in D-D discharges. The detection efficiency was calculated with Monte Carlo code MCNP-4B for 16.7 MeV gammas. The pulse height analysis of the gamma rays resulted in the D-3He fusion power of 110±30 kW in this experiment.

  19. A proton activation diagnostic to measure D-3He reaction yields

    NASA Astrophysics Data System (ADS)

    Lierzer, J. R.; Wenzel, K. W.; Petrasso, R. D.; Lo, D. H.; Coleman, J. W.; Li, C. K.; Hsieh, E.; Bernat, T.

    1992-10-01

    We are developing activation diagnostics for monitoring energetic charged-particle fluxes in space and laboratory plasmas. More immediately, we plan to use activation to measure the time-integrated proton flux from D-3He fusion reactions in Alcator C-MOD, providing a measure of the time-averaged D-3He fusion rate. We demonstrated the technique's feasibility by inducing significant gamma activity in a titanium sample exposed to D-3He protons created in our Cockcroft-Walton generator. The titanium target received a fluence of 5.5×109 protons at 14.7 MeV (of order what a 3-cm2 target should receive from one shot in Alcator C-MOD) and became activated by the48Ti(p,n)48V reaction. The activity's spectrum from a high-purity germanium (HPGe) detector showed the characteristic 0.984- and 1.312-MeV lines of 48V. The measured activity agreed reasonably well with theory. An absence of activity at those energies before D-3He activation eliminated background or D-D product-induced activity as the gamma source. We intend to repeat the experiment with a chromium target to evaluate that material's diagnostic potential.

  20. D3 dopamine and kappa opioid receptor alterations in human brain of cocaine-overdose victims.

    PubMed

    Mash, D C; Staley, J K

    1999-06-29

    Cocaine is thought to be addictive because chronic use leads to molecular adaptations within the mesolimbic dopamine (DA) circuitry, which affects motivated behavior and emotion. Although the reinforcing effects of cocaine are mediated primarily by blockade of DA uptake, reciprocal signaling between DA and endogenous opioids has important implications for understanding cocaine dependence. We have used in vitro autoradiography and ligand binding to map D3 DA and kappa opioid receptors in the human brains of cocaine-overdose victims. The number of D3 binding sites was increased one-to threefold over the nucleus accumbens and ventromedial sectors of the caudate and putamen from cocaine-overdose victims, as compared to age-matched and drug-free control subjects. D3 receptor/cyclophilin mRNA ratios in the nucleus accumbens were increased sixfold in cocaine-overdose victims over control values, suggesting that cocaine exposure also affects the expression of D3 receptor mRNA. The number of kappa opioid receptors in the nucleus accumbens and other corticolimbic areas from cocaine fatalities was increased twofold as compared to control values. Cocaine-overdose victims exhibiting preterminal excited delirium had a selective upregulation of kappa receptors measured also in the amygdala. Understanding the complex regulatory profiles of DA and opioid synaptic markers that occur with chronic misuse of cocaine may suggest multitarget strategies for treating cocaine dependence.

  1. Serum calcium level of freshwater snake, Natrix piscator, in response to vitamin D3 administration.

    PubMed

    Srivastav, A K; Srivastav, S P; Srivastav, S K; Swarup, K

    1986-01-01

    The effect of i.m. injection of vitamin D3 (25 IU/100 g b.wt) on serum calcium level was investigated in Natrix piscator. This treatment evokes hypercalcemia at day 3 which progresses up to day 5. Thereafter, a decline was observed in the serum calcium level at day 10 and day 15.

  2. Vitamins D2 and D3 in new world primates: influence on calcium absorption.

    PubMed

    Hunt, R D; Garcia, F G; Hegsted, D M; Kaplinsky, N

    1967-08-25

    In Cebus albifrons monkeys it was demonstrated that vitamin D(3) promotes the intestinal absorption of calcium-47 and that vitamin D(2) does not increase absorption above that seen in monkeys deficient in vitamin D. These data support previous observations that vitamin D(2) is not effective in preventing metabolic bone disease in this species.

  3. Draft Genome Sequence of Williamsia sp. Strain D3, Isolated From the Darwin Mountains, Antarctica

    PubMed Central

    Makhalanyane, Thulani P.; Aislabie, Jackie M.

    2014-01-01

    Actinobacteria are the dominant taxa in Antarctic desert soils. Here, we describe the first draft genome of a member of the genus Williamsia (strain D3) isolated from Antarctic soil. The genome of this psychrotolerant bacterium may help to elucidate crucial survival mechanisms for organisms inhabiting cold desert soil systems. PMID:24459282

  4. Collective States of D(D3) Non-Abelian Anyons

    NASA Astrophysics Data System (ADS)

    Finch, P. E.; Frahm, H.

    2013-11-01

    We study an exactly solvable model of non-Abelian anyons symmetric under the quantum double of the dihedral group D3 on a one-dimensional lattice. Bethe ansatz methods are employed to compute the ground states of this model in different regions of the parameter space. The finite size spectrum is studied and the corresponding low energy field theories are identified.

  5. Dopamine D3 receptors as a therapeutic target for methamphetamine dependence.

    PubMed

    Paterson, Neil E; Vocci, Frank; Sevak, Rajkumar J; Wagreich, Eric; London, Edythe D

    2014-01-01

    Methamphetamine (MA) use disorders are major public health problems nationally and worldwide and treatment remains an unmet need. (1) To review preclinical and clinical studies identifying the dopamine D3 receptor as a therapeutic target for substance use disorders (SUDs), including MA dependence, (2) to consider buspirone (Buspar®) as a potential medication based on its dopamine D3 receptor antagonist properties, and (3) to evaluate the safety and initial efficacy of buspirone in a pilot study of MA-dependent individuals. Literature on the dopamine D3 receptor as a therapeutic target and on the potential of buspirone as a novel therapy for MA dependence was reviewed. The cardiovascular and subjective effects of intravenous MA challenge were assessed in five non-treatment seeking individuals. Participants met DSM-IV criteria for MA dependence and were treated subacutely (9 days) with buspirone (60 mg daily). The literature identified the dopamine D3 receptor as a therapeutic target for MA dependence, a safe and approved medication, and a valuable opportunity to re-purpose buspirone for treating MA dependence and perhaps other SUDs. Pilot data (n = 5) indicated that buspirone is safe in MA-using individuals and comparison against historical placebo data from this laboratory suggested that at least some aspects of the subjective properties of MA may be diminished during buspirone treatment. Future studies should include a small-scale, placebo-controlled Phase IIa trial of buspirone in MA dependence.

  6. Dynamical D4-D8 and D3-D7 branes in supergravity

    SciTech Connect

    Binetruy, Pierre; Sasaki, Misao; Uzawa, Kunihito

    2009-07-15

    We present a class of dynamical solutions for intersecting D4-D8 and D3-D7 brane systems in ten-dimensional type IIA and IIB supergravity. We discuss if these solutions can be recovered in lower-dimensional effective theories for the warped compactification of a general p-brane system. It is found that an effective p+1-dimensional description is not possible in general due to the entanglement of the transverse coordinates and the p+1-dimensional coordinates in the metric components. For the D4-D8 brane system, the dynamical solutions reduces to a static warped AdS{sub 6}xS{sup 4} geometry in a certain spacetime region. For the D3-D7 brane system, we find a dynamical solution whose metric form is similar to that of a D3-brane solution. The main difference is the existence of a nontrivial dilaton configuration in the D3-D7 solution. Then we discuss cosmology of these solutions. We find that they behave like a Kasner-type cosmological solution at {tau}{yields}{infinity}, while it reduces to a warped static solution at {tau}{yields}0, where {tau} is the cosmic time.

  7. Comparison of metabolism of vitamins D2 and D3 in children with nutritional rickets.

    PubMed

    Thacher, Tom D; Fischer, Philip R; Obadofin, Michael O; Levine, Michael A; Singh, Ravinder J; Pettifor, John M

    2010-09-01

    Children with calcium-deficiency rickets may have increased vitamin D requirements and respond differently to vitamin D(2) and vitamin D(3). Our objective was to compare the metabolism of vitamins D(2) and D(3) in rachitic and control children. We administered an oral single dose of vitamin D(2) or D(3) of 1.25 mg to 49 Nigerian children--28 with active rickets and 21 healthy controls. The primary outcome measure was the incremental change in vitamin D metabolites. Baseline serum 25-hydroxyvitamin D [25(OH)D] concentrations ranged from 7 to 24 and 15 to 34 ng/mL in rachitic and control children, respectively (p < .001), whereas baseline 1,25-dihydroxyvitamin D [1,25(OH)(2)D] values (mean ± SD) were 224 ± 72 and 121 ± 34 pg/mL, respectively (p < .001), and baseline 24,25-dihydroxyvitamin D [24,25(OH)(2)D] values were 1.13 ± 0.59 and 4.03 ± 1.33 ng/mL, respectively (p < .001). The peak increment in 25(OH)D was on day 3 and was similar with vitamins D(2) and D(3) in children with rickets (29 ± 17 and 25 ± 11 ng/mL, respectively) and in control children (33 ± 13 and 31 ± 16 ng/mL, respectively). 1,25(OH)(2)D rose significantly (p < .001) and similarly (p = .18) on day 3 by 166 ± 80 and 209 ± 83 pg/mL after vitamin D(2) and D(3) administration, respectively, in children with rickets. By contrast, control children had no significant increase in 1,25(OH)(2)D (19 ± 28 and 16 ± 38 pg/mL after vitamin D(2) and D(3) administration, respectively). We conclude that in the short term, vitamins D(2) and D(3) similarly increase serum 25(OH)D concentrations in rachitic and healthy children. A marked increase in 1,25(OH)(2)D in response to vitamin D distinguishes children with putative dietary calcium-deficiency rickets from healthy children, consistent with increased vitamin D requirements in children with calcium-deficiency rickets. © 2010 American Society for Bone and Mineral

  8. Evolutionary importance for the membrane enhancement of the production of vitamin D3 in the skin of poikilothermic animals.

    PubMed

    Holick, M F; Tian, X Q; Allen, M

    1995-04-11

    The photoproduction of vitamin D in the skin was essential for the evolutionary development of terrestrial vertebrates. During exposure to sunlight, previtamin D3 formed in the skin is isomerized to vitamin D3 (calciol) by a temperature-dependent process. Since early land vertebrates were poikilothermic, the relatively slow conversion of previtamin D3 to vitamin D3 at ambient temperature put them at serious risk for developing vitamin D deficiency, thus leading to a poorly mineralized skeleton that could have ultimately halted further evolutionary development of vertebrates on land. We evaluated the rate of isomerization of previtamin D3 to vitamin D3 in the skin of iguanas and found the isomerization rate was enhanced by 1100% and 1700% at 25 degrees C and 5 degrees C, respectively. It is likely that the membrane entrapment of previtamin D3 in its s-cis,s-cis conformation is responsible for the markedly enhanced conversion of previtamin D3 to vitamin D3. The membrane-enhanced production of vitamin D3 ensures the critical supply of vitamin D3 to poikilothermic animals such as iguanas.

  9. Menthol Enhances an Antiproliferative Activity of 1alpha,25-Dihydroxyvitamin D(3) in LNCaP Cells.

    PubMed

    Park, Eun-Jung; Kim, Su-Hwa; Kim, Byung-Joo; Kim, Sung-Young; So, Insuk; Jeon, Ju-Hong

    2009-03-01

    1alpha,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)], the most active form of vitamin D(3), and its analogues have therapeutic benefits for prostate cancer treatment. However, the development of hypercalcemia is an obstacle to clinical applications of 1alpha,25(OH)(2)D(3) for cancer therapy. In this study, we provide evidence that menthol, a key component of peppermint oil, increases an anti-proliferation activity of 1alpha,25(OH)(2)D(3) in LNCaP prostate cancer cells. We found that menthol per se does not exhibit antiproliferative activity, but it is able to enhance 1alpha,25(OH)(2)D(3)-mediated growth inhibition in LNCaP cells. Fluorometric assays using Fura-2 showed that 1alpha,25(OH)(2)D(3) does not induce acute Ca(2+) response, whereas menthol evokes an increase in [Ca(2+)](i), which suggests that cross-talks of menthol-induced Ca(2+) signaling with 1alpha,25(OH)(2)D(3)-mediated growth inhibition pathways. In addition, Western blot analysis revealed that 1alpha,25(OH)(2)D(3) and menthol cooperatively modulate the expression of bcl-2 and p21 which provides the insight into the molecular mechanisms underlying the enhanced 1alpha,25(OH)(2)D(3)-mediated growth inhibition by menthol. Thus, our findings suggest that menthol may be a useful natural compound to enhance therapeutic effects of 1alpha,25(OH)(2)D(3).

  10. SU-E-T-492: Influence of Clipping PTV in Build-Up Region On IMRT Plan Quality and Deliverability

    SciTech Connect

    Sharma, S; Manigandan, D; Sahai, P; Biswas, A; Subramani, V; Chander, S; Julkha, P; Rath, G

    2015-06-15

    Purpose: To study the influence of clipping PTV from body contour on plan quality and deliverability in build-up region for superficial target. Methods: Five previously treated patients of post-operative carcinoma of parotid were re-planned for IMRT (6MV X-rays, sliding window technique, five fields and 60Gy/30 fractions) using eclipse treatment planning system (TPS) by keeping dose volume constraints and all other parameters constant, only PTV was clipped from body contour by 0mm, 1mm, 2mm and 3mm respectively. Planned fluence was transferred to previously scanned solid water phantom by placing I’matriXX array at 0.5cm depth (2mm slab+3mm inherent). Fluence was delivered by Varian CL2300C/D linac at 99.5cm source to detector distance. Measured fluence was compared with TPS dose plane using 2D gamma evaluation using 3%/3mm DTA criteria. Total MU (monitor unit) required to deliver a plan was also noted. For plan quality, PTV, maximum-dose, minimum-dose, coverage index (CI=PTV volume covered by prescription dose/PTV) and heterogeneity index HI=D5/D95 were analyzed using dose volume histogram (DVH). Results: The Result of gamma function analysis for I’matriXX and TPS were 97.63±1.79%, 97.48±0.99, 98.08±0.89% and 98.01±0.78% at 0.5cm build-up depth for 0, 1, 2 and 3mm PTV clipping, respectively. I’matriXX measured dose was higher compared to TPS. Total MU required for delivering a plan were 552±61, 503±47, 436±24 and 407±22. Maximum-dose to PTV was 6635.80±62.01cGy, 6635.80±40.60cGy, 6608.43±51.07cGy and 6564.20±28.51cGy. Similarly, minimum-dose to PTV was 3306.23±458.56cGy, 3546.57±721.01cGy, 4591.43±298.81cGy and 4861.90±412.40cGy. CI was 0.9347±0.020, 0.9398±0.021, 0.9448±0.022 and 0.9481±0.021. Similarly, HI was 1.089±0.015, 1.084±0.014, 1.078±0.009 and 1.074±0.008 for 0, 1, 2 and 3mm PTV clipping, respectively. Conclusion: Gamma function analysis resulted in almost similar results. However, I’matriXX was overestimating the dose

  11. Downregulation of Runx2 by 1,25-Dihydroxyvitamin D3 Induces the Transdifferentiation of Osteoblasts to Adipocytes

    PubMed Central

    Kim, Jung Ha; Seong, Semun; Kim, Kabsun; Kim, Inyoung; Jeong, Byung-Chul; Kim, Nacksung

    2016-01-01

    1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) indirectly stimulates bone formation, but little is known about its direct effect on bone formation. In this study, we observed that 1,25(OH)2D3 enhances adipocyte differentiation, but inhibits osteoblast differentiation during osteogenesis. The positive role of 1,25(OH)2D3 in adipocyte differentiation was confirmed when murine osteoblasts were cultured in adipogenic medium. Additionally, 1,25(OH)2D3 enhanced the expression of adipocyte marker genes, but inhibited the expression of osteoblast marker genes in osteoblasts. The inhibition of osteoblast differentiation and promotion of adipocyte differentiation mediated by 1,25(OH)2D3 were compensated by Runx2 overexpression. Our results suggest that 1,25(OH)2D3 induces the transdifferentiation of osteoblasts to adipocytes via Runx2 downregulation in osteoblasts. PMID:27213351

  12. Effects of supplemental vitamin D3 on serum 25-hydroxycholecalciferol and growth of preweaning and nursery pigs.

    PubMed

    Flohr, J R; Tokach, M D; Dritz, S S; Derouchey, J M; Goodband, R D; Nelssen, J L; Henry, S C; Tokach, L M; Potter, M L; Goff, J P; Koszewski, N J; Horst, R L; Hansen, E L; Fruge, E D

    2014-01-01

    Four experiments were conducted to investigate the effects of varying concentrations of supplemental vitamin D3 on pig growth, feed preference, serum 25-hydroxycholecalciferol [25(OH)D3] , and bone mineralization of nursing and weanling pigs. In Exp. 1, 270 pigs (1.71 ± 0.01 kg BW) were administered 1 of 3 oral vitamin D3 dosages (none, 40,000, or 80,000 IU vitamin D3) on d 1 or 2 of age. Increasing oral vitamin D3 increased serum 25(OH)D3 on d 10 and 20 (quadratic, P < 0.01) and d 30 (linear, P < 0.01). No differences were observed in ADG before weaning or for nursery ADG, ADFI, or G:F. Vitamin D3 concentration had no effect on bone ash concentration or bone histological traits evaluated on d 19 or 35. In Exp. 2, 398 barrows (initially 7 d of age) were used in a 2 × 2 split plot design to determine the influence of vitamin D3 before (none or 40,000 IU vitamin D3 in an oral dose) or after weaning (1,378 or 13,780 IU vitamin D3/kg in nursery diets from d 21 to 31 of age) in a 45-d trial. Before weaning (7 to 21 d of age), oral vitamin D3 dose did not influence growth but increased (P < 0.01) serum 25(OH)D3 at weaning (d 21) and tended (P = 0.08) to increase 25(OH)D3 on d 31. Increasing dietary vitamin D3 concentration from d 21 to 31 increased (P < 0.01) serum 25(OH)D3 on d 31. Neither the oral vitamin D3 dose nor nursery vitamin D3 supplements influenced nursery ADG, ADFI, or G:F. In Exp. 3, 864 pigs (initially 21 d of age) were allotted to 1 of 2 water solubilized vitamin D3 treatments (none or 16,516 IU/L vitamin D3 provided in the drinking water from d 0 to 10) in a 30-d study. Providing vitamin D3 increased serum 25(OH)D3 concentrations on d 10, 20, and 30; however, vitamin D3 supplementation did not affect overall (d 0 to 30) ADG, ADFI, or G:F. In Exp. 4, 72 pigs were used in a feed preference study consisting of 2 feed preference comparisons. Pigs did not differentiate diets containing either 1,378 or 13,780 IU vitamin D3/kg but consumed less (P < 0.01) of

  13. Serum Vitamin D3 Level in Patients with Female Pattern Hair Loss

    PubMed Central

    Banihashemi, Mahnaz; Nahidi, Yalda; Meibodi, Naser Tayyebi; Jarahi, Lida; Dolatkhah, Mojgan

    2016-01-01

    Background: Female pattern hair loss (FPHL) is the most common cause of alopecia in women, characterized by diffuse nonscarring hair loss in frontal, central, and parietal areas of the scalp. Pathophysiology of FPHL is still not well known, and it is probably a multifactorial genetic trait. FPHL is also observed in women without increased androgen levels, which raises the likelihood of androgen-independent mechanisms and explains the lack of response to antiandrogen treatments in some patients. Vitamin D is a factor that has recently been considered in dealing with these patients. The purpose of this study was to evaluate the serum levels of Vitamin D in patients with FPHL and compare it with healthy controls. Methods: In this case-control study, 45 women with FPHL were evaluated as well as the same number of healthy women matched for age, hours spent under sunlight per day, and body mass index. Serum 25(OH) D3 level was measured using ELISA. Results: 60% of FPHL patients were in 15–30 years old age group with the mean standard deviation (SD) age of 29.11 (7.30) years. In the majority of patients (66.7%), severity of hair loss was Ludwig I. Mean (SD) serum Vitamin D3 level in patient and control group was 13.45 (8.40) and 17.16 (8.96), respectively. T-test showed a significant difference between the two groups in terms of Vitamin D3 serum levels (P = 0.04). Conclusions: This study indicated the correlation between the incidence of FPHL and decreased serum levels of Vitamin D3. It is recommended to evaluate serum Vitamin D3 levels as well as other hormone assays in these patients. PMID:27625563

  14. Immunoregulation of Inflammatory and Inhibitory Cytokines by Vitamin D3 in Patients with Inflammatory Bowel Diseases.

    PubMed

    Alhassan Mohammed, H; Mirshafiey, A; Vahedi, H; Hemmasi, G; Moussavi Nasl Khameneh, A; Parastouei, K; Saboor-Yaraghi, A A

    2017-06-01

    Inflammatory bowel disease (IBD) is a group of idiopathic, chronic and relapsing inflammatory conditions of the gastrointestinal tract, caused by an aberrant and exaggerated immunological response in the gut. Supplementation of vitamin D3 in patients with IBD exerts both direct and indirect regulatory roles on the naïve T cells, thereby maintaining a balance between inflammatory and inhibitory cytokines. The direct actions of vitamin D3 on naïve T cells result in the proliferation of more regulatory T cells and inhibitory cytokines such as IL-4, IL-10 and IL-5. The binding of vitamin D to dendritic cells (DCs) through vitamin D receptors inhibits the action of IL-12 on DCs, resulting in the downregulation of Th1 and Th17. On the other hand, this interaction favours Th2 and Treg upregulation and facilitates the maintenance of immune homoeostasis between inflammatory and inhibitory cytokines which is essentially significant in the management of patients with IBD. The aim of this review was to explore the current and mounting scientific evidence on the roles of vitamin D3 in immunoregulation of inflammatory and inhibitory cytokines in patients with IBDs. An extensive literature search was conducted using keywords such as Vitamin D3*, IBD*, inflammatory cytokines*, inhibitory cytokines*, naïve-T-cells* and antigen presenting cells* through PubMed, SCOPUS and MEDLINE search engines. The results of the accumulated bodies of research that have been conducted demonstrate that vitamin D3 plays a major role not only in the immunoregulation of cytokines involved in the pathogenesis of IBDs but also in many other inflammatory disorders. © 2017 The Foundation for the Scandinavian Journal of Immunology.

  15. Unrecognized vitamin D3 deficiency is common in Parkinson disease: Harvard Biomarker Study.

    PubMed

    Ding, Hongliu; Dhima, Kaltra; Lockhart, Kaitlin C; Locascio, Joseph J; Hoesing, Ashley N; Duong, Karen; Trisini-Lipsanopoulos, Ana; Hayes, Michael T; Sohur, U Shivraj; Wills, Anne-Marie; Mollenhauer, Brit; Flaherty, Alice W; Hung, Albert Y; Mejia, Nicte; Khurana, Vikram; Gomperts, Stephen N; Selkoe, Dennis J; Schwarzschild, Michael A; Schlossmacher, Michael G; Hyman, Bradley T; Sudarsky, Lewis R; Growdon, John H; Scherzer, Clemens R

    2013-10-22

    To conclusively test for a specific association between the biological marker 25-hydroxy-vitamin D3, a transcriptionally active hormone produced in human skin and liver, and the prevalence and severity of Parkinson disease (PD). We used liquid chromatography/tandem mass spectrometry to establish an association specifically between deficiency of 25-hydroxy-vitamin D3 and PD in a cross-sectional and longitudinal case-control study of 388 patients (mean Hoehn and Yahr stage of 2.1 ± 0.6) and 283 control subjects free of neurologic disease nested in the Harvard Biomarker Study. Plasma levels of 25-hydroxy-vitamin D3 were associated with PD in both univariate and multivariate analyses with p values = 0.0034 and 0.047, respectively. Total 25-hydroxy-vitamin D levels, the traditional composite measure of endogenous and exogenous vitamin D, were deficient in 17.6% of patients with PD compared with 9.3% of controls. Low 25-hydroxy-vitamin D3 as well as total 25-hydroxy-vitamin D levels were correlated with higher total Unified Parkinson's Disease Rating Scale scores at baseline and during follow-up. Our study reveals an association between 25-hydroxy-vitamin D3 and PD and suggests that thousands of patients with PD in North America alone may be vitamin D-deficient. This finding has immediate relevance for individual patients at risk of falls as well as public health, and warrants further investigation into the mechanism underlying this association.

  16. Molecular characterization and phylogenetic analysis of full-genome HBV subgenotype D3 sequences from Serbia.

    PubMed

    Stanojević, Boban; Osiowy, Carla; Schaefer, Stephan; Bojović, Ksenija; Blagojević, Jelena; Nešić, Milica; Yamashita, Shunichi; Stamenković, Gorana

    2011-08-01

    Hepatitis B virus (HBV) is classified into 8 genotypes with distinct geographical distribution. Genotype D (HBV/D) has the widest distribution area and is comprised of 7 subgenotypes. Subgenotypes D1, D2 and D3 appear worldwide, while D4-D7 have a more restricted distribution. Within the Mediterranean area, HBV/D and subgenotype D3 are the most prevalent. The purpose of this study was to characterize the full genome of Serbian HBV/D3 isolates by comparison and phylogenetic analysis with HBV/D3 sequences (66 samples) found in GeneBank/DDBJ databases from different parts of the world. Isolates were obtained from three patients diagnosed with chronic hepatitis B (HBsAg+). All three isolates have two very rare nucleotide substitutions, A929T and T150A, which indicate the same ancestor. Phylogenetic analysis of HBV/D3 genome sequences throughout the world follows an ethno-geographical origin of isolates with rare exceptions, which could be explained by human travelling and migration. The geographically close but ethnically different Serbian and Italian isolates clustered in the same subnode, and on a common branch with strains from Northern Canada. To test the apparently close HBV phylogenetic relationship between completely separated patients from Serbia and Northern Canada we analyzed in depth a 440 bp region of the HBsAg from Canadian (n=73) and Serbian (n=70) isolates. The constructed parsimony tree revealed that strains from Serbia and Northern Canada fell along the same branch which indicates independent evolution within regions of each country. Considering that HBsAg sequence has limited variability for phylogenetic analyses, our hypothesis needs further confirmation with more HBV complete genome sequences.

  17. High-Dose Vitamin D3 during Tuberculosis Treatment in Mongolia. A Randomized Controlled Trial.

    PubMed

    Ganmaa, Davaasambuu; Munkhzul, Baatar; Fawzi, Wafaie; Spiegelman, Donna; Willett, Walter C; Bayasgalan, Purev; Baasansuren, Erkhembayar; Buyankhishig, Burneebaatar; Oyun-Erdene, Sereeter; Jolliffe, David A; Xenakis, Theodoros; Bromage, Sabri; Bloom, Barry R; Martineau, Adrian R

    2017-09-01

    Existing trials of adjunctive vitamin D in the treatment of pulmonary tuberculosis (PTB) are variously limited by small sample sizes, inadequate dosing regimens, and high baseline vitamin D status among participants. Comprehensive analyses of the effects of genetic variation in the vitamin D pathway on response to vitamin D supplementation are lacking. To determine the effect of high-dose vitamin D3 on response to antimicrobial therapy for PTB and to evaluate the influence of single-nucleotide polymorphisms (SNPs) in vitamin D pathway genes on response to adjunctive vitamin D3. We conducted a clinical trial in 390 adults with PTB in Ulaanbaatar, Mongolia, who were randomized to receive four biweekly doses of 3.5 mg (140,000 IU) vitamin D3 (n = 190) or placebo (n = 200) during intensive-phase antituberculosis treatment. The intervention elevated 8-week serum 25-hydroxyvitamin D concentrations (154.5 nmol/L vs. 15.2 nmol/L in active vs. placebo arms, respectively; 95% confidence interval for difference, 125.9-154.7 nmol/L; P < 0.001) but did not influence time to sputum culture conversion overall (adjusted hazard ratio, 1.09; 95% confidence interval, 0.86-1.36; P = 0.48). Adjunctive vitamin D3 accelerated sputum culture conversion in patients with one or more minor alleles for SNPs in genes encoding the vitamin D receptor (rs4334089, rs11568820) and 25-hydroxyvitamin D 1α-hydroxylase (CYP27B1: rs4646536) (adjusted hazard ratio ≥ 1.47; P for interaction ≤ 0.02). Vitamin D3 did not influence time to sputum culture conversion in the study population overall. Effects of the intervention were modified by SNPs in VDR and CYP27B1. Clinical trial registered with www.clinicaltrials.gov (NCT01657656).

  18. Vitamin D3 Supplementation and Childhood Diarrhea: A Randomized Controlled Trial

    PubMed Central

    Maroof, Zabihullah; Chandramohan, Daniel; Bruce, Jane; Mughal, M. Zulf; Bhutta, Zulfiqar; Walraven, Gijs; Masher, Mohammad I.; Ensink, Jeroen H.J.; Manaseki-Holland, Semira

    2013-01-01

    OBJECTIVE: To investigate the effect of vitamin D3 supplementation on the incidence and risk for first and recurrent diarrheal illnesses among children in Kabul, Afghanistan. METHODS: This double-blind placebo-controlled trial randomized 3046 high-risk 1- to 11-month-old infants to receive 6 quarterly doses of oral vitamin D3 (cholecalciferol 100 000 IU) or placebo in inner city Kabul. Data on diarrheal episodes (≥3 loose/liquid stools in 24 hours) was gathered through active and passive surveillance over 18 months of follow-up. Time to first diarrheal illness was analyzed by using Kaplan-Meier plots. Incidence rates and hazard ratios (HRs) were calculated by using recurrent event Poisson regression models. RESULTS: No significant difference existed in survival time to first diarrheal illness (log rank P = .55). The incidences of diarrheal episodes were 3.43 (95% confidence interval [CI], 3.28–3.59) and 3.59 per child-year (95% CI, 3.44–3.76) in the placebo and intervention arms, respectively. Vitamin D3 supplementation was found to have no effect on the risk for recurrent diarrheal disease in either intention-to-treat (HR, 1.05; 95% CI, 0.98–1.17; P = .15) or per protocol (HR, 1.05; 95% CI, 0.98–1.12; P = .14) analyses. The lack of preventive benefit remained when the randomized population was stratified by age groups, nutritional status, and seasons. CONCLUSIONS: Quarterly supplementation with vitamin D3 conferred no reduction on time to first illness or on the risk for recurrent diarrheal disease in this study. Similar supplementation to comparable populations is not recommended. Additional research in alternative settings may be helpful in elucidating the role of vitamin D3 supplementation for prevention of diarrheal diseases. PMID:24019420

  19. Serum Vitamin D3 Level in Patients with Female Pattern Hair Loss.

    PubMed

    Banihashemi, Mahnaz; Nahidi, Yalda; Meibodi, Naser Tayyebi; Jarahi, Lida; Dolatkhah, Mojgan

    2016-01-01

    Female pattern hair loss (FPHL) is the most common cause of alopecia in women, characterized by diffuse nonscarring hair loss in frontal, central, and parietal areas of the scalp. Pathophysiology of FPHL is still not well known, and it is probably a multifactorial genetic trait. FPHL is also observed in women without increased androgen levels, which raises the likelihood of androgen-independent mechanisms and explains the lack of response to antiandrogen treatments in some patients. Vitamin D is a factor that has recently been considered in dealing with these patients. The purpose of this study was to evaluate the serum levels of Vitamin D in patients with FPHL and compare it with healthy controls. In this case-control study, 45 women with FPHL were evaluated as well as the same number of healthy women matched for age, hours spent under sunlight per day, and body mass index. Serum 25(OH) D3 level was measured using ELISA. 60% of FPHL patients were in 15-30 years old age group with the mean standard deviation (SD) age of 29.11 (7.30) years. In the majority of patients (66.7%), severity of hair loss was Ludwig I. Mean (SD) serum Vitamin D3 level in patient and control group was 13.45 (8.40) and 17.16 (8.96), respectively. T-test showed a significant difference between the two groups in terms of Vitamin D3 serum levels (P = 0.04). This study indicated the correlation between the incidence of FPHL and decreased serum levels of Vitamin D3. It is recommended to evaluate serum Vitamin D3 levels as well as other hormone assays in these patients.

  20. Solar UV Doses of Young Americans and Vitamin D3 Production

    PubMed Central

    Pope, Stanley James; Grant, William Burgess; Holick, Michael Francis

    2011-01-01

    Background: Sunlight contains ultraviolet B (UVB) radiation (290–315 nm) that affects human health in both detrimental (skin cancers) and beneficial (vitamin D3) ways. Serum 25-hydroxyvitamin D concentrations from young Americans (≤ 19 years) show that many have deficient (< 50 nmol/L, 20 ng/mL) or insufficient (< 75 nmol/L, 30 ng/mL) vitamin D levels, indicating that they are not getting enough sun exposure. Those findings are in conflict with some calculated, published values that suggest people make “ample” vitamin D3 (~ 1,000 IU/day) from their “casual,” or everyday, outdoor exposures even if they diligently use sunscreens with sun protection factor (SPF) 15. Objective: We estimated how much vitamin D3 young Americans (n = ~ 2,000) produce from their everyday outdoor ultraviolet doses in the North (45°N) and South (35°N) each season of the year with and without vacationing. Methods: For these vitamin D3 calculations, we used geometric conversion factors that change planar to whole-body doses, which previous calculations did not incorporate. Results: Our estimates suggest that American children may not be getting adequate outdoor UVB exposures to satisfy their vitamin D3 needs all year, except some Caucasians during the summer if they do not diligently wear sunscreens except during beach vacations. Conclusion: These estimates suggest that most American children may not be going outside enough to meet their minimal (~ 600 IU/day) or optimal (≥ 1,200 IU/day) vitamin D requirements. PMID:21852226

  1. 25-Hydroxyvitamin D3 Deficiency Independently Predicts Cognitive Impairment in Patients with Systemic Lupus Erythematosus

    PubMed Central

    Tay, Sen Hee; Ho, Chung Shun; Ho, Roger Chun-Man; Mak, Anselm

    2015-01-01

    Objectives Cognitive dysfunction has been reported in 20–80% of SLE patients. Converging evidence has indicated the importance of vitamin D as a neuroimmunomodulator for cognitive function. In this study, we evaluated the relationship between vitamin D and cognitive dysfunction. Methods Consecutive age- and gender-matched SLE patients and healthy controls (HCs) were administered Automated Neuropsychological Assessment Metrics in this cross-sectional study. The primary outcome was the total throughput score (TTS). Anxiety and depression were measured using the Hospital Anxiety and Depression Scale (HADS). Levels of 25-hydroxyvitamin D [25(OH)D3 and total 25(OH)D] were measured using Liquid Chromatography-Tandem Mass Spectrometry. Results In total, 61 SLE patients and 61 HCs were studied. SLE patients scored significantly lower than HCs in the TTS (p = 0.004). There were no statistically significant differences in 25(OH)D3 levels, total 25(OH)D levels and total 25(OH)D deficiency between SLE patients and HCs. However, more SLE patients had 25(OH)D3 deficiency compared to HCs [12 (19.7%) versus 2 (3.3%), p = 0.003]. Deficiency of 25(OH)D3 (β = -63.667, SE = 27.456, p = 0.025), but not other vitamin D variables, independently predicted worse TTS after adjusting for age, education, gender, ethnicity, HADS-Total, duration of SLE, SELENA-SLEDAI, SLICC/ACR Damage Index and cumulative steroid dose in SLE patients. Age (β = -4.261, SE = 0.866, p < 0.001) was the only predictor of TTS after adjusting for education, gender, ethnicity, HADS-Total, vitamin D levels or status in HCs. Conclusions Deficiency of 25(OH)D3, a potentially modifiable risk factor, independently predicted cognitive impairment in SLE patients. PMID:26636681

  2. 1α,25-Dihydroxyvitamin D3 Regulates Mitochondrial Oxygen Consumption and Dynamics in Human Skeletal Muscle Cells.

    PubMed

    Ryan, Zachary C; Craig, Theodore A; Folmes, Clifford D; Wang, Xuewei; Lanza, Ian R; Schaible, Niccole S; Salisbury, Jeffrey L; Nair, K Sreekumaran; Terzic, Andre; Sieck, Gary C; Kumar, Rajiv

    2016-01-15

    Muscle weakness and myopathy are observed in vitamin D deficiency and chronic renal failure, where concentrations of the active vitamin D3 metabolite, 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3), are low. To evaluate the mechanism of action of 1α,25(OH)2D3 in skeletal muscle, we examined mitochondrial oxygen consumption, dynamics, and biogenesis and changes in expression of nuclear genes encoding mitochondrial proteins in human skeletal muscle cells following treatment with 1α,25(OH)2D3. The mitochondrial oxygen consumption rate (OCR) increased in 1α,25(OH)2D3-treated cells. Vitamin D3 metabolites lacking a 1α-hydroxyl group (vitamin D3, 25-hydroxyvitamin D3, and 24R,25-dihydroxyvitamin D3) decreased or failed to increase OCR. 1α-Hydroxyvitamin D3 did not increase OCR. In 1α,25(OH)2D3-treated cells, mitochondrial volume and branching and expression of the pro-fusion protein OPA1 (optic atrophy 1) increased, whereas expression of the pro-fission proteins Fis1 (fission 1) and Drp1 (dynamin 1-like) decreased. Phosphorylated pyruvate dehydrogenase (PDH) (Ser-293) and PDH kinase 4 (PDK4) decreased in 1α,25(OH)2D3-treated cells. There was a trend to increased PDH activity in 1α,25(OH)2D3-treated cells (p = 0.09). 83 nuclear mRNAs encoding mitochondrial proteins were changed following 1α,25(OH)2D3 treatment; notably, PDK4 mRNA decreased, and PDP2 mRNA increased. MYC, MAPK13, and EPAS1 mRNAs, which encode proteins that regulate mitochondrial biogenesis, were increased following 1α,25(OH)2D3 treatment. Vitamin D receptor-dependent changes in the expression of 1947 mRNAs encoding proteins involved in muscle contraction, focal adhesion, integrin, JAK/STAT, MAPK, growth factor, and p53 signaling pathways were observed following 1α,25(OH)2D3 treatment. Five micro-RNAs were induced or repressed by 1α,25(OH)2D3. 1α,25(OH)2D3 regulates mitochondrial function, dynamics, and enzyme function, which are likely to influence muscle strength. © 2016 by The American Society

  3. Effects of supplemental vitamin D3 on feed intake, carcass characteristics, tenderness, and muscle properties of beef steers.

    PubMed

    Karges, K; Brooks, J C; Gill, D R; Breazile, J E; Owens, F N; Morgan, J B

    2001-11-01

    Research was conducted to determine the effects of supplemental dietary vitamin D3 on DMI, carcass traits, Warner Bratzler shear (WBS) force, calpastatin activity, plasma minerals, pH (0, 3, 12, and 24 h after slaughter), water-holding capacity (WHC), and sensory characteristics of three muscles. Pre-slaughter vitamin D3 treatments included no supplemental vitamin D3, 6 x 106 IU (MIU) of vitamin D3 for 4 d, or 6 MIU of vitamin D3 for 6 d. Cattle were slaughtered and carcasses were chilled for 48 h before removal of steaks from the longissimus, gluteus medius, and biceps femoris muscles. Steaks were aged at 2 degrees C for 7, 14, or 21 d before cooking to a final internal temperature of 70 degrees C for WBS and sensory panel analysis. Dry matter intake was lower for steers supplemented with vitamin D3 for 4 or 6 d. Live and carcass weights were lower (P < 0.05) in steers supplemented with vitamin D3. Supplementing 6 MIU/6 d of vitamin D3 decreased (P < 0.05) WBS values of gluteus steaks (pooled over aging times). Longissimus steaks from steers supplemented with vitamin D3 for 6 d had lower (P < 0.05) WBS force values than these steaks from control steers or steers fed vitamin D3 for 4 d at 7 d postmortem. Biceps femoris steaks from steers receiving vitamin D3 for 4 d had higher WBS values than steaks from control steers at 14 and 21 d postmortem. Feeding vitamin D3 at 6 MIU for 6 d decreased (P < 0.05) the percentage of steaks that had WBS values > or = 3.86 kg for all steaks. Feeding vitamin D3 had no effect on palatability traits evaluated by trained panelists. Blood Ca concentrations were greater (P < 0.05) when vitamin D3 was fed and with increased vitamin D3 feeding time. Feeding vitamin D3 for 6 d (vs 4 d) delayed pH decline for all muscle types after 0, 3, and 12 h postmortem. Water-holding capacity was increased (P > 0.02) after 0 h, 24 h, and 21 d postmortem when vitamin D3 was fed and was greater at 0 and 24 h if vitamin D3 was fed for 6 d rather than 4 d

  4. 1α,25-Dihydroxyvitamin D3 Regulates Mitochondrial Oxygen Consumption and Dynamics in Human Skeletal Muscle Cells*

    PubMed Central

    Ryan, Zachary C.; Craig, Theodore A.; Folmes, Clifford D.; Wang, Xuewei; Lanza, Ian R.; Schaible, Niccole S.; Salisbury, Jeffrey L.; Nair, K. Sreekumaran; Terzic, Andre; Sieck, Gary C.; Kumar, Rajiv

    2016-01-01

    Muscle weakness and myopathy are observed in vitamin D deficiency and chronic renal failure, where concentrations of the active vitamin D3 metabolite, 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3), are low. To evaluate the mechanism of action of 1α,25(OH)2D3 in skeletal muscle, we examined mitochondrial oxygen consumption, dynamics, and biogenesis and changes in expression of nuclear genes encoding mitochondrial proteins in human skeletal muscle cells following treatment with 1α,25(OH)2D3. The mitochondrial oxygen consumption rate (OCR) increased in 1α,25(OH)2D3-treated cells. Vitamin D3 metabolites lacking a 1α-hydroxyl group (vitamin D3, 25-hydroxyvitamin D3, and 24R,25-dihydroxyvitamin D3) decreased or failed to increase OCR. 1α-Hydroxyvitamin D3 did not increase OCR. In 1α,25(OH)2D3-treated cells, mitochondrial volume and branching and expression of the pro-fusion protein OPA1 (optic atrophy 1) increased, whereas expression of the pro-fission proteins Fis1 (fission 1) and Drp1 (dynamin 1-like) decreased. Phosphorylated pyruvate dehydrogenase (PDH) (Ser-293) and PDH kinase 4 (PDK4) decreased in 1α,25(OH)2D3-treated cells. There was a trend to increased PDH activity in 1α,25(OH)2D3-treated cells (p = 0.09). 83 nuclear mRNAs encoding mitochondrial proteins were changed following 1α,25(OH)2D3 treatment; notably, PDK4 mRNA decreased, and PDP2 mRNA increased. MYC, MAPK13, and EPAS1 mRNAs, which encode proteins that regulate mitochondrial biogenesis, were increased following 1α,25(OH)2D3 treatment. Vitamin D receptor-dependent changes in the expression of 1947 mRNAs encoding proteins involved in muscle contraction, focal adhesion, integrin, JAK/STAT, MAPK, growth factor, and p53 signaling pathways were observed following 1α,25(OH)2D3 treatment. Five micro-RNAs were induced or repressed by 1α,25(OH)2D3. 1α,25(OH)2D3 regulates mitochondrial function, dynamics, and enzyme function, which are likely to influence muscle strength. PMID:26601949

  5. QM Computations on Complete Nucleic Acids Building Blocks: Analysis of the Sarcin-Ricin RNA Motif Using DFT-D3, HF-3c, PM6-D3H, and MM Approaches.

    PubMed

    Kruse, Holger; Havrila, Marek; Šponer, Jiřı

    2014-06-10

    A set of conformations obtained from explicit solvent molecular dynamics (MD) simulations of the Sarcin-Ricin internal loop (SRL) RNA motif is investigated using quantum mechanical (QM, TPSS-D3/def2-TZVP DFT-D3) and molecular mechanics (MM, AMBER parm99bsc0+χol3 force field) methods. Solvent effects are approximated using implicit solvent methods (COSMO for DFT-D3; GB and PB for MM). Large-scale DFT-D3 optimizations of the full 11-nucleotide motif are compared to MM results and reveal a higher flexibility of DFT-D3 over the MM in the optimization procedure. Conformational energies of the SRL motif expose significant differences in the DFT-D3 and MM energy descriptions that explain difficulties in MD simulations of the SRL motif. The TPSS-D3 data are in excellent agreement with results obtained by the hybrid functionals PW6B95-D3 and M06-2X. Computationally more efficient methods such as PM6-D3H and HF-3c show promising but partly inconsistent results. It is demonstrated that large-scale DFT-D3 computations on complete nucleic acids building blocks are a viable tool to complement the picture obtained from MD simulations and can be used as benchmarks for faster computational methods. Methodological challenges of large-scale QM computations on nucleic acids such as missing solvent-solute interactions and the truncation of the studied systems are discussed.

  6. P elements inserted in the vicinity of or within the Drosophila snRNP SmD3 gene nested in the first intron of the Ornithine Decarboxylase Antizyme gene affect only the expression of SmD3.

    PubMed Central

    Schenkel, Heide; Hanke, Susanne; De Lorenzo, Cécilia; Schmitt, Rolf; Mechler, Bernard M

    2002-01-01

    The Drosophila gene for snRNP SmD3 (SmD3) is contained in reverse orientation within the first intron of the Ornithine Decarboxylase Antizyme (AZ) gene. Previous studies show that two closely linked P elements cause the gutfeeling phenotype characterized by embryonic lethality and aberrant neuronal and muscle cell differentiation. However, the exact nature of the gene(s) affected in the gutfeeling phenotype remained unknown. This study shows that a series of P inserts located within the 5'-untranslated region (5'-UTR) of SmD3 or its promoter affects only the expression of SmD3. Our analysis reveals that the gutfeeling phenotype associ