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. 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…

  3. 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.

  4. 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.

  5. Leveraging the Deliverance Phenomenon: Penteco/Charismatic Vista.

    PubMed

    Asamoah, Moses Kumi

    2016-10-01

    This article reflects on the deliverance concept within Classical Pentecostalism and Neo-Pentecostalism against historical and contemporary considerations. The research design combined ethnography and case study. Participant observation and in-depth interviews were used for data collection. Findings include: overstretched demonic mentality; the notion that the Penteco/Charismatic believer cannot be possessed but could be harassed by demons; and dehumanizing situations inherent in deliverance practice. It is recommended that sanity, care and collaboration be established amongst deliverance practitioners, psychologists, psychiatrists, professional counsellors as well as other business experts to ensure a holistic deliverance practice and also to enhance the dignity and value of the deliverance ministry in Ghana and Africa at large. PMID:26912091

  6. 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 UNDER THE ENERGY POLICY AND CONSERVATION ACT (âAPPLIANCE LABELING RULEâ) Pt. 305, App. D3 Appendix D3...

  7. Deliverable water from small NEOs to DRLO

    NASA Astrophysics Data System (ADS)

    Jedicke, Robert; Sercel, Joel; Morenz, Karen; Gertsch, Leslie S.

    2015-11-01

    We have developed a simplified mission model to estimate the quantity of deliverable water from small NEOs to distant retrograde lunar orbit (DRLO) as a function of Earth-return trip time and Δv. Our model is designed to be analytically simple, computationally efficient, and close enough to optimal to provide a realistic but conservative assessment of the relevant parameters. The challenge stems from the fact that we are not considering a mission to a specific, known target, but rather missions to the ensemble of NEOs in a model population. To further simplify the analysis we treat Earth's heliocentric orbit as circular with a semi-major axis of 1 au and zero inclination.

  8. [Active vitamin D3 analog].

    PubMed

    Takata, Shinjiro

    2015-10-01

    Vitamin D is a fat-soluble vitamin and exerts effects on skeletal and extraskeletal health in children and adults of all ages. Vitamin D insufficiency is related to low muscle strength, increasing body sway, falls in the elderly. Supplementation with vitamin D reduces risk of osteoporotic fracture, and improves muscle strength and postural balance to prevent the elderly from fall. The preferred vitamin D analog for daily supplementation is cholecalciferol (vitamin D3). The active form of vitamin D3 is 1,25-dihydroxy-vitamin D3. Alfacalcidol, calcitriol and eldecalcitol are used to treat osteoporosis in Japan. Randomized placebo-controlled, double-blinded clinical trial for osteoporotic subjects showed that eldecalcitol is more efficacious to increase bone mineral density and prevent vertebral and wrist fractures in osteoporotic patients with vitamin D sufficiency than alfacalcidol. PMID:26529933

  9. 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.

  10. 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

  11. Vitamin D3 and D3 metabolites in young goats fed varying amounts of calcium and vitamin D3.

    PubMed

    Hines, T G; Horst, R L; Littledike, E T; Beitz, D C; Jacobson, N L

    1986-02-01

    Twenty-four male goats, 2 to 4 wk of age, were allotted to four dietary treatments in a 2 X 2 factorial design and, for 20 wk, were fed a milk diet at 12.5% body weight. Treatments varied in amounts of supplemental calcium and vitamin D3. Daily allowances per kilogram body weight were: 9.4 IU vitamin D3 (basal), 9.4 IU vitamin D3 plus 406 mg calcium carbonate (basal plus Ca), 940 IU vitamin D3 (basal plus D3), and 940 IU vitamin D3 plus 406 mg calcium carbonate (basal plus Ca plus D3). At the end of wk 7, a corn supplement was added to all diets at 1% body weight daily. Addition of vitamin D3 to the diet resulted in a dramatic increase in plasma concentrations of vitamin D3. Goats in the basal plus D3 and basal plus Ca plus D3 groups had nearly 100 X greater concentrations of vitamin D3 than goats in the basal and basal plus Ca groups. When greater amounts of vitamin D3 were fed, dietary calcium interacted to decrease plasma vitamin D3 concentrations. Plasma concentrations of 25-hydroxyvitamin D3 were unaffected by additional dietary calcium but were increased by dietary vitamin D3, increasing sixfold to seven-fold in the basal plus D3 and basal plus Ca plus D3 groups. Supplemental calcium resulted in decreased plasma 1,25-dihydroxyvitamin D3. No signs of vitamin D toxicity were noted. The physiological responses reported implicate the goat as a potential animal model for vitamin D research in dairy cattle. PMID:3009577

  12. Transuranic Waste Program Framework Agreement - December Deliverable July 2012

    SciTech Connect

    Jones, Patricia

    2012-07-19

    Framework agreement deliverables are: (1) 'DOE/NNSA commits to complete removal of all non-cemented above-ground EM Legacy TRU and newly generated TRU currently-stored at Area G as of October 1, 2011, by no later than June 30, 2014. This inventory of above-ground TRU is defined as 3706 cubic meters of material.' (2) 'DOE commits to the complete removal of all newly generated TRU received in Area G during FY 2012 and 2013 by no later than December 31, 2014.' (3) 'Based on projected funding profiles, DOE/NNSA will develop by December 31, 2012, a schedule, including pacing milestones, for disposition of the below-ground TRU requiring retrieval at Area G.' Objectives are to: (1) restore the 'Core Team' to develop the December, 2012 deliverable; (2) obtain agreement on the strategy for below ground water disposition; and (3) establish timeline for completion of the deliverable. Below Grade Waste Strategy is to: (1) Perform an evaluation on below grade waste currently considered retrievable TRU; (2) Only commit to retrieve waste that must be retrieved; (3) Develop the Deliverable including Pacing Milestones based on planned commitments; (4) Align all Regulatory Documents for Consistency; and (5) answer these 3 primary questions, is the waste TRU; is the waste retrievable, can retrieval cause more harm than benefit?

  13. Policy.

    ERIC Educational Resources Information Center

    Evans, Judith L.; And Others

    1995-01-01

    This theme issue is devoted to discussions of early childhood policy issues. "Creating a Shared Vision: How Policy Affects Early Childhood Care and Development" (Judith L. Evans) defines policy, discusses the motivation for changing or creating national policy and the process for changing such policies, and provides a sample design for an early…

  14. 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...

  15. 7 CFR 15d.3 - Compliance.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 7 Agriculture 1 2012-01-01 2012-01-01 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...

  16. 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...

  17. 7 CFR 15d.3 - Compliance.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 7 Agriculture 1 2011-01-01 2011-01-01 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...

  18. 7 CFR 15d.3 - Compliance.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 1 2014-01-01 2014-01-01 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...

  19. Vitamin D3 toxicity in dairy cows.

    PubMed

    Littledike, E T; Horst, R L

    1982-05-01

    Large parenteral doses of vitamin D3 (15 to 17.5 x 10(6) IU vitamin D3) were associated with prolonged hypercalcemia, hyperphosphatemia, and large increases of vitamin D3 and its metabolites in the blood plasma of nonlactating nonpregnant and pregnant Jersey cows. Calcium concentrations 1 day postpartum were higher in cows treated with vitamin D3 about 32 days prepartum (8.8 mg/100 ml) than in control cows (5.5 mg/100 ml). None of the cows treated with vitamin D3 showed signs of milk fever during the peripartal period; however, 22% of the control cows developed clinical signs of milk fever during this period. Signs of vitamin D3 toxicity were not observed in nonlactating nonpregnant cows; however, pregnant cows commonly developed severe signs of vitamin D3 toxicity and 10 of 17 cows died. There was widespread metastatic calcification in the cows that died. Because of the extreme toxicity of vitamin D3 in pregnant Jersey cows and the low margin of safety between doses of vitamin D3 that prevent milk fever and doses that induce milk fever, we concluded that vitamin D3 cannot be used practically to prevent milk fever when injected several weeks prepartum. PMID:6286738

  20. Effects of vitamin D3, 25-hydroxyvitamin D3, and 24,25-dihydroxyvitamin D3 on parathyroid hormone secretion.

    PubMed

    Cantley, L K; Russell, J B; Lettieri, D S; Sherwood, L M

    1987-07-01

    The active vitamin D metabolite 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] causes marked suppression of both pre-proparathyroid hormone messenger RNA (pre-proPTH mRNA) and parathyroid hormone (PTH) secretion. These effects are dose dependent and reversible when tested in an in vitro primary tissue culture cell system using normal bovine parathyroid cells. In the current studies, the precursors of 1,25(OH)2D3 and the related metabolite 24,25-dihydroxyvitamin D3 [24,25(OH)2D3], were used in the same culture system to test for possible regulatory effects. The results were compared with identically prepared cells exposed to 1,25(OH)2D3. In short-term studies (30-120 minutes), none of the vitamin D-related compounds produced any effect on PTH secretion. In long-term studies (24-48 hours, using primary tissue culture in the presence of test agents), neither vitamin D3 nor 25(OH)D3 affected PTH secretion or pre-proPTH mRNA over the concentration range 10(-11)-10(-7) M. On the other hand, 24,25(OH)2D3 produced significant suppression of both pre-proPTH mRNA (77% of control, P less than .01) and PTH secretion (75% of control, P less than .005) at 10(-7) M. By comparison, 10(-11) M 1,25(OH)2D3 produced levels of suppression (25-30%) of both pre-proPTH mRNA and PTH secretion comparable to 10(-7) M 24,25(OH)2D3, while even greater suppression (40-50%) occurred at 10(-9)-10(-7) M 1,25(OH)2D3. From these studies, we conclude that vitamin D3 and 25(OH)D3 do not have significant effects on PTH synthesis and secretion over the range of doses tested.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3040201

  1. Natural Gas Deliverability Task Force report: A joint FERC/DOE project. [Contains glossary

    SciTech Connect

    Not Available

    1992-09-01

    The purpose of the FERC/DOE Natural Gas Deliverability Task Force Report was threefold: (1) to review current deliverability data for utility, accuracy, and timeliness; (2) to identify mechanisms for closing significant gaps in information resulting from changing market structures; and (3) to ensure that technologies are available to meet the needs of the emerging, competitive natural gas industry.

  2. 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.

  3. 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 projec&tacute;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.

  4. Vitamin D3 and brain development.

    PubMed

    Eyles, D; Brown, J; Mackay-Sim, A; McGrath, J; Feron, F

    2003-01-01

    Evidence for the presence of the vitamin D receptor in brain implies this vitamin may have some function in this organ. This study investigates whether vitamin D(3) acts during brain development. We demonstrate that rats born to vitamin D(3)-deficient mothers had profound alterations in the brain at birth. The cortex was longer but not wider, the lateral ventricles were enlarged, the cortex was proportionally thinner and there was more cell proliferation throughout the brain. There were reductions in brain content of nerve growth factor and glial cell line-derived neurotrophic factor and reduced expression of p75(NTR), the low-affinity neurotrophin receptor. Our findings would suggest that low maternal vitamin D(3) has important ramifications for the developing brain. PMID:12710973

  5. [Vitamin D3 poisoning--case report].

    PubMed

    Heinritzi, K; Hänichen, T; Rambeck, W; Hermanns, W

    2000-12-01

    Over 650 pigs died within a couple hours in a fattening unit with approximately 3,000 fattening spaces. The pigs showed vomiting, dyspnea, kyphosis, sunken flanks, diarrhea, and polyuria. Another striking symptom of the pigs, besides the apathy, was the aphonia, due to the calcification of the vocal cords. An acute vitamin D3-intoxication was found to be the cause. The pathologic findings, especially the histologic detection of calcification processes of the soft tissues, lead to the suspect of an intoxication with a vitamin D-like substance. Between 39,000 and 196,000 IU/kg of vitamin D3 have been detected in a ready-to-use food mix. 8.8 million IU/kg of crystaline vitamin D3 were found in an open whey bag. An explanation how vitamin D came into the bag could not be clarified to this point. PMID:11155516

  6. Resolvin D3 and Aspirin-Triggered Resolvin D3 Are Protective for Injured Epithelia.

    PubMed

    Colby, Jennifer K; Abdulnour, Raja-Elie E; Sham, Ho Pan; Dalli, Jesmond; Colas, Romain A; Winkler, Jeremy W; Hellmann, Jason; Wong, Blenda; Cui, Ye; El-Chemaly, Souheil; Petasis, Nicos A; Spite, Matthew; Serhan, Charles N; Levy, Bruce D

    2016-07-01

    Acute lung injury is a life-threatening condition caused by disruption of the alveolar-capillary barrier leading to edema, influx of inflammatory leukocytes, and impaired gas exchange. Specialized proresolving mediators biosynthesized from essential fatty acids, such as docosahexaenoic acid, have tissue protective effects in acute inflammation. Herein, we found that the docosahexaenoic acid-derived mediator resolvin D3 (RvD3): 4S,11R,17S-trihydroxydocosa-5Z,7E,9E,13Z,15E,19Z-hexaenoic acid was present in uninjured lungs, and increased significantly 24 to 72 hours after hydrochloric acid-initiated injury. Because of its delayed enzymatic degradation, we used aspirin-triggered (AT)-RvD3: 4S,11R,17R-trihydroxydocosa-5Z,7E,9E,13Z,15E,19Z-hexaenoic acid, a 17R-epimer of RvD3, for in vivo experiments. Histopathological correlates of acid injury (alveolar wall thickening, edema, and leukocyte infiltration) were reduced in mice receiving AT-RvD3 1 hour after injury. AT-RvD3-treated mice had significantly reduced edema, as demonstrated by lower wet/dry weight ratios, increased epithelial sodium channel γ expression, and more lymphatic vessel endothelial hyaluronan receptor 1-positive vascular endothelial growth factor receptor 3-positive lymphatic vessels. Evidence for counterregulation of NF-κB by RvD3 and AT-RvD3 was seen in vitro and by AT-RvD3 in vivo. Increases in lung epithelial cell proliferation and bronchoalveolar lavage fluid levels of keratinocyte growth factor were observed with AT-RvD3, which also promoted cutaneous re-epithelialization. Together, these data demonstrate protective actions of RvD3 and AT-RvD3 for injured mucosa that accelerated restoration of epithelial barrier and function. PMID:27171898

  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. Deliverable navigation for multicriteria step and shoot IMRT treatment planning

    PubMed Central

    Craft, David; Richter, Christian

    2012-01-01

    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. PMID:23221364

  9. 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.

  10. "Scrubbing" Data for D3M

    ERIC Educational Resources Information Center

    Mercurius, Neil

    2005-01-01

    Data-driven decision-making (D3M) appears to be the new buzz phrase for this century, the information age. On the education front, teachers and administrators are engaging in data-centered dialog in grade-level meetings, lounges, hallways, and classrooms as they brainstorm toward closing the gap in student achievement. Clearly, such discussion…

  11. 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...

  12. 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...

  13. 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...

  14. 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...

  15. 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...

  16. Vitamin D3 in Fat Tissue

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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) metho...

  17. 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

  18. Effective hydrodynamics of black D3-branes

    NASA Astrophysics Data System (ADS)

    Emparan, Roberto; Hubeny, Veronika E.; Rangamani, Mukund

    2013-06-01

    The long-wavelength effective field theory of world-volume fluctuations of black D3-branes is shown to be a hydrodynamical system to leading order in a gradient expansion. We study the system on a fiducial `cutoff' surface: the fluctuating geometry imprints its dynamics on the surface via an induced stress tensor whose conservation encapsulates the hydrodynamical description. For a generic non-extremal D3-brane, as we move our cutoff surface from the asymptotically flat near-boundary region to the near-horizon region, this hydrodynamical system interpolates between a non-conformal relativistic fluid and a non-relativistic incompressible fluid. We also consider the dependence on the deviation from extremality of the D3-branes. In the near-extremal case we recover the description in terms of a conformal relativistic fluid encountered in the AdS/CFT context. We argue that this system allows us therefore to explore the various connections that have hitherto been suggested relating the dynamics of gravitational systems and fluid dynamics. In particular, we go on to show that the blackfold effective field theory approach allows us to capture this hydrodynamical behaviour and moreover subsumes the constructions encountered in the fluid/gravity correspondence and the black hole membrane paradigm, providing thereby a universal language to explore the effective dynamics of black branes.

  19. 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

  20. 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.

  1. 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.

  2. Human keratinocyte line HaCaT metabolizes 1alpha-hydroxyvitamin D3 and vitamin D3 to 1alpha,25-dihydroxyvitamin D3 (calcitriol).

    PubMed

    Lehmann, B; Pietzsch, J; Kämpf, A; Meurer, M

    1998-11-01

    Cultured human keratinocytes have the property to hydroxylate exogenous 25-hydroxyvitamin D3 (25OHD3) at the C-1alpha position thus producing 1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3). In this study we investigated whether keratinocytes can also hydroxylate vitamin D3 and one of its metabolites at the C-25 position. We could demonstrate that HaCaT keratinocytes can metabolize 1alpha-hydroxyvitamin D3 (1alpha-OHD3) and vitamin D3 to 1alpha,25(OH)2D3. Identification of the generated product as 1alpha,25(OH)2D3 was based on its elution pattern in two different high performance liquid chromatography systems, on its specific binding in a calf thymus receptor assay and on its gas chromatography-mass spectrometry characteristics. The hydroxylation of vitamin D3 to 1alpha,25(OH)2D3 was dose- and time-dependent. Bovine serum albumin added up to 1.5% (w/v) to the culture medium greatly increased the hydroxylation rates. These results show that HaCaT cells have the capacity to hydroxylate vitamin D3 at the C-1/25 positions. The generation of endogenous 1alpha,25(OH)2D3 from vitamin D3 within the skin may indicate a novel pathway which is of importance for the regulation of epidermal cell growth and differentiation. PMID:9833978

  3. Intersecting D3-branes and holography

    NASA Astrophysics Data System (ADS)

    Constable, Neil R.; Erdmenger, Johanna; Guralnik, Zachary; Kirsch, Ingo

    2003-11-01

    We study a defect conformal field theory describing D3-branes intersecting over two space-time dimensions. This theory admits an exact Lagrangian description which includes both two- and four-dimensional degrees of freedom, has (4,4) supersymmetry and is invariant under global conformal transformations. Both two- and four-dimensional contributions to the action are conveniently obtained in a two-dimensional (2,2) superspace. In a suitable limit, the theory has a dual description in terms of a probe D3-brane wrapping an AdS3×S1 slice of AdS5×S5. We consider the AdS/CFT dictionary for this setup. In particular we find classical probe fluctuations corresponding to the holomorphic curve wy=cα'. These fluctuations are dual to defect fields containing massless two-dimensional scalars which parametrize the classical Higgs branch, but do not correspond to states in the Hilbert space of the CFT. We also identify probe fluctuations which are dual to BPS superconformal primary operators and to their descendants. A nonrenormalization theorem is conjectured for the correlators of these operators, and verified to order g2.

  4. Automated D/3 to Visio Analog Diagrams

    Energy Science and Technology Software Center (ESTSC)

    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 diagrammore » 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.« less

  5. 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.

  6. 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.

  7. Isolation and identification of vitamin D3, 25-hydroxyvitamin D3, 1,25-dihydroxyvitamin D3 and 1,24,25-trihydroxyvitamin D3 in Solanum malacoxylon incubated with ruminal fluid.

    PubMed

    Skliar, M I; Boland, R L; Mourino, A; Tojo, G

    1992-12-01

    It has been shown that Solanum malacoxylon contains 1 alpha,25-dihydroxyvitamin D3-glycoside. The presence of vitamin D3 and 25-hydroxyvitamin D3 has also been suggested. In the present study vitamin D3 and three of its metabolites, including 1 alpha,25-dihydroxyvitamin D3, were detected in plant leaf extracts preincubated with ruminal fluid (SMRF). Extraction of SMRF with non-polar organic solvents and purification of the lipid extract by TLC followed by HPLC yielded nine ultraviolet-absorbing (264 nm) peaks. Four of them comigrated on a Zorbax-Sil HPLC column with synthetic standards of vitamin D3, 25-hydroxyvitamin D3, 1 alpha,25-dihydroxyvitamin D3 and 1,24R,25-trihydroxyvitamin D3, respectively. These compounds were unequivocally identified by means of mass spectrometry. The results confirm that Solanum malacoxylon contains, in addition to 1 alpha,25-dihydroxyvitamin D3, vitamin D3, 25-hydroxyvitamin D3 and possibly other as yet unidentified derivatives. As 1,24,25-trihydroxyvitamin D3 is absent in plant extracts not incubated with ruminal fluid, the data also indicate that rumen microbes may convert 1 alpha,25-dihydroxyvitamin D3 into 1,24,25-trihydroxyvitamin D3. PMID:1335278

  8. Metabolism of 20-hydroxyvitamin D3 by mouse liver microsomes.

    PubMed

    Cheng, Chloe Y S; Slominski, Andrzej T; Tuckey, Robert C

    2014-10-01

    20-Hydroxyvitamin D3 [20(OH)D3], the major product of CYP11A1 action on vitamin D3, is biologically active and like 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] can inhibit proliferation and promote differentiation of a range of cells, and has anti-inflammatory properties. However, unlike 1,25(OH)2D3, it does not cause toxic hypercalcemia at high doses and is therefore a good candidate for therapeutic use to treat hyperproliferative and autoimmune disorders. In this study we analyzed the ability of mouse liver microsomes to metabolize 20(OH)D3. The two major products were identified from authentic standards as 20,24-dihydroxyvitamin D3 [20,24(OH)2D3] and 20,25-dihydroxyvitamin D3 [20,25(OH)2D3]. The reactions for synthesis of these two products from 20(OH)D3 displayed similar Km values suggesting that they were catalyzed by the same cytochrome P450. Some minor metabolites were produced by reactions with higher Km values for 20(OH)D3. Some metabolites gave mass spectra suggesting that they were the result of hydroxylation followed by dehydrogenation. One product had an increase in the wavelength for maximum absorbance from 263nm seen for 20(OH)D3, to 290nm, suggesting a new double bond was interacting with the vitamin D-triene chromophore. The two major products, 20,24(OH)2D3 and 20,25(OH)2D3 have both previously been shown to have higher potency for inhibition of colony formation by melanoma cells than 20(OH)D3, thus it appears that metabolism of 20(OH)D3 by mouse liver microsomes can generate products with enhanced activity. PMID:25138634

  9. Metabolism of 20-hydroxyvitamin D3 by mouse liver microsomes

    PubMed Central

    Cheng, Chloe Y.S.; Slominski, Andrzej T.; Tuckey, Robert C.

    2014-01-01

    20-Hydroxyvitamin D3 [20(OH)D3], the major product of CYP11A1 action on vitamin D3, is biologically active and like 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] can inhibit proliferation and promote differentiation of a range of cells, and has anti-inflammatory properties. However, unlike 1,25(OH)2D3, it does not cause toxic hypercalcemia at high doses and is therefore a good candidate for therapeutic use to treat hyperproliferative and autoimmune disorders. In this study we analyzed the ability of mouse liver microsomes to metabolize 20(OH)D3. The two major products were identified from authentic standards as 20,24-dihydroxyvitamin D3 [20,24(OH)2D3] and 20,25-dihydroxyvitamin D3 [20,25(OH)2D3]. The reactions for synthesis of these two products from 20(OH)D3 displayed similar Km values suggesting that they were catalyzed by the same cytochrome P450. Some minor metabolites were produced by reactions with higher Km values for 20(OH)D3. Some metabolites gave mass spectra suggesting that they were the result of hydroxylation followed by dehydrogenation. One product had an increase in the wavelength for maximum absorbance from 263 nm seen for 20(OH)D3, to 290 nm, suggesting a new double bond was interacting with the vitamin D-triene chromophore. The two major products, 20,24(OH)2D3 and 20,25(OH)2D3 have both previously been shown to have higher potency for inhibition of colony formation by melanoma cells than 20(OH)D3, thus it appears that metabolism of 20(OH)D3 by mouse liver microsomes can generate products with enhanced activity. PMID:25138634

  10. Deliverable navigation for multicriteria IMRT treatment planning by combining shared and individual apertures

    NASA Astrophysics Data System (ADS)

    Fredriksson, Albin; Bokrantz, Rasmus

    2013-11-01

    We consider the problem of deliverable Pareto surface navigation for step-and-shoot intensity-modulated radiation therapy. This problem amounts to calculation of a collection of treatment plans with the property that convex combinations of plans are directly deliverable. Previous methods for deliverable navigation impose restrictions on the number of apertures of the individual plans, or require that all treatment plans have identical apertures. We introduce simultaneous direct step-and-shoot optimization of multiple plans subject to constraints that some of the apertures must be identical across all plans. This method generalizes previous methods for deliverable navigation to allow for treatment plans with some apertures from a collective pool and some apertures that are individual. The method can also be used as a post-processing step to previous methods for deliverable navigation in order to improve upon their plans. By applying the method to subsets of plans in the collection representing the Pareto set, we show how it can enable convergence toward the unrestricted (non-navigable) Pareto set where all apertures are individual.

  11. 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

  12. 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.

  13. 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.

  14. Remedial investigation information management: Integrating IRPIMS electronic deliverables with environmental GIS applications

    SciTech Connect

    Ford, K.L.; O`Neil, S.M.; Kaufman, N.E.

    1994-12-31

    US Air Force (USAF) headquarters requires Installation Restoration Program Information Management System (IRPIMS) deliverables for environmental data generated at USAF installations under the Installation Restoration Program (IRP). By integrating Geographical Information Systems (GIS) applications with these electronic deliverables as part of Remedial Investigations (RI), quality control and information usability are notably increased. The GIS/database link creates a dynamic environmental model of the installation and offers numerous uses. There is also the potential to yield long-term cost savings. The greatest resource of the IRPIMS electronic deliverable is database content. IRPIMS contains survey, field and analytical data collected during an RI. This database can then be tapped, and the format can be modified to be used with a variety of other data management or geographical information systems. Enhancing the IRPIMS database with GIS capabilities requires an initial investment of time and resources. However, the effort should be greatly reduced in the future, since the integration procedures can themselves be automated.

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

    PubMed

    Boateng, Comfort A; Bakare, Oluyomi M; Zhan, Jia; Banala, Ashwini K; Burzynski, Caitlin; Pommier, Elie; Keck, Thomas M; Donthamsetti, Prashant; Javitch, Jonathan A; Rais, Rana; Slusher, Barbara S; Xi, Zheng-Xiong; Newman, Amy Hauck

    2015-08-13

    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

  16. 26 CFR 1.1503(d)-3 - Foreign use.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 12 2014-04-01 2014-04-01 false Foreign use. 1.1503(d)-3 Section 1.1503(d)-3...) INCOME TAXES (CONTINUED) Administrative Provisions and Other Rules § 1.1503(d)-3 Foreign use. (a) Foreign use—(1) In general. Except as provided in paragraph (c) of this section, a foreign use of a...

  17. 26 CFR 1.1503(d)-3 - Foreign use.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 12 2012-04-01 2012-04-01 false Foreign use. 1.1503(d)-3 Section 1.1503(d)-3...) INCOME TAXES (CONTINUED) Administrative Provisions and Other Rules § 1.1503(d)-3 Foreign use. (a) Foreign use—(1) In general. Except as provided in paragraph (c) of this section, a foreign use of a...

  18. 26 CFR 1.1503(d)-3 - Foreign use.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 12 2011-04-01 2011-04-01 false Foreign use. 1.1503(d)-3 Section 1.1503(d)-3...) INCOME TAXES (CONTINUED) Administrative Provisions and Other Rules § 1.1503(d)-3 Foreign use. (a) Foreign use—(1) In general. Except as provided in paragraph (c) of this section, a foreign use of a...

  19. 26 CFR 1.1503(d)-3 - Foreign use.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 12 2013-04-01 2013-04-01 false Foreign use. 1.1503(d)-3 Section 1.1503(d)-3...) INCOME TAXES (CONTINUED) Administrative Provisions and Other Rules § 1.1503(d)-3 Foreign use. (a) Foreign use—(1) In general. Except as provided in paragraph (c) of this section, a foreign use of a...

  20. 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...

  1. 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...

  2. 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...

  3. 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...

  4. 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...

  5. 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.

  6. 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 LABOR JOB CORPS PROGRAM UNDER TITLE IV-B OF THE JOB TRAINING PARTNERSHIP ACT Funding, Site...

  7. 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...

  8. 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...

  9. 48 CFR 252.232-7013 - Performance-Based Payments-Deliverable-Item Basis.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 48 Federal Acquisition Regulations System 3 2014-10-01 2014-10-01 false Performance-Based Payments-Deliverable-Item Basis. 252.232-7013 Section 252.232-7013 Federal Acquisition Regulations System DEFENSE ACQUISITION REGULATIONS SYSTEM, DEPARTMENT OF DEFENSE CLAUSES AND FORMS SOLICITATION PROVISIONS AND CONTRACT CLAUSES Text of Provisions...

  10. 77 FR 37032 - Capacity Deliverability Across the Midwest; Independent Transmission System Operator, Inc.; PJM...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-06-20

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF ENERGY Federal Energy Regulatory Commission Capacity Deliverability Across the Midwest; Independent Transmission System Operator, Inc.; PJM Interconnection, L.L.C. Seam; Notice Establishing Comment Period On June 11, 2012, the Commission issued a notice...

  11. Cosmic D- and DF-strings from D3D3: Black strings and BPS limit

    SciTech Connect

    Kim, Taekyung; Kim, Yoonbai; Kyae, Bumseok; Lee, Jungjai

    2008-03-15

    We study D- and DF-strings in a D3D3 system by using Dirac-Born-Infeld type action. In the presence of an electric flux from the transverse direction, we discuss gravitating thick D-string solutions of a spatial manifold, S{sup 2}xR{sup 1}, in which straight D-strings stretched along the R{sup 1} direction are attached to the south and north poles of the two-sphere. There is a horizon along its equator, which means the structure of black strings is formed. We also discuss the BPS limit for thin parallel D- and DF-strings in both flat and curved spacetime. We obtain the BPS sum rule for an arbitrarily-separated multistring configuration with a Gaussian type tachyon potential. At the site of each thin BPS D(F)-string, the pressure takes a finite value. We find that there exists a maximum deficit angle {pi} in the conical geometry induced by thin BPS D- and DF-strings.

  12. 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.

  13. 21 CFR 172.380 - Vitamin D3.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... incorporation by reference in accordance with 5 U.S.C. 552(a) and 1 CFR part 51. You may obtain copies from the... 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...

  14. 21 CFR 172.380 - Vitamin D 3;.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... incorporation by reference in accordance with 5 U.S.C. 552(a) and 1 CFR part 51. You may obtain copies from the... 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...

  15. 21 CFR 172.380 - Vitamin D3.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... incorporation by reference in accordance with 5 U.S.C. 552(a) and 1 CFR part 51. You may obtain copies from the... 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...

  16. 21 CFR 172.380 - Vitamin D3.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... incorporation by reference in accordance with 5 U.S.C. 552(a) and 1 CFR part 51. You may obtain copies from the... 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...

  17. 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.

  18. 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.

  19. The D3 dopamine receptor: From structural interactions to function.

    PubMed

    Fiorentini, Chiara; Savoia, Paola; Bono, Federica; Tallarico, Paola; Missale, Cristina

    2015-09-01

    Novel structural and functional aspects of the dopamine (DA) D3 receptors (D3R) have been recently described. D3R expressed in dopaminergic neurons have been classically considered to play the role of autoreceptors inhibiting, as the D2R, DA release. However, evidence for D3R-mediated neurotrophic and neuroprotective effects on DA neurons suggests their involvement in preventing pathological alterations leading to neurodegeneration. On the other hand, given its localization and functional role at postsynaptic striatal levels, the D3R may also be involved in the pathogenesis of movement disorders and psychiatric diseases. Functional interactions of D3R with other receptor systems are crucial for the modulation of several physiological events. On this line, the discovery that the D3R can form heteromers with other receptors has opened the possibility of uncover novel molecular mechanisms of brain functions and dysfunctions. This paper summarizes the functional and physical interactions of D3R with other receptors both at pre-synaptic sites, where it is co-expressed with the D2R and nicotinic receptors, and at post-synaptic sites where it interacts with the DA D1 receptors (D1R). The biochemical and functional properties of the D1R-D3R heteromer will be especially discussed. Both D1R and D3R have been in fact implicated in several disorders, including schizophrenia and motor dysfunctions. Therefore, the D1R-D3R heteromer may represent a potential drug target for the treatment of these diseases. PMID:25532864

  20. Developmental Vitamin D3 deficiency alters the adult rat brain.

    PubMed

    Féron, F; Burne, T H J; Brown, J; Smith, E; McGrath, J J; Mackay-Sim, A; Eyles, D W

    2005-03-15

    There is growing evidence that Vitamin D(3) (1,25-dihydroxyvitamin D(3)) is involved in brain development. We have recently shown that the brains of newborn rats from Vitamin D(3) deficient dams were larger than controls, had increased cell proliferation, larger lateral ventricles, and reduced cortical thickness. Brains from these animals also had reduced expression of nerve growth factor (NGF) and glial cell line-derived neurotrophic factor. The aim of the current study was to examine if there were any permanent outcomes into adulthood when the offspring of Vitamin D(3) deficient dams were restored to a normal diet. The brains of adult rats were examined at 10 weeks of age after Vitamin D(3) deficiency until birth or weaning. Compared to controls animals that were exposed to transient early Vitamin D(3) deficiency had larger lateral ventricles, reduced NGF protein content, and reduced expression of a number genes involved in neuronal structure, i.e. neurofilament or MAP-2 or neurotransmission, i.e. GABA-A(alpha4). We conclude that transient early life hypovitaminosis D(3) not only disrupts brain development but leads to persistent changes in the adult brain. In light of the high incidence of hypovitaminosis D(3) in women of child-bearing age, the public health implications of these findings warrant attention. PMID:15763180

  1. Feeding 25-hydroxyvitamin D3 to improve beef tenderness.

    PubMed

    Wertz, A E; Knight, T J; Trenkle, A; Sonon, R; Horst, R L; Huff-Lonergan, E J; Beitz, D C

    2004-05-01

    The objective of this trial was to determine if a single oral bolus of 25-hydroxyvitamin D3 (25-OH D3) given at various times before slaughter would enhance the tenderness of beef loin steaks. One hundred eight crossbred steers were allotted to 18 pens so that the mean weight of the cattle in each pen was similar. Treatments (25-OH D3 dose [62.5 or 125 mg]) and time of administration of the single oral bolus (4, 7, 21, or 35 d before slaughter) were assigned randomly to each pen of steers. Serial plasma samples were collected at each bolus administration time for control animals. For steers assigned to a treatment group, a baseline blood sample was collected before bolus administration and at each subsequent administration when other treatment groups received their bolus. Plasma samples were assayed for 25-OH D3 and calcium concentrations. Troponin-T degradation and Warner-Bratzler shear force were measured as indicators of tenderness for loin steaks collected at slaughter and aged for 6 or 14 d postmortem. Muscle samples, collected concurrently, were assayed for 25-OH D3 and calcium concentrations. A single oral bolus of 25-OH D3 was sufficient to increase plasma 25-OH D3 concentrations (P < 0.001) through slaughter, regardless of dose or time of bolus administration. The single oral bolus of 25-OH D3, however, did not increase plasma calcium concentrations (P > 0.05). As a result, neither troponin-T degradation nor Warner-Bratzler shear force was improved (P > 0.05) by treatment. Muscle 25-OH D3 concentrations were increased (P > 0.001) by treatment with 25-OH D3. Although sustained plasma 25-OH D3 concentrations did not increase plasma or muscle calcium at slaughter nor influence tenderness, the use of 25-OH D3 as a nutritional means of improving beef tenderness is in its infancy, and more research to delineate an effective dose and the potential interaction of seasonal exposure to ultraviolet light is warranted. PMID:15144081

  2. Role of 25-hydroxyvitamin D3 dose in determining rat 1,25-dihydroxyvitamin D3 production

    SciTech Connect

    Vieth, R.; McCarten, K.; Norwich, K.H. )

    1990-05-01

    To understand the relationships among (1) the dose of 25-hydroxyvitamin D (25(OH)D) in vivo, (2) the activity of 1-hydroxylase in renal mitochondria, and (3) the production of 1,25-dihydroxyvitamin D (1,25(OH)2D) in vivo, we gave rats different chronic or acute doses of 25-hydroxyvitamin D3 (25(OH)D3). We followed the metabolism of intracardially administered (25-hydroxy-26,27-methyl-3H)cholecalciferol (25(OH)(3H)D3) for 24 h before killing by measuring extracts of serum by chromatography. Specific activity of 1-hydroxylase in kidney was measured at death. In rats given 0-2,000 pmol 25(OH)D3 chronically by mouth, there was a dose-dependent decline in the percent of serum radioactivity made up of 1,25-dihydroxy-(26,27-methyl-3H)cholecalciferol (1,25(OH)2(3H)D3) as well as a decline in mitochondrial 1-hydroxylase, and these correlated significantly (r = 0.83, P less than 0.001). Serum %1,25(OH)2(3H)D3 in this experiment ranged from 0.8 to 42%. A small part of this range could be accounted for by a faster metabolic clearance rate (MCR) of 1,25(OH)2D3 from rats supplemented with 25(OH)D3 (MCR, 2.12 +/- 0.10 ml/min) compared with rats restricted in vitamin D (MCR, 0.94 +/- 0.06 ml/min, P less than 0.001). The activity of 1-hydroxylase was by far the major factor determining serum %1,25(OH)2(3H)D3. When different acute doses of 25(OH)D3 were given to rats with identical specific activities of 1-hydroxylase, the resulting 1,25(OH)2D3 concentrations in serum correlated with the 25(OH)D3 dose (r = 0.99, P less than 0.001). We conclude that the behavior of 1-hydroxylase in vivo is analogous to the classic behavior in vitro of an enzyme functioning below its Michaelis constant (Km). The amount of 1-hydroxylase present in renal mitochondria determines the fraction (not simply the quantity) of 25(OH)D metabolized to 1,25(OH)2D3 in vivo.

  3. Tissue distribution of 7-dehydrocholesterol, vitamin D3 and 25-hydroxyvitamin D3 in several species of fishes.

    PubMed

    Takeuchi, A; Okano, T; Sayamoto, M; Sawamura, S; Kobayashi, T; Motosugi, M; Yamakawa, T

    1986-02-01

    A high-performance liquid chromatographic (HPLC) method for simultaneous determination of 7-dehydrocholesterol (7-DHC), vitamin D3 and 25-hydroxyvitamin D3 (25-OH-D3) in tissues of fishes was established, and using this method the tissue distribution of the sterols in lamprey (Entosphenus japonicus), great blue shark (Prionace glauca), skipjack (Katsuwonus pelamis) and albacore (Thunnus alalunga) was investigated. The results are summarized in the following: Although the alimentary canal, gall bladder and roe of lamprey and the alimentary canal of great blue shark contained comparatively high levels of 7-DHC (higher than 2,000 ng/wet tissue g), the other tissues of lamprey and great blue shark and all tissues of skipjack and albacore contained only low levels of 7-DHC (lower than 1,000 ng/g). There was no significant correlation between the levels of 7-DHC and vitamin D3. The contents of 7-DHC in the skin of skipjack and albacore were only 1/1,000 of those in the skin of rats. Although the contents of vitamin D3 in the liver of skipjack and albacore were extremely high (41,240 and 21,000 ng/g, respectively), those in the skin were very low (454 and 257 ng/g, respectively). 25-OH-D3 was detected in the viscera of skipjack, but the levels were not very high (lower than 150 ng/g). These levels were not significantly correlated with those of vitamin D3. The results suggest that large quantities of vitamin D3 in the liver of skipjack and albacore are supplied by other biosynthetic routes or by intake of vitamin D3 rather than by photochemical biosynthesis. PMID:3012050

  4. Novel Gemini vitamin D(3) analogs have potent antitumor activity.

    PubMed

    Saito, Tsuyako; Okamoto, Ryoko; Haritunians, Talin; O'Kelly, James; Uskokovic, Milan; Maehr, Hubert; Marczak, Stanislaw; Jankowski, Pawel; Badr, Riem; Koeffler, H Phillip

    2008-11-01

    The active form of vitamin D(3), 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], modulates proliferation and induces differentiation of many cancer cells. A new class of analogs of vitamin D(3) has been synthesized, having two side-chains attached to carbon-20 (Gemini) and deuterium substituted on one side-chain. We have examined six of these analogs for their ability to inhibit growth of myeloid leukemia (HL-60), prostate (LNCaP, PC-3, DU145), lung (H520), colon (HT-29), and breast (MCF-7) cancer cell lines. Dose-response clonogenic studies showed that all six analogs had greater antiproliferative activities against cancer cells than 1,25(OH)(2)D(3). Although they had similar potency, the most active of these analogs was BXL-01-0120. BXL-01-0120 was 529-fold more potent than 1,25(OH)(2)D(3) in causing 50% clonal growth inhibition (ED(50)) of HL-60 cells. Pulse-exposure studies demonstrated that exposure to BXL-01-120 (10(-9)M, 48h) resulted in 85% clonal inhibition of HL-60 growth. BXL-01-0120 (10(-11)M, 4 days) induced the differentiation marker, CD11b. Also, morphologically differentiation was more prominent compared to 1,25(OH)(2)D(3). Annexin V assay showed that BXL-01-0120 (10(-10)M, 4 days) induced significantly (p<0.05) more apoptosis than 1,25(OH)(2)D(3). In summary, these analogs have a unique structure resulting in extremely potent inhibition of clonal proliferation of various types of cancer cells, especially HL-60 cells. PMID:18938245

  5. 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

  6. 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

  7. Vitamin D3 and cardiovascular function in rats.

    PubMed Central

    Weishaar, R E; Simpson, R U

    1987-01-01

    We have previously identified a receptor for 1,25-dihydroxyvitamin D3 in myocardial cells (Simpson, R.U. 1983. Circulation. 68:239.). To establish the relevance of this observation, we evaluated the role of the prohormone vitamin D3 in regulating cardiovascular function. In rats maintained on a vitamin D3-deficient diet for nine weeks, increases in systolic blood pressure (BP) and serum creatine phosphokinase (CPK) were observed. These increases coincided with a reduction of serum calcium from 10.3 to 5.6 mg/dl. However, while serum calcium remained depressed throughout the study, increases in BP and serum CPK were transient. After nine weeks of vitamin D3-depletion, but not after six weeks, ventricular and vascular muscle contractile function were also markedly enhanced. The increase in ventricular contractile function could not be prevented by maintaining serum calcium at 9.0 mg/dl during the period of D3-depletion. These observations suggest a primary role for the vitamin D3-endocrine system in regulating cardiovascular function. PMID:3034981

  8. Enzyme immunoassay for measuring 25-hydroxyvitamin D3 in serum.

    PubMed

    Lind, C; Chen, J; Byrjalsen, I

    1997-06-01

    We developed a rapid, competitive enzyme immunoassay (EIA) for measuring 25-hydroxyvitamin D3 [25(OH)D3] in serum. The EIA was based upon 25(OH)D3-3-hemisuccinate covalently coupled to secondary amino groups grafted onto the polystyrene surface of microtiter wells. Optimal coupling conditions were established, and we found that inclusion of 40 mumol/L chloramine T, an agent not previously described for use in coupling to these plates, resulted in both more reproducible coupling as well as more than a twofold increase in the coupling efficiency. Before EIA, 25(OH)D3 was extracted from the serum samples by acetonitrile, and the redissolved extract was incubated with polyclonal rabbit antibody raised against 1,25-dihydroxyvitamin D3-3-hemisuccinate conjugated to bovine serum albumin. Peroxidase-labeled antibody raised in goat against rabbit immunoglobulins was used for detection. The detection limit of the EIA was 4.4 micrograms/L; recovery 102%; on-plate CV 11%; within-run CV including extraction 12%, and between-run CV 15%. There was no clinically important cross-reactivity with other vitamin D metabolites, and results obtained by the EIA were compared with results obtained by a previously described RIA. PMID:9191544

  9. D 3 -Brane Model Building and the Supertrace Rule

    NASA Astrophysics Data System (ADS)

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

    2016-04-01

    A common way to obtain standard-model-like Lagrangians in string theory is to place D 3 -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 D 3 -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 D 3 -branes for constructing computationally controllable models for physics beyond the standard model problematic.

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

    PubMed

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

    2016-04-01

    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. PMID:27104696

  11. Efficient framework for deformable 2D-3D registration

    NASA Astrophysics Data System (ADS)

    Fluck, Oliver; Aharon, Shmuel; Khamene, Ali

    2008-03-01

    Using 2D-3D registration it is possible to extract the body transformation between the coordinate systems of X-ray and volumetric CT images. Our initial motivation is the improvement of accuracy of external beam radiation therapy, an effective method for treating cancer, where CT data play a central role in radiation treatment planning. Rigid body transformation is used to compute the correct patient setup. The drawback of such approaches is that the rigidity assumption on the imaged object is not valid for most of the patient cases, mainly due to respiratory motion. In the present work, we address this limitation by proposing a flexible framework for deformable 2D-3D registration consisting of a learning phase incorporating 4D CT data sets and hardware accelerated free form DRR generation, 2D motion computation, and 2D-3D back projection.

  12. 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. PMID:26713090

  13. 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

  14. Ghost-Free, Finite, Fourth-Order D=3 Gravity

    NASA Astrophysics Data System (ADS)

    Deser, S.

    2009-09-01

    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. Bitropic D3 Dopamine Receptor Selective Compounds s Potential Antipsychotics.

    PubMed

    Luedtke, Robert R; Rangel-Barajas, Claudia; Malik, Mahinder; Reichert, David E; Mach, R H

    2015-01-01

    Neuropsychiatric disorders represent a substantial social and health care issue. The National Institutes of Health estimates that greater than 2 million adults suffer from neuropsychiatric disorders in the USA. These individuals experience symptoms that can include auditory hallucinations, delusions, unrealistic beliefs and cognitive dysfunction. Although antipsychotic medications are available, suboptimal therapeutic responses are observed for approximately one-third of patients. Therefore, there is still a need to explore new pharmacotherapeutic strategies for the treatment of neuropsychiatric disorders. Many of the medications that are used clinically to treat neuropsychiatric disorders have a pharmacological profile that includes being an antagonist at D2-like (D2, D3 and D4) dopamine receptor subtypes. However, dopamine receptor subtypes are involved in a variety of neuronal circuits that include movement coordination, cognition, emotion, affect, memory and the regulation of prolactin. Consequently, antagonism at D2-like receptors can also contribute to some of the adverse side effects associated with the long-term use of antipsychotics including the a) adverse extrapyramidal symptoms associated with the use of typical antipsychotics and b) metabolic side effects (weight gain, hyperglycemia, increased risk of diabetes mellitus, dyslipidemia and gynecomastia) associated with atypical antipsychotic use. Preclinical studies suggest that D3 versus D2 dopamine receptor selective compounds might represent an alternative strategy for the treatment of the symptoms of schizophrenia. In this review we discuss a) how bitropic Nphenylpiperazine D3 dopamine receptor selective compounds have been developed by modification of the primary (orthosteric) and secondary (allosteric or modulatory) pharmacophores to optimize D3 receptor affinity and D2/D3 binding selectivity ratios and b) the functional selectivity of these compounds. Examples of how these compounds might be

  16. 21 CFR 584.725 - 25-Hydroxyvitamin D3.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 6 2014-04-01 2014-04-01 false 25-Hydroxyvitamin D3. 584.725 Section 584.725 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS FOOD SUBSTANCES AFFIRMED AS GENERALLY RECOGNIZED AS SAFE IN FEED...

  17. 21 CFR 584.725 - 25-Hydroxyvitamin D3.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 6 2013-04-01 2013-04-01 false 25-Hydroxyvitamin D3. 584.725 Section 584.725 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS FOOD SUBSTANCES AFFIRMED AS GENERALLY RECOGNIZED AS SAFE IN FEED...

  18. 21 CFR 584.725 - 25-Hydroxyvitamin D3.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false 25-Hydroxyvitamin D3. 584.725 Section 584.725 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS FOOD SUBSTANCES AFFIRMED AS GENERALLY RECOGNIZED AS SAFE IN FEED...

  19. 21 CFR 584.725 - 25-Hydroxyvitamin D3.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 6 2011-04-01 2011-04-01 false 25-Hydroxyvitamin D3. 584.725 Section 584.725 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS FOOD SUBSTANCES AFFIRMED AS GENERALLY RECOGNIZED AS SAFE IN FEED...

  20. 21 CFR 584.725 - 25-Hydroxyvitamin D3.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 6 2012-04-01 2012-04-01 false 25-Hydroxyvitamin D3. 584.725 Section 584.725 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS FOOD SUBSTANCES AFFIRMED AS GENERALLY RECOGNIZED AS SAFE IN FEED...

  1. Quantum Electrodynamics in d =3 from the ɛ Expansion

    NASA Astrophysics Data System (ADS)

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

    2016-04-01

    We study quantum electrodynamics in d =3 coupled to Nf flavors of fermions. The theory flows to an IR fixed point for Nf larger than some critical number Nfc. For Nf≤Nfc, 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 -2 ɛ to study the three-dimensional conformal theory. We compute, in perturbation theory, the IR dimensions of fermion bilinear and quadrilinear operators. For small Nf, a quadrilinear operator can become relevant in the IR and destabilize the fixed point. Therefore, the epsilon expansion can be used to estimate Nfc. 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 -2 ɛ that correspond to the additional conserved currents at d =3 and compute their infrared dimensions.

  2. Disruption of nicotine conditioning by dopamine D(3) receptor ligands.

    PubMed

    Le Foll, B; Schwartz, J-C; Sokoloff, P

    2003-02-01

    Tobacco smoking is the first cause of preventable death in modern countries. Nicotine replacement therapy or sustained release bupropion helps smoking cessation, but relapse rates are still very high. Nicotine, like other drugs of abuse, activates the dopamine mesolimbic system, which originates in the ventral tegmental area and projects notably to the nucleus accumbens. Situations or environmental stimuli previously associated with cigarette smoking, for example, smell of cigarette smoke, can elicit craving in abstinent smokers and promote relapse. Reducing the effects of nicotine-associated cues might therefore have potential therapeutic utility for smoking cessation. Such an approach has been validated for cocaine in animals, by using the dopamine D(3) receptor-selective partial agonist BP 897, which inhibits cocaine cue-induced drug-seeking behavior. Here we show that rats repeatedly injected with nicotine in a particular environment develop nicotine-conditioned locomotor responses, accompanied by an increase in D(3) receptor expression in the nucleus accumbens. This conditioned behavior was inhibited by BP 897 or a selective D(3) receptor antagonist, suggesting that antagonizing dopamine selectively at the D(3) receptor disrupts nicotine-conditioned effects and might represent a novel therapeutic approach for smoking cessation. PMID:12610655

  3. 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. PMID:27081967

  4. 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.

  5. 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.

  6. 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.

  7. Unification and D3-branes in F-theory

    SciTech Connect

    Heckman, Jonathan J.

    2012-07-27

    A central ingredient in many string based Grand Unified Theories (GUTs) is p-branes filling our spacetime and wrapping some number of internal directions. In this talk we discuss the potential role of D3-branes sitting at a point of the internal geometry in an F-theory GUT. These D3-branes can naturally realize additional superconformal sectors which can couple to the states of the Standard Model. We explain how detailed features of these sectors and their impact on the visible sector can be extracted. Additionally, we explain how in scenarios where the scale of conformal symmetry breaking is close to the weak scale, this extra sector can modify the physics of the Higgs.

  8. 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.

  9. Dosimetric quality, accuracy, and deliverability of modulated radiotherapy treatments for spinal metastases.

    PubMed

    Kairn, Tanya; Papworth, Daniel; Crowe, Scott B; Anderson, Jennifer; Christie, David R H

    2016-01-01

    Cancer often metastasizes to the vertebra, and such metastases can be treated successfully using simple, static posterior or opposed-pair radiation fields. However, in some cases, including when re-irradiation is required, spinal cord avoidance becomes necessary and more complex treatment plans must be used. This study evaluated 16 sample intensity-modulated radiation therapy (IMRT) and volumetric-modulated arc therapy (VMAT) treatment plans designed to treat 6 typical vertebral and paraspinal volumes using a standard prescription, with the aim of investigating the advantages and limitations of these treatment techniques and providing recommendations for their optimal use in vertebral treatments. Treatment plan quality and beam complexity metrics were evaluated using the Treatment And Dose Assessor (TADA) code. A portal-imaging-based quality assurance (QA) system was used to evaluate treatment delivery accuracy, and radiochromic film measurements were used to provide high-resolution verification of treatment plan dose accuracy, especially in the steep dose gradient regions between each vertebral target and spinal cord. All treatment modalities delivered approximately the same doses and the same levels of dose heterogeneity to each planning target volume (PTV), although the minimum PTV doses in the vertebral plans were substantially lower than the prescription, because of the requirement that the plans meet a strict constraint on the dose to the spinal cord and cord planning risk volume (PRV). All plans met required dose constraints on all organs at risk, and all measured PTV-cord dose gradients were steeper than planned. Beam complexity analysis suggested that the IMRT treatment plans were more deliverable (less complex, leading to greater QA success) than the VMAT treatment plans, although the IMRT plans also took more time to deliver. The accuracy and deliverability of VMAT treatment plans were found to be substantially increased by limiting the number of monitor

  10. 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.

  11. 21 CFR 172.380 - Vitamin D 3.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... accordance with 5 U.S.C. 552(a) and 1 CFR part 51. You may obtain copies from the United States Pharmacopeial.../federal-register/cfr/ibr-locations.html. (c) The additive may be used as follows: (1) At levels not to... 21 Food and Drugs 3 2014-04-01 2014-04-01 false Vitamin D 3. 172.380 Section 172.380 Food...

  12. Role of the D3 dopamine receptor in nicotine sensitization.

    PubMed

    Smith, Laura N; Bachus, Susan E; McDonald, Craig G; Smith, Robert F

    2015-08-01

    Adolescent cigarette use is associated with reduced quitting success and continued smoking in adulthood. Interestingly, polymorphisms of the dopamine D3 receptor (DRD3) gene have been associated with smoking behavior, and the receptor is expressed in an age- and brain region-dependent manner that suggests relevance to addiction. Here, we investigate the possible role of dopamine-related receptors, including DRD3 and an intriguing splice variant known as D3nf, in nicotine-induced sensitization. In adolescent and adult male rats, we examined (1) alterations occurring in dopamine receptor-related mRNAs (DRD1, DRD2, DRD3 and D3nf) at two time points during a sensitizing regimen of nicotine and (2) whether DRD3 antagonism either during the initial treatment (induction) or at a later challenge exposure (expression) is able to block nicotine sensitization. Nicotine-induced changes were seen for DRD3 and D3nf mRNAs in the nucleus accumbens shell early in repeated exposure in both age groups. DRD3 antagonism only blocked the induction of sensitization in adolescents and did not block the expression of sensitization in either age group. Adolescents and adults showed opposite DRD1 mRNA responses to nicotine treatment, while no age- and nicotine-related changes in DRD2 mRNA were observed. These data reveal important age-dependent regulation of DRD1- and DRD3-related mRNAs during the course of nicotine exposure. Furthermore, they highlight a requirement for DRD3 signaling in the development of adolescent nicotine sensitization, suggesting it may represent an appropriate target in the prevention of nicotine dependence initiated at this age. PMID:25907750

  13. Metabolism of 1alpha-hydroxyvitamin D3 by cytochrome P450scc to biologically active 1alpha,20-dihydroxyvitamin D3.

    PubMed

    Tuckey, Robert C; Janjetovic, Zorica; Li, Wei; Nguyen, Minh N; Zmijewski, Michal A; Zjawiony, Jordan; Slominski, Andrzej

    2008-12-01

    Cytochrome P450scc (CYP11A1) metabolizes vitamin D3 to 20-hydroxyvitamin D3 as the major product, with subsequent production of dihydroxy and trihydroxy derivatives. The aim of this study was to determine whether cytochrome P450scc could metabolize 1alpha-hydroxyvitamin D3 and whether products were biologically active. The major product of 1alpha-hydroxyvitamin D3 metabolism by P450scc was identified by mass spectrometry and NMR as 1alpha,20-dihydroxyvitamin D3. Mass spectrometry of minor metabolites revealed the production of another dihydroxyvitamin D3 derivative, two trihydroxy-metabolites made via 1alpha,20-dihydroxyvitamin D3 and a tetrahydroxyvitamin D3 derivative. The Km for 1alpha-hydroxyvitamin D3 determined for P450scc incorporated into phospholipid vesicles was 1.4 mol substrate/mol phospholipid, half that observed for vitamin D3. The kcat was 3.0 mol/min/mol P450scc, 6-fold lower than that for vitamin D3. 1alpha,20-Dihydroxyvitamin D3 inhibited DNA synthesis by human epidermal HaCaT keratinocytes propagated in culture, in a time- and dose-dependent fashion, with a potency similar to that of 1alpha,25-dihydroxyvitamin D3. 1alpha,20-Dihydroxyvitamin D3 (10 microM) enhanced CYP24 mRNA levels in HaCaT keratinocytes but the potency was much lower than that reported for 1alpha,25-dihydroxyvitamin D3. We conclude that the presence of the 1-hydroxyl group in vitamin D3 does not alter the major site of hydroxylation by P450scc which, as for vitamin D3, is at C20. The major product, 1alpha,20-dihydroxyvitamin D3, displays biological activity on keratinocytes and therefore might be useful pharmacologically. PMID:19000766

  14. Barriers to optimizing vitamin D3 intake for the elderly.

    PubMed

    Heaney, Robert P

    2006-04-01

    Available data on metabolic utilization of vitamin D3 indicate a total daily requirement of approximately 4000 international units (iu) (100 microg) or twice the current tolerable upper intake level (UL). In young individuals, most of this comes from the skin. However, cutaneous vitamin D3 synthesis declines with age, creating a need for increasing oral intake to maintain optimal serum 25-hydroxyvitamin D [25(OH)D] concentrations. Estimates of the population distribution of serum 25(OH)D values, coupled with available dose-response data, indicate that it would require input of an additional 2600 iu/d (65 microg/d) of oral vitamin D3 to ensure that 97.5% of older women have 25(OH)D values at or above desirable levels. The age-related decline in cutaneous input, taken together with the UL, creates a substantial barrier to the deployment of public health strategies to optimize vitamin D status in the elderly. PMID:16549492

  15. Dopamine D2/D3 receptor availability and venturesomeness.

    PubMed

    Bernow, Nina; Yakushev, Igor; Landvogt, Christian; Buchholz, Hans-Georg; Smolka, Michael N; Bartenstein, Peter; Lieb, Klaus; Gründer, Gerhard; Vernaleken, Ingo; Schreckenberger, Mathias; Fehr, Christoph

    2011-08-30

    The construct of impulsivity is considered as a major trait of personality. There is growing evidence that the mesolimbic dopamine system plays an important role in the modulation of impulsivity and venturesomeness, the two key components within the impulsivity-construct. The aim of the present study was to explore an association between trait impulsivity measured with self-assessment and the dopaminergic neurotransmission as measured by positron emission tomography (PET) in a cohort of healthy male subjects. In vivo D2/D3 receptor availability was determined with [(18)F]fallypride PET in 18 non-smoking healthy subjects. The character trait impulsivity was measured using the Impulsiveness-Venturesomeness-Empathy questionnaire (I7). Image processing and statistical analysis was performed on a voxel-by-voxel basis using statistical parametric mapping (SPM) software. The I7 subscale venturesomeness correlated positively with the D2/D3 receptor availability within the left temporal cortex and the thalamus. Measures on the I7 subscale impulsiveness and empathy did not correlate with the D2/D3 receptor availability in any brain region investigated. Our results suggest the involvement of extrastriatal dopaminergic neurotransmission in venturesomeness, a component of impulsivity. PMID:21689908

  16. Metabolism of 20-Hydroxyvitamin D3 and 20,23-Dihydroxyvitamin D3 by Rat and Human CYP24A1

    PubMed Central

    Tieu, Elaine W.; Li, Wei; Chen, Jianjun; Kim, Tae-Kang; Ma, Dejian; Slominski, Andrzej T.; Tuckey, Robert C.

    2015-01-01

    CYP11A1 hydroxylates vitamin D3 producing 20S-hydroxyvitamin D3 [20(OH)D3] and 20S,23-dihydroxyvitamin D3 [20,23(OH)2D3] as the major and most characterized metabolites. Both display immuno-regulatory and anti-cancer properties while being non-calcemic. A previous study indicated 20(OH)D3 can be metabolized by rat CYP24A1 to products including 20S,24-dihydroxyvitamin D3 [20,24(OH)2D3] and 20S,25-dihydroxyvitamin D3, with both producing greater inhibition of melanoma colony formation than 20(OH)D3. The aim of this study was to characterize the ability of rat and human CYP24A1 to metabolize 20(OH)D3 and 20,23(OH)2D3. Both isoforms metabolized 20(OH)D3 to the same dihydroxyvitamin D species with no secondary metabolites being observed. Hydroxylation at C24 produced both enantiomers of 20,24(OH)2D3. For rat CYP24A1 the preferred initial site of hydroxylation was at C24 whereas the human enzyme preferred C25. 20,23(OH)2D3 was initially metabolized to 20S,23,24-trihydroxyvitamin D3 and 20S,23,25-trihydroxyvitamin D3 by rat and human CYP24A1 as determined by NMR, with both isoforms showing a preference for initial hydroxylation at C25. CYP24A1 was able to further oxidize these metabolites in a series of reactions which included the cleavage of C23-C24 bond, as indicated by high resolution mass spectrometry of the products, analogous to the catabolism of 1,25(OH)2D3 via the C24-oxidation pathway. Similar catalytic efficiencies were observed for the metabolism of 20(OH)D3 and 20,23(OH)2D3 by human CYP24A1 and were lower than for the metabolism of 1,25(OH)2D3. We conclude that rat and human CYP24A1 metabolizes 20(OH)D3 producing only dihydroxyvitamin D3 species as products which retain biological activity, whereas 20,23(OH)2D3 undergoes multiple oxidations which include cleavage of the side chain. PMID:25727742

  17. Fucoidan from Turbinaria conoides: a multifaceted 'deliverable' to combat pancreatic cancer progression.

    PubMed

    Delma, Caroline R; Somasundaram, Somasundaram T; Srinivasan, Guru Prasad; Khursheed, Md; Bashyam, Murali D; Aravindan, Natarajan

    2015-03-01

    The presence of occult metastases at the time of diagnosis together with the lack of effective chemotherapies pose a dire need for designing new and targeted therapeutics for pancreatic cancer. Fucoidans from brown algae can be regarded as potential candidates in view of their antioxidant, anti-cancer and anti-angiogenic potential. Herein, we investigated the antioxidant and anti-cancer effects of fucoidans, sulfated polysaccharides from Turbinaria conoides (TCFE) in pancreatic cancer cell lines. TCFE exerted significant antioxidant activities against various free radicals. Significant inhibition of cell proliferation and, induction of apoptotic cell death were observed in pancreatic cancer cells in response to TCFE. Also, TCFE exhibited significant anti-angiogenic potential. Evidently, gelatin zymography revealed that TCFE inhibited matrix metalloproteases -2 and -9 activities in pancreatic cancer cells. These results clearly indicate that TCFE could serve as a potential 'deliverable' to alleviate pancreatic cancer progression by inhibiting tumor cell proliferation and angiogenesis. PMID:25541359

  18. 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…

  19. 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

    2016-01-01

    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. PMID:27455504

  20. 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

  1. Hydroxylation of 20-hydroxyvitamin D3 by human CYP3A4.

    PubMed

    Cheng, Chloe Y S; Slominski, Andrzej T; Tuckey, Robert C

    2016-05-01

    20S-Hydroxyvitamin D3 [20(OH)D3] is the biologically active major product of the action of CYP11A1 on vitamin D3 and is present in human plasma. 20(OH)D3 displays similar therapeutic properties to 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], but without causing hypercalcaemia and therefore has potential for development as a therapeutic drug. CYP24A1, the kidney mitochondrial P450 involved in inactivation of 1,25(OH)2D3, can hydroxylate 20(OH)D3 at C24 and C25, with the products displaying more potent inhibition of melanoma cell proliferation than 20(OH)D3. CYP3A4 is the major drug-metabolising P450 in liver endoplasmic reticulum and can metabolise other active forms of vitamin D, so we examined its ability to metabolise 20(OH)D3. We found that CYP3A4 metabolises 20(OH)D3 to three major products, 20,24R-dihydroxyvitamin D3 [20,24R(OH)2D3], 20,24S-dihydroxyvitamin D3 [20,24S(OH)2D3] and 20,25-dihydroxyvitamin D3 [20,25(OH)2D3]. 20,24R(OH)2D3 and 20,24S(OH)2D3, but not 20,25(OH)2D3, were further metabolised to trihydroxyvitamin D3 products by CYP3A4 but with low catalytic efficiency. The same three primary products, 20,24R(OH)2D3, 20,24S(OH)2D3 and 20,25(OH)2D3, were observed for the metabolism of 20(OH)D3 by human liver microsomes, in which CYP3A4 is a major CYP isoform present. Addition of CYP3A family-specific inhibitors, troleandomycin and azamulin, almost completely inhibited production of 20,24R(OH)2D3, 20,24S(OH)2D3 and 20,25(OH)2D3 by human liver microsomes, further supporting that CYP3A4 plays the major role in 20(OH)D3 metabolism by microsomes. Since both 20,24R(OH)2D3 and 20,25(OH)2D3 have previously been shown to display enhanced biological activity in inhibiting melanoma cell proliferation, our results show that CYP3A4 further activates, rather than inactivates, 20(OH)D3. PMID:26970587

  2. 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

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

    PubMed

    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

  4. Synthesis and composition of vitamin D-3 metabolites in Solanum malacoxylon.

    PubMed

    Esparza, M S; Vega, M; Boland, R L

    1982-12-17

    The synthesis of vitamin D-3 hydroxylated metabolites in Solanum malacoxylon was investigated. When crude leaf homogenates and subcellular fractions were incubated with [3H]vitamin D-3 and [3H]25-hydroxy-vitamin D-3 under conditions described for animal vitamin D-3-25-hydroxylase and 25-hydroxy-vitamin D-3-1 alpha-hydroxylase, respectively, labelled metabolites identified on the basis of their chromatographic properties as 25-hydroxy-vitamin D-3 and 1,25-dihydroxy-vitamin D-3 were formed. Other unidentified product metabolites were also detected. Vitamin D-3-25-hydroxylase activity was localized in microsomes and 25-hydroxy-vitamin D-3-1 alpha-hydroxylase in mitochondria and microsomes. Chromatography of sterols isolated from leaf extracts preincubated with beta-glucosidase on Sephadex LH-20 columns permitted the isolation of three biologically active fractions with elution properties similar to vitamin D-3, 25-hydroxy-vitamin D-3 and 1,25-dihydroxy-vitamin D-3, respectively. Ultraviolet spectra characteristic of vitamin D-3 and its metabolites were obtained after purification of the fractions by TLC. Co-chromatography of individual fractions with authentic metabolites on TLC provided further evidence that the plant contains vitamin D-3, 25-hydroxy-vitamin D-3 and 1,25-dihydroxy-vitamin D-3 as glucoside derivatives. These results suggest that a similar pathway of vitamin D-3 hydroxylation as in animals may be operative in S. malacoxylon. PMID:6295509

  5. Recent update of the RPLUS2D/3D codes

    NASA Technical Reports Server (NTRS)

    Tsai, Y.-L. Peter

    1991-01-01

    The development of the RPLUS2D/3D codes is summarized. These codes utilize LU algorithms to solve chemical non-equilibrium flows in a body-fitted coordinate system. The motivation behind the development of these codes is the need to numerically predict chemical non-equilibrium flows for the National AeroSpace Plane Program. Recent improvements include vectorization method, blocking algorithms for geometric flexibility, out-of-core storage for large-size problems, and an LU-SW/UP combination for CPU-time efficiency and solution quality.

  6. Transformations of Carbides During Tempering of D3 Tool Steel

    NASA Astrophysics Data System (ADS)

    Nykiel, Tadeusz; Hryniewicz, Tadeusz

    2014-06-01

    The studies were performed on D3 tool steel hardened after austenitizing at 1050 °C during 30 min and tempering at 200-700 °C. Based on the diffraction studies performed from the extraction replicas, using electron microscopy, it was found that after 120-min tempering in the consecutive temperatures, the following types of carbides occur: Apart from higher mentioned carbides, there are also big primary carbides and fine secondary M7C3 carbides occurring, which did not dissolve during austenitizing.

  7. Non-perturbative effects on a fractional D3-brane

    NASA Astrophysics Data System (ADS)

    Ferretti, Gabriele; Petersson, Christoffer

    2009-03-01

    In this note we study the Script N = 1 abelian gauge theory on the world volume of a single fractional D3-brane. In the limit where gravitational interactions are not completely decoupled we find that a superpotential and a fermionic bilinear condensate are generated by a D-brane instanton effect. A related situation arises for an isolated cycle invariant under an orientifold projection, even in the absence of any gauge theory brane. Moreover, in presence of supersymmetry breaking background fluxes, such instanton configurations induce new couplings in the 4-dimensional effective action, including non-perturbative contributions to the cosmological constant and non-supersymmetric mass terms.

  8. 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.

  9. The dopamine D3 receptor gene and posttraumatic stress disorder.

    PubMed

    Wolf, Erika J; Mitchell, Karen S; Logue, Mark W; Baldwin, Clinton T; Reardon, Annemarie F; Aiello, Alison; Galea, Sandro; Koenen, Karestan C; Uddin, Monica; Wildman, Derek; Miller, Mark W

    2014-08-01

    The dopamine D3 receptor (DRD3) gene has been implicated in schizophrenia, autism, and substance use-disorders and is related to emotion reactivity, executive functioning, and stress-responding, processes impaired in posttraumatic stress disorder (PTSD). The aim of this candidate gene study was to evaluate DRD3 polymorphisms for association with PTSD. The discovery sample was trauma-exposed White, non-Hispanic U.S. veterans and their trauma-exposed intimate partners (N = 491); 60.3% met criteria for lifetime PTSD. The replication sample was 601 trauma-exposed African American participants living in Detroit, Michigan; 23.6% met criteria for lifetime PTSD. Genotyping was based on high-density bead chips. In the discovery sample, 4 single nucleotide polymorphisms (SNPs), rs2134655, rs201252087, rs4646996, and rs9868039, showed evidence of association with PTSD and withstood correction for multiple testing. The minor alleles were associated with reduced risk for PTSD (OR range = 0.59 to 0.69). In the replication sample, rs2251177, located 149 base pairs away from the most significant SNP in the discovery sample, was nominally associated with PTSD in men (OR = 0.32). Although the precise role of the D3 receptor in PTSD is not yet known, its role in executive functioning and emotional reactivity, and the sensitivity of the dopamine system to environmental stressors could potentially explain this association. PMID:25158632

  10. The Dopamine D3 Receptor Gene and Posttraumatic Stress Disorder

    PubMed Central

    Wolf, Erika J.; Mitchell, Karen S.; Logue, Mark W.; Baldwin, Clinton T.; Reardon, Annemarie F.; Aiello, Alison; Galea, Sandro; Koenen, Karestan C.; Uddin, Monica; Wildman, Derek; Miller, Mark W.

    2014-01-01

    The dopamine D3 receptor (DRD3) gene has been implicated in schizophrenia, autism, and substance use-disorders and is related to emotion reactivity, executive functioning, and stress-responding, processes impaired in posttraumatic stress disorder (PTSD). This aim of this candidate gene study was to evaluate DRD3 polymorphisms for association with PTSD. The discovery sample was trauma-exposed white, non-Hispanic veterans and their trauma-exposed intimate partners (N = 491); 60% met criteria for lifetime PTSD. The replication sample was 601 trauma-exposed African American participants; 24% met criteria for lifetime PTSD. Genotyping was based on high-density bead chips. In the discovery sample, four single nucleotide polymorphisms (SNPs), rs2134655, rs201252087, rs4646996, and rs9868039, showed evidence of association with PTSD and withstood correction for multiple testing. The minor alleles were associated with reduced risk for PTSD (odds ratio range: 0.59 – 0.69). In the replication sample, rs2251177, located 149 base pairs away from the most significant SNP in the discovery sample, was nominally associated with PTSD in men (odds ratio: 0.32). Although the precise role of the D3 receptor in PTSD is not yet known, its role in executive functioning and emotional reactivity, and the sensitivity of the dopamine system to environmental stressors, could potentially explain this association. PMID:25158632

  11. 750 GeV diphotons from a D3-brane

    NASA Astrophysics Data System (ADS)

    Heckman, Jonathan J.

    2016-05-01

    Motivated by the recently reported diphoton excess at 750 GeV observed by both CMS and ATLAS, we study string-based particle physics models which can accommodate this signal. Quite remarkably, although Grand Unified Theories in F-theory tend to impose tight restrictions on candidate extra sectors, the case of a probe D3-brane near an E-type Yukawa point naturally leads to a class of strongly coupled models capable of accommodating the observed signature. In these models, the visible sector is realized by intersecting 7-branes, and the 750 GeV resonance is a scalar modulus associated with motion of the D3-brane in the direction transverse to the Standard Model 7-branes. Integrating out heavy 3-7 string messenger states leads to dimension five operators for gluon fusion production and diphoton decays. Due to the unified structure of interactions, these models also predict that there should be additional decay channels to ZZ and Zγ. We also comment on models with distorted unification, where both the production mechanism and decay channels can differ.

  12. Evidence for triangular D3h symmetry in 12C.

    PubMed

    Marín-Lámbarri, D J; Bijker, R; Freer, M; Gai, M; Kokalova, Tz; Parker, D J; Wheldon, C

    2014-07-01

    We report a measurement of a new high spin Jπ=5- state at 22.4(2) MeV in 12C which fits very well to the predicted (ground state) rotational band of an oblate equilateral triangular spinning top with a D3h symmetry characterized by the sequence 0+, 2+, 3-, 4±, 5- with almost degenerate 4+ and 4- (parity doublet) states. Such a D3h symmetry was observed in triatomic molecules, and it is observed here for the first time in nuclear physics. We discuss a classification of other rotation-vibration bands in 12C such as the (0+) Hoyle band and the (1-) bending mode band and suggest measurements in search of the predicted ("missing") states that may shed new light on clustering in 12C and light nuclei. In particular, the observation (or nonobservation) of the predicted ("missing") states in the Hoyle band will allow us to conclude the geometrical arrangement of the three alpha particles composing the Hoyle state at 7.654 MeV in 12C. PMID:25032922

  13. 16 CFR Appendix D3 to Part 305 - Water Heaters-Oil

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... RULEâ) Pt. 305, App. D3 Appendix D3 to Part 305—Water Heaters—Oil Range Information Capacity First hour... 16 Commercial Practices 1 2014-01-01 2014-01-01 false Water Heaters-Oil D3 Appendix D3 to Part 305 Commercial Practices FEDERAL TRADE COMMISSION REGULATIONS UNDER SPECIFIC ACTS OF CONGRESS ENERGY AND...

  14. Regulation of Mycobacterium-specific mononuclear cell responses by 25-hydroxyvitamin D3

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The active vitamin D metabolite, 1,25-dihydroxyvitamin D3 (1,25[OH]2D3), has been shown to be an important regulator of innate and adaptive immune function. In addition, synthesis of 1,25(OH)2D3 from 25-hydroxyvitamin D3 (25[OH]D3) by the enzyme 1alpha-hydroxylase in monocytes upon activation by TLR...

  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. 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

  17. 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.

  18. Wear and friction behavior of Zr implanted D3 steel

    SciTech Connect

    Akbas, N.; Saklakoglu, I.E.; Monteiro, O.R.; Brown, I.G.

    2001-08-23

    Multicharged, pure, high current and pulsed ion beams of Zr have been extracted from a metal vapor vacuum arc (MEVVA) source and implanted into AISI D3 (C: 2-2,35%, Mn: 0,60%, Si: 0,60%, Cr: 11-13,50%, Ni: 0,30%, W: 1%, V: 1%) tool steel samples at the 3,6.1016, 5.1016 and 1.1017 ions/cm2 doses. The wear resistance and friction coefficient have been estimated using pin-on-disc wear tests. Implantation of Zr decreased the wear loss and friction coefficient. RBS, AES and SEM Microprobe analyses were used as a guide for explanation of implantation's effects.

  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. PMID:26387052

  20. The use of vitamin D3 and its metabolites to improve beef tenderness.

    PubMed

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

    2004-01-01

    Three experiments were conducted to determine whether feeding 25-hydroxyvitamin D3 (25-OH D3) or 1,25-dihydroxyvitamin D3 (1,25-(OH)2 D3) improves the tenderness of longissimus dorsi (LD), semimembranosus (SM), and infraspinatus (IF) muscles similar to supplemental vitamin D3 without leaving residual vitamin D3 and its metabolites in muscle. In the first two experiments, 24 crossbred steers were used to determine the effects of different oral amounts of 1,25-(OH)2 D3 (Exp. 1; n = 12) and 25-OH D3 (Exp. 2; n = 12) on plasma Ca2+ concentrations. In the third experiment, crossbred steers were allotted randomly to one of four treatments: 1) control placebo (n = 7); 2) 5 x 10(6) IU of vitamin D3/d (n = 9) for 9 d and harvested 2 d after last treatment; 3) single, 125-mg dose of 25-OH D3 (n = 8) 4 d before harvest; or 4) single, 500-microg dose of 1,25-(OH)2 D3 (n = 9) 3 d before harvest. The LD and SM steaks from each animal were aged for 8, 14, or 21 d, whereas steaks from the IF were aged for 14 or 21 d. All steaks were analyzed for tenderness by Warner-Bratzler shear force and for troponin-T degradation by Western blot analysis. Supplementing steers with vitamin D3 increased (P < 0.01) the concentration of vitamin D3 and 25-OH D3 in all muscles sampled. Feeding steers 25-OH D3 increased (P < 0.05) the concentration of 25-OH D3 in meat, but to an amount less than half that of cattle treated with vitamin D3. Supplemental 1,25-(OH)2 D3 did not affect (P < 0.10) shear force values; however, there was a trend (P < 0.10) for supplemental vitamin D3 and 25-OH D3 to produce LD steaks with lower shear values after 8 and 14 d of aging, and lower (P < 0.10) shear force values for the SM aged for 21 d. Analysis of Western blots indicated that LD steaks from cattle supplemented with vitamin D3 and 25-OH D3 had greater (P < 0.05) troponin-T degradation. Antemortem supplementation of 25-OH D3 seems to increase postmortem proteolysis and tenderness in the LD and SM without

  1. Anti-proliferative activity of 25-hydroxyvitamin D3 in human prostate cells.

    PubMed

    Munetsuna, Eiji; Kawanami, Rie; Nishikawa, Miyu; Ikeda, Shinnosuke; Nakabayashi, Sachie; Yasuda, Kaori; Ohta, Miho; Kamakura, Masaki; Ikushiro, Shinichi; Sakaki, Toshiyuki

    2014-02-15

    1α-Hydroxylation of 25-hydroxyvitamin D3 is believed to be essential for its biological effects. In this study, we evaluated the biological activity of 25(OH)D3 itself comparing with the effect of cell-derived 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3). First, we measured the cell-derived 1α,25(OH)2D3 level in immortalized human prostate cell (PZ-HPV-7) using [(3)H]-25(OH)D3. The effects of the cell-derived 1α,25(OH)2D3 on vitamin D3 24-hydroxylase (CYP24A1) mRNA level and the cell growth inhibition were significantly lower than the effects of 25(OH)D3 itself added to cell culture. 25-Hydroxyvitamin D3 1α-hydroxylase (CYP27B1) gene knockdown had no significant effects on the 25(OH)D3-dependent effects, whereas vitamin D receptor (VDR) gene knockdown resulted in a significant decrease in the 25(OH)D3-dependent effects. These results strongly suggest that 25(OH)D3 can directly bind to VDR and exerts its biological functions. DNA microarray and real-time RT-PCR analyses suggest that semaphorin 3B, cystatin E/M, and cystatin D may be involved in the antiproliferative effect of 25(OH)D3. PMID:24291609

  2. Comparative effects of 1α-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 on transporters and enzymes in fxr(+/+) and fxr(-/-) mice.

    PubMed

    Chow, Edwin C Y; Durk, Matthew R; Maeng, Han-Joo; Pang, K Sandy

    2013-10-01

    Previous studies have shown that 1α,25-dihydroxyvitamin D3 [1,25(OH)2 D3 ] treatment in mice resulted in induction of intestinal and renal Cyp24a1 and Trpv6 expression, increased hepatic Cyp7a1 expression and activity, as well as higher renal Mdr1/P-gp expression. The present study compared the equimolar efficacies of 1α-hydroxyvitamin D3 [1α(OH)D3 ] (6 nmol/kg i.p. q2d × 4), a lipophilic precursor with a longer plasma half-life that is converted to 1,25(OH)2 D3 , and 1,25(OH)2 D3 on vitamin D receptor (VDR) target genes. To clarify whether changes in VDR genes was due to VDR and not secondary, farnesoid X receptor (FXR)-directed effects, namely, lower Cyp7a1 expression in rat liver due to increased bile acid absorption, wildtype [fxr(+/+)] and FXR knockout [fxr(-/-)] mice were used to distinguish between VDR and FXR effects. With the exception that hepatic Sult2a1 mRNA was increased equally well by 1α(OH)D3 and 1,25(OH)2 D3 , 1α(OH)D3 treatment led to higher increases in hepatic Cyp7a1, renal Cyp24a1, VDR, Mdr1 and Mrp4, and intestinal Cyp24a1 and Trpv6 mRNA expression in both fxr(+/+) and fxr(-/-) mice compared to 1,25(OH)2 D3 treatment. A similar induction in protein expression and microsomal activity of hepatic Cyp7a1 and renal P-gp and Mrp4 protein expression was noted for both compounds. A higher intestinal induction of Trpv6 was observed, resulting in greater hypercalcemic effect following 1α(OH)D3 treatment. The higher activity of 1α(OH)D3 was explained by its rapid conversion to 1,25(OH)2 D3 in tissue sites, furnishing higher plasma and tissue 1,25(OH)2 D3 levels compared to following 1,25(OH)2 D3 -treatment. In conclusion, 1α(OH)D3 exerts a greater effect on VDR gene induction than equimolar doses of 1,25(OH)2 D3 in mice. PMID:23897575

  3. 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. PMID:27018098

  4. 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. PMID:27508895

  5. 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).

  6. Long-term effects of 1,25-dihydroxy vitamin D3 and 24,25-dihydroxy vitamin D3 in renal osteodystrophy.

    PubMed

    Muirhead, N; Adami, S; Sandler, L M; Fraser, R A; Catto, G R; Edward, N; O'Riordan, J L

    1982-01-01

    Twenty-three patients with end-stage renal failure on maintenance haemodialysis were treated with 1,25-dihydroxy vitamin D3 or 24-25-dihydroxy vitamin D3 for 3-32 months (total 232 patient months). Treatment with 1,25-dihydroxy vitamin D3 was marked by symptomatic, biochemical and histological improvements in the majority of patients. In contrast, treatment with 24,25-dihydroxy vitamin D3 produced no biochemical or histological improvements and such patients developed severe symptomatic bone disease. Successful renal transplantation resulted in rapid improvement in symptoms, biochemistry and bone histology in nine of 10 patients irrespective of whether prior treatment was with 1,25-dihydroxy vitamin D3, 24,25-dihydroxy vitamin D3 or both. During treatment with 1,25-dihydroxy vitamin D3 progressive reduction in dosage was required in the majority of patients because of hypercalcaemia, which was rapidly corrected by stopping treatment for a few days. Hypercalcaemia did not occur until serum alkaline phosphatase (AP) and amino terminal parathyroid hormone (N-PTH) had fallen towards normal. Treatment failure was uncommon in 1,25-dihydroxy vitamin D3-treated patients and was characterized by the early development of hypercalcaemia. Addition of 24,25-dihydroxy vitamin D3 in such patients rendered the hypercalcaemia more manageable but did not lead to any further improvement in biochemistry or bone histology. Treatment with 24,25-dihydroxy vitamin D3 was accompanied by the development of severe symptomatic bone disease in the majority of patients and a characteristic pattern of biochemical abnormalities with hypocalcaemia and rises in AP and N-PTH. Substitution of 1,25-dihydroxy vitamin D3 treatment for 24,25-dihydroxy vitamin D3 in these patients resulted in prompt improvement in clinical, biochemical and histological abnormalities. Successful renal transplantation was accompanied by rapid resolution of clinical, biochemical and histological features of renal

  7. A Randomised, Cross-Over Study to Estimate the Influence of Food on the 25-Hydroxyvitamin D3 Serum Level after Vitamin D3 Supplementation

    PubMed Central

    Cavalier, Etienne; Jandrain, Bernard; Coffiner, Monte; Da Silva, Stéphanie; De Niet, Sophie; Vanderbist, Francis; Souberbielle, Jean-Claude

    2016-01-01

    Vitamin D3 is known to be liposoluble and its release could be a factor limiting the rate of absorption. It was presumed that the presence of fat could favor absorption of vitamin D3. However, as bioavailability is related not only to the active molecules but also to the formulations and excipients used, the optimization of the pharmaceutical form of vitamin D3 is also important. The objective of this study was to evaluate if there is a food effect on absorption when a high dose of vitamin D3 is completely solubilized in an oily solution. In the present cross-over study, 88 subjects were randomized and received a single dose of 50,000 IU of vitamin D3 in fasting state or with a standardized high-fat breakfast. Assessment of serum concentrations of 25 hydroxyvitamin D3 (25(OH)D3) was performed three, five, seven, 14, 30 and 60 days after supplementation. In fed and fast conditions, the 25(OH)D3 serum concentrations were significantly higher than the baseline value three days after administration and remained significantly higher during the first month. No significant difference between fasting vs. fed conditions was observed. It is therefore concluded that the vitamin D3 absorption from an oily solution was not influenced by the presence or absence of a meal. PMID:27213447

  8. 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.

  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. 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.

  11. 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.

  12. Exposure to Cigarette Smoke Reduces Vitamin D3 in the Blood Stream and Respiratory Tract

    MedlinePlus

    ... respiratory tract Share | Exposure to cigarette smoke reduces vitamin D3 in the blood stream and respiratory tract ... be understood as to how smoke causes inflammation. Vitamin D3 has anti-inflammatory and anti-bacterial effects. ...

  13. 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.

  14. 26 CFR 1.1244(d)-3 - Stock dividend, recapitalizations, changes in name, etc.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 11 2010-04-01 2010-04-01 true Stock dividend, recapitalizations, changes in name, etc. 1.1244(d)-3 Section 1.1244(d)-3 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES Special Rules for Determining Capital Gains and Losses § 1.1244(d)-3 Stock...

  15. 12 CFR 563d.3b-6 - Liability for certain statements by savings associations.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 12 Banks and Banking 5 2010-01-01 2010-01-01 false Liability for certain statements by savings associations. 563d.3b-6 Section 563d.3b-6 Banks and Banking OFFICE OF THRIFT SUPERVISION, DEPARTMENT OF THE TREASURY SECURITIES OF SAVINGS ASSOCIATIONS Regulations § 563d.3b-6 Liability for certain statements by savings associations. This...

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  17. 26 CFR 301.6104(d)-3 - Tax-exempt organization subject to harassment campaign.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... campaign. 301.6104(d)-3 Section 301.6104(d)-3 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... Returns and Records § 301.6104(d)-3 Tax-exempt organization subject to harassment campaign. (a) In general... a copy (as otherwise required by § 301.6104(d)-1(a)) that it reasonably believes is part of...

  18. 26 CFR 301.6104(d)-3 - Tax-exempt organization subject to harassment campaign.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... campaign. 301.6104(d)-3 Section 301.6104(d)-3 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... Returns and Records § 301.6104(d)-3 Tax-exempt organization subject to harassment campaign. (a) In general... a copy (as otherwise required by § 301.6104(d)-1(a)) that it reasonably believes is part of...

  19. 26 CFR 301.6104(d)-3 - Tax-exempt organization subject to harassment campaign.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... campaign. 301.6104(d)-3 Section 301.6104(d)-3 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... Returns and Records § 301.6104(d)-3 Tax-exempt organization subject to harassment campaign. (a) In general... a copy (as otherwise required by § 301.6104(d)-1(a)) that it reasonably believes is part of...

  20. 26 CFR 1.1244(d)-3 - Stock dividend, recapitalizations, changes in name, etc.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 11 2011-04-01 2011-04-01 false Stock dividend, recapitalizations, changes in name, etc. 1.1244(d)-3 Section 1.1244(d)-3 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Special Rules for Determining Capital Gains and Losses § 1.1244(d)-3...

  1. 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...

  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, 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...

  4. 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...

  5. 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...

  6. Treatment of an intramammary bacterial infection with 25-hydroxyvitamin D(3).

    PubMed

    Lippolis, John D; Reinhardt, Timothy A; Sacco, Randy A; Nonnecke, Brian J; Nelson, Corwin D

    2011-01-01

    Deficiency of serum levels of 25-hydroxyvitamin D(3) 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-dihydroxyvitamin D(3) produced by activated immune cells at sites of infection, and that synthesis of 1,25-dihydroxyvitamin D(3) is dependent on the availability of 25-hydroxyvitamin D(3). Thus, increasing the availability of 25(OH)D(3) for immune cell synthesis of 1,25-dihydroxyvitamin D(3) at sites of infection has been hypothesized to aid in clearance of the infection. This report details the treatment of an acute intramammary infection with infusion of 25-hydroxyvitamin D(3) to the site of infection. Ten lactating cows were infected with in one quarter of their mammary glands. Half of the animals were treated intramammary with 25-hydroxyvitamin D(3). The 25-hydroxyvitamin D(3) treated animal showed significantly lower bacterial counts in milk and showed reduced symptomatic affects of the mastitis. It is significant that treatment with 25-hydroxyvitamin D(3) reduced the severity of an acute bacterial infection. This finding suggested a significant non-antibiotic complimentary role for 25-hydroxyvitamin D(3) in the treatment of infections in compartments naturally low in 25-hydroxyvitamin D(3) such as the mammary gland and by extension, possibly upper respiratory tract infections. PMID:21991312

  7. Transformation of 25- and 1 alpha-hydroxyvitamin D3 to 1 alpha, 25-dihydroxyvitamin D3 by using Streptomyces sp. strains.

    PubMed Central

    Sasaki, J; Mikami, A; Mizoue, K; Omura, S

    1991-01-01

    To enzymatically synthesize vitamin D derivatives, we screened about 300 Streptomyces sp. strains. Streptomyces sclerotialus FERM BP-1370 and Streptomyces roseoporus FERM BP-1574 were found to have the ability to convert 25-hydroxyvitamin D3 and 1 alpha-hydroxyvitamin D3, respectively, to 1 alpha, 25-dihydroxyvitamin D3. The average rates of 1 alpha hydroxylation of 25-hydroxyvitamin D3 were 6.9 micrograms liter-1 min-1 with FERM BP-1370 and 7.0 micrograms liter-1 min-1 with FERM BP-1574. The specific cytochrome P-450 inhibitors carbon monoxide, SKF-525-A, and metyrapone inhibited the hydroxylation of 1 alpha- and 25-hydroxyvitamin D3 to 1 alpha, 25-dihydroxyvitamin D3 by FERM BP-1370 and FERM BP-1574. The cytochromes P-450 of these strains were detected by reduced CO difference spectra in the whole-cell suspensions. The appearance of cytochrome P-450 suggests that the cytochromes P-450 of FERM BP-1370 and FERM BP-1574 carry out the hydroxylation of 25- and 1 alpha-hydroxyvitamin D3 to 1 alpha, 25-dihydroxyvitamin D3. PMID:1746944

  8. 1 alpha-hydroxyvitamin D3 plus 25-hydroxyvitamin D3 reduces parturient paresis in dairy cows fed high dietary calcium.

    PubMed

    Hodnett, D W; Jorgensen, N A; Deluca, H F

    1992-02-01

    The effectiveness of a combination of 1 alpha-hydroxyvitamin D3 and 25-hydroxyvitamin D3 for reducing incidence of parturient paresis in aged Holstein cows was tested. Intramuscular injection of .5 mg of 1 alpha-hydroxyvitamin D3 plus 4 mg of 25-hydroxyvitamin D3 increased plasma 1,25-dihydroxyvitamin D concentrations through parturition. Treatment with 1 alpha-hydroxyvitamin D3 plus 25-hydroxyvitamin D3 raised prepartum serum Ca approximately 2 mg/dl and prepartum serum P approximately 4 to 5 mg/dl higher than untreated controls. Both treated and control cows had approximately a 2-mg/dl decrease in serum Ca following parturition. The prepartum diet of alfalfa silage and hay was supplemented with a grain mixture supplying 100 g of Ca/d from ground limestone. Under these dietary conditions, incidence of parturient paresis was reduced from 33 to 8%. In a separate experiment, treatment with 1 alpha-hydroxyvitamin D3 plus 25-hydroxyvitamin D3 did not reduce incidence of parturient paresis when cows consumed mixed diets of different feed-stuff composition. Further experiments are required to determine specifically the factor or factors responsible for the difference in response to active vitamin D compound administration between the two experiments. Prepartum dietary Ca intake may be one such factor. PMID:1560144

  9. Comparison of 1,25(OH)2D3 and 24,25(OH)2D3 in the long-term treatment of renal osteodystrophy.

    PubMed

    Muirhead, N; Catto, G R; Edward, N; Fraser, R A; O'Riordan, J L; Papapoulos, S E; Adami, S

    1980-01-01

    24,25(OH)2D3 has been compared with 1,25(OH)2D3 in the treatment of renal osteodystrophy. Treatment with 24, 25(OH)2D3 2 micrograms/day for 5-7 months was accompanied by deterioration in clinical, biochemical, radiological and histological features of osteodystrophy with no increase in Ca absorption. In contrast, treatment with 1,25(OH)2D3 0.25--1 microgram/day for 6-15 months resulted in rapid improvement in clinical, biochemical, radiological and histological features and a return of Ca absorption to normal. It is concluded that in the dose used 24,25(OH)2D3 alone is not an effective treatment for renal osteodystrophy. PMID:6972529

  10. Dopamine D3 Receptor Is Necessary for Ethanol Consumption: An Approach with Buspirone

    PubMed Central

    Leggio, Gian Marco; Camillieri, Giovanni; Platania, Chiara B M; Castorina, Alessandro; Marrazzo, Giuseppina; Torrisi, Sebastiano Alfio; Nona, Christina N; D'Agata, Velia; Nobrega, José; Stark, Holger; Bucolo, Claudio; Le Foll, Bernard; Drago, Filippo; Salomone, Salvatore

    2014-01-01

    Mesolimbic dopamine (DA) controls drug- and alcohol-seeking behavior, but the role of specific DA receptor subtypes is unclear. We tested the hypothesis that D3R gene deletion or the D3R pharmacological blockade inhibits ethanol preference in mice. D3R-deficient mice (D3R−/−) and their wild-type (WT) littermates, treated or not with the D3R antagonists SB277011A and U99194A, were tested in a long-term free choice ethanol-drinking (two-bottle choice) and in a binge-like ethanol-drinking paradigm (drinking in the dark, DID). The selectivity of the D3R antagonists was further assessed by molecular modeling. Ethanol intake was negligible in D3R−/− and robust in WT both in the two-bottle choice and DID paradigms. Treatment with D3R antagonists inhibited ethanol intake in WT but was ineffective in D3R−/− mice. Ethanol intake increased the expression of RACK1 and brain-derived neurotrophic factor (BDNF) in both WT and D3R−/−; in WT there was also a robust overexpression of D3R. Thus, increased expression of D3R associated with activation of RACK1/BDNF seems to operate as a reinforcing mechanism in voluntary ethanol intake. Indeed, blockade of the BDNF pathway by the TrkB selective antagonist ANA-12 reversed chronic stable ethanol intake and strongly decreased the striatal expression of D3R. Finally, we evaluated buspirone, an approved drug for anxiety disorders endowed with D3R antagonist activity (confirmed by molecular modeling analysis), that resulted effective in inhibiting ethanol intake. Thus, DA signaling via D3R is essential for ethanol-related reward and consumption and may represent a novel therapeutic target for weaning. PMID:24584330

  11. Dopamine D3 receptor is necessary for ethanol consumption: an approach with buspirone.

    PubMed

    Leggio, Gian Marco; Camillieri, Giovanni; Platania, Chiara B M; Castorina, Alessandro; Marrazzo, Giuseppina; Torrisi, Sebastiano Alfio; Nona, Christina N; D'Agata, Velia; Nobrega, José; Stark, Holger; Bucolo, Claudio; Le Foll, Bernard; Drago, Filippo; Salomone, Salvatore

    2014-07-01

    Mesolimbic dopamine (DA) controls drug- and alcohol-seeking behavior, but the role of specific DA receptor subtypes is unclear. We tested the hypothesis that D3R gene deletion or the D3R pharmacological blockade inhibits ethanol preference in mice. D3R-deficient mice (D3R(-/-)) and their wild-type (WT) littermates, treated or not with the D3R antagonists SB277011A and U99194A, were tested in a long-term free choice ethanol-drinking (two-bottle choice) and in a binge-like ethanol-drinking paradigm (drinking in the dark, DID). The selectivity of the D3R antagonists was further assessed by molecular modeling. Ethanol intake was negligible in D3R(-/-) and robust in WT both in the two-bottle choice and DID paradigms. Treatment with D3R antagonists inhibited ethanol intake in WT but was ineffective in D3R(-/-) mice. Ethanol intake increased the expression of RACK1 and brain-derived neurotrophic factor (BDNF) in both WT and D3R(-/-); in WT there was also a robust overexpression of D3R. Thus, increased expression of D3R associated with activation of RACK1/BDNF seems to operate as a reinforcing mechanism in voluntary ethanol intake. Indeed, blockade of the BDNF pathway by the TrkB selective antagonist ANA-12 reversed chronic stable ethanol intake and strongly decreased the striatal expression of D3R. Finally, we evaluated buspirone, an approved drug for anxiety disorders endowed with D3R antagonist activity (confirmed by molecular modeling analysis), that resulted effective in inhibiting ethanol intake. Thus, DA signaling via D3R is essential for ethanol-related reward and consumption and may represent a novel therapeutic target for weaning. PMID:24584330

  12. 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.

  13. 25-Hydroxyvitamin D(3) suppresses PTH synthesis and secretion by bovine parathyroid cells.

    PubMed

    Ritter, C S; Armbrecht, H J; Slatopolsky, E; Brown, A J

    2006-08-01

    Active vitamin D compounds repress parathyroid hormone (PTH) gene transcription and block chief cell hyperplasia, making them integral tools in the treatment of secondary hyperparathyroidism in patients with chronic kidney disease. Recently, human parathyroid glands have been shown to express 25-hydroxyvitamin D 1alpha-hydroxylase (1alphaOHase), but documentation of the 1alphaOHase activity in parathyroid cells and its potential role in activating 25-hydroxyvitamin D(3) (25(OH)D(3)) to 1,25-dihydroxyvitamin D(3) (1,25(OH)2D3) have not been reported. The relative potencies of 25(OH)D(3) and 1,25(OH)(2)D(3) in reducing PTH secretion and mRNA were determined in primary cultures of bovine parathyroid cells (bPTC). The effects of blocking 1alphaOHase activity on suppression of PTH mRNA and induction of 24-hydroxylase mRNA were examined. Vitamin D receptor (VDR) affinities were estimated by intact cell competitive binding assay. Metabolism of 25(OH)D(3) by bPTC was assessed using a radioimmunoassay that measures all 1-hydroxylated metabolites of vitamin D. 25(OH)D(3) suppressed PTH secretion and mRNA (ED(50)=2 nM), but was several hundred times less potent than 1,25(OH)(2)D(3). The lower potency of 25(OH)D(3) correlated with its lower VDR affinity. bPTCs converted 25(OH)D(3) to 1-hydroxylated metabolites, but the rate of conversion was low. Inhibition of 1alphaOHase with the cytochrome P450 inhibitor clotrimazole did not block 25(OH)D(3)-mediated suppression of PTH. Clotrimazole enhanced 24-hydroxylase mRNA induction, presumably by inhibiting catabolism of 25(OH)D(3). In conclusion, 25(OH)D(3) suppresses PTH synthesis by parathyroid cells, possibly by direct activation of the VDR. PMID:16807549

  14. 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

  15. 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

  16. Use of 1 alpha-hydroxyvitamin D3 to prevent bovine parturient paresis. VI. Concentrations of vitamin D metabolites and vitamin D3 equivalence in milk.

    PubMed

    Bar, A; Sachs, M; Perlman, R

    1986-11-01

    Concentration of vitamin D metabolites was determined in the milk of control and 1 alpha-hydroxyvitamin D3-injected (700 micrograms) cows that calved 36 to 43 h after treatment. Milk samples were taken 60 h after calving. Concentrations of vitamin D, 25-hydroxyvitamin D, 24,25-dihydroxyvitamin D, and 1,25-dihydroxyvitamin D in milk of the control cows were 372 +/- 24, 264 +/- 68, 68 +/- 26, and 21 +/- 3 ng/L, respectively. Concentrations of vitamin D metabolites in the milk of the treated cows did not differ significantly from those of controls. Concentration of 1 alpha-hydroxyvitamin D3 in milk of treated cows was less than 20 ng/L. In a second experiment, cows were injected twice, at 72-h intervals, with 350 micrograms 1 alpha-hydroxyvitamin D3. Milk was taken 60 h after parturition from cows that calved 37 to 60 h after the second injection. The vitamin D3 equivalence of the milk was 40 +/- 3 IU/L. Results indicate that injection of 700 micrograms 1 alpha-hydroxyvitamin D3 did not affect the concentration of vitamin D metabolites or the vitamin D3 equivalence of milk taken 60 h after calving. PMID:3027149

  17. 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

  18. 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. PMID:26298833

  19. Recent methods for measuring dopamine D3 receptor occupancy in vivo: importance for drug development.

    PubMed

    Le Foll, Bernard; Wilson, Alan A; Graff, Ariel; Boileau, Isabelle; Di Ciano, Patricia

    2014-01-01

    There is considerable interest in developing highly selective dopamine (DA) D3 receptor ligands for a variety of mental health disorders. DA D3 receptors have been implicated in Parkinson's disease, schizophrenia, anxiety, depression, and substance use disorders. The most concrete evidence suggests a role for the D3 receptor in drug-seeking behaviors. D3 receptors are a subtype of D2 receptors, and traditionally the functional role of these two receptors has been difficult to differentiate. Over the past 10-15 years a number of compounds selective for D3 over D2 receptors have been developed. However, translating these findings into clinical research has been difficult as many of these compounds cannot be used in humans. Therefore, the functional data involving the D3 receptor in drug addiction mostly comes from pre-clinical studies. Recently, with the advent of [(11)C]-(+)-PHNO, it has become possible to image D3 receptors in the human brain with increased selectivity and sensitivity. This is a significant innovation over traditional methods such as [(11)C]-raclopride that cannot differentiate between D2 and D3 receptors. The use of [(11)C]-(+)-PHNO will allow for further delineation of the role of D3 receptors. Here, we review recent evidence that the role of the D3 receptor has functional importance and is distinct from the role of the D2 receptor. We then introduce the utility of analyzing [(11)C]-(+)-PHNO binding by region of interest. This novel methodology can be used in pre-clinical and clinical approaches for the measurement of occupancy of both D3 and D2 receptors. Evidence that [(11)C]-(+)-PHNO can provide insights into the function of D3 receptors in addiction is also presented. PMID:25071579

  20. Noncalcemic actions of 1,25-dihydroxyvitamin D3 and clinical applications.

    PubMed

    Holick, M F

    1995-08-01

    Vitamin D is absolutely essential for the maintenance of a healthy skeleton. Without vitamin D, children develop rickets and adults exacerbate their osteoporosis and develop osteomalacia. Casual exposure to sunlight is the major source of vitamin D for most people. During exposure to sunlight, ultraviolet B photons photolyze cutaneous stores of 7-dehydrocholesterol to previtamin D3. Previtamin D3 undergoes a thermal isomerization to form vitamin D3. Increased skin pigmentation, changes in latitude, time of day, sunscreen use, and aging can have a marked influence on the cutaneous production of vitamin D3. Once vitamin D3 is formed in the skin or ingested in the diet, it must be hydroxylated in the liver and kidney to 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. It is now recognized that a wide variety of tissues and cells, both related to calcium metabolism and unrelated to calcium metabolism, are target sites for 1,25(OH)2D3. 1,25(OH)2D3 stimulates intestinal calcium absorption and mobilizes stem cells to mobilize calcium stores from bone. Noncalcemic tissues that possess receptors for 1,25(OH)2D3 respond to the hormone in a variety of ways. Of great interest is that 1,25(OH)2D3 is a potent antiproliferative and prodifferentiation mediator. As a result, 1,25(OH)2D3 and its analogs have wide clinical application in such diverse clinical disorders as rheumatoid and psoriatic arthritis; diabetes mellitus type I; hypertension; cardiac arrhythmias; seizure disorders; cancers of the breast, prostate, and colon; some leukemias and myeloproliferative disorders; chemotherapy-induced hair loss; and skin rejuvenation as well as skin diseases like psoriasis and ichthyosis. PMID:8579891

  1. 1alpha,25-dihydroxyvitamin D3 rapidly inhibits fibroblast-induced collagen gel contraction.

    PubMed

    Greiling, D; Thieroff-Ekerdt, R

    1996-06-01

    1alpha,25-Dihydroxyvitamin D3 (1,25-D3) inhibits the proliferation of fibroblasts in vitro in monolayer culture. We investigated the effect of 1,25-D3 on normal murine and human fibroblasts cultured in collagen type I gels, which more closely resembles the in vivo situation in the dermis. In this culture system 1,25-D3 had no effect on fibroblast proliferation; however, the fibroblast-induced collagen gel contraction was inhibited in a time- and concentration-dependent manner in the nanomolar concentration range. 25-Hydroxyvitamin D3 and 24,25-dihydroxyvitamin D3 were inactive. 1,25-D3 had no effect in fibroblasts lacking a functional vitamin D receptor. Pretreatment of fibroblasts in monolayer culture for 5 min was sufficient to trigger the inhibition of collagen gel contraction. Nifedipine increased collagen gel contraction and counteracted the effect of 1,25-D3. The inhibition of collagen gel contraction by 1,25-D3 is supposed to be mediated by the vitamin D receptor because a functional vitamin D receptor is required, and vitamin D metabolites with low affinity to the vitamin D receptor were inactive. Brief pretreatment of fibroblasts was sufficient to trigger the inhibitory effect of 1,25-D3, suggesting a nongenomic effect. A genomic mode of action could not be ruled out, however, because the inhibition was first measured after 24 h. The antagonism of the calcium channel antagonist nifedipine probably represents the sum of two opposite effects rather than supporting evidence for a nongenomic mode of action of 1,25-D3. In conclusion, 1,25-D3 has a specific and rapidly triggered inhibitory effect on fibroblast-induced collagen gel contraction. PMID:8752663

  2. Improved bioavailability of vitamin D3 using a β-lactoglobulin-based coagulum.

    PubMed

    Diarrassouba, Fatoumata; Garrait, Ghislain; Remondetto, Gabriel; Alvarez, Pedro; Beyssac, Eric; Subirade, Muriel

    2015-04-01

    Vitamin D3 (D3) was encapsulated within a water-soluble matrix, formed by promoting the βlg/D3 complex by acidification. The capacity of the βlg-based coagulum to increase the long term stability of D3 in cold storage, upon exposure to intensive UV-light, and in the presence and absence of intestinal proteases, was evaluated. Additionally, the impact of the sequestration of D3 within the matrix of βlg-based coagulum on its bioavailability was determined in vivo with force-fed rats. The water solubility, long-term storage and UV-light stability of D3 were significantly increased (p < 0.0001) due to the high encapsulation efficiency (94.5 ± 1.8%). The βlg-based coagulum was not rapidly disrupted by the proteases in the intestines, leading to a slow release of D3, increased uptake of D3 and subsequent enhancement of the bioavailability of D3 in rats. PMID:25442565

  3. Food protein-based microspheres for increased uptake of vitamin D3.

    PubMed

    Diarrassouba, Fatoumata; Garrait, Ghislain; Remondetto, Gabriel; Alvarez, Pedro; Beyssac, Eric; Subirade, Muriel

    2015-04-15

    To protect vitamin D3 during cold storage and exposure to UV-light, vitamin D3 has been entrapped in microspheres formed by bovine protein β-lactoglobulin (βlg) and lysozyme (Lyso) from egg white. The behaviour of the βlg/Lyso microspheres in simulated intestinal fluid and their impact on the kinetic release of D3 were determined. The impact of the D3-loaded βlg/Lyso microspheres on the bioavailability of D3 was evaluated in vivo by force-feeding rats. The data indicate that the βlg/Lyso microspheres effectively improved the stability of D3, which was readily released in the intestines. The release kinetics were accelerated in the presence of proteolytic enzymes. The bioavailability of D3 was improved, as confirmed by the significant increase in the serum levels of 25-hydroxy-D3 in rats. The current work demonstrates that water soluble proteins were used to substantially increase the bioavailability of the lipophilic vitamin, and thus can serve in the oral delivery of D3. PMID:25466126

  4. Characterization of the translocation process of vitamin D3 from the skin into the circulation.

    PubMed

    Tian, X Q; Chen, T C; Lu, Z; Shao, Q; Holick, M F

    1994-08-01

    The cutaneous synthesis of vitamin D3 and the subsequent translocation of vitamin D3 into the circulation are two key steps in the vitamin D endocrine system. To study the kinetic aspects of cutaneous synthesis and translocation of vitamin D3, both in vitro and in vivo chicken models have been developed. To assess the capacity of chicken skin to generate vitamin D3, the concentrations of 7-dehydrocholesterol (7-DHC) in different skin areas were determined. It was found that the highest concentration of 7-DHC was in the leg skin (3524 +/- 937 ng cm-2), which was about 30 times greater than that in the back (120 +/- 62 ng cm-2). Whole body exposure of chickens to UV-B radiation (0.5 J cm-2) resulted in the production of previtamin D3 (preD3) in the skin of the legs and feet (43 +/- 7 and 54 +/- 17 ng cm-2, respectively), whereas no preD3 was detected in the back skin. In vitro, at 40 C, the forward (k1) and reverse (k2) rate constants of the preD3<-->vitamin D3 reaction in the leg skin were greatly increased compared to those in n-hexane (k1, 0.367 vs. 0.0369 h-1; k2, 0.042 vs. 0.0059 h-1). In vivo, the determined rate constants k1, k2, and k3 for the consecutive reactions preD3<-->vitamin D3-->vitamin D3 were 0.257, 0.034, and 0.114 h-1, respectively. To evaluate the circulating concentration of vitamin D3 in response to UV-B radiation, chicken legs were irradiated. The time course revealed a 4-fold increase in the circulating concentration of vitamin D3, with a peak about 30 h postradiation. No appreciable amount of preD3 could be detected in the circulation in the early hours after UV-B radiation, suggesting the existence of a process responsible for the specific translocation of vitamin D3 from the skin into the circulation. PMID:8033813

  5. Effects of Solanum malacoxylon extract on rachitic chicks. Comparative study with vitamin D3.

    PubMed

    Cañas, F M; Ortiz, O E; Asteggiano, C A; Pereira, R D

    1977-10-20

    A comparative study of the effects of vitamin D3 and of a partially purified extract of Solanum malacoxylon has been carried out in rachitic chicks. Vitamin D3 and Solanum malacoxylon increased intestinal calcium absorption and serum calcium levels. They normalized the bone water and ash content. Vitamin D3 produced an increase of serum phosphate while Solanum malacoxylon further decreased the already low phosphate values. Vitamin D3 significantly increased the body weight increment of rachitic chicks, but Solanum malacoxylon did not. It appears that Solanum malacoxylon duplicates certain actions of vitamin D but lacks its phosphate-regulating and growth-promoting actions. PMID:198068

  6. 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

  7. Changes at Big Mountain High School: A Teaching Case. Final Deliverable.

    ERIC Educational Resources Information Center

    Smith, BetsAnn; Louis, Karen Seashore

    This case study using pseudonyms was prepared for class discussion in training teachers and administrators who have some responsibility for building-level policy. Big Mountain is a well-established, comprehensive high school that served over 1,450 students in grades 10-12. Considerable autonomy is given to teachers, who have control their teaching…

  8. 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

  9. Serum 25-Hydroxyvitamin D3 and Mammography Density among Mexican Women.

    PubMed

    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

  10. Regulation and functional characterization of a rat recombinant dopamine D3 receptor.

    PubMed

    Cox, B A; Rosser, M P; Kozlowski, M R; Duwe, K M; Neve, R L; Neve, K A

    1995-09-01

    We stably expressed a rat D3 receptor cDNA in C6 glioma cells (C6-D3 cells), quantifying receptor expression with the radioligands [125I]epidepride (KD = 0.1 nM) and [3H]spiperone (KD = 0.7 nM). As reported previously for D2 receptors, quinpirole induced a 9-16% increase in the rate of extracellular acidification by C6-D3 cells. The acidification was inhibited by epidepride and by the Na+/H+ antiporter inhibitors, amiloride and methylisobutylamiloride, but pertussis toxin treatment had no effect on quinpirole-induced extracellular acidification. These data suggest that D3 receptor stimulation of Na+/H+ exchange in C6 glioma cells is not mediated by the pertussis toxin-sensitive G proteins, Gi or G(o). Overnight treatment of C6-D3 cells with N-propylnorapomorphine, dopamine, or quinpirole resulted in large concentration-dependent increases (up to 500%) in the density of D3 receptors on membranes prepared from the cells. Antagonists had smaller, variable effects on the density of D3 receptors in C6-D3 cells, except for domperidone, which significantly increased the density of D3 receptors. Treatment with pertussis toxin had no effect on the agonist-induced receptor up-regulation, indicating that an interaction with pertussis toxin-sensitive G proteins was not required. Densitometry analysis of Northern blots of RNA prepared from C6-D3 cells showed no significant N-propylnorapomorphine-induced increase in D3 receptor message. Treatment with cycloheximide, however, completely prevented receptor up-regulation by N-propylnorapomorphine. Pretreatment of C6-D2 cells with 10 microM DA resulted in a substantial heterologous sensitization, in which isoproterenol-stimulated adenylyl cyclase activity was enhanced more than twofold.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8525456

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

    PubMed Central

    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

    2015-01-01

    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. PMID:26691774

  12. 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

  13. 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

    2015-01-01

    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. PMID:26691774

  14. 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

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

    PubMed

    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 [(11)C]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

  16. Identification of key residues involved in the activation and signaling properties of dopamine D3 receptor.

    PubMed

    Kota, Kokila; Kuzhikandathil, Eldo V; Afrasiabi, Milad; Lacy, Brett; Kontoyianni, Maria; Crider, A Michael; Song, Daniel

    2015-09-01

    The dopamine D3 receptor exhibits agonist-dependent tolerance and slow response termination (SRT) signaling properties that distinguish it from the closely-related D2 receptors. While amino acid residues important for D3 receptor ligand binding have been identified, the residues involved in activation of D3 receptor signaling and induction of signaling properties have not been determined. In this paper, we used cis and trans isomers of a novel D3 receptor agonist, 8-OH-PBZI, and site-directed mutagenesis to identify key residues involved in D3 receptor signaling function. Our results show that trans-8-OH-PBZI, but not cis-8-OH-PBZI, elicit the D3 receptor tolerance and SRT properties. We show that while both agonists require a subset of residues in the orthosteric binding site of D3 receptors for activation of the receptor, the ability of the two isomers to differentially induce tolerance and SRT is mediated by interactions with specific residues in the sixth transmembrane helix and third extracellular loop of the D3 receptor. We also show that unlike cis-8-OH-PBZI, which is a partial agonist at the dopamine D2S receptor and full agonist at dopamine D2L receptor, trans-8-OH-PBZI is a full agonist at both D2S and D2L receptors. The different effect of the two isomers on D3 receptor signaling properties and D2S receptor activation correlated with differential effects of the isomers on agonist-induced mouse locomotor activity. The two isomers of 8-OH-PBZI represent novel pharmacological tools for in silico D3 and D2 receptor homology modeling and for determining the role of D3 receptor tolerance and SRT properties in signaling and behavior. PMID:26116441

  17. 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

  18. 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

  19. 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.

  20. 16 CFR Appendix D3 to Part 305 - Water Heaters-Oil

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 16 Commercial Practices 1 2010-01-01 2010-01-01 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...

  1. 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...

  2. 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 payments. 31.3406(d)-3 Section 31.3406(d)-3 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) EMPLOYMENT TAXES AND COLLECTION OF INCOME TAX AT SOURCE EMPLOYMENT TAXES AND COLLECTION OF INCOME TAX AT SOURCE Collection...

  3. Vitamin D3 regulates cell viability in gastric cancer and cholangiocarcinoma.

    PubMed

    Baek, Sungmin; Lee, Young-Suk; Shim, Hye-Eun; Yoon, Sik; Baek, Sun-Yong; Kim, Bong-Seon; Oh, Sae-Ock

    2011-09-01

    A low serum level of vitamin D has been associated with an increased incidence of gastrointestinal tract cancers. However, the effects of vitamin D3 have not been investigated in gastric cancer and cholangiocarcinoma. In the present study, we found that vitamin D3 treatment significantly suppressed the viability of gastric cancer and cholangiocarcinoma cells. Moreover, vitamin D3 had a synergistic effect with other anti-cancer drugs, such as paclitaxel, adriamycin, and vinblastine, for suppressing cell viability. To determine the underlying mechanism involved in the regulation of viability by vitamin D3, we examined the effects of vitamin D3 on expression of hedgehog signaling target genes, which has been associated with gastric cancer and cholangiocarcinoma. Vitamin D3 treatment decreased the level of mRNA expression of patched1, Gli1, cyclin D1, and Bcl2, suggesting the possibility that vitamin D3 may act through regulation of hedgehog signaling. From the above results, we conclude that vitamin D3 regulates cell viability in gastric cancer and cholangiocarcinoma. PMID:22025972

  4. 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... 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...

  5. Dopamine D3 Receptors Inhibit Hippocampal Gamma Oscillations by Disturbing CA3 Pyramidal Cell Firing Synchrony.

    PubMed

    Lemercier, Clément E; Schulz, Steffen B; Heidmann, Karin E; Kovács, Richard; Gerevich, Zoltan

    2015-01-01

    Cortical gamma oscillations are associated with cognitive processes and are altered in several neuropsychiatric conditions such as schizophrenia and Alzheimer's disease. Since dopamine D3 receptors are possible targets in treatment of these conditions, it is of great importance to understand their role in modulation of gamma oscillations. The effect of D3 receptors on gamma oscillations and the underlying cellular mechanisms were investigated by extracellular local field potential and simultaneous intracellular sharp micro-electrode recordings in the CA3 region of the hippocampus in vitro. D3 receptors decreased the power and broadened the bandwidth of gamma oscillations induced by acetylcholine or kainate. Blockade of the D3 receptors resulted in faster synchronization of the oscillations, suggesting that endogenous dopamine in the hippocampus slows down the dynamics of gamma oscillations by activation of D3 receptors. Investigating the underlying cellular mechanisms for these effects showed that D3 receptor activation decreased the rate of action potentials (APs) during gamma oscillations and reduced the precision of the AP phase coupling to the gamma cycle in CA3 pyramidal cells. The results may offer an explanation how selective activation of D3 receptors may impair cognition and how, in converse, D3 antagonists may exert pro-cognitive and antipsychotic effects. PMID:26779018

  6. 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.

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  8. 17 CFR 240.14d-3 - Filing and transmission of tender offer statement.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... tender offer statement. 240.14d-3 Section 240.14d-3 Commodity and Securities Exchanges SECURITIES AND... tender offer statement. (a) Filing and transmittal. No bidder shall make a tender offer if, after... subject company's securities for which the tender offer is made, unless as soon as practicable on the...

  9. Effect of vitamin D3 on chemokine levels and regulatory T-cells in pulmonary tuberculosis.

    PubMed

    Harishankar, M; Anbalagan, S; Selvaraj, P

    2016-05-01

    1,25-Dihydroxyvitamin D3 [1,25(OH)2D3] the active form of vitamin D3 acts as an immunomodulator in various immune cells. The present study is aimed to study the effect of 1,25(OH)2D3 on chemokine levels and regulatory T-cells in 51 healthy controls (HCs) and 50 pulmonary tuberculosis (PTB) patients. Peripheral blood mononuclear cells were cultured with culture filtrate antigen (CFA) of Mycobacterium tuberculosis in the presence or absence of 1,25(OH)2D3 at 10(-7)M concentration for 72h and the percentage positive regulatory T-cell subsets were studied using flow cytometry. The chemokine levels were estimated in the culture supernatants by ELISA. 1,25(OH)2D3 significantly upregulated the frequency of regulatory T-cell subsets while suppressed the production of chemokine levels in CFA stimulated cultures of HCs and PTB patients (p<0.05). Correlation analysis revealed a significant negative correlation between CD4+Foxp3+ regulatory T-cells and MCP-1, MIP-1β and IP-10 in CFA stimulated with 1,25(OH)2D3 treated cells (p<0.05). The results suggested that 1,25(OH)2D3 upregulated regulatory T-cells and act as anti-inflammatory by downregulating chemokine levels which could be beneficial to protect the host from inflammation and tissue damage during infection. PMID:26927615

  10. Dopamine D3 Receptors Inhibit Hippocampal Gamma Oscillations by Disturbing CA3 Pyramidal Cell Firing Synchrony

    PubMed Central

    Lemercier, Clément E.; Schulz, Steffen B.; Heidmann, Karin E.; Kovács, Richard; Gerevich, Zoltan

    2016-01-01

    Cortical gamma oscillations are associated with cognitive processes and are altered in several neuropsychiatric conditions such as schizophrenia and Alzheimer’s disease. Since dopamine D3 receptors are possible targets in treatment of these conditions, it is of great importance to understand their role in modulation of gamma oscillations. The effect of D3 receptors on gamma oscillations and the underlying cellular mechanisms were investigated by extracellular local field potential and simultaneous intracellular sharp micro-electrode recordings in the CA3 region of the hippocampus in vitro. D3 receptors decreased the power and broadened the bandwidth of gamma oscillations induced by acetylcholine or kainate. Blockade of the D3 receptors resulted in faster synchronization of the oscillations, suggesting that endogenous dopamine in the hippocampus slows down the dynamics of gamma oscillations by activation of D3 receptors. Investigating the underlying cellular mechanisms for these effects showed that D3 receptor activation decreased the rate of action potentials (APs) during gamma oscillations and reduced the precision of the AP phase coupling to the gamma cycle in CA3 pyramidal cells. The results may offer an explanation how selective activation of D3 receptors may impair cognition and how, in converse, D3 antagonists may exert pro-cognitive and antipsychotic effects. PMID:26779018

  11. Functional Regulation of Dopamine D3 Receptor through Interaction with PICK1

    PubMed Central

    Zheng, Mei; Zhang, Xiaohan; Min, Chengchun; Choi, Bo-Gil; Oh, In-Joon; Kim, Kyeong-Man

    2016-01-01

    PICK1, a PDZ domain-containing protein, is known to increase the reuptake activities of dopamine transporters by increasing their expressions on the cell surface. Here, we report a direct and functional interaction between PICK1 and dopamine D3 receptors (D3R), which act as autoreceptors to negatively regulate dopaminergic neurons. PICK1 colocalized with both dopamine D2 receptor (D2R) and D3R in clusters but exerted different functional influences on them. The cell surface expression, agonist affinity, endocytosis, and signaling of D2R were unaffected by the coexpression of PICK1. On the other hand, the surface expression and tolerance of D3R were inhibited by the coexpression of PICK1. These findings show that PICK1 exerts multiple effects on D3R functions. PMID:27169823

  12. 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

  13. 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

  14. Vitamin D3 alters microglia immune activation by an IL-10 dependent SOCS3 mechanism.

    PubMed

    Boontanrart, Mandy; Hall, Samuel D; Spanier, Justin A; Hayes, Colleen E; Olson, Julie K

    2016-03-15

    Microglia become activated immune cells during infection or disease in the central nervous system (CNS). However, the mechanisms that downregulate activated microglia to prevent immune-mediated damage are not completely understood. Vitamin D3 has been suggested to have immunomodulatory affects, and high levels of vitamin D3 have been correlated with a decreased risk for developing some neurological diseases. Recent studies have demonstrated the synthesis of active vitamin D3, 1,25-dihydroxyvitamin D3, within the CNS, but its cellular source and neuroprotective actions remain unknown. Therefore, we wanted to determine whether microglia can respond to vitamin D3 and whether vitamin D3 alters immune activation of microglia. We have previously shown that microglia become activated by IFNγ or LPS or by infection with virus to express pro-inflammatory cytokines, chemokines, and effector molecules. In this study, activated microglia increased the expression of the vitamin D receptor and Cyp27b1, which encodes the enzyme for converting vitamin D3 into its active form, thereby enhancing their responsiveness to vitamin D3. Most importantly, the activated microglia exposed to vitamin D3 had reduced expression of pro-inflammatory cytokines, IL-6, IL-12, and TNFα, and increased expression of IL-10. The reduction in pro-inflammatory cytokines was dependent on IL-10 induction of suppressor of cytokine signaling-3 (SOCS3). Therefore, vitamin D3 increases the expression of IL-10 creating a feedback loop via SOCS3 that downregulates the pro-inflammatory immune response by activated microglia which would likewise prevent immune mediated damage in the CNS. PMID:26943970

  15. 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

  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. PMID:16098191

  17. 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. PMID:24968784

  18. Kinetic studies of 25-hydroxy-19-nor-vitamin D3 and 1 alpha,25-dihydroxy-19-nor-vitamin D3 hydroxylation by CYP27B1 and CYP24A1.

    PubMed

    Urushino, Naoko; Nakabayashi, Sachie; Arai, Midori A; Kittaka, Atsushi; Chen, Tai C; Yamamoto, Keiko; Hayashi, Keiko; Kato, Shigeaki; Ohta, Miho; Kamakura, Masaki; Ikushiro, Shinichi; Sakaki, Toshiyuki

    2007-09-01

    Our previous study demonstrated that 25-hydroxy-19-nor-vitamin D(3) [25(OH)-19-nor-D(3)] inhibited the proliferation of immortalized noncancerous PZ-HPV-7 prostate cells similar to 1 alpha,25-dihydroxyvitamin D(3) [1 alpha,25(OH)(2)D(3)], suggesting that 25(OH)-19-nor-D(3) might be converted to 1 alpha,25-dihydroxy-19-nor-vitamin D(3) [1 alpha,25(OH)(2)-19-nor-D(3)] by CYP27B1 before exerting its antiproliferative activity. Using an in vitro cell-free model to study the kinetics of CYP27B1-dependent 1 alpha-hydroxylation of 25(OH)-19-nor-D(3) and 25-hydroxyvitamin D(3) [25(OH)D(3)] and CYP24A1-dependent hydroxylation of 1 alpha,25(OH)-19-nor-D(3) and 1 alpha,25(OH)(2)D(3), we found that k(cat)/K(m) for 1 alpha-hydroxylation of 25(OH)-19-nor-D(3) was less than 0.1% of that for 25(OH)D(3), and the k(cat)/K(m) value for 24-hydroxylation was not significantly different between 1 alpha,25(OH)(2)-19-nor-D(3) and 1 alpha,25(OH)(2)D(3). The data suggest a much slower formation and a similar rate of degradation of 1 alpha,25(OH)(2)-19-nor-D(3) compared with 1 alpha,25(OH)(2)D(3). We then analyzed the metabolites of 25(OH)D(3) and 25(OH)-19-nor-D(3) in PZ-HPV-7 cells by high-performance liquid chromatography. We found that a peak that comigrated with 1 alpha,25(OH)(2)D(3) was detected in cells incubated with 25(OH)D(3), whereas no 1 alpha,25(OH)(2)-19-nor-D(3) was detected in cells incubated with 25(OH)-19-nor-D(3). Thus, the present results do not support our previous hypothesis that 25(OH)-19-nor-D(3) is converted to 1 alpha,25(OH)(2)-19-nor-D(3) by CYP27B1 in prostate cells to inhibit cell proliferation. We hypothesize that 25(OH)-19-nor-D(3) by itself may have a novel mechanism to activate vitamin D receptor or it is metabolized in prostate cells to an unknown metabolite with antiproliferative activity without 1 alpha-hydroxylation. Thus, the results suggest that 25(OH)-19-nor-D(3) has potential as an attractive agent for prostate cancer therapy. PMID:17553915

  19. 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).

  20. 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. PMID:22916880

  1. Effect of 1,25-dihydroxyvitamin D3 on phospholipid metabolism in cultured bovine parathyroid cells.

    PubMed

    Sugimoto, T; Ritter, C; Slatopolsky, E; Morrissey, J

    1988-06-01

    There is evidence that 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] affects phospholipid metabolism of intestine, kidney, and bone. There are no such studies concerning the parathyroid gland, which is also a target tissue for 1,25-(OH)2D3. In this investigation we examined the effect of 1,25-(OH)2D3 on the incorporation of radiolabeled choline, inositol, serine, and ethanolamine into the phospholipids of cultured bovine parathyroid cells. Treatment with 10(-8) M 1,25-(OH)2D3 for 48 h caused a significant decrease in [14C]choline incorporation, although there were no differences in the incorporation of radiolabeled inositol, serine, or ethanolamine. Time-course and dose-response evaluations of the 1,25-(OH)2D3 effect revealed that the decrease in [14C]choline incorporation was seen within 12 h of incubation and occurred with as little as 10(-9) M, respectively. In contrast, neither 10(-7) M 25-hydroxyvitamin D3 nor 10(-7) M 24,25-(OH)2D3 caused significant changes in [14C]choline incorporation. When 5 X 10(-6) M cycloheximide was added to the medium, the inhibitory effect of 1,25-(OH)2D3 on [14C]choline incorporation was completely abolished. A significant decrease in phosphatidylcholine content was observed after treatment with 10(-8) M 1,25-(OH)2D3 for 96 h. 1,25-(OH)2D3 did not cause a dramatic change in the fatty acid composition of the phosphatidylcholine. The present studies demonstrate that in parathyroid cells 1,25-(OH)2D3 causes a decrease in [14C]choline incorporation, which could be due to a decrease in the synthesis of phosphatidylcholine or increased degradation. This effect is specific for 1,25-(OH)2D3 and requires new protein synthesis. PMID:3131114

  2. 79 FR 46993 - Food Additives Permitted for Direct Addition to Food for Human Consumption; Vitamin D3

    Federal Register 2010, 2011, 2012, 2013, 2014

    2014-08-12

    ... to Food for Human Consumption; Vitamin D 3 AGENCY: Food and Drug Administration, HHS. ACTION: Final... to provide for the safe use of vitamin D 3 as a nutrient supplement in meal replacement beverages.... 172.380 (21 CFR 172.380), Vitamin D 3 , to provide for the safe use of vitamin D 3 as a...

  3. Dose response to vaginal administration of 1,25-dihydroxyvitamin D3 to cows.

    PubMed

    Okura, N; Yamagishi, N; Naito, Y; Koiwa, M

    2007-07-01

    It was previously reported that intravaginal (IVAG) administration of 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) might be protective against bovine hypocalcaemia. In the present study, various doses of exogenous 1,25(OH)(2)D(3) were administered IVAG to ovariectomised cows, and the subsequent changes in the biochemical parameters of the blood were measured to assess the characteristics of vaginal absorption. Five cows received 1,25(OH)(2)D(3) IVAG at a dose of 0.125, 0.25, 0.5, or 1.0microg/kg of body weight (BW) or intravenously at a dose of 1.0microg/kg BW. Dosing was at intervals of at least two weeks in a 5x5 Latin square design. Vaginally administered 1,25(OH)(2)D(3) was absorbed in a dose-dependent manner. There was no correlation between the IVAG dose of 1,25(OH)(2)D(3) and subsequent changes in plasma calcium concentrations. The bioavailability of 1,25(OH)(2)D(3) administered IVAG at 1.0microg/kg BW was approximately 93%. PMID:16759888

  4. 1,25-Dihydroxyvitamin D3 and retinoid X receptor expression in human colorectal neoplasms.

    PubMed Central

    Kane, K F; Langman, M J; Williams, G R

    1995-01-01

    Epidemiological studies suggest that 1,25-dihydroxyvitamin D3 (D3) protects against colorectal carcinogenesis. Animal and in vitro studies show an antiproliferative effect of D3 in a variety of tumours including those of large bowel origin. D3 actions are mediated by D3 receptors (VDR) alone or by VDR in conjunction with retinoid X receptors (RXRs) in all D3 responsive tissues. The expression of mRNAs encoding VDR and RXRs in normal and malignant human colorectum was determined. Full length VDR (4.6 kB), RXR alpha (5.5 kB), and RXR gamma (3.5 and 7 kB) mRNAs were expressed in all tissues, but RXR beta mRNA was not expressed in any. VDR expression was reduced in 12 carcinomas relative to paired normal mucosa, and RXR alpha expression was reduced in nine. There was no correlation between VDR or RXR alpha expression and the site, grade of differentiation, or Dukes's staging of the tumour. The finding of persistent VDR and RXR coexpression in all colorectal tumours provides a rational basis for exploring a role for D3 in the treatment of colorectal malignancy. Images Figure 1 Figure 2 PMID:7883226

  5. Homology modeling of dopamine D2 and D3 receptors: molecular dynamics refinement and docking evaluation.

    PubMed

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

    2012-01-01

    Dopamine (DA) receptors, a class of G-protein coupled receptors (GPCRs), have been targeted for drug development for the treatment of neurological, psychiatric and ocular disorders. The lack of structural information about GPCRs and their ligand complexes has prompted the development of homology models of these proteins aimed at structure-based drug design. Crystal structure of human dopamine D(3) (hD(3)) receptor has been recently solved. Based on the hD(3) receptor crystal structure we generated dopamine D(2) and D(3) receptor models and refined them with molecular dynamics (MD) protocol. Refined structures, obtained from the MD simulations in membrane environment, were subsequently used in molecular docking studies in order to investigate potential sites of interaction. The structure of hD(3) and hD(2L) receptors was differentiated by means of MD simulations and D(3) selective ligands were discriminated, in terms of binding energy, by docking calculation. Robust correlation of computed and experimental K(i) was obtained for hD(3) and hD(2L) receptor ligands. In conclusion, the present computational approach seems suitable to build and refine structure models of homologous dopamine receptors that may be of value for structure-based drug discovery of selective dopaminergic ligands. PMID:22970199

  6. Homology Modeling of Dopamine D2 and D3 Receptors: Molecular Dynamics Refinement and Docking Evaluation

    PubMed Central

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

    2012-01-01

    Dopamine (DA) receptors, a class of G-protein coupled receptors (GPCRs), have been targeted for drug development for the treatment of neurological, psychiatric and ocular disorders. The lack of structural information about GPCRs and their ligand complexes has prompted the development of homology models of these proteins aimed at structure-based drug design. Crystal structure of human dopamine D3 (hD3) receptor has been recently solved. Based on the hD3 receptor crystal structure we generated dopamine D2 and D3 receptor models and refined them with molecular dynamics (MD) protocol. Refined structures, obtained from the MD simulations in membrane environment, were subsequently used in molecular docking studies in order to investigate potential sites of interaction. The structure of hD3 and hD2L receptors was differentiated by means of MD simulations and D3 selective ligands were discriminated, in terms of binding energy, by docking calculation. Robust correlation of computed and experimental Ki was obtained for hD3 and hD2L receptor ligands. In conclusion, the present computational approach seems suitable to build and refine structure models of homologous dopamine receptors that may be of value for structure-based drug discovery of selective dopaminergic ligands. PMID:22970199

  7. 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. PMID:25266821

  8. 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

  9. Pramipexole inhibits MPTP toxicity in mice by dopamine D3 receptor dependent and independent mechanisms.

    PubMed

    Ramirez, Andres D; Wong, Stephen K-F; Menniti, Frank S

    2003-08-15

    The role of dopamine D3 receptors was investigated in mediating the neuroprotective effect of the dopamine D2/D3 receptor agonist (S)-2-amino-4,5,6,7-tetrahydro-6-propylamine-benzothiazole (pramipexole) in vivo. Pramipexole retained the ability to inhibit 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopamine depletion in mice in which the dopamine D3 receptor had been deleted. However, the neuroprotective efficacy was reduced in the dopamine D3 receptor-deleted mice compared to that in littermates expressing the wildtype receptor. Furthermore, the dopamine D3 receptor selective antagonist 2-(3-[4-(2-tert-butyl-6-trifluoromethyl-4-pyrimidinyl)-1-piperazinyl]propylthio)-4-pyrimidinol (A-437203) partially inhibited the neuroprotective effect of pramipexole in dopamine D3 receptor expressing mice but not in receptor-deleted mice. These results indicate that pramipexole protects dopamine neurons from MPTP-induced toxicity by mechanisms that are both dependent and independent of an interaction with dopamine D3 receptors. PMID:12954356

  10. Regulation of calcium signaling in dendritic cells by 1,25-dihydroxyvitamin D3.

    PubMed

    Shumilina, Ekaterina; Xuan, Nguyen Thi; Matzner, Nicole; Bhandaru, Madhuri; Zemtsova, Irina M; Lang, Florian

    2010-06-01

    Dendritic cells (DCs) are antigen-presenting cells that provide a link between innate and adaptive immunity. Ca(2+)-dependent signaling plays a central regulatory role in DC responses to diverse antigens. DCs are a primary target of 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], a secosteroid hormone, that, in addition to its well-established action on Ca(2+) homeostasis, possesses immunomodulatory properties. Surprisingly, nothing is known about its effects on DC cytosolic Ca(2+) activity. The present study explored whether 1,25(OH)(2)D(3) modifies the intracellular Ca(2+) concentration ([Ca(2+)](i)) in DCs. Here we show that mouse DCs expressed K(+)-independent (NCX1-3) and K(+)-dependent (NCKX1, 3, 4, and 5) Na(+)/Ca(2+) exchangers. Acute application of LPS (100 ng/ml) to DCs increased [Ca(2+)](i), an effect significantly blunted by prior incubation with 1,25(OH)(2)D(3). 1,25(OH)(2)D(3) increased the membrane abundance of the NCKX1 protein, up-regulated the K(+)- and Na(+)-dependent Ca(2+) entry and enhanced the K(+)-dependent Na(+)/Ca(2+) exchanger currents. The NCKX blocker 3',4'-dichlorobenzamyl (DBZ) reversed the inhibitory effect of 1,25(OH)(2)D(3) on the LPS-induced increase of [Ca(2+)](i). Expression of the costimulatory molecule CD86 was down-regulated by 1,25(OH)(2)D(3), an effect reversed by DBZ. In summary, 1,25(OH)(2)D(3) blunts the LPS-induced increase in [Ca(2+)](i) by stimulation of Na(+)/Ca(2+) exchanger-dependent Ca(2+) extrusion, an effect that contributes to 1,25(OH)(2)D(3)-mediated immunosuppression. The results disclose completely novel mechanisms in the regulation of DC maturation and function. PMID:20124438

  11. Vitamin D3 potentiates the antitumorigenic effects of arsenic trioxide in human leukemia (HL-60) cells

    PubMed Central

    2014-01-01

    Background Arsenic trioxide (ATO) is a novel form of therapy that has been found to aid acute promyelocytic leukemia (APL) patients. Our laboratory has demonstrated that ATO-induced cytotoxicity in human leukemia (HL-60) cells is mediated by oxidative stress. Pro-oxidants have been known to play a role in free radical-mediated oxidative stress. Vitamin D3, (Vit D3) an active metabolite of vitamin D has been reported to inhibit the growth of number neoplasms such as prostate, breast, colorectal, leukemia, and skin cancers. The goal of the present research was to use (HL-60) cells as an in vitro test model to evaluate whether low doses of Vit D3 potentiate the toxicity of ATO and whether this toxic action is mediated via apoptotic mechanisms. Method HL-60 cells were treated either with a pharmacologic dose of ATO alone and with several low doses of Vit D3. Cell survival was determined by MTT assay. Cell apoptosis was measured both by flow cytometry assessment, and DNA laddering assay. Results MTT assay indicated that Vit D3 co-treatment potentiates ATO toxicity in HL-60 cells in a dose dependent manner. A statistically significant and dose-dependent increase (p <0.05) was recorded in annexin V positive cells (apoptotic cells) with increasing doses of Vit D3 in ATO-treated cells. This finding was confirmed by the result of DNA laddering assay showing clear evidence of nucleosomal DNA fragmentation in vitamin and ATO co-treated cells. Conclusion The present study indicates that Vit D3 potentiates the antitumor effects of ATO. This potentiation is mediated at least in part, through induction of phosphatidylserine externalization and nucleosomal DNA fragmentation. These findings highlight the potential impact of Vit D3 in promoting the pharmacological effect of ATO, suggesting a possible future role of Vit D3/ATO combination therapy in patients with acute promyelocytic leukemia (APL). PMID:24661615

  12. Benzothiadiazole (BTH) activates sterol pathway and affects vitamin D3 metabolism in Solanum malacoxylon cell cultures.

    PubMed

    Burlini, Nedda; Iriti, Marcello; Daghetti, Anna; Faoro, Franco; Ruggiero, Antonietta; Bernasconi, Silvana

    2011-11-01

    Benzo-(1,2,3)-thiadiazole-7-carbothioic acid S-methyl ester (BTH), a particularly efficient inducer of systemic acquired resistance (SAR), was developed as an immunizing agent to sensitize various crop species against pathogen infections. Recent works highlighted its activating effect on different metabolic pathways, concerning both primary and secondary metabolites. In this study, we investigated the effect of BTH treatment on sterol levels and vitamin D(3) metabolism in Solanum malacoxylon cultures. Calli of S. malacoxylon were incubated in Gamborg B5 liquid medium alone or added with 50 μM BTH for different times (one, two or three cycles of light). Histocytochemical investigations performed on our experimental system using 3,3'-diaminobenzidine (DAB) for hydrogen peroxide (H(2)O(2)) detection and phloroglucinol for lignin staining showed that BTH causes H(2)O(2) accumulation and lignin deposition in treated calli. Gas chromatographic analysis of principal cell membrane sterols (β-sitosterol, campesterol, stigmasterol) showed that BTH transiently increases their cellular levels. Callus cultures were found to contain also cholesterol, 7-dehydrocholesterol, the putative precursor of vitamin D(3), and the hydroxylated metabolites 25-hydroxyvitamin D(3) [25(OH)D(3)] and 1α,25-dihydroxyvitamin D(3) [1α,25(OH)(2)D(3)]. BTH treatment enhanced 7-dehydrocholesterol while reduced cholesterol. HPLC analysis of sample extracts showed that BTH does not affect the cell content of vitamin D(3), though results of ELISA tests highlighted that this elicitor moderately enhances the levels of 25(OH)D(3) and 1α,25(OH)(2)D(3) metabolites. In conclusion, BTH treatment not only causes cell wall strengthening, a typical plant defence response, as just described in other experimental models, but in the same time increases the cellular level of the main sterols and 7-dehydrocholesterol. PMID:21779826

  13. 1,25-Dihydroxyvitamin-D3 Induces Avian β-Defensin Gene Expression in Chickens

    PubMed Central

    Zhang, Guolong; Ouyang, Linghua; Robinson, Kelsy; Tang, Yanqiang; Zhu, Qing; Li, Diyan; Hu, Yaodong; Liu, Yiping

    2016-01-01

    Host defense peptides (HDPs) play a critical role in innate immunity. Specific modulation of endogenous HDP synthesis by dietary compounds has been regarded as a novel approach to boost immunity and disease resistance in animal production. 1,25-dihydroxy vitamin D3 (1,25D3) is well known as a powerful HDP inducer in humans, but limited information about the effect of 1,25D3 on HDPs in poultry is available. Here, we sought to examine whether 1,25D3 could stimulate avian β-defensin (AvBD) expression in chickens. We used chicken embryo intestinal epithelial cells (CEIEPCs) and peripheral blood mononuclear cells (PBMCs) to study the effect of 1,25D3 on the expression of AvBDs. We observed that 1,25D3 is able to up-regulate the expression of several AvBDs in CEIEPCs and PBMCs, whereas it increased the amounts of AvBD4 mRNA in CEIEPCs only in the presence of lipopolysaccharide (LPS). On the other hand, LPS treatment not only inhibited the expression of CYP24A1 but also altered the expression pattern of VDR in CEIEPCs. Furthermore, AvBDs were not directly regulated by 1,25D3, as cycloheximide completely blocked 1,25D3-induced expression of AvBDs. Our observations suggest that 1,25D3 is capable of inducing AvBD gene expression and is a potential antibiotic alternative through augmentation of host innate immunity as well as disease control in chickens. PMID:27135828

  14. Modulation of the Bovine Innate Immune Response by Production of 1alpha,25-Dihydroxyvitamin D3 in Bovine Monocytes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In cattle, the kidney has been the only known site for production of 1,25-dihydroxyvitamin D3 (1,25[OH]2D3) from 25-hydroxyvitamin D3 25(OH)D3 by 1alpha-hydroxylase (1alpha-OHase). However, recent studies have shown that human monocytes express 1alpha-OHase and produce 1,25(OH)2D3 in response to to...

  15. 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.

  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. PMID:27349735

  17. E3-brane instantons and baryonic operators for D3-branes on toric singularities

    NASA Astrophysics Data System (ADS)

    Forcella, Davide; García-Etxebarria, Iñaki; Uranga, Angel

    2009-03-01

    We consider the couplings induced on the world-volume field theory of D3-branes at local toric Calabi-Yau singularities by euclidean D3-brane (E3-brane) instantons wrapped on (non-compact) holomorphic 4-cycles. These instantons produce insertions of BPS baryonic or mesonic operators of the four-dimensional Script N = 1 quiver gauge theory. We argue that these systems underlie, via the near-horizon limit, the familiar AdS/CFT map between BPS operators and D3-branes wrapped on supersymmetric 3-cycles on the 5d horizon. The relation implies that there must exist E3-brane instantons with appropriate fermion mode spectrum and couplings, such that their non-perturbative effects on the D3-branes induce operators forming a generating set for all BPS operators of the quiver CFT. We provide a constructive argument for this correspondence, thus supporting the picture.

  18. D3 receptor test in vitro predicts decreased cocaine self-administration in rats.

    PubMed

    Caine, S B; Koob, G F; Parsons, L H; Everitt, B J; Schwartz, J C; Sokoloff, P

    1997-07-01

    The three dopamine agonists with highest reported D3 receptor selectivity in vitro, pramipexole, quinelorane and PD128,907, decreased self-administration of a high dose of cocaine in rats as a result of a leftward shift in the cocaine dose-effect function. In contrast the D3 preferring antagonist nafadotride increased cocaine self-administration. Moreover the relative potencies of these and other D2-like dopamine agonists (lisuride, 7-OH-DPAT, quinpirole, apomorphine, bromocriptine) to modulate cocaine self-administration were highly correlated with their relative potencies for increasing mitogenesis in vitro in cell lines expressing D3 but not D2 receptors. These results support the hypothesis that the D3 receptor may be an important target for pharmacotherapies for cocaine abuse and dependence. PMID:9243643

  19. Regulation of human tonsillar T-cell proliferation by the active metabolite of vitamin D3.

    PubMed Central

    Nunn, J D; Katz, D R; Barker, S; Fraher, L J; Hewison, M; Hendy, G N; O'Riordan, J L

    1986-01-01

    We have examined the effects of 1,25(OH)2D3 on T-cell populations isolated by buoyant density and E rosetting from human tonsils. Cell proliferation was assessed by measuring the incorporation of 125iododeoxyuridine; interleukin-2 (IL-2) production was measured using an IL-2-dependent cell line, and the number of 1,25(OH)2D3 receptors was measured by whole-cell nuclear association assay. At a concentration of 10(-7) M, 1,25(OH)2D3 inhibited mitogen-induced T-cell proliferation in all E+ T-cell populations. This effect was more pronounced in the cells from the intermediate and high density layers and was reflected both in cell proliferative responses and in relative IL-2 synthesis. By adding the 1,25(OH)2D3 during the course of the mitogen assay, we demonstrated that activation of the T cell precedes the 1,25(OH)2D3-mediated inhibition. Cells that had been preincubated with mitogen in the presence of the 1,25(OH)2D3 were refractory to further stimulation by mitogens. Receptors for 1,25(OH)2D3 could not be detected in unstimulated T cells. However, activation led to the expression of high-affinity receptors for 1,25(OH)2D3. Co-incubation of the cells with mitogen and 1,25(OH)2D3 increased the number of receptors compared with mitogen alone. The effects provide further evidence for the hypothesis that 1,25(OH)2D3 is an important potential modulator of the immune system through its action on T cells. Taking our observations in conjunction with the known capacity of monocytes to hydroxylate the precursor metabolite (and thus synthesize the active form of cholecalciferol), the results support the suggestion that 1,25(OH)2D3 plays a role as a local mediator of mononuclear phagocyte-T cell interaction in human lymphomedullary tissues. PMID:3026959

  20. Regulation of Mycobacterium-specific mononuclear cell responses by 25-hydroxyvitamin D3.

    PubMed

    Nelson, Corwin D; Nonnecke, Brian J; Reinhardt, Timothy A; Waters, W Ray; Beitz, Donald C; Lippolis, John D

    2011-01-01

    The active vitamin D metabolite, 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), has been shown to be an important regulator of innate and adaptive immune function. In addition, synthesis of 1,25(OH)(2)D(3) from 25-hydroxyvitamin D(3) (25(OH)D(3)) by the enzyme 1α-hydroxylase in monocytes upon activation by TLR signaling has been found to regulate innate immune responses of monocytes in an intracrine fashion. In this study we wanted to determine what cells expressed 1α-hydroxylase in stimulated peripheral blood mononuclear cell (PBMC) cultures and if conversion of 25(OH)D(3) to 1,25(OH)(2)D(3) in PBMC cultures regulated antigen-specific immune responses. Initially, we found that stimulation of PBMCs from animals vaccinated with Mycobacterium bovis (M. bovis) BCG with purified protein derivative of M. bovis (M. bovis PPD) induced 1α-hydroxylase gene expression and that treatment with a physiological concentration of 25(OH)D(3) down-regulated IFN-γ and IL-17F gene expression. Next, we stimulated PBMCs from M. bovis BCG-vaccinated and non-vaccinated cattle with M. bovis PPD and sorted them by FACS according to surface markers for monocytes/macrophages (CD14), B cells (IgM), and T cells (CD3). Sorting the PBMCs revealed that 1α-hydroxylase expression was induced in the monocytes and B cells, but not in the T cells. Furthermore, treatment of stimulated PBMCs with 25(OH)D(3) down-regulated antigen-specific IFN-γ and IL-17F responses in the T cells, even though 1α-hydroxylase expression was not induced in the T cells. Based on evidence of no T cell 1α-hydroxylase we hypothesize that activated monocytes and B cells synthesize 1,25(OH)(2)D(3) and that 1,25(OH)(2)D(3) down-regulates antigen-specific expression of IFN-γ and IL-17F in T cells in a paracrine fashion. PMID:21738762

  1. 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

  2. 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

  3. 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. PMID:24462727

  4. 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

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

    DOE PAGESBeta

    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 [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

  6. 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. PMID:26909847

  7. 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

  8. 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.

  9. Synthesis, Pharmacological Evaluation and Molecular Modeling Studies of Triazole Containing Dopamine D3 Receptor Ligands

    PubMed Central

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

    2015-01-01

    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. PMID:25556097

  10. 1,25-Dihydroxyvitamin D3 enhances neural stem cell proliferation and oligodendrocyte differentiation.

    PubMed

    Shirazi, Hasti Atashi; Rasouli, Javad; Ciric, Bogoljub; Rostami, Abdolmohamad; Zhang, Guang-Xian

    2015-04-01

    1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) has recently been found to suppress experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Although its effect was attributed to an anti-inflammatory mechanism, it is not clear whether this treatment can also directly act on neural cells to promote CNS recovery. The present study investigates the effect of various concentrations of 1,25(OH)2D3 on neural stem cell (NSC) proliferation and their differentiation to oligodendrocytes, the myelinating cells. We have, for the first time, shown that NSCs constitutively express vitamin D receptor (VDR), which can be upregulated by 1,25(OH)2D3. This vitamin significantly enhanced proliferation of NSCs, and enhanced their differentiation into neurons and oligodendrocytes, but not astrocytes. NSCs treated with 1,25(OH)2D3 showed increased expression of NT-3, BDNF, GDNF and CNTF, important neurotrophic factors for neural cell survival and differentiation. Overall, we demonstrated that 1,25(OH)2D3 has a direct effect on NSC proliferation, survival, and neuron/oligodendrocyte differentiation, thus representing a novel mechanism underlying its remyelinating and neuroprotective effect in MS/EAE therapy. PMID:25681066

  11. Photoaffinity labeling of the 1,25-dihydroxyvitamin D-3 receptor.

    PubMed

    Brown, T A; DeLuca, H F

    1991-03-01

    Underivatized 1,25-dihydroxy[26,27-3H]vitamin D-3 was successfully used to photoaffinity label the 1,25-dihydroxyvitamin D-3 receptor. The covalent incorporation of tritium into the receptor protein was induced by ultraviolet irradiation of the receptor-1,25-dihydroxy[26,27-3H]vitamin D-3 complex in crude pig intestinal nuclear extract. The amount of incorporated label increased with increasing time of irradiation and was dependent on light of wavelengths 220-280 nm. Sodium dodecyl sulfate polyacrylamide gel electrophoresis and fluorography were used to demonstrate that label was incorporated primarily into the 1,25-dihydroxyvitamin D-3 receptor. In addition, the label incorporation was eliminated by competition with a 100-fold excess nonradioactive 1,25-dihydroxyvitamin D-3, indicating that the label was specific for the steroid binding site. Since 1,25-(OH)2[26,27-3H]vitamin D-3 is readily available and requires no special precautions for its preparation and handling, it should be a useful photoaffinity label for future studies of the receptor. PMID:1849006

  12. Adequate Vitamin D3 Supplementation During Pregnancy: Decreasing the Prevalence of Asthma and Food Allergies

    PubMed Central

    Finkel, Jonathan; Cira, Courtney; Mazzella, Leanne; Bartyzel, Jim; Ramanna, Annisce; Strimel, Kayla; Waturuocha, Amara; Musser, Nathan; Burress, James; Brammer, Sarah; Wetzel, Robert; Horzempa, Joseph

    2016-01-01

    Vitamin D is a secosterol that is naturally synthesized in the skin upon contact with ultraviolet rays. This vitamin can also be acquired from dietary and nutritional supplements. The active form, vitamin D3, is primarily responsible for calcium homeostasis and bone health. However, many recent studies have associated low levels of vitamin D3 with asthma and food allergies. In this review, we discuss literature to explore the potential that vitamin D3 deficiency may be contributing toward the development of asthma and food allergies. These studies indicate that mothers who supplement with doses of vitamin D3 recommended for daily consumption (400 IU) by the United States Food and Drug Administration is not enough to deliver adequate levels to breastfed infants. Because sufficient vitamin D3 serum levels correlate with a low incidence of asthma and food allergies, high dose vitamin D3 supplementation (4000 IU) by pregnant and breastfeeding women may limit the development of asthma and food allergies in newborns. PMID:27213185

  13. The vitamin D3 metabolite-type activity of Solanum malacoxylon.

    PubMed

    Basudde, C D; Humphreys, D J

    1976-01-01

    1. Administration of an aqueous extract of the dried leaves of Solanum malacoxylon (DLSM) to rats causes a rapid hyperphosphataemia and a decrease in plasma alkaline phosphatase activity; the two effects are typical of 1,25(OH)2D3, the hormonally active metabolite of vitamin D3. 2. DLSM, like both vitamin D3 and parathyroid hormone, increases plasma calcium and citrate levels in rats. The effect of DLSM in influencing plasma citrate, and the role of this important metabolite in mineral metabolism is discussed. 3. A decrease of plasma magnesium levels occurs in rats following treatment with DLSM. This decrease, which is associated with a renal loss of this cation, is remarkably similar to that produced by hypervitaminosis D3. 4. Prolonged administration of DLSM to vitamin D deficient rats causes a polyuria, hypercalciuria, hyperphosphaturia, hypermagnesuria, an increase in urinary total hydroxyproline, an increase in plasma total hexosamines, and a corresponding decrease in the bone total hexosamines. These effects, some of which can also be produced by hyperparathyroidism, or following the administration of parathyroid extract (PTE), large doses of vitamin D3, or 1,25(OH)2D3, suggest that DLSM, like the latter compounds, is capable of causing bone mineral mobilization, and the dissolution of bone organic matrix. PMID:212224

  14. 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. PMID:25645960

  15. 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. PMID:24943852

  16. 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

    2016-01-01

    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. PMID:27323139

  17. 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

  18. 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

  19. Comparative effect of 25(OH)D3 and 1,25(OH)2D3 on Th17 cell differentiation.

    PubMed

    Fawaz, Lama; Mrad, May F; Kazan, Jalal M; Sayegh, Souraya; Akika, Reem; Khoury, Samia J

    2016-05-01

    Vitamin D is a secosteroid hormone that plays an important regulatory role in calcium homeostasis and bone metabolism. Immune cells can both produce and respond to 1,25(OH)2D3. CD4+ T cells from vitamin D receptor (VDR) KO mice produce higher levels of IFN-γ and IL-17 than their wild type counterparts, and play a crucial role in the pathogenesis of autoimmune diseases (AID). We are particularly interested in studying the effect of vitamin D on pathogenic Th17 cells in humans. We investigated the in vitro effect of 1,25(OH)2D3 and 25(OH)D3 on the differentiation and cytokine production of primary CD4+ T cells from normal donors, and cultured in Th17 polarizing conditions. Both forms of vitamin D reduced the expression of pathogenic Th17 markers and their secretion of pro-inflammatory cytokines (IL-17A, IFN-γ). Furthermore, both vitamin D forms induced an expansion of CD25hi cells and upregulated their expression of CTLA-4 and Foxp3 regulatory markers. PMID:27041081

  20. 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. PMID:22921834

  1. 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

  2. Vitamin D3 inhibits TNFα-induced latent HIV reactivation in J-LAT cells.

    PubMed

    Nunnari, G; Fagone, P; Lazzara, F; Longo, A; Cambria, D; Di Stefano, G; Palumbo, M; Malaguarnera, L; Di Rosa, Michelino

    2016-07-01

    1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) is known to suppress NF-kB activity by interfering with its pathways. The aim of this study was to investigate the ability of 1,25(OH)2D3 in reducing the reactivation of the HIV virus J-LAT cells, an established model of latently infected cells, which were treated with TNFalpha (100 ng/ml) for 2 h with or without 24 h 1,25(OH)2D3 (100 nM) pretreatment. Reactivation of HIV RNA in J-LAT was evaluated in terms of green fluorescent protein (GFP) expression. The same experimental setting was repeated on T cells from HIV-infected patients. Treatment with TNFalpha was associated with a 16 % increase in GFP+ cells and a five-fold increase in unspliced HIV RNA expression (p < 0.04). Pretreatment of J-LAT cells with 1,25(OH)2D3 for 24 h followed by TNFalpha (100 ng/ml) for 2 h reduced the percentage of GFP+ cells by 8 %; moreover, a 2.4-fold decrease in unspliced HIV RNA expression was observed (p < 0.002). In T cells from patients, treatment with TNFalpha significantly increased unspliced HIV RNA expression (sixfold increase, p < 0.02), whereas prestimulation with 1,25(OH)2D3 reduced its expression (2.5-fold decrease, p < 0.02) compared to controls.1,25(OH)2D3 is able to reduce the ability of TNFalpha to upregulate the transcription of HIV RNA from latently infected cells. These data provide further understanding of the pathogenic mechanisms regulating viral reactivation from latent reservoirs, along with new insight in viral internalization. PMID:27295094

  3. Retinoic acid and 1,25-dihydroxyvitamin D3 stimulate osteoclast formation by different mechanisms

    SciTech Connect

    Scheven, B.A.; Hamilton, N.J. )

    1990-01-01

    The effects of retinoic acid (RA) and 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) on osteoclast formation were examined in intact fetal long bones of different ages/developmental stages maintained in organ culture using a chemically defined medium with or without the presence of serum. Besides stimulating bone resorption, RA and 1,25-(OH)2D3 increased the number of osteoclasts in 19-day-old fetal rat tibiae. Likewise, these bone-resorbing agents induced and stimulated osteoclast formation in 19- and 18-day-old metatarsal bones which were osteoclast-free at the beginning of the culture. The response to 1,25-(OH)2D3 was greatly enhanced by 10% fetal bovine serum (FBS) irrespective of the developmental stage of the long bone. The response to RA was not. Light microscopic autoradiography after labeling of the cultures with tritiated thymidine showed that both RA and 1,25-(OH)2D3 induced osteoclast differentiation from proliferating and postmitotic precursors. However, neither agent was able to stimulate proliferation of osteoclast progenitor cells in the older bones (19 days). Studies on the formation of osteoclast-like (tartrate-resistant acid phosphatase positive) cells in bone marrow cultures indicated that FBS was a potent inducer of osteoclast-like cell formation. In the presence of FBS, 1,25-(OH)2D3 significantly stimulated this response, but RA did not. The results demonstrate that although both RA and 1,25-(OH)2D3 stimulate osteoclast formation from proliferating and postmitotic precursors in long bones in vitro, they do so by different mechanisms.

  4. 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. PMID:26851125

  5. 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

  6. The action spectrum for vitamin D3: initial skin reaction and prolonged exposure.

    PubMed

    van Dijk, Arjan; den Outer, Peter; van Kranen, Henk; Slaper, Harry

    2016-07-01

    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

  7. 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. PMID:26248819

  8. Impact of Vitamin D3 Dietary Supplement Matrix on Clinical Response

    PubMed Central

    Finnell, John S.; Bhandiwad, Anup; Oberg, Erica; Suhaila, Lena; Bradley, Ryan

    2014-01-01

    Context: As a result of research suggesting increased health risk with low serum 25-hydroxycholecalciferol (25(OH)D), health care providers are measuring it frequently. Providers and patients are faced with treatment choices when low status is identified. Objective: To compare the safety and efficacy of three vitamin D3 dietary supplements with different delivery matrices. Setting and Design: A 12-week, parallel group, single-masked, clinical trial was conducted in Seattle, Washington and Kailua Kona, Hawaii. Sixty-six healthy adults with (25(OH)D) <33 ng/mL were randomly assigned to take one of three D3 supplements, ie, a chewable tablet (TAB), an oil-emulsified drop (DROP), or an encapsulated powder (CAP) at a label-claimed dose of 10,000 IU/day. Actual D3 content was assessed by a third party and the results adjusted based on the actual D3 content administered. Mean change in 25(OH)D/mcg D3 administered; difference in the proportion of D3 insufficient participants (ie, 25(OH)D ≤30 ng/mL) reaching sufficiency (ie, 25(OH)D ≥30 ng/mL); and mean change in serum 1, 25-dihydroxycholecalciferol were measured. Results: In two of the three products tested, the measured vitamin D3 content varied considerably from the label-claimed dose. Differences in 25(OH)D/mcg D3 administered were significantly different between groups (P = .04; n = 55). Pairwise comparisons demonstrated DROP resulted in a greater increase than TAB (P < .05) but not than CAP. TAB was not different from CAP. The proportions reaching sufficiency were: 100% (TAB and CAP) and 80% (DROP) (P = .03 between groups; n = 55). 1, 25-Dihydroxycholecalciferol did not change significantly in any group. Conclusions: Oil-emulsified vitamin D3 supplements resulted in a greater mean change in serum 25(OH)D concentration, but fewer patients reaching vitamin D sufficiency, than chewable or encapsulated supplements. PMID:24684456

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

    PubMed

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

    2016-03-15

    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

  10. 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

  11. 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

  12. Hypovitaminosis D3, Leukopenia, and Human Serotonin Transporter Polymorphism in Anorexia Nervosa and Bulimia Nervosa

    PubMed Central

    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. PMID:26903713

  13. Vitamin D3 mediated effects on postprandial leukocyte activation and arterial stiffness in men and women.

    PubMed

    Klop, B; van de Geijn, G-J M; Birnie, E; Njo, T L; Janssen, H W; Jansen, H G; Jukema, J W; Elte, J W F; Castro Cabezas, M

    2014-05-01

    Postprandial inflammation is considered to be pro-atherogenic. Vitamin D can reduce inflammation and arterial stiffness. We hypothesized that vitamin D3 improves postprandial arterial elasticity by the modulation of leukocyte activation. Healthy volunteers underwent two oral fat-loading tests (OFLTs). The augmentation index (AIx) and flow cytometric quantification of leukocyte activation markers were measured. After the first OFLT, 100 000 IU of vitamin D3 was administered and a second OFLT was carried out 7 days later. Six men and six women were included. A favorable reduction in AIx was found after vitamin D3 supplementation (P=0.042) in both genders. After vitamin D3, exclusively in women a reduction in the area under the postprandial curve for monocytes CD11b and CD35 by 10.5% (P=0.016) and 12.5% (P=0.04) and neutrophil CD11b by 17.0% (P=0.014) was observed. In conclusion, vitamin D3 probably increased postprandial arterial elasticity in men and women, but reduced postprandial leukocyte activation exclusively in women. PMID:24619107

  14. 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. PMID:26903713

  15. Babesia bovis: biosynthesis and localisation of 12D3 antigen in bovine erythrocytes.

    PubMed

    Harper, G S; Hibbs, A R; East, I J; Waltisbuhl, D J; Jorgensen, W K; Riddles, P W

    1996-11-01

    The 12D3 antigen of Babesia bovis was found to be synthesised rapidly in cultured parasites, and localised to both the apical complex of the merozoite and the cytoplasm of the parasitised erythrocyte. Amino-terminal sequencing suggested that the nascent protein had been processed and differences between the predicted and measured molecular weights suggested post-translational modification. The major proportion of 12D3 appeared in the soluble compartment of the parasitised erythrocytes with a molecular weight consistent with no further processing. A significant proportion of the protein required extraction by sodium carbonate, suggesting association with membranous components. The timing of release of soluble 12D3 was coincident with haemoglobin release and this probably reflects a non-specific lysis of the erythrocyte. Synthesis of recombinant BV12D3 was achieved in baculovirus-infected SF9 insect epithelial cells. The product was of the same molecular weight as the native 12D3 and polyclonal antibodies raised against the recombinant protein reacted with both the recombinant and native forms of the antigen. PMID:9024870

  16. 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

    2016-03-01

    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

  17. 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. PMID:27534559

  18. 1,25-Dihydroxyvitamin D3 and Development of Tuberculosis in Cattle

    PubMed Central

    Rhodes, S. G.; Terry, L. A.; Hope, J.; Hewinson, R. G.; Vordermeier, H. M.

    2003-01-01

    This report describes the presence and activity of 1,25-dihydroxyvitamin D3 (1,25-D3) in experimental bovine tuberculosis. Animals that went on to develop tuberculous lesions exhibited a rapid transient increase in serum 1,25-D3 within the first 2 weeks following infection with Mycobacterium bovis. 1,25-D3-positive mononuclear cells were later identified in all tuberculous granulomas by immunohistochemical staining of postmortem lymph node tissue. These results suggest a role for 1,25-D3 both at the onset of infection and in the development of the granuloma in these infected animals. Using a monoclonal antibody to the vitamin D receptor (VDR) as a VDR agonist, we confirmed that activation of the vitamin D pathway profoundly depresses antigen-specific, but not mitogenic, bovine peripheral blood T-cell responses (proliferation and gamma interferon production). Investigation of the mechanism of this suppression showed that the VDR antibody modified the expression of CD80 by accessory cells, such that a significant positive correlation between T-cell proliferation and accessory cell CD80 emerged. PMID:14607878

  19. 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. PMID:27189542

  20. Breakdown of three-dimensional Dirac semimetal state in pressurized C d3A s2

    NASA Astrophysics Data System (ADS)

    Zhang, Shan; Wu, Qi; Schoop, Leslie; Ali, Mazhar N.; Shi, Youguo; Ni, Ni; Gibson, Quinn; Jiang, Shang; Sidorov, Vladimir; Yi, Wei; Guo, Jing; Zhou, Yazhou; Wu, Desheng; Gao, Peiwen; Gu, Dachun; Zhang, Chao; Jiang, Sheng; Yang, Ke; Li, Aiguo; Li, Yanchun; Li, Xiaodong; Liu, Jing; Dai, Xi; Fang, Zhong; Cava, Robert J.; Sun, Liling; Zhao, Zhongxian

    2015-04-01

    We report an observation of a pressure-induced breakdown of the three-dimensional Dirac semimetal (3D-DSM) state in C d3A s2 , evidenced by a series of in situ high-pressure synchrotron x-ray diffraction and single-crystal transport measurements. We find that C d3A s2 undergoes a structural phase transition from a metallic tetragonal phase in space group I 41/a c d to a semiconducting monoclinic phase in space group P 21/c at critical pressure 2.57 GPa; above this pressure, an activation energy gap appears, accompanied by distinct switches in Hall resistivity slope and electron mobility. These changes of crystal symmetry and corresponding transport properties manifest the breakdown of the 3DDSM state in pressurized C d3A s2 .

  1. Visualization of dopamine D3-like receptors in human brain with [125I]epidepride.

    PubMed

    Murray, A M; Ryoo, H; Joyce, J N

    1992-12-01

    In sections of human brain containing the striatum (caudate, nucleus, putamen, nucleus accumbens) the competition for binding of [125I]epidepride by compounds with differing selectivity for dopamine D2 and D3 receptors was examined. Domperidone showed higher affinity for D2-like than D3-like sites whereas 7-OH-DPAT (7-hydroxy-2-(N,N-di-n-propylamino)tetralin) and quinpirole demonstrated the reverse selectivity. The pattern of [125I]epidepride binding in the presence of a high concentration of domperidone was negligible in the dorsal striatum but indicated islands of dense binding to D3-like receptors in the nucleus accumbens and ventral putamen. PMID:1359976

  2. 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.

  3. 70 FR 36021 - Food Additives Permitted for Direct Addition to Food for Human Consumption; Vitamin D3

    Federal Register 2010, 2011, 2012, 2013, 2014

    2005-06-22

    ... (68 FR 9000), FDA issued a final rule permitting the safe use of vitamin D 3 as a nutrient supplement... to Food for Human Consumption; Vitamin D 3 AGENCY: Food and Drug Administration, HHS. ACTION: Final... additive regulations authorizing the use of vitamin D 3 as a nutrient supplement in calcium-fortified...

  4. 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

  5. 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

  6. 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

  7. 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

  8. The role of receptor topology in the vitamin D3 uptake and Ca(2+) response systems.

    PubMed

    Morrill, Gene A; Kostellow, Adele B; Gupta, Raj K

    2016-09-01

    The steroid hormone, vitamin D3, regulates gene transcription via at least two receptors and initiates putative rapid response systems at the plasma membrane. The vitamin D receptor (VDR) binds vitamin D3 and a second receptor, importin-4, imports the VDR-vitamin D3 complex into the nucleus via nuclear pores. Here we present evidence that the Homo sapiens VDR homodimer contains two transmembrane (TM) helices ((327)E - D(342)), two TM "half-helix" ((264)K N(276)), one or more large channels, and 16 cholesterol binding (CRAC/CARC) domains. The importin-4 monomer exhibits 3 pore-lining regions ((226)E - L(251); (768)V - G(783); (876)S - A(891)) and 16 CRAC/CARC domains. The MEMSAT algorithm indicates that VDR and importin-4 may not be restricted to cytoplasm and nucleus. VDR homodimer TM helix-topology predicts insertion into the plasma membrane, with two 84 residue C-terminal regions being extracellular. Similarly, MEMSAT predicts importin-4 insertion into the plasma membrane with 226 residue extracellular N-terminal regions and 96 residue C-terminal extracellular loops; with the pore-lining regions contributing gated Ca(2+) channels. The PoreWalker algorithm indicates that, of the 427 residues in each VDR monomer, 91 line the largest channel, including two vitamin D3 binding sites and residues from both the TM helix and "half-helix". Cholesterol-binding domains also extend into the channel within the ligand binding region. Programmed changes in bound cholesterol may regulate both membrane Ca(2+) response systems and vitamin D3 uptake as well as receptor internalization by the endomembrane system culminating in uptake of the vitamin D3-VDR-importin-4 complex into the nucleus. PMID:27369077

  9. 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. PMID:27257625

  10. 1,25-Dihydroxyvitamin D3 prevents toluene diisocyanate-induced airway epithelial barrier disruption.

    PubMed

    Li, Wenjia; Dong, Hangming; Zhao, Haijin; Song, Jiafu; Tang, Haixiong; Yao, Lihong; Liu, Laiyu; Tong, Wancheng; Zou, Mengchen; Zou, Fei; Cai, Shaoxi

    2015-07-01

    The loss of airway epithelial integrity contributes significantly to asthma pathogenesis. Evidence suggests that vitamin D plays an important role in the prevention and treatment of asthma. However, its role in airway epithelial barrier function remains uncertain. We have previously demonstrated impaired epithelial junctions in a model of toluene diisocyanate (TDI)-induced asthma. In the present study, we hypothesized that 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] may prevent TDI-induced epithelial barrier disruption. Male BALB/c mice were dermally sensitized and then challenged with TDI. The mice were then administered 1,25(OH)2D3 intraperitoneally prior to challenge with TDI. For in vitro experiments, 16HBE bronchial epithelial cells were cultured and stimulated with TDI-human serum albumin (HSA). The results revealed that the mice treated with 1,25(OH)2D3 displayed decreased airway hyperresponsiveness (AHR), suppressed neutrophil and eosinophil infiltration into the airways, as well as an increased E-cadherin and zonula occludens-1 (ZO-1) expression at the cell-cell contact sites. In vitro, exposure of the cells to TDI-HSA induced a rapid decline in transepithelial electrical resistance (TER) and an increase in cell permeability, followed by a decrease in occludin expression and the redistribution of E-cadherin, accompanied by a significant upregulation in the levels of phosphorylated extracellular signal-regulated kinase (ERK)1/2. These effects were all partly reversed by treatment with either 1,25(OH)2D3 or an ERK1/2 inhibitor. In conclusion, the findings of our study demonstrate that 1,25(OH)2D3 prevents TDI-induced epithelial barrier disruption, and that the ERK1/2 pathway may play a role in this process. PMID:25998793

  11. 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. PMID:27291692

  12. The Association of 25-Hydroxyvitamin D3 and D2 with Behavioural Problems in Childhood

    PubMed Central

    Tolppanen, Anna-Maija; Sayers, Adrian; Fraser, William D.; Lewis, Glyn; Zammit, Stanley; Lawlor, Debbie A.

    2012-01-01

    Background Higher serum concentrations of 25-hydroxyvitamin D (25(OH)D), an indicator of vitamin D synthesis and intake, have been associated with better mental health and cognitive function. Concentrations of 1,25-dihydroxyvitamin D3 (the active vitamin D3 metabolite) have been associated with openness and extrovert behaviour, but 25(OH)D concentrations have not been associated with behavioural problems in humans. Methods We investigated the prospective association between the different forms of 25(OH)D - 25(OH)D3 and 25(OH)D2– and childhood behavioural problems in Avon Longitudinal Study of Parents and Children (ALSPAC). Serum 25(OH)D3 and 25(OH)D2 concentrations were assessed at mean age 9.9 years. Incident behavioural problems were assessed with Strengths and Difficulties Questionnaire (SDQ; emotional symptoms, conduct problems, hyperactivity-inattention problems, peer relationship problems and pro-social behaviour subscales and total difficulties score) at mean age 11.7. Sample sizes varied between 2413-2666 depending on the outcome. Results Higher 25(OH)D3 concentrations were weakly associated with lower risk of prosocial problems (fully adjusted odds ratio: OR (95% confidence interval: CI) 0.85 (0.74, 0.98)). Serum 25(OH)D3 or 25(OH)D2 concentrations were not associated with other subscales of SDQ or total difficulties score after adjusting for concfounders and other measured analytes related to vitamin D. Conclusions Our findings do not support the hypothesis that 25-hydroxyvitamin D status in childhood has important influences on behavioural traits in humans. PMID:22808099

  13. Whole cell bioconversion of vitamin D3 to calcitriol using Pseudonocardia sp. KCTC 1029BP.

    PubMed

    Kang, Dae-Jung; Im, Jong-Hyuk; Kang, Jae-Hoon; Kim, Kyoung Heon

    2015-07-01

    Calcitriol is an important drug used for treating osteoporosis, which can be produced from vitamin D3. The current method of producing calcitriol from vitamin D3 during cultivation of microbial cells results in low yields of calcitriol and high purification costs. Therefore, in this study, the steps of cell cultivation and bioconversion of vitamin D3 to calcitriol were separated. Cells of Pseudonocardia sp. KCTC 1029BP were utilized as a whole cell catalyst to produce a high level and yield of calcitriol from vitamin D3. In addition, the effects of bioconversion buffers, cyclodextrins, and metal salts on the production of calcitriol were comparatively examined and selected for incorporation in the bioconversion medium, and their compositions were statistically optimized. The optimal bioconversion medium was determined as consisting of 15 mM Trizma base, 25 mM sodium succinate, 2 mM MgSO4, 0.08% β-cyclodextrin, 0.1% NaCl, 0.2% K2HPO4, and 0.03% MnCl2. Using this optimal bioconversion medium, 61.87 mg/L of calcitriol, corresponding to a 30.94% mass yield from vitamin D3, was produced in a 75-L fermentor after 9 days. This calcitriol yield was 3.6 times higher than that obtained using a bioconversion medium lacking β-cyclodextrin, NaCl, K2HPO4, and MnCl2. In conclusion, utilizing whole cells of Pseudonocardia sp. KCTC 1029BP together with the optimal bioconversion medium markedly enhanced the production of calcitriol from vitamin D3. PMID:25666830

  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. 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.

  16. 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. PMID:27279805

  17. The local production of 1,25(OH)2D3 promotes osteoblast and osteocyte maturation.

    PubMed

    Turner, Andrew G; Hanrath, Maarten A; Morris, Howard A; Atkins, Gerald J; Anderson, Paul H

    2014-10-01

    Maintenance of an adequate vitamin D status, as indicated by the level of circulating 25-hydroxyvitamin D (25(OH)D), is associated with higher bone mass and decreased risk of fracture. However, the molecular actions of vitamin D hormone (1,25(OH)2D3) in bone are complex, and include stimulation of osteoclastogenesis via RANK-ligand up-regulation, as well as the inhibition of mineralisation. We hypothesise that these divergent data may be reconciled by autocrine actions of 1,25(OH)2D3 which effect skeletal maintenance, as opposed to endocrine 1,25(OH)2D3 which acts to maintain serum calcium homeostasis. We have previously described local metabolism of 1,25(OH)2D3 within osteoblasts, with effects on gene expression and cell function. The aim of the current study was to investigate potential autocrine actions of 1,25(OH)2D3 within cells that exhibit osteocyte-like properties. Late osteoblastic MLO-A5 cells were cultured in the presence of 25(OH)D for 9 days with gene expression analysed pre- and post-mineralisation. Gene expression analysis revealed maturation within this time frame to an osteocyte-like stage, evidenced by increased Dmp1 and Phex mRNA expression. Expression of Cyp27b1 in 25(OH)D treated MLO-A5 cells was associated with elevated media levels of 1,25(OH)2D3 (p<0.05), induction of Cyp24a1 (p<0.001) and elevated ratios of Opg:Rankl mRNA (p<0.01). Chronic 25(OH)D exposure also increased osteocalcin mRNA in MLO-A5 cells, which contrasted with the dose-dependent inhibition of osteocalcin mRNA observed with acute treatment in MLO-Y4 cells (p<0.01). Treatment of MLO-Y4 cells with 25(OH)D also inhibited Phex mRNA expression (p<0.05), whilst Enpp1 gene expression was induced (p<0.01). Overall, the current study demonstrates that osteocyte-like cells convert physiological levels of 25(OH)D to 1,25(OH)2D3, with changes in gene expression that are consistent with increased osteocyte maturation. Although the physiological role of local metabolism of 1,25(OH)2D3

  18. Response of keloid fibroblasts to Vitamin D3 and quercetin treatment - in vitro study

    PubMed Central

    Mathangi Ramakrishnan, K.; Babu, M.; Lakshmi Madhavi, M.S.

    2015-01-01

    Summary 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. PMID:27279805

  19. Randomized, blinded trial of vitamin D3 for treating aromatase inhibitor-associated musculoskeletal symptoms (AIMSS).

    PubMed

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

    2016-02-01

    The purpose of the study was to evaluate the efficacy and safety of vitamin D3 at 4000 IU/day as a treatment option for aromatase inhibitor-associated musculoskeletal symptoms (AIMSS) when compared with the usual care dose of 600 IU D3. We conducted a 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 stages I-IIIA breast cancer, taking AI and experiencing AIMSS [breast cancer prevention trial symptom scale-musculoskeletal (BCPT-MS) subscale ≥1.5] 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 4000 IU D3 (n = 57) daily for 6 months. The primary endpoint was a change in AIMSS from baseline (after 1 month run-in) on the BCPT-MS (general MS pain, joint pain, muscle stiffness, range for each question: 0 = not at all to 4 = extremely). 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. 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

  20. 24R,25-Dihydroxyvitamin D3 Protects against Articular Cartilage Damage following Anterior Cruciate Ligament Transection in Male Rats.

    PubMed

    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

  1. 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

  2. Suppression of murine experimental autoimmune encephalomyelitis development by 1,25-dihydroxyvitamin D3 with autophagy modulation.

    PubMed

    Zhen, Chao; Feng, Xuedan; Li, Zhe; Wang, Yabo; Li, Bin; Li, Lin; Quan, Moyuan; Wang, Gaoning; Guo, Li

    2015-03-15

    Multiple sclerosis (MS) has been associated with a history of sub-optimal exposure to ultraviolet light, implicating vitamin D3 as a possible protective agent. We evaluated whether 1,25(OH)2D3 attenuates the progression of experimental autoimmune encephalomyelitis (EAE), and explored its potential mechanisms. EAE was induced in C57BL/6 mice via immunization with MOG35-55, and some mice received 1,25(OH)2D3. 1,25(OH)2D3 inhibited EAE progression. Additionally, 1,25(OH)2D3 reduced inflammation, demyelination, and neuron loss in the spinal cord. The protective effect of 1,25(OH)2D3 was associated with significantly elevated expression of Beclin1, increased Bcl-2/Bax ratio, and decreased LC3-II accumulation. Thus, 1,25(OH)2D3 may represent a promising new MS treatment. PMID:25773147

  3. Non-Iterative Rigid 2D/3D Point-Set Registration Using Semidefinite Programming

    NASA Astrophysics Data System (ADS)

    Khoo, Yuehaw; Kapoor, Ankur

    2016-07-01

    We describe a convex programming framework for pose estimation in 2D/3D point-set registration with unknown point correspondences. We give two mixed-integer nonlinear program (MINP) formulations of the 2D/3D registration problem when there are multiple 2D images, and propose convex relaxations for both of the MINPs to semidefinite programs (SDP) that can be solved efficiently by interior point methods. Our approach to the 2D/3D registration problem is non-iterative in nature as we jointly solve for pose and correspondence. Furthermore, these convex programs can readily incorporate feature descriptors of points to enhance registration results. We prove that the convex programs exactly recover the solution to the original nonconvex 2D/3D registration problem under noiseless condition. We apply these formulations to the registration of 3D models of coronary vessels to their 2D projections obtained from multiple intra-operative fluoroscopic images. For this application, we experimentally corroborate the exact recovery property in the absence of noise and further demonstrate robustness of the convex programs in the presence of noise.

  4. 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. PMID:10415668

  5. 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

  6. Revised Damping Parameters for the D3 Dispersion Correction to Density Functional Theory.

    PubMed

    Smith, Daniel G A; Burns, Lori A; Patkowski, Konrad; Sherrill, C David

    2016-06-16

    Since the original fitting of Grimme's DFT-D3 damping parameters, the number and quality of benchmark interaction energies has increased significantly. Here, conventional benchmark sets, which focus on minimum-orientation radial curves at the expense of angular diversity, are augmented by new databases such as side chain-side chain interactions (SSI), which are composed of interactions gleaned from crystal data and contain no such minima-focused bias. Moreover, some existing databases such as S22×5 are extended to shorter intermolecular separations. This improved DFT-D3 training set provides a balanced description of distances, covers the entire range of interaction types, and at 1526 data points is far larger than the original training set of 130. The results are validated against a new collection of 6773 data points and demonstrate that the effect of refitting the damping parameters ranges from no change in accuracy (LC-ωPBE-D3) to an almost 2-fold decrease in average error (PBE-D3). PMID:27203625

  7. 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.

  8. Dynamical D4-D8 and D3-D7 branes in supergravity

    NASA Astrophysics Data System (ADS)

    Binetruy, Pierre; Sasaki, Misao; Uzawa, Kunihito

    2009-07-01

    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 AdS6×S4 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 τ→∞, while it reduces to a warped static solution at τ→0, where τ is the cosmic time.

  9. 25-Hydroxyvitamin D3-Deficiency Enhances Oxidative Stress and Corticosteroid Resistance in Severe Asthma Exacerbation

    PubMed Central

    Yang, Xiaoqiong; Cheng, Yuanyuan; zhang, Yun; Wang, Xiaoyun; Wang, Xing; Xie, Tao; Li, Guoping; Liu, Zhigang; Zhong, Nanshan

    2014-01-01

    Oxidative stress plays a significant role in exacerbation of asthma. The role of vitamin D in oxidative stress and asthma exacerbation remains unclear. We aimed to determine the relationship between vitamin D status and oxidative stress in asthma exacerbation. Severe asthma exacerbation patients with 25-hydroxyvitamin D3-deficiency (V-D deficiency) or 25-hydroxyvitamin D-sufficiency (V-D sufficiency) were enrolled. Severe asthma exacerbation with V-D-deficiency showed lower forced expiratory volume in one second (FEV1) compared to that with V-D-sufficiency. V-D-deficiency intensified ROS release and DNA damage and increased TNF-α, OGG1 and NFκB expression and NFκB phosphorylation in severe asthma exacerbation. Supplemental vitamin D3 significantly increased the rates of FEV1 change and decreased ROS and DNA damage in V-D-deficiency. Vitamin D3 inhibited LPS-induced ROS and DNA damage and were associated with a decline in TNF-α and NFκB in epithelial cells. H2O2 reduces nuclear translocation of glucocorticoid receptors in airway epithelial cell lines. V-D pretreatment enhanced the dexamethasone-induced nuclear translocation of glucocorticoid receptors in airway epithelial cell lines and monocytes from 25-hydroxyvitamin D3-deficiency asthma patients. These findings indicate that V-D deficiency aggravates oxidative stress and DNA damage, suggesting a possible mechanism for corticosteroid resistance in severe asthma exacerbation. PMID:25380286

  10. 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.

  11. 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.

  12. Treatment of an intramammary bacterial infection with 25-hydroxyvitamin D3

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  13. Oriented Gaussian mixture models for nonrigid 2D/3D coronary artery registration.

    PubMed

    Baka, N; Metz, C T; Schultz, C J; van Geuns, R-J; Niessen, W J; van Walsum, T

    2014-05-01

    2D/3D registration of patient vasculature from preinterventional computed tomography angiography (CTA) to interventional X-ray angiography is of interest to improve guidance in percutaneous coronary interventions. In this paper we present a novel feature based 2D/3D registration framework, that is based on probabilistic point correspondences, and show its usefulness on aligning 3D coronary artery centerlines derived from CTA images with their 2D projection derived from interventional X-ray angiography. The registration framework is an extension of the Gaussian mixture model (GMM) based point-set registration to the 2D/3D setting, with a modified distance metric. We also propose a way to incorporate orientation in the registration, and show its added value for artery registration on patient datasets as well as in simulation experiments. The oriented GMM registration achieved a median accuracy of 1.06 mm, with a convergence rate of 81% for nonrigid vessel centerline registration on 12 patient datasets, using a statistical shape model. The method thereby outperformed the iterative closest point algorithm, the GMM registration without orientation, and two recently published methods on 2D/3D coronary artery registration. PMID:24770908

  14. Clinicopathological Studies on Vitamin D3 Toxicity and Therapeutic Evaluation of Aloe vera in Rats

    PubMed Central

    Chavhan, Sambhaji G.; Brar, R. S.; Banga, H. S.; Sandhu, H. S.; Sodhi, S.; Gadhave, P. D.; Kothule, V. R.; Kammon, A. M.

    2011-01-01

    A study was conducted to examine the clinical signs, hematological, biochemical and histopathological changes in vitamin D3 toxicity at a dose rate 2 mg/kg b.wt. of vitamin D3 and to assess the protective effect of Aloe vera in vitamin D3 toxicity. The clinical signs observed were anorexia, progressive weight loss, difficulty in movement and respiration, diarrhea, epistaxis, subnormal body temperature and nervous signs before death. Mortality was observed in treated rats between day 10 and day 19 of treatment. The gross postmortem changes observed were severe emaciation, white chalky deposits on epicardial surface of heart, pin point white deposits on cortical surface of kidneys with pale yellow discoloration and diffused white deposits on serosal surface of stomach and intestine with bloody ingesta in lumen. The hematological changes included non-significant increase in hemoglobin and total leukocyte count and significant increase in relative neutrophil count. The biochemical changes observed were significant increase in plasma concentration of calcium, phosphorus and blood urea nitrogen, whereas a significant decrease in the concentration of albumin and total plasma protein was observed. The histopathological lesions included calcification of various organs, viz., tongue, stomach, intestines, kidney, heart, aorta, larynx, trachea, lungs, spleen, choroid plexus arteries of brain and vas deferens. The Aloe vera juice (2.5% in drinking water) has no protective effect on vitamin D3 toxicity (2 mg/kg b.wt.). PMID:21430919

  15. Are plasma 1,25-dihydroxyvitamin D3 concentrations appropriate after successful kidney transplantation?

    PubMed

    Caravaca, F; Fernández, M A; Cubero, J; Aparicio, A; Jimenez, F; García, M C

    1998-01-01

    We studied 28 patients with parathyroid hormone (PTH) concentrations >65 pg/ml immediately prior to kidney transplant and who had stable allograft function with serum creatinine <2 mg/dl. After 12-18 months of transplantation, biochemical parameters (including 25-hydroxy- and 1,25-dihydroxy-vitamin D3) were studied. Patients were divided into three groups according to their PTH concentrations. Patients with renal transplant were compared with 50 healthy subjects and 20 patients with primary hyperparathyroidism. The mean 1,25-dihydroxy-vitamin D3 concentration of the transplant patients did not differ from the controls, but was lower than in patients with primary hyperparathyroidism. Using univariate linear regression analysis, 1,25-dihydroxy vitamin D3 correlated positively with PTH (P=0.008) and serum calcium (P=0.0015), and inversely with creatinine clearance (P=0.01). However, it did not correlate significantly with serum phosphorus. Our data suggest that renal transplant recipients may have an inappropriate production of 1,25-dihydroxy vitamin D3; suboptimal allograft function may be a major limiting factor. PMID:9568829

  16. 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.

  17. Excitation of type II anterior caudate neurons by stimulation of dopamine D3 receptors.

    PubMed

    Piercey, M F; Hyslop, D K; Hoffmann, W E

    1997-07-11

    Previous studies have demonstrated that both direct- and indirect-acting dopamine (DA) receptor agonists excite type II neurons in the anterior caudate (CN) by stimulation of DA receptors belonging to the D2 receptor subfamily (D2, D3, D4 receptor subtypes). In the present study, pramipexole, a D3-preferring DA agonist effective in treating Parkinson's disease, excited type II anterior CN neurons. As with other direct-acting agonists, excitation of the CN neurons occurred only at doses above those that silenced DA neurons in the substantia nigra pars compacta (SNPC). Although more potent than pramipexole in inhibiting SNPC cells, PNU-91356A, a D2-preferring agonist, did not excite type II CN cells. The D3-preferring antagonist (+)-AJ76 was weaker than haloperidol, a D2-preferring antagonist, in reversing the effects of amphetamine on firing rates in dopaminergic neurons in both the SNPC and the CN. However, in relationship to its potency in the SNPC, (+)-AJ76 was more potent than haloperidol in the CN. PNU-101387, a selective D4 antagonist, did not alter amphetamine-induced stimulation of type II CN neurons. We conclude that DA agonists may excite type II anterior CN neurons via D3 receptor activation. The stimulation of these neurons may contribute to the anti-parkinsonian effects of pramipexole. PMID:9262154

  18. 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.

  19. Policy Problematization

    ERIC Educational Resources Information Center

    Webb, P. Taylor

    2014-01-01

    This article places Michel Foucault's concept of "problematization" in relation to educational policy research. My goal is to examine a key assumption of policy related to "solving problems" through such technologies. I discuss the potential problematization has to alter conceptions of policy research; and, through this…

  20. Serum 25-hydroxyvitamin D3 levels are elevated in South Indian patients with ischemic heart disease.

    PubMed

    Rajasree, S; Rajpal, K; Kartha, C C; Sarma, P S; Kutty, V R; Iyer, C S; Girija, G

    2001-01-01

    Several lines of evidence point to a possible relationship between vitamin D and cardiovascular disease. Animal experiments and observational studies in humans suggest vitamin D to be arteriotoxic and an association of high intake of vitamin D with increased incidence of ischemic heart disease (IHD). The major source of vitamin D in adults is vitamin D synthesized in the skin through exposure to the sun. In tropical environment there is a possibility of high level of solar exposure and enhanced serum levels of vitamin D in the population. We explored the relation between serum level of 25-hydroxyvitamin D3 and IHD in a case-control study involving 143 patients with either angiographic evidence of coronary artery disease or patients with acute myocardial infarction and 70 controls, all men in the age group of 45-65 years. Fasting blood samples were collected, serum separated and serum levels of 25-hydroxyvitamin D3 was measured by protein binding radioligand assay. Serum levels of cholesterol, triglyceride, calcium, magnesium and inorganic phosphate were also determined. Prevalences of diabetes, hypertension and smoking history were noted. Statistical comparisons of variables between cases and controls were done using chi2-tests. Multivariate logistic regression analysis was done to examine the association of IHD with serum levels of 25-hydroxyvitamin D3 controlling for selected variables. Serum levels of 25-hydroxyvitamin D3, calcium, inorganic phosphate, total cholesterol, low density lipoprotein and triglycerides were elevated in a higher proportion of patients, compared to controls. Serum levels of 25-OH-D3 above 222.5 nmol/l (89 ng/ml) was observed in 59.4% of cases compared to 22.1% in controls (p < 0.001; unadjusted odds ratio (OR): 5.17; 95% confidence interval (CI): 2.62-10.21). When controlled for age and selected variables using the multivariate logistic regression, the adjusted OR relating elevated serum 25-hydroxyvitamin D3 levels (> or = 222.5 nmol

  1. 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. PMID:26601949

  2. 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

  3. Effects of vitamin D3 stimulation of thioredoxin-interacting protein in hepatocellular carcinoma

    PubMed Central

    Hamilton, James P.; Potter, James J.; Koganti, Lahari; Meltzer, Stephen J.; Mezey, Esteban

    2014-01-01

    Aim Thioredoxin-interacting protein (TXNIP) promotes oxidative stress by inactivating thioredoxin (TXN). This protein is involved in diverse disease processes, including insulin resistance, atherosclerosis and carcinogenesis. The aim of the present study was to measure the expression and function of TXNIP in in vitro models of liver disease, as well as in primary human hepatocellular carcinoma (HCC) tissue specimens. In addition, we wanted to determine the effects of vitamin D3-induced TXNIP stimulation in HCC-derived cell lines. Methods TXNIP expression was measured by quantitative reverse transcription polymerase chain reaction and western blots. TXNIP expression was stimulated by vitamin D exposure and by transfection. Cell proliferation, apoptosis and reactive oxygen species were determined by standard assays. Results TXNIP expression levels were low in HCC cell lines, and vitamin D3 stimulated TXNIP expression in vitro. In HCC cells transfected with a TXNIP expression vector or treated with exogenous vitamin D3, there was a reduction in cell proliferation and an increase in apoptosis. Cells expressing TXNIP were markedly susceptible to oxidative injury induced by cobalt chloride or bacterial lipopolysaccharide. TXNIP expression was reduced or absent in a majority of primary human HCC specimens relative to matching, non-cancerous liver tissue. Conclusion TXNIP expression is low or absent in human HCC specimens and HCC-derived cell lines. Vitamin D3 stimulates TXNIP expression, resulting in diminished proliferation and enhanced apoptosis. Liver cells expressing TXNIP are primed for oxidative injury. These findings suggest that stimulation of TXNIP expression, by factors such as vitamin D3, may attenuate carcinogenesis in patients with chronic liver disease. PMID:24451003

  4. 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

  5. The inhibitory kinetics and mechanism of dietary vitamins D3 and B2 on xanthine oxidase.

    PubMed

    Lin, Suyun; Zhang, Guowen; Liao, Yijing; Gong, Deming

    2016-06-15

    Dietary guidelines to promote health are usually based on the patterns' prediction on disease risk of foods and nutrients. Overactivity of xanthine oxidase (XO) is the underlying cause of gout. Herein, the inhibitory kinetics and mechanism of dietary vitamins D3 and B2 on XO were investigated by multispectroscopic methods and a molecular modeling technique. The results showed that vitamin D3 competitively inhibited XO with an inhibition constant of 26.93 ± 0.42 μM by inserting into the active cavity of XO interacting with the surrounding amino acid residues through hydrogen bond and van der Waals forces. Vitamin D3 bound to XO thereby induced the structural compactness of XO which in turn hindered the binding of substrate xanthine to cause the inhibition on XO. Vitamin B2 exhibited a mixed-type inhibition by binding to the vicinity of the active cavity with an inhibition constant of 37.76 ± 0.87 μM through hydrophobic interactions and a feeble hydrogen bond, and it induced the unfolding of the XO structure and an increase of the flexible loops (β-turns and random coils) which might move to cover the active pocket and reduce the binding of the substrate xanthine, and then lead to a lower catalytic activity of the enzyme. In addition, vitamins D3 and B2 showed a synergistic effect on inhibiting the activity of XO in a certain range of concentration. These findings may provide new insights into the inhibitory mechanism of vitamins D3 and B2 on XO and functional research of the vitamins in the supplementary treatment of gout. PMID:27241164

  6. 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

  7. Discriminative stimulus properties of the dopamine D3 antagonist PNU-99194A.

    PubMed

    Franklin, S R; Baker, L E; Svensson, K A

    1998-07-01

    It was recently documented that the relatively selective dopamine D3 receptor antagonist, PNU-99194A, is capable of establishing discriminative stimulus control in rats and that the discriminative cue associated with this compound is not similar to that produced by psychostimulants. The present experiment further characterized the discriminative stimulus properties of PNU-99194A by examining several other dopaminergic agents for stimulus generalization in 23 male Sprague-Dawley rats trained to discriminate 10 mg/kg PNU-99194A (SC, 15 min) from vehicle in a two-choice discrimination procedure under an FR10 schedule of food reinforcement. Rats achieved a criterion of ten consecutive sessions with correct lever choice after a median of 35.5 sessions (range 23-78). In substitution tests, the non-selective D2 receptor antagonist, haloperidol (0.01- 0.1 mg/kg), and the mixed D2/D3 antagonists, amisulpiride (3.2-32 mg/kg) and sulpiride (32-200 mg/kg), failed to produce stimulus generalization, while the D3-preferring antagonists, (-)-DS121 (1-10 mg/kg) and (+)-AJ76 (3.2-32 mg/kg), produced complete stimulus generalization. Direct and indirect DA agonists, including apomorphine (0.01-0.32 mg/kg) and d-amphetamine (0.1-1 mg/kg), the D1 agonist SKF38393 (10-100 mg/kg), the D2 selective agonist PNU-95666E (0.32-3.2 mg/kg) and the D3-preferring agonist pramipexole (0.032-1 mg/kg), all produced non-significant amounts of drug-appropriate responding and significantly reduced response rate. It is concluded that PNU-99194A produces a distinctive subjective cue which is probably based on D3 receptor antagonism. PMID:9694525

  8. Metabolism of vitamin D3 in human osteoblasts: evidence for autocrine and paracrine activities of 1 alpha,25-dihydroxyvitamin D3.

    PubMed

    Atkins, Gerald J; Anderson, Paul H; Findlay, David M; Welldon, Katie J; Vincent, Cristina; Zannettino, Andrew C W; O'Loughlin, Peter D; Morris, Howard A

    2007-06-01

    Circulating 1 alpha,25-dihydroxyvitamin D(3) (1,25D) derives from renal conversion of 25-hydroxyvitamin D(3) (25D), by the 25D 1 alpha-hydroxylase (CYP27B1). Blood 25D levels, but not 1,25D levels, are the best indicator of vitamin D status and predict fracture risk in the elderly. We examined the extent to which osteoblasts can metabolize 25D. Well-characterized human primary osteoblasts and osteosarcoma (OS) cell lines were examined for the expression and regulation of genes associated with vitamin D metabolism, using real-time PCR. Primary osteoblasts and OS cell lines were found to express CYP27B1 mRNA and secreted detectable 1,25D in response to 25D. Of the OS cell lines tested, HOS expressed the most CYP27B1 mRNA and secreted the highest levels of 1,25D. All osteoblastic cells examined up-regulated expression of the catabolic regulator of 1,25D, the 25-hydroxyvitamin D-24-hydroxylase (CYP24), when incubated with either 1,25D or 25D. Exposure to physiological levels of 25D resulted in up-regulated transcription of the 1,25D responsive genes, osteocalcin (OCN), osteopontin (OPN) and RANKL. Specific knockdown of CYP27B1 in HOS cells using siRNA resulted in up to 80% reduction in both 1,25D secretion and the transcription of OCN and CYP24, strongly implying that the 25D effect in osteoblasts is preceded by conversion to 1,25D. Incubation with 25D, like 1,25D, inhibited primary osteoblast proliferation and promoted in vitro mineralization. Finally, we detected expression by osteoblasts of receptors for vitamin D binding protein (DBP), cubilin and megalin, suggesting that osteoblasts are able to internalize DBP-25D complexes in vivo. Together, our results suggest that autocrine, and perhaps paracrine, pathways of vitamin D(3) metabolism may regulate key osteoblast functions independently of circulating, kidney derived 1,25D. Our results are therefore consistent with the reported benefits of maintaining a healthy vitamin D status in the elderly to reduce the risk of

  9. Modulation of the bovine innate immune response by production of 1alpha,25-dihydroxyvitamin D(3) in bovine monocytes.

    PubMed

    Nelson, C D; Reinhardt, T A; Thacker, T C; Beitz, D C; Lippolis, J D

    2010-03-01

    In cattle, the kidney has been the only known site for production of 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] from 25-hydroxyvitamin D(3) [25(OH)D(3)] by 1alpha-hydroxylase (1alpha-OHase). Based on human studies, it was hypothesized that bovine monocytes could produce 1,25(OH)(2)D(3) upon activation and 1,25(OH)(2)D(3) would regulate expression of vitamin D-responsive genes in monocytes. First, the effects of 1,25(OH)(2)D(3) on bovine monocytes isolated from peripheral blood were tested. Treatment of nonstimulated monocytes with 1,25(OH)(2)D(3) increased expression of the gene for the vitamin D 24-hydroxylase (24-OHase) enzyme by 51+/-13 fold, but 1,25(OH)(2)D(3) induction of 24-OHase expression was blocked by lipopolysaccharide (LPS) stimulation. In addition, 1,25(OH)(2)D(3) increased the gene expression of inducible nitric oxide synthase and the chemokine RANTES (regulated upon activation, normal T-cell expressed and secreted) in LPS-stimulated monocytes 69+/-13 and 40+/-12 fold, respectively. Next, the ability of bovine monocytes to express 1alpha-OHase and produce 1,25(OH)(2)D(3) was tested. Activation of monocytes with LPS, tripalmitoylated lipopeptide (Pam3CSK4), or peptidoglycan caused 43+/-9, 17+/-3, and 19+/-3 fold increases in 1alpha-OHase gene expression, respectively. Addition of 25(OH)D(3) to LPS-stimulated monocytes enhanced expression of inducible nitric oxide synthase and RANTES and nitric oxide production in a dose-dependent manner, giving evidence that activated monocytes convert 25(OH)D(3) to 1,25(OH)(2)D(3). In conclusion, bovine monocytes produce 1,25(OH)(2)D(3) in response to toll-like receptor signaling, and 1,25(OH)(2)D(3) production in monocytes increased the expression of genes involved in the innate immune system. Vitamin D status of cattle might be important for optimal innate immune function because 1,25(OH)(2)D(3) production in activated monocytes and subsequent upregulation of inducible nitric oxide synthase and RANTES expression

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

    PubMed Central

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

    2013-01-01

    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. PMID:23578663

  11. Evaluation of static pressure drops and PM10 and TSP emissions for modified 1D-3D cyclones

    SciTech Connect

    Holt, G.A.; Baker, R.V.; Hughs, S.E.

    1999-12-01

    Five modifications of a standard 1D3D cyclone were tested and compared against the standard 1D3D design in the areas of particulate emissions and static pressure drop across the cyclone. The modifications to the 1D3D design included a 2D2D inlet, a 2D2D air outlet, a D/3 trash exit, an expansion chamber with a D/3 trash exit, and a tapered air outlet duct. The 1D3D modifications that exhibited a significant improvement in reducing both PM10 and total suspended particulate (TSP) emissions were the designs with the 2D2D inlet and air exhaust combined with either the conical D/3 tail cone or the expansion chamber. In reference to the standard 1D3D cyclone, the average reduction in PM10 emissions was 24 to 29% with a 29 to 35% reduction observed in TSP emissions. The modifications with the tapered air outlets did not show any significant improvements in controlling PM10 emissions. However, the modification with the tapered air outlet/expansion chamber combination exhibited statistical significance in reducing TSP emissions by 18% compared to the 1D3D cyclone. All modifications tested exhibited lower static pressure drops than the standard 1D3D.

  12. Design, synthesis and evaluation of bitopic arylpiperazinephenyl-1,2,4-oxadiazoles as preferential dopamine D3 receptor ligands.

    PubMed

    Cao, Yongkai; Min, Chengchun; Acharya, Srijan; Kim, Kyeong-Man; Cheon, Seung Hoon

    2016-01-15

    The dopamine D3 receptor (D3R) was proposed as a therapeutic target for drug development to treat drug abuse and addiction and neuropsychiatric disorders. Several D3R-selective modulators over the dopamine D2 receptor (D2R) can avoid extrapyramidal symptoms (EPS) and hyperprolactinemia. However, few biased D3R ligands were identified or showed a narrow range of selectivity at the D3R over D2R because of their high sequence homology. Herein, we designed, synthesized and evaluated the binding affinity of a series of bitopic ligands: arypiperazine-phenyl-1,2,4-oxadiazoles. Compound 9e·HCl was the most potent and selective D3R modulator among these bitopic ligands. Molecular modeling revealed that D3R selectivity depends on the divergence of secondary binding pocket (SBP) in D3R and D2R. Specifically, non-conserved Tyr36, EL1 especially non-conserved Thr92 and Gly94, and EL2 Val180, Cys181 and Ser182 of D3R may contribute to D3R specificity over D2R. PMID:26707842

  13. 1,25D3 potentiates cisplatin antitumor activity by p73 induction in a squamous cell carcinoma model

    PubMed Central

    Ma, Yingyu; Yu, Wei-Dong; Hershberger, Pamela A.; Flynn, Geraldine; Kong, Rui-Xian; Trump, Donald L.; Johnson, Candace S.

    2008-01-01

    1,25D3 exhibits anti-tumor activity in a variety of cancers including squamous cell carcinoma (SCC). Intrinsic resistance of SCC cells to cisplatin was observed and led to the investigation into whether 1,25D3 sensitizes SCC cells to cisplatin. Pretreatment with 1,25D3 followed by cisplatin enhanced growth inhibition in SCC cells compared with 1,25D3 alone, as assessed by cytotoxicity and in vitro clonogenic assays. In addition, 1,25D3 sensitized SCC cells to cisplatin-mediated apoptosis. Treatment of tumor-bearing C3H mice with 1,25D3 prior to cisplatin reduced clonogenic survival using in vivo excision clonogenic assay. These results were not observed in a 1,25D3-resistant SCC variant, indicating the critical role of 1,25D3 in sensitizing SCC cells to cisplatin. Further, a marked decrease in fractional tumor volume was observed when SCC tumor-bearing mice were treated with 1,25D3 prior to cisplatin as compared to either agent administered alone. Cisplatin has been shown to modulate p73 protein level in certain cancer cells. Our data showed that p73 level was not affected by cisplatin, but increased by 1,25D3 in SCC cells. Knocking down p73 by siRNA protected SCC cells against 1,25D3 and cisplatin-mediated clonogenic cell kill and apoptosis. Increasing p73 protein level by knocking down UFD2a, which mediates p73 degradation, promoted 1,25D3 and cisplatin-mediated clonogenic cell kill. These results suggest that 1,25D3 potentiates cisplatin anti-tumor activity in vitro and in vivo in a SCC model system, possibly through p73 induction and apoptosis. The combination treatment may provide a more effective therapeutic regimen in cancer treatment. PMID:18790784

  14. Photoaffinity labeling of serum vitamin D binding protein by 3-deoxy-3-azido-25-hydroxyvitamin D3

    SciTech Connect

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

    1987-06-30

    3-Deoxy-3-azido-25-hydroxyvitamin D3 was covalently incorporated in the 25-hydroxyvitamin D3 binding site of purified human plasma vitamin D binding protein. Competition experiments showed that 3-deoxy-3-azido-25-hydroxyvitamin D3 and 25-hydroxyvitamin D3 bind at the same site on the protein. Tritiated 3-deoxy-3-azido-25-hydroxyvitamin D3 was synthesized from tritiated 25-hydroxyvitamin D3, retaining the high specific activity of the parent compound. The tritiated azido label bound reversibly to human vitamin D binding protein in the dark and covalently to human vitamin D binding protein after exposure to ultraviolet light. Reversible binding of tritiated 3-deoxy-3-azido-25-hydroxyvitamin D3 was compared to tritiated 25-hydroxyvitamin D3 binding to human vitamin D binding protein. Scatchard analysis of the data indicated equivalent maximum density binding sites with a KD,app of 0.21 nM for 25-hydroxyvitamin D3 and a KD,app of 1.3 nM for the azido derivative. Covalent binding was observed only after exposure to ultraviolet irradiation, with an average of 3% of the reversibly bound label becoming covalently bound to vitamin D binding protein. The covalent binding was reduced 70-80% when 25-hydroxyvitamin D3 was present, indicating strong covalent binding at the vitamin D binding site of the protein. When tritiated 3-deoxy-3-azido-25-hydroxyvitamin D3 was incubated with human plasma in the absence and presence of 25-hydroxyvitamin D3, 12% of the azido derivative was reversibly bound to vitamin D binding protein. After ultraviolet irradiation, four plasma proteins covalently bound the azido label, but vitamin D binding protein was the only protein of the four that was unlabeled in the presence of 25-hydroxyvitamin D3.

  15. Sequestration and microsomal C-25 hydroxylation of (/sup 3/H)-vitamin D3 by the rat liver

    SciTech Connect

    Gascon-Barre, M.; Elbaz, H.; Therrien-Ferland, D.

    1985-03-01

    A study of the vitamin D3 (D3) 25-hydroxylase was undertaken in an in vivo-in vitro model. (/sup 3/H)-D3 (0.7, 1.0, 10, or 100 nmol/100 g of body weight) was injected into the portal vein and the liver was excised 18 seconds later. The liver homogenate was then submitted to differential centrifugation and the amount of (/sup 3/H)-D3 incorporated in the subcellular fractions was evaluated. The microsomal fraction was also incubated in vitro and the appearance of (/sup 3/H)-25-hydroxyvitamin D3 (25(OH)D3) was determined by high performance liquid chromatography (HPLC). Results showed that the fractional liver (/sup 3/H)-D3 uptake varied between 37 percent and 48 percent of the dose injected. The intracellular distribution of (/sup 3/H)-D3 showed that most of the vitamin was incorporated into the microsomal fraction (45% to 50% of the intracellular (/sup 3/H)-D3) except at the highest dose of (/sup 3/H)-D3 where the cytosolic fraction contained the highest amount (56.4%) of the incorporated vitamin. Mathematical analysis of the intracellular (/sup 3/H)-D3 distribution showed that the microsomal fraction was the only subcellular fraction that was found to incorporate (/sup 3/H)-D3 in relation to the total liver uptake of the vitamin. The apparent Michaelis-Menten kinetics of the (/sup 3/H)-D3-25-hydroxylase showed that with substrate concentration of up to 88.5 nM, the apparent Km and Vmax were 28.2 nM and 25.8 fentomoles (fmol) X min-1 X mg microsomal pro-1, respectively, but the reaction lost considerable efficiency with higher substrate concentrations.

  16. 1,25D3 enhances antitumor activity of gemcitabine and cisplatin in human bladder cancer models

    PubMed Central

    Ma, Yingyu; Yu, Wei-Dong; Trump, Donald L.; Johnson, Candace S.

    2010-01-01

    Background 1,25 dihydroxyvitamin D3 (1,25D3) potentiates the cytotoxic effects of several common chemotherapeutic agents. The combination of gemcitabine and cisplatin (GC) is a current standard chemotherapy regimen for bladder cancer. We investigated whether 1,25D3 could enhance the antitumor activity of GC in bladder cancer model systems. Methods Human bladder cancer T24 and UMUC3 cells were pretreated with 1,25D3 followed by GC. Apoptosis were assessed by annexin V staining. Caspase activation was examined by immunoblot analysis and substrate-based caspase activity assay. The cytotoxic effects were examined using MTT and in vitro clonogenic assay. p73 protein levels were assessed by immunoblot analysis. Knockdown of p73 was achieved by siRNA. The in vivo antitumor activity was assessed by in vivo excision clonogenic assay and tumor regrowth delay in the T24 xenograft model. Results 1,25D3 pretreatment enhanced GC-induced apoptosis and the activities of caspases- 8, 9 and 3 in T24 and UMUC3 cells. 1,25D3 synergistically reduced GC-suppressed surviving fraction in T24 cells. 1,25D3, gemcitabine, or cisplatin induced p73 accumulation, which was enhanced by GC or 1,25D3 and GC. p73 expression was lower in human primary bladder tumor tissue compared with adjacent normal tissue. Knockdown of p73 increased clonogenic capacity of T24 cells treated with 1,25D3, GC or 1,25D3 and GC. 1,25D3 and GC combination enhanced tumor regression compared with 1,25D3 or GC alone. Conclusions 1,25D3 potentiates GC-mediated growth inhibition in human bladder cancer models in vitro and in vivo, which involves p73 induction and apoptosis. PMID:20564622

  17. 26,27-Hexafluoro-1,25-dihydroxyvitamin D3 (F6-1,25(OH)2D3) prevents osteoporosis induced by immobilization combined with ovariectomy in the rat.

    PubMed

    Okumura, H; Yamamuro, T; Higuchi, S; Harada, M; Takamura, T; Otomo, S; Aihara, H; Ikekawa, N; Kobayashi, T

    1990-05-01

    The effect of 26,27-hexafluoro-1,25-dihydroxyvitamin D3 (F6-1,25(OH)2D3) on experimental osteoporosis in the rat induced by a combination of immobilization and ovariectomy was evaluated. F6-1,25(OH)2D3 increased the femur score and the photo-density. The administration of F6-1,25(OH)2D3 also significantly increased the dry weight, the ash weight and the ash content of the bone. Both F6-1,25(OH)2D3 and 1 alpha(OH)D3 showed a nearly dose-dependent effect and significant inhibition of the decrease of bone mass. Histomorphometry revealed a significant decrease of resorption by the administration of F6-1,25(OH)2D3. Bone formation rate in the F6-1,25(OH)2D3 treated group significantly decreased compared with the vehicle group. In conclusion, the pharmacological effective dose of F6-1,25(OH)2D3 was considered to prevent the osteoporotic decrease of bone mass by suppressing the elevated bone turnover. PMID:2350614

  18. Increased renal catabolism of 1,25-dihydroxyvitamin D3 in murine X-linked hypophosphatemic rickets.

    PubMed Central

    Tenenhouse, H S; Yip, A; Jones, G

    1988-01-01

    The hypophosphatemic (Hyp) mouse, a murine homologue of human X-linked hypophosphatemic rickets, is characterized by renal defects in brush border membrane phosphate transport and vitamin D3 metabolism. The present study was undertaken to examine whether elevated renal 25-hydroxyvitamin D3-24-hydroxylase activity in Hyp mice is associated with increased degradation of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] by side chain oxidation. Metabolites of 1,25(OH)2D3 were separated by HPLC on Zorbax SIL and identified by comparison with standards authenticated by mass spectrometry. Production of 1,24,25-trihydroxyvitamin D3, 24-oxo-1,25-dihydroxyvitamin D3, and 24-oxo-1,23,25-trihydroxyvitamin D3 was twofold greater in mitochondria from mutant Hyp/Y mice than from normal +/Y littermates. Enzyme activities, estimated by the sum of the three products synthesized per milligram mitochondrial protein under initial rate conditions, were used to estimate kinetic parameters. The apparent Vmax was significantly greater for mitochondria from Hyp/Y mice than from +/Y mice (0.607 +/- 0.064 vs. 0.290 +/- 0.011 pmol/mg per protein per min, mean +/- SEM, P less than 0.001), whereas the apparent Michaelis-Menten constant (Km) was similar in both genotypes (23 +/- 2 vs. 17 +/- 5 nM). The Km for 1,25(OH)2D3 was approximately 10-fold lower than that for 25-hydroxyvitamin D3 [25(OH)D3], indicating that 1,25(OH)2D3 is perhaps the preferred substrate under physiological conditions. In both genotypes, apparent Vmax for 25(OH)D3 was fourfold greater than that for 1,25(OH)2D3, suggesting that side chain oxidation of 25(OH)D3 may operate at pharmacological concentrations of substrate. The present results demonstrate that Hyp mice exhibit increased renal catabolism of 1,25(OH)2D3 and suggest that elevated degradation of vitamin D3 hormone may contribute significantly to the clinical phenotype in this disorder. PMID:3339128

  19. Supplemental vitamin D3 concentration and biological type of steers. II. Tenderness, quality, and residues of beef.

    PubMed

    Montgomery, J L; King, M B; Gentry, J G; Barham, A R; Barham, B L; Hilton, G G; Blanton, J R; Horst, R L; Galyean, M L; Morrow, K J; Wester, D B; Miller, M F

    2004-07-01

    Vitamin D3 was orally supplemented to determine the supplemental dose that improved beef tenderness in different cattle breed types. Feedlot steers (n = 142) were arranged in a 4 x 3 factorial arrangement consisting of four levels of supplemental vitamin D3 (0, 0.5, 1, and 5 million IU/steer daily) administered for eight consecutive days antemortem using three biological types (Bos indicus, Bos Taurus-Continental, and Bos Taurus-English). Warner-Bratzler shear force (WBSF) was measured at 3, 7, 10, 14, and 21 d postmortem, and trained sensory analysis was conducted at 7 d postmortem on LM, semimembranosus, gluteus medius, and supraspinatus steaks. Concentrations of vitamin D3 and the metabolites 25-hydroxyvitamin D3, and 1,25-dihydroxyvitamin D3 were determined in the LM, liver, kidney, and plasma. Biological type of cattle did not interact (P > 0.10) with vitamin D3 supplementation for sensory or tenderness traits, suggesting that feeding vitamin D3 for 8 d before slaughter affected the different biological types of cattle similarly. Supplementing steers with 0.5, 1, or 5 million IU/(steer(d) decreased (P < 0.05) LM WBSF at 7, 10, 14, and 21 d postmortem compared with controls, and vitamin D3 treatments of 0.5, 1, and 5 million IU decreased (P < 0.05) semimembranosus WBSF at 3, 7, and 14 d postmortem. In general, vitamin D3-induced improvements in WBSF were most consistent and intense in LM steaks. Sensory panel tenderness was improved (P < 0.05) by all vitamin D3 treatments in LM steaks. Sensory traits ofjuiciness, flavor, connective tissue, and off-flavor were not (P > 0.05) affected by vitamin D3 treatments. All vitamin D3 treatments decreased micro-calpain activity and increased muscle Ca concentrations (P < 0.05). Vitamin D3 concentrations were increased (P < 0.05) by supplementation in all tissues tested (liver, kidney, LM, and plasma); however, cooking steaks to 71 degrees C decreased (P < 0.05) treatment residue effects. The vitamin D metabolite 1

  20. Potent activation of dopamine D3/D2 heterodimers by the antiparkinsonian agents, S32504, pramipexole and ropinirole.

    PubMed

    Maggio, Roberto; Scarselli, Marco; Novi, Francesca; Millan, Mark J; Corsini, Giovanni U

    2003-11-01

    Recombinant, human dopamine D3 and D2 receptors form functional heterodimers upon co-expression in COS-7 cells. Herein, actions of the antiparkinsonian agents, S32504, ropinirole and pramipexole, at D3/D2L heterodimers were compared to their effects at the respective monomers and at split, chimeric D3trunk/D2tail and D2trunk/D3tail receptors: the trunk incorporated transmembrane domains (TDs) I-V and the tail TDs VI and VII. In binding assays with the antagonist [3H]nemonapride, all agonists were potent ligands of D3 receptors showing, respectively, 100-, 18- and 56-fold lower affinity at D2L receptors, mimicking the selective D3 receptor antagonist, S33084 (100-fold). At D3trunk/D2tail receptors, except for ropinirole, all drugs showed lower affinities than at D3 sites, whereas for D2trunk/D3tail receptors, affinities of all drugs were higher than at D2L sites. The proportion of high affinity binding sites recognized by S32504, pramipexole and ropinirole in membranes derived from cells co-expressing D3 and D2L sites was higher than in an equivalent mixture of membranes from cells expressing D3 or D2L sites, consistent with the promotion of heterodimer formation. In contrast, the percentage of high and low affinity sites (biphasic isotherms) recognized by S33084 was identical. Functional actions were determined by co-transfection of a chimeric adenylyl cyclase (AC)-V/VI insensitive to D3 receptors. Accordingly, D3 receptor-transfected cells were irresponsive whereas, in D2L receptor-transfected cells, agonists suppressed forskolin-stimulated cAMP production with modest potencies. In cells co-transfected with D3 and D2L receptors, S32504, ropinirole and pramipexole potently suppressed AC-V/VI with EC50s 33-, 19- and 11-fold lower than at D2L receptors, respectively. S32504 also suppressed AC-V/VI activity at split D3trunk/D2tail and D2trunk/D3tail chimeras transfected into COS-7 cells. In conclusion, antiparkinson agents behave as potent agonists at D3/D2

  1. The 2ν1 overtone band of H28SiD3

    NASA Astrophysics Data System (ADS)

    Cané, E.; Fusina, L.; Bürger, H.; Litz, M.

    2012-12-01

    The 2ν1 (A1) Si-H stretching overtone band of HSiD3 has been recorded at a resolution of ca. 0.009 cm-1 between 4200 and 4400 cm-1. About 790 ro-vibration transitions of the H28SiD3 isotopologue have been assigned, with J' up to 24 and K up to 21. The spectrum evidences the existence of several perturbations. The assigned transitions have been analyzed either neglecting or including in the model A1/E Coriolis-type interactions between v1 = 2 and nearby dark states. The standard deviation of all the fits is, however, more than one order of magnitude larger than the estimated experimental precision and is independent of the adopted model.

  2. High-resistance liquid-crystal lens array for rotatable 2D/3D autostereoscopic display.

    PubMed

    Chang, Yu-Cheng; Jen, Tai-Hsiang; Ting, Chih-Hung; Huang, Yi-Pai

    2014-02-10

    A 2D/3D switchable and rotatable autostereoscopic display using a high-resistance liquid-crystal (Hi-R LC) lens array is investigated in this paper. Using high-resistance layers in an LC cell, a gradient electric-field distribution can be formed, which can provide a better lens-like shape of the refractive-index distribution. The advantages of the Hi-R LC lens array are its 2D/3D switchability, rotatability (in the horizontal and vertical directions), low driving voltage (~2 volts) and fast response (~0.6 second). In addition, the Hi-R LC lens array requires only a very simple fabrication process. PMID:24663563

  3. Analysis results from the Los Alamos 2D/3D program

    SciTech Connect

    Boyack, B.E.; Cappiello, M.W.; Harmony, S.C.; Shire, P.R.; Siebe, D.A.

    1987-01-01

    Los Alamos National Laboratory is a participant in the 2D/3D program. Activities conducted at Los Alamos National Laboratory in support of 2D/3D program goals include analysis support of facility design, construction, and operation; provision of boundary and initial conditions for test-facility operations based on analysis of pressurized water reactors; performance of pretest and posttest predictions and analyses; and use of experimental results to validate and assess the single- and multi-dimensional, nonequilibrium features in the Transient Reactor Analysis Code (TRAC). During fiscal year 1987, Los Alamos conducted analytical assessment activities using data from the Slab Core Test Facility, The Cylindrical Core Test Facility, and the Upper Plenum Test Facility. Finally, Los Alamos continued work to provide TRAC improvements. In this paper, Los Alamos activities during fiscal year 1987 will be summarized; several significant accomplishments will be described in more detail to illustrate the work activities at Los Alamos.

  4. 2D/3D Program work summary report, [January 1988--December 1992

    SciTech Connect

    Damerell, P. S.; Simons, J. W.

    1993-06-01

    The 2D/3D Program was carried out by Germany, Japan and the United States to investigate the thermal-hydraulics of a PWR large-break LOCA. A contributory approach was utilized in which each country contributed significant effort to the program and all three countries shared the research results. Germany constructed and operated the Upper Plenum Test Facility (UPTF), and Japan constructed and operated the Cylindrical Core Test Facility (CCTF) and the Slab Core Test Facility (SCTF). The US contribution consisted of provision of advanced instrumentation to each of the three test facilities, and assessment of the TRAC computer code against the test results. Evaluations of the test results were carried out in all three countries. This report summarizes the 2D/3D Program in terms of the contributing efforts of the participants.

  5. Aspects of 1,25-dihydroxyvitamin D3 binding sites in fish: an autoradiographic study.

    PubMed

    Bidman, H J; Radu, I; Stumpf, W E

    1997-01-01

    The distribution of specific binding sites for vitamin D3 in adult female and male Xiphophorus helleri is studies after injection of tritiated 1,25-dihydroxyvitamin D3 (vitamin D) by thaw-mount autoradiography. Five hours after injection of labeled vitamin D specific nuclear binding is present in brain, pituitary, skin, gills, cartilage, gut, liver, pancreas, spleen, kidney, muscle, ovary, and testis. Cytoplasmic binding exists strongest in gills, gut, and kidney while it is comparatively weak in hepatocytes. In reproductive organs cytoplasmic retention of radioactivity is also present in oocytes. Weak nuclear labeling exists in interstitial cells in ovary. Conspicuous nuclear labeling exists in active lobules of testis, while inactive lobules show occasionally a few labeled cells. The results demonstrate specific binding and retention of vitamin D in many target organs of teleost fish, suggesting an extensive and multifunctional regulatory role of this steroid hormone of sunlight. PMID:9747110

  6. Cytoscape tools for the web age: D3.js and Cytoscape.js exporters

    PubMed Central

    Ono, Keiichiro; Demchak, Barry; Ideker, Trey

    2014-01-01

    In this paper we present new data export modules for Cytoscape 3 that can generate network files for Cytoscape.js and D3.js. Cytoscape.js exporter is implemented as a core feature of Cytoscape 3, and D3.js exporter is available as a Cytoscape 3 app. These modules enable users to seamlessly export network and table data sets generated in Cytoscape to popular JavaScript library readable formats. In addition, we implemented template web applications for browser-based interactive network visualization that can be used as basis for complex data visualization applications for bioinformatics research. Example web applications created with these tools demonstrate how Cytoscape works in modern data visualization workflows built with traditional desktop tools and emerging web-based technologies. This interactivity enables researchers more flexibility than with static images, thereby greatly improving the quality of insights researchers can gain from them. PMID:25520778

  7. Identification of extracellular signal-regulated kinase 3 as a new interaction partner of cyclin D3

    SciTech Connect

    Sun Maoyun; Wei Yuanyan; Yao Luyang; Xie Jianhui; Chen Xiaoning; Wang Hanzhou; Jiang Jianhai; Gu Jianxin . E-mail: jxgu@shmu.edu.cn

    2006-02-03

    Cyclin D3, like cyclin D1 and D2 isoforms, is a crucial component of the core cell cycle machinery in mammalian cells. It also exhibits its unique properties in many other physiological processes. In the present study, using yeast two-hybrid screening, we identified ERK3, an atypical mitogen-activated protein kinase (MAPK), as a cyclin D3 binding partner. GST pull-down assays showed that cyclin D3 interacts directly and specifically with ERK3 in vitro. The binding of cyclin D3 and ERK3 was further confirmed in vivo by co-immunoprecipitation assay and confocal microscopic analysis. Moreover, carboxy-terminal extension of ERK3 was responsible for its association with intact cyclin D3. These findings further expand distinct roles of cyclin D3 and suggest the potential activity of ERK3 in cell proliferation.

  8. Interface for 15VSM-5 and Elektronika D3-28 minicomputers with digital measuring instruments

    SciTech Connect

    Udovichenko, N.A.; Polikarpov, Yu.I.; Makushkin, B.V.

    1987-07-01

    A device is described for data input (up to 8 decimal digits in 8421 code) into 15VSM-5 and Elektronika D3-28 minicomputers from four measuring instruments: a V7-21 voltmeter and three Ch3-54 frequency counters. Data from the voltmeter are entered by software interrogation and data from the frequency counters are entered by software interrupts. The device is implemented by TTL integrated circuits.

  9. Functionalized Ergot-alkaloids as potential dopamine D3 receptor agonists for treatment of schizophrenia

    NASA Astrophysics Data System (ADS)

    Ivanova, Bojidarka; Spiteller, Michael

    2012-12-01

    The relationship between the molecular structure and physical properties of functionalized naturally occurred Ergot-alkaloids as potential dopamine D3 receptor agonists is presented. The molecular modeling of the ergoline-skeleton is based on the comprehensive theoretical study of the binding affinity of the isolated chemicals towards the active sites of the D3 sub-type receptor (D3R) loops. The studied proton accepting ability under physiological conditions allows classifying four types of monocationics, characterizing with the different binding modes to D3R involving selected amino acid residues to the active sites. These results marked the pharmaceutical potential and clinical usage of the reported compounds as antipsychotic drugs for Schizophrenia treatment, since they allowed evaluating the highlights of the different hypothesizes of the biochemical causes the illness. The applied complex approach for theoretical and experimental elucidation, including quantum chemistry method, electrospray ionization (ESI) and matrix assisted laser desorption/ionization (MALDI) mass spectrometric (MS) methods, nuclear magnetic resonance and vibrational IR and Raman spectroscopy on the isolated fifteen novel derivatives (1)-(15) and their different protonated forms (1a)-(15a) evidenced a strong dependence of molecular conformation, physical properties and binding affinity. Thus, the semi-synthetic functionalization of the naturally occurred products (NPs), provided significant possibilities to further molecular drugs-design and development of novel derivatives with wanted biological function, using the established profile of selected classes/families of NPs. The work described chiefly the non-linear (NL) approach for the interpretation of the mass chromatograms on the performed hybrid high performance liquid chromatography (HPLC) tandem MS/MS and MS/MS/MS experiments, discussing the merits and great diversity of instrumentation flexibility, thus achieving fundamental

  10. Taurine attenuates D-[3H]aspartate release evoked by depolarization in ischemic corticostriatal slices.

    PubMed

    Molchanova, Svetlana M; Oja, Simo S; Saransaari, Pirjo

    2006-07-12

    Taurine is thought to be protective in ischemia due to its neuroinhibitory effects. The present aim was to assess the ability of taurine to attenuate glutamate release evoked by ischemia and to determine which component of this release is affected. The release of preloaded D-[(3)H]aspartate (a non-metabolized analog of glutamate) from superfused murine corticostriatal slices was used as index of glutamate release. Preincubation of corticostriatal slices with 10 mM taurine reduced the D-[(3)H]aspartate release evoked by either chemical ischemia (0.5 mM NaCN in glucose-free medium) or oxygen-glucose deprivation. The taurine uptake inhibitor guanidinoethanesulfonate (5 mM), the glycine receptor antagonist strychnine (0.1 mM) and the GABA(A) receptor antagonist bicuculline (0.1 mM) did not block the taurine effect. To determine which component of ischemia-induced glutamate release is affected by taurine, three pathways of this release were pharmacologically modeled. Unlabeled D-aspartate (0.5 mM) and hypo-osmotic medium (NaCl reduced by 50 mM) evoked D-[(3)H]aspartate release via homoexchange and hypo-osmotic release pathways, respectively. Taurine did not influence these pathways. However, it suppressed the synaptic release of D-[(3)H]aspartate evoked by the voltage-gated sodium channel opener veratridine (0.1 mM). Taurine thus reduces glutamate release under ischemic conditions by affecting the depolarization-evoked component. PMID:16781687

  11. Vitamin D3 intake modulates diaphragm but not peripheral muscle force in young mice.

    PubMed

    Ray, Andrew D; Personius, Kirkwood E; Williamson, David L; Dungan, Cory M; Dhillon, Samjot S; Hershberger, Pamela A

    2016-05-15

    Recent data support an important role for vitamin D in respiratory health. We tested the hypothesis that dietary vitamin D3 (VD3) intake modulates diaphragm (DIA) strength. Four-week-old female A/J mice (n = 10/group) were randomized to receive diets containing 100 IU VD3/kg (low), 1,000 IU VD3/kg (reference), or 10,000 IU VD3/kg (pharmacologic). After 6 wk of dietary intervention, plasma 25-hydroxyvitamin D3 (25D3) levels, DIA and extensor digitorum longus (EDL) in vitro contractile properties, and fiber cross-sectional area (CSA) were measured. Myosin heavy chain (MHC) composition and Akt/Foxo3A growth signaling were studied in the DIA and tibialis anterior. Mice fed the low, reference, and pharmacologic diets had average 25D3 levels of 7, 21, and 59 ng/ml, respectively. Maximal DIA force, twitch force, and fiber CSA were reduced 26%, 28%, and 10% (P < 0.01), respectively, in mice receiving the low-VD3 diet compared with the reference and pharmacologic diets. EDL force parameters were unaltered by diet. Effects of VD3 intake on DIA force were not observed in mice that began dietary intervention at 12 wk of age. VD3 intake did not alter the MHC composition of the DIA, indicating that decreases in force and CSA in young mice were not due to a switch in fiber type. Paradoxically, low VD3 intake was associated with activation of anabolic signaling in muscle (hyperphosphorylation of Akt and Foxo3A and decreased expression of autophagy marker LC3). These studies identify a potential role of dietary VD3 in regulating DIA development and insulin sensitivity. PMID:26968027

  12. Association of vitamin D3 with alveolar bone regeneration in dogs

    PubMed Central

    Hong, Hsiang-Hsi; Yen, Tzung-Hai; Hong, Adrienne; Chou, Ting-An

    2015-01-01

    Designed sockets prepared on the mandibles of nine Beagle dogs were divided into three groups: Calcitriol +Alloplast, Alloplast and Empty. Five of the nine dogs received Vit.D3 and calcium supplement (Vit.D/Ca group), while the other four dogs without supplements were assigned to Non-Vit.D/Ca group. After 4 weeks, the extent of vertical ridge resorption (VRR), bone density (density), new bone formation (NBF) and implant stability quotient (ISQ) were measured. Following systemic Vit.D/Ca administration, the Empty subgroup showed significant differences from the Calcitriol + Alloplast subgroup on variants NBF/Density/VRR and the Alloplast subgroup on items NBF/Density/ISQ/VRR. Alternatively, the Calcitriol + Alloplast subgroup revealed higher values of NBF/Density/ISQ (P < 0.001) and a lower VRR value (P = 0.001) than the Alloplast subgroup. Although there were no significant differences in NBF (P = 0.349), density (P = 0.796), ISQ (P = 0.577) and VRR (0.979) comparisons on alloplast treatment between the Vit.D/Ca and Non-Vit.D/Ca groups, local application with Calcitriol + Alloplast demonstrated better NBF/Density/ISQ (P = 0.02 to <0.001) effects than which of Alloplast subgroups. Consequently, the results showed that both systemic and local vitamin D3 treatment might accelerate bone regeneration in dogs. Within the using dose, systemic vitamin D3 treatment displayed a superior stimulating effect than local vitamin D3 application did. PMID:25753943

  13. 26 CFR 31.3406(d)-3 - Special 30-day rules for certain reportable payments.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... COLLECTION OF INCOME TAX AT SOURCE Collection of Income Tax at Source § 31.3406(d)-3 Special 30-day rules for... not qualify for, or the payor does not apply, the 90-day grace period described in § 1.6049-5(d)(2)(ii... 26 Internal Revenue 15 2013-04-01 2013-04-01 false Special 30-day rules for certain...

  14. 26 CFR 31.3406(d)-3 - Special 30-day rules for certain reportable payments.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... COLLECTION OF INCOME TAX AT SOURCE Collection of Income Tax at Source § 31.3406(d)-3 Special 30-day rules for... not qualify for, or the payor does not apply, the 90-day grace period described in § 1.6049-5(d)(2)(ii... 26 Internal Revenue 15 2012-04-01 2012-04-01 false Special 30-day rules for certain...

  15. 26 CFR 31.3406(d)-3 - Special 30-day rules for certain reportable payments.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... COLLECTION OF INCOME TAX AT SOURCE Collection of Income Tax at Source § 31.3406(d)-3 Special 30-day rules for... not qualify for, or the payor does not apply, the 90-day grace period described in § 1.6049-5(d)(2)(ii... 26 Internal Revenue 15 2011-04-01 2011-04-01 false Special 30-day rules for certain...

  16. Adjustment of foreign EQ-5D-3L utilities can increase their transferability

    PubMed Central

    Oddershede, Lars; Petersen, Karin Dam

    2015-01-01

    Background Foreign utilities of the EQ-5D-3L (3-level version of the EuroQol-5 Dimension of health questionnaire) are not readily transferrable to economic evaluations conducted from a national perspective. It has been advised to avoid transferring mean utilities from one country to another without adjusting them; yet no such method exists. Purpose The present study aimed to develop a method for adjusting mean utilities to increase their transferability from one country to another. Methods Seven datasets containing EQ-5D-3L answers were valued using value sets from four countries: the UK, the Netherlands, Germany, and Spain. Hereby, seven mean utility values were obtained for each country. This allowed for three pairwise comparisons: 1) UK mean values vs Dutch mean values; 2) UK mean values vs German mean values; and 3) UK mean values vs Spanish mean values. For each of these three comparisons, a regression model was fitted using the mean UK utilities as the dependent variable and the other country’s mean utilities as the independent variable. The coefficients from the three regression models were validated using results from a published article containing mean utilities obtained by valuing the EQ-5D-3L data using all four value sets. Results The findings suggested that adjustment of foreign utilities may increase transferability between countries where value sets are not comparable. It was possible to adjust the mean utilities valued by the Dutch and German value sets to make them reflect mean UK utilities as there were substantial differences between these value sets. Transferability of the Spanish mean utility values was not improved as the Spanish and UK value sets are sufficiently similar. Conclusion It is feasible to adjust foreign mean utilities of the EQ-5D-3L to make them reflect national preferences for health. PMID:26719715

  17. Calcinogenic factor in Solanum malacoxylon: evidence that it is 1,25-dihydroxyvitamin D3-glycoside.

    PubMed

    Wasserman, R H; Henion, J D; Haussler, M R; McCain, T A

    1976-11-19

    After glycosidic cleavage of the water-soluble vitamin D-like principle of the calcinogenic plant Solanum malacoxylon, the active lipophilic portion was purified by column chromatography and analyzed by combined gas chromatography and mass spectrometry. It was identified as 1,25-dihydroxyvitamin D3, the active form of vitamin D. Thus this active metabolite of vitamin D exists in the plant world, and its presence probably accounts for pathologic calcification in grazing animals ingesting Solanum malacoxylon. PMID:982048

  18. Follicular keratosis of the chin treated with 1.24R-dihydroxyvitamin D3 ointment.

    PubMed

    Yanagihara, Makoto; Takeda, Kiminobu; Tanabe, Hiroshi; Abe, Shinya; Ishizaki, Hiroshi

    2007-01-01

    In follicular keratosis of the chin, keratotic follicular papules occur on the chin and jaw due to localized prolonged pressure and friction on the naked skin. We present one patient with this disorder. The dermatoscopic examination revealed many well-demarcated yellow spindle bodies in the patchy lesion. Therapy with 1.24R-dihydroxyvitamin D3 ointment was effective during the treatment but had no residual positive effect. PMID:17845168

  19. Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics

    NASA Astrophysics Data System (ADS)

    Sokoloff, Pierre; Giros, Bruno; Martres, Marie-Pascale; Bouthenet, Marie-Louise; Schwartz, Jean-Charles

    1990-09-01

    A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. The D3 receptor is localized to limbic areas of the brain, which are associated with cognitive, emotional and endocrine functions. It seems to mediate some of the effects of antipsychotic drugs and drugs used against Parkinson's disease, that were previously thought to interact only with D2 receptors.

  20. Dopamine D3 receptor-preferring agonist enhances the subjective effects of cocaine in humans.

    PubMed

    Newton, Thomas F; Haile, Colin N; Mahoney, James J; Shah, Ravi; Verrico, Christopher D; De La Garza, Richard; Kosten, Thomas R

    2015-11-30

    Pramipexole is a D3 dopamine receptor-preferring agonist indicated for the treatment of Parkinson disease. Studies associate pramipexole with pathological gambling and impulse control disorders suggesting a role for D3 receptors in reinforcement processes. Clinical studies showed pramipexole decreased cocaine craving and reversed central deficits in individuals with cocaine use disorder. Preclinical studies have shown acute administration of pramipexole increases cocaine's reinforcing effects whereas other reports suggest chronic pramipexole produces tolerance to cocaine. In a randomized, double-blind, placebo-controlled study we examined the impact of pramipexole treatment on the subjective effects produced by cocaine in volunteers with cocaine use disorder. Volunteers received pramipexole titrated up to 3.0mg/d or placebo over 15 days. Participants then received intravenous cocaine (0, 20 and 40mg) on day 15. Cardiovascular and subjective effects were obtained with visual analog scales at time points across the session. Pramipexole alone increased peak heart rate following saline and diastolic blood pressure following cocaine. Pramipexole produced upwards of two-fold increases in positive subjective effects ratings following cocaine. These results indicate that chronic D3 receptor activation increases the subjective effects of cocaine in humans. Caution should be used when prescribing pramipexole to patients that may also use cocaine. PMID:26239766

  1. D-3 phosphoinositide metabolism in cells treated with platelet-derived growth factor.

    PubMed Central

    Whiteford, C C; Best, C; Kazlauskas, A; Ulug, E T

    1996-01-01

    Despite extensive analysis of phosphoinositide 3-hydroxykinases (PI 3-kinases) at the molecular level, comparatively little is known about the mechanisms by which products of these enzymes exert their expected second-messenger functions. This study examines the metabolism of D-3 phosphoinositides in mouse Ph-N2 fibroblasts lacking the platelet-derived growth factor (PDGF) alpha-receptor. Treatment of these cultures with BB PDGF, but not AA PDGF, resulted in transient activation of PI 3-kinase activity measured in vitro. Treatment of myo-[3H]inositol-labelled Ph-N2 cells with BB PDGF resulted in the rapid induction of PtdIns(3,4)P2 and PtdIns(3,4,5)P3 and, to a smaller extent, PtdIns3P. The appearance of PtdIns(3,4,5)P3 preceded that of PtdIns(3,4)P2 and PtdIns3P after the addition of PDGF, suggesting that PtdIns(4,5)P2 is the preferred substrate of the agoniststimulated PI 3-kinase in intact cells. Treatment of both resting and PDGF-stimulated cells with the fungal metabolite wortmannin resulted in pronounced, selective effects on the levels of all D-3 phosphoinositides. Kinetic studies with this PI 3-kinase inhibitor revealed the presence of at least two independent routes for the biosynthesis of D-3 phosphoinositides in PDGF-treated cells. PMID:8920990

  2. Formulation of Nanoliposomal Vitamin D3 for Potential Application in Beverage Fortification

    PubMed Central

    Mohammadi, Maryam; Ghanbarzadeh, Babak; Hamishehkar, Hamed

    2014-01-01

    Purpose: Vitamin D, a liposoluble vitamin has many benefits on health. Encapsulation of bioactives in lipid-based carrier systems like nanoliposomes preserves their native properties against oxidation over time along with providing its stable aqueous dispersion. Methods: In the current study, vitamin D3 nanoliposomes were prepared using thin-film hydration-sonication method and fully characterized by different instrumental techniques. Results: According to FTIR and DSC results, no interaction was observed between encapsulated nutraceutical and liposome constituents. The particle size and size distribution (Span value) were calculated 82–90 nm and 0.70–0.85, respectively. TEM analysis showed nano sized globular and bilayer vesicles. In all formations, the encapsulation efficiency of vitamin D3 was calculated more than 93%. Addition of cholesterol to lecithin bilayer increased the negative zeta potential from -29 to -43mV. Conclusion: The results of this study concluded that the liposomal nanoparticles may be introduced as a suitable carrier for fortification of beverages with vitamin D3. PMID:25671191

  3. Triangular D3h Symmetry in the Rotation-Vibration Spectrum of 12C

    NASA Astrophysics Data System (ADS)

    Gai, Moshe

    2015-02-01

    Our recent measurements of new states in 12C including the second 2+ at 10 MeV and the high spin 5- state at 22.4 MeV allow us to study the Rotation-Vibration spectrum of 12C from which evidence for a new (D3h) geometrical symmetry emerges. The data fit very well to the predicted (ground state) rotational band of an oblate equilateral triangular spinning top with a D3h symmetry characterized by the sequence of states: 0+, 2+, 3-, 4+/-, 5- with almost degenerate 4+ and 4- (parity doublet) states. Such a D3h symmetry was observed in triatomic molecules, and it is observed in 12C for the first time in nuclear physics. The triatomic like structure in nuclei is reminiscent of the discovery of diatomic α+14C structure in 18O. We discuss a classification of other rotation-vibration bands in 12C such as the (0+) Hoyle band and the (1-) bending mode band and suggest measurements in search of the predicted ("missing") states that may shed new light on clustering in 12C and light nuclei. In particular, the observation (or non observation) of the predicted ("missing") states in the Hoyle band will allow us to conclude the geometrical arrangement of the three alpha particles composing the Hoyle state at 7.654 MeV in 12C.

  4. 2-D/3-D ECE imaging data for validation of turbulence simulations

    NASA Astrophysics Data System (ADS)

    Choi, Minjun; Lee, Jaehyun; Yun, Gunsu; Lee, Woochang; Park, Hyeon K.; Park, Young-Seok; Sabbagh, Steve A.; Wang, Weixing; Luhmann, Neville C., Jr.

    2015-11-01

    The 2-D/3-D KSTAR ECEI diagnostic can provide a local 2-D/3-D measurement of ECE intensity. Application of spectral analysis techniques to the ECEI data allows local estimation of frequency spectra S (f) , wavenumber spectra S (k) , wavernumber and frequency spectra S (k , f) , and bispectra b (f1 ,f2) of ECE intensity over the 2-D/3-D space, which can be used to validate turbulence simulations. However, the minimum detectable fluctuation amplitude and the maximum detectable wavenumber are limited by the temporal and spatial resolutions of the diagnostic system, respectively. Also, the finite measurement area of the diagnostic channel could introduce uncertainty in the spectra estimation. The limitations and accuracy of the ECEI estimated spectra have been tested by a synthetic ECEI diagnostic with the model and/or fluctuations calculated by GTS. Supported by the NRF of Korea under Contract No. NRF-2014M1A7A1A03029881 and NRF-2014M1A7A1A03029865 and by U.S. DOE grant DE-FG02-99ER54524.

  5. Effect of Cyclosporin A on the Uptake of D3-Selective PET Radiotracers in Rat Brain

    PubMed Central

    Tu, Zhude; Li, Shihong; Xu, Jinbin; Chu, Wenhua; Jones, Lynne A.; Luedtke, Robert R.; Mach, Robert H.

    2011-01-01

    Introduction Four benzamide analogs having a high affinity and selectivity for D3 versus D2 receptors were radiolabeled with 11C or 18F for in vivo evaluation. Methods Precursors were synthesized and the four D3 selective benzamide analogs were radiolabeled. The tissue distribution and brain uptake of the four compounds were evaluated in control rats and rats pretreated with cyclosporin A, a modulator of P-glycoprotein and an inhibitor of other ABC efflux transporters that contribute to the blood brain barrier. MicroPET imaging was carried out for [11C]6 in a control and a cyclosporin A pre-treated rat. Results All four compounds showed low brain uptake in control rats at 5 and 30 min post-injection; despite recently reported rat behavioral studies conducted on analogs 6 (WC-10) and 7 (WC-44). Following administration of cyclosporin A, increased brain uptake was observed with all four PET radiotracers at both 5 and 30 min post-i.v. injection. An increase in brain uptake following modulation/inhibition of the ABC transporters was also observed in the microPET study. Conclusions These data suggest that D3 selective conformationally-flexible benzamide analogs which contain a N-2-methoxyphenylpiperazine moiety are substrates for P-glycoprotein or other ABC transporters expressed at the blood-brain barrier, and that PET radiotracers containing this pharmacophore may display low brain uptake in rodents due to the action of these efflux transporters. PMID:21718948

  6. Association study between schizophrenia and dopamine D3 receptor gene polymorphism

    SciTech Connect

    Tanaka, Toshihisa; Takahashi, Makoto; Maeda, Masaya

    1996-07-26

    Crocq et al. reported the existence of an association between schizophrenia and homozygosity of a BalI polymorphism in the first exon of the dopamine D3 receptor (DRD3) gene. In response to this report, further studies were conducted; however, these studies yielded conflicting results. In the present study, we examined 100 unrelated Japanese schizophrenics and 100 normal controls to determine any association between this polymorphism and schizophrenia. Results suggest that neither allele nor genotype frequencies of the DRD3 gene in the schizophrenics as a whole are significantly different from those of the controls. Further, we found no association between any allele or genotype and any clinical subtype based on family history of schizophrenia and age-at-onset. A significantly high frequency of homozygosity of a dopamine D3 receptor gene allele was not observed in the schizophrenics as a whole, or in clinical subtypes. Our results suggest that an association between the dopamine D3 receptor gene and schizophrenia is unlikely to exist. 26 refs., 1 tab.

  7. Intestinal MUC2 mucin supramolecular topology by packing and release resting on D3 domain assembly.

    PubMed

    Nilsson, Harriet E; Ambort, Daniel; Bäckström, Malin; Thomsson, Elisabeth; Koeck, Philip J B; Hansson, Gunnar C; Hebert, Hans

    2014-07-15

    MUC2 is the major gel-forming mucin of the colon forming a protective gel barrier organized into an inner stratified and an outer loose layer. The MUC2 N-terminus (D1-D2-D'D3 domains) has a dual function in building a net-like structure by disulfide-bonded trimerization and packing the MUC2 polymer into an N-terminal concatenated polygonal platform with the C-termini extending perpendicularly by pH- and calcium-dependent interactions. We studied the N-terminal D'D3 domain by producing three recombinant variants, with or without Myc tag and GFP (green fluorescent protein), and analyzed these by gel filtration, electron microscopy and single particle image processing. The three variants were all trimers when analyzed upon denaturing conditions but eluted as hexamers upon gel filtration under native conditions. Studies by electron microscopy and three-dimensional maps revealed cage-like structures with 2- and 3-fold symmetries. The structure of the MUC2 D3 domain confirms that the MUC2 mucin forms branched net-like structures. This suggests that the MUC2 mucin is stored with two N-terminal concatenated ring platforms turned by 180° against each other, implicating that every second unfolded MUC2 net in mature mucus is turned upside down. PMID:24816392

  8. Dopamine D3 receptor-preferring agonists induce neurotrophic effects on mesencephalic dopamine neurons.

    PubMed

    Du, Fang; Li, Rui; Huang, Yuangui; Li, Xuping; Le, Weidong

    2005-11-01

    Anti-parkinsonian agents, pramipexole (PPX) and ropinirole (ROP), have been reported to possess neuroprotective properties, both in vitro and in vivo. The mechanisms underlying neuroprotection afforded by the D3-preferring receptor agonists remain poorly understood. The present study demonstrates that incubation of primary mesencephalic cultures with PPX and ROP or the conditioned medium from PPX- or ROP-treated primary cultures induced a marked increase in the number of dopamine (DA) neurons in the cultures. Similar effects can be observed after incubating with the conditioned medium derived from PPX- and ROP-treated substantia nigra astroglia. Meanwhile, PPX and ROP can protect the primary cells from insult of 1-methyl-4-phenylpyridinium (MPP+), the active metabolite of the neurotoxin 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP). Furthermore, the neurotrophic effects of PPX and ROP on mesencephalic dopamine neurons could be significantly blocked by D3 receptor antagonist, but not by D2 receptor antagonist. Moreover, we found that the levels of glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) in the conditioned medium of mesencephalic cultures treated with PPX and ROP were significantly increased. Blocking GDNF and BDNF with the neutralizing antibodies, the neurotrophic effects of PPX and ROP were greatly diminished. These results suggest that D3 dopamine receptor-preferring agonists, PPX and ROP, exert neurotrophic effects on cultured DA neurons by modulating the production of endogenous GDNF and BDNF, which may participate in their neuroprotection. PMID:16307585

  9. Enhancement of Vitamin D Metabolites in the Eye following Vitamin D3 Supplementation and UV-B Irradiation

    PubMed Central

    Lin, Yanping; Ubels, John L.; Schotanus, Mark P.; Yin, Zhaohong; Pintea, Victorina; Hammock, Bruce D.; Watsky, Mitchell A.

    2013-01-01

    Purpose This study was designed to measure vitamin D metabolites in the aqueous and vitreous humor and in tear fluid, and to determine if dietary vitamin D3 supplementation affects these levels. We also determined if the corneal epithelium can synthesize vitamin D following UV-B exposure. Methods Rabbits were fed a control or vitamin D3 supplemented diet. Pilocarpine-stimulated tear fluid was collected and aqueous and vitreous humor were drawn from enucleated eyes. Plasma vitamin D was also measured. To test for epithelial vitamin D synthesis, a human corneal limbal epithelial cell line was irradiated with two doses of UV-B (10 and 20 mJ/cm2/day for three days) and vitamin D was measured in control or 7-dehydrocholesterol treated culture medium. Measurements were made using mass spectroscopy. Results 25(OH)-vitamin D3 and 24,25(OH)2-vitamin D3 increased significantly following D3 supplementation in all samples except vitreous humor. Tear fluid and aqueous humor had small but detectable 1,25(OH)2-vitamin D3 levels. Vitamin D2 metabolites were observed in all samples. Vitamin D3 levels were below the detection limit for all samples. Minimal vitamin D3 metabolites were observed in control and UV-B-irradiated epithelial culture medium except following 7-dehydrocholesterol treatment, which resulted in a UV-B-dose dependent increase in vitamin D3, 25(OH)-vitamin D3 and 24,25(OH)2-vitamin D3. Conclusions There are measurable concentrations of vitamin D metabolites in tear fluid and aqueous and vitreous humor, and oral vitamin D supplementation affects vitamin D metabolite concentrations in the anterior segment of the eye. In addition, the UV exposure results lead us to conclude that corneal epithelial cells are likely capable of synthesizing vitamin D3 metabolites in the presence of 7-dehydrocholesterol following UV-B exposure. PMID:22632164

  10. Effects of 1,25-dihydroxyvitamin D3 on colonic calcium transport in vitamin D-deficient and normal rats.

    PubMed

    Favus, M J; Langman, C B

    1984-03-01

    To determine whether prior vitamin D intake influences the intestinal calcium absorptive action of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], we measured in vitro the two unidirectional transepithelial fluxes of calcium across descending colon segments from rats fed either a vitamin D-deficient or normal diet and injected with either 10, 25, or 75 ng of 1,25(OH)2D3 or vehicle alone. Vitamin D deficiency abolished net calcium absorption [J net, -2 +/- 2 vs. 12 +/- 2 (SE) nmol X cm-2 X h-1, P less than 0.001], and 10 ng of 1,25(OH)2D3 raised J net to levels found in normal rats. Larger doses (25 and 75 ng) increased J net above levels in normal rats given the same dose. In normal rats only 75 ng of 1,25(OH)2D3 increased calcium J net above vehicle control values (12 +/- 2 vs. 38 +/- 4 nmol X cm-2 X h-1, P less than 0.001). Circulating 1,25(OH)2D3 measured by radioreceptor assay was well correlated with calcium transport. For each dose of 1,25(OH)2D3 higher serum 1,25(OH)2D3 levels were reached in vitamin D-deficient rats. Only the 75-ng dose increased circulating 1,25(OH)2D3 and colonic calcium transport in normal rats. Intravenous [3H]-1,25(OH)2D3 disappeared more rapidly from the circulation of normal rats, suggesting that accelerated metabolic degradative processes for 1,25(OH)2D3 may be present in normal but not in vitamin D-deficient rats and may account for the lack of a biological response to 1,25(OH)2D3 in normal animals. PMID:6546644

  11. Factors associated with 1,25-dihydroxyvitamin D3 concentrations in liver transplant recipients: a prospective observational longitudinal study.

    PubMed

    Prytuła, Agnieszka; Walle, Johan Vande; Van Vlierberghe, Hans; Kaufman, Jean-Marc; Fiers, Tom; Dehoorne, Jo; Raes, Ann

    2016-04-01

    The aim of the study was to identify factors associated with 1,25(OH)2D3 concentrations in liver transplant recipients with emphasis on the renal function and catabolism. We also tested the hypothesis that tacrolimus increases 1,25(OH)2D3 concentrations. Serum 25(OH)D3, 1,25(OH)2D3, and 24,25(OH)2D3 were measured in 41 patients before, at 2 weeks and 3 months after transplantation. Dose-adjusted tacrolimus concentration was used as a surrogate marker of CYP3A4 activity. Factors associated with 1,25(OH)2D3 were identified using multivariate linear regression analysis. The median 1,25(OH)2D3 levels remained stable: 55 versus 46 pg/ml (P = 0.36) despite an increase in 25(OH)D3 from 18 ng/ml at baseline to 26 ng/ml (P = 0.03), serum albumin (34 to 41 g/l, P = 0.02), and comparable eGFR at baseline and month 3 (94 and 92 ml/min, respectively, P = 0.15). At 3 months 19 % of patients had 1,25(OH)2D3 < 25 pg/ml. Low eGFR and a low dose-adjusted tacrolimus concentration were both independently associated with 1,25(OH)2D3 at 3 months. Liver transplant recipients with impaired renal function or a low dose-adjusted tacrolimus concentration suggesting a high CYP3A4 are at risk of low 1,25(OH)2D3 concentrations. The use of tacrolimus does not lead to an increase in 1,25(OH)2D3 concentrations in a clinical setting. PMID:26433738

  12. Prolonged treatment with pramipexole promotes physical interaction of striatal dopamine D3 autoreceptors with dopamine transporters to reduce dopamine uptake.

    PubMed

    Castro-Hernández, Javier; Afonso-Oramas, Domingo; Cruz-Muros, Ignacio; Salas-Hernández, Josmar; Barroso-Chinea, Pedro; Moratalla, Rosario; Millan, Mark J; González-Hernández, Tomás

    2015-02-01

    The dopamine (DA) transporter (DAT), a membrane glycoprotein expressed in dopaminergic neurons, clears DA from extracellular space and is regulated by diverse presynaptic proteins like protein kinases, α-synuclein, D2 and D3 autoreceptors. DAT dysfunction is implicated in Parkinson's disease and depression, which are therapeutically treated by dopaminergic D2/D3 receptor (D2/D3R) agonists. It is, then, important to improve our understanding of interactions between D3R and DAT. We show that prolonged administration of pramipexole (0.1mg/kg/day, 6 to 21 days), a preferential D3R agonist, leads to a decrease in DA uptake in mouse striatum that reflects a reduction in DAT affinity for DA in the absence of any change in DAT density or subcellular distribution. The effect of pramipexole was absent in mice with genetically-deleted D3R (D3R(-/-)), yet unaffected in mice genetically deprived of D2R (D2R(-/-)). Pramipexole treatment induced a physical interaction between D3R and DAT, as assessed by co-immunoprecipitation and in situ proximity ligation assay. Furthermore, it promoted the formation of DAT dimers and DAT association with both D2R and α-synuclein, effects that were abolished in D3R(-/-) mice, yet unaffected in D2R(-/-) mice, indicating dependence upon D3R. Collectively, these data suggest that prolonged treatment with dopaminergic D3 agonists provokes a reduction in DA reuptake by dopaminergic neurons related to a hitherto-unsuspected modification of the DAT interactome. These observations provide novel insights into the long-term antiparkinson, antidepressant and additional clinical actions of pramipexole and other D3R agonists. PMID:25511804

  13. Cariprazine for the Treatment of Schizophrenia: A Review of this Dopamine D3-Preferring D3/D2 Receptor Partial Agonist.

    PubMed

    Citrome, Leslie

    2016-01-01

    Cariprazine is an antipsychotic medication and received approval by the U.S. Food and Drug Administration for the treatment of schizophrenia in September 2015. Cariprazine is a dopamine D3 and D2 receptor partial agonist, with a preference for the D3 receptor. Cariprazine is also a partial agonist at the serotonin 5-HT1A receptor and acts as an antagonist at 5-HT2B and 5-HT2A receptors. The recommended dose range of cariprazine for the treatment of schizophrenia is 1.5-6 mg/d; the starting dose of 1.5 mg/d is potentially therapeutic. Cariprazine is administered once daily and is primarily metabolized in the liver through the CYP3A4 enzyme system and, to a lesser extent, by CYP2D6. There are two active metabolites of note, desmethyl-cariprazine and didesmethyl-cariprazine; the latter's half-life is substantially longer than that for cariprazine and systemic exposure to didesmethyl-cariprazine is several times higher than that for cariprazine. Three positive, 6-week, Phase 2/3, randomized controlled trials in acute schizophrenia demonstrated superiority of cariprazine over placebo. Pooled responder rates were 31% for cariprazine 1.5-6 mg/d vs. 21% for placebo, resulting in a number needed to treat (NNT) of 10. In a 26-72 week, randomized withdrawal study, significantly fewer patients relapsed in the cariprazine group compared with placebo (24.8% vs. 47.5%), resulting in an NNT of 5. The most commonly encountered adverse events (incidence ≥5% and at least twice the rate of placebo) are extrapyramidal symptoms (number needed to harm [NNH] 15 for cariprazine 1.5-3 mg/d vs. placebo and NNH 10 for 4.5-6 mg/d vs. placebo) and akathisia (NNH 20 for 1.5-3 mg/d vs. placebo and NNH 12 for 4.5-6 mg/d vs. placebo). Short-term weight gain appears small (approximately 8% of patients receiving cariprazine 1.5-6 mg/d gained ≥7% body weight from baseline, compared with 5% for those randomized to placebo, resulting in an NNH of 34). Cariprazine is associated with no clinically

  14. Summer/winter differences in the serum 25-hydroxyvitamin D3 and parathyroid hormone levels of Japanese women

    NASA Astrophysics Data System (ADS)

    Nakamura, K.; Nashimoto, Mitsue; Yamamoto, Masaharu

    Serum 25-hydroxyvitamin D3 [25(OH)D3] is produced in the skin in response to exposure to ultraviolet radiation, and is a good indicator of vitamin D nutritional status. The aim of this study was to determine summer/winter differences in serum 25(OH)D3 and parathyroid hormone (PTH) in Japanese women and how the summer and winter values are related. The subjects were 122 healthy Japanese women aged 45-81 years (average age: 65.7 years). They were medically examined twice, in September 1997 and February 1999. Serum 25(OH)D3 and intact PTH were determined by high-performance liquid chromatography and a two-site immunoradiometric assay respectively. Lifestyle information was obtained through an interview. The seasonal differences (winter minus summer) in 25(OH)D3 [Δ25(OH)D3] and intact PTH concentrations were -18.8 nmol/l (SD 19.2, P<0.0001) and 0.98pmol/l (SD 1.02, P<0.0001) respectively. The correlation coefficient between summer (x) and winter (y) 25(OH)D3 levels was 0.462 (P<0.0001), with a linearly fitted line of y=0.42x+26.4. This relationship was interpreted as subjects with higher summer 25(OH)D3 values having greater reductions in winter 25(OH)D3 concentrations. There were inter-individual differences in Δ25(OH)D3, although the summer and winter 25(OH)D3 concentrations were well-correlated. Since Δ25(OH)D3 was not associated with any of the lifestyle factors, seasonal differences in the 25(OH)D3 concentrations of an individual appeared to reflect her ability to produce 25(OH)D3 photochemically in the skin. Sun bathing would be a less effective means of attaining adequate vitamin D nutritional status in a person with a small seasonal difference in 25(OH)D3, i.e., one with a low 25(OH)D3 level.

  15. Diminished internalization and action of 1,25-dihydroxyvitamin D3 in dermal fibroblasts cultured from New World primates

    SciTech Connect

    Adams, J.S.; Gacad, M.A.; Baker, A.J.; Kheun, G.; Rude, R.K.

    1985-06-01

    We investigated the occurrence of 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3)-resistant osteomalacia in the New World primate colony of Saguinus imperator at the Los Angeles Zoo. The mean serum concentration of 1,25-(OH)2D3 was elevated 5-fold in the New World primates compared to that in their Old World counterparts. The specific internalization of 0.6 nM (/sup 3/H)1,25-(OH)2D3 by cultured dermal fibroblasts from New World primates was reduced 75% compared to that by cells from Old World primates or man. The decrease in hormone uptake resulted from a decrease in the number of high affinity intracellular binding sites for 1,25-(OH)2D3 and apparently caused a 90-95% reduction in 1,25-(OH)2D3-induced 25-hydroxyvitamin-D3-24-hydroxylase activity. There was no alteration in the capacity or avidity of New World primate serum for 1,25-(OH)2D3 compared to that of serum from Old World primates. These data suggest that the occurrence of vitamin D-resistant osteomalacia in New World primates is the result of decreased high affinity, receptor-mediated uptake of 1,25-(OH)2D3 by the target cell.

  16. Reduced D2/D3 Receptor Binding of Extrastriatal and Striatal Regions in Temporal Lobe Epilepsy

    PubMed Central

    Bernedo Paredes, Viviane E.; Buchholz, Hans-Georg; Gartenschläger, Martin; Breimhorst, Markus

    2015-01-01

    Objective Dopamine is an endogenous neuromodulator in cortical circuits and the basal ganglia. In animal models of temporal lobe epilepsy (TLE), seizure threshold is modulated to some extent by dopamine, with D1-receptors having a pro- and D2-receptors an anticonvulsant effect. We aimed to extend our previously reported results on decreased D2/D3 receptor binding in the lateral epileptogenic temporal lobe and to correlate them with demographic and seizure variables to gain a more comprehensive understanding of the underlying involvement of the dopaminergic system in the epileptogenesis of TLE. Methods To quantify D2/D3 receptor binding, we studied 21 patients with TLE and hippocampal sclerosis (13 left- and eight right-sided) and 18 controls using PET with the high-affinity dopamine D2/D3-receptor ligand 18F-Fallypride to image striatal and extrastriatal binding. TLE was defined by interictal and ictal video-EEG, MRI and 18F-Fluorodeoxyglucose PET. Voxel-based statistical and regions-of-interest analyses were performed. Results 18F-Fallypride binding potential was significantly reduced in the affected temporal lobe and bilateral putamen. A positive correlation between age at onset of epilepsy and [18F]FP BPnd (binding potential non-displaceable) in temporal regions on the epileptogenic side was found, as well as a negative correlation between epilepsy duration and [18F]FP BPnd in the temporal pole on the epileptogenic side and a positive correlation between the estimated number of lifetime GTCS and [18F]FP BPnd in the hippocampus on the epileptogenic side. Significance The areas of reduced D2/D3 receptor availability correspond to “the irritative zone” surrounding the epileptogenic area. Moreover, reduced D2/D3 receptor availability was detectable in the basal ganglia, which are suspected to be involved in a control circuit for epileptic seizures. The correlational analysis additionally suggests that increased epilepsy duration leads to increasing impairment of

  17. Use of 25-hydroxyvitamin D3 and vitamin E to improve tenderness of beef from the longissimus dorsi of heifers.

    PubMed

    Carnagey, K M; Huff-Lonergan, E J; Trenkle, A; Wertz-Lutz, A E; Horst, R L; Beitz, D C

    2008-07-01

    The objective of this trial was to determine whether a single bolus of 25-hydroxyvitamin D(3) (25-OH D(3)), vitamin E, or a combination of the 2 would improve the tenderness of steaks from the LM of beef heifers. Forty-eight Angus crossbred heifers were allotted randomly to 8 pens. Six heifers were in each pen, and there were 2 pens per treatment. The 4 treatments included control (no 25-OH D(3) or vitamin E); 25-OH D(3) (500 mg of 25-OH D(3) administered as a one-time oral bolus 7 d before slaughter); vitamin E (1,000 IU of vitamin E administered daily as a top-dress for 104 d before slaughter); or combination (500 mg of 25-OH D(3) administered as a one-time oral bolus 7 d before slaughter and 1,000 IU of vitamin E administered daily as a top-dress for 104 d before slaughter). Blood samples were obtained on the day that heifers were allotted to treatments, on the day 25-OH D(3) was administered, and on the day before slaughter. Plasma calcium concentration was increased when 25-OH D(3) was administered with or without vitamin E (P < 0.007). In LM, calcium concentration tended to increase (P = 0.10) when 25-OH D(3) was administered alone but not when 25-OH D(3) was administered with vitamin E. Concentrations of 25-OH D(3) and 1,25-dihydroxyvitamin D(3) in plasma were increased when 25-OH D(3) was administered with or without vitamin E (P < 0.001). Steaks from heifers treated with 25-OH D(3) or vitamin E, but not both, tended to have lower Warner-Bratzler shear force than steaks in the control group at 14 d postmortem (P = 0.08). Postmortem protein degradation as measured by Western blot of the 30-kDa degradation product of troponin-T was increased with all treatments after 3 d postmortem (P D(3) fed as an oral bolus 7 d before slaughter or 1,000 IU of vitamin E administered daily for 104 d before slaughter alone, but not in combination, effectively decreased Warner-Bratzler shear

  18. Pro-inflammatory signaling by 24,25-dihydroxyvitamin D3 in HepG2 cells.

    PubMed

    Wehmeier, Kent; Onstead-Haas, Luisa M; Wong, Norman C W; Mooradian, Arshag D; Haas, Michael J

    2016-08-01

    The vitamin D metabolite 24,25-dihydroxyvitamin D3 (24, 25[OH]2D3) was shown to induce nongenomic signaling pathways in resting zone chondrocytes and other cells involved in bone remodeling. Recently, our laboratory demonstrated that 24,25-[OH]2D3 but not 25-hydroxyvitamin D3, suppresses apolipoprotein A-I (apo A-I) gene expression and high-density lipoprotein (HDL) secretion in hepatocytes. Since 24,25-[OH]2D3 has low affinity for the vitamin D receptor (VDR) and little is known with regard to how 24,25-[OH]2D3 modulates nongenomic signaling in hepatocytes, we investigated the capacity of 24,25-[OH]2D3 to activate various signaling pathways relevant to apo A-I synthesis in HepG2 cells. Treatment with 24,25-[OH]2D3 resulted in decreased peroxisome proliferator-activated receptor alpha (PPARα) expression and retinoid-X-receptor alpha (RXRα) expression. Similarly, treatment of hepatocytes with 50 nM 24,25-[OH]2D3 for 1-3 h induced PKCα activation as well as c-jun-N-terminal kinase 1 (JNK1) activity and extracellular-regulated kinase 1/2 (ERK1/2) activity. These changes in kinase activity correlated with changes in c-jun phosphorylation, an increase in AP-1-dependent transcriptional activity, as well as repression of apo A-I promoter activity. Furthermore, treatment with 24,25-[OH]2D3 increased IL-1β, IL-6, and IL-8 expression by HepG2 cells. These observations suggest that 24,25-[OH]2D3 elicits several novel rapid nongenomic-mediated pro-inflammatory protein kinases targeting AP1 activity, increasing pro-inflammatory cytokine expression, potentially impacting lipid metabolism and hepatic function. PMID:27234962

  19. Association between striatal dopamine D2/D3 receptors and brain activation during visual attention: effects of sleep deprivation.

    PubMed

    Tomasi, D; Wang, G-J; Volkow, N D

    2016-01-01

    Sleep deprivation (SD) disrupts dopamine (DA) signaling and impairs attention. However, the interpretation of these concomitant effects requires a better understanding of dopamine's role in attention processing. Here we test the hypotheses that D2/D3 receptors (D2/D3R) in dorsal and ventral striatum would distinctly regulate the activation of attention regions and that, by decreasing D2/D3, SD would disrupt these associations. We measured striatal D2/D3R using positron emission tomography with [(11)C]raclopride and brain activation to a visual attention (VA) task using 4-Tesla functional magnetic resonance imaging. Fourteen healthy men were studied during rested wakefulness and also during SD. Increased D2/D3R in striatum (caudate, putamen and ventral striatum) were linearly associated with higher thalamic activation. Subjects with higher D2/D3R in caudate relative to ventral striatum had higher activation in superior parietal cortex and ventral precuneus, and those with higher D2/D3R in putamen relative to ventral striatum had higher activation in anterior cingulate. SD impaired the association between striatal D2/D3R and VA-induced thalamic activation, which is essential for alertness. Findings suggest a robust DAergic modulation of cortical activation during the VA task, such that D2/D3R in dorsal striatum counterbalanced the stimulatory influence of D2/D3R in ventral striatum, which was not significantly disrupted by SD. In contrast, SD disrupted thalamic activation, which did not show counterbalanced DAergic modulation but a positive association with D2/D3R in both dorsal and ventral striatum. The counterbalanced dorsal versus ventral striatal DAergic modulation of VA activation mirrors similar findings during sensorimotor processing (Tomasi et al., 2015) suggesting a bidirectional influence in signaling between the dorsal caudate and putamen and the ventral striatum. PMID:27244237

  20. Genetic blockade of the dopamine D3 receptor enhances hippocampal expression of PACAP and receptors and alters their cortical distribution.

    PubMed

    Marzagalli, R; Leggio, G M; Bucolo, C; Pricoco, E; Keay, K A; Cardile, V; Castorina, S; Salomone, S; Drago, F; Castorina, A

    2016-03-01

    Dopamine D3 receptors (D3Rs) are implicated in several aspects of cognition, but their role in aversive conditioning has only been marginally uncovered. Investigations have reported that blockade of D3Rs enhances the acquisition of fear memories, a phenomenon tightly linked to the neuropeptide pituitary adenylate cyclase-activating peptide (PACAP). However, the impact of D3R ablation on the PACAPergic system in regions critical for the formation of new memories remains unexplored. To address this issue, levels of PACAP and its receptors were compared in the hippocampus and cerebral cortex (CX) of mice devoid of functional D3Rs (D3R(-/-)) and wild-types (WTs) using a series of comparative immunohistochemical and biochemical analyses. Morphometric and stereological data revealed increased hippocampal area and volume in D3R(-/-) mice, and augmented neuronal density in CA1 and CA2/3 subfields. PACAP levels were increased in the hippocampus of D3R(-/-) mice. Expression of PACAP receptors was also heightened in mutant mice. In the CX, PACAP immunoreactivity (IR), was restricted to cortical layer V in WTs, but was distributed throughout layers IV-VI in D3R(-/-) mice, along with increased mRNAs, protein concentration and staining scores. Consistently, PAC1, VPAC1 and VPAC2 IRs were variably redistributed in CX, with a general upregulation in cortical layers II-IV in knockout animals. Our interpretation of these findings is that disturbed dopamine neurotransmission due to genetic D3R blockade may enhance the PACAP/PAC1-VPAC axis, a key endogenous system for the processing of fear memories. This could explain, at least in part, the facilitated acquisition and consolidation of aversive memories in D3R(-/-) mice. PMID:26718601

  1. 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. PMID:26580782

  2. In vitro effects of 1α,25(OH)2D3-glycosides from Solbone A (Solanum glaucophyllum leaves extract; Herbonis AG) compared to synthetic 1α,25(OH)2D3 on myogenesis.

    PubMed

    Gili, Valeria; Pardo, Verónica Gonzalez; Ronda, Ana C; De Genaro, Pablo; Bachmann, Heini; Boland, Ricardo; de Boland, Ana Russo

    2016-05-01

    The presence of glycoside derivatives of 1α,25(OH)2D3 endows plants to gradual release of the free bioactive form of 1α,25(OH)2D3 from its glycoconjugates by endogenous animal tissue glycosidases. This results in increased half-life of the hormone in blood when purified plant fractions are administered for therapeutic purposes. In this work, we evaluated the role 1α,25(OH)2D3-glycosides enriched natural product (Solbone A) from Solanum glaucophyllum leaf extract compared with synthetic 1α,25(OH)2D3 on myogenic differentiation in C2C12 myoblasts. For these, differentiation markers and myogenic parameters were studied in C2C12 myoblasts. Results showed that Solbone A, likewise the synthetic hormone, increased creatine kinase activity at day 2 after differentiation induction (60%, p<0.05). Solbone A and synthetic 1α,25(OH)2D3 increased vitamin D3 receptor protein expression at 10nM (50% and 30%, respectively) and the transcription factor myogenin (80%, p<0.05). However, tropomyosin expression was not affected by both compounds. In addition, myosin heavy chain (MHC) protein expression was increased 30% at day 2 of differentiation. Solbone A or synthetic 1α,25(OH)2D3 had no effects on myogenin nor MHC cell localization. Cellular mass increased with myogenesis progression, being Solbone A more effective than synthetic 1α,25(OH)2D3. Finally, Solbone A, as well as synthetic 1α,25(OH)2D3, augmented the index fusion of cultured muscle fibers. In conclusion, these results demonstrated that Solbone A exhibit at least equal or greater effects on early myoblast differentiation as synthetic hormone, suggesting that plant glycosides could be an effective, accessible and cheaper substitute for synthetic 1α,25(OH)2D3 to promote muscle growth. PMID:26968127

  3. 68 FR 9000 - Food Additives Permitted for Direct Addition to Food for Human Consumption; Vitamin D3

    Federal Register 2010, 2011, 2012, 2013, 2014

    2003-02-27

    ... to Food for Human Consumption; Vitamin D 3 AGENCY: Food and Drug Administration, HHS. ACTION: Final... provide for the safe use of vitamin D 3 as a nutrient supplement in calcium-fortified fruit juices and... for Vitamin D for Adults, Children, and Infants B. Estimated Daily Intake for Vitamin D C....

  4. 70 FR 69435 - Food Additives Permitted for Direct Addition to Food for Human Consumption; Vitamin D3

    Federal Register 2010, 2011, 2012, 2013, 2014

    2005-11-16

    ... to Food for Human Consumption; Vitamin D 3 AGENCY: Food and Drug Administration, HHS. ACTION: Final... provide for the safe use of vitamin D 3 as a nutrient supplement in cheese and cheese products at a level..., DC 20004. The petition proposed to amend the food additive regulations in Sec. 172.380 Vitamin D...

  5. Vitamin D3 deficiency increases DNA damage and the oxidative burst of neutrophils in a hypertensive rat model.

    PubMed

    Machado, Carla da Silva; Venancio, Vinicius Paula; Aissa, Alexandre Ferro; Hernandes, Lívia Cristina; de Mello, Michela Bianchi; Del Lama, José Eduardo Cavalcanti; Marzocchi-Machado, Cleni Mara; Bianchi, Maria Lourdes Pires; Antunes, Lusânia Maria Greggi

    2016-03-01

    Deficiency of vitamin D3, a lipophilic micronutrient, plays a role in the development of some chronic diseases. Vitamin D3 deficiency affects 25-50% of the human population and has been associated with increased risk for development of hypertension. DNA damage induced by reactive oxygen species (ROS) occurs more often in hypertensive than in normotensive individuals, and vitamin D3 status can influence this relationship. The aim of this study was to evaluate whether a diet supplemented with (10,000 IU/kg) or deficient in (0 IU/kg) vitamin D3, compared to a vitamin D3 control diet (1000 IU/kg), would modulate DNA damage and ROS production in spontaneously hypertensive rats (SHR) and normotensive control Wistar-Kyoto (WKY) rats after 12 weeks of treatment. ROS production was assessed by measuring the oxidative burst of neutrophils. DNA damage was evaluated using the comet assay in peripheral blood and the micronucleus test in bone marrow and peripheral blood. Vitamin D3 supplementation did not induce DNA damage and did not change neutrophil ROS production in SHR and WKY rats. Vitamin D3 deficiency induced neutrophil ROS production and a high frequency of micronucleus formation in the bone marrow and peripheral blood of SHR rats only, and induced DNA damage (comet) in peripheral blood of both SHR and WKY rats. In conclusion, vitamin D3 deficiency showed a more pronounced effect on hypertensive animals. Population studies are needed to test whether this relationship also exists in humans. PMID:26994490

  6. 17 CFR 270.17d-3 - Exemption relating to certain joint enterprises or arrangements concerning payment for...

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... CFR 270.17d-1), to the extent necessary to permit any such person or principal underwriter to enter... management investment company. 270.17d-3 Section 270.17d-3 Commodity and Securities Exchanges SECURITIES AND... registered open-end management investment company. An affiliated person of, or principal underwriter for,...

  7. 26 CFR 20.2056(d)-3 - Marital deduction; effect of disclaimers of pre-January 1, 1977 transfers.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 14 2014-04-01 2013-04-01 true Marital deduction; effect of disclaimers of pre-January 1, 1977 transfers. 20.2056(d)-3 Section 20.2056(d)-3 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) ESTATE AND GIFT TAXES ESTATE TAX; ESTATES OF DECEDENTS DYING AFTER AUGUST 16, 1954 Taxable Estate §...

  8. GPU accelerated generation of digitally reconstructed radiographs for 2-D/3-D image registration.

    PubMed

    Dorgham, Osama M; Laycock, Stephen D; Fisher, Mark H

    2012-09-01

    Recent advances in programming languages for graphics processing units (GPUs) provide developers with a convenient way of implementing applications which can be executed on the CPU and GPU interchangeably. GPUs are becoming relatively cheap, powerful, and widely available hardware components, which can be used to perform intensive calculations. The last decade of hardware performance developments shows that GPU-based computation is progressing significantly faster than CPU-based computation, particularly if one considers the execution of highly parallelisable algorithms. Future predictions illustrate that this trend is likely to continue. In this paper, we introduce a way of accelerating 2-D/3-D image registration by developing a hybrid system which executes on the CPU and utilizes the GPU for parallelizing the generation of digitally reconstructed radiographs (DRRs). Based on the advancements of the GPU over the CPU, it is timely to exploit the benefits of many-core GPU technology by developing algorithms for DRR generation. Although some previous work has investigated the rendering of DRRs using the GPU, this paper investigates approximations which reduce the computational overhead while still maintaining a quality consistent with that needed for 2-D/3-D registration with sufficient accuracy to be clinically acceptable in certain applications of radiation oncology. Furthermore, by comparing implementations of 2-D/3-D registration on the CPU and GPU, we investigate current performance and propose an optimal framework for PC implementations addressing the rigid registration problem. Using this framework, we are able to render DRR images from a 256×256×133 CT volume in ~24 ms using an NVidia GeForce 8800 GTX and in ~2 ms using NVidia GeForce GTX 580. In addition to applications requiring fast automatic patient setup, these levels of performance suggest image-guided radiation therapy at video frame rates is technically feasible using relatively low cost PC

  9. Denoising, deconvolving, and decomposing photon observations. Derivation of the D3PO algorithm

    NASA Astrophysics Data System (ADS)

    Selig, Marco; Enßlin, Torsten A.

    2015-02-01

    The analysis of astronomical images is a non-trivial task. The D3PO algorithm addresses the inference problem of denoising, deconvolving, and decomposing photon observations. Its primary goal is the simultaneous but individual reconstruction of the diffuse and point-like photon flux given a single photon count image, where the fluxes are superimposed. In order to discriminate between these morphologically different signal components, a probabilistic algorithm is derived in the language of information field theory based on a hierarchical Bayesian parameter model. The signal inference exploits prior information on the spatial correlation structure of the diffuse component and the brightness distribution of the spatially uncorrelated point-like sources. A maximum a posteriori solution and a solution minimizing the Gibbs free energy of the inference problem using variational Bayesian methods are discussed. Since the derivation of the solution is not dependent on the underlying position space, the implementation of the D3PO algorithm uses the nifty package to ensure applicability to various spatial grids and at any resolution. The fidelity of the algorithm is validated by the analysis of simulated data, including a realistic high energy photon count image showing a 32 × 32 arcmin2 observation with a spatial resolution of 0.1 arcmin. In all tests the D3PO algorithm successfully denoised, deconvolved, and decomposed the data into a diffuse and a point-like signal estimate for the respective photon flux components. A copy of the code is available at the CDS via anonymous ftp to http://cdsarc.u-strasbg.fr (ftp://130.79.128.5) or via http://cdsarc.u-strasbg.fr/viz-bin/qcat?J/A+A/574/A74

  10. The 1,25D3 -MARRS receptor/PDIA3/ERp57 and lifespan.

    PubMed

    Nemere, Ilka; Garbi, Natalio; Winger, Quinton

    2015-03-01

    Using MRI on mice bearing a targeted knockout (KO) of the 1,25D3 -MARRS receptor/PDIA3/ERp57 we found that they had decreased body fat relative to their littermate (LM) controls, a condition associated with increased lifespan. Others have found that lower body fat is correlated with decreased lipid droplets in intestinal cells that may be mediated by a factor secreted by germ cells (possibly estradiol). In a reducing environment estradiol competed for binding to the 1,25D3-MARRS receptor/PDIA3/ERp57. A consequence of this was that estradiol stimulated calcium uptake in enterocytes isolated from LM mice. In time course studies, lipid droplets increased in response to 1 nM estradiol from 1-5 D of culture, relative to corresponding controls, while at 6 and 7 D this steroid decreased lipid droplets. Enterocytes from LM or KOs incubated with estradiol for 1-4 D showed the hormone increased lipid droplets. Using the 4 D culture period, 1 and 10 nM estradiol significantly increased the number of lipid droplets in cells from LM mice by 40-60%, compared to equivalent conditions in KO mice. In assessing signal transduction pathways, the hormone increased phospho-Akt levels, but no differences were observed in phospho-mTORC1, or phospho-S6K (although cells from chicks did exhibit a hormone-mediated difference). Finally, the remaining mice (which had stopped reproducing) were allowed to die naturally and lifespan recorded. LM mice lived 687 ± 77 D (without an outlying value) while KO mice lived 740 D ± 80 D. These data suggest the 25D3 -MARRS receptor/PDIA3/ERp57 may contribute to the length of lifespan in mammals. PMID:25283641

  11. Cosubstrate-induced dynamics of D-3-hydroxybutyrate dehydrogenase from Pseudomonas putida.

    PubMed

    Paithankar, Karthik S; Feller, Claudia; Kuettner, E Bartholomeus; Keim, Antje; Grunow, Marlis; Sträter, Norbert

    2007-11-01

    D-3-Hydroxybutyrate dehydrogenase from Pseudomonas putida belongs to the family of short-chain dehydrogenases/reductases. We have determined X-ray structures of the D-3-hydroxybutyrate dehydrogenase from Pseudomonas putida, which was recombinantly expressed in Escherichia coli, in three different crystal forms to resolutions between 1.9 and 2.1 A. The so-called substrate-binding loop (residues 187-210) was partially disordered in several subunits, in both the presence and absence of NAD(+). However, in two subunits, this loop was completely defined in an open conformation in the apoenzyme and in a closed conformation in the complex structure with NAD(+). Structural comparisons indicated that the loop moves as a rigid body by about 46 degrees . However, the two small alpha-helices (alphaFG1 and alphaFG2) of the loop also re-orientated slightly during the conformational change. Probably, the interactions of Val185, Thr187 and Leu189 with the cosubstrate induced the conformational change. A model of the binding mode of the substrate D-3-hydroxybutyrate indicated that the loop in the closed conformation, as a result of NAD(+) binding, is positioned competent for catalysis. Gln193 is the only residue of the substrate-binding loop that interacts directly with the substrate. A translation, libration and screw (TLS) analysis of the rigid body movement of the loop in the crystal showed significant librational displacements, describing the coordinated movement of the substrate-binding loop in the crystal. NAD(+) binding increased the flexibility of the substrate-binding loop and shifted the equilibrium between the open and closed forms towards the closed form. The finding that all NAD(+) -bound subunits are present in the closed form and all NAD(+) -free subunits in the open form indicates that the loop closure is induced by cosubstrate binding alone. This mechanism may contribute to the sequential binding of cosubstrate followed by substrate. PMID:17958702

  12. Safety and T Cell Modulating Effects of High Dose Vitamin D3 Supplementation in Multiple Sclerosis

    PubMed Central

    Smolders, Joost; Peelen, Evelyn; Thewissen, Mariëlle; Cohen Tervaert, Jan Willem; Menheere, Paul; Hupperts, Raymond; Damoiseaux, Jan

    2010-01-01

    Background A poor vitamin D status has been associated with a high disease activity of multiple sclerosis (MS). Recently, we described associations between vitamin D status and peripheral T cell characteristics in relapsing remitting MS (RRMS) patients. In the present study, we studied the effects of high dose vitamin D3 supplementation on safety and T cell related outcome measures. Methodology/Principal Findings Fifteen RRMS patients were supplemented with 20 000 IU/d vitamin D3 for 12 weeks. Vitamin D and calcium metabolism were carefully monitored, and T cell characteristics were studied by flowcytometry. All patients finished the protocol without side-effects, hypercalcaemia, or hypercalciuria. The median vitamin D status increased from 50 nmol/L (31–175) at week 0 to 380 nmol/L (151–535) at week 12 (P<0.001). During the study, 1 patient experienced an exacerbation of MS and was censored from the T cell analysis. The proportions of (naïve and memory) CD4+ Tregs remained unaffected. Although Treg suppressive function improved in several subjects, this effect was not significant in the total cohort (P = 0.143). An increased proportion of IL-10+ CD4+ T cells was found after supplementation (P = 0.021). Additionally, a decrease of the ratio between IFN-γ+ and IL-4+ CD4+ T cells was observed (P = 0.035). Conclusion/Significance Twelve week supplementation of high dose vitamin D3 in RRMS patients was well tolerated and did not induce decompensation of calcium metabolism. The skewing towards an anti-inflammatory cytokine profile supports the evidence on vitamin D as an immune-modulator, and may be used as outcome measure for upcoming randomized placebo-controlled trials. Trial Registration Clinicaltrials.gov NCT00940719 PMID:21179201

  13. Actin and Keratin are Binding Partners of the 1,25D3-MARRS Receptor/PDIA3/ERp57

    PubMed Central

    LeBlanc, Tremaine; Nemere, lka

    2014-01-01

    We have shown that the 1,25D3-MARRS receptor is necessary for the rapid, pre-genomic effects of 1,25(OH)2D3 on phosphate and/or calcium absorption in chick intestines. However, a clear understanding of the proteins involved in the signaling mechanisms by which the 1,25D3-MARRS receptor facilitates 1,25(OH)2D3-mediated phosphate or calcium uptake, as well as other cellular effects, is still under investigation. We used co-immunoprecipitation studies and mass spectroscopy to identify actin and keratin as proteins that interact with the 1,25D3-MARRS receptor. Using confocal microscopy, we visualized 1,25(OH)2D3- MARRS receptor localizations relative to actin and/or keratin distribution in chick enterocytes. Cells cultured in media containing phenol red had the 1,25D3-MARRS receptor and actin localized largely in the nucleus, which was dispersed upon addition of (OH)2 1,25(OH)2D3. In the absence of phenol red, staining was cytoplasmic. Addition of steroid caused diminished staining at 10 s and 30 s, with a return of intensity between 1 and 5 min. Nuclear staining was observed after 1 min. We found that F-actin concentrations are maximal when 1,25D3-MARRS receptor localizations within enterocytes are low suggesting that cyclical conversions of F-actin to G-actin are involved in the 1,25(OH)2D3-mediated redistribution of the 1,25D3-MARRS receptor within the cell. We also found that keratin distribution remains constant with 1,25(OH)2D3 exposure when Factin depolymerizes into G-actin, which suggests that actin and keratin work in concert to facilitate hormonemediated redistribution of the 1,25D3-MARRS receptor. We subsequently investigated whether the cyclical redistribution was related to either 1,25(OH)2D3-stimulated phosphate or calcium uptake, but no congruent pattern was found. PMID:26029286

  14. CAP-D3 Promotes Bacterial Clearance in Human Intestinal Epithelial Cells by Repressing Expression of Amino Acid Transporters

    PubMed Central

    Kemp, Jacqueline R.; Nickerson, Kourtney P.; Deutschman, Emily; Kim, Yeojung; West, Gail; Sadler, Tammy; Stylianou, Eleni; Krokowski, Dawid; Hatzoglou, Maria; de la Motte, Carol; Rubin, Brian P.; Fiocchi, Claudio

    2015-01-01

    BACKGROUND & AIMS Defects in colonic epithelial barrier defenses are associated with ulcerative colitis (UC). The proteins that regulate bacterial clearance in the colonic epithelium have not been completely identified. The chromosome-associated protein D3 (dCAP-D3), regulates responses to bacterial infection. We examined whether CAP-D3 promotes bacterial clearance in human colonic epithelium. METHODS Clearance of Salmonella or adherent-invasive Escherichia coli LF82 was assessed by gentamycin protection assays in HT-29 and Caco-2 cells expressing small hairpin RNAs against CAP-D3. We used immunoblot assays to measure levels of CAP-D3 in colonic epithelial cells from patients with UC and healthy individuals (controls). RNA sequencing identified genes activated by CAP-D3. We analyzed the roles of CAP-D3 target genes in bacterial clearance using gentamycin protection and immunofluorescence assays and studies with pharmacologic inhibitors. RESULTS CAP-D3 expression was reduced in colonic epithelial cells from patients with active UC. Reduced CAP-D3 expression decreased autophagy and impaired intracellular bacterial clearance by HT-29 and Caco-2 colonic epithelial cells. Lower levels of CAP-D3 increased transcription of genes encoding SLC7A5 and SLC3A2, whose products heterodimerize to form an amino acid transporter in HT-29 cells following bacterial infection; levels of SLC7A5–SLC3A2 were increased in tissues from patients with UC, compared with controls. Reduced CAP-D3 in HT-29 cells resulted in earlier recruitment of SLC7A5 to Salmonella-containing vacuoles, increased activity of mTORC1, and increased survival of bacteria. Inhibition of SLC7A5–SLC3A2 or mTORC1 activity rescued the bacterial clearance defects of CAP-D3– deficient cells. CONCLUSIONS CAP-D3 downregulates transcription of genes that encode amino acid transporters (SLC7A5 and SLC3A2) to promote bacterial autophagy by colon epithelial cells. Levels of CAP-D3 protein are reduced in patients with

  15. Quasi-stationary simulations of the directed percolation universality class in d = 3 dimensions

    NASA Astrophysics Data System (ADS)

    Sander, Renan S.; de Oliveira, Marcelo M.; Ferreira, Silvio C.

    2009-08-01

    We present quasi-stationary simulations of three-dimensional models with a single absorbing configuration, namely the contact process (CP), the susceptible-infected-susceptible (SIS) model and the contact replication process (CRP). The moment ratios of the order parameters for the DP class in three dimensions were set up using the well established SIS and CP models. We also show that the mean-field exponent for d = 3 reported previously for the CRP (Ferreira 2005 Phys. Rev. E 71 017104) is a transient observed in the spreading analysis.

  16. Structural insights into the catalytic reaction trigger and inhibition of D-3-hydroxybutyrate dehydrogenase.

    PubMed

    Kanazawa, Hiroki; Hoque, Md Mominul; Tsunoda, Masaru; Suzuki, Kaoru; Yamamoto, Tamotsu; Kawai, Gota; Kondo, Jiro; Takénaka, Akio

    2016-07-01

    D-3-Hydroxybutyrate dehydrogenase catalyzes the reversible conversion of acetoacetate and D-3-hydroxybutyrate. These ketone bodies are both energy-storage forms of acetyl-CoA. In order to clarify the structural mechanisms of the catalytic reaction with the cognate substrate D-3-hydroxybutyrate and of the inhibition of the reaction by inhibitors, the enzyme from Alcaligenes faecalis has been analyzed by X-ray crystallography in liganded states with the substrate and with two types of inhibitor: malonate and methylmalonate. In each subunit of the tetrameric enzyme, the substrate is trapped on the nicotinamide plane of the bound NAD(+). An OMIT map definitively shows that the bound ligand is D-3-hydroxybutyrate and not acetoacetate. The two carboxylate O atoms form four hydrogen bonds to four conserved amino-acid residues. The methyl group is accommodated in the nearby hydrophobic pocket so that the formation of a hydrogen bond from the OH group of the substrate to the hydroxy group of Tyr155 at the active centre is facilitated. In this geometry, the H atom attached to the C(3) atom of the substrate in the sp(3) configuration is positioned at a distance of 3.1 Å from the nicotinamide C(4) atom in the direction normal to the plane. In addition, the donor-acceptor relationship of the hydrogen bonds suggests that the Tyr155 OH group is allowed to ionize by the two donations from the Ser142 OH group and the ribose OH group. A comparison of the protein structures with and without ligands indicates that the Gln196 residue of the small movable domain participates in the formation of additional hydrogen bonds. It is likely that this situation can facilitate H-atom movements as the trigger of the catalytic reaction. In the complexes with inhibitors, however, their principal carboxylate groups interact with the enzyme in a similar way, while the interactions of other groups are changed. The crucial determinant for inhibition is that the inhibitors have no active H atom at C

  17. Dopamine D3 Receptors Mediate the Discriminative Stimulus Effects of Quinpirole in Free-Feeding Rats

    PubMed Central

    Baladi, Michelle G.; Newman, Amy H.

    2010-01-01

    The discriminative stimulus effects of dopamine (DA) D3/D2 receptor agonists are thought to be mediated by D2 receptors. To maintain responding, access to food is often restricted, which can alter neurochemical and behavioral effects of drugs acting on DA systems. This study established stimulus control with quinpirole in free-feeding rats and tested the ability of agonists to mimic and antagonists to attenuate the effects of quinpirole. The same antagonists were studied for their ability to attenuate quinpirole-induced yawning and hypothermia. DA receptor agonists apomorphine and lisuride, but not amphetamine and morphine, occasioned responding on the quinpirole lever. The discriminative stimulus effects of quinpirole were attenuated by the D3 receptor-selective antagonist N-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-trans-but-2-enyl}-4-pyridine-2-yl-benzamide HCl (PG01037) and the nonselective D3/D2 receptor antagonist raclopride, but not by the D2 receptor-selective antagonist 3-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]methyl-1H-indole (L-741,626); the potencies of PG01037 and raclopride to antagonize this effect of quinpirole paralleled their potencies to antagonize the ascending limb of the quinpirole yawning dose-response curve (thought to be mediated by D3 receptors). L-741,626 selectively antagonized the descending limb of the quinpirole yawning dose-response curve, and both L-741,626 and raclopride, but not PG01037, antagonized the hypothermic effects of quinpirole (thought to be mediated by D2 receptors). Food restriction (10 g/day/7 days) significantly decreased quinpirole-induced yawning without affecting the quinpirole discrimination. Many discrimination studies on DA receptor agonists use food-restricted rats; together with those studies, the current experiment using free-feeding rats suggests that feeding conditions affecting the behavioral effects of direct-acting DA receptor agonists might also have an impact on the effects of indirect

  18. Milk fever controls: comparison of 1-alpha and vitamin D3 in conjunction with induced parturition.

    PubMed

    McMurray, C H; Rice, D A; McBride, P S

    1980-08-30

    The efficacies of vitamin D3 and its 1-alpha hydroxyl derivative (1-alpha) in controlling clinical milk fever, hypocalcaemia and hypophosphataemia in parturient cows have been compared. A corticosteroid was used in some cases to optimise and control the interval between prophylactic treatment and parturition. Our observations suggest that the combination of 1-alpha and corticosteroid was particularly valuable and could be used in the development of a successful prophylactic regime. This conclusion is supported by both clinical and biochemical measurements. PMID:6255674

  19. Recombination of H3(+) and D3(+) Ions in a Flowing Afterglow Plasma

    NASA Technical Reports Server (NTRS)

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

    1995-01-01

    The analysis of flowing afterglow plasmas containing H3(+) or D3(+) ions indicates that the de-ionization of such plasmas does not occur by simple dissociative recombination of ions with electrons. An alternative model of de-ionization is proposed in which electrons are captured into H3(**) auto-ionization Rydberg states that are stabilized by collisional mixing of the Rydberg molecules' angular momenta. The proposed mechanism would enable de-ionization to occur without the need for dissociative recombination by the mechanisms of potential-surface crossings.

  20. Deep inelastic scattering off a plasma with flavor from the D3-D7 brane model

    SciTech Connect

    Ballon Bayona, C. A.; Boschi-Filho, Henrique; Braga, Nelson R. F.

    2010-04-15

    We investigate the propagation of a spacelike flavor current in a strongly coupled N=2 super Yang-Mills plasma using the D3-D7 brane model at finite temperature. The partonic contribution to the plasma structure functions is obtained from the imaginary part of the retarded current-current commutator. At high temperatures we find a nonvanishing result, for a high energy current, indicating absorption of the flavor current by the quark constituents of the plasma. At low temperatures there is no quark contribution to the plasma structure functions.

  1. 25-Hydroxyvitamin D3-23-hydroxylase, a renal enzyme in several animal species.

    PubMed

    Engstrom, G W; Reinhardt, T A; Horst, R L

    1986-10-01

    The presence of 23,25-dihydroxyvitamin D3 has been demonstrated in vivo and in vitro by a number of laboratories. In order to evaluate the significance of 23-hydroxylation, renal 23-hydroxylase activity was compared to renal 24-hydroxylase activity in several species before and after treatment with 1,25-dihydroxyvitamin D3. The maximum activity of 23-hydroxylase varied widely among species. Treatment of animals with 1,25-dihydroxyvitamin D3 24 h and again 2 h prior to assay of renal tissue resulted in a 1.7- to 5.2-fold increase in 23-hydroxylase activity and a 3.8- to 20.6-fold increase in 24-hydroxylase activity compared to untreated controls. Maximum activity for both 23- and 24-hydroxylase required the enzyme substrate, 25-hydroxyvitamin D3, and an optimum concentration (30 mM) of an oxidizable substrate such as L-malate to supply the reducing equivalents of NADPH needed. Addition of 10 mumol of magnesium chloride resulted in 19 and 24% increases in activity for 23- and 24-hydroxylase, respectively. L-Malate supported the hydroxylation reactions better than succinate, alpha-ketoglutarate, or pyruvate. The apparent Km of calf renal 23-hydroxylase was 5.7 +/- 1.0 microM and of 24-hydroxylase, 2.0 +/- 0.2 microM. Apparent Km's for 23-hydroxylase varied from a low of 2.7 +/- 0.3 microM in the sheep to a high of 19.1 +/- 0.5 microM in the chick, and for 24-hydroxylase from 0.5 +/- 0.1 microM for the chick to 2.0 +/- 0.2 microM for the calf. Maximum velocity values (Vmax) ranged from 40 +/- 9 pmol/min/g for 23-hydroxylase in the chick to 396 +/- 92 in the calf, and for 24-hydroxylase from 108 +/- 89 pmol/min/g in the chick to 851 +/- 88 in the pig. These results help explain the in vivo metabolite concentrations and the predominance of the C(24)- over C(23)-oxidation pathways. Renal 23-hydroxylase was similar to 24-hydroxylase in that it was inhibited by carbon monoxide (63%), cyanide (51%), and antimycin (67%), required molecular oxygen, and functioned best at

  2. Production of 22-hydroxy metabolites of vitamin d3 by cytochrome p450scc (CYP11A1) and analysis of their biological activities on skin cells.

    PubMed

    Tuckey, Robert C; Li, Wei; Shehabi, Haleem Z; Janjetovic, Zorica; Nguyen, Minh N; Kim, Tae-Kang; Chen, Jianjun; Howell, Danielle E; Benson, Heather A E; Sweatman, Trevor; Baldisseri, Donna M; Slominski, Andrzej

    2011-09-01

    Cytochrome P450scc (CYP11A1) can hydroxylate vitamin D(3), producing 20S-hydroxyvitamin D(3) [20(OH)D(3)] and 20S,23-dihydroxyvitamin D(3) [20,23(OH)(2)D(3)] as the major metabolites. These are biologically active, acting as partial vitamin D receptor (VDR) agonists. Minor products include 17-hydroxyvitamin D(3), 17,20-dihydroxyvitamin D(3), and 17,20,23-trihydroxyvitamin D(3). In the current study, we have further analyzed the reaction products from cytochrome P450scc (P450scc) action on vitamin D(3) and have identified two 22-hydroxy derivatives as products, 22-hydroxyvitamin D(3) [22(OH)D(3)] and 20S,22-dihydroxyvitamin D(3) [20,22(OH)(2)D(3)]. The structures of both of these derivatives were determined by NMR. P450scc could convert purified 22(OH)D(3) to 20,22(OH)(2)D(3). The 20,22(OH)(2)D(3) could also be produced from 20(OH)D(3) and was metabolized to a trihydroxyvitamin D(3) product. We compared the biological activities of these new derivatives with those of 20(OH)D(3), 20,23(OH)(2)D(3), and 1α,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)]. 1,25(OH)(2)D(3), 20(OH)D(3), 22(OH)D(3), 20,23(OH)(2)D(3), and 20,22(OH)(2)D(3) significantly inhibited keratinocyte proliferation in a dose-dependent manner. The strongest inducers of involucrin expression (a marker of keratinocyte differentiation) were 20,23(OH)(2)D(3), 20,22(OH)(2)D(3), 20(OH)D(3), and 1,25(OH)(2)D(3), with 22(OH)D(3) having a heterogeneous effect. Little or no stimulation of CYP24 mRNA expression was observed for all the analogs tested except for 1,25(OH)(2)D(3). All the compounds stimulated VDR translocation from the cytoplasm to the nucleus with 22(OH)D(3) and 20,22(OH)(2)D(3) having less effect than 1,25(OH)(2)D(3) and 20(OH)D(3). Thus, we have identified 22(OH)D(3) and 20,22(OH)(2)D(3) as products of CYP11A1 action on vitamin D(3) and shown that, like 20(OH)D(3) and 20,23(OH)(2)D(3), they are active on keratinocytes via the VDR, however, showing a degree of phenotypic heterogeneity in comparison

  3. High vitamin D3 diet administered during active colitis negatively affects bone metabolism in an adoptive T cell transfer model

    PubMed Central

    Larmonier, C. B.; McFadden, R.-M. T.; Hill, F. M.; Schreiner, R.; Ramalingam, R.; Besselsen, D. G.; Ghishan, F. K.

    2013-01-01

    Decreased bone mineral density (BMD) represents an extraintestinal complication of inflammatory bowel disease (IBD). Vitamin D3 has been considered a viable adjunctive therapy in IBD. However, vitamin D3 plays a pleiotropic role in bone modeling and regulates the bone formation-resorption balance, depending on the physiological environment, and supplementation during active IBD may have unintended consequences. We evaluated the effects of vitamin D3 supplementation during the active phase of disease on colonic inflammation, BMD, and bone metabolism in an adoptive IL-10−/− CD4+ T cell transfer model of chronic colitis. High-dose vitamin D3 supplementation for 12 days during established disease had negligible effects on mucosal inflammation. Plasma vitamin D3 metabolites correlated with diet, but not disease, status. Colitis significantly reduced BMD. High-dose vitamin D3 supplementation did not affect cortical bone but led to a further deterioration of trabecular bone morphology. In mice fed a high vitamin D3 diet, colitis more severely impacted bone formation markers (osteocalcin and bone alkaline phosphatase) and increased bone resorption markers, ratio of receptor activator of NF-κB ligand to osteoprotegrin transcript, plasma osteoprotegrin level, and the osteoclast activation marker tartrate-resistant acid phosphatase (ACp5). Bone vitamin D receptor expression was increased in mice with chronic colitis, especially in the high vitamin D3 group. Our data suggest that vitamin D3, at a dose that does not improve inflammation, has no beneficial effects on bone metabolism and density during active colitis or may adversely affect BMD and bone turnover. These observations should be taken into consideration in the planning of further clinical studies with high-dose vitamin D3 supplementation in patients with active IBD. PMID:23639807

  4. Dopamine D3 receptor is decreased and D2 receptor is elevated in the striatum of Parkinson's disease.

    PubMed

    Ryoo, H L; Pierrotti, D; Joyce, J N

    1998-09-01

    The mesolimbic dopamine (DA) system preferentially innervates the D3 receptor, whereas the D2 receptor is, in addition, a target of the nigrostriatal DA system. In human brain D3 receptors and D3 mRNA-expressing neurons are largely segregated to brain regions that are the targets of the mesolimbic DA system and the efferents of the "limbic striatum." Thus, D3 receptors may regulate effects of DA on the "limbic" cortico-striatal-pallidal-thalamic-cortical loop. The nigrostriatal DA system is considerably more damaged in Parkinson's disease (PD) than the mesolimbic DA system. We report here, using radioligands selective for the D2 and D3 receptor, that these receptors are independently changed in PD. Tissue collected at autopsy from nine subjects with a diagnosis of PD and eight age-matched subjects with no evidence of a neurologic disorder was processed for [125I]epidepride binding to D2 receptors, [125I] trans-7-OH-PIPAT binding to D3 receptors, [125I]RTI-55 for the DA transporter (DAT), and immunoautoradiography for tyrosine hydroxylase (TH) using autoradiographic methods. Dopaminergic innervation to the caudal putamen was profoundly reduced and to a lesser extent in the rostral putamen in PD. DAT sites but not TH protein levels were reduced in the nucleus accumbens (NAS) in PD compared with age-matched control subjects. This is consistent with a loss of dopaminergic innervation from the mesolimbic DA system but elevation in TH production. D3 receptors were significantly reduced in PD by 40-45% particularly in the NAS and putamen. D2 receptors were elevated in PD in the dorsal putamen by 15%. The reduction in D3 receptor number was not observed in PD cases with a diagnosis of less than 10 years. The changes in DA D3 receptor number is interesting in light of the development of antiparkinsonian agents that are D3-preferring agonists. PMID:9756147

  5. Use of 24-F-1,25-dihydroxyvitamin D3 to prevent parturient paresis in dairy cows.

    PubMed

    Goff, J P; Horst, R L; Beitz, D C; Littledike, E T

    1988-05-01

    Forty-one aged Jersey cows were fed a high Ca diet prior to parturition to predispose them to parturient paresis. Twenty-one of the cows were treated with 24-F-1,25-dihydroxyvitamin D3, a synthetic analogue of 1,25-dihydroxyvitamin D3, 7 d before the expected parturition. Treated cows received either 100 micrograms (n = 7) or 150 micrograms (n = 14) of 24-F-1,25-dihydroxyvitamin D3, intramuscularly at 7-d intervals until the cow calved. Incidence of parturient paresis among untreated animals was 85% (17/20). Injections of 100 micrograms of 24-F-1,25-dihydroxyvitamin D3 reduced the incidence of parturient paresis to 43% (3/7), whereas 150 micrograms injections of 24-F-1,25-dihydroxyvitamin D3 reduced the incidence of parturient paresis to 29% (4/14). Plasma concentrations of hydroxyproline were not elevated prior to parturition in 24-F-1,25-dihydroxyvitamin D3-treated cows, indicating that treatment did not stimulate bone resorption and that the ability of 24-F-1,25-dihydroxyvitamin D3 to prevent parturient paresis likely resides in its ability to stimulate intestinal Ca absorption prior to parturition. Further, cows treated with 24-F-1,25-dihydroxyvitamin D3 that developed parturient paresis had lower than normal plasma concentrations of 1,25-dihydroxyvitamin D, indicating that 24-F-1,25-dihydroxyvitamin D3 treatment impairs the metabolism of 25-hydroxyvitamin D in response to hypocalcemia. These data suggest that injection of 24-F-1,25-dihydroxyvitamin D3, delivered at 7-d intervals prior to parturition, can effectively reduce incidence of parturient paresis in dairy cows. PMID:3397418

  6. Novel ring A stereoisomers of 2-methyl-1alpha,25-dihydroxyvitamin D(3) and 2-methyl-20-epi-1alpha,25-dihydroxyvitamin D(3): transactivation of target genes and modulation of differentiation in human promyelocytic leukemia (HL-60) cells.

    PubMed

    Nakagawa, K; Kurobe, M; Ozono, K; Konno, K; Fujishima, T; Takayama, H; Okano, T

    2000-03-15

    We evaluated the biological activity of two sets of ring A stereoisomers of 2-methyl-1alpha,25-dihydroxyvitamin D(3) (2-methyl-1alpha,25(OH)(2)D(3)) and 2-methyl-20-epi-1alpha, 25-dihydroxyvitamin D(3) (2-methyl-20-epi-1alpha,25(OH)(2)D(3)) in terms of the following: transactivation of a rat 25-hydroxyvitamin D(3)-24-hydroxylase gene promoter including two vitamin D response elements (VDREs) and a human osteocalcin gene promoter including a VDRE in transfected human osteosarcoma (MG-63) cells; a vitamin D receptor (VDR)-mediated response using a VDR-GAL4 one-hybrid luciferase reporter system and a retinoid X receptor alpha (RXRalpha)-mediated response using an expressed VDR/RXRalpha-GAL4 modified two-hybrid luciferase reporter system in transfected human epitheloid carcinoma, cervix (HeLa) cells; and modulation of cell surface CD11b antigen expression in human leukemia (HL-60) cells. All the diastereomers of both analogues exhibited unique biological activity profiles depending upon the configurations of the C-1 and C-3 hydroxyl groups, the C-2 methyl group in ring A, and the C-20 methyl group in the side chain. Of the eight possible diastereomers of the 2-methyl analogues, 2alpha-methyl-1alpha,25(OH)(2)D(3) was the most potent and exhibited comparable or even greater biological potency than 1alpha,25(OH)(2)D(3). Of the eight possible diastereomers of the 2-methyl-20-epi analogues, 2alpha-methyl-20-epi-1alpha,25(OH)(2)D(3) was the most potent and exhibited 100- to 200-fold higher transcriptional potencies than 1alpha,25(OH)(2)D(3) and exceptionally high cell regulatory activities. 2beta-methyl-20-epi-1alpha,25(OH)(2)D(3) was nearly as potent as its 2-epimer, 2alpha-methyl-20-epi-1alpha,25(OH)(2)D(3), whereas its 20-epimer, 2beta-methyl-1alpha,25(OH)(2)D(3), was almost completely biologically inactive. In these respects, it can be postulated that the double modification of 2-methyl substitution and 20-epimerization to 1alpha,25(OH)(2)D(3) induces remarkable changes

  7. Structural Analysis of Substrate and Effector Binding in Mycobacterium tuberculosis D-3-Phosphoglycerate Dehydrogenase

    SciTech Connect

    Dey, Sanghamitra; Burton, Rodney L.; Grant, Gregory A.; Sacchettini, James C.

    2008-08-20

    The crystal structure of Mycobacterium tuberculosis D-3-phosphoglycerate dehydrogenase has been solved with bound effector, L-serine, and substrate, hydroxypyruvic acid phosphate, at resolutions of 2.7 and 2.4 {angstrom}, respectively. The subunits display the same extreme asymmetry as seen in the apo-structure and provide insight into the mode of serine binding and closure of the active site. Mutagenesis studies confirm the identity of the main residues involved in serine binding and suggest that the poly glycine stretch in the loop that contains the locus for the 160{sup o} rotation that leads to subunit asymmetry may have a larger role in folding than in catalysis. The lack of electron density for the cofactor, NADH, in any of the crystals examined led us to study binding by stopped flow kinetic analysis. The kinetic data suggest that productive NADH binding, that would support catalytic turnover, is dependent on the presence of substrate. This observation, along with the binding of substrate in the active site, but in an unproductive conformation, suggests a possible mechanism where initial binding of substrate leads to enhanced interaction with cofactor accompanied by a rearrangement of catalytically critical residue side chains. Furthermore, comparison to the structure of a truncated form of human D-3-phosphoglycerate dehydrogenase with cofactor and a substrate analog, provides insight into the conformational changes that occur during catalysis.

  8. Local Metric Learning in 2D/3D Deformable Registration With Application in the Abdomen

    PubMed Central

    Chou, Chen-Rui; Mageras, Gig; Pizer, Stephen

    2015-01-01

    In image-guided radiotherapy (IGRT) of disease sites subject to respiratory motion, soft tissue deformations can affect localization accuracy. We describe the application of a method of 2D/3D deformable registration to soft tissue localization in abdomen. The method, called registration efficiency and accuracy through learning a metric on shape (REALMS), is designed to support real-time IGRT. In a previously developed version of REALMS, the method interpolated 3D deformation parameters for any credible deformation in a deformation space using a single globally-trained Riemannian metric for each parameter. We propose a refinement of the method in which the metric is trained over a particular region of the deformation space, such that interpolation accuracy within that region is improved. We report on the application of the proposed algorithm to IGRT in abdominal disease sites, which is more challenging than in lung because of low intensity contrast and nonrespiratory deformation. We introduce a rigid translation vector to compensate for nonrespiratory deformation, and design a special region-of-interest around fiducial markers implanted near the tumor to produce a more reliable registration. Both synthetic data and actual data tests on abdominal datasets show that the localized approach achieves more accurate 2D/3D deformable registration than the global approach. PMID:24771575

  9. Efficient implementation of the rank correlation merit function for 2D/3D registration.

    PubMed

    Figl, M; Bloch, C; Gendrin, C; Weber, C; Pawiro, S A; Hummel, J; Markelj, P; Pernus, F; Bergmann, H; Birkfellner, W

    2010-10-01

    A growing number of clinical applications using 2D/3D registration have been presented recently. Usually, a digitally reconstructed radiograph is compared iteratively to an x-ray image of the known projection geometry until a match is achieved, thus providing six degrees of freedom of rigid motion which can be used for patient setup in image-guided radiation therapy or computer-assisted interventions. Recently, stochastic rank correlation, a merit function based on Spearman's rank correlation coefficient, was presented as a merit function especially suitable for 2D/3D registration. The advantage of this measure is its robustness against variations in image histogram content and its wide convergence range. The considerable computational expense of computing an ordered rank list is avoided here by comparing randomly chosen subsets of the DRR and reference x-ray. In this work, we show that it is possible to omit the sorting step and to compute the rank correlation coefficient of the full image content as fast as conventional merit functions. Our evaluation of a well-calibrated cadaver phantom also confirms that rank correlation-type merit functions give the most accurate results if large differences in the histogram content for the DRR and the x-ray image are present. PMID:20844334

  10. Sequential Synthesis of 3d-3d'-4f Heterometallic Heptanuclear Clusters in between Lacunary Polyoxometalates.

    PubMed

    Sato, Rinta; Suzuki, Kosuke; Minato, Takuo; Yamaguchi, Kazuya; Mizuno, Noritaka

    2016-03-01

    In this work, we have successfully created several unprecedented discrete 3d-3d'-4f heterotrimetallic clusters in between lacunary polyoxometalates (POMs). By the three-step sequential introduction of metal cations into a trivacant lacunary POM TBA4H6[A-α-SiW9O34] (TBA = tetra-n-butylammonium) in organic media, five kinds of sandwich-type POMs with double-diamond-shaped 3d-3d'-4f heptanuclear clusters (IIIFeM4Ln2, TBAnHm[FeM4{Ln(L)2}2O2(A-α-SiW9O34)2], M = Mn(3+), Cu(2+); Ln = Gd(3+), Dy(3+), Lu(3+); L = acac (acetylacetonate), hfac (hexafluoroacetylacetonate)) were successfully synthesized for the first time. By introduction of two [Ln(L)2](+) units on the ends of pentanuclear clusters [FeMn4O18(OH)2](23-) and [FeCu4O18(OH)2](27-), the magnetic interactions between Mn(3+)-Mn(3+) and Cu(2+)-Cu(2+) could be modulated. Among a series of the heterometallic heptanuclear compounds, IIIFeMn4Lu2 exhibited the slow magnetic relaxation characteristic for a single-molecule magnet under the zero applied magnetic fields. PMID:26914662

  11. A new gold-standard dataset for 2D/3D image registration evaluation

    NASA Astrophysics Data System (ADS)

    Pawiro, Supriyanto; Markelj, Primoz; Gendrin, Christelle; Figl, Michael; Stock, Markus; Bloch, Christoph; Weber, Christoph; Unger, Ewald; Nöbauer, Iris; Kainberger, Franz; Bergmeister, Helga; Georg, Dietmar; Bergmann, Helmar; Birkfellner, Wolfgang

    2010-02-01

    In this paper, we propose a new gold standard data set for the validation of 2D/3D image registration algorithms for image guided radiotherapy. A gold standard data set was calculated using a pig head with attached fiducial markers. We used several imaging modalities common in diagnostic imaging or radiotherapy which include 64-slice computed tomography (CT), magnetic resonance imaging (MRI) using T1, T2 and proton density (PD) sequences, and cone beam CT (CBCT) imaging data. Radiographic data were acquired using kilovoltage (kV) and megavoltage (MV) 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 and image data quality. The markers of three dimensional (3D) and two dimensional (2D) images were segmented using Analyze 9.0 (AnalyzeDirect, Inc) and an in-house software. The projection distance errors (PDE) and the expected target registration errors (TRE) over all the image data sets were found to be less than 1.7 mm and 1.3 mm, respectively. The gold standard data set, obtained with state-of-the-art imaging technology, has the potential to improve the validation of 2D/3D registration algorithms for image guided therapy.

  12. FoxD3 deficiency promotes breast cancer progression by induction of epithelial–mesenchymal transition

    SciTech Connect

    Chu, Tian-Li; Zhao, Hong-Meng; Li, Yue; Chen, Ao-Xiang; Sun, Xuan; Ge, Jie

    2014-04-04

    Highlights: • FOXD3 is down-regulated in breast cancer tissues. • FOXD3 inhibits breast cancer cell proliferation and invasion. • FoxD3 deficiency induces epithelial–mesenchymal transition. - Abstract: The transcription factor forkhead box D3 (FOXD3) plays an important role in the development of neural crest and gastric cancer cells. However, the function and mechanisms of FOXD3 in the breast tumorigenesis and progression is still limited. Here, we report that FOXD3 is a tumor suppressor of breast cancer tumorigenicity and aggressiveness. We found that FOXD3 is down-regulated in breast cancer tissues. Patients with low FOXD3 expression have a poor outcome. Depletion of FOXD3 expression promotes breast cancer cell proliferation and invasion in vitro, whereas overexpression of FOXD3 inhibits breast cancer cell proliferation and invasion both in vitro and in vivo. In addition, depletion of FOXD3 is linked to epithelial–mesenchymal transition (EMT)-like phenotype. Our results indicate FOXD3 exhibits tumor suppressive activity and may be useful for breast therapy.

  13. The genetics of addiction: alcohol-dependence and D3 dopamine receptor gene.

    PubMed

    Gorwood, P; Limosin, F; Batel, P; Duaux, E; Gouya, L; Adès, J

    2001-11-01

    Alcohol-dependence is a complex phenotype, with behavioral, psychological, pharmacological, medical and social dimensions. Aggregation studies, adoption and twin researches have demonstrated that the vulnerability to alcohol-dependence is at least in part linked to genetic factors, the genetic vulnerability to alcoholism being mainly not substance-specific. There are numerous candidate genes, but the D3 dopamine receptor is specifically located in the limbic area, and in particular in the nucleus accumbens, which are involved in reward and reinforcement behavior. Furthermore, a previous collaborative study showed that homozygosity for the Ball DRD3 locus was more frequently observed in opiate dependent patients with high sensation seeking scores. In this study, we analyzed the distribution of Ball DRD3 polymorphism in a new sample of 131 French male alcoholic-patients (DSM III-R criteria) and 68 healthy controls matched for sex and origins. Although we replicated the higher sensation seeking score in alcohol-dependent patients with comorbid dependence, we found no significant difference in the DRD3 gene polymorphism between controls and alcoholic patients, regardless of sensation seeking score, addictive or psychiatric comorbidity, alcoholism typology, and clinical specificities of alcoholism. There is good evidence that gene coding for the dopamine receptor D3 does not play a major role in the genetic vulnerability to alcoholism. PMID:11762133

  14. The Agrobacterium tumefaciens virD3 gene is not essential for tumorigenicity on plants.

    PubMed Central

    Vogel, A M; Das, A

    1992-01-01

    Genetic studies indicate that three of the four polypeptides encoded within the virD operon of the Agrobacterium tumefaciens Ti plasmid are essential for virulence. In order to determine whether the fourth polypeptide, VirD3, has any role in virulence, complementation analysis was used. An A. tumefaciens strain, A348 delta D, which lacked the entire virD operon in the Ti plasmid pTiA6, was constructed. Plasmids containing defined regions of the virD operon were introduced into this strain, and virulence was tested by the strains' abilities to form tumors on Kalanchoe leaves, tomato stems, and potato tubers. As expected, deletion of the virD operon led to an avirulent phenotype. The virulence of this strain could be restored by providing virD1, virD2, and virD4 in trans. No requirement for virD3 in tumor formation was observed in these assays. Images PMID:1629176

  15. Reactor safety issues resolved by the 2D/3D Program. International Agreement Report

    SciTech Connect

    Damerell, P.S.; Simons, J.W.

    1993-07-01

    The 2D/3D Program studied multidimensional thermal-hydraulics in a PWR core and primary system during the end-of-blowdown and post-blowdown phases of a large-break LOCA (LBLOCA), and during selected small-break LOCA (SBLOCA) transients. The program included tests at the Cylindrical Core Test Facility (CCTF), the Slab Core Test Facility (SCTF), and the Upper Plenum Test Facility (UPTF), and computer analyses using TRAC. Tests at CCTF investigated core thermal-hydraulics and overall system behavior while tests at SCTF concentrated on multidimensional core thermal-hydraulics. The UPTF tests investigated two-phase flow behavior in the downcomer, upper plenum, tie plate region, and primary loops. TRAC analyses evaluated thermal-hydraulic behavior throughout the primary system in tests as well as in PWRs. This report summarizes the test and analysis results in each of the main areas where improved information was obtained in the 2D/3D Program. The discussion is organized in terms of the reactor safety issues investigated.

  16. Progressive attenuation fields: Fast 2D-3D image registration without precomputation

    SciTech Connect

    Rohlfing, Torsten; Russakoff, Daniel B.; Denzler, Joachim; Mori, Kensaku; Maurer, Calvin R. Jr.

    2005-09-15

    Computation of digitally reconstructed radiograph (DRR) images is the rate-limiting step in most current intensity-based algorithms for the registration of three-dimensional (3D) images to two-dimensional (2D) projection images. This paper introduces and evaluates the progressive attenuation field (PAF), which is a new method to speed up DRR computation. A PAF is closely related to an attenuation field (AF). A major difference is that a PAF is constructed on the fly as the registration proceeds; it does not require any precomputation time, nor does it make any prior assumptions of the patient pose or limit the permissible range of patient motion. A PAF effectively acts as a cache memory for projection values once they are computed, rather than as a lookup table for precomputed projections like standard AFs. We use a cylindrical attenuation field parametrization, which is better suited for many medical applications of 2D-3D registration than the usual two-plane parametrization. The computed attenuation values are stored in a hash table for time-efficient storage and access. Using clinical gold-standard spine image data sets from five patients, we demonstrate consistent speedups of intensity-based 2D-3D image registration using PAF DRRs by a factor of 10 over conventional ray casting DRRs with no decrease of registration accuracy or robustness.

  17. Neurovascular coupling to D2/D3 dopamine receptor occupancy using simultaneous PET/functional MRI

    PubMed Central

    Sander, Christin Y.; Hooker, Jacob M.; Catana, Ciprian; Normandin, Marc D.; Alpert, Nathaniel M.; Knudsen, Gitte M.; Vanduffel, Wim; Rosen, Bruce R.; Mandeville, Joseph B.

    2013-01-01

    This study employed simultaneous neuroimaging with positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) to demonstrate the relationship between changes in receptor occupancy measured by PET and changes in brain activity inferred by fMRI. By administering the D2/D3 dopamine receptor antagonist [11C]raclopride at varying specific activities to anesthetized nonhuman primates, we mapped associations between changes in receptor occupancy and hemodynamics [cerebral blood volume (CBV)] in the domains of space, time, and dose. Mass doses of raclopride above tracer levels caused increases in CBV and reductions in binding potential that were localized to the dopamine-rich striatum. Moreover, similar temporal profiles were observed for specific binding estimates and changes in CBV. Injection of graded raclopride mass doses revealed a monotonic coupling between neurovascular responses and receptor occupancies. The distinct CBV magnitudes between putamen and caudate at matched occupancies approximately matched literature differences in basal dopamine levels, suggesting that the relative fMRI measurements reflect basal D2/D3 dopamine receptor occupancy. These results can provide a basis for models that relate dopaminergic occupancies to hemodynamic changes in the basal ganglia. Overall, these data demonstrate the utility of simultaneous PET/fMRI for investigations of neurovascular coupling that correlate neurochemistry with hemodynamic changes in vivo for any receptor system with an available PET tracer. PMID:23723346

  18. Analysis results from the Los Alamos 2D/3D program

    SciTech Connect

    Boyack, B.E.; Cappiello, M.W.; Stumpf, H.; Shire, P.; Gilbert, J.; Hedstrom, J.

    1986-01-01

    Los Alamos National Laboratory is a participant in the 2D/3D program. Activities conducted at Los Alamos National Laboratory in support of 2D/3D program goals include analysis support of facility design, construction, and operation; provision of boundary and initial conditions for test facility operations based on analysis of pressurized water reactors; performance of pretest and posttest predictions and analyses; and use of experimental results to validate and assess the single- and multidimensional nonequilibrium features in the Transient Reactor Analysis Code (TRAC). During Fiscal Year 1986, Los Alamos conducted analytical assessment activities using data from the Cylindrical Core Test Facility and the Slab Core Test Facility. Los Alamos also continued to provide support analysis for the planning of Upper Plenum Test Facility experiments. Finally, Los Alamos either completed or is currently working on three areas of TRAC modeling improvement. In this paper, Los Alamos activities during Fiscal Year 1986 are summarized; several significant accomplishments are described in more detail to illustrate the work activities at Los Alamos.

  19. Optimization of the All-D Peptide D3 for Aβ Oligomer Elimination

    PubMed Central

    Klein, Antonia Nicole; Ziehm, Tamar; Tusche, Markus; Buitenhuis, Johan; Bartnik, Dirk; Boeddrich, Annett; Wiglenda, Thomas; Wanker, Erich; Funke, Susanne Aileen; Brener, Oleksandr; Gremer, Lothar; Kutzsche, Janine; Willbold, Dieter

    2016-01-01

    The aggregation of amyloid-β (Aβ) is postulated to be the crucial event in Alzheimer’s disease (AD). In particular, small neurotoxic Aβ oligomers are considered to be responsible for the development and progression of AD. Therefore, elimination of thesis oligomers represents a potential causal therapy of AD. Starting from the well-characterized d-enantiomeric peptide D3, we identified D3 derivatives that bind monomeric Aβ. The underlying hypothesis is that ligands bind monomeric Aβ and stabilize these species within the various equilibria with Aβ assemblies, leading ultimately to the elimination of Aβ oligomers. One of the hereby identified d-peptides, DB3, and a head-to-tail tandem of DB3, DB3DB3, were studied in detail. Both peptides were found to: (i) inhibit the formation of Thioflavin T-positive fibrils; (ii) bind to Aβ monomers with micromolar affinities; (iii) eliminate Aβ oligomers; (iv) reduce Aβ-induced cytotoxicity; and (v) disassemble preformed Aβ aggregates. The beneficial effects of DB3 were improved by DB3DB3, which showed highly enhanced efficacy. Our approach yielded Aβ monomer-stabilizing ligands that can be investigated as a suitable therapeutic strategy against AD. PMID:27105346

  20. Image-based RSA: Roentgen stereophotogrammetric analysis based on 2D-3D image registration.

    PubMed

    de Bruin, P W; Kaptein, B L; Stoel, B C; Reiber, J H C; Rozing, P M; Valstar, E R

    2008-01-01

    Image-based Roentgen stereophotogrammetric analysis (IBRSA) integrates 2D-3D image registration and conventional RSA. Instead of radiopaque RSA bone markers, IBRSA uses 3D CT data, from which digitally reconstructed radiographs (DRRs) are generated. Using 2D-3D image registration, the 3D pose of the CT is iteratively adjusted such that the generated DRRs resemble the 2D RSA images as closely as possible, according to an image matching metric. Effectively, by registering all 2D follow-up moments to the same 3D CT, the CT volume functions as common ground. In two experiments, using RSA and using a micromanipulator as gold standard, IBRSA has been validated on cadaveric and sawbone scapula radiographs, and good matching results have been achieved. The accuracy was: |mu |< 0.083 mm for translations and |mu| < 0.023 degrees for rotations. The precision sigma in x-, y-, and z-direction was 0.090, 0.077, and 0.220 mm for translations and 0.155 degrees , 0.243 degrees , and 0.074 degrees for rotations. Our results show that the accuracy and precision of in vitro IBRSA, performed under ideal laboratory conditions, are lower than in vitro standard RSA but higher than in vivo standard RSA. Because IBRSA does not require radiopaque markers, it adds functionality to the RSA method by opening new directions and possibilities for research, such as dynamic analyses using fluoroscopy on subjects without markers and computer navigation applications. PMID:17706656

  1. Species differences in the binding kinetics of 25-hydroxyvitamin D3 to vitamin D binding protein.

    PubMed

    Vieth, R; Kessler, M J; Pritzker, K P

    1990-10-01

    The specific binding of 25-hydroxyvitamin D3 to its binding protein was studied in serum of the human, rhesus monkey, cow, horse, and rat. The free fraction of 25-hydroxyvitamin D3 in the rat was 0.34 +/- 0.15 pmol free/nmol total (+/- SD) and this was lower than in any of the other species (p less than 0.01). In the human, the free fraction was 1.5 +/- 0.32 pmol free/nmol total, which was higher than in any of the other species (p less than 0.001). The differences in the free fraction were mainly due to differences in dissociation constant. The relative levels of free 25-hydroxyvitamin D should be taken into account when extrapolating findings about vitamin D metabolism in animals to the human. A technical outcome of this study is that of the species tested, vitamin D binding protein from rat serum is the most suitable as a reagent component for methods used to measure total 25-hydroxyvitamin D by competitive protein binding assay. PMID:2078829

  2. Vitamin D-induced ectodomain shedding of TNF receptor 1 as a nongenomic action: D3 vs D2 derivatives.

    PubMed

    Yang, Won Seok; Yu, Hoon; Kim, Jin Ju; Lee, Mee Jeong; Park, Su-Kil

    2016-01-01

    As a nongenomic action, 1,25-dihydroxyvitamin D3 (1,25D3) induces L-type Ca(2+) channel-mediated extracellular Ca(2+) influx in human aortic smooth muscle cells (HASMCs), which activates a disintegrin and metalloprotease 10 (ADAM10) to cleave and shed the ectodomain of tumor necrosis factor receptor 1 (TNFR1). In this study, we examined the potencies of other vitamin D3 and D2 analogs to stimulate the ectodomain shedding of TNFR1 in HASMCs. 25-Hydroxyvitamin D3 (25D3), a precursor of 1,25D3, and elocalcitol, an analog of 1,25D3, caused ectodomain shedding of TNFR1 within 30 min, whereas 1,25-dihydroxyvitamin D2 (1,25D2) and paricalcitol, a derivative of 1,25D2, did not. Both 25D3 and elocalcitol rapidly induced extracellular Ca(2+) influx and markedly increased intracellular Ca(2+), while 1,25D2 and paricalcitol caused only small increases in intracellular Ca(2+). 25D3- and elocalcitol-induced TNFR1 ectodomain sheddings were abolished by verapamil and in Ca(2+)-free media. Both 25D3 and elocalcitol caused the translocation of ADAM10 to the cell surface, which was inhibited by verapamil, while 1,25D2 and paricalcitol did not cause ADAM10 translocation. When ADAM10 was depleted by ADAM10-siRNA, 25D3 and elocalcitol could not induce ectodomain shedding of TNFR1. The plasma membrane receptor, endoplasmic reticulum stress protein 57 (ERp57), but not the classic vitamin D receptor, mediated the nongenomic action of vitamin D to induce ectodomain shedding of TNFR1. In summary, like 1,25D3, 25D3 and elocalcitol caused ADAM10-mediated ectodomain shedding of TNFR1, whereas 1,25D2 and paricalcitol did not. The difference may depend on their affinities to ERp57 through which extracellular Ca(2+) influx is induced. PMID:26385608

  3. Significant Effects of Oral Phenylbutyrate and Vitamin D3 Adjunctive Therapy in Pulmonary Tuberculosis: A Randomized Controlled Trial

    PubMed Central

    Kamal, S. M. Mostafa; Arifuzzaman, Abu Saleh Mohammad; Rahim, Zeaur; Khan, Lamia; Haq, Md. Ahsanul; Zaman, Khaliqu; Bergman, Peter; Brighenti, Susanna; Gudmundsson, Gudmundur H.; Agerberth, Birgitta; Raqib, Rubhana

    2015-01-01

    Background Development of new tuberculosis (TB) drugs and alternative treatment strategies are urgently required to control the global spread of TB. Previous results have shown that vitamin D3 (vitD3) and 4-phenyl butyrate (PBA) are potent inducers of the host defense peptide LL-37 that possess anti-mycobacterial effects. Objective To examine if oral adjunctive therapy with 5,000IU vitD3 or 2x500 mg PBA or PBA+vitD3 to standard chemotherapy would lead to enhanced recovery in sputum smear-positive pulmonary TB patients. Methods Adult TB patients (n = 288) were enrolled in a randomized, double-blind, placebo-controlled trial conducted in Bangladesh. Primary endpoints included proportions of patients with a negative sputum culture at week 4 and reduction in clinical symptoms at week 8. Clinical assessments and sputum smear microscopy were performed weekly up to week 4, fortnightly up to week 12 and at week 24; TB culture was performed at week 0, 4 and 8; concentrations of LL-37 in cells, 25-hydroxyvitamin D3 (25(OH)D3) in plasma and ex vivo bactericidal function of monocyte-derived macrophages (MDM) were determined at week 0, 4, 8, 12 and additionally at week 24 for plasma 25(OH)D3. Results At week 4, 71% (46/65) of the patients in the PBA+vitD3-group (p = 0.001) and 61.3% (38/62) in the vitD3-group (p = 0.032) were culture negative compared to 42.2% (27/64) in the placebo-group. The odds of sputum culture being negative at week 4 was 3.42 times higher in the PBA+vitD3-group (p = 0.001) and 2.2 times higher in vitD3-group (p = 0.032) compared to placebo. The concentration of LL-37 in MDM was significantly higher in the PBA-group compared to placebo at week 12 (p = 0.034). Decline in intracellular Mtb growth in MDM was earlier in the PBA-group compared to placebo (log rank 11.38, p = 0.01). Conclusion Adjunct therapy with PBA+vitD3 or vitD3 or PBA to standard short-course therapy demonstrated beneficial effects towards clinical recovery and holds potential for host

  4. 1,25-Dihydroxyvitamin D3 enhances the susceptibility of breast cancer cells to doxorubicin-induced oxidative damage.

    PubMed

    Ravid, A; Rocker, D; Machlenkin, A; Rotem, C; Hochman, A; Kessler-Icekson, G; Liberman, U A; Koren, R

    1999-02-15

    1,25-Dihydroxyvitamin D3 (1,25(OH)2D3), the hormonal form of vitamin D, has anticancer activity in vivo and in vitro. Doxorubicin exerts its cytotoxic effect on tumor cells mainly by two mechanisms: (a) generation of reactive oxygen species (ROS); and (b) inhibition of topoisomerase II. We studied the combined cytotoxic action of 1,25(OH)2D3 and doxorubicin on MCF-7 breast cancer cells. Pretreatement with 1,25(OH)2D3 resulted in enhanced cytotoxicity of doxorubicin. The average enhancing effect after a 72-h pretreatment with 1,25(OH)2D3 (10 nM) followed by a 24-h treatment with 1 microg/ml doxorubicin was 74+/-9% (mean +/- SE). Under these experimental conditions, 1,25(OH)2D3 on its own did not affect cell number or viability. 1,25(OH)2D3 also enhanced the cytotoxic activity of another ROS generating quinone, menadione, but did not affect cytotoxicity induced by the topoisomerase inhibitor etoposide. The antioxidant N-acetylcysteine slightly reduced the cytotoxic activity of doxorubicin but had a marked protective effect against the combined action of 1,25(OH)2D3 and doxorubicin. These results indicate that ROS are involved in the interaction between 1,25(OH)2D3 and doxorubicin. 1,25(OH)2D3 also increased doxorubicin cytotoxicity in primary cultures of rat cardiomyocytes. Treatment of MCF-7 cells with 1,25(OH)2D3 alone markedly reduced the activity, protein, and mRNA levels of the cytoplasmic antioxidant enzyme Cu/Zn superoxide dismutase, which indicated that the hormone inhibits its biosynthesis. This reduction in the antioxidant capacity of the cells could account for the synergistic interaction between 1,25(OH)2D3 and doxorubicin and may also suggest increased efficacy of 1,25(OH)2D3 or its analogues in combination with other ROS-generating anticancer therapeutic modalities. PMID:10029076

  5. Use of 25-hydroxyvitamin D3 and dietary calcium to improve tenderness of beef from the round of beef cows.

    PubMed

    Carnagey, K M; Huff-Lonergan, E J; Lonergan, S M; Trenkle, A; Horst, R L; Beitz, D C

    2008-07-01

    The objective of this trial was to determine how 25-hydroxyvitamin D(3) (25-OH D(3)) supplementation, altering supplemental dietary calcium, or their combination influence postmortem biochemical and tenderness changes in muscles from the round of mature cows. Twenty-seven Angus cows (3 to 7 yr old) were allotted randomly to 9 pens with 3 cows per pen. Treatments were arranged in a 3 x 3 factorial design with 3 dosages of 25-OH D(3) (0, 250, or 500 mg of 25-OH D(3) administered as a 1-time oral bolus 7 d before slaughter) and 3 percentages of supplemental limestone (0.5, 0.75, and 1.0%) replenished in the diet for 3 d before slaughter and after a 2-wk limestone withdrawal. Plasma samples were obtained during the feeding period. Upon slaughter, adductor, gracilus, pectineus, sartorius, semimembranosus, vastus intermedius, and vastus lateralis muscles were obtained and aged for 1, 3, or 7 d. Calcium concentrations were increased in plasma when 250 or 500 mg of 25-OH D(3) were administered (P D(3) were administered. Concentrations of 25-OH D(3) in meat and in plasma and 1,25-dihydroxyvitamin D(3) [1,25-(OH)(2) D(3)] in plasma were increased when 25-OH D(3) was administered (P D(3) or 1,25-(OH)(2) D(3) in meat or in plasma. Calpastatin activity was affected by treatments only in the gracilus and vastus intermedius muscles (P D(3) has some influence on muscle characteristics known to improve tenderness, but improved tenderness was not observed. PMID:18344286

  6. 1,25-Dihydroxyvitamin D3 Enhances Innate Immune Responses of Bovine Mammary Epithelial Cells that are Triggered by Toll-like Receptor Signaling

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Recently, 1,25-dihydroxyvitamin D3 (1,25[OH]2D3) has been found to play an important role in the bovine innate immune response. 1,25(OH)2D3 is the active vitamin D metabolite and is produced from the major circulating metabolite, 25-hydroxyvitamin D3, by the enzyme 1alpha-hydroxylase (1alpha-OHase)...

  7. Overexpressed cyclin D3 contributes to retaining the growth inhibitor p27 in the cytoplasm of thyroid tumor cells

    PubMed Central

    Baldassarre, Gustavo; Belletti, Barbara; Bruni, Paola; Boccia, Angelo; Trapasso, Francesco; Pentimalli, Francesca; Barone, Maria Vittoria; Chiappetta, Gennaro; Vento, Maria Teresa; Spiezia, Stefania; Fusco, Alfredo; Viglietto, Giuseppe

    1999-01-01

    The majority of thyroid carcinomas maintain the expression of the cell growth suppressor p27, an inhibitor of cyclin-dependent kinase-2 (Cdk2). However, we find that 80% of p27-expressing tumors show an uncommon cytoplasmic localization of p27 protein, associated with high Cdk2 activity. To reproduce such a situation, a mutant p27 devoid of its COOH-terminal nuclear-localization signal was generated (p27-NLS). p27-NLS accumulates in the cytoplasm and fails to induce growth arrest in 2 different cell lines, indicating that cytoplasm-residing p27 is inactive as a growth inhibitor, presumably because it does not interact with nuclear Cdk2. Overexpression of cyclin D3 may account in part for p27 cytoplasmic localization. In thyroid tumors and cell lines, cyclin D3 expression was associated with cytoplasmic localization of p27. Moreover, expression of cyclin D3 in thyroid carcinoma cells induced cytoplasmic retention of cotransfected p27 and rescued p27-imposed growth arrest. Endogenous p27 also localized prevalently to the cytoplasm in normal thyrocytes engineered to stably overexpress cyclin D3 (PC-D3 cells). In these cells, cyclin D3 induced the formation of cytoplasmic p27–cyclin D3–Cdk complexes, which titrated p27 away from intranuclear complexes that contain cyclins A–E and Cdk2. Our results demonstrate a novel mechanism that may contribute to overcoming the p27 inhibitory threshold in transformed thyroid cells. PMID:10510327

  8. The Impact of Vitamin D3 Supplementation on Mechanisms of Cell Calcium Signaling in Chronic Kidney Disease

    PubMed Central

    Lajdova, Ingrid; Spustova, Viera; Oksa, Adrian; Kaderjakova, Zuzana; Chorvat, Dusan; Morvova, Marcela; Sikurova, Libusa; Marcek Chorvatova, Alzbeta

    2015-01-01

    Intracellular calcium concentration in peripheral blood mononuclear cells (PBMCs) of patients with chronic kidney disease (CKD) is significantly increased, and the regulatory mechanisms maintaining cellular calcium homeostasis are impaired. The purpose of this study was to examine the effect of vitamin D3 on predominant regulatory mechanisms of cell calcium homeostasis. The study involved 16 CKD stages 2-3 patients with vitamin D deficiency treated with cholecalciferol 7000–14000 IU/week for 6 months. The regulatory mechanisms of calcium signaling were studied in PBMCs and red blood cells. After vitamin D3 supplementation, serum concentration of 25(OH)D3 increased (P < 0.001) and [Ca2+]i decreased (P < 0.001). The differences in [Ca2+]i were inversely related to differences in 25(OH)D3 concentration (P < 0.01). Vitamin D3 supplementation decreased the calcium entry through calcium release activated calcium (CRAC) channels and purinergic P2X7 channels. The function of P2X7 receptors was changed in comparison with their baseline status, and the expression of these receptors was reduced. There was no effect of vitamin D3 on P2X7 pores and activity of plasma membrane Ca2+-ATPases. Vitamin D3 supplementation had a beneficial effect on [Ca2+]i decreasing calcium entry via CRAC and P2X7 channels and reducing P2X7 receptors expression. PMID:26064953

  9. Expression of 1alpha-HYD and 24-HYD in bovine kidney mediated by vitamin D3 supplementation.

    PubMed

    Rezende, L R; Delgado, E F; Júnior, A R L; Gasparin, G; Jorge, E C; Mourão, G B; Coutinho, L L

    2013-01-01

    In order to better understand vitamin D3 in cattle metabolism, we quantified 1alpha-HYD and 24-HYD gene expression. In the kidneys of 35 male Nellore cattle, these were divided into a control group and two treatment groups (2 x 10(6) international units of vitamin D3 administered for 2 or 8 consecutive days pre-slaughter). Vitamin D3 supplementation resulted in a significant increase in 1alpha-HYD gene expression; however, significantly increased 24-HYD gene expression was only detected in cattle that had 8 days of supplementation. The finding of upregulation of 24-HYD due to vitamin D supplementation is in line with the expected rise in 24,25-di-hydroxy-vitamin D3 synthesis observed when plasma vitamin D3 concentrations are high, stimulating excretion by the organism. On the other hand, upregulation of 1alpha-HYD was unexpected, since vitamin D3 supplementation has been reported to impact these two genes in opposite directions. We conclude that vitamin D3 metabolism in these animals is more complex than previously reported. PMID:24391007

  10. Low dose pramipexole causes D3 receptor-independent reduction of locomotion and responding for a conditioned reinforcer.

    PubMed

    McCormick, P N; Fletcher, P J; Wilson, V S; Browne, J D C; Nobrega, J N; Remington, G J

    2015-02-01

    Pramipexole is a clinically important dopamine receptor agonist with reported selectivity for dopamine D3 receptors over other dopaminergic and non-dopaminergic sites. Many of its behavioural effects are therefore attributed to D3 receptor activity. Here we relate pramipexole's ex vivo D2 and D3 receptor binding (measured using [(3)H]-(+)-PHNO binding experiments) to its effects on locomotion and operant responding for primary and conditioned reinforcers. We show that pramipexole has inhibitory behavioural effects on all three behaviours at doses that occupy D3 but not D2 receptor. However, these effects are 1) not inhibited by a D3 selective dose of the antagonist SB-277011-A, and 2) present in D3 receptor knockout mice. These results suggest that a pharmacological mechanism other than D3 receptor activity must be responsible for these behavioural effects. Finally, our receptor binding results also suggest that these behavioural effects are independent of D2 receptor activity. However, firmer conclusions regarding D2 involvement would be aided by further pharmacological or receptor knock-out experiments. The implications of our findings for the understanding of pramipexole's behavioural and clinical effects are discussed. PMID:25283483

  11. Recording Cultural Heritage Using Terrestrial Laserscanning - Dealing with the System, the Huge Datasets they Create and Ways to Extract the Necessary Deliverables you can Work with

    NASA Astrophysics Data System (ADS)

    Christofori, E.; Bierwagen, J.

    2013-07-01

    Recording Cultural Heritage objects using terrestrial laserscanning becomes more and more popular over the last years. Since terrestrial Laserscanning System (TLS) Manufacturers have strongly increased the amount and speed of data captured with a single scan at each system upgrade and cutting down system costs the use of TLS Systems for recording cultural heritage is an option for recording worth to think about beside traditional methods like Photogrammetric. TLS Systems can be a great tool for capturing complex cultural heritage object within a short amount of time beside the traditional methods but can be a nightmare to handle for further process if not used right while capturing. Furthermore TLS Systems still have to be recognized as survey equipment, even though some of the manufactures promote them as everyday tool. They have to be used in an intelligent way having in mind the clients and the individual cultural objects needs. Thus the efficient way to use TLS Systems for data recording becomes a relevant topic to deal with the huge Amount of data the Systems collect while recording. Already small projects can turn into huge Pointcloud Datasets that End user, like Architects or Archaeologist neither can't deal with as their technical equipment doesn't fit the requirements of the Dataset nor do they have the software tools to use the Data as the current software tools still are high prized. Even the necessary interpretation of the Dataset can be a tough task if the people who have to work on with the Pointcloud aren't educated right in order to understand TLS and the results it creates. The use of TLS Systems has to have in mind the project requirements of the individual Heritage Object, like the required accuracy, standards for Levels of Details (e.g. "Empfehlungen für die Baudokumentation, Günther Eckstein, Germany"), the required kind of Deliverables (Visualization, 2D Drawings, True Deformation Drawings, 3D Models, BIM or 4D - Animations) as well as the

  12. 1,25-Dihydroxyvitamin D3 inhibition of col1a1 promoter expression in calvariae from neonatal transgenic mice

    NASA Technical Reports Server (NTRS)

    Bedalov, A.; Salvatori, R.; Dodig, M.; Kapural, B.; Pavlin, D.; Kream, B. E.; Clark, S. H.; Woody, C. O.; Rowe, D. W.; Lichtler, A. C.

    1998-01-01

    We studied the effect of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) on organ cultures of transgenic mouse calvariae containing segments of the Col1a1 promoter extending to -3518, -2297, -1997, -1794, -1763, and -1719 bp upstream of the transcription start site fused to the chloramphenicol acetyltransferase (CAT) reporter gene. 1,25(OH)2D3 had a dose-dependent inhibitory effect on the expression of the -3518 bp promoter construct (ColCAT3.6), with maximal inhibition of about 50% at 10 nM. This level of inhibition was consistent with the previously observed effect on the endogenous Col1a1 gene in bone cell models. All of the shorter constructs were also inhibited by 10 nM 1,25(OH)2D3, suggesting that the sequences required for 1, 25(OH)2D3 inhibition are downstream of -1719 bp. The inhibitory effect of 1,25(OH)2D3 on transgene mRNA was maintained in the presence of the protein synthesis inhibitor cycloheximide, suggesting that the inhibitory effect on Col1a1 gene transcription does not require de novo protein synthesis. We also examined the in vivo effect of 1,25(OH)2D3 treatment of transgenic mice on ColCAT activity, and found that 48 h treatment caused a dose-dependent inhibition of CAT activity in calvariae comparable to that observed in organ cultures. In conclusion, we demonstrated that 1,25(OH)2D3 inhibits Col1A1 promoter activity in transgenic mouse calvariae, both in vivo and in vitro. The results indicate that there is a 1, 25(OH)2D3 responsive element downstream of -1719 bp. The inhibitory effect does not require new protein synthesis.

  13. Blockade of [11C](+)-PHNO binding in human subjects by the dopamine D3 receptor antagonist ABT-925.

    PubMed

    Graff-Guerrero, Ariel; Redden, Laura; Abi-Saab, Walid; Katz, David A; Houle, Sylvain; Barsoum, Penny; Bhathena, Anahita; Palaparthy, Ramesh; Saltarelli, Mario D; Kapur, Shitij

    2010-04-01

    Dopamine D3 receptors are preferentially localized in the limbic system and midbrain, and thus may be involved in the pathophysiology of neuropsychiatry disorders. [11C](+)-PHNO is the first preferential D3 receptor radioligand in humans, yet there are no blockade studies with a D3 receptor antagonist in humans. This study characterized the blockade of [11C](+)-PHNO binding by ABT-925, a D3 receptor antagonist, in healthy male subjects. Sixteen subjects underwent 2-3 positron emission tomography (PET) scans, at baseline and following one or two doses of ABT-925 ranging from 50 mg to 600 mg. Receptor occupancies were estimated for globus pallidus, substantia nigra, caudate, putamen, and ventral striatum. At the 600-mg dose (n=9), ABT-925 receptor occupancy (mean+/-s.d.) was higher in substantia nigra (75+/-10%) and globus pallidus (64+/-22%) than in ventral striatum (44+/-17%), caudate (40+/-18%) and putamen (38+/-17%) (ANOVA: F4,140=15.02, p<0.001). The fractions of [11C](+)-PHNO binding attributable to D3 receptors in D3 receptor-rich regions were 100% (substantia nigra) and 90% (globus pallidus), and in D2 receptor-rich regions were 55% (caudate) and 53% (putamen). The ED50 of ABT-925 was 4.37 microg/ml across regions. Our results demonstrate that [11C](+)-PHNO binding can be blocked by a D3 receptor antagonist and confirm preclinical findings that [11C](+)-PHNO signal in the substantia nigra and globus pallidus is mainly reflective of its binding to D3 receptors. Thus, [11C](+)-PHNO seems a suitable PET radiotracer to estimate D3 receptor occupancy in humans. PMID:19751545

  14. Combined use of vitamin D3and metformin exhibits synergistic chemopreventive effects on colorectal neoplasia in rats and mice

    PubMed Central

    Li, Wan; Wang, Qi-Long; Liu, Xia; Dong, Shu-Hong; Li, Hong-Xia; Li, Chun-Yang; Guo, Li-Shu; Gao, Jing-Miao; Berger, Nathan A.; Li, Li; Ma, Lan; Wu, Yong-Jie

    2015-01-01

    Vitamin D3 and metformin are widely used in humans for regulating mineral metabolism and as an anti-diabetic drug respectively; and both of them have been shown to have chemopreventive effects against various tumors. This study was designed to investigate the potential synergistic chemopreventive effects of vitamin D3 and metformin against the development of early colon neoplasia in two models. The first model was a 1, 2-dimethylhydrazine dihydrochloride (DMH) induced colon cancer rat model and the second, a DMH-dextran sodium sulfate (DSS) induced colitis-associated colon neoplasia mouse model. Compared to either vitamin D3 or metformin alone, combined use of vitamin D3 and metformin showed more pronounced effect in reducing the numbers of aberrant crypt foci (ACF) and tumor in the colon. The most prominent inhibitory effects were observed in the vitamin D3 medium dose (100 IU/kg/day) and metformin medium dose (120 mg/kg/day) combination group. Furthermore, our results showed that enhancement of metformin’s chemopreventive effects by vitamin D3 was associated with down-regulation of S6P expression, via the AMPK (IGF-1)/mTOR pathway. In addition, and enhancement of vitamin D3’s chemopreventive effects by metformin was associated with inhibition of the protein expressions of c-Myc and Cyclin D1, via the vitamin D receptor/β-catenin pathway. These findings show that combined use of vitamin D3 and metformin exhibits synergistic effects against the development of early colon neoplasia. They suggest that the combined use of vitamin D3 and metformin may represent a novel strategy for chemoprevention of colorectal cancer. PMID:25416412

  15. Socioeconomic status is associated with striatal dopamine D2/D3 receptors in healthy volunteers but not in cocaine abusers.

    PubMed

    Wiers, Corinde E; Shokri-Kojori, Ehsan; Cabrera, Elizabeth; Cunningham, Samantha; Wong, Christopher; Tomasi, Dardo; Wang, Gene-Jack; Volkow, Nora D

    2016-03-23

    Positron emission tomography (PET) studies in animals and humans have shown that social status is associated with striatal dopamine D2/D3 receptor (D2/D3R) availability. That is, higher social hierarchy and higher scores on questionnaires assessing social status correlated positively with striatal D2/D3R availability in animals and humans respectively. Furthermore, subordinate monkeys were vulnerable to cocaine self-administration, suggesting that alternations in social hierarchy can change D2/D3R availability and vulnerability to cocaine use. Here, we investigated whether socioeconomic status (SES) measured with the Hollingshead scale is associated with striatal D2D/3R availability using [(11)C]raclopride PET in 38 cocaine abusers and 42 healthy controls matched for age and education. Compared to controls, cocaine abusers showed lower D2/D3R availability in the caudate, putamen and ventral striatum (all p≤0.001). Despite matching groups for education, SES scores were lower in cocaine abusers than controls (p<0.001). In the control group only, SES scores significantly correlated with D2/D3R in caudate (r=0.35, p=0.024) and putamen (r=0.39, p=0.011) but not in ventral striatum (p=0.61); all corrected for age. The study confirms that SES is associated with striatal D2/D3R availability in healthy human volunteers. However, reductions in D2/D3R availability in cocaine abusers may be driven by factors other than SES such as chronic cocaine exposure. PMID:26828302

  16. Regulation of Motility, Invasion and Metastatic Potential of Squamous Cell Carcinoma by 1,25D3

    PubMed Central

    Ma, Yingyu; Yu, Wei-Dong; Su, Bing; Seshadri, Mukund; Luo, Wei; Trump, Donald L.; Johnson, Candace S.

    2012-01-01

    BACKGROUND 1,25D3, the active metabolite of vitamin D, has been shown to exhibit broad spectrum anti-tumor activity in xenograft animal models. However, its activity against metastatic disease has not been extensively investigated. METHODS Squamous cell carcinoma (SCC) or 1,25D3-resistant variant SCC-DR cells were treated with 1,25D3. Actin organization was examined by immunofluorescence assay. Cell migration was assessed by “wound” healing and chemotactic migration assay. Cell invasion was assessed by Matrigel-based invasion assay and in situ zymography. MMP-2 and MMP-9 expression and secretion was examined by immunoblot analysis and ELISA, respectively. E-cadherin expression was assessed by flow cytometry, immunoblot analysis and immunohistochemistry. Knockdown of E-cadherin was achieved by siRNA. Experimental metastasis mouse model was done by intravenous injection of tumor cells. Lung tumor development was assessed by magnetic resonance imaging, gross observation and histology. RESULTS SCC cellular morphology and actin organization were altered by 10 nM of 1,25D3. 1,25D3 inhibited SCC cell motility and invasion, which was associated with reduced expression and secretion of MMP-2 and MMP-9. 1,25D3 promoted the expression of E-cadherin. These findings were not observed in SCC-DR cells. Knock down of E-cadherin rescued 1,25D3-inhibited cell migration. Intravenous injection of SCC or SCC-DR cells resulted in the establishment of extensive pulmonary lesions in saline-treated C3H mice. Treatment with 1,25D3 resulted in a marked reduction in the formation of lung tumor colonies in animals injected with SCC but not SCC-DR cells. CONCLUSIONS 1,25D3 suppresses SCC cell motility, invasion and metastasis, partially through the promotion of E-cadherin-mediated cell-cell adhesion. PMID:22833444

  17. 1α,25(OH)2D3 differentially regulates miRNA expression in human bladder cancer cells

    PubMed Central

    Ma, Yingyu; Hu, Qiang; Luo, Wei; Pratt, Rachel N.; Glenn, Sean T.; Liu, Song; Trump, Donald L.; Johnson, Candace S.

    2014-01-01

    Bladder cancer is the fourth most commonly diagnosed cancer in men and eighth leading cause of cancer-related death in the US. Epidemiological and experimental studies strongly suggest a role for 1α,25(OH)2D3 in cancer prevention and treatment. The antitumor activities of 1α,25(OH)2D3 are mediated by the induction of cell cycle arrest, apoptosis, differentiation and the inhibition of angiogenesis and metastasis. MiRNAs play important regulatory roles in cancer development and progression. However, the role of 1α,25(OH)2D3 in the regulation of miRNA expression and the potential impact in bladder cancer has not been investigated. Therefore, we studied 1α,25(OH)2D3-regulated miRNA expression profiles in human bladder cancer cell line 253J and the highly tumorigenic and metastatic derivative line 253J-BV by miRNA qPCR panels. 253 J and 253J-BV cells express endogenous vitamin D receptor (VDR) which can be further induced by 1α,25(OH)2D3. VDR target gene 24-hydroxylase was induced by 1α,25(OH)2D3 in both cell lines, indicating functional 1α,25(OH)2D3 signaling. The miRNA qPCR panel assay results showed that 253J and 253J-BV cells have distinct miRNA expression profiles. Further, 1α,25(OH)2D3 differentially regulated miRNA expression profiles in 253J and 253 J-BV cells in a dynamic manner. Pathway analysis of the miRNA target genes revealed distinct patterns of contribution to the molecular functions and biological processes in the two cell lines. In conclusion, 1α,25(OH)2D3 differentially regulates the expression of miRNAs, which may contribute to distinct biological functions, in human bladder 253J and 253J-BV cells. PMID:25263658

  18. Using prepulse inhibition to detect functional D3 receptor antagonism: effects of WC10 and WC44.

    PubMed

    Weber, Martin; Chang, Wei-Li; Durbin, John P; Park, Paula E; Luedtke, Robert R; Mach, Robert H; Swerdlow, Neal R

    2009-08-01

    Prepulse inhibition of startle (PPI) is an operational measure of sensorimotor gating that is impaired in schizophrenia. Treatment with mixed dopamine D2/D3 antagonists diminishes schizophrenia symptoms, and opposes dopamine agonist-induced PPI deficits in rats. There are reasons to believe that functional D3 receptor antagonists might offer more favorable therapeutic profiles compared to current antipsychotics. However, D3-related drug discovery is hampered by the absence of assays sensitive to D3-mediated (antipsychotic) properties in vivo. Here, we characterized two putative D3-active compounds - WC10 and WC44 - in a PPI-based screening assay, comparing the sensitivity of test compounds to oppose PPI deficits induced by the mixed D1/D2-like agonist apomorphine vs. the preferential D3 agonist pramipexole in rats. WC10, WC44 (0, 1, 3, 10 mg/kg, each), and the preferential D2 antagonist L741,626 (0, 1 mg/kg) were studied, in combination with apomorphine (0, 0.5 mg/kg), or pramipexole (0, 1 mg/kg). L741,626 prevented apomorphine-, but not pramipexole-induced PPI deficits. WC10, but not WC44, prevented apomorphine-induced PPI deficits; both compounds opposed pramipexole-induced PPI deficits, suggesting functional D3 and D1/D2 antagonist profiles for WC10, and functional D3 receptor antagonism for WC44. This assay may be valuable for detecting predominantly D3 vs. D2 receptor-linked mechanisms of action in vivo. PMID:19426754

  19. Role of 1,25-Dihydroxy Vitamin D3 and Parathyroid Hormone in Urinary Calcium Excretion in Calcium Stone Formers

    PubMed Central

    Kim, Won Tae; Kim, Yong-June; Yun, Seok Joong; Shin, Kyung-Sub; Choi, Young Deuk; Kim, Wun-Jae

    2014-01-01

    Purpose To find out the possible role of 1,25(OH)2 vitamin D3 [1,25(OH)2D3] and parathyroid hormone (PTH) as intrinsic factors in urinary calcium stone formers (SFs), we investigated their relationship with serum and urinary biochemical parameters. Materials and Methods A total of 326 calcium SFs (male: 204, female: 122) were enrolled and underwent outpatient metabolic evaluations including 1,25(OH)2D3 and PTH as well as serum and 24-hour urinary biochemical parameters. As control, 163 age- and sex-matched (2:1) individuals (non-SFs) who have never urinary stone episode were included. Results 1,25(OH)2D3 level was positively correlated with urinary calcium excretion (r=0.347, p<0.001). The hypercalciuric group and recurrent SFs had higher serum 1,25(OH)2D3 levels than the normocalciuric group (p<0.001) and first SFs (p=0.050). In the adjusted multiple linear regression analysis, serum 1,25(OH)2D3 level (β=0.259, p<0.001) and serum PTH level (β=-0.160, p<0.001) were significantly correlated with urinary calcium excretion. The patients in highest tertile of 1,25(OH)2D3 had a more than 3.1 fold risk of hypercalciuria than those in the lowest tertile (odds ratio=3.14, 95% confidence interval: 1.431-6.888, p=0.004). No correlation was observed between PTH and 1,25(OH)2D3 (R=0.005, p=0.929) in calcium SFs, while a negative correlation was found in controls (R=-0.269, p=0.001). Conclusion 1,25(OH)2D3 was closely correlated with urinary calcium excretion, and high 1,25(OH)2D3 levels were detected in the hypercalciuric group and in recurrent SFs. However, 1,25(OH)2D3 was not correlated with PTH in calcium SFs. These findings suggest that 1,25(OH)2D3 might be important intrinsic factor for altered calcium regulation in SFs. PMID:25048492

  20. 1,25-Dihydroxyvitamin D3 promotes tolerogenic dendritic cells with functional migratory properties in NOD mice.

    PubMed

    Ferreira, Gabriela B; Gysemans, Conny A; Demengeot, Jocelyne; da Cunha, João Paulo M C M; Vanherwegen, An-Sofie; Overbergh, Lut; Van Belle, Tom L; Pauwels, Femke; Verstuyf, Annemieke; Korf, Hannelie; Mathieu, Chantal

    2014-05-01

    The biologically active form of vitamin D, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], is able to promote the generation of tolerogenic mature dendritic cells (mDCs) with an impaired ability to activate autoreactive T cells. These cells could represent a reliable tool for the promotion or restoration of Ag-specific tolerance through vaccination strategies, for example in type 1 diabetes patients. However, successful transfer of 1,25(OH)2D3-treated mDCs (1,25D3-mDCs) depends on the capacity of 1,25(OH)2D3 to imprint a similar tolerogenic profile in cells derived from diabetes-prone donors as from diabetes-resistant donors. In this study, we examined the impact of 1,25(OH)2D3 on the function and phenotype of mDCs originating from healthy (C57BL/6) and diabetes-prone (NOD) mice. We show that 1,25(OH)2D3 is able to imprint a phenotypic tolerogenic profile on DCs derived from both mouse strains. Both NOD- and C57BL/6-derived 1,25D3-mDCs decreased the proliferation and activation of autoreactive T cells in vitro, despite strain differences in the regulation of cytokine/chemokine expression. In addition, 1,25D3-mDCs from diabetes-prone mice expanded CD25(+)Foxp3(+) regulatory T cells and induced intracellular IL-10 production by T cells in vitro. Furthermore, 1,25D3-mDCs exhibited an intact functional migratory capacity in vivo that favors homing to the liver and pancreas of adult NOD mice. More importantly, when cotransferred with activated CD4(+) T cells into NOD.SCID recipients, 1,25D3-mDCs potently dampened the proliferation of autoreactive donor T cells in the pancreatic draining lymph nodes. Altogether, these results argue for the potential of 1,25D3-mDCs to restore Ag-specific immune tolerance and arrest autoimmune disease progression in vivo. PMID:24663679

  1. Inhibition of insulin- and insulin-like growth factor-I-stimulated growth of human breast cancer cells by 1,25-dihydroxyvitamin D3 and the vitamin D3 analogue EB1089.

    PubMed

    Vink-van Wijngaarden, T; Pols, H A; Buurman, C J; Birkenhäger, J C; van Leeuwen, J P

    1996-05-01

    1,25 Dihydroxyvitamin D3 (1,25-(OH)2D3) and a number of synthetic vitamin D3 analogues with low calcaemic activity, have been shown to inhibit breast cancer cell growth in vitro as well as in vivo. The purpose of the present study was to investigate a possible interaction of 1,25-(OH)2D3 and the vitamin D3 analogue EB1089 with the insulin-IGF-I regulatory system. The oestrogen receptor-positive MCF-7 human breast cancer cells used in this study are able to grow autonomously and their growth is stimulated by insulin. In order to avoid interference of IGF-binding proteins (IGF-BPs), we used an analogue of IGF-I, long R3 IGF-I, which stimulated MCF-7 cell growth similar to insulin. The growth stimulation by insulin and by long R3 IGF-I was completely inhibited by 1,25-(OH)2D3 and EB1089. Autonomous growth was also inhibited by 1,25-(OH)2D3 and EB1089. The analogue EB1089 was active at 50 times lower concentrations than 1,25-(OH)2D3. It was shown that growth inhibition was not achieved through downregulation of insulin and IGF-I binding after 48 h. Paradoxically, after prolonged treatment (8 days), an upregulation of insulin and IGF-I binding was observed. Two possible intracellular mediators of the insulin-IGF mitogenic signal are C-FOS and mitogen-activated protein (MAP) kinase. Insulin-induced C-FOS mRNA was inhibited by 1,25-(OH)2D3, suggesting that it could be involved in the growth inhibition by 1,25-(OH)2D3. MAP kinase activation appeared not to be involved in growth stimulation by both insulin and IGF-I. Together, the present study demonstrates that vitamin D3 compounds can block the mitogenic activity of insulin and IGF-I, which may contribute to their tumour suppressive activity observed in vivo. PMID:9081364

  2. 1α,25(OH)2-3-Epi-Vitamin D3, a Natural Physiological Metabolite of Vitamin D3: Its Synthesis, Biological Activity and Crystal Structure with Its Receptor

    PubMed Central

    Molnár, Ferdinand; Sigüeiro, Rita; Sato, Yoshiteru; Araujo, Clarisse; Schuster, Inge; Antony, Pierre; Peluso, Jean; Muller, Christian; Mouriño, Antonio; Moras, Dino; Rochel, Natacha

    2011-01-01

    Background The 1α,25-dihydroxy-3-epi-vitamin-D3 (1α,25(OH)2-3-epi-D3), a natural metabolite of the seco-steroid vitamin D3, exerts its biological activity through binding to its cognate vitamin D nuclear receptor (VDR), a ligand dependent transcription regulator. In vivo action of 1α,25(OH)2-3-epi-D3 is tissue-specific and exhibits lowest calcemic effect compared to that induced by 1α,25(OH)2D3. To further unveil the structural mechanism and structure-activity relationships of 1α,25(OH)2-3-epi-D3 and its receptor complex, we characterized some of its in vitro biological properties and solved its crystal structure complexed with human VDR ligand-binding domain (LBD). Methodology/Principal Findings In the present study, we report the more effective synthesis with fewer steps that provides higher yield of the 3-epimer of the 1α,25(OH)2D3. We solved the crystal structure of its complex with the human VDR-LBD and found that this natural metabolite displays specific adaptation of the ligand-binding pocket, as the 3-epimer maintains the number of hydrogen bonds by an alternative water-mediated interaction to compensate the abolished interaction with Ser278. In addition, the biological activity of the 1α,25(OH)2-3-epi-D3 in primary human keratinocytes and biochemical properties are comparable to 1α,25(OH)2D3. Conclusions/Significance The physiological role of this pathway as the specific biological action of the 3-epimer remains unclear. However, its high metabolic stability together with its significant biologic activity makes this natural metabolite an interesting ligand for clinical applications. Our new findings contribute to a better understanding at molecular level how natural metabolites of 1α,25(OH)2D3 lead to significant activity in biological systems and we conclude that the C3-epimerization pathway produces an active metabolite with similar biochemical and biological properties to those of the 1α,25(OH)2D3. PMID:21483824

  3. Oral supplementation with 25(OH)D3 versus vitamin D3: effects on 25(OH)D levels, lower extremity function, blood pressure, and markers of innate immunity

    Technology Transfer Automated Retrieval System (TEKTRAN)

    To test the effect of 25(OH)D3 (HyD) compared to vitamin D3 on serum 25-hydroxyvitamin D levels (25(OH)D), lower extremity function, blood pressure, and markers of innate immunity. Twenty healthy postmenopausal women with an average 25(OH)D level of 13.23.9 ng/mL (meanSD) and a mean age of 61.57.2 y...

  4. Two-Dimensional Mapping of the He D3/Hβ Emission Ratio in Solar Prominences

    NASA Astrophysics Data System (ADS)

    Wiehr, Eberhard; Stellmacher, Goetz; Hirzberger, Johann

    2007-01-01

    Solar prominences have been simultaneously observed in the integrated light of the He D3 and the Hβ emissions on two successive days, using the SST on La Palma with its tip-tilt mirror locked on a nearby white-light limb facular grain. The spatial and the temporal variation of the integrated line intensities and their ratio shows mainly two characteristics: (A) Constant emission ratio (even) in regions with substantial intensity variations and (B) varying emission ratio (often) tightly related to intensity structures of the prominence. (A) May be explained by a different number of superposing threads along the line of sight having very similar physical state. (B) Indicates threads with different intrinsic physical states; these may depend on the gas pressure or the inner structure of each thread, i.e., the “packing density,” affecting the penetration of ionizing EUV radiation, which affects the He I level populations and thus the rate of the triplet excitation.

  5. Supergravity Analysis of Hybrid Inflation Model from D3--D7 System

    SciTech Connect

    Koyama, Fumikazu; Tachikawa, Yuji; Watari, Taizan

    2003-11-20

    The slow-roll inflation is a beautiful paradigm, yet the inflaton potential can hardly be sufficiently flat when unknown gravitational effects are taken into account. However, the hybrid inflation models constructed in D = 4 N = 1 supergravity can be consistent with N = 2 supersymmetry, and can be naturally embedded into string theory. This article discusses the gravitational effects carefully in the string model, using D = 4 supergravity description. We adopt the D3--D7 system of Type IIB string theory compactified on K3 x T^2/Z_2 orientifold for definiteness. It turns out that the slow-roll parameter can be sufficiently small despite the non-minimal Kahler potential of the model. The conditions for this to happen are clarified in terms of string vacua. We also find that the geometry obtained by blowing up singularity, which is necessary for the positive vacuum energy, is stabilized by introducing certain 3-form fluxes.

  6. Lightweight compact 2D/3D autostereoscopic LCD backlight for games, monitor, and notebook applications

    NASA Astrophysics Data System (ADS)

    Eichenlaub, Jesse B.

    1998-04-01

    At the 1997 conference DTI first reported on a low cost, thin, lightweight backlight for LCDs that generates a special illumination pattern to create autostereoscopic 3D images and can switch to conventional diffuse illumination for 2D images. The backlight is thin and efficient enough for use in portable computer and hand held games, as well as thin desktop displays. The system has been embodied in 5' (13 cm) diagonal backlights for gambling machines, and in the 12.1' (31 cm) diagonal DTI Virtual Window(TM) desktop product. During the past year, DTI has improved the technology considerably, reducing crosstalk, increasing efficiency, improving components for mass production, and developing prototypes that move the 3D viewing zones in response to the observer's head position. The paper will describe the 2D/3D backlights, improvements that have been made to their function, and their embodiments within the latest display products and prototypes.

  7. Geometrical symmetries of nuclear systems: {{ D }}_{3h} and {{ T }}_{d} symmetries in light nuclei

    NASA Astrophysics Data System (ADS)

    Bijker, Roelof

    2016-07-01

    The role of discrete (or point-group) symmetries in α-cluster nuclei is discussed in the framework of the algebraic cluster model which describes the relative motion of the α-particles. Particular attention is paid to the discrete symmetry of the geometric arrangement of the α-particles, and the consequences for the structure of the corresponding rotational bands. The method is applied to study cluster states in the nuclei 12C and 16O. The observed level sequences can be understood in a simple way as a consequence of the underlying discrete symmetry that characterizes the geometrical configuration of the α-particles, i.e. an equilateral triangle with {{ D }}3h symmetry for 12C, and a tetrahedron with {{ T }}d symmetry for 16O. The structure of rotational bands provides a fingerprint of the underlying geometrical configuration of α-particles.

  8. Behavioural effects of the dopamine D3 receptor agonist 7-OH-DPAT in rats.

    PubMed

    Ferrari, F; Giuliani, D

    1995-01-01

    The putative selective dopamine (DA) D3 receptor agonist, 7-OH-DPAT (25-4000 micrograms kg-1), enhanced stretching-yawning and penile erection in male rats, besides respectively increasing and decreasing sedation at low (25-200 micrograms kg-1) and high (1600 and 4000 micrograms kg-1) doses and inducing stereotypy from 800 micrograms kg-1 upwards. The DA D2 antagonist, (-) eticlopride (10 and 20 micrograms kg-1), antagonized stretching-yawning and penile erection induced by a low dose of 7-OH-DPAT (50 micrograms kg-1) but not those produced by high doses (1600 and 4000 micrograms kg-1), when stereotyped behaviour, on the other hand, was potently inhibited. Comparative experiments performed with the DA agonist SND 919 gave similar results. PMID:8668649

  9. In vivo evidence for a novel pathway of vitamin D3 metabolism initiated by P450scc and modified by CYP27B1

    PubMed Central

    Slominski, Andrzej T.; Kim, Tae-Kang; Shehabi, Haleem Z.; Semak, Igor; Tang, Edith K. Y.; Nguyen, Minh N.; Benson, Heather A. E.; Korik, Elena; Janjetovic, Zorica; Chen, Jianjun; Yates, Charles R.; Postlethwaite, Arnold; Li, Wei; Tuckey, Robert C.

    2012-01-01

    We define previously unrecognized in vivo pathways of vitamin D3 (D3) metabolism generating novel D3-hydroxyderivatives different from 25-hydroxyvitamin D3 [25(OH)D3] and 1,25(OH)2D3. Their novel products include 20-hydroxyvitamin D3 [20(OH)D3], 22(OH)D3, 20,23(OH)2D3, 20,22(OH)2D3, 1,20(OH)2D3, 1,20,23(OH)3D3, and 17,20,23(OH)3D3 and were produced by placenta, adrenal glands, and epidermal keratinocytes. We detected the predominant metabolite [20(OH)D3] in human serum with a relative concentration ∼20 times lower than 25(OH)D3. Use of inhibitors and studies performed with isolated mitochondria and purified enzymes demonstrated involvement of the steroidogenic enzyme cytochrome P450scc (CYP11A1) as well as CYP27B1 (1α-hydroxylase). In placenta and adrenal glands with high CYP11A1 expression, the predominant pathway was D3 → 20(OH)D3 → 20,23(OH)2D3 → 17,20,23(OH)3D3 with further 1α-hydroxylation, and minor pathways were D3 → 25(OH)D3 → 1,25(OH)2D3 and D3 → 22(OH)D3 → 20,22(OH)2D3. In epidermal keratinocytes, we observed higher proportions of 22(OH)D3 and 20,22(OH)2D3. We also detected endogenous production of 20(OH)D3, 22(OH) D3, 20,23(OH)2D3, 20,22(OH)2D3, and 17,20,23(OH)3D3 by immortalized human keratinocytes. Thus, we provide in vivo evidence for novel pathways of D3 metabolism initiated by CYP11A1, with the product profile showing organ/cell type specificity and being modified by CYP27B1 activity. These findings define the pathway intermediates as natural products/endogenous bioregulators and break the current dogma that vitamin D is solely activated through the sequence D3 → 25(OH)D3 → 1,25(OH)2D3.—Slominski, A. T., Kim, T.-K., Shehabi, H. Z., Semak, I., Tang, E. K. Y., Nguyen, M. N., Benson, H. A. E., Korik, E., Janjetovic, Z., Chen, J., Yates, C. R., Postlethwaite, A., Li, W., Tuckey, R. C. In vivo evidence for a novel pathway of vitamin D3 metabolism initiated by P450scc and modified by CYP27B1. PMID:22683847

  10. Proton and Alpha Core Imaging of OMEGA D^3He Implosions

    NASA Astrophysics Data System (ADS)

    Petrasso, R. D.; Frenje, J. A.; Seguin, F. H.; Li, C. K.; Schwartz, B. E.; Stoeckl, C.; Radha, P. B.; Delettrez, J. A.; Meyerhofer, D. D.; Roberts, S.; Sangster, T. C.; Soures, J. M.

    2002-11-01

    Measurements of the nuclear burn region are important for investigating the extent of the burn, the presence of burn asymmetries, the effects of mix and thermal conduction on the burn region, and the accuracy of code predictions. Charged-fusion-product core images have been obtained at OMEGA for implosions of D^3He-filled capsules with both thin and thick shells. Using multiple pinholes, images are reconstructed from 3.0-MeV and 14.7-MeV protons and 3.6-MeV alphas. For thin-shell, all three particles escape at bang time and their images reflect the different burn regions for DD and D^3He reactions. In contrast, for thick-shell implosions, only the 14.7-MeV proton can penetrate the capsule ρR at bang time, and the burn region reflects the effects of compression and mix. At first shock coalescence, when the ρR is far below its peak value, all three particles may also escape from the capsule. As mix has been experimentally shown to be inconsequential at this instant, meaningful comparisons of 1-D simulations with experiments can be made. This work was supported in part by the U.S. DOE Office of Inertial Confinement Fusion (Grant number DE-FG03-99DP00300 and Cooperative Agreement number DE-FC03-92SF19460), LLE (subcontract P0410025G), and LLNL (subcontract B313975. (Petrasso: Visiting Senior Scientist at LLE.)

  11. The Second International Standard for Vitamin D: crystalline vitamin D3*

    PubMed Central

    Coward, K. H.; Irwin, J. O.

    1954-01-01

    This report was presented to the Subcommittee on Fat-Soluble Vitamins of the WHO Expert Committee on Biological Standardization in 1949 by the Vitamin D Sub-Committee of the Accessory Food Factors Committee of the Medical Research Council of Great Britain and formed the evidence on which the first-mentioned subcommittee based its recommendation of the adoption of crystalline vitamin D3 as the International Standard for Vitamin D, replacing the solution of irradiated ergosterol which had been adopted as Standard in 1931. The Vitamin D Sub-Committee organized a collaborative assay in which 32 laboratories in seven countries participated. In addition to 29g of crystalline vitamin D3 generously contributed by five firms, the following preparations were compared for vitamin D activity by biological tests on rats or chicks or both: the then current International Standard, a preparation of the purest calciferol obtainable, the British Standards Institution (BSI) Standard, the United States Pharmacopeia (USP) Reference Cod Liver Oil, and the Swedish provisional standard. Altogether 29 rat assays and 25 chick assays were carried out, and the results were subjected to standard methods of analysis. The BSI Standard and the pure calciferol were found less potent than the Old Standard (potency ratios: 0.916 and 0.933, respectively); and the New Standard may be slightly less potent (0.981), but it is more potent than the BSI Standard (1.071). The USP Reference Oil is less potent than the BSI Standard (0.949), the Old Standard (0.896), and the New Standard (0.886). The fiducial range is generally less than 10%, but even where it is greater, it is still satisfactory for a biological test. PMID:13199651

  12. Converging evidence implicates the dopamine D3 receptor gene in vulnerability to schizophrenia.

    PubMed

    Zhang, Fuquan; Fan, Hua; Xu, Yong; Zhang, Kerang; Huang, Xuezhu; Zhu, Yan; Sui, Manqiu; Sun, Gaoxiang; Feng, Kun; Xu, Bo; Zhang, Xiaoqian; Su, Zhonghua; Peng, Chunqing; Liu, Pozi

    2011-07-01

    The dopamine D3 receptor has been implicated in the pathophysiology of schizophrenia (SZ). A glycine-to-serine polymorphism at codon 9 of the dopamine D3 receptor gene (DRD3), rs6280, has been widely studied for its association with SZ, but with conflicting results. Altered levels of DRD3 mRNA have also been reported in SZ compared with normal controls. Moreover, it has been suggested that DRD3 is subject to recent positive selection in European populations. To explore the potential role of DRD3 in SZ from these various aspects, we conducted a threefold study. First, we tested the genetic association of rs6280 with SZ in 685 SZ patients and 768 normal controls. Second, we examined DRD3 mRNA levels in peripheral leukocytes in a subset of 37 patients and 37 controls. Finally, we investigated the possible recent positive selection on DRD3 in an East Asian population. Consequently, we observed that the genotypic distribution of rs6280 was nominally associated with SZ (P = 0.045), with the ancestral CC genotype being significantly over-represented in SZ patients. DRD3 mRNA levels were significantly lower in patients than in controls (P = 5.91E-5). The derived C-allele of rs6280 might have been subject to recent positive selection (P < 0.001) in the East Asian population. Taken together, our results suggest that DRD3, a gene possibly under natural selection, might be involved in vulnerability to SZ in the Han Chinese population. These findings may further add to the body of data implicating DRD3 as a schizophrenia risk gene. PMID:21595009

  13. Locally adaptive 2D-3D registration using vascular structure model for liver catheterization.

    PubMed

    Kim, Jihye; Lee, Jeongjin; Chung, Jin Wook; Shin, Yeong-Gil

    2016-03-01

    Two-dimensional-three-dimensional (2D-3D) registration between intra-operative 2D digital subtraction angiography (DSA) and pre-operative 3D computed tomography angiography (CTA) can be used for roadmapping purposes. However, through the projection of 3D vessels, incorrect intersections and overlaps between vessels are produced because of the complex vascular structure, which makes it difficult to obtain the correct solution of 2D-3D registration. To overcome these problems, we propose a registration method that selects a suitable part of a 3D vascular structure for a given DSA image and finds the optimized solution to the partial 3D structure. The proposed algorithm can reduce the registration errors because it restricts the range of the 3D vascular structure for the registration by using only the relevant 3D vessels with the given DSA. To search for the appropriate 3D partial structure, we first construct a tree model of the 3D vascular structure and divide it into several subtrees in accordance with the connectivity. Then, the best matched subtree with the given DSA image is selected using the results from the coarse registration between each subtree and the vessels in the DSA image. Finally, a fine registration is conducted to minimize the difference between the selected subtree and the vessels of the DSA image. In experimental results obtained using 10 clinical datasets, the average distance errors in the case of the proposed method were 2.34±1.94mm. The proposed algorithm converges faster and produces more correct results than the conventional method in evaluations on patient datasets. PMID:26824922

  14. Vitamin D3 in cancer prevention and therapy: the nutritional issue.

    PubMed

    Chirumbolo, Salvatore

    2015-09-01

    The action of vitamin D3, in its biological form 1α,25(OH)2vitD3 or calcitriol, may be summarized as a steroid-like hormone able to modulate basic functions of cell encompassing energy balance, stress response, mitochondria biogenesis, intracellular calcium oscillations, and replication/apoptosis mechanisms leading to cell survival. Moreover, calcitriol exerts a potent role as an innate and adaptive immune cytokine as immunity is closely related to self-maintenance through its energetic/metabolic balance and homeostasis of cell turnover. Therefore, vitamin D might be the ancestral form of survival hormones developed with calcified vertebrate bearing skeleton in order to survive far from water. This characteristic may suggest that the role of dietary vitamin D in preventing cancer is simply ancillary to the many factors playing a major role in contrasting impairment in energy balance and cell survival. Most probably, the immune role of calcitriol might be included in the maintenance, mostly by adipose tissue, of an anti-inflammatory, tolerant immune status, depending on the immune tolerance and modulation from the gut. A balance closely modulated by the leptin axis, which when impairments in metabolism occur, such as in insulin resistance or obesity, calcitriol is unable to face at this imbalance, while leptin plays a major role and cancer progression may be promoted. Furthermore, this mechanism promotes epithelial/mesenchymal transition-mediated fibrosis, leading to cancer resistance to immune control and drug action. Interestingly, this pathologic picture is triggered by deficiency in vitamin D from the diet. Therefore, a dietary habit including vitamin D sources, besides flavonoids, may ameliorate lifestyle and health span in most individuals, depending on their genetic background. PMID:26057218

  15. 1,25-dyhydroxyvitamin D3 attenuates L-DOPA-induced neurotoxicity in neural stem cells.

    PubMed

    Jang, Wooyoung; Park, Hyun-Hee; Lee, Kyu-Yong; Lee, Young Joo; Kim, Hee-Tae; Koh, Seong-Ho

    2015-04-01

    The neurotoxicity of levodopa (L-DOPA) on neural stem cells (NSCs) and treatment strategies to protect NSCs from this neurotoxicity remain to be elucidated. Recently, an active form of vitamin D3 has been reported to display neuroprotective properties. Therefore, we investigated the protective effect of 1,25-dyhydroxyvitamin D3 (calcitriol) on L-DOPA-induced NSC injury. We measured cell viability via the cell counting kit-8 (CCK-8) and lactate dehydrogenase (LDH) assays and Annexin V/PI staining followed by flow cytometry, cell proliferation using the BrdU and colony-forming unit (CFU) assays, cell differentiation via immunocytochemistry, the levels of free radicals via 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) staining, apoptosis via DAPI and TUNEL staining, and intracellular signaling protein expression via Western blot. Antibody microarrays were also employed to detect changes in the expression of prosurvival- and death-related proteins. Treatment of NSCs with L-DOPA reduced their viability and proliferation. This treatment also increased the levels of free radicals and decreased the expression levels of intracellular signaling proteins that are associated with cell survival. However, simultaneous exposure to calcitriol significantly reduced these effects. The calcitriol-mediated protection against L-DOPA toxicity was blocked by the phosphoinositide 3-kinase (PI3K) inhibitor LY294004. L-DOPA also inhibited the expression of Nestin and Ki-67, and co-treatment with calcitriol alleviated these effects. The expression levels of GFAP, DCX, and Tuj1 were not significantly affected by treatment with L-DOPA or calcitriol. Calcitriol protects against L-DOPA-induced NSC injury by promoting prosurvival signaling, including activation of the PI3K pathway, and reducing oxidative stress. PMID:25102940

  16. Is the metabolism of 25-hydroxyvitamin D3 age-dependent in dairy cows?

    PubMed

    Wilkens, Mirja R; Cohrs, Imke; Lifschitz, Adrian L; Fraser, David R; Olszewski, Katharina; Schröder, Bernd; Breves, Gerhard

    2013-07-01

    It has recently been demonstrated that prepartum administered 25-hydroxyvitamin D3 (25-OHD3) is a promising candidate to assist the maintenance of peripartal calcium homeostasis in dairy cows. Since the incidence of peripartal hypocalcemia and the reported beneficial effects of the treatment are both associated with the lactation number, we investigated pharmacokinetic aspects of 25-OHD3 related to the age of dairy cows. The daily oral administration of 3mg 25-OHD3 in rapeseed oil as well as a treatment with 4 and 6mg included in the feed during the last eight to ten days of gestation resulted in linear dosage- and age-dependent increases in plasma 25-OHD3. After parturition the administration was stopped and blood samples were taken to calculate the plasma half-life. Irrespective of the supplemented dosage, cows starting the 2nd lactation showed a significantly longer plasma half-life of 25-OHD3 than cows starting the 3rd or higher lactation. Age-dependent differences in the increase of plasma 25-OHD3 could already be found before parturition when calcium homeostasis was not yet significantly challenged. Additionally, no correlations between plasma half-life of 25-OHD3 and 1,25-dihydroxyvitamin D3, PTH or the bone resorption marker CrossLaps were observed after parturition. Thus we conclude that the influence of the lactation number on the pharmacokinetics of 25-OHD3 is related directly to the age of the cows. This article is part of a Special Issue entitled 'Vitamin D Workshop'. PMID:23220546

  17. The identification of a selective dopamine D2 partial agonist, D3 antagonist displaying high levels of brain exposure.

    PubMed

    Holmes, Ian P; Blunt, Richard J; Lorthioir, Olivier E; Blowers, Stephen M; Gribble, Andy; Payne, Andrew H; Stansfield, Ian G; Wood, Martyn; Woollard, Patrick M; Reavill, Charlie; Howes, Claire M; Micheli, Fabrizio; Di Fabio, Romano; Donati, Daniele; Terreni, Silvia; Hamprecht, Dieter; Arista, Luca; Worby, Angela; Watson, Steve P

    2010-03-15

    The identification of a highly selective D(2) partial agonist, D(3) antagonist tool molecule which demonstrates high levels of brain exposure and selectivity against an extensive range of dopamine, serotonin, adrenergic, histamine, and muscarinic receptors is described. PMID:20153647

  18. No evidence of association between structural polymorphism at the dopamine D3 receptor locus and alcoholism in the Japanese

    SciTech Connect

    Higuchi, Susumu; Muramatsu, Taro; Matsushita, Sachio; Murayama, Masanobu

    1996-07-26

    Dopaminergic systems mediate reward mechanisms and are involved in reinforcing self-administration of dependence-forming substances, including alcohol. Studies have reported that polymorphisms of the dopamine D2 receptor, whose structure and function are similar to those of the dopamine D3 receptor, increase the susceptibility to alcoholism. The observations led to the examination of the possible association between a structural polymorphism of the D3 receptor gene and alcoholism. Genotyping results, employing a PCR-RFLP method, showed no difference in allele and genotype frequencies of the D3 BalI polymorphism (Ser{sup 9}/Gly{sup 9}) between Japanese alcoholics and controls. Moreover, these frequencies were not altered in alcoholics with inactive aldehyde dehydrogenase-2 (ALDH2), a well-defined negative risk factor for alcoholism. These results strongly suggest that the dopamine D3 receptor is not associated with alcoholism. 19 refs., 1 fig., 1 tab.

  19. Population policy.

    PubMed

    1987-03-01

    Participants in the Seminar on Population Policies for Top-level Policy Makers and Program Managers, meeting in Thailand during January 1987, examined the challenges now facing them regarding the implementation of fertility regulation programs in their respective countries -- Bangladesh, China, India, Indonesia, Malaysia, Nepal, Pakistan, the Philippines, the Republic of Korea, and Thailand. This Seminar was organized to coincide with the completion of an Economic and Social Commission for Asia and the Pacific (ESCAP) study investigating the impact and efficiency of family planning programs in the region. Country studies were reviewed at the Seminar along with policy issues about the status of women, incentive and disincentive programs, and socioeconomic factors affecting fertility. In Bangladesh the government recognizes population growth as its top priority problem related to the socioeconomic development of the country and is working to promote a reorientation strategy from the previous clinic-oriented to a multidimensional family welfare program. China's family planning program seeks to postpone marraige, space the births of children between 3-5 years, and promote the 1-child family. Its goal is to reduce the rate of natural increase from 12/1000 in 1978 to 5/1000 by 1985 and 0 by 2000. India's 7th Five-Year-Plan (1986-90) calls for establishing a 2-child family norm by 2000. In Indonesia the government's population policy includes reducing the rate of population growth, achieving a redistribution of the population, adjusting economic factors, and creating prosperous families. The government of Indonesia reversed its policy to reduce the population growth rate in 1984 and announced its goal of achieving a population of 70 million by 2100 in order to support mass consumption industries. It has created an income tax deduction system favoring large families and maternity benefits for women who have up to 5 children as incentives. Nepal's official policy is to

  20. Localization of dopamine D3 receptors to mesolimbic and D2 receptors to mesostriatal regions of human forebrain.

    PubMed Central

    Murray, A M; Ryoo, H L; Gurevich, E; Joyce, J N

    1994-01-01

    We characterized the binding of [125I]epidepride to dopamine D2-like and D3-like receptors in tissue sections of human striatum. The competition for binding of [125I]epidepride by domperidone, quinpirole, and 7-hydroxy-N,N-di(1-propyl)-2-aminotetralin (7-OH-DPAT) was best fit by assuming one site in the caudate but two sites in nucleus accumbens. Guanosine 5'-[beta, gamma-imido]triphosphate showed a large modulatory influence in agonist inhibition of [125I]epidepride binding in caudate but not in nucleus accumbens. The binding of [125I]epidepride in the presence of 7-OH-DPAT (1000-fold selective for D3-like versus D2-like sites) and domperidone (20-fold selective for D2-like versus D3-like sites) was used to quantify the numbers of D2-like and D3-like receptors in areas of human brain. The distribution of D2-like and D3-like receptors was largely nonoverlapping. Binding of [125I]epidepride to D3-like receptors was negligible in the dorsal striatum but was concentrated in islands of dense binding in the nucleus accumbens and ventral putamen that aligned with acetylcholinesterase-poor striosomes. Binding to D3-like receptors was also enriched in the internal globus pallidus, ventral pallidum, septum, islands of Calleja, nucleus basalis, amygdalostriatal transition nucleus of the amygdala, central nucleus of the amygdala, and ventral tegmental area. Binding of [125I]epidepride to D2 but not D3 receptors was detected in cortex and hippocampus. Images PMID:7972046

  1. The Role of the Vitamin D Receptor and ERp57 in Photoprotection by 1α,25-Dihydroxyvitamin D3

    PubMed Central

    Sequeira, Vanessa B.; Rybchyn, Mark S.; Tongkao-on, Wannit; Gordon-Thomson, Clare; Malloy, Peter J.; Nemere, Ilka; Norman, Anthony W.; Reeve, Vivienne E.; Halliday, Gary M.; Feldman, David

    2012-01-01

    UV radiation (UVR) is essential for formation of vitamin D3, which can be hydroxylated locally in the skin to 1α,25-dihydroxyvitamin D3 [1,25-(OH)2D3]. Recent studies implicate 1,25-(OH)2D3 in reduction of UVR-induced DNA damage, particularly thymine dimers. There is evidence that photoprotection occurs through the steroid nongenomic pathway for 1,25-(OH)2D3 action. In the current study, we tested the involvement of the classical vitamin D receptor (VDR) and the endoplasmic reticulum stress protein 57 (ERp57), in the mechanisms of photoprotection. The protective effects of 1,25-(OH)2D3 against thymine dimers were abolished in fibroblasts from patients with hereditary vitamin D-resistant rickets that expressed no VDR protein, indicating that the VDR is essential for photoprotection. Photoprotection remained in hereditary vitamin D-resistant rickets fibroblasts expressing a VDR with a defective DNA-binding domain or a mutation in helix H1 of the classical ligand-binding domain, both defects resulting in a failure to mediate genomic responses, implicating nongenomic responses for photoprotection. Ab099, a neutralizing antibody to ERp57, and ERp57 small interfering RNA completely blocked protection against thymine dimers in normal fibroblasts. Co-IP studies showed that the VDR and ERp57 interact in nonnuclear extracts of fibroblasts. 1,25-(OH)2D3 up-regulated expression of the tumor suppressor p53 in normal fibroblasts. This up-regulation of p53, however, was observed in all mutant fibroblasts, including those with no VDR, and with Ab099; therefore, VDR and ERp57 are not essential for p53 regulation. The data implicate the VDR and ERp57 as critical components for actions of 1,25-(OH)2D3 against DNA damage, but the VDR does not require normal DNA binding or classical ligand binding to mediate photoprotection. PMID:22322599

  2. Effect of 1,25-dihydroxyvitamin D3 on the Wnt pathway in non-malignant colonic cells.

    PubMed

    Gröschel, Charlotte; Aggarwal, Abhishek; Tennakoon, Samawansha; Höbaus, Julia; Prinz-Wohlgenannt, Maximilian; Marian, Brigitte; Heffeter, Petra; Berger, Walter; Kállay, Enikő

    2016-01-01

    Epidemiological studies suggest a correlation between vitamin D deficiency and colorectal cancer (CRC) incidence. The majority of sporadic tumors develop from premalignant lesions with aberrant activation of the Wnt/β-catenin signaling pathway. The adenoma cell line LT97 harbors an adenomatous polypos