Science.gov

Sample records for atiksu ve biyokatilarinda

  1. Learning the value of VE

    SciTech Connect

    Sperling, R.B.

    1989-03-03

    Describing lessons learned from Value Engineers (VE) studies at a government-funded research laboratory reveals how project managers were encouraged to use VE and how their projects benefited from the VE savings. The five major lessons were: An officer of ''free'' VE is a low-risk incentive to encourage the use of VE; More costs savings can be identified by VE studies than cost reviews or design reviews; Large projects can benefit from repeat VE studies; VE teams can identify surprising savings when allowed to challenge all design criteria; VE programs can be costs effective even though return on investment may vary among projects. 6 tabs.

  2. The VE/CAD synergism

    SciTech Connect

    Sperling, R.B.

    1993-03-19

    Value Engineering (VE) and Computer-Aided Design (CAD) can be used synergistically to reduce costs and improve facilities designs. The cost and schedule impacts of implementing alternative design ideas developed by VE teams can be greatly reduced when the drawings have been produced with interactive CAD systems. To better understand the interrelationship between VE and CAD, the fundamentals of the VE process are explained; and example of a VE proposal is described and the way CAD drawings facilitated its implementation is illustrated.

  3. 23 CFR 627.7 - VE programs.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 23 Highways 1 2014-04-01 2014-04-01 false VE programs. 627.7 Section 627.7 Highways FEDERAL HIGHWAY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION ENGINEERING AND TRAFFIC OPERATIONS VALUE ENGINEERING § 627.7 VE programs. (a) The STA shall establish and sustain a VE program under which VE analyses are...

  4. 23 CFR 627.7 - VE programs.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 23 Highways 1 2013-04-01 2013-04-01 false VE programs. 627.7 Section 627.7 Highways FEDERAL HIGHWAY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION ENGINEERING AND TRAFFIC OPERATIONS VALUE ENGINEERING § 627.7 VE programs. (a) The STA shall establish and sustain a VE program under which VE analyses are...

  5. 47 CFR 97.513 - VE session manager requirements.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 47 Telecommunication 5 2010-10-01 2010-10-01 false VE session manager requirements. 97.513 Section... SERVICES AMATEUR RADIO SERVICE Qualifying Examination Systems § 97.513 VE session manager requirements. (a) A VE session manager may be selected by the VE team for each examination session. The VE session...

  6. 40 CFR 35.926 - Value engineering (VE).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 1 2014-07-01 2014-07-01 false Value engineering (VE). 35.926 Section... engineering (VE). (a) Value engineering proposal. All step 2 grant applications for projects having a... completion of VE analysis and submittal of VE summary reports). (b) Value engineering analysis. For projects...

  7. 40 CFR 35.926 - Value engineering (VE).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 1 2010-07-01 2010-07-01 false Value engineering (VE). 35.926 Section... engineering (VE). (a) Value engineering proposal. All step 2 grant applications for projects having a... completion of VE analysis and submittal of VE summary reports). (b) Value engineering analysis. For projects...

  8. 40 CFR 35.926 - Value engineering (VE).

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 1 2011-07-01 2011-07-01 false Value engineering (VE). 35.926 Section... engineering (VE). (a) Value engineering proposal. All step 2 grant applications for projects having a... completion of VE analysis and submittal of VE summary reports). (b) Value engineering analysis. For projects...

  9. 40 CFR 35.926 - Value engineering (VE).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 1 2012-07-01 2012-07-01 false Value engineering (VE). 35.926 Section... engineering (VE). (a) Value engineering proposal. All step 2 grant applications for projects having a... completion of VE analysis and submittal of VE summary reports). (b) Value engineering analysis. For projects...

  10. 40 CFR 35.926 - Value engineering (VE).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 1 2013-07-01 2013-07-01 false Value engineering (VE). 35.926 Section... engineering (VE). (a) Value engineering proposal. All step 2 grant applications for projects having a... completion of VE analysis and submittal of VE summary reports). (b) Value engineering analysis. For projects...

  11. Using VE to Strategically Plan Our Future

    SciTech Connect

    Margie Jeffs; Lori Braase; Alison Conner; Darcie Martinson; Jodi Grgich

    2009-06-01

    The Value Engineering (VE) Methodology is an effective tool for business or project strategic planning. In conjunction with the “Balanced Scorecard Approach” (Drs. Robert Kaplan, PhD, and David Norton, PhD, from the Balanced Scorecard Collaborative/Palladium Group), function analysis can be used to develop strategy maps and scorecards. The FAST diagram provides an integrated approach to strategy map development by formulating a cause and effect relationship and establishing the “how” and “why” behind the strategy map. By utilizing the VE Job Plan, one is able to move from strategic thinking all the way through to execution of the strategy.

  12. How T cells trigger the dissociation of the endothelial receptor phosphatase VE-PTP from VE-cadherin.

    PubMed

    Vockel, Matthias; Vestweber, Dietmar

    2013-10-03

    The vascular endothelial (VE) receptor protein tyrosine phosphatase (VE-PTP) associates with VE-cadherin and supports endothelial cell contact integrity. This complex is rapidly dissociated by adhesion of leukocytes to endothelial cells or by vascular endothelial growth factor. We have shown recently that this dissociation is indeed required for the opening of endothelial cell contacts during leukocyte extravasation in vivo. The leukocyte receptor and signaling mechanism that stimulates VE-cadherin/VE-PTP dissociation are unknown. Here, we identify vascular cell adhesion molecule 1 as the relevant receptor for lymphocytes in this process. As signaling steps downstream of this receptor, we determined the activation of Rac1, the generation of reactive oxygen species by nicotinamide adenine dinucleotide phosphate oxidase and the activation of the redox-sensitive tyrosine kinase Pyk2 as essential for VE-cadherin/VE-PTP dissociation. These signaling steps are also required for the dissociation induced by VE growth factor. Searching for the molecular mechanism of complex dissociation, we found that a model substrate of VE-PTP represented by a tyrosine-phosphorylated peptide of Tie-2 dissociates VE-PTP from VE-cadherin when introduced with the help of a Tat peptide. We suggest that lymphocyte binding to vascular cell adhesion molecule 1 triggers a signaling process that enables a VE-PTP substrate to dissociate VE-PTP from VE-cadherin, thereby facilitating efficient transmigration.

  13. JoVE: the Journal of Visualized Experiments.

    PubMed

    Vardell, Emily

    2015-01-01

    The Journal of Visualized Experiments (JoVE) is the world's first scientific video journal and is designed to communicate research and scientific methods in an innovative, intuitive way. JoVE includes a wide range of biomedical videos, from biology to immunology and bioengineering to clinical and translation medicine. This column describes the browsing and searching capabilities of JoVE, as well as its additional features (including the JoVE Scientific Education Database designed for students in scientific fields).

  14. The veA gene is necessary for the negative regulation of the veA expression in Aspergillus nidulans.

    PubMed

    Kim, Hyoun-Young; Han, Kap-Hoon; Lee, Mimi; Oh, Miae; Kim, Hee-Seo; Zhixiong, Xie; Han, Dong-Min; Jahng, Kwang-Yeop; Kim, Jong Hwa; Chae, Keon-Sang

    2009-08-01

    The veA gene is one of the key genes in regulating sexual development of Aspergillus nidulans. During the study on the veA gene, it was observed that the veA expression level is slightly higher in a veA1 mutant than in a wild type at 37 degrees C, suggesting that the wild type veA gene is necessary for the negative regulation of the veA expression. In the veA1 mutant, the veA expression was higher than in a wild type grown at 42 degrees C but equal at 30 degrees C. Furthermore, in a veA deletion mutant having its own promoter and the N-terminus of the VeA ORF, expression of the N-terminus by the veA promoter was highly up-regulated, supporting the possibility that the veA gene is important for the negative regulation of the veA expression. Analyses of the lacZ transcript and the beta-galactosidase activity from the reporter strains in the veA1 background, which were constructed by transformation of the lacZ reporter plasmids containing the lacZ gene under the control of the intact or the truncated veA promoters from the -943 to +262 bp region, showed that the truncated promoters produced more veA transcript and higher beta-galactosidase activity than the intact one at 30 degrees C, but equal at 42 degrees C. In addition, the serial-deletion analysis of the veA promoter identified a crucial region in the promoter from -943 to -740 bp for this derepression of the veA expression. Taken together, these results indicated that the veA gene is necessary for the negative regulation of the veA expression. Moreover, the veA expression was derepressed in the light-illuminated condition, where the VeA protein is hardly transported into the nucleus.

  15. 47 CFR 97.513 - VE session manager requirements.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 47 Telecommunication 5 2011-10-01 2011-10-01 false VE session manager requirements. 97.513 Section 97.513 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) SAFETY AND SPECIAL RADIO SERVICES AMATEUR RADIO SERVICE Qualifying Examination Systems § 97.513 VE session manager requirements. (a...

  16. 47 CFR 97.513 - VE session manager requirements.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 47 Telecommunication 5 2014-10-01 2014-10-01 false VE session manager requirements. 97.513 Section 97.513 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) SAFETY AND SPECIAL RADIO SERVICES AMATEUR RADIO SERVICE Qualifying Examination Systems § 97.513 VE session manager requirements. (a...

  17. 47 CFR 97.513 - VE session manager requirements.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 47 Telecommunication 5 2012-10-01 2012-10-01 false VE session manager requirements. 97.513 Section 97.513 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) SAFETY AND SPECIAL RADIO SERVICES AMATEUR RADIO SERVICE Qualifying Examination Systems § 97.513 VE session manager requirements. (a...

  18. 47 CFR 97.513 - VE session manager requirements.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 47 Telecommunication 5 2013-10-01 2013-10-01 false VE session manager requirements. 97.513 Section 97.513 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) SAFETY AND SPECIAL RADIO SERVICES AMATEUR RADIO SERVICE Qualifying Examination Systems § 97.513 VE session manager requirements. (a...

  19. 23 CFR 627.9 - Conducting a VE analysis.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... FEDERAL HIGHWAY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION ENGINEERING AND TRAFFIC OPERATIONS VALUE ENGINEERING § 627.9 Conducting a VE analysis. (a) A VE analysis should be conducted as early as practicable in... that consider alternative construction materials; and (2) Be conducted based on: (i) An engineering and...

  20. 23 CFR 627.9 - Conducting a VE analysis.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... FEDERAL HIGHWAY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION ENGINEERING AND TRAFFIC OPERATIONS VALUE ENGINEERING § 627.9 Conducting a VE analysis. (a) A VE analysis should be conducted as early as practicable in... that consider alternative construction materials; and (2) Be conducted based on: (i) An engineering and...

  1. Naïve Bayes classification in R

    PubMed Central

    2016-01-01

    Naïve Bayes classification is a kind of simple probabilistic classification methods based on Bayes’ theorem with the assumption of independence between features. The model is trained on training dataset to make predictions by predict() function. This article introduces two functions naiveBayes() and train() for the performance of Naïve Bayes classification. PMID:27429967

  2. Corium Spreading Over Concrete: The Vulcano VE-U7 and VE-U8 Tests

    SciTech Connect

    Journeau, Christophe; Boccaccio, Eric; Fouquart, Pascal; Jegou, Claude; Piluso, Pascal

    2002-07-01

    Two experiments have been performed in the VULCANO facility in which prototypic corium has been spread over concrete. In the VE-U7 test, a mixture representative of what can be expected at the opening of EPR reactor-pit gate has been spread on siliceous concrete and on a reference channel in inert refractory ceramic. The spreading progression was not much affected by the presence of concrete and sparging gases. In the VE-U8 test, a UO{sub 2}-ZrO{sub 2} mixture, prototypic of in-vessel corium, has been spread over a lime-siliceous concrete. Although residual power was not simulated in this experiment, up to 2 cm of concrete have been eroded during the test. Results in terms of spreading behaviour, effects of gases, concrete erosion and thermal attack are presented and discussed. (authors)

  3. The nature of very low luminosity objects (VeLLOs)

    NASA Astrophysics Data System (ADS)

    Vorobyov, Eduard I.; Elbakyan, Vardan; Dunham, Michael M.; Guedel, Manuel

    2017-03-01

    Aims: The nature of very low luminosity objects (VeLLOs) with the internal luminosity Lobj ≤ 0.1 L⊙ is investigated by means of numerical modeling coupling the core collapse simulations with the stellar evolution calculations. Methods: The gravitational collapse of a large sample of model cores in the mass range 0.1-2.0 M⊙ is investigated. Numerical simulations were started at the pre-stellar phase and terminated at the end of the embedded phase when 90% of the initial core mass had been accreted onto the forming protostar plus disk system. The disk formation and evolution was studied using numerical hydrodynamics simulations, while the formation and evolution of the central star was calculated using a stellar evolution code. Three scenarios for mass accretion from the disk onto the star were considered: hybrid accretion in which a fraction of accreted energy absorbed by the protostar depends on the accretion rate, hot accretion wherein a fraction of accreted energy is constant, and cold accretion wherein all accretion energy is radiated away. Results: Our conclusions on the nature of VeLLOs depend crucially on the character of protostellar accretion. In the hybrid accretion scenario, most VeLLOs (90.6%) are expected to be the first hydrostatic cores (FHSCs) and only a small fraction (9.4%) are true protostars. In the hot accretion scenario, all VeLLOs are FHSCs due to overly high photospheric luminosity of protostars. In the cold accretion scenario, on the contrary, the majority of VeLLOs belong to the Class I phase of stellar evolution. The reason is that the stellar photospheric luminosity, which sets the floor for the total internal luminosity of a young star, is lower in cold accretion, thus enabling more VeLLOs in the protostellar stage. VeLLOs are relatively rare objects occupying 7%-11% of the total duration of the embedded phase and their masses do not exceed 0.3 M⊙. When compared with published observations inferring a fraction of VeLLOs in the

  4. Regulation of endothelial barrier function by p120-catenin∙VE-cadherin interaction

    PubMed Central

    Garrett, Joshua P.; Lowery, Anthony M.; Adam, Alejandro P.; Kowalczyk, Andrew P.; Vincent, Peter A.

    2017-01-01

    Endothelial p120-catenin (p120) maintains the level of vascular endothelial cadherin (VE-Cad) by inhibiting VE-Cad endocytosis. Loss of p120 results in a decrease in VE-Cad levels, leading to the formation of monolayers with decreased barrier function (as assessed by transendothelial electrical resistance [TEER]), whereas overexpression of p120 increases VE-Cad levels and promotes a more restrictive monolayer. To test whether reduced endocytosis mediated by p120 is required for VE-Cad formation of a restrictive barrier, we restored VE-Cad levels using an endocytic-defective VE-Cad mutant. This endocytic-defective mutant was unable to rescue the loss of TEER associated with p120 or VE-Cad depletion. In contrast, the endocytic-defective mutant was able to prevent sprout formation in a fibrin bead assay, suggesting that p120•VE-Cad interaction regulates barrier function and angiogenic sprouting through different mechanisms. Further investigation found that depletion of p120 increases Src activity and that loss of p120 binding results in increased VE-Cad phosphorylation. In addition, expression of a Y658F–VE-Cad mutant or an endocytic-defective Y658F–VE-Cad double mutant were both able to rescue TEER independently of p120 binding. Our results show that in addition to regulating endocytosis, p120 also allows the phosphorylated form of VE-Cad to participate in the formation of a restrictive monolayer. PMID:27852896

  5. GloVe C++ v. 1.0

    SciTech Connect

    Cox, Jonathan A.

    2015-12-02

    This code implements the GloVe algorithm for learning word vectors from a text corpus. It uses a modern C++ approach. This algorithm is described in the open literature in the referenced paper by Pennington, Jeffrey, Richard Socher, and Christopher D. Manning.

  6. So They've Dictated a Story....Now What?

    ERIC Educational Resources Information Center

    Garman, Dorothy

    1978-01-01

    Suggestions are made for a five-day cycle of activities that can be used with primary students to reinforce language from stories they've dictated. Some activities are teacher-directed, while others can be completed independently. The activities can also be adapted to group-dictated stories. (Author/SJL)

  7. 47 CFR 97.509 - Administering VE requirements.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... SERVICES AMATEUR RADIO SERVICE Qualifying Examination Systems § 97.509 Administering VE requirements. (a) Each examination for an amateur operator license must be administered by a team of at least 3 VEs at an... person who holds an amateur operator license of the class specified below: (i) Amateur Extra, Advanced or...

  8. 47 CFR 97.509 - Administering VE requirements.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... SERVICES AMATEUR RADIO SERVICE Qualifying Examination Systems § 97.509 Administering VE requirements. (a) Each examination for an amateur operator license must be administered by a team of at least 3 VEs at an... person who holds an amateur operator license of the class specified below: (i) Amateur Extra, Advanced or...

  9. 47 CFR 97.509 - Administering VE requirements.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... SERVICES AMATEUR RADIO SERVICE Qualifying Examination Systems § 97.509 Administering VE requirements. (a) Each examination for an amateur operator license must be administered by a team of at least 3 VEs at an... person who holds an amateur operator license of the class specified below: (i) Amateur Extra, Advanced or...

  10. 47 CFR 97.509 - Administering VE requirements.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... SERVICES AMATEUR RADIO SERVICE Qualifying Examination Systems § 97.509 Administering VE requirements. (a) Each examination for an amateur operator license must be administered by a team of at least 3 VEs at an... person who holds an amateur operator license of the class specified below: (i) Amateur Extra, Advanced or...

  11. 47 CFR 97.509 - Administering VE requirements.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... SERVICES AMATEUR RADIO SERVICE Qualifying Examination Systems § 97.509 Administering VE requirements. (a) Each examination for an amateur operator license must be administered by a team of at least 3 VEs at an... person who holds an amateur operator license of the class specified below: (i) Amateur Extra, Advanced or...

  12. Langley VEDIT for NOS/VE usage manual

    NASA Technical Reports Server (NTRS)

    Heaney, Margaret A.

    1987-01-01

    The use of the VEDIT editor on the CDC Network Operating System/Virtual Environment (NOS/VE) is discussed. The VEDIT, a utility, allows a user to edit files line by line (line mode). How to access and the use of VEDIT are explained. The parameters and the format of the individual commands are defined. Examples are included.

  13. Isolation of a Ve homolog, mVe1, and its relationship to Verticillium wilt resistance in Mentha longifolia (L.) Huds.

    PubMed

    Vining, Kelly; Davis, Thomas

    2009-08-01

    As a step toward greater understanding of the genetics of verticillium wilt resistance in plants, we report the sequencing of a candidate wilt resistance gene, mVe1, from the mint diploid model species, Mentha longifolia (Lamiaceae). mVe1 is a putative homolog of tomato (Solanum lycopersicum L.) verticillium wilt (Ve) resistance genes. The mVe1 gene has a coding region of 3,051 bp. The predicted mVe1 protein contains a leucine-rich repeat domain, a common feature of plant disease resistance proteins. We compared 13 mVe1 alleles from three mint species. These alleles shared 96.2-99.6% nucleotide identity. We analyzed four M. longifolia populations segregating with respect to mVe1 alleles and wilt resistance versus susceptibility and found one association between mVe1 genotype and wilt phenotype. We conclude that mVe1 may play a role in mint verticillium wilt resistance, but variation for resistance in our segregating progenies is likely polygenic. Therefore, further investigations of mVe1 and identification of additional candidate genes are both warranted.

  14. Integration of APECS and VE-Suite for Data Overlay

    SciTech Connect

    McCorkel, Doug; Bivins, Gerrick; Jordan, Terry; Bryden, Mark; Zitney, S.E.; Widmann, John; Osawe, Maxwell

    2008-06-01

    In the design of advanced power generation facilities, process simulation tools are being utilized to model plant behavior and quickly analyze results. While such tools enable investigation of crucial aspects of plant design, typical commercial process simulators still do not explore some plant design information, including high-fidelity data from computational fluid dynamics (CFD) models of complex thermal and fluid flow phenomena, economics data used for policy decisions, operational data after the plant is constructed, and as-built information for use in as-designed models. Software tools must be created that allow disparate sources of information to be integrated for facilitating accurate and effective plant design. At the Department of Energy’s (DOE) National Energy Technology Laboratory (NETL), the Advanced Process Engineering Co-Simulator (APECS) has been developed as an integrated software suite that combines process simulation (e.g., Aspen Plus®) and high-fidelity equipment simulation (e.g., FLUENT®). In this paper, the integration of the high-fidelity CFD data with overall process data in a virtual power simulation environment will be described. More specifically, we will highlight VE-Suite, an open-source virtual engineering (VE) software toolkit, and its support of Aspen Plus® Hierarchy blocks via the VE-AspenUnit.

  15. Integration of APECS and VE-Suite for data overlay

    SciTech Connect

    McCorkel, D.; Bivins, G.; Jordan, T.; Bryden, M.; Zitney, S.; Widmann, J.; Osawe, M.

    2008-01-01

    In the design of advanced power generation facilities, process simulation tools are being utilized to model plant behavior and quickly analyze results. While such tools enable investigation of crucial aspects of plant design, typical commercial process simulators still do not explore some plant design information, including high-fidelity data from computational fluid dynamics (CFD) models of complex thermal and fluid flow phenomena, economics data used for policy decisions, operational data after the plant is constructed, and as-built information for use in as-designed models. Software tools must be created that allow disparate sources of information to be integrated for facilitating accurate and effective plant design. At the Department of Energy’s (DOE) National Energy Technology Laboratory (NETL), the Advanced Process Engineering Co-Simulator (APECS) has been developed as an integrated software suite that combines process simulation (e.g., Aspen Plus®) and high-fidelity equipment simulation (e.g., FLUENT®). In this paper, the integration of the high-fidelity CFD data with overall process data in a virtual power simulation environment will be described. More specifically, we will highlight VE-Suite, an open-source virtual engineering (VE) software toolkit, and its support of Aspen Plus® Hierarchy blocks via the VE-AspenUnit.

  16. Did the addition of concurrent chemotherapy to conventional radiotherapy improve survival for patients with HPV+ve and HPV-ve Oropharynx cancer? A population-based study.

    PubMed

    Hall, Stephen F; Liu, Fei-Fei; O'Sullivan, Brian; Shi, Willa; Rohland, Susan; Griffiths, Rebecca; Groome, Patti

    2017-10-10

    In the absence of clear evidence on the efficacy of concurrent chemoradiotherapy (CRT) over conventional radiotherapy (RT) for HPV+ve and for HPV-ve oropharyngeal cancer (OPC), this study compares the treatments and outcomes from pre-CRT years to post-CRT years. A population-based retrospective treatment-effectiveness study based on all patients with OPC treated in Ontario Canada in 1998, 1999, 2003 and 2004. Charts were reviewed, tissue samples were requested and tissue was tested for p16 or in situ hybridisation. Overall survival (OS) and disease-specific survival (DSS) were compared by treatment era and by treatment type for all 1028 patients, for 865 treated for cure and for 610 with HPV status. There was no improvement in OS comparing pre-CRT to post-CRT eras for the HPV+ve patients (P=0.147) or for the HPV-ve patients (P=0.362). There was no difference in OS comparing CRT to RT for the HPV+ve cohort (HR=0.948 (0.642-1.400)) or for the HPV-ve patients (HR=1.083 (0.68-1.727)). In these 'real-world' patients what appeared to be improvements in OS with CRT in clinical trials were confounded by HPV status in Ontario. CRT did not improve outcomes for HPV+ve or for HPV-ve patients.

  17. Ectopic expression of a Ve homolog VvVe gene from Vitis vinifera enhances defense response to Verticillium dahliae infection in tobacco.

    PubMed

    Tang, Juan; Lin, Jing; Yang, Yuwen; Chen, Tianzi; Ling, Xitie; Zhang, Baolong; Chang, Youhong

    2016-01-15

    Verticillium wilt is a soil borne disease that can cause devastating losses to the production of many economically important crops. A Ve1 homologous gene responding to Verticillium dahliae infection was identified in Vitis vinifera cv. "HeiFeng" by semi-quantitative reverse transcription polymerase chain reaction and was designated as VvVe. The overexpression of VvVe in transgenic Nicotiana benthamiana plants significantly enhanced the resistance to isolate V991 of V. dahliae when compared with the wild type plants. The expressions of defense-related genes including the salicylic acid regulated gene pathogen-related 1 (PR1) but not PR2, the ethylene- and jasmonic acid-regulated genes ethylene response factor 1 (ERF1) and lipoxygenase (LOX) were significantly increased due to over expression of VvVe. And greater accumulation of active oxygen, callose and phenylalanine-ammonia lyase were observed in the leaves of transgenic VvVe tobacco plants than the wild type when under infection by V. dahliae. Moreover, the hypersensitive response mimicking cell death was exclusively occurred in the transgenic VvVe tobacco plants but not in the wild type. Taken together, the VvVe gene is a Ve1 like gene which involves in the signal cascade of salicylic acid, jasmonate, and ethylene defense pathways and enhances defense response to V. dahliae infection in the transgenic tobacco. Copyright © 2015 Elsevier B.V. All rights reserved.

  18. Regulation of endothelial barrier function by p120-catenin∙VE-cadherin interaction.

    PubMed

    Garrett, Joshua P; Lowery, Anthony M; Adam, Alejandro P; Kowalczyk, Andrew P; Vincent, Peter A

    2017-01-01

    Endothelial p120-catenin (p120) maintains the level of vascular endothelial cadherin (VE-Cad) by inhibiting VE-Cad endocytosis. Loss of p120 results in a decrease in VE-Cad levels, leading to the formation of monolayers with decreased barrier function (as assessed by transendothelial electrical resistance [TEER]), whereas overexpression of p120 increases VE-Cad levels and promotes a more restrictive monolayer. To test whether reduced endocytosis mediated by p120 is required for VE-Cad formation of a restrictive barrier, we restored VE-Cad levels using an endocytic-defective VE-Cad mutant. This endocytic-defective mutant was unable to rescue the loss of TEER associated with p120 or VE-Cad depletion. In contrast, the endocytic-defective mutant was able to prevent sprout formation in a fibrin bead assay, suggesting that p120•VE-Cad interaction regulates barrier function and angiogenic sprouting through different mechanisms. Further investigation found that depletion of p120 increases Src activity and that loss of p120 binding results in increased VE-Cad phosphorylation. In addition, expression of a Y658F-VE-Cad mutant or an endocytic-defective Y658F-VE-Cad double mutant were both able to rescue TEER independently of p120 binding. Our results show that in addition to regulating endocytosis, p120 also allows the phosphorylated form of VE-Cad to participate in the formation of a restrictive monolayer. © 2017 Garrett et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

  19. Arctic Boreal Vulnerability Experiment (ABoVE) Science Cloud

    NASA Astrophysics Data System (ADS)

    Duffy, D.; Schnase, J. L.; McInerney, M.; Webster, W. P.; Sinno, S.; Thompson, J. H.; Griffith, P. C.; Hoy, E.; Carroll, M.

    2014-12-01

    The effects of climate change are being revealed at alarming rates in the Arctic and Boreal regions of the planet. NASA's Terrestrial Ecology Program has launched a major field campaign to study these effects over the next 5 to 8 years. The Arctic Boreal Vulnerability Experiment (ABoVE) will challenge scientists to take measurements in the field, study remote observations, and even run models to better understand the impacts of a rapidly changing climate for areas of Alaska and western Canada. The NASA Center for Climate Simulation (NCCS) at the Goddard Space Flight Center (GSFC) has partnered with the Terrestrial Ecology Program to create a science cloud designed for this field campaign - the ABoVE Science Cloud. The cloud combines traditional high performance computing with emerging technologies to create an environment specifically designed for large-scale climate analytics. The ABoVE Science Cloud utilizes (1) virtualized high-speed InfiniBand networks, (2) a combination of high-performance file systems and object storage, and (3) virtual system environments tailored for data intensive, science applications. At the center of the architecture is a large object storage environment, much like a traditional high-performance file system, that supports data proximal processing using technologies like MapReduce on a Hadoop Distributed File System (HDFS). Surrounding the storage is a cloud of high performance compute resources with many processing cores and large memory coupled to the storage through an InfiniBand network. Virtual systems can be tailored to a specific scientist and provisioned on the compute resources with extremely high-speed network connectivity to the storage and to other virtual systems. In this talk, we will present the architectural components of the science cloud and examples of how it is being used to meet the needs of the ABoVE campaign. In our experience, the science cloud approach significantly lowers the barriers and risks to organizations

  20. Relation between VE/VCO2 slope and maximum phonation time in chronic heart failure patients.

    PubMed

    Izawa, Kazuhiro P; Watanabe, Satoshi; Brubaker, Peter H; Tochimoto, Shinobu; Hirano, Yasuyuki; Matsushima, Shinya; Suzuki, Tomohiro; Oka, Koichiro; Saito, Takashi; Omori, Yutaka; Suzuki, Kengo; Osada, Naohiko; Omiya, Kazuto; Shimizu, Hiroyuki; Akashi, Yoshihiro J

    2014-12-01

    This study aimed to determine the relation between the regression slope relating minute ventilation to carbon dioxide output (VE/VCO2 slope) and maximum phonation time (MPT), and the MPT required to attain a threshold value for VE/VCO2 slope of ≤ 34 in chronic heart failure (CHF) patients. This cross-sectional study enrolled 115 CHF patients (mean age, 54.5 years; men, 84.9%). VE/VCO2 slope was assessed during cardiopulmonary exercise testing (CPX). Thereafter, patients were divided into 2 groups according to exercise capacity: VE/VCO2 slope ≤ 34 (VE/VCO2 ≤ 34 group, n = 81) and VE/VCO2 slope > 34 (VE/VCO2 > 34 group, n = 34). For MPT measurements, all patients produced a sustained vowel/a:/ for as long as possible during respiratory effort from the seated position. All subjects showed significant negative correlation between VE/VCO2 slope and MPT (r = -0.51, P < 0.001). After adjustment for clinical characteristics, MPT was significantly higher in the VE/VCO2 ≤ 34 group vs VE/VCO2 > 34 group (21.4 ± 6.4 vs 17.4 ± 4.3 s, F = 7.4, P = 0.007). The appropriate MPT cut-off value for identifying a VE/VCO2 slope ≤ 34 was 18.12 seconds. An MPT value of 18.12 seconds may be a useful target value for identifying CHF patients with a VE/VCO2 slope ≤ 34 and for risk management in these patients.

  1. Aspergillus nidulans VeA subcellular localization is dependent on the importin alpha carrier and on light.

    PubMed

    Stinnett, Suzanne M; Espeso, Eduardo A; Cobeño, Laura; Araújo-Bazán, Lidia; Calvo, Ana M

    2007-01-01

    The veA gene is a light-dependent regulator governing development and secondary metabolism in Aspergillus nidulans. We have identified a putative bipartite nuclear localization signal (NLS) motif in the A. nidulans VeA amino acid sequence and demonstrated its functionality when expressed in yeast. Furthermore, migration of VeA to the nucleus was dependent on the importin alpha. This bipartite NLS is also functional when VeA is expressed in A. nidulans. Interestingly, we found that VeA migration to the nucleus is light-dependent. While in the dark VeA is located mainly in the nuclei, under light VeA is found abundantly in the cytoplasm. The VeA1 mutant protein (lacking the first 36 amino acids at the N-terminus) was found predominantly in the cytoplasm independent of illumination. This indicates that the truncated bipartite NLS in VeA1 is not functional and fails to respond to light. These results might explain the lack of the morphological light-dependent response in strains carrying the veA1 allele. We also evaluated the effect of light on production of the mycotoxin sterigmatocystin in a veA wild-type and the veA1 mutant strains and found that the highest amount of toxin was produced by the veA+ strain growing in the dark, condition favouring accumulation of VeA in the nucleus.

  2. VE1 immunohistochemistry predicts BRAF V600E mutation status and clinical outcome in colorectal cancer

    PubMed Central

    Schafroth, Christian; Galván, José A.; Centeno, Irene; Koelzer, Viktor H.; Dawson, Heather E.; Sokol, Lena; Rieger, Gregor; Berger, Martin D.; Hädrich, Marion; Rosenberg, Robert; Nitsche, Ulrich; Schnüriger, Beat; Langer, Rupert; Inderbitzin, Daniel; Lugli, Alessandro; Zlobec, Inti

    2015-01-01

    Aim VE1 is a monoclonal antibody detecting mutant BRAFV600E protein by immunohistochemistry. Here we aim to determine the inter-observer agreement and concordance of VE1 with mutational status, investigate heterogeneity in colorectal cancers and metastases and determine the prognostic effect of VE1 in colorectal cancer patients. Methods Concordance of VE1 with mutational status and inter-observer agreement were tested on a pilot cohort of colorectal cancers (n = 34), melanomas (n = 23) and thyroid cancers (n = 8). Two prognostic cohorts were evaluated (n = 259, Cohort 1 and n = 226, Cohort 2) by multiple-punch tissue microarrays. VE1 staining on preoperative biopsies (n = 118 patients) was compared to expression in resections. Primary tumors and metastases from 13 patients were tested for VE1 heterogeneity using a tissue microarray generated from all available blocks (n = 100 blocks). Results Inter-observer agreement was 100% (kappa = 1.0). Concordance between VE1 and V600E mutation was 98.5%. Cohort 1: VE1 positivity (seen in 13.5%) was associated with older age (p = 0.0175) and MLH1 deficiency (p < 0.0001). Cohort 2: VE1 positivity (seen in 12.8%) was associated with female gender (p = 0.0016), right-sided tumor location (p < 0.0001), higher tumor grade (p < 0.0001) and mismatch repair (MMR)-deficiency (p < 0.0001). In survival analysis, MMR status and postoperative therapy were identified as possible confounding factors. Adjusting for these features, VE1 was an unfavorable prognostic factor. Preoperative biopsy staining matched resections in all cases except one. No heterogeneity was found across any primary/metastatic tumor blocks. Conclusion VE1 is highly concordant for V600E and homogeneously expressed suggesting staining can be analysed on resection specimens, preoperative biopsies, metastatic lesions and tissue microarrays. PMID:26496026

  3. Decreased expression of VE-cadherin and claudin-5 and increased phosphorylation of VE-cadherin in vascular endothelium in nasal polyps.

    PubMed

    Yukitatsu, Yoriko; Hata, Masaki; Yamanegi, Koji; Yamada, Naoko; Ohyama, Hideki; Nakasho, Keiji; Kojima, Yusuke; Oka, Hideki; Tsuzuki, Kenzo; Sakagami, Masafumi; Terada, Nobuyuki

    2013-06-01

    VE-cadherin and claudin-5 are major components of adherens and tight junctions of vascular endothelial cells and a decrease in their expression and an increase in the tyrosine-phosphorylation of VE-cadherin are associated with an increase in endothelial paracellular permeability. To clarify the mechanism underlying the development of edema in nasal polyps, we studied these molecules in polyp microvessels. Normal inferior turbinate mucosal tissues and nasal polyps from patients treated with or without glucocorticoid were stained for VE-cadherin or claudin-5 and CD31 by a double-immunofluorescence method and the immunofluorescence intensities were graded 1-3 with increasing intensity. To correct for differences in fluorescence intensity attributable to a different endothelial area being exposed in a section or to the thickness of a section, the relative immunofluorescence intensity was estimated by dividing the grade of VE-cadherin or claudin-5 by that of CD31 in each microvessel. Tyrosine-phosphorylation of VE-cadherin was examined by Western blot analysis. The relative intensities of VE-cadherin and claudin-5 in the CD31-positive microvessels significantly decreased in the following order; inferior turbinate mucosa, treated polyps and untreated polyps. The ratio of tyrosine-phosphorylated VE-cadherin to VE-cadherin was significantly higher in untreated polyps than in the inferior turbinate mucosa and treated polyps, between which no significant difference in the ratio was seen. Thus, in nasal polyps, the barrier function of endothelial adherens and tight junctions is weakened, although glucocorticoid treatment improves this weakened barrier function.

  4. Rac1 functions as a reversible tension modulator to stabilize VE-cadherin trans-interaction

    PubMed Central

    Daneshjou, Nazila; Sieracki, Nathan; van Nieuw Amerongen, Geerten P.; Conway, Daniel E.; Schwartz, Martin A.

    2015-01-01

    The role of the RhoGTPase Rac1 in stabilizing mature endothelial adherens junctions (AJs) is not well understood. In this paper, using a photoactivatable probe to control Rac1 activity at AJs, we addressed the relationship between Rac1 and the dynamics of vascular endothelial cadherin (VE-cadherin). We demonstrated that Rac1 activation reduced the rate of VE-cadherin dissociation, leading to increased density of VE-cadherin at AJs. This response was coupled to a reduction in actomyosin-dependent tension across VE-cadherin adhesion sites. We observed that inhibiting myosin II directly or through photo-release of the caged Rho kinase inhibitor also reduced the rate of VE-cadherin dissociation. Thus, Rac1 functions by stabilizing VE-cadherin trans-dimers in mature AJs by counteracting the actomyosin tension. The results suggest a new model of VE-cadherin adhesive interaction mediated by Rac1-induced reduction of mechanical tension at AJs, resulting in the stabilization of VE-cadherin adhesions. PMID:25559184

  5. Building Students' Understanding of Quadratic Equation Concept Using Naïve Geometry

    ERIC Educational Resources Information Center

    Fachrudin, Achmad Dhany; Putri, Ratu Ilma Indra; Darmawijoyo

    2014-01-01

    The purpose of this research is to know how Naïve Geometry method can support students' understanding about the concept of solving quadratic equations. In this article we will discuss one activities of the four activities we developed. This activity focused on how students linking the Naïve Geometry method with the solving of the quadratic…

  6. Genetic dissection of Verticillium wilt resistance mediated by tomato Ve1.

    PubMed

    Fradin, Emilie F; Zhang, Zhao; Juarez Ayala, Juan C; Castroverde, Christian D M; Nazar, Ross N; Robb, Jane; Liu, Chun-Ming; Thomma, Bart P H J

    2009-05-01

    Vascular wilt diseases caused by soil-borne pathogens are among the most devastating plant diseases worldwide. The Verticillium genus includes vascular wilt pathogens with a wide host range. Although V. longisporum infects various hosts belonging to the Cruciferaceae, V. dahliae and V. albo-atrum cause vascular wilt diseases in over 200 dicotyledonous species, including economically important crops. A locus responsible for resistance against race 1 strains of V. dahliae and V. albo-atrum has been cloned from tomato (Solanum lycopersicum) only. This locus, known as Ve, comprises two closely linked inversely oriented genes, Ve1 and Ve2, that encode cell surface receptor proteins of the extracellular leucine-rich repeat receptor-like protein class of disease resistance proteins. Here, we show that Ve1, but not Ve2, provides resistance in tomato against race 1 strains of V. dahliae and V. albo-atrum and not against race 2 strains. Using virus-induced gene silencing in tomato, the signaling cascade downstream of Ve1 is shown to require both EDS1 and NDR1. In addition, NRC1, ACIF, MEK2, and SERK3/BAK1 also act as positive regulators of Ve1 in tomato. In conclusion, Ve1-mediated resistance signaling only partially overlaps with signaling mediated by Cf proteins, type members of the receptor-like protein class of resistance proteins.

  7. Tomato Ve disease resistance genes encode cell surface-like receptors

    PubMed Central

    Kawchuk, Lawrence M.; Hachey, John; Lynch, Dermot R.; Kulcsar, Frank; van Rooijen, Gijs; Waterer, Doug R.; Robertson, Albert; Kokko, Eric; Byers, Robert; Howard, Ronald J.; Fischer, Rainer; Prüfer, Dirk

    2001-01-01

    In tomato, Ve is implicated in race-specific resistance to infection by Verticillium species causing crop disease. Characterization of the Ve locus involved positional cloning and isolation of two closely linked inverted genes. Expression of individual Ve genes in susceptible potato plants conferred resistance to an aggressive race 1 isolate of Verticillium albo-atrum. The deduced primary structure of Ve1 and Ve2 included a hydrophobic N-terminal signal peptide, leucine-rich repeats containing 28 or 35 potential glycosylation sites, a hydrophobic membrane-spanning domain, and a C-terminal domain with the mammalian E/DXXXLφ or YXXφ endocytosis signals (φ is an amino acid with a hydrophobic side chain). A leucine zipper-like sequence occurs in the hydrophobic N-terminal signal peptide of Ve1 and a Pro-Glu-Ser-Thr (PEST)-like sequence resides in the C-terminal domain of Ve2. These structures suggest that the Ve genes encode a class of cell-surface glycoproteins with receptor-mediated endocytosis-like signals and leucine zipper or PEST sequences. PMID:11331751

  8. Understanding the Nature of VeLLOs Through Interferometric Millimeter Observations

    NASA Astrophysics Data System (ADS)

    Huard, Tracy L.; Pound, M. W.; Mundy, L. G.; Dunham, M. M.

    2013-01-01

    Since a new class of embedded sources, referred to as Very Low Luminosity Objects (VeLLOs), was discovered using Spitzer Space Telescope observations, the number of known VeLLOs has been slowly growing. Still, their nature remains unclear: they may be progenitors of typical low-mass stars or of brown dwarfs. The VeLLOs with millimeter observations demonstrate that they sustain outflows with a wide range of energetics, suggesting VeLLOs may represent an inhomogeneous group. For example, the large-scale outflow driven by a VeLLO in core IRAM 04191+1522 is three orders of magnitude stronger than the weak, compact outflow driven by VeLLO L1014-IRS, despite these sources having comparable luminosities. We have conducted a survey of eight confirmed and candidate VeLLOs, obtaining CO(2-1) and 1.3-mm continuum CARMA observations, to study their small-scale outflows and inner (< 3000 AU) envelopes. Our observations reveal previously undetected outflows and inner envelopes of 10-200 Jupiter masses. Since these envelopes represent reservoirs for future accretion, we identify which VeLLOs are likely protostars and which are likely proto-brown dwarfs based on these envelope masses.

  9. VE-cadherin interacts with cell polarity protein Pals1 to regulate vascular lumen formation.

    PubMed

    Brinkmann, Benjamin F; Steinbacher, Tim; Hartmann, Christian; Kummer, Daniel; Pajonczyk, Denise; Mirzapourshafiyi, Fatemeh; Nakayama, Masanori; Weide, Thomas; Gerke, Volker; Ebnet, Klaus

    2016-09-15

    Blood vessel tubulogenesis requires the formation of stable cell-to-cell contacts and the establishment of apicobasal polarity of vascular endothelial cells. Cell polarity is regulated by highly conserved cell polarity protein complexes such as the Par3-aPKC-Par6 complex and the CRB3-Pals1-PATJ complex, which are expressed by many different cell types and regulate various aspects of cell polarity. Here we describe a functional interaction of VE-cadherin with the cell polarity protein Pals1. Pals1 directly interacts with VE-cadherin through a membrane-proximal motif in the cytoplasmic domain of VE-cadherin. VE-cadherin clusters Pals1 at cell-cell junctions. Mutating the Pals1-binding motif in VE-cadherin abrogates the ability of VE-cadherin to regulate apicobasal polarity and vascular lumen formation. In a similar way, deletion of the Par3-binding motif at the C-terminus of VE-cadherin impairs apicobasal polarity and vascular lumen formation. Our findings indicate that the biological activity of VE-cadherin in regulating endothelial polarity and vascular lumen formation is mediated through its interaction with the two cell polarity proteins Pals1 and Par3.

  10. VE-cadherin interacts with cell polarity protein Pals1 to regulate vascular lumen formation

    PubMed Central

    Brinkmann, Benjamin F.; Steinbacher, Tim; Hartmann, Christian; Kummer, Daniel; Pajonczyk, Denise; Mirzapourshafiyi, Fatemeh; Nakayama, Masanori; Weide, Thomas; Gerke, Volker; Ebnet, Klaus

    2016-01-01

    Blood vessel tubulogenesis requires the formation of stable cell-to-cell contacts and the establishment of apicobasal polarity of vascular endothelial cells. Cell polarity is regulated by highly conserved cell polarity protein complexes such as the Par3-aPKC-Par6 complex and the CRB3-Pals1-PATJ complex, which are expressed by many different cell types and regulate various aspects of cell polarity. Here we describe a functional interaction of VE-cadherin with the cell polarity protein Pals1. Pals1 directly interacts with VE-cadherin through a membrane-proximal motif in the cytoplasmic domain of VE-cadherin. VE-cadherin clusters Pals1 at cell–cell junctions. Mutating the Pals1-binding motif in VE-cadherin abrogates the ability of VE-cadherin to regulate apicobasal polarity and vascular lumen formation. In a similar way, deletion of the Par3-binding motif at the C-terminus of VE-cadherin impairs apicobasal polarity and vascular lumen formation. Our findings indicate that the biological activity of VE-cadherin in regulating endothelial polarity and vascular lumen formation is mediated through its interaction with the two cell polarity proteins Pals1 and Par3. PMID:27466317

  11. Primate embryogenesis predicts the hallmarks of human naïve pluripotency

    PubMed Central

    Nichols, Jennifer

    2017-01-01

    ABSTRACT Naïve pluripotent mouse embryonic stem cells (ESCs) resemble the preimplantation epiblast and efficiently contribute to chimaeras. Primate ESCs correspond to the postimplantation embryo and fail to resume development in chimaeric assays. Recent data suggest that human ESCs can be ‘reset’ to an earlier developmental stage, but their functional capacity remains ill defined. Here, we discuss how the naïve state is inherently linked to preimplantation epiblast identity in the embryo. We hypothesise that distinctive features of primate development provide stringent criteria to evaluate naïve pluripotency in human and other primate cells. Based on our hypothesis, we define 12 key hallmarks of naïve pluripotency, five of which are specific to primates. These hallmarks may serve as a functional framework to assess human naïve ESCs. PMID:28096211

  12. Alternative Routes to Induce Naïve Pluripotency in Human Embryonic Stem Cells.

    PubMed

    Duggal, Galbha; Warrier, Sharat; Ghimire, Sabitri; Broekaert, Dorien; Van der Jeught, Margot; Lierman, Sylvie; Deroo, Tom; Peelman, Luc; Van Soom, Ann; Cornelissen, Ria; Menten, Björn; Mestdagh, Pieter; Vandesompele, Jo; Roost, Matthias; Slieker, Roderick C; Heijmans, Bastiaan T; Deforce, Dieter; De Sutter, Petra; De Sousa Lopes, Susana Chuva; Heindryckx, Björn

    2015-09-01

    Human embryonic stem cells (hESCs) closely resemble mouse epiblast stem cells exhibiting primed pluripotency unlike mouse ESCs (mESCs), which acquire a naïve pluripotent state. Efforts have been made to trigger naïve pluripotency in hESCs for subsequent unbiased lineage-specific differentiation, a common conundrum faced by primed pluripotent hESCs due to heterogeneity in gene expression existing within and between hESC lines. This required either ectopic expression of naïve genes such as NANOG and KLF2 or inclusion of multiple pluripotency-associated factors. We report here a novel combination of small molecules and growth factors in culture medium (2i/LIF/basic fibroblast growth factor + Ascorbic Acid + Forskolin) facilitating rapid induction of transgene-free naïve pluripotency in hESCs, as well as in mESCs, which has not been shown earlier. The converted naïve hESCs survived long-term single-cell passaging, maintained a normal karyotype, upregulated naïve pluripotency genes, and exhibited dependence on signaling pathways similar to naïve mESCs. Moreover, they undergo global DNA demethylation and show a distinctive long noncoding RNA profile. We propose that in our medium, the FGF signaling pathway via PI3K/AKT/mTORC induced the conversion of primed hESCs toward naïve pluripotency. Collectively, we demonstrate an alternate route to capture naïve pluripotency in hESCs that is fast, reproducible, supports naïve mESC derivation, and allows efficient differentiation. © 2015 AlphaMed Press.

  13. Differential migratory properties of monocytes isolated from human subjects naïve and non-naïve to Cannabis.

    PubMed

    Sexton, Michelle; Silvestroni, Aurelio; Möller, Thomas; Stella, Nephi

    2013-06-01

    This study evaluates the migratory potential of monocytes isolated from two groups of human subjects: naïve and non-naïve to Cannabis. Phytocannabinoids (pCB), the bioactive agents produced by the plant Cannabis, regulate the phenotype and function of immune cells by interacting with CB1 and CB2 receptors. It has been shown that agents influencing the phenotype of circulating monocytes influence the phenotype of macrophages and the outcome of immune responses. To date, nothing is known about the acute and long-term effects of pCB on human circulating monocytes. Healthy subjects were recruited for a single blood draw. Monocytes were isolated, fluorescently labeled and their migration quantified using a validated assay that employs near infrared fluorescence and modified Boyden chambers. CB1 and CB2 receptor mRNA expression was quantified by qPCR. Monocytes from all subjects (n = 10) responded to chemokine (c-c motif) ligand 2 (CCL2) and human serum stimuli. Acute application of pCB significantly inhibited both the basal and CCL2-stimulated migration of monocytes, but only in subjects non-naïve to Cannabis. qPCR analysis indicates that monocytes from subjects non-naïve to Cannabis express significantly more CB1 mRNA. The phenotype of monocytes isolated from subjects non-naïve to Cannabis is significantly different from monocytes isolated from subjects naïve to Cannabis. Only monocytes from subjects non-naïve to Cannabis respond to acute exposure to pCB by reducing their overall migratory capacity. Our study suggests that chronic exposure to Cannabis affects the phenotype of circulating monocytes and accordingly could influence outcome of inflammatory responses occurring in injured tissues.

  14. VeA of Aspergillus niger increases spore dispersing capacity by impacting conidiophore architecture.

    PubMed

    Wang, Fengfeng; Dijksterhuis, Jan; Wyatt, Timon; Wösten, Han A B; Bleichrodt, Robert-Jan

    2015-01-01

    Aspergillus species are highly abundant fungi worldwide. Their conidia are among the most dominant fungal spores in the air. Conidia are formed in chains on the vesicle of the asexual reproductive structure called the conidiophore. Here, it is shown that the velvet protein VeA of Aspergillus niger maximizes the diameter of the vesicle and the spore chain length. The length and width of the conidiophore stalk and vesicle were reduced nearly twofold in a ΔveA strain. The latter implies a fourfold reduced surface area to develop chains of spores. Over and above this, the conidial chain length was approximately fivefold reduced. The calculated 20-fold reduction in formation of conidia by ΔveA fits the 8- to 17-fold decrease in counted spore numbers. Notably, morphology of the ΔveA conidiophores of A. niger was very similar to that of wild-type Aspergillus sydowii. This suggests that VeA is key in conidiophore architecture diversity in the fungal kingdom. The finding that biomass formation of the A. niger ΔveA strain was reduced twofold shows that VeA not only impacts dispersion capacity but also colonization capacity of A. niger.

  15. Mutational analysis of the Ve1 immune receptor that mediates Verticillium resistance in tomato.

    PubMed

    Zhang, Zhao; Song, Yin; Liu, Chun-Ming; Thomma, Bart P H J

    2014-01-01

    Pathogenic Verticillium species are economically important plant pathogens that cause vascular wilt diseases in hundreds of plant species. The Ve1 gene of tomato confers resistance against race 1 strains of Verticillium dahliae and V. albo-atrum. Ve1 encodes an extracellular leucine-rich repeat (eLRR) receptor-like protein (RLP) that serves as a cell surface receptor for recognition of the recently identified secreted Verticillium effector Ave1. To investigate recognition of Ave1 by Ve1, alanine scanning was performed on the solvent exposed β-strand/β-turn residues across the eLRR domain of Ve1. In addition, alanine scanning was also employed to functionally characterize motifs that putatively mediate protein-protein interactions and endocytosis in the transmembrane domain and the cytoplasmic tail of the Ve1 protein. Functionality of the mutant proteins was assessed by screening for the occurrence of a hypersensitive response upon co-expression with Ave1 upon Agrobacterium tumefaciens-mediated transient expression (agroinfiltration). In order to confirm the agroinfiltration results, constructs encoding Ve1 mutants were transformed into Arabidopsis and the transgenes were challenged with race 1 Verticillium. Our analyses identified several regions of the Ve1 protein that are required for functionality.

  16. VE/VCO2 slope and its prognostic value in patients with chronic heart failure.

    PubMed

    Shen, Yuqin; Zhang, Xiaoyu; Ma, Wenlin; Song, Haoming; Gong, Zhu; Wang, Qiang; Che, Lin; Xu, Wenjun; Jiang, Jinfa; Xu, Jiahong; Yan, Wenwen; Zhou, Lin; Ni, Y I; Li, Guanghe; Zhang, Qiping; Wang, Lemin

    2015-04-01

    The minute ventilation/carbon dioxide production (VE/VCO2) slope has been widely demonstrated to have strong prognostic value in patients with chronic heart failure (CHF), and the risk of mortality is believed to increase when the VE/VCO2 slope is >32.8; however, there is little evidence concerning the prognostic value of the VE/VCO2 slope in Chinese patients. In the present study, the prognostic value of the VE/VCO2 slope was investigated in patients with CHF. A total of 258 subjects underwent symptom-limited cardiopulmonary exercise testing (CPET) and were divided into CHF (113 males and 16 females; LVEF <0.49) and control (106 males and 23 females) groups. The cardiac-related events over a median 33.7-month follow-up period subsequent to the CPET were evaluated using receiver operating characteristic curve analysis. The VE/VCO2 slope was significantly different between the CHF and control groups (P<0.001). The area under the curve (AUC) for the VE/VCO2 slope in predicting cardiac-related mortalities in the patients with CHF was 0.670 (P<0.05), and the sensitivity and specificity of the VE/VCO2 slope were 0.667 and 0.620, respectively. The optimal threshold of the VE/VCO2 slope for predicting cardiac-related mortalities in patients with CHF was ≥39.3. The AUC for the VE/VCO2 slope in predicting cardiac-related hospitalizations in patients with CHF was 0.682 (P<0.05), and the sensitivity and specificity of the VE/VCO2 slope were 0.631 and 0.778, respectively. The optimal threshold of the VE/VCO2 slope for predicting cardiac-related hospitalizations in patients with CHF was ≥32.9. In conclusion, ventilatory efficiency decreases in patients with CHF. The VE/VCO2 slope is a strong predictor of cardiac-related mortalities in the patients with CHF analyzed.

  17. Holographic wavefront sensor based on Karhunen-Loève decomposition

    NASA Astrophysics Data System (ADS)

    Anzuola, Esdras; Zepp, Andreas; Gladysz, Szymon; Stein, Karin

    2016-09-01

    In this paper we introduce the use of Karhunen-Loève functions as a basis set to decompose atmospheric phase aberrations in a digital holographic wavefront sensor (HWS). We show that the intermodal crosstalk when using Karhunen-Loève functions is reduced in comparison to the Zernike decomposition. Additionally, the sensor's response showed an improved linearity and better robustness to scintillation. Intermodal crosstalk remains a significant problem for this sensor but operation of an adaptive optics system based on HWS is less challenging when using Karhunen-Loève functions instead of Zernike polynomials.

  18. Thalamic Shape Abnormalities in Antipsychotic Naïve Schizophrenia

    PubMed Central

    Danivas, Vijay; Kalmady, Sunil V.; Venkatasubramanian, Ganesan; Gangadhar, Bangalore N.

    2013-01-01

    Background: Neurodevelopmental hypothesis of schizophrenia states abnormal pruning as one of the pathogenetic mechanism in schizophrenia. Though thalamic volume abnormalities have been documented, the shape differences of thalamus in antipsychotic-free schizophrenia in comparison with age- and sex-matched healthy volunteers need validation. Materials and Methods: We examined antipsychotic naïve schizophrenia patients (n=60) and age- and sex-matched healthy volunteers (n=44). The thalamic shape abnormalities were analyzed from their coded structural magnetic resonance imaging (MRI) data using three-dimensional automated image analysis software, FMRIB's (Oxford Center for the functional MRI of the brain) tools-FIRST (FMRIB's Integrated Registration and Segmentation Tool) by creating deformable mesh model. Correlation with the psychopathology scores was carried out using F-statistics. Results: Patients with schizophrenia showed significant inward deformations in the regions corresponding to anterior, ventromedial, mediodorsal, and pulvinar nuclei. There was a direct correlation between negative syndrome score and the deformation in the right mediodorsal and right pulvinar nuclei. Conclusion: The inward deformations of thalamus in antipsychotic naive schizophrenia patients correspond to those nuclei which have reciprocal connections with frontal, superior temporal, and anterior cingulate regions and support the neurodevelopmental hypothesis of schizophrenia. PMID:23833340

  19. The interplays among technology and content, immersant and VE

    NASA Astrophysics Data System (ADS)

    Song, Meehae; Gromala, Diane; Shaw, Chris; Barnes, Steven J.

    2010-01-01

    The research program aims to explore and examine the fine balance necessary for maintaining the interplays between technology and the immersant, including identifying qualities that contribute to creating and maintaining a sense of "presence" and "immersion" in an immersive virtual reality (IVR) experience. Building upon and extending previous work, we compare sitting meditation with walking meditation in a virtual environment (VE). The Virtual Meditative Walk, a new work-in-progress, integrates VR and biofeedback technologies with a self-directed, uni-directional treadmill. As immersants learn how to meditate while walking, robust, real-time biofeedback technology continuously measures breathing, skin conductance and heart rate. The physiological states of the immersant will in turn affect the audio and stereoscopic visual media through shutter glasses. We plan to test the potential benefits and limitations of this physically active form of meditation with data from a sitting form of meditation. A mixed-methods approach to testing user outcomes parallels the knowledge bases of the collaborative team: a physician, computer scientists and artists.

  20. VeA Regulates Conidiation, Gliotoxin Production, and Protease Activity in the Opportunistic Human Pathogen Aspergillus fumigatus

    PubMed Central

    Dhingra, Sourabh; Andes, David

    2012-01-01

    Invasive aspergillosis by Aspergillus fumigatus is a leading cause of infection-related mortality in immunocompromised patients. In this study, we show that veA, a major conserved regulatory gene that is unique to fungi, is necessary for normal morphogenesis in this medically relevant fungus. Although deletion of veA results in a strain with reduced conidiation, overexpression of this gene further reduced conidial production, indicating that veA has a major role as a regulator of development in A. fumigatus and that normal conidiation is only sustained in the presence of wild-type VeA levels. Furthermore, our studies revealed that veA is a positive regulator in the production of gliotoxin, a secondary metabolite known to be a virulent factor in A. fumigatus. Deletion of veA resulted in a reduction of gliotoxin production with respect to that of the wild-type control. This reduction in toxin coincided with a decrease in gliZ and gliP expression, which is necessary for gliotoxin biosynthesis. Interestingly, veA also influences protease activity in this organism. Specifically, deletion of veA resulted in a reduction of protease activity; this is the first report of a veA homolog with a role in controlling fungal hydrolytic activity. Although veA affects several cellular processes in A. fumigatus, pathogenicity studies in a neutropenic mouse infection model indicated that veA is dispensable for virulence. PMID:23087369

  1. Naïve averaged, naïve pooled, and population pharmacokinetics of orally administered marbofloxacin in juvenile harbor seals.

    PubMed

    KuKanich, Butch; Huff, David; Riviere, Jim E; Papich, Mark G

    2007-02-01

    To determine the pharmacokinetics of marbofloxacin after oral administration in juvenile harbor seals (Phoca vitulina) at a dose of 5 mg/kg (2.3 mg/lb) and to compare pharmacokinetic variables after pharmacokinetic analysis by naïve averaged, naïve pooled, and nonlinear mixed-effects modeling. Original study. Animals-33 male and 22 female juvenile seals being treated for various conditions. Blood collection was limited to < or = 3 samples/seal. Plasma marbofloxacin concentrations were measured via high-pressure liquid chromatography with UV detection. Mean +/- SE dose of marbofloxacin administered was 5.3 +/- 0.1 mg/kg (2.4 +/- 0.05 mg/lb). The terminal half-life, volume of distribution (per bioavailability), and clearance (per bioavailability) were approximately 5 hours, approximately 1.4 L/kg, and approximately 3 mL/min/kg, respectively (values varied slightly with the method of calculation). Maximum plasma concentration and area under the plasma-time concentration curve were approximately 3 microg/mL and 30 h x microg/mL, respectively. Naïve averaged and naïve pooled analysis appeared to yield a better fit to the population, but nonlinear mixed-effects modeling yielded a better fit for individual seals. Values of pharmacokinetic variables were similar regardless of the analytic method used. Pharmacokinetic variability can be assessed with nonlinear mixed-effects modeling, but not with naïve averaged or naïve pooled analysis. Visual observation by experienced trainers revealed no adverse effects in treated seals. Plasma concentrations attained with a dosage of 5 mg/kg every 24 hours would be expected to be efficacious for treatment of infections caused by susceptible bacteria (excluding Pseudomonas aeruginosa).

  2. Deposit information in gasoline engines: Part I. Base oil effects in sequence VE deposits

    SciTech Connect

    Supp, J.A.; Kornbrekke, R.E.; Roby, S.H.

    1994-12-01

    Base oil effects on sludge and deposit formation in the ASTM Sequence VE were studied with blends made using the same American Petroleum Institute (API) SG performance package and the same viscosity improver. One percent of the dispersant was removed from the formulation to accentuate base oil effects. Nine tests on six different 100N base oils were run. Sequence VE test lubricant drain analyses show differences in insolubles, viscosity, and particle size with base stock variations. The most significant base oil factors which can be used to predict Sequence VE sludge ratings are the base oil saturate content, polar content, and volatility. While all oils studied passed the Sequence VE API SG engine varnish and piston varnish requirements, higher levels of poly-nuclear aromatics (PNA`s) are shown to increase the severity of these ratings.

  3. [Effect of dietary VE on the contents of salivary acid and MDA in RBC membrane].

    PubMed

    Wang, F; Dong, Z; Zhang, Y; Chen, Y

    1997-05-01

    Vitamin E can protect membrane from the damage of lipid peroxidation, Salivary acid is the residual of carbohydrate on the membrane. To evaluate the effect of dietary VE on salivary acid, the contents of MDA and salivary acid of erythrocyte (RBC) membrane of rats were measured. The rats were fed with different amounts of dietary VE and stayed at different temperatures. The results revealed that the content of salivary acid of RBC membrane reduced markly (P < 0.01) and the content of MDA of RBC membrane was stable (P > 0.05) after the rats were exposed to cold for 10 days. High dietary VE intake increased the content of salivary acid of RBC membrane (P < 0.01). There was no correlation between the content of salivary acid and MDA of RBC membrane. It suggested that dietary VE could raise the content of salivary acid in RBC membrane, but it can not be explained by the reduction of LPO.

  4. Rab5-mediated VE-cadherin internalization regulates the barrier function of the lung microvascular endothelium

    PubMed Central

    Yang, Junjun; Yao, Wei; Qian, Guisheng; Wei, Zhenghua

    2016-01-01

    The small GTPase Rab5 has been well defined to control the vesicle-mediated plasma membrane protein transport to the endosomal compartment. However, its function in the internalization of vascular endothelial (VE)-cadherin, an important component of adherens junctions, and as a result regulating the endothelial cell polarity and barrier function remain unknown. Here, we demonstrated that lipopolysaccharide (LPS) simulation markedly enhanced the activation and expression of Rab5 in human pulmonary microvascular endothelial cells (HPMECs), which is accompanied by VE-cadherin internalization. In parallel, LPS challenge also induced abnormal cell polarity and dysfunction of the endothelial barrier in HPMECs. LPS stimulation promoted the translocation of VE-cadherin from the plasma membrane to intracellular compartments, and intracellularly expressed VE-cadherin was extensively colocalized with Rab5. Small interfering RNA (siRNA)-mediated depletion of Rab5a expression attenuated the disruption of LPS-induced internalization of VE-cadherin and the disorder of cell polarity. Furthermore, knockdown of Rab5 inhibited the vascular endothelial hyperpermeability and protected endothelial barrier function from LPS injury, both in vitro and in vivo. These results suggest that Rab5 is a critical mediator of LPS-induced endothelial barrier dysfunction, which is likely mediated through regulating VE-cadherin internalization. These findings provide evidence, implicating that Rab5a is a potential therapeutic target for preventing endothelial barrier disruption and vascular inflammation. PMID:26112597

  5. Rab5-mediated VE-cadherin internalization regulates the barrier function of the lung microvascular endothelium.

    PubMed

    Yang, Junjun; Yao, Wei; Qian, Guisheng; Wei, Zhenghua; Wu, Guangyu; Wang, Guansong

    2015-12-01

    The small GTPase Rab5 has been well defined to control the vesicle-mediated plasma membrane protein transport to the endosomal compartment. However, its function in the internalization of vascular endothelial (VE)-cadherin, an important component of adherens junctions, and as a result regulating the endothelial cell polarity and barrier function remain unknown. Here, we demonstrated that lipopolysaccharide (LPS) simulation markedly enhanced the activation and expression of Rab5 in human pulmonary microvascular endothelial cells (HPMECs), which is accompanied by VE-cadherin internalization. In parallel, LPS challenge also induced abnormal cell polarity and dysfunction of the endothelial barrier in HPMECs. LPS stimulation promoted the translocation of VE-cadherin from the plasma membrane to intracellular compartments, and intracellularly expressed VE-cadherin was extensively colocalized with Rab5. Small interfering RNA (siRNA)-mediated depletion of Rab5a expression attenuated the disruption of LPS-induced internalization of VE-cadherin and the disorder of cell polarity. Furthermore, knockdown of Rab5 inhibited the vascular endothelial hyperpermeability and protected endothelial barrier function from LPS injury, both in vitro and in vivo. These results suggest that Rab5 is a critical mediator of LPS-induced endothelial barrier dysfunction, which is likely mediated through regulating VE-cadherin internalization. These findings provide evidence, implicating that Rab5a is a potential therapeutic target for preventing endothelial barrier disruption and vascular inflammation.

  6. Naïve Chicks Prefer Hollow Objects

    PubMed Central

    Schill, Jana; Nencini, Andrea Maria; Vallortigara, Giorgio

    2016-01-01

    Biological predispositions influence approach and avoid responses from the time of birth or hatching. Neonates of species that require parental care (e.g. human babies and chicks of the domestic fowl) are attracted by stimuli associated with animate social partners, such as face-like configurations, biological motion and self-propulsion. The property of being filled is used as a cue of animacy by 8-month-old human infants but it is not known whether this reflects the effect of previous experience. We used chicks of the domestic fowl (Gallus gallus) to investigate whether the property of being filled vs. hollow elicits spontaneous or learned preferences. To this aim we tested preferences of naïve and imprinted chicks for hollow and closed cylinders. Contrary to our expectations, we documented an unlearned attraction for hollow stimuli. The preference for hollow stimuli decreased when chicks were imprinted on filled stimuli but did not increase when chicks were imprinted on hollow stimuli, suggesting that hollowness is not crucial to determine affiliative responses for imprinting objects. When chicks were imprinted on occluded stimuli that could be either filled or hollow, the preference for hollow stimuli emerged again, showing that imprinting does not disrupt the spontaneous preference for hollow objects. Further experiments revealed that hollow objects were mainly attractive by means of depth cues such as darker innards, more than as places to hide or as objects with high contrast. Our findings point to predisposed preferences for hollow objects, and suggest that early predispositions might be driven by factors different from animacy cues. PMID:27851773

  7. Naïve Chicks Prefer Hollow Objects.

    PubMed

    Versace, Elisabetta; Schill, Jana; Nencini, Andrea Maria; Vallortigara, Giorgio

    2016-01-01

    Biological predispositions influence approach and avoid responses from the time of birth or hatching. Neonates of species that require parental care (e.g. human babies and chicks of the domestic fowl) are attracted by stimuli associated with animate social partners, such as face-like configurations, biological motion and self-propulsion. The property of being filled is used as a cue of animacy by 8-month-old human infants but it is not known whether this reflects the effect of previous experience. We used chicks of the domestic fowl (Gallus gallus) to investigate whether the property of being filled vs. hollow elicits spontaneous or learned preferences. To this aim we tested preferences of naïve and imprinted chicks for hollow and closed cylinders. Contrary to our expectations, we documented an unlearned attraction for hollow stimuli. The preference for hollow stimuli decreased when chicks were imprinted on filled stimuli but did not increase when chicks were imprinted on hollow stimuli, suggesting that hollowness is not crucial to determine affiliative responses for imprinting objects. When chicks were imprinted on occluded stimuli that could be either filled or hollow, the preference for hollow stimuli emerged again, showing that imprinting does not disrupt the spontaneous preference for hollow objects. Further experiments revealed that hollow objects were mainly attractive by means of depth cues such as darker innards, more than as places to hide or as objects with high contrast. Our findings point to predisposed preferences for hollow objects, and suggest that early predispositions might be driven by factors different from animacy cues.

  8. Secondary Metabolism and Development Is Mediated by LlmF Control of VeA Subcellular Localization in Aspergillus nidulans

    PubMed Central

    Palmer, Jonathan M.; Theisen, Jeffrey M.; Duran, Rocio M.; Grayburn, W. Scott; Calvo, Ana M.; Keller, Nancy P.

    2013-01-01

    Secondary metabolism and development are linked in Aspergillus through the conserved regulatory velvet complex composed of VeA, VelB, and LaeA. The founding member of the velvet complex, VeA, shuttles between the cytoplasm and nucleus in response to alterations in light. Here we describe a new interaction partner of VeA identified through a reverse genetics screen looking for LaeA-like methyltransferases in Aspergillus nidulans. One of the putative LaeA-like methyltransferases identified, LlmF, is a negative regulator of sterigmatocystin production and sexual development. LlmF interacts directly with VeA and the repressive function of LlmF is mediated by influencing the localization of VeA, as over-expression of llmF decreases the nuclear to cytoplasmic ratio of VeA while deletion of llmF results in an increased nuclear accumulation of VeA. We show that the methyltransferase domain of LlmF is required for function; however, LlmF does not directly methylate VeA in vitro. This study identifies a new interaction partner for VeA and highlights the importance of cellular compartmentalization of VeA for regulation of development and secondary metabolism. PMID:23341778

  9. Discrimination of Stem Cell Status after Subjecting Cynomolgus Monkey Pluripotent Stem Cells to Naïve Conversion

    PubMed Central

    Honda, Arata; Kawano, Yoshihiro; Izu, Haruna; Choijookhuu, Narantsog; Honsho, Kimiko; Nakamura, Tomonori; Yabuta, Yukihiro; Yamamoto, Takuya; Takashima, Yasuhiro; Hirose, Michiko; Sankai, Tadashi; Hishikawa, Yoshitaka; Ogura, Atsuo; Saitou, Mitinori

    2017-01-01

    Experimental animal models have played an indispensable role in the development of human induced pluripotent stem cell (iPSC) research. The derivation of high-quality (so-called “true naïve state”) iPSCs of non-human primates enhances their application and safety for human regenerative medicine. Although several attempts have been made to convert human and non-human primate PSCs into a truly naïve state, it is unclear which evaluation methods can discriminate them as being truly naïve. Here we attempted to derive naïve cynomolgus monkey (Cm) (Macaca fascicularis) embryonic stem cells (ESCs) and iPSCs. Several characteristics of naïve Cm ESCs including colony morphology, appearance of naïve-related mRNAs and proteins, leukaemia inhibitory factor dependency, and mitochondrial respiration were confirmed. Next, we generated Cm iPSCs and converted them to a naïve state. Transcriptomic comparison of PSCs with early Cm embryos elucidated the partial achievement (termed naïve-like) of their conversion. When these were subjected to in vitro neural differentiation, enhanced differentiating capacities were observed after naïve-like conversion, but some lines exhibited heterogeneity. The difficulty of achieving contribution to chimeric mouse embryos was also demonstrated. These results suggest that Cm PSCs could ameliorate their in vitro neural differentiation potential even though they could not display true naïve characteristics. PMID:28349944

  10. VE-cadherin RGD motifs promote metastasis and constitute a potential therapeutic target in melanoma and breast cancers

    PubMed Central

    Bartolomé, Rubén A.; Torres, Sofía; de Val, Soledad Isern; Escudero-Paniagua, Beatriz; Calviño, Eva; Teixidó, Joaquín; Casal, J. Ignacio

    2017-01-01

    We have investigated the role of vascular-endothelial (VE)-cadherin in melanoma and breast cancer metastasis. We found that VE-cadherin is expressed in highly aggressive melanoma and breast cancer cell lines. Remarkably, inactivation of VE-cadherin triggered a significant loss of malignant traits (proliferation, adhesion, invasion and transendothelial migration) in melanoma and breast cancer cells. These effects, except transendothelial migration, were induced by the VE-cadherin RGD motifs. Co-immunoprecipitation experiments demonstrated an interaction between VE-cadherin and α2β1 integrin, with the RGD motifs found to directly affect β1 integrin activation. VE-cadherin-mediated integrin signaling occurred through specific activation of SRC, ERK and JNK, including AKT in melanoma. Knocking down VE-cadherin suppressed lung colonization capacity of melanoma or breast cancer cells inoculated in mice, while pre-incubation with VE-cadherin RGD peptides promoted lung metastasis for both cancer types. Finally, an in silico study revealed the association of high VE-cadherin expression with poor survival in a subset of melanoma patients and breast cancer patients showing low CD34 expression. These findings support a general role for VE-cadherin and other RGD cadherins as critical regulators of lung and liver metastasis in multiple solid tumours. These results pave the way for cadherin-specific RGD targeted therapies to control disseminated metastasis in multiple cancers. PMID:27966446

  11. Structure of artificial and natural VE-cadherin-based adherens junctions.

    PubMed

    Taveau, Jean-Christophe; Dubois, Mathilde; Le Bihan, Olivier; Trépout, Sylvain; Almagro, Sébastien; Hewat, Elizabeth; Durmort, Claire; Heyraud, Stéphanie; Gulino-Debrac, Danielle; Lambert, Olivier

    2008-04-01

    In vascular endothelium, adherens junctions between endothelial cells are composed of VE-cadherin (vascular endothelial cadherin), an adhesive receptor that is crucial for the proper assembly of vascular structures and the maintenance of vascular integrity. As a classical cadherin, VE-cadherin links endothelial cells together by homophilic interactions mediated by its extracellular part and associates intracellularly with the actin cytoskeleton via catenins. Although, from structural crystallographic data, a dimeric structure arranged in a trans orientation has emerged as a potential mechanism of cell-cell adhesion, the cadherin organization within adherens junctions remains controversial. Concerning VE-cadherin, its extracellular part possesses the capacity to self-associate in solution as hexamers consisting of three antiparallel cadherin dimers. VE-cadherin-based adherens junctions were reconstituted in vitro by assembly of a VE-cadherin EC (extracellular repeat) 1-EC4 hexamer at the surfaces of liposomes. The artificial adherens junctions revealed by cryoelectron microscopy appear as a two-dimensional self-assembly of hexameric structures. This cadherin organization is reminiscent of that found in native desmosomal junctions. Further structural studies performed on native VE-cadherin junctions would provide a better understanding of the cadherin organization within adherens junctions. Homophilic interactions between cadherins are strengthened intracellularly by connection to the actin cytoskeleton. Recently, we have discovered that annexin 2, an actin-binding protein connects the VE-cadherin-catenin complex to the actin cytoskeleton. This novel link is labile and promotes the endothelial cell switch from a quiescent to an angiogenic state.

  12. An Overview of the 2017 Airborne Campaign for NASA's Arctic Boreal Vulnerability Experiment (ABoVE)

    NASA Astrophysics Data System (ADS)

    Miller, C. E.; Goetz, S. J.; Griffith, P. C.; Margolis, H. A.; Kasischke, E. S.

    2016-12-01

    Airborne research during ABoVE will link field-based, process-level studies with geospatial data products derived from satellite remote sensing, spanning the critical intermediate space and time scales that are essential for a comprehensive understanding of scaling issues across the ABoVE Study Domain and extrapolation to the pan-Arctic. ABoVE airborne campaigns provide remote sensing data with higher spatial and temporal resolution than available from satellite sensors as well as measurements that are not currently available from space. Addtionally, ABoVE airborne campaigns provide unique opportunities to validate satellite data for northern high latitude ecosystems, develop and advance fundamental remote sensing science, and explore scientific insights from innovative sensor combinations. ABoVE envisions major airborne campaigns in 2017 and 2019 with the potential for less comprehensive bridging activities in 2018. The strategy involves Foundational Measurements made with the NASA facility instruments UAVSAR, AirMOSS LVIS and AVIRIS-NG. These will provide domain-wide sampling and coverage of ABoVE field sites. Additional measurements will be made by other sensors with an emphasis on higher resolution coverage over specific field sites or portions of the experimental domain. The strategy will seek to leverage complementary NASA airborne activities such as ICEBridge and SnowEx, pre-launch airborne acquisitions for NISAR, HyspIRi and ASCENDS, as well as activities sponsored by partner agencies. Coordination with ongoing or planned Canadian airborne remote sensing (eg lidar-based boreal forest inventories) is key to this approach. Selections for participation in the 2017 airborne campaign will be announced in Fall 2016. We will provide an overview of the 2017 campaign structure, timing, the measurements to be acquired, and how these all integrate into the broader ABoVE science strategy.

  13. Interfacing with in-Situ Data Networks during the Arctic Boreal Vulnerability Experiment (ABoVE)

    NASA Astrophysics Data System (ADS)

    McInerney, M.; Griffith, P. C.; Duffy, D.; Hoy, E.; Schnase, J. L.; Sinno, S.; Thompson, J. H.

    2014-12-01

    The Arctic Boreal Vulnerability Experiment (ABoVE) is designed to improve understanding of the causes and impacts of ecological changes in Arctic/boreal regions, and will integrate field-based studies, modeling, and data from airborne and satellite remote sensing. ABoVE will result in a fuller understanding of ecosystem vulnerability and resilience to environmental change in the Arctic and boreal regions of western North America, and provide scientific information required to develop options for societal responses to the impacts of these changes. The studies sponsored by NASA during ABoVE will be coordinated with research and in-situ monitoring activities being sponsored by a number of national and international partners. The NASA Center for Climate Simulation at the Goddard Space Flight Center has partnered with the NASA Carbon Cycle & Ecosystems Office to create a science cloud designed for this field campaign - the ABoVE Science Cloud (ASC). The ASC combines high performance computing with emerging technologies to create an environment specifically designed for large-scale modeling, analysis of remote sensing data, copious disk storage with integrated data management, and integration of core variables from in-situ networks identified by the ABoVE Science Definition Team. In this talk, we will present the scientific requirements driving the development of the ABoVE Science Cloud, discuss the necessary interfaces, both computational and human, with in-situ monitoring networks, and show examples of how the ASC is being used to meet the needs of the ABoVE campaign.

  14. Establishment and Maintenance of the Human Naïve CD4+ T-Cell Compartment

    PubMed Central

    Silva, Susana L.; Sousa, Ana E.

    2016-01-01

    The naïve CD4+ T-cell compartment is considered essential to guarantee immune competence throughout life. Its replenishment with naïve cells with broad diverse receptor repertoire, albeit with reduced self-reactivity, is ensured by the thymus. Nevertheless, cumulative data support a major requirement of post-thymic proliferation both for the establishment of the human peripheral naïve compartment during the accelerated somatic growth of childhood, as well as for its lifelong maintenance. Additionally, a dynamic equilibrium is operating at the cell level to fine-tune the T-cell receptor threshold to activation and survival cues, in order to counteract the continuous naïve cell loss by death or conversion into memory/effector cells. The main players in these processes are low-affinity self-peptide/MHC and cytokines, particularly IL-7. Moreover, although naïve CD4+ T-cells are usually seen as a homogeneous population regarding stage of maturation and cell differentiation, increasing evidence points to a variety of phenotypic and functional subsets with distinct homeostatic requirements. The paradigm of cells committed to a distinct lineage in the thymus are the naïve regulatory T-cells, but other functional subpopulations have been identified based on their time span after thymic egress, phenotypic markers, such as CD31, or cytokine production, namely IL-8. Understanding the regulation of these processes is of utmost importance to promote immune reconstitution in several clinical settings, namely transplantation, persistent infections, and aging. In this mini review, we provide an overview of the mechanisms underlying human naïve CD4+ T-cell homeostasis, combining clinical data, experimental studies, and modeling approaches. PMID:27843891

  15. A Novel Feature Selection Technique for Text Classification Using Naïve Bayes

    PubMed Central

    Dey Sarkar, Subhajit; Goswami, Saptarsi; Agarwal, Aman; Aktar, Javed

    2014-01-01

    With the proliferation of unstructured data, text classification or text categorization has found many applications in topic classification, sentiment analysis, authorship identification, spam detection, and so on. There are many classification algorithms available. Naïve Bayes remains one of the oldest and most popular classifiers. On one hand, implementation of naïve Bayes is simple and, on the other hand, this also requires fewer amounts of training data. From the literature review, it is found that naïve Bayes performs poorly compared to other classifiers in text classification. As a result, this makes the naïve Bayes classifier unusable in spite of the simplicity and intuitiveness of the model. In this paper, we propose a two-step feature selection method based on firstly a univariate feature selection and then feature clustering, where we use the univariate feature selection method to reduce the search space and then apply clustering to select relatively independent feature sets. We demonstrate the effectiveness of our method by a thorough evaluation and comparison over 13 datasets. The performance improvement thus achieved makes naïve Bayes comparable or superior to other classifiers. The proposed algorithm is shown to outperform other traditional methods like greedy search based wrapper or CFS. PMID:27433512

  16. Optimum Vehicle Component Integration with InVeST (Integrated Vehicle Simulation Testbed)

    SciTech Connect

    Ng, W; Paddack, E; Aceves, S

    2001-12-27

    We have developed an Integrated Vehicle Simulation Testbed (InVeST). InVeST is based on the concept of Co-simulation, and it allows the development of virtual vehicles that can be analyzed and optimized as an overall integrated system. The virtual vehicle is defined by selecting different vehicle components from a component library. Vehicle component models can be written in multiple programming languages running on different computer platforms. At the same time, InVeST provides full protection for proprietary models. Co-simulation is a cost-effective alternative to competing methodologies, such as developing a translator or selecting a single programming language for all vehicle components. InVeST has been recently demonstrated using a transmission model and a transmission controller model. The transmission model was written in SABER and ran on a Sun/Solaris workstation, while the transmission controller was written in MATRIXx and ran on a PC running Windows NT. The demonstration was successfully performed. Future plans include the applicability of Co-simulation and InVeST to analysis and optimization of multiple complex systems, including those of Intelligent Transportation Systems.

  17. Establishment of cell-cell junctions depends on the oligomeric states of VE-cadherin

    PubMed Central

    Bibert, Stéphanie; Ayari, Hélène; Riveline, Daniel; Concord, Evelyne; Hermant, Bastien; Vernet, Thierry; Gulino-Debrac, Danièle

    2008-01-01

    Specifically expressed at intercellular adherens junctions of endothelial cells, VE-cadherin is a receptor that exhibits particular self-association properties. Indeed, in vitro studies demonstrated that the extracellular part of VE-cadherin elaborates Ca++-dependent hexameric structures. We hypothesized that this assembly could be at the basis of a new cadherin-mediated cell-cell adhesion mechanism. To verify this assumption, we first demonstrated that VE-cadherin can elaborate hexamers at the cell surface of confluent endothelial cells. Second, mutations were introduced within the extracellular part of VE-cadherin to destabilize the hexamer. Following an in vitro screening, three mutants were selected, among which, one is able to elaborate only dimers. The selected mutations were expressed as C-terminal Green Fluorescent Protein fusions in CHO cells. Despite their capacity to elaborate nascent cell-cell contacts, the mutants seem to be rapidly degraded and or internalized. Altogether, our results suggest that the formation of VE-cadherin hexamers protects this receptor and might allow the elaboration of mature endothelial cell-cell junctions. PMID:18343874

  18. First-year medical students' naïve beliefs about respiratory physiology.

    PubMed

    Badenhorst, Elmi; Mamede, Silvia; Abrahams, Amaal; Bugarith, Kishor; Friedling, Jacqui; Gunston, Geney; Kelly-Laubscher, Roisin; Schmidt, Henk G

    2016-09-01

    The present study explored the nature and frequency of physiology naïve beliefs by investigating novices' understanding of the respiratory system. Previous studies have shown considerable misconceptions related to physiology but focused mostly on specific physiological processes of normal respiration. Little is known about novices' broader understanding of breathing in a clinical context. Our study hypothesized that naïve beliefs could hamper participants' ability to understand the interrelatedness of respiratory structures and functions related to breathing during a clinical complication. The study entailed both quantitative and qualitative foci. A two-tier test was designed and administered to 211 first-year medical students. Participants were asked to choose the correct answer out of a set of four options and to substantiate their choices. Questions were purposefully left open to elicit a wide range of responses. Statistical analysis (SPSS) was done to evaluate the frequency of naïve beliefs. Thematic analysis was used to determine themes within the raw data. The majority of participants selected incorrect answers in the multiple-choice question part of the questionnaire. Results from the thematic analysis yielded a considerable range of naïve beliefs about gas exchange, foundational physics, airflow, anatomic structures, and breathing pathways. An awareness of the existence of such naive beliefs in respiratory physiology will allow educators to address them in their teaching and thereby prevent naïve beliefs transforming into misconceptions. Copyright © 2016 The American Physiological Society.

  19. Vascular endothelial tyrosine phosphatase (VE-PTP)-null mice undergo vasculogenesis but die embryonically because of defects in angiogenesis

    PubMed Central

    Dominguez, Melissa G.; Hughes, Virginia C.; Pan, Li; Simmons, Mary; Daly, Christopher; Anderson, Keith; Noguera-Troise, Irene; Murphy, Andrew J.; Valenzuela, David M.; Davis, Samuel; Thurston, Gavin; Yancopoulos, George D.; Gale, Nicholas W.

    2007-01-01

    Development of the vascular system depends on the highly coordinated actions of a variety of angiogenic regulators. Several of these regulators are members of the tyrosine kinase superfamily, including VEGF receptors and angiopoietin receptors, Tie1 and Tie2. Tyrosine kinase signaling is counter-regulated by the activity of tyrosine phosphatases, including vascular endothelial protein tyrosine phosphatase (VE-PTP), which has previously been shown to modulate Tie2 activity. We generated mice in which VE-PTP is replaced with a reporter gene. We confirm that VE-PTP is expressed in endothelium and also show that VE-PTP is highly expressed in the developing outflow tract of the heart and later is expressed in developing heart valves. Vasculogenesis occurs normally in mice lacking VE-PTP; however, angiogenesis is abnormal. Angiogenic defects in VE-PTP-null mice were most pronounced in the yolk sac and include a complete failure to elaborate the primitive vascular scaffold into higher-order branched arteries, veins, and capillaries. VE-PTP continues to be expressed into adulthood in the vasculature and heart valves, suggesting later roles in vascular development or homeostasis. VE-PTP is also expressed in the vasculature of growing tumors, suggesting that VE-PTP may be a new potential target for angiogenic therapies. PMID:17360632

  20. Nitric oxide disrupts VE-cadherin complex in murine microvascular endothelial cells.

    PubMed

    González, D; Herrera, B; Beltrán, A; Otero, K; Quintero, G; Rojas, A

    2003-04-25

    Vascular endothelial cadherin (VE-cadherin), which is localized at adherent junctions, is involved in the control of vascular permeability. A growing body of evidence indicates that NO modulates the movement of fluid and proteins out of the vasculature. In this paper, we investigated whether NO can disrupt the VE-cadherin complex. We found that treatment with two NO donors (SIN-1 and SNAP) markedly reduced the amount of VE-cadherin in a murine microvascular endothelial cell line (H5V) as demonstrated by immunoprecipitation analysis, cellular ELISA, and Northern blot analysis. Beta- and gamma-catenins were also found to be affected by the two NO donors. Moreover, the disruption of the complex, induced by NO donors, correlated with increases in vascular permeability using both in vivo and in vitro models. These results clearly demonstrate a role for NO in vascular permeability.

  1. VeA and LaeA transcriptional factors regulate ochratoxin A biosynthesis in Aspergillus carbonarius.

    PubMed

    Crespo-Sempere, A; Marín, S; Sanchis, V; Ramos, A J

    2013-09-16

    Ochratoxin A (OTA) is a mycotoxin with nephrotoxic, teratogenic and immunotoxic properties which represents a serious risk for human and animal health. Aspergillus carbonarius is considered the main OTA-producing species in grapes and products such as raisins, wine or juices, although it has also been isolated from coffee, cocoa and cereals. Till now not much information is available about regulatory mechanisms of OTA production by A. carbonarius. A better understanding of how environmental factors influence OTA production and which genes are involved in its regulation could help us design new control strategies. In this study, we have evaluated the role of VeA and LaeA transcriptional factors, which have been shown to regulate secondary metabolism in response to light in A. carbonarius. To this aim, veA and laeA genes were deleted in an ochratoxigenic A. carbonarius strain by targeted gene replacement using Agrobacterium tumefaciens-mediated transformation. Loss of veA and laeA in A. carbonarius yields to an organism with slight differences in vegetative growth but a strong reduction in conidial production. A drastic decrease of OTA production that ranged from 68.5 to 99.4% in ΔveA and ΔlaeA null mutants was also observed, which was correlated with a downregulation of a nonribosomal peptide synthetase involved in OTA biosynthesis. These findings suggest that VeA and LaeA have an important role regulating conidiation and OTA biosynthesis in response to light in A. carbonarius in a similar way to other fungi where functions of VeA and LaeA have been previously described. This is the first report of a transcriptional factor governing the production of OTA by A. carbonarius. © 2013 Elsevier B.V. All rights reserved.

  2. Lessons about Virtual-Environment Software Systems from 20 years of VE building

    PubMed Central

    Taylor, Russell M.; Jerald, Jason; VanderKnyff, Chris; Wendt, Jeremy; Borland, David; Marshburn, David; Sherman, William R.; Whitton, Mary C.

    2010-01-01

    What are desirable and undesirable features of virtual-environment (VE) software architectures? What should be present (and absent) from such systems if they are to be optimally useful? How should they be structured? To help answer these questions we present experience from application designers, toolkit designers, and VE system architects along with examples of useful features from existing systems. Topics are organized under the major headings of: 3D space management, supporting display hardware, interaction, event management, time management, computation, portability, and the observation that less can be better. Lessons learned are presented as discussion of the issues, field experiences, nuggets of knowledge, and case studies. PMID:20567602

  3. Stüve-Wiedemann Syndrome: Update on Clinical and Genetic Aspects

    PubMed Central

    Romeo Bertola, Débora; Honjo, Rachel S.; Baratela, Wagner A.R.

    2016-01-01

    Stüve-Wiedemann syndrome is a rare autosomal recessive disorder characterized by bowed long bones, joint restrictions, dysautonomia, and respiratory and feeding difficulties, leading to death in the neonatal period and infancy in several occasions. Since the first cases in 1971, much has been learned about this condition, including its molecular basis - mutations in the leukemia inhibitory factor receptor gene (LIFR) -, natural history and management possibilities. This review aims to highlight the clinical aspects, radiological features, molecular findings, and management strategies in Stüve-Wiedemann syndrome. PMID:27194968

  4. Virtual endoscopy (VE) of the basal cisterns: its value in planning the neurosurgical approach.

    PubMed

    Boor, S; Resch, K M; Perneczky, A; Stoeter, P

    1998-12-01

    Virtual endoscopy (VE) is a postprocessing technique based on a diverging ray casting algorithm to create perspective 3 D-images from computed tomographic angiography (CTA) and high resolution magnetic resonance imaging (MR) data. By applying VE to aneurysms, tumors, and vascular compression syndromes within the basal cisterns, endoscopic-like views of these structures are achieved from an intracisternal point above the cranial base. These views closely simulate the surgeon's impression during intraoperative endoscopy or microscopy and facilitate preoperative planning of different approaches.

  5. 76 FR 24883 - DNB Exports LLC, and AFI Elektromekanikanik Ve Elektronik San. Tic. Ltd. Sti. v. Barsan Global...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-05-03

    ... From the Federal Register Online via the Government Publishing Office FEDERAL MARITIME COMMISSION DNB Exports LLC, and AFI Elektromekanikanik Ve Elektronik San. Tic. Ltd. Sti. v. Barsan Global... Commission (``Commission'') by DNB Exports LLC (``DNB''), and AFI Elektromekanikanik Ve Elektronik San. Tic...

  6. The utility of BRAF V600E mutation-specific antibody VE1 for the diagnosis of hairy cell leukemia.

    PubMed

    Uppal, Guldeep; Ly, Vandi; Wang, Zi-Xuan; Bajaj, Renu; Solomides, Charalambos C; Banks, Peter M; Medeiros, L Jeffrey; Peiper, Stephen C; Gong, Jerald Z

    2015-01-01

    BRAF V600E mutation is characteristic of hairy cell leukemia (HCL). A V600E mutation-specific antibody, VE1, has been recently developed. We studied the diagnostic utility of this antibody in HCL and compared it with other B-cell neoplasms. VE1 activity was assessed using immunohistochemistry in 90 mature B-cell neoplasms, including HCL (n = 17), HCL variant (n = 6), chronic lymphocytic leukemia (CLL) (n = 20), and 47 other B-cell lymphomas. Most (87/90) specimens were formalin-fixed, paraffin-embedded bone marrow (BM) biopsy specimens decalcified in either hydrochloric acid or formic acid. VE1 was positive in 15 (88%) cases of HCL and two (10%) cases of CLL and was negative in all other tumors assessed. The VE1-positive HCL cases showed uniform staining in all tumor cells, but intensity was variable. The two VE1-negative HCL cases had BRAF V600 mutations proven by molecular analysis. The two CLL cases positive with VE1 showed an atypical staining pattern with expression in a minority of lymphoma cells. Immunohistochemistry using the VE1 antibody had a sensitivity of 88% and a specificity of 97% for HCL. VE1 immunohistochemistry is a useful and convenient surrogate for detecting BRAF V600E mutation in BM biopsy specimens decalcified with hydrochloric or formic acid-based solutions. Copyright© by the American Society for Clinical Pathology.

  7. Broad taxonomic characterization of Verticillium wilt resistance genes reveals an ancient origin of the tomato Ve1 immune receptor.

    PubMed

    Song, Yin; Zhang, Zhao; Seidl, Michael F; Majer, Aljaz; Jakse, Jernej; Javornik, Branka; Thomma, Bart P H J

    2017-02-01

    Plant-pathogenic microbes secrete effector molecules to establish themselves on their hosts, whereas plants use immune receptors to try and intercept such effectors in order to prevent pathogen colonization. The tomato cell surface-localized receptor Ve1 confers race-specific resistance against race 1 strains of the soil-borne vascular wilt fungus Verticillium dahliae which secrete the Ave1 effector. Here, we describe the cloning and characterization of Ve1 homologues from tobacco (Nicotiana glutinosa), potato (Solanum tuberosum), wild eggplant (Solanum torvum) and hop (Humulus lupulus), and demonstrate that particular Ve1 homologues govern resistance against V. dahliae race 1 strains through the recognition of the Ave1 effector. Phylogenetic analysis shows that Ve1 homologues are widely distributed in land plants. Thus, our study suggests an ancient origin of the Ve1 immune receptor in the plant kingdom.

  8. HIV integrase variability and genetic barrier in antiretroviral naïve and experienced patients

    PubMed Central

    2011-01-01

    Background HIV-1 integrase (IN) variability in treatment naïve patients with different HIV-1 subtypes is a major issue. In fact, the effect of previous exposure to antiretrovirals other than IN inhibitors (INI) on IN variability has not been satisfactorily defined. In addition, the genetic barrier for specific INI resistance mutations remains to be calculated. Methods IN variability was analyzed and compared with reverse transcriptase (RT) and protease (PR) variability in 41 treatment naïve and 54 RT inhibitor (RTI) and protease inhibitor (PRI) experienced patients from subjects infected with subtype B and non-B strains. In addition, four HIV-2 strains were analyzed in parallel. Frequency and distribution of IN mutations were compared between HAART-naïve and RTI/PI-experienced patients; the genetic barrier for 27 amino acid positions related to INI susceptibility was calculated as well. Results Primary mutations associated with resistance to INI were not detected in patients not previously treated with this class of drug. However, some secondary mutations which have been shown to contribute to INI resistance were found. Only limited differences in codon usage distribution between patient groups were found. HIV-2 strains from INI naïve patients showed the presence of both primary and secondary resistance mutations. Conclusion Exposure to antivirals other than INI does not seem to significantly influence the emergence of mutations implicated in INI resistance. HIV-2 strain might have reduced susceptibility to INI. PMID:21453487

  9. Microencapsulation of an anti-VE-cadherin antibody secreting 1B5 hybridoma cells.

    PubMed

    Orive, G; Hernández, R M; Gascón, A R; Igartua, M; Rojas, A; Pedraz, J L

    2001-12-01

    Accumulating experimental evidence demonstrates that tumor growth and lethality are dependent on angiogenesis. Based on this concept, there is growing interest in the use of antiangiogenesis agents to inhibit tumor expansion. Compelling data implicate vascular endothelium (VE)-cadherin (an endothelium specific protein) as a key factor in the last step of angiogenesis, where the endothelial cells join one to each other and form microtubules (future blood vessels). We propose a novel approach to the inhibition of angiogenesis by immobilizing VE-cadherin-secreting hybridoma cells in alginate-agarose microcapsules. Hybridoma cells can be protected with biocompatible and semipermeable membranes that permit exit of anti-VE-cadherin monoclonal antibodies but not entry of cellular immune mediators. Stability studies were performed to select the suitable microcapsule for cell immobilization. Alginate and agarose solid beads coated with poly-L-lysine and alginate were chosen according to their stability and diffusional properties. 1B5 hybridoma cells were grown within the microcapsules and secreted anti-VE-cadherin antibodies during the 9 days of culture, reaching a cumulative concentration of 1.7 microg/mL. This antibody concentration inhibited microtubule formation (87%) in the in vitro angiogenesis Matrigel assay. Moreover, the antiangiogenic effect observed was antibody concentration related. These findings open a new alternative for the inhibition or prevention of angiogenesis and demonstrates the feasibility of using microencapsulated cells as a control-drug delivery system. Copyright 2001 John Wiley & Sons, Inc.

  10. Using Drama to Promote Argumentation in Science Education: The Case of "Should've"

    ERIC Educational Resources Information Center

    Archila, Pablo Antonio

    2017-01-01

    The purpose of this study was to use drama as a springboard for promoting argumentation among 91 first-semester undergraduate medical students (56 females and 35 males, 16-30 years old) in Colombia during a complete teaching-learning sequence (TLS) supervised by the same teacher. The drama used was the play "Should've," written by Nobel…

  11. "You've Got the Power": Documentary Film as a Tool of Environmental Adult Education

    ERIC Educational Resources Information Center

    Clover, Darlene E.

    2011-01-01

    Educators call for more creative means to combat the moribund narratives of contemporary environmentalism. Using visual methodology and environmental adult education theory, this article discusses how a documentary film titled "You've Got the Power" works to pose questions about complex environmental issues and develop critical thinking…

  12. Behaviour of equine influenza virus in a naïve population: a practitioner's perspective.

    PubMed

    Major, D A; Jones, B

    2011-07-01

    We describe the behaviour of equine influenza (EI) virus infection in a naïve population as observed by equine veterinary practitioners. The clinical signs displayed by infected horses and the highly contagious nature of the disease are discussed, as well as the treatment and management of infected horses.

  13. Orbital frontal cortex in treatment naïve pediatric obsessive-compulsive disorder

    PubMed Central

    MacMaster, Frank; Vora, Anvi; Easter, Phillip; Rix, Carrie; Rosenberg, David

    2010-01-01

    The orbital frontal cortex (OFC) has been implicated in obsessive-compulsive disorder (OCD). Twenty-eight treatment-naïve pediatric OCD patients and twenty-one controls were examined using magnetic resonance imaging. OCD patients had larger right but not left OFC white matter volume than controls. This is fresh evidence implicating white matter in OCD. PMID:20074911

  14. Informed and Uninformed Naïve Assessment Constructors' Strategies for Item Selection

    ERIC Educational Resources Information Center

    Fives, Helenrose; Barnes, Nicole

    2017-01-01

    We present a descriptive analysis of 53 naïve assessment constructors' explanations for selecting test items to include on a summative assessment. We randomly assigned participants to an informed and uninformed condition (i.e., informed participants read an article describing a Table of Specifications). Through recursive thematic analyses of…

  15. First-Year Medical Students' Naïve Beliefs about Respiratory Physiology

    ERIC Educational Resources Information Center

    Badenhorst, Elmi; Mamede, Silvia; Abrahams, Amaal; Bugarith, Kishor; Friedling, Jacqui; Gunston, Geney; Kelly-Laubscher, Roisin; Schmidt, Henk G.

    2016-01-01

    The present study explored the nature and frequency of physiology naïve beliefs by investigating novices' understanding of the respiratory system. Previous studies have shown considerable misconceptions related to physiology but focused mostly on specific physiological processes of normal respiration. Little is known about novices' broader…

  16. Naïve prey exhibit reduced antipredator behavior and survivorship.

    PubMed

    Martin, Charles W

    2014-01-01

    Prey naiveté has been hypothesized to be one of the major driving forces behind population declines following the introduction of novel predators or release of inexperienced prey into predator rich environments. In these cases, naïve prey may lack sufficient antipredator behavior and, as a result, suffer increased mortality. Despite this, some evidence suggests that many prey utilize a generalized response to predators. Here, the naiveté hypothesis is tested using a predator-prey pair sharing an evolutionary history: the red swamp crayfish (Procambarus clarkii Girard, 1852) and largemouth bass (Micropterus salmoides Lacépède, 1802). Using farm-reared, naïve crayfish and wild-caught, experienced individuals, laboratory experiments demonstrated that naïve, farmed crayfish lack behavioral responses to chemical cues from bass, both in terms of movement and use of structural refuge. In contrast, experienced crayfish responded strongly to the same cues. In a subsequent field tethering experiment, these naïve individuals suffered a three-fold increase in predation rate. Based on these results, recognition of predators may not be innate in all prey, and previous experience and learning likely play a key role in the development of antipredator behavior.

  17. "You've Got the Power": Documentary Film as a Tool of Environmental Adult Education

    ERIC Educational Resources Information Center

    Clover, Darlene E.

    2011-01-01

    Educators call for more creative means to combat the moribund narratives of contemporary environmentalism. Using visual methodology and environmental adult education theory, this article discusses how a documentary film titled "You've Got the Power" works to pose questions about complex environmental issues and develop critical thinking…

  18. Targeting VE-PTP activates TIE2 and stabilizes the ocular vasculature

    PubMed Central

    Shen, Jikui; Frye, Maike; Lee, Bonnie L.; Reinardy, Jessica L.; McClung, Joseph M.; Ding, Kun; Kojima, Masashi; Xia, Huiming; Seidel, Christopher; Silva, Raquel Lima e; Dong, Aling; Hackett, Sean F.; Wang, Jiangxia; Howard, Brian W.; Vestweber, Dietmar; Kontos, Christopher D.; Peters, Kevin G.; Campochiaro, Peter A.

    2014-01-01

    Retinal and choroidal neovascularization (NV) and vascular leakage contribute to visual impairment in several common ocular diseases. The angiopoietin/TIE2 (ANG/TIE2) pathway maintains vascular integrity, and negative regulators of this pathway are potential therapeutic targets for these diseases. Here, we demonstrated that vascular endothelial-protein tyrosine phosphatase (VE-PTP), which negatively regulates TIE2 activation, is upregulated in hypoxic vascular endothelial cells, particularly in retinal NV. Intraocular injection of an anti–VE-PTP antibody previously shown to activate TIE2 suppressed ocular NV. Furthermore, a small-molecule inhibitor of VE-PTP catalytic activity (AKB-9778) activated TIE2, enhanced ANG1-induced TIE2 activation, and stimulated phosphorylation of signaling molecules in the TIE2 pathway, including AKT, eNOS, and ERK. In mouse models of neovascular age-related macular degeneration, AKB-9778 induced phosphorylation of TIE2 and strongly suppressed NV. Ischemia-induced retinal NV, which is relevant to diabetic retinopathy, was accentuated by the induction of ANG2 but inhibited by AKB-9778, even in the presence of high levels of ANG2. AKB-9778 also blocked VEGF-induced leakage from dermal and retinal vessels and prevented exudative retinal detachments in double-transgenic mice with high expression of VEGF in photoreceptors. These data support targeting VE-PTP to stabilize retinal and choroidal blood vessels and suggest that this strategy has potential for patients with a wide variety of retinal and choroidal vascular diseases PMID:25180601

  19. Naïve prey exhibit reduced antipredator behavior and survivorship

    PubMed Central

    2014-01-01

    Prey naiveté has been hypothesized to be one of the major driving forces behind population declines following the introduction of novel predators or release of inexperienced prey into predator rich environments. In these cases, naïve prey may lack sufficient antipredator behavior and, as a result, suffer increased mortality. Despite this, some evidence suggests that many prey utilize a generalized response to predators. Here, the naiveté hypothesis is tested using a predator–prey pair sharing an evolutionary history: the red swamp crayfish (Procambarus clarkii Girard, 1852) and largemouth bass (Micropterus salmoides Lacépède, 1802). Using farm-reared, naïve crayfish and wild-caught, experienced individuals, laboratory experiments demonstrated that naïve, farmed crayfish lack behavioral responses to chemical cues from bass, both in terms of movement and use of structural refuge. In contrast, experienced crayfish responded strongly to the same cues. In a subsequent field tethering experiment, these naïve individuals suffered a three-fold increase in predation rate. Based on these results, recognition of predators may not be innate in all prey, and previous experience and learning likely play a key role in the development of antipredator behavior. PMID:25392763

  20. The Karhunen-Loève Transform for bioastronomy and SETI

    NASA Astrophysics Data System (ADS)

    Maccone, C.

    2006-02-01

    I present here a short description of the Karhunen-Loève Transform (KLT) used to detect very weak radio signals over narrow-band and wide-band extraterrestrial telecommunications out of the cosmic background noise. It appears that the KLT is more appropriate than the well known Fourier Transform (FT).

  1. First-Year Medical Students' Naïve Beliefs about Respiratory Physiology

    ERIC Educational Resources Information Center

    Badenhorst, Elmi; Mamede, Silvia; Abrahams, Amaal; Bugarith, Kishor; Friedling, Jacqui; Gunston, Geney; Kelly-Laubscher, Roisin; Schmidt, Henk G.

    2016-01-01

    The present study explored the nature and frequency of physiology naïve beliefs by investigating novices' understanding of the respiratory system. Previous studies have shown considerable misconceptions related to physiology but focused mostly on specific physiological processes of normal respiration. Little is known about novices' broader…

  2. Informed and Uninformed Naïve Assessment Constructors' Strategies for Item Selection

    ERIC Educational Resources Information Center

    Fives, Helenrose; Barnes, Nicole

    2017-01-01

    We present a descriptive analysis of 53 naïve assessment constructors' explanations for selecting test items to include on a summative assessment. We randomly assigned participants to an informed and uninformed condition (i.e., informed participants read an article describing a Table of Specifications). Through recursive thematic analyses of…

  3. Analysis of Naïve Bayes Algorithm for Email Spam Filtering across Multiple Datasets

    NASA Astrophysics Data System (ADS)

    Fitriah Rusland, Nurul; Wahid, Norfaradilla; Kasim, Shahreen; Hafit, Hanayanti

    2017-08-01

    E-mail spam continues to become a problem on the Internet. Spammed e-mail may contain many copies of the same message, commercial advertisement or other irrelevant posts like pornographic content. In previous research, different filtering techniques are used to detect these e-mails such as using Random Forest, Naïve Bayesian, Support Vector Machine (SVM) and Neutral Network. In this research, we test Naïve Bayes algorithm for e-mail spam filtering on two datasets and test its performance, i.e., Spam Data and SPAMBASE datasets [8]. The performance of the datasets is evaluated based on their accuracy, recall, precision and F-measure. Our research use WEKA tool for the evaluation of Naïve Bayes algorithm for e-mail spam filtering on both datasets. The result shows that the type of email and the number of instances of the dataset has an influence towards the performance of Naïve Bayes.

  4. Rabies virus infection in Eptesicus fuscus bats born in captivity (naïve bats).

    PubMed

    Davis, April D; Jarvis, Jodie A; Pouliott, Craig; Rudd, Robert J

    2013-01-01

    The study of rabies virus infection in bats can be challenging due to quarantine requirements, husbandry concerns, genetic differences among animals, and lack of medical history. To date, all rabies virus (RABV) studies in bats have been performed in wild caught animals. Determining the RABV exposure history of a wild caught bat based on the presence or absence of viral neutralizing antibodies (VNA) may be misleading. Previous studies have demonstrated that the presence of VNA following natural or experimental inoculation is often ephemeral. With this knowledge, it is difficult to determine if a seronegative, wild caught bat has been previously exposed to RABV. The influence of prior rabies exposure in healthy, wild caught bats is unknown. To investigate the pathogenesis of RABV infection in bats born in captivity (naïve bats), naïve bats were inoculated intramuscularly with one of two Eptesicus fuscus rabies virus variants, EfV1 or EfV2. To determine the host response to a heterologous RABV, a separate group of naïve bats were inoculated with a Lasionycteris noctivagans RABV (LnV1). Six months following the first inoculation, all bats were challenged with EfV2. Our results indicate that naïve bats may have some level of innate resistance to intramuscular RABV inoculation. Additionally, naïve bats inoculated with the LnV demonstrated the lowest clinical infection rate of all groups. However, primary inoculation with EfV1 or LnV did not appear to be protective against a challenge with the more pathogenic EfV2.

  5. Modelling pathogen log10 reduction values achieved by activated sludge treatment using naïve and semi naïve Bayes network models.

    PubMed

    Carvajal, Guido; Roser, David J; Sisson, Scott A; Keegan, Alexandra; Khan, Stuart J

    2015-11-15

    Risk management for wastewater treatment and reuse have led to growing interest in understanding and optimising pathogen reduction during biological treatment processes. However, modelling pathogen reduction is often limited by poor characterization of the relationships between variables and incomplete knowledge of removal mechanisms. The aim of this paper was to assess the applicability of Bayesian belief network models to represent associations between pathogen reduction, and operating conditions and monitoring parameters and predict AS performance. Naïve Bayes and semi-naïve Bayes networks were constructed from an activated sludge dataset including operating and monitoring parameters, and removal efficiencies for two pathogens (native Giardia lamblia and seeded Cryptosporidium parvum) and five native microbial indicators (F-RNA bacteriophage, Clostridium perfringens, Escherichia coli, coliforms and enterococci). First we defined the Bayesian network structures for the two pathogen log10 reduction values (LRVs) class nodes discretized into two states (< and ≥ 1 LRV) using two different learning algorithms. Eight metrics, such as Prediction Accuracy (PA) and Area Under the receiver operating Curve (AUC), provided a comparison of model prediction performance, certainty and goodness of fit. This comparison was used to select the optimum models. The optimum Tree Augmented naïve models predicted removal efficiency with high AUC when all system parameters were used simultaneously (AUCs for C. parvum and G. lamblia LRVs of 0.95 and 0.87 respectively). However, metrics for individual system parameters showed only the C. parvum model was reliable. By contrast individual parameters for G. lamblia LRV prediction typically obtained low AUC scores (AUC < 0.81). Useful predictors for C. parvum LRV included solids retention time, turbidity and total coliform LRV. The methodology developed appears applicable for predicting pathogen removal efficiency in water treatment

  6. In vitro Culture of Naïve Human Bone Marrow Mesenchymal Stem Cells: A Stemness Based Approach

    PubMed Central

    Pal, Bidisha; Das, Bikul

    2017-01-01

    Human bone marrow derived mesenchymal stem cells (BM-MSCs) resides in their niches in close proximity to hematopoietic stem cells (HSCs). These naïve MSCs have tremendous potential in regenerative therapeutics, and may also be exploited by cancer and infectious disease agents. Hence, it is important to study the physiological and pathological roles of naïve MSC. However, our knowledge of naïve MSCs is limited by lack of appropriate isolation and in vitro culture methods. Established culture methods use serum rich media, and serial passaging for retrospective isolation of MSCs. These primed MSCs may not reflect the true physiological and pathological roles of naive MSCs (Figure 1). Therefore, there is a strong need for direct isolation and in vitro culture of naïve MSCs to study their stemness (self-renewal and undifferentiated state) and developmental ontogeny. We have taken a niche-based approach on stemness to better maintain naïve MSCs in vitro. In this approach, stemness is broadly divided as niche dependent (extrinsic), niche independent (intrinsic) and niche modulatory (altruistic or competitive). Using this approach, we were able to maintain naïve CD271+/CD133+ BM-MSCs for 2 weeks. Furthermore, this in vitro culture system helped us to identify naïve MSCs as a protective niche site for Mycobacterium tuberculosis, the causative organism of pulmonary tuberculosis. In this review, we discuss the in vitro culture of primed vs. naïve human BM derived MSCs with a special focus on how a stemness based approach could facilitate the study of naïve BM-MSCs. PMID:28884113

  7. Human α(2)β(1)(HI) CD133(+VE) epithelial prostate stem cells express low levels of active androgen receptor.

    PubMed

    Williamson, Stuart C; Hepburn, Anastasia C; Wilson, Laura; Coffey, Kelly; Ryan-Munden, Claudia A; Pal, Deepali; Leung, Hing Y; Robson, Craig N; Heer, Rakesh

    2012-01-01

    Stem cells are thought to be the cell of origin in malignant transformation in many tissues, but their role in human prostate carcinogenesis continues to be debated. One of the conflicts with this model is that cancer stem cells have been described to lack androgen receptor (AR) expression, which is of established importance in prostate cancer initiation and progression. We re-examined the expression patterns of AR within adult prostate epithelial differentiation using an optimised sensitive and specific approach examining transcript, protein and AR regulated gene expression. Highly enriched populations were isolated consisting of stem (α(2)β(1)(HI) CD133(+VE)), transiently amplifying (α(2)β(1)(HI) CD133(-VE)) and terminally differentiated (α(2)β(1)(LOW) CD133(-VE)) cells. AR transcript and protein expression was confirmed in α(2)β(1)(HI) CD133(+VE) and CD133(-VE) progenitor cells. Flow cytometry confirmed that median (±SD) fraction of cells expressing AR were 77% (±6%) in α(2)β(1)(HI) CD133(+VE) stem cells and 68% (±12%) in α(2)β(1)(HI) CD133(-VE) transiently amplifying cells. However, 3-fold lower levels of total AR protein expression (peak and median immunofluorescence) were present in α(2)β(1)(HI) CD133(+VE) stem cells compared with differentiated cells. This finding was confirmed with dual immunostaining of prostate sections for AR and CD133, which again demonstrated low levels of AR within basal CD133(+VE) cells. Activity of the AR was confirmed in prostate progenitor cells by the expression of low levels of the AR regulated genes PSA, KLK2 and TMPRSS2. The confirmation of AR expression in prostate progenitor cells allows integration of the cancer stem cell theory with the established models of prostate cancer initiation based on a functional AR. Further study of specific AR functions in prostate stem and differentiated cells may highlight novel mechanisms of prostate homeostasis and insights into tumourigenesis.

  8. Budget Impact of Enzalutamide for Chemotherapy-Naïve Metastatic Castration-Resistant Prostate Cancer.

    PubMed

    Bui, Cat N; O'Day, Ken; Flanders, Scott; Oestreicher, Nina; Francis, Peter; Posta, Linda; Popelar, Breanna; Tang, Hong; Balk, Mark

    2016-02-01

    Prostate cancer is expected to account for approximately one quarter of all new diagnoses of cancer in American men in 2015. The cost of prostate cancer care is expected to reach $15.1 billion by the year 2020, up from $11.9 billion in 2010. Given the high burden of prostate cancer, health care payers are interested in quantifying the potential budget impact of new therapies. To estimate the budget impact of enzalutamide for the treatment of chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) from a U.S. payer perspective. A model was developed to assess the budget impact of enzalutamide for treatment of chemotherapy-naïve mCRPC patients in a hypothetical 1-million-member U.S. health plan over a 1-year time horizon. Comparators included abiraterone acetate, sipuleucel-T, radium Ra 223 dichloride, and docetaxel. Epidemiologic data, including National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) incidence rates, were used to estimate the number of chemotherapy-naïve mCRPC patients. Dosing, administration, duration of therapy, and adverse event rates were based on package inserts and pivotal studies. Drug costs were obtained from RED BOOK and Centers for Medicare & Medicaid Services (CMS) average sales price pricing files, costs of administration and monitoring from the CMS physician fee schedule, and adverse events from the Agency for Healthcare Research and Quality Healthcare Cost and Utilization Project and published literature. Market shares were estimated for each comparator before and after adoption of enzalutamide. The incremental aggregate budget impact, per patient per year (PPPY), per patient per month (PPPM), and per member per month (PMPM), was calculated. One-way sensitivity analyses were performed. In a population of 115 chemotherapy-naïve mCRPC patients, adopting enzalutamide had an annual incremental budget impact of $510,641 ($4,426 PPPY, $369 PPPM, and $0.04 PMPM). Results were most sensitive to

  9. Interactions between Naïve and Infected Macrophages Reduce Mycobacterium tuberculosis Viability

    PubMed Central

    Hartman, Michelle L.; Kornfeld, Hardy

    2011-01-01

    A high intracellular bacillary load of Mycobacterium tuberculosis in macrophages induces an atypical lysosomal cell death with early features of apoptosis that progress to necrosis within hours. Unlike classical apoptosis, this cell death mode does not appear to diminish M. tuberculosis viability. We previously reported that culturing heavily infected macrophages with naïve macrophages produced an antimicrobial effect, but only if naïve macrophages were added during the pre-necrotic phase of M. tuberculosis-induced cell death. In the present study we investigated the mechanism of antimicrobial activity in co-cultures, anticipating that efferocytosis of bacilli in apoptotic bodies would be required. Confocal microscopy revealed frustrated phagocytosis of M. tuberculosis-infected macrophages with no evidence that significant numbers of bacilli were transferred to the naïve macrophages. The antimicrobial effect of naïve macrophages was retained when they were separated from infected macrophages in transwells, and conditioned co-culture supernatants transferred antimicrobial activity to cultures of infected macrophages alone. Antimicrobial activity in macrophage co-cultures was abrogated when the naïve population was deficient in IL-1 receptor or when the infected population was deficient in inducible nitric oxide synthase. The participation of nitric oxide suggested a conventional antimicrobial mechanism requiring delivery of bacilli to a late endosomal compartment. Using macrophages expressing GFP-LC3 we observed the induction of autophagy specifically by a high intracellular load of M. tuberculosis. Bacilli were identified in LC3-positive compartments and LC3-positive compartments were confirmed to be acidified and LAMP1 positive. Thus, the antimicrobial effect of naïve macrophages acting on M. tuberculosis in heavily-infected macrophages is contact-independent. Interleukin-1 provides an afferent signal that induces an as yet unidentified small molecule which

  10. Balance deficits and ADHD symptoms in medication-naïve school-aged boys

    PubMed Central

    Konicarova, Jana; Bob, Petr; Raboch, Jiri

    2014-01-01

    Background and objectives Functional disturbances developed early in life include balance deficits which are linked to dysfunctions of higher levels of cognitive and motor integration. According to our knowledge, there are only a few studies suggesting that balance deficits are related to behavioral disturbances in attention-deficit/hyperactivity disorder (ADHD). Methods We tested the extent to which balance deficits were related to ADHD symptoms in 35 medication-naïve boys of school age (8–11 years) and compared the results with a control group of 30 boys of the same age. Results ADHD symptoms in medication-naïve boys had specific relationships to disturbances of postural and gait balance. Conclusion To our knowledge, this study provides the first evidence in the medical literature for a direct relationship between ADHD symptoms and balance deficits, that cannot be attributed to medication and the presence of any neurological disease. PMID:24476629

  11. Naïve Bayes classification using 2D pharmacophore feature triplet vectors.

    PubMed

    Watson, Paul

    2008-01-01

    A naïve Bayes classifier, employed in conjunction with 2D pharmacophore feature triplet vectors describing the molecules, is presented and validated. Molecules are described using a vector where each element in the vector contains the number of times a particular triplet of atom-based features separated by a set of topological distances occurs. Using the feature triplet vectors it is possible to generate naïve Bayes classifiers that predict whether molecules are likely to be active against a given target (or family of targets). Two retrospective validation experiments were performed using a range of actives from WOMBAT, the Prous Integrity database, and the Arena screening library. The performance of the classifiers was evaluated using enrichment curves, enrichment factors, and the BEDROC metric. The classifiers were found to give significant enrichments for the various test sets.

  12. Full Scale Tests of Wood Propellers on a VE-7 Airplane in the Propeller Research Tunnel

    NASA Technical Reports Server (NTRS)

    Weick, Fred E

    1929-01-01

    The investigation described in this report was made primarily to afford a comparison between propeller tests in the new propeller research tunnel and flight tests and small model tests on propellers. Three wood propellers which had been previously tested in flight on a VE-7 airplane, and of which models had also been tested in a wind tunnel, were tested again on a VE-7 airplane in the propeller research tunnel. The results of these tests are in fair agreement with those of the flight and model tests. Tests were also made with the tail surfaces removed, and with both the wing and tail surfaces removed. It was found that the effect of the tail surfaces on the propeller characteristics was negligible, but that the wings reduced the maximum propulsive efficiency about 5 percent. (author)

  13. Interleukin-2 alters distribution of CD144 (VE-cadherin) in endothelial cells.

    PubMed

    Kim, Dae Won; Zloza, Andrew; Broucek, Joseph; Schenkel, Jason M; Ruby, Carl; Samaha, Georges; Kaufman, Howard L

    2014-05-06

    High-dose IL-2 (HDIL2) is approved for the treatment of metastatic melanoma and renal cell carcinoma, but its use is limited in part by toxicity related to the development of vascular leak syndrome (VLS). Therefore, an understanding of the mechanisms that underlie the initiation and progression of HDIL2-induced increases in endothelial cell (EC) permeability leading to VLS are of clinical importance. We established a novel ex vivo approach utilizing primary human pulmonary microvascular ECs to evaluate EC barrier dysfunction in response to IL-2. Complementary in vitro studies using exogenous IL-2 and ex vivo studies using serum from patients treated with IL-2 demonstrate that HDIL2 induces VLS through CD144 (vascular endothelial (VE)-cadherin) redistribution. These findings provide new insight into how IL-2 induces VLS and identifies VE-cadherin as a potential target for preventing IL-2-related VLS.

  14. Gender differences in non-motor symptoms in early, drug naïve Parkinson's disease.

    PubMed

    Picillo, Marina; Amboni, Marianna; Erro, Roberto; Longo, Katia; Vitale, Carmine; Moccia, Marcello; Pierro, Angela; Santangelo, Gabriella; De Rosa, Anna; De Michele, Giuseppe; Santoro, Lucio; Orefice, Giuseppe; Barone, Paolo; Pellecchia, Maria Teresa

    2013-11-01

    Gender differences in brain structure and function may lead to differences in the clinical expression of neurological diseases, including Parkinson's disease (PD). Few studies reported gender-related differences in the burden of non-motor symptoms (NMS) in treated PD patients, but this matter has not been previously explored in drug-naïve PD patients. This study is to assess gender differences in the prevalence of NMS in a large sample of early, drug-naïve PD patients compared with age and sex-matched healthy controls. Two hundred early, drug-naïve PD patients and ninety-three age and sex-matched healthy controls were included in the study. Frequency of NMS was evaluated by means of the Non-Motor Symptoms Questionnaire. The difference in gender distribution of NMS was evaluated with the χ (2) exact test; multiple comparisons were corrected with the Benjamini-Hochberg method. Male PD patients complained of problems having sex and taste/smelling difficulties significantly more frequently than female PD patients. Furthermore, men with PD complained more frequently of dribbling, sadness/blues, loss of interest, anxiety, acting during dreams, and taste/smelling difficulties as compared to healthy control men, while female PD patients reported more frequently loss of interest and anxiety as compared with healthy control women. This study shows specific sex-related patterns of NMS in drug-naïve PD. In contrast with previous data, female PD patients did not present higher prevalence of mood symptoms as compared to male PD patients. Comparison with healthy controls showed that some NMS classically present in premotor and early stage of disease (i.e., acting out during dreams, taste/smelling difficulties) are more frequent in male than in female patients.

  15. Naïve realism: folk fallacies in the design and use of visual displays.

    PubMed

    Smallman, Harvey S; Cook, Maia B

    2011-07-01

    Often implicit in visual display design and development is a gold standard of photorealism. By approximating direct perception, photorealism appeals to users and designers by being both attractive and apparently effortless. The vexing result from numerous performance evaluations, though, is that increasing realism often impairs performance. Smallman and St. John (2005) labeled misplaced faith in realistic information display Naïve Realism and theorized it resulted from a triplet of folk fallacies about perception. Here, we illustrate issues associated with the wider trend towards realism by focusing on a specific current trend for high-fidelity perspective view (3D) geospatial displays. In two experiments, we validated Naïve Realism for different terrain understanding tasks, explored whether certain individuals are particularly prone to Naïve Realism, and determined the ability of task feedback to mitigate Naïve Realism. Performance was measured for laying and judging a concealed route across realistic terrain shown in different display formats. Task feedback was either implicit, in Experiment 1, or explicit in Experiment 2. Prospective and retrospective intuitions about the best display formats for the tasks were recorded and then related to task performance and participant spatial ability. Participants generally intuited they would perform tasks better with more realism than they actually required. For example, counter to intuitions, lowering fidelity of the terrain display revealed the gross scene layout needed to lay a well-concealed route. Individuals of high spatial ability calibrated their intuitions with only implicit task feedback, whereas those of low spatial ability required salient, explicit feedback to calibrate their intuitions about display realism. Results are discussed in the wider context of applying perceptual science to display design, and combating folk fallacies.

  16. Abacavir-Reactive Memory T Cells Are Present in Drug Naïve Individuals

    PubMed Central

    Lucas, Andrew; Lucas, Michaela; Strhyn, Anette; Keane, Niamh M.; McKinnon, Elizabeth; Pavlos, Rebecca; Moran, Ellen M.; Meyer-Pannwitt, Viola; Gaudieri, Silvana; D’Orsogna, Lloyd; Kalams, Spyros; Ostrov, David A.; Buus, Søren; Peters, Bjoern; Mallal, Simon; Phillips, Elizabeth

    2015-01-01

    Background Fifty-five percent of individuals with HLA-B*57:01 exposed to the antiretroviral drug abacavir develop a hypersensitivity reaction (HSR) that has been attributed to naïve T-cell responses to neo-antigen generated by the drug. Immunologically confirmed abacavir HSR can manifest clinically in less than 48 hours following first exposure suggesting that, at least in some cases, abacavir HSR is due to re-stimulation of a pre-existing memory T-cell population rather than priming of a high frequency naïve T-cell population. Methods To determine whether a pre-existing abacavir reactive memory T-cell population contributes to early abacavir HSR symptoms, we studied the abacavir specific naïve or memory T-cell response using HLA-B*57:01 positive HSR patients or healthy controls using ELISpot assay, intra-cellular cytokine staining and tetramer labelling. Results Abacavir reactive CD8+ T-cell responses were detected in vitro in one hundred percent of abacavir unexposed HLA-B*57:01 positive healthy donors. Abacavir-specific CD8+ T cells from such donors can be expanded from sorted memory, and sorted naïve, CD8+ T cells without need for autologous CD4+ T cells. Conclusions We propose that these pre-existing abacavir-reactive memory CD8+ T-cell responses must have been primed by earlier exposure to another foreign antigen and that these T cells cross-react with an abacavir-HLA-B*57:01-endogenous peptide ligand complex, in keeping with the model of heterologous immunity proposed in transplant rejection. PMID:25674793

  17. The challenging definition of naïve patient for biological drug use.

    PubMed

    Biggioggero, Martina; Danova, Marco; Genovese, Umberto; Locatelli, Francesco; Meroni, Pier Luigi; Pane, Fabrizio; Scaglione, Francesco

    2015-06-01

    Biosimilar is defined by The European Medical Agency as a biological medicinal product, which is similar but not identical to the biological drug already authorized. The biosimilar and its reference product are expected to display the same safety and efficacy profile and are generally used to treat the same conditions. The Italian Medicines Agency considers biosimilars as a valid therapeutic option with an economic advantage, especially in primary naïve patients with no previous exposure to the originator or with a sufficiently long wash-out period ("secondary naïve"). The identification of "secondary naïve" is not well defined and can be subjected to different variables, mainly the drug biologic effect and its immunogenicity. The first one depends on the type of biologics and on their mechanism of action. The second one is related to the fact that biologicals may be immunogenic and can trigger an anti-drug antibody response (ADA). ADA may behave as neutralizing antibodies blocking the active site of the biological but can also recognize other epitopes favoring the formation of immune-complexes that eventually affect the pharmacodynamics. Moreover, the concomitant immune-suppressive treatment can affect the immunogenicity, even if the exact mechanism remains unknown. In conclusion, the development and use of biosimilars represent a tool for increasing health system sustainability. However it is of paramount importance to distinguish between the pharmacodynamics of a given drug and its immunogenicity being the two aspects unrelated. Thus a detailed definition of "secondary naïve" patients is challenging, and may be related to both the two parameters. Copyright © 2015 Elsevier B.V. All rights reserved.

  18. A Ve homologous gene from Gossypium barbadense, Gbvdr3, enhances the defense response against Verticillium dahliae.

    PubMed

    Chen, Tianzi; Kan, Jialiang; Yang, Yuwen; Ling, Xitie; Chang, Youhong; Zhang, Baolong

    2016-01-01

    The tomato Ve1 gene and several Ve1 homologues are involved in the resistance to Verticillium dahliae. Here, we report on another Ve homologous gene, Gbvdr3, from a Verticillium wilt-resistant cotton cultivar, Gossypium barbadense Hai7124, which has a 3207-bp region that encodes a predicted receptor-like protein. Transient expression analyses indicated that Gbvdr3 is localized in the plasma membrane, and virus-induced gene silencing of Gbvdr3 compromised the resistance of Hai7124 cotton to a defoliating strain of V. dahliae, V991, but not to a non-defoliating strain, BP2. This resistance pattern was further confirmed by over-expression of Gbvdr3 in transgenic Arabidopsis, which significantly elevated the expression of the ethylene-regulated gene GST2, the ethylene- and jasmonic acid-regulated defense-related genes PR3 and PDF1.2, and the salicylic acid-regulated genes PR1 and PR5, but not the PR2 gene. It also triggered the accumulation of hydrogen peroxide and callose at early time points during infection by the V991 defoliating strain. In contrast, elevated accumulation of hydrogen peroxide or callose in Gbvdr3-expressed Arabidopsis leaves was not apparent under infection by the non-defoliating strain, BP2. These results suggested that Gbvdr3 is involved in the resistance to a unique spectrum of defoliating V. dahliae strains.

  19. Dopamine transporter availability in motor subtypes of de novo drug-naïve Parkinson's disease.

    PubMed

    Moccia, Marcello; Pappatà, Sabina; Picillo, Marina; Erro, Roberto; Coda, Anna Rita Daniela; Longo, Katia; Vitale, Carmine; Amboni, Marianna; Brunetti, Arturo; Capo, Giuseppe; Salvatore, Marco; Barone, Paolo; Pellecchia, Maria Teresa

    2014-11-01

    Tremor dominant (TD) and akinetic-rigid type (ART) are two motor subtypes of Parkinson's disease associated with different disease progression and neurochemical/neuropathological features. The role of presynaptic nigrostriatal dopaminergic damage is still controversial, poorly explored, and only assessed in medicated patients. In this study, we investigated with FP-CIT SPECT the striatal dopamine transporter (DAT) availability in drug-naïve PD patients with ART and TD phenotypes. Fifty-one de novo, drug-naïve patients with PD underwent FP-CIT SPECT studies. Patients were evaluated with Unified Parkinson's Disease Rating Scale (UPDRS) part III and Hoehn and Yahr scale (H&Y) and divided into ART (24/51) and TD (27/51) according to UPDRS part III. ART and TD patients were not different with regard to age, gender, and disease duration. However, compared to TD, ART patients presented higher UPDRS part III (p = 0.01) and H&Y (p = 0.02) and lower DAT availability in affected and unaffected putamen (p = 0.008 and p = 0.007, respectively), whereas no differences were found in caudate. Moreover, in the whole group of patients, rigidity and bradykinesia, but not tremor scores of UPDRS part III were significantly related to FP-CIT binding in the putamen. These results suggest that in newly diagnosed drug-naïve PD patients DAT availability might be different between ART and TD in relation to different disease severity.

  20. Determining the extent and dynamics of surface water for the ABoVE field campaign

    NASA Astrophysics Data System (ADS)

    Carroll, M.; Sohlberg, R. A.; Townshend, J. R.; DiMiceli, C.

    2013-12-01

    The proposed Arctic and Boreal Vulnerability Experiment (ABoVE) will conduct multi-disciplinary studies to explore and quantify the linkages between all of the individual components of the ecosystem. One common thread identified in the final report for the scoping study for ABoVE is the need for maps of the location, extent and dynamics of surface water to connect the different disciplines. Water represents a transport vehicle for nutrients and other solutes, provides habitat for flora and fauna, and has a controlling effect on surface energy exchange yet it remains one of the least characterized features of the study region. We have been selected to develop a new dataset to represent surface water in the ABoVE study region at 30m spatial resolution for 3 epochs (1991, 2001, 2011). These data will be used to identify and quantify the change in surface water over the past 2 decades in the North American High Arctic. In this presentation we will describe the project and give the status of processing as well as early results from select locations.

  1. Inter-Cellular Exchange of Cellular Components via VE-Cadherin-Dependent Trans-Endocytosis

    PubMed Central

    Sakurai, Takashi; Woolls, Melissa J.; Jin, Suk-Won

    2014-01-01

    Cell-cell communications typically involve receptor-mediated signaling initiated by soluble or cell-bound ligands. Here, we report a unique mode of endocytosis: proteins originating from cell-cell junctions and cytosolic cellular components from the neighboring cell are internalized, leading to direct exchange of cellular components between two adjacent endothelial cells. VE-cadherins form transcellular bridges between two endothelial cells that are the basis of adherence junctions. At such adherens junction sites, we observed the movement of the entire VE-cadherin molecule from one endothelial cell into the other with junctional and cytoplasmic components. This phenomenon, here termed trans-endocytosis, requires the establishment of a VE-cadherin homodimer in trans with internalization proceeding in a Rac1-, and actomyosin-dependent manner. Importantly, the trans-endocytosis is not dependent on any known endocytic pathway including clathrin-dependent endocytosis, macropinocytosis or phagocytosis. This novel form of cell-cell communications, leading to a direct exchange of cellular components, was observed in 2D and 3D-cultured endothelial cells as well as in the developing zebrafish vasculature. PMID:24603875

  2. Diesel Exhaust Particle Exposure Causes Redistribution of Endothelial Tube VE-Cadherin

    PubMed Central

    Chao, Ming-Wei; Kozlosky, John; Po, Iris P.; Strickland, Pamela Ohman; Svoboda, Kathy K. H.; Cooper, Keith; Laumbach, Robert; Gordon, Marion K.

    2010-01-01

    Whether diesel exhaust particles (DEPs) potentially have a direct effect on capillary endothelia was examined by following the adherens junction component, vascular endothelial cell cadherin (VE-cadherin). This molecule is incorporated into endothelial adherens junctions at the cell surface, where it forms homodimeric associations with adjacent cells and contributes to the barrier function of the vasculature (Dejana et al., 2008; Venkiteswaran et al., 2002; Villasante et al., 2007). Human umbilical vein endothelial cells (HUVECs) that were pre-formed into capillary-like tube networks in vitro were exposed to DEPs for 24 hr. After exposure, the integrity of VE-cadherin in adherens junctions was assessed by immunofluorescence analysis, and demonstrated that increasing concentrations of DEPs caused increasing redistribution of VE-cadherin away from the cell-cell junctions toward intracellular locations. Since HUVEC tube networks are three-dimensional structures, whether particles entered the endothelial cells or tubular lumens was also examined. The data indicate that translocation of the particles does occur. The results, obtained in a setting that removes the confounding effects of inflammatory cells or blood components, suggest that if DEPs encounter alveolar capillaries in vivo, they may be able to directly affect the endothelial cell-cell junctions. PMID:20887764

  3. A Multilayer Naïve Bayes Model for Analyzing User's Retweeting Sentiment Tendency

    PubMed Central

    Wang, Mengmeng; Zuo, Wanli; Wang, Ying

    2015-01-01

    Today microblogging has increasingly become a means of information diffusion via user's retweeting behavior. Since retweeting content, as context information of microblogging, is an understanding of microblogging, hence, user's retweeting sentiment tendency analysis has gradually become a hot research topic. Targeted at online microblogging, a dynamic social network, we investigate how to exploit dynamic retweeting sentiment features in retweeting sentiment tendency analysis. On the basis of time series of user's network structure information and published text information, we first model dynamic retweeting sentiment features. Then we build Naïve Bayes models from profile-, relationship-, and emotion-based dimensions, respectively. Finally, we build a multilayer Naïve Bayes model based on multidimensional Naïve Bayes models to analyze user's retweeting sentiment tendency towards a microblog. Experiments on real-world dataset demonstrate the effectiveness of the proposed framework. Further experiments are conducted to understand the importance of dynamic retweeting sentiment features and temporal information in retweeting sentiment tendency analysis. What is more, we provide a new train of thought for retweeting sentiment tendency analysis in dynamic social networks. PMID:26417367

  4. Feature weighted naïve Bayes algorithm for information retrieval of enterprise systems

    NASA Astrophysics Data System (ADS)

    Wang, Li; Ji, Ping; Qi, Jing; Shan, Siqing; Bi, Zhuming; Deng, Weiguo; Zhang, Naijing

    2014-01-01

    Automated information retrieval is critical for enterprise information systems to acquire knowledge from the vast amount of data sets. One challenge in information retrieval is text classification. Current practices rely heavily on the classical naïve Bayes algorithm due to its simplicity and robustness. However, results from this algorithm are not always satisfactory. In this article, the limitations of the naïve Bayes algorithm are discussed, and it is found that the assumption on the independence of terms is the main reason for an unsatisfactory classification in many real-world applications. To overcome the limitations, the dependent factors are considered by integrating a term frequency-inverse document frequency (TF-IDF) weighting algorithm in the naïve Bayes classification. Moreover, the TF-IDF algorithm itself is improved so that both frequencies and distribution information are taken into consideration. To illustrate the effectiveness of the proposed method, two simulation experiments were conducted, and the comparisons with other classification methods have shown that the proposed method has outperformed other existing algorithms in terms of precision and index recall rate.

  5. Naïve Simplicity: The Overlooked Piece of the Complexity-Simplicity Paradigm.

    PubMed

    Schwartz, Franklin W; Liu, Ganming; Aggarwal, Pradeep; Schwartz, Cynthia M

    2017-09-01

    Concepts of simplicity and complexity in modeling have been explored in papers, editorials, and talks. The concept is not well understood because there are at least two flavors of simplicity. Modelers envision simplicity (i.e., elegant simplicity) as the sought-after goal in modeling, but naïve simplicity, which is the focus of this paper, is commonly unrecognized and dangerous. The problem is that naïve or simple ideas are often mistaken for settled science and come with the prospect of being more wrong than right. The concept of the so-called simplicity cycle, in relation to classical problems of carbon-14 age and salinity in closed-basin lakes, is used to illustrate these points. The emerging problems of water-mosquitoes-diseases show the value of mapping new problems to the simplicity cycle. Researchers can "know what they do not know" and avoid the dangers of naïve simplicity. © 2017, National Ground Water Association.

  6. VE-cadherin trans-interactions modulate Rac activation and enhancement of lung endothelial barrier by iloprost.

    PubMed

    Birukova, Anna A; Tian, Yufeng; Dubrovskyi, Oleksii; Zebda, Noureddine; Sarich, Nicolene; Tian, Xinyong; Wang, Yingxiao; Birukov, Konstantin G

    2012-10-01

    Small GTPase Rac is important regulator of endothelial cell (EC) barrier enhancement by prostacyclin characterized by increased peripheral actin cytoskeleton and increased interactions between VE-cadherin and other adherens junction (AJ) proteins. This study utilized complementary approaches including siRNA knockdown, culturing in Ca(2+) -free medium, and VE-cadherin blocking antibody to alter VE-cadherin extracellular interactions to investigate the role of VE-cadherin outside-in signaling in modulation of Rac activation and EC barrier regulation by prostacyclin analog iloprost. Spatial analysis of Rac activation in pulmonary EC by FRET revealed additional spike in iloprost-induced Rac activity at the sites of newly formed cell-cell junctions. In contrast, disruption of VE-cadherin extracellular trans-interactions suppressed iloprost-activated Rac signaling and attenuated EC barrier enhancement and cytoskeletal remodeling. These inhibitory effects were associated with decreased membrane accumulation and activation of Rac-specific guanine nucleotide exchange factors (GEFs) Tiam1 and Vav2. Conversely, plating of pulmonary EC on surfaces coated with extracellular VE-cadherin domain further promoted iloprost-induced Rac signaling. In the model of thrombin-induced EC barrier recovery, blocking of VE-cadherin trans-interactions attenuated activation of Rac pathway during recovery phase and delayed suppression of Rho signaling and restoration of EC barrier properties. These results suggest that VE-cadherin outside-in signaling controls locally Rac activity stimulated by barrier protective agonists. This control is essential for maximal EC barrier enhancement and accelerated barrier recovery.

  7. VE-cadherin trans-interactions modulate Rac activation and enhancement of lung endothelial barrier by iloprost

    PubMed Central

    Birukova, Anna A.; Tian, Yufeng; Dubrovskyi, Oleksii; Zebda, Noureddine; Sarich, Nicolene; Tian, Xinyong; Wang, Yingxiao; Birukov, Konstantin G.

    2012-01-01

    Small GTPase Rac is important regulator of endothelial cell (EC) barrier enhancement by prostacyclin characterized by increased peripheral actin cytoskeleton and increased interactions between VE-cadherin and other adherens junction (AJ) proteins. This study utilized complementary approaches including siRNA knockdown, culturing in Ca2+-free medium, and VE-cadherin blocking antibody to alter VE-cadherin extracellular interactions to investigate the role of VE-cadherin outside-in signaling in modulation of Rac activation and EC barrier regulation by prostacyclin analog iloprost. Spatial analysis of Rac activation in pulmonary EC by FRET revealed additional spike in iloprost-induced Rac activity at the sites of newly formed cell-cell junctions. In contrast, disruption of VE-cadherin extracellular trans-interactions suppressed iloprost-activated Rac signaling and attenuated EC barrier enhancement and cytoskeletal remodeling. These inhibitory effects were associated with decreased membrane accumulation and activation of Rac-specific guanine nucleotide exchange factors (GEF) Tiam1 and Vav2. Conversely, plating of pulmonary EC on surfaces coated with extracellular VE-cadherin domain further promoted iloprost-induced Rac signaling. In the model of thrombin-induced EC barrier recovery, blocking of VE-cadherin trans-interactions attenuated activation of Rac pathway during recovery phase and delayed suppression of Rho signaling and restoration of EC barrier properties. These results suggest that VE-cadherin outside-in signaling controls locally Rac activity stimulated by barrier protective agonists. This control is essential for maximal EC barrier enhancement and accelerated barrier recovery. PMID:22213015

  8. p120-Catenin prevents neutrophil transmigration independently of RhoA inhibition by impairing Src dependent VE-cadherin phosphorylation

    PubMed Central

    Alcaide, Pilar; Martinelli, Roberta; Newton, Gail; Williams, Marcie R.; Adam, Alejandro; Vincent, Peter A.

    2012-01-01

    Leukocyte transendothelial migration (TEM) is regulated by several signaling pathways including Src family kinases (SFK) and the small RhoGTPases. Previous studies have shown that vascular endothelial-cadherin (VE-cad) forms a complex with β-,γ-, and p120-catenins and this complex disassociates to form a transient gap during leukocyte TEM. Additionally, p120-catenin (p120-1A) overexpression in human umbilical vein endothelial cells (HUVEC) stabilizes VE-cad surface expression, prevents tyrosine phosphorylation of VE-cad, and inhibits leukocyte TEM. Based on reports showing that p120 overexpression in fibroblasts or epithelial cells inhibits RhoA and activates Rac and Cdc42 GTPases, and on other reports showing that RhoA activation in endothelial cells is necessary for leukocyte TEM, we reasoned that p120 overexpression inhibited TEM through inhibition of RhoA. To test this idea, we overexpressed a mutant p120 isoform, p120-4A, which does not interact with RhoA. p120-4A colocalized with VE-cad in HUVEC junctions and enhanced VE-cad surface expression, similar to overexpression of p120-1A. Interestingly, overexpression of either p120-4A or p120-1A dramatically blocked TEM, and overexpression of p120-1A in HUVEC did not affect RhoA basal activity or activation of RhoA and Rac induced by thrombin or ICAM-1 crosslinking. In contrast, biochemical studies revealed that overexpression of p120-1A reduced activated pY416-Src association with VE-cad. In summary, p120 overexpression inhibits neutrophil TEM independently of an effect on RhoA or Rac and instead blocks TEM by preventing VE-cad tyrosine phosphorylation and association of active Src with the VE-cad complex. PMID:22648953

  9. Stem cells. m6A mRNA methylation facilitates resolution of naïve pluripotency toward differentiation.

    PubMed

    Geula, Shay; Moshitch-Moshkovitz, Sharon; Dominissini, Dan; Mansour, Abed AlFatah; Kol, Nitzan; Salmon-Divon, Mali; Hershkovitz, Vera; Peer, Eyal; Mor, Nofar; Manor, Yair S; Ben-Haim, Moshe Shay; Eyal, Eran; Yunger, Sharon; Pinto, Yishay; Jaitin, Diego Adhemar; Viukov, Sergey; Rais, Yoach; Krupalnik, Vladislav; Chomsky, Elad; Zerbib, Mirie; Maza, Itay; Rechavi, Yoav; Massarwa, Rada; Hanna, Suhair; Amit, Ido; Levanon, Erez Y; Amariglio, Ninette; Stern-Ginossar, Noam; Novershtern, Noa; Rechavi, Gideon; Hanna, Jacob H

    2015-02-27

    Naïve and primed pluripotent states retain distinct molecular properties, yet limited knowledge exists on how their state transitions are regulated. Here, we identify Mettl3, an N(6)-methyladenosine (m(6)A) transferase, as a regulator for terminating murine naïve pluripotency. Mettl3 knockout preimplantation epiblasts and naïve embryonic stem cells are depleted for m(6)A in mRNAs, yet are viable. However, they fail to adequately terminate their naïve state and, subsequently, undergo aberrant and restricted lineage priming at the postimplantation stage, which leads to early embryonic lethality. m(6)A predominantly and directly reduces mRNA stability, including that of key naïve pluripotency-promoting transcripts. This study highlights a critical role for an mRNA epigenetic modification in vivo and identifies regulatory modules that functionally influence naïve and primed pluripotency in an opposing manner. Copyright © 2015, American Association for the Advancement of Science.

  10. Transgenerational soil-mediated differences between plants experienced or naïve to a grass invasion.

    PubMed

    Deck, Anna; Muir, Adrianna; Strauss, Sharon

    2013-10-01

    Invasive species may undergo rapid change as they invade. Native species persisting in invaded areas may also experience rapid change over this short timescale relative to native populations in uninvaded areas. We investigated the response of the native Achillea millefolium to soil from Holcus lanatus-invaded and uninvaded areas, and we sought to determine whether differential responses between A. millefolium from invaded (invader experienced) and uninvaded (invader naïve) areas were mediated by soil community changes. Plants grown from seed from experienced and naïve areas responded differently to invaded and uninvaded soil with respect to germination time, biomass, and height. Overall, experienced plants grew faster and taller than their naïve counterparts. Naïve native plants showed negative feedbacks with their home soil and positive feedbacks with invaded soil; experienced plants were less responsive to soil differences. Our results suggest that native plants naïve to invasion may be more sensitive to soil communities than experienced plants, consistent with recent studies. While differences between naïve and experienced plants are transgenerational, our design cannot differentiate between differences that are genetically based, plastic, or both. Regardless, our results highlight the importance of seed source and population history in restoration, emphasizing the restoration potential of experienced seed sources.

  11. Transgenerational soil-mediated differences between plants experienced or naïve to a grass invasion

    PubMed Central

    Deck, Anna; Muir, Adrianna; Strauss, Sharon

    2013-01-01

    Invasive species may undergo rapid change as they invade. Native species persisting in invaded areas may also experience rapid change over this short timescale relative to native populations in uninvaded areas. We investigated the response of the native Achillea millefolium to soil from Holcus lanatus-invaded and uninvaded areas, and we sought to determine whether differential responses between A. millefolium from invaded (invader experienced) and uninvaded (invader naïve) areas were mediated by soil community changes. Plants grown from seed from experienced and naïve areas responded differently to invaded and uninvaded soil with respect to germination time, biomass, and height. Overall, experienced plants grew faster and taller than their naïve counterparts. Naïve native plants showed negative feedbacks with their home soil and positive feedbacks with invaded soil; experienced plants were less responsive to soil differences. Our results suggest that native plants naïve to invasion may be more sensitive to soil communities than experienced plants, consistent with recent studies. While differences between naïve and experienced plants are transgenerational, our design cannot differentiate between differences that are genetically based, plastic, or both. Regardless, our results highlight the importance of seed source and population history in restoration, emphasizing the restoration potential of experienced seed sources. PMID:24198931

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

    PubMed

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

    2014-08-01

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

  13. Fixed bimonthly aflibercept in naïve and switched neovascular age-related macular degeneration patients: one year outcomes

    PubMed Central

    Warwick, Alasdair N; Leaver, Hannah H; Lotery, Andrew J; Goverdhan, Srini V

    2016-01-01

    AIM To determine real life clinical outcomes in poorly responsive and treatment-naïve neovascular age related macular degeneration (nvAMD) patients using bimonthly fixed dosing aflibercept regimen. METHODS This was a retrospective study of 165 eyes with nvAMD started on aflibercept at Southampton Eye Unit between June 2013 and June 2014. Patients were either switched from pro re nata (PRN) ranibizumab/bevacizumab due to poor response (107 eyes), or treatment-naïve (58 eyes). Patients initially received 3-monthly intravitreal aflibercept injections followed by 2-monthly fixed doses. Clinic visits were scheduled at month 0, 4, 10 and 12. Mean change in best-corrected visual acuity (BCVA) and central retinal thickness (CRT) from baseline were assessed using the Wilcoxon signed-rank test. The proportion of patients maintaining BCVA (<15 letters loss) at 12mo was also evaluated. RESULTS Mean BCVA change at month 12 was +3.29 and +4.67 letters in the switched and naïve aflibercept groups respectively (P<0.01). BCVA was maintained in 95.3% of switched and 96.6% of naïve patients. CRT at month 12 showed a decrease of -6.16 µm in the switched group and -35.36 µm in the naïve group (P<0.01). Patients previously treated with ranibizumab/bevacizumab had on average received 7.4 ranibizumab/bevacizumab injections over 12.6mo, attending 10 clinic visits. The fixed dosing aflibercept regimen required an average of 7.1 injections (naïve group), 7.5 injections (switched group) and 4 clinic visits per year. CONCLUSION Fixed bimonthly aflibercept is effective in both treatment-naïve and poorly responsive nvAMD patients. Adopting a fixed dosing regimen can reduce patient burden without compromising on outcomes. PMID:27588271

  14. A recombinant bivalent fusion protein rVE confers active and passive protection against Yersinia enterocolitica infection in mice.

    PubMed

    Singh, Amit Kumar; Kingston, Joseph Jeyabalaji; Murali, Harishchandra Sripathy; Batra, Harsh Vardhan

    2014-03-05

    In the present study, a bivalent chimeric protein rVE comprising immunologically active domains of Yersinia pestis LcrV and YopE was assessed for its prophylactic abilities against Yersinia enterocolitica O:8 infection in murine model. Mice immunized with rVE elicited significantly higher antibody titers with substantial contribution from the rV component (3:1 ratio). Robust and significant resistance to Y. enterocolitica infection with 100% survival (P<0.001) was seen in rVE vaccinated mice when intra peritoneal (I.P.) challenged with 10(8)CFU of Y. enterocolitica O:8 against the 75%, 60% and 75% survival seen in mice immunized with rV, rE, rV+rE, respectively. Macrophage monolayer supplemented with anti-rVE polysera illustrated efficient protection (89.41% survival) against challenge of Y. enterocolitica O:8. In contrast to sera from sham-immunized mice, immunization with anti-rVE polysera provided complete protection to BALB/c mice against I.P. challenge with 10(8)CFU of Y. enterocolitica O:8 and developed no conspicuous signs of infection in necropsy. The histopathological analysis of microtome sections confirmed significantly reduced lesion size or no lesion in liver and intestine upon infection in anti-rVE immunized mice. The findings from this study demonstrated the fusion protein rVE as a potential candidate subunit vaccine and showed the functional role of antibodies in protection against Y. enterocolitica infections. Copyright © 2014 Elsevier Ltd. All rights reserved.

  15. Radiosensitization of Human Leukemic HL-60 Cells by ATR Kinase Inhibitor (VE-821): Phosphoproteomic Analysis

    PubMed Central

    Šalovská, Barbora; Fabrik, Ivo; Ďurišová, Kamila; Link, Marek; Vávrová, Jiřina; Řezáčová, Martina; Tichý, Aleš

    2014-01-01

    DNA damaging agents such as ionizing radiation or chemotherapy are frequently used in oncology. DNA damage response (DDR)—triggered by radiation-induced double strand breaks—is orchestrated mainly by three Phosphatidylinositol 3-kinase-related kinases (PIKKs): Ataxia teleangiectasia mutated (ATM), DNA-dependent protein kinase (DNA-PK) and ATM and Rad3-related kinase (ATR). Their activation promotes cell-cycle arrest and facilitates DNA damage repair, resulting in radioresistance. Recently developed specific ATR inhibitor, VE-821 (3-amino-6-(4-(methylsulfonyl)phenyl)-N-phenylpyrazine-2-carboxamide), has been reported to have a significant radio- and chemo-sensitizing effect delimited to cancer cells (largely p53-deficient) without affecting normal cells. In this study, we employed SILAC-based quantitative phosphoproteomics to describe the mechanism of the radiosensitizing effect of VE-821 in human promyelocytic leukemic cells HL-60 (p53-negative). Hydrophilic interaction liquid chromatography (HILIC)-prefractionation with TiO2-enrichment and nano-liquid chromatography—tandem mass spectrometry (LC-MS/MS) analysis revealed 9834 phosphorylation sites. Proteins with differentially up-/down-regulated phosphorylation were mostly localized in the nucleus and were involved in cellular processes such as DDR, all phases of the cell cycle, and cell division. Moreover, sequence motif analysis revealed significant changes in the activities of kinases involved in these processes. Taken together, our data indicates that ATR kinase has multiple roles in response to DNA damage throughout the cell cycle and that its inhibitor VE-821 is a potent radiosensitizing agent for p53-negative HL-60 cells. PMID:25003641

  16. Effects of Risperidone on Cytokine Profile in Drug-Naïve First-Episode Psychosis

    PubMed Central

    Noto, Cristiano; Ota, Vanessa Kiyomi; Gouvea, Eduardo S.; Rizzo, Lucas B.; Spindola, Leticia M. N.; Honda, Pedro H. S.; Cordeiro, Quirino; Belangero, Sintia Iole; Bressan, Rodrigo Affonseca; Gadelha, Ary; Maes, Michael

    2015-01-01

    Background: There is robust evidence that schizophrenia is characterized by immune-inflammatory abnormalities, including variations on cytokine levels. The results of previous studies, however, are heterogeneous due to several confounding factors, such as the effects of antipsychotic drugs. Therefore, research on drug-naïve first-episode psychosis (FEP) patients is essential to elucidate the role of immune processes in that disorder. Methods: The aim of this study is to compare cytokine levels (IL-2, IL-10, IL-4, IL-6, IFN-γ, TNF-α, and IL-17) in drug-naïve FEP patients both before and after treatment with risperidone for 10 weeks, and to investigate possible associations between cytokine levels and clinical responses to treatment and presence of depressive symptoms. It this study, we included 55 drug-naïve FEP patients who had repeated measurements of cytokine levels and 57 healthy controls. Results: We found that FEP patients had significantly higher IL-6, IL-10 and TNF-α levels than healthy controls. After risperidone treatment, these three cytokines and additionally IL-4 decreased significantly. No significant difference was found between the post-treatment cytokine levels in FEP patients and in healthy controls, suggesting that these alterations in cytokine profiles are a state marker of FEP. No significant association was found between risperidone-induced changes in cytokines and the clinical response to treatment or the presence of depression. There was a significant inverse association between the risperidone-induced changes in IL-10 and the negative symptoms. Conclusions: In conclusion, our results show a specific cytokine profile in FEP patients (monocytic and regulatory T-cell activation) and suggest immunoregulatory effects of risperidone treatment, characterized by suppressant effects on monocytic, Th2, and T-regulatory functions. PMID:25522386

  17. Effects of risperidone on cytokine profile in drug-naïve first-episode psychosis.

    PubMed

    Noto, Cristiano; Ota, Vanessa Kiyomi; Gouvea, Eduardo S; Rizzo, Lucas B; Spindola, Leticia M N; Honda, Pedro H S; Cordeiro, Quirino; Belangero, Sintia Iole; Bressan, Rodrigo Affonseca; Gadelha, Ary; Maes, Michael; Brietzke, Elisa

    2014-10-31

    There is robust evidence that schizophrenia is characterized by immune-inflammatory abnormalities, including variations on cytokine levels. The results of previous studies, however, are heterogeneous due to several confounding factors, such as the effects of antipsychotic drugs. Therefore, research on drug-naïve first-episode psychosis (FEP) patients is essential to elucidate the role of immune processes in that disorder. The aim of this study is to compare cytokine levels (IL-2, IL-10, IL-4, IL-6, IFN-γ, TNF-α, and IL-17) in drug-naïve FEP patients both before and after treatment with risperidone for 10 weeks, and to investigate possible associations between cytokine levels and clinical responses to treatment and presence of depressive symptoms. It this study, we included 55 drug-naïve FEP patients who had repeated measurements of cytokine levels and 57 healthy controls. We found that FEP patients had significantly higher IL-6, IL-10 and TNF-α levels than healthy controls. After risperidone treatment, these three cytokines and additionally IL-4 decreased significantly. No significant difference was found between the post-treatment cytokine levels in FEP patients and in healthy controls, suggesting that these alterations in cytokine profiles are a state marker of FEP. No significant association was found between risperidone-induced changes in cytokines and the clinical response to treatment or the presence of depression. There was a significant inverse association between the risperidone-induced changes in IL-10 and the negative symptoms. In conclusion, our results show a specific cytokine profile in FEP patients (monocytic and regulatory T-cell activation) and suggest immunoregulatory effects of risperidone treatment, characterized by suppressant effects on monocytic, Th2, and T-regulatory functions. © The Author 2015. Published by Oxford University Press on behalf of CINP.

  18. Serum uric acid is associated with apathy in early, drug-naïve Parkinson's disease.

    PubMed

    Picillo, Marina; Santangelo, Gabriella; Moccia, Marcello; Erro, Roberto; Amboni, Marianna; Prestipino, Elio; Longo, Katia; Vitale, Carmine; Spina, Emanuele; Orefice, Giuseppe; Barone, Paolo; Pellecchia, Maria Teresa

    2016-04-01

    Both low serum uric acid (UA) levels and apathy are considered biomarkers of cognitive decline and dementia in Parkinson's disease (PD). There is an urgent need to combine different biomarkers to predict disease course in PD. Data on the relationship between serum UA levels and apathy in PD are lacking. The aim of this study is to evaluate the relationship between serum UA levels and pure apathy in early, drug-naïve PD patients. Forty-nine early, drug-naïve PD patients were enrolled and stratified into two groups using the median serum UA levels at diagnosis (Group 1 serum UA ≤ 4.8 mg/dl; Group 2 serum UA > 4.8 mg/dl). The cohort was followed for the first 2 years of disease. Apathy was evaluated with the Apathy Evaluation Scale (AES). Patients with lower serum UA levels presented significant higher AES score compared to patients with higher serum UA levels. Regression analysis showed that baseline serum UA levels were significant determinants of AES scores at both baseline and 2-year follow up, irrespective of gender, age, attention/executive functions and dopamine replacement therapy when applicable. This is the first study showing a link between serum UA levels and apathy in non-demented, non-depressed, early, drug-naïve PD, being lower serum UA levels associated with greater apathy. Further follow up of our patients and replication of this observation in independent cohorts are needed to establish if this combination of biomarkers may help in characterizing a subgroup of PD patients at diagnosis.

  19. Anesthetic Sevoflurane Causes Neurotoxicity Differently in Neonatal Naïve and Alzheimer's Disease Transgenic Mice

    PubMed Central

    Lu, Yan; Wu, Xu; Dong, Yuanlin; Xu, Zhipeng; Zhang, Yiying; Xie, Zhongcong

    2010-01-01

    Background Recent studies have suggested that children having surgery under anesthesia could be at an increased risk for the development of learning disabilities, but whether anesthetics contribute to this learning disability is unclear. We therefore set out to assess effects of sevoflurane, the most commonly used inhalation anesthetic, on caspase activation, apoptosis, β-amyloid protein levels, and neuroinflammation in brain tissues of neonatal naïve and Alzheimer's disease (AD) transgenic mice. Methods Six-day-old naïve and AD transgenic [B6.Cg-Tg(amyloid precursor protein swe, PSEN1dE9)85Dbo/J] mice were treated with sevoflurane. The mice were euthanized at the end of the anesthesia and brain tissues were harvested, and were then subjected to Western blot, immunocytochemistry, ELISA and real-time polymerase chain reaction. Results Here we show for the first time that sevoflurane anesthesia induced caspase activation and apoptosis, altered amyloid precursor protein processing, and increased β-amyloid protein levels in the brain tissues of the neonatal mice. Furthermore, the sevoflurane anesthesia led to a greater degree of neurotoxicity in the brain tissues of the AD transgenic mice as compared to the naïve mice, and increased tumor necrosis factor-α levels only in the brain tissues of the AD transgenic mice. Finally, inositol 1,4,5-trisphosphate receptor antagonist 2-APB attenuated the sevoflurane-induced caspase-3 activation and β-amyloid protein accumulation in vivo. Conclusion These results suggest that sevoflurane may induce the neurotoxicity in neonatal mice. AD transgenic mice could be more venerable to such neurotoxicity. These findings should promote more studies to determine the potential neurotoxicity of anesthesia in animals and humans, especially in children. PMID:20460993

  20. Dipeptidyl Peptidase-4 Inhibitor Increases Vascular Leakage in Retina through VE-cadherin Phosphorylation

    PubMed Central

    Lee, Choon-Soo; Kim, Yun Gi; Cho, Hyun-Jai; Park, Jonghanne; Jeong, Heewon; Lee, Sang-Eun; Lee, Seung-Pyo; Kang, Hyun-Jae; Kim, Hyo-Soo

    2016-01-01

    The inhibitors of CD26 (dipeptidyl peptidase-4; DPP4) have been widely prescribed to control glucose level in diabetic patients. DPP4-inhibitors, however, accumulate stromal cell-derived factor-1α (SDF-1α), a well-known inducer of vascular leakage and angiogenesis both of which are fundamental pathophysiology of diabetic retinopathy. The aim of this study was to investigate the effects of DPP4-inhibitors on vascular permeability and diabetic retinopathy. DPP4-inhibitor (diprotin A or sitagliptin) increased the phosphorylation of Src and vascular endothelial-cadherin (VE-cadherin) in human endothelial cells and disrupted endothelial cell-to-cell junctions, which were attenuated by CXCR4 (receptor of SDF-1α)-blocker or Src-inhibitor. Disruption of endothelial cell-to-cell junctions in the immuno-fluorescence images correlated with the actual leakage of the endothelial monolayer in the transwell endothelial permeability assay. In the Miles assay, vascular leakage was observed in the ears into which SDF-1α was injected, and this effect was aggravated by DPP4-inhibitor. In the model of retinopathy of prematurity, DPP4-inhibitor increased not only retinal vascularity but also leakage. Additionally, in the murine diabetic retinopathy model, DPP4-inhibitor increased the phosphorylation of Src and VE-cadherin and aggravated vascular leakage in the retinas. Collectively, DPP4-inhibitor induced vascular leakage by augmenting the SDF-1α/CXCR4/Src/VE-cadherin signaling pathway. These data highlight safety issues associated with the use of DPP4-inhibitors. PMID:27381080

  1. Towards the Integration of APECS with VE-Suite to Create a Comprehensive Virtual Engineering Environment

    SciTech Connect

    McCorkle, D.; Yang, C.; Jordan, T.; Swensen, D.; Zitney, S.E.; Bryden, M.

    2007-06-01

    Modeling and simulation tools are becoming pervasive in the process engineering practice of designing advanced power generation facilities. These tools enable engineers to explore many what-if scenarios before cutting metal or constructing a pilot scale facility. While such tools enable investigation of crucial plant design aspects, typical commercial process simulation tools such as Aspen Plus®, gPROMS®, and HYSYS® still do not explore some plant design information, including computational fluid dynamics (CFD) models for complex thermal and fluid flow phenomena, economics models for policy decisions, operational data after the plant is constructed, and as-built information for use in as-designed models. Software tools must be created that allow disparate sources of information to be integrated if environments are to be constructed where process simulation information can be accessed. At the Department of Energy’s (DOE) National Energy Technology Laboratory (NETL), the Advanced Process Engineering Co-Simulator (APECS) has been developed as an integrated software suite that combines process simulation (e.g., Aspen Plus) and high-fidelity equipment simulation (e.g., Fluent® CFD), together with advanced analysis capabilities including case studies, sensitivity analysis, stochastic simulation for risk/uncertainty analysis, and multi-objective optimization. In this paper, we discuss the initial phases of integrating APECS with the immersive and interactive virtual engineering software, VE-Suite, developed at Iowa State University and Ames Laboratory. VE-Suite utilizes the ActiveX (OLE Automation) controls in Aspen Plus wrapped by the CASI library developed by Reaction Engineering International to run the process simulation and query for unit operation results. This integration permits any application that uses the VE-Open interface to integrate with APECS co-simulations, enabling construction of the comprehensive virtual engineering environment needed for the

  2. Poisoning by Brachiaria brizantha in flocks of naïve and experienced sheep.

    PubMed

    Faccin, Tatiane C; Riet-Correa, Franklin; Rodrigues, Fernando S; Santos, Ariany C; Melo, Gleice K A; Silva, Jonilson A; Ferreira, Rubiane; Itavo, Camila C B F; Lemos, Ricardo A A

    2014-05-01

    The aim of this work was to study the effects of protodioscin ingestion in two different flocks of sheep: a flock of 23 crossbreed Mato Grosso do Sul Native sheep raised on Brachiaria spp. pastures from birth (experienced flock) in the state of Mato Grosso do Sul; and another flock (naïve flock) of 18 crossbred Dorper × Santa Inês sheep raised in the state of Paraná in Paspalum notatum and Lolium multiflorum pastures. The two flocks grazed together in a Brachiaria brizantha pasture during a 140-day period in the rainy season. At the beginning of the experiment and every 14 days thereafter, blood samples were collected for determination of serum activities of gamma-glutamyl transferase (GGT) and aspartate aminotransferase (AST), and for determination of the icterus index. On the same days, samples of young, mature and old B. brizantha leaves were collected for protodioscin quantification. Naïve sheep were more susceptible to poisoning by B. brizantha than experienced sheep. Six sheep in the naïve flock were poisoned, and two of these died. Two sheep in the experienced flock were poisoned, and one of them died. The mean activities of serum GGT and AST were significantly higher in the naïve flock, also evidencing a higher susceptibility to the poison. These results suggest that flocks of sheep include animals with different degrees of resistance to Brachiaria spp. poisoning and that culling the susceptible animals may considerably increase of the resistance of the flock. The clinical signs and the lesions were similar to those previously reported. However, in sheep with black coats, the main clinical sign was weight loss without photosensitization-mediated dermatitis. One sheep from the experienced flock presented cirrhosis, with clinical signs of exercise intolerance. The protodioscin concentration (% DM) ranged from 0.87% to 2.58% (mean ± SD: 1.64 ± 0.58) in young leaves, 1.16%-2.53% (1.67 ± 0.44) in mature leaves and 0.98%-2.07% (1.52 ± 0

  3. Pressure distribution on wing ribs of the VE-7 and TS airplanes in flight

    NASA Technical Reports Server (NTRS)

    Rhode, R V

    1927-01-01

    This paper is the first of a series of notes, each of which presents the complete results of pressure distribution tests made by the National Advisory Committee for Aeronautics, on single-wing ribs of the VE-7 and TS airplanes for a particular condition of flight. The level flight results are presented here in the form of curves and show the comparison between the pressure distribution over a representative thin wing, R.A.F.-15, and a moderately thick wing, U.S.A.-27, throughout the range of angle of attack.

  4. Hepatitis B virus reverse transcriptase mutations in treatment Naïve chronic hepatitis B patients.

    PubMed

    Singla, Bhupesh; Chakraborti, Anuradha; Sharma, Bal Krishan; Kapil, Shweta; Chawla, Yogesh K; Arora, Sunil K; Das, Ashim; Dhiman, Radha K; Duseja, Ajay

    2013-07-01

    Mutations in the reverse transcriptase (RT) region of the hepatitis B virus (HBV) genome lead to decreased susceptibility to nucleos(t)ide analogs approved for treatment of HBV infection. The aim of this study was to detect and analyze pre-existing HBV RT mutations in treatment naïve patients with chronic hepatitis B. Seventy one chronic HBV treatment naïve patients were enrolled from January 2009 to June 2011. HBV RT sequence analysis was done by using direct bidirectional sequencing of semi-nested PCR products. HBV genotypes were determined by multiplex PCR. Genotype D was found in 64 patients (90.1%) followed by genotype C and A which were present in 5 (7.0%) and 2 (2.8%) patients respectively. The results of the RT sequence analysis showed mutations in 34 (47.9%) patients. The rtH248N mutation was the most common mutation, accounting for 47.1% patients. Other common mutations included rtD263E/S, rtM129L, rtF122L/V/I, rtS135Y/H, rtQ149K, rtL91I, rtH126R, rtC256S/G, rtY257W, rtS259T and rtE271D, which were present in 26.5% (9/34), 29.4% (10/34), 20.6% (7/34), 20.6% (7/34), 20.6% (7/34), 17.6% (6/34), 14.7% (5/34), 14.7% (5/34), 11.8% (4/34), 11.8% (4/34) and 11.8% (4/34) patients respectively. The known primary drug resistance mutations were found in 3 (8.8%) patients. The present study shows the presence of RT amino acid substitutions in treatment-naïve patients with chronic hepatitis B, which may decrease susceptibility to available oral antiviral drugs. On the basis of the finding of this study, genotypic testing is recommended before the start of therapy in naïve patients, so that suitable antiviral drugs can be prescribed.

  5. Aluminum-Oxide Temperatures on the Mark VB, VE, VR, 15, and Mark 25 Assemblies

    SciTech Connect

    Aleman, S.E.

    2001-07-17

    The task was to compute the maximum aluminum-oxide and oxide-coolant temperatures of assemblies cladded in 99+ percent aluminum. The assemblies considered were the Mark VB, VE, V5, 15 and 25. These assemblies consist of nested slug columns with individual uranium slugs cladded in aluminum cans. The CREDIT code was modified to calculate the oxide film thickness and the aluminum-oxide temperature at each axial increment. This information in this report will be used to evaluate the potential for cladding corrosion of the Mark 25 assembly.

  6. Modified Karhunen-Loéve expansion for evaluating skin-colour-associated melanoma risk factors.

    PubMed

    Cevenini, G; Borzelli, G; Rubegni, P; Massai, M R; Andreassi, L; Barbini, P

    2000-07-01

    An approach based on the modified Karhunen-Loéve expansion (MKLE) of constitutive and facultative skin colour data acquired by colorimeters in melanoma patients and healthy control subjects, was used to identify two colour features defining skin-colour-associated risk of melanoma. None of four common statistical classifiers trained on colour features were sufficiently accurate for allowing skin colour alone to be used for classification purposes, though a Bayesian quadratic classifier matched the transformed data well. This study supersedes the indeterminate character of most common clinical criteria based on qualitative factors and, irrespective of the results of classification, provides objective skin colour information for the prevention of melanoma.

  7. Research on micro-blog character analysis based on Naïve Bayes

    NASA Astrophysics Data System (ADS)

    Liu, Yun; Liu, Tong; Wang, Yanbo J.

    2015-07-01

    With the development of Information Technology, people have entered the era of Big Data, and the demand for intelligent information is more intense. How to make computer provide more personalized and efficient service for all walks of life, is something worth exploring. In this paper, we aim to predict user's character by analyzing the textual content of his/her micro-blog, which is the foundation of Personalized Service. Our study describes the method of creating a prediction model about user's character by using Bayesian algorithms. Experimental results show that the Naïve Bayes approach is a valid and promoted analytic method in micro-blog character analysis.

  8. Physical Characterization Of 2002 Ve68, A Quasi-moon Of Venus.

    NASA Astrophysics Data System (ADS)

    Barajas, Tzitlaly; Hicks, M. D.; Mayes, D.; Rhoades, H.; Somers, J.; Garcia, K.; Foster, J.; Truong, T.

    2011-05-01

    The Near-Earth Object (NEO) 2002 VE68 was discovered by the LONEOS Survey on November 11, 2002 (MPEC 2002-V52). With a semi-major axis of 0.723 AU, 2002 VE68 is in a 1:1 mean motion resonance with Venus and can be considered a quasi-satellite of the planet. Orbital integrations by Mikkola et al. (2004) suggest that 2002 VE68 was likely an NEO injected into its current orbit by a close Earth encounter approximately 7000 years ago and will remain a Venusian quasi-satellite for another 500 years. This object has been designated a Potentially Hazardous Asteroid by the Minor Planet Center. We took advantage of the object's 2010 apparition to collect rotationally resolved Bessel BVRI photometry over the course of three nights (November 10/12/13 2010) using the JPL Table Mountain 0.6-m telescope near Wrightwood, California. The object's mean colors (B-R=1.106+/-0.019 mag; V-R=0.419+/-0.021 mag; R-I=0.348+/-0.014 mag) are most compatible with an X-type spectral classification (Bus Taxonomy). A slight reflectance dip at 0.55 micron is consistent with the deep 0.50 micron feature observed in the spectrum of the E-type asteroid 2867 Steins (Weissman et al. 2008). The spectral resolution that our BVRI photometry affords is often insufficient to resolve the E-M-P sub-classes within the X-spectral complex (Tholen Taxonomy; Zelner et al. 1985). After converting the photometry from magnitude to flux units, we found a best-fit synodic period P_syn = 13.50+/-0.01 hr. Our photometry yields an absolute magnitude H_v=20.59+/-0.02 mag, implying an effective diameter D 200m (rho=0.25). The lightcurve amplitude of 2002 VE68 ( 0.9 mag) suggests that it may be a contact binary.

  9. Persistent opioid use following cesarean delivery: patterns and predictors among opioid-naïve women.

    PubMed

    Bateman, Brian T; Franklin, Jessica M; Bykov, Katsiaryna; Avorn, Jerry; Shrank, William H; Brennan, Troyen A; Landon, Joan E; Rathmell, James P; Huybrechts, Krista F; Fischer, Michael A; Choudhry, Niteesh K

    2016-09-01

    The incidence of opioid-related death in women has increased 5-fold over the past decade. For many women, their initial opioid exposure will occur in the setting of routine medical care. Approximately 1 in 3 deliveries in the United States is by cesarean, and opioids are commonly prescribed for postsurgical pain management. The objective of this study was to determine the risk that opioid-naïve women prescribed opioids after cesarean delivery will subsequently become consistent prescription opioid users in the year following delivery and to identify predictors for this behavior. We identified women in a database of commercial insurance beneficiaries who underwent cesarean delivery and who were opioid naïve in the year prior to delivery. To identify persistent users of opioids, we used trajectory models, which group together patients with similar patterns of medication filling during follow-up, based on patterns of opioid dispensing in the year following cesarean delivery. We then constructed a multivariable logistic regression model to identify independent risk factors for membership in the persistent user group. A total of 285 of 80,127 (0.36%, 95% confidence interval, 0.32-0.40), opioid-naïve women became persistent opioid users (identified using trajectory models based on monthly patterns of opioid dispensing) following cesarean delivery. Demographics and baseline comorbidity predicted such use with moderate discrimination (c statistic = 0.73). Significant predictors included a history of cocaine abuse (risk, 7.41%; adjusted odds ratio, 6.11, 95% confidence interval, 1.03-36.31) and other illicit substance abuse (2.36%; adjusted odds ratio, 2.78, 95% confidence interval, 1.12-6.91), tobacco use (1.45%; adjusted odds ratio, 3.04, 95% confidence interval, 2.03-4.55), back pain (0.69%; adjusted odds ratio, 1.74, 95% confidence interval, 1.33-2.29), migraines (0.91%; adjusted odds ratio, 2.14, 95% confidence interval, 1.58-2.90), antidepressant use (1

  10. Aluminum-Oxide Temperatures on the Mark VB, VE, VR, 15, and Mark 25 Assemblies

    SciTech Connect

    Aleman, S.E.

    2001-07-17

    The task was to compute the maximum aluminum-oxide and oxide-coolant temperatures of assemblies cladded in 99 plus percent aluminum. The assemblies considered were the Mark VB, VE, V5, 15 and 25. These assemblies consist of nested slug columns with individual uranium slugs cladded in aluminum cans. The CREDIT code was modified to calculate the oxide film thickness and the aluminum-oxide temperature at each axial increment. The information in this report will be used to evaluate the potential for cladding corrosion of the Mark 25 assembly.

  11. Endocrine therapy for hormone treatment-naïve advanced breast cancer.

    PubMed

    Martin, Miguel; Lopez-Tarruella, Sara; Gilarranz, Yolanda Jerez

    2016-08-01

    A proportion of patients with hormone receptor-positive locally advanced or metastatic breast cancer will not have received prior endocrine therapy. However, there are limited clinical data specifically in these patients. We conducted a review of randomized phase II and III clinical studies of anastrozole, letrozole, exemestane, palbociclib, and fulvestrant to determine the evidence base supporting use of specific endocrine therapies in this patient population. From our findings, there is a paucity of clinical studies in patients with endocrine therapy-naïve disease; however, it appears that first-line treatment effects are consistent between patients who have and have not received prior endocrine treatment.

  12. VE-cadherin is a critical molecule for trophoblast-endothelial cell interaction in decidual spiral arteries

    SciTech Connect

    Bulla, Roberta; Villa, Antonello; Bossi, Fleur; Cassetti, Arianna; Radillo, Oriano; Spessotto, Paola; De Seta, Francesco; Guaschino, Secondo; Tedesco, Francesco . E-mail: tedesco@univ.trieste.it

    2005-02-01

    Fetal cytotrophoblasts colonize the decidual spiral arteries during pregnancy and partially replace the endothelium by an as yet unknown mechanism. To clarify this issue, we cocultured trophoblast cells (TCs) and decidual endothelial cells (DECs) isolated from first trimester placentae and found by electron microscopic analysis that TCs adhered to DECs and migrated through the interendothelial junctions within 24 h. Since extravillous TCs were shown by FACS analysis to express vascular-endothelial (VE)-cadherin and platelet endothelial cell adhesion molecule-1 (PECAM)-1, we investigated the role of these junctional molecules in TC adhesion to DECs and transendothelial migration of cytotrophoblasts. Both VE-cadherin and PECAM-1 were present at the contact sites between TCs and DECs in decidual sections. TC adhesion and migration were markedly inhibited by mAbs to VE-cadherin and marginally by mAb to PECAM-1. Increased expression of VE-cadherin was observed at the contact areas between TCs and DECs, whereas PECAM-1 was found to be redistributed from intercellular junctions. The induction of apoptosis of DECs by TCs, as the mechanism responsible for their replacement, was ruled out by the negative staining with TUNEL of DECs cocultured with TCs and the absence of DNA fragmentation. In conclusion, VE-cadherin is involved in transendothelial migration of TCs, and replacement of DECs by TCs is not the result of apoptosis.

  13. Dephosphorylation of Y685-VE-Cadherin Involved in Pulmonary Microvascular Endothelial Barrier Injury Induced by Angiotensin II

    PubMed Central

    Wang, Zhiwei; Dai, Feifeng; Liu, Huagang; Ren, Wei; Chang, Jinxing; Li, Bowen

    2016-01-01

    Angiotensin II (AngII) caused pulmonary microvascular endothelial barrier injury, which induced acute aortic dissection (AAD) combined with acute lung injury (ALI). However, the exact mechanism is unclear. We investigated the role of dephosphorylation of Y685-VE-cadherin in the AngII induced pulmonary microvascular endothelial barrier injury. Mice or pulmonary microvascular endothelial cells (PMVECs) were divided into control group, AngII group, AngII+PP2 (Src kinase inhibitor) group, and PP2 group. PP2 was used to inhibit the phosphorylation of Y685-VE-cadherin. Pathological changes, infiltration of macrophages and neutrophils, and pulmonary microvascular permeability were used to determine the pulmonary microvascular endothelial barrier function. Flow cytometry was used to determine the apoptosis of PMVECs, and immunofluorescence was used to determine the skeletal arrangement. Transendothelial resistance was used to detect the permeability of endothelial barrier. Phosphorylation of Y685-VE-cadherin was significantly reduced after AngII stimulation (P < 0.05), together with skeletal rearrangement, and elevation of endothelial permeability which finally induced endothelial barrier injury. After PP2 interference, the phosphorylation of Y685-VE-cadherin was further reduced and the endothelial permeability was further elevated. These data indicated that AngII could induce pulmonary injury by triggering endothelial barrier injury, and such process may be related to the dephosphorylation of Y685-VE-cadherin and the endothelial skeletal rearrangement. PMID:28119542

  14. Dephosphorylation of Y685-VE-Cadherin Involved in Pulmonary Microvascular Endothelial Barrier Injury Induced by Angiotensin II.

    PubMed

    Wu, Zhiyong; Wang, Zhiwei; Dai, Feifeng; Liu, Huagang; Ren, Wei; Chang, Jinxing; Li, Bowen

    2016-01-01

    Angiotensin II (AngII) caused pulmonary microvascular endothelial barrier injury, which induced acute aortic dissection (AAD) combined with acute lung injury (ALI). However, the exact mechanism is unclear. We investigated the role of dephosphorylation of Y685-VE-cadherin in the AngII induced pulmonary microvascular endothelial barrier injury. Mice or pulmonary microvascular endothelial cells (PMVECs) were divided into control group, AngII group, AngII+PP2 (Src kinase inhibitor) group, and PP2 group. PP2 was used to inhibit the phosphorylation of Y685-VE-cadherin. Pathological changes, infiltration of macrophages and neutrophils, and pulmonary microvascular permeability were used to determine the pulmonary microvascular endothelial barrier function. Flow cytometry was used to determine the apoptosis of PMVECs, and immunofluorescence was used to determine the skeletal arrangement. Transendothelial resistance was used to detect the permeability of endothelial barrier. Phosphorylation of Y685-VE-cadherin was significantly reduced after AngII stimulation (P < 0.05), together with skeletal rearrangement, and elevation of endothelial permeability which finally induced endothelial barrier injury. After PP2 interference, the phosphorylation of Y685-VE-cadherin was further reduced and the endothelial permeability was further elevated. These data indicated that AngII could induce pulmonary injury by triggering endothelial barrier injury, and such process may be related to the dephosphorylation of Y685-VE-cadherin and the endothelial skeletal rearrangement.

  15. Aspergillus fumigatus spore proteomics and genetics reveal that VeA represses DefA-mediated DNA damage response.

    PubMed

    Shin, Kwang-Soo; Park, Hee-Soo; Kim, Young; Heo, In-Beom; Kim, Young Hwan; Yu, Jae-Hyuk

    2016-10-04

    Aspergillus fumigatus reproduces and infects host by forming a high number of small asexual spores (conidia). The velvet proteins are global transcriptional regulators governing the complex process of conidiogenesis in this fungus. Here, to further understand the velvet-mediated regulation, we carried out comparative proteomic analyses of conidia of wild type (WT) and three velvet mutants (ΔveA, ΔvelB and ΔvosA). Cluster analysis of 184 protein spots showing at least 1.5-fold differential accumulation between WT and mutants reveal the clustering of WT- ΔveA and ΔvelB-ΔvosA. Among 43 proteins identified by Nano-LC-ESI-MS/MS, 23 including several heat shock proteins showed more than two-fold reduction in both the ∆velB and ∆vosA conidia. On the contrary, three proteins exhibited more than five-fold increase in ∆veA only, including the putative RNA polymerase II degradation factor DefA. The deletion of defA resulted in a reduced number of conidia and restricted colony growth. In addition, the defA deletion mutant conidia showed hypersensitivity against the DNA damaging agents NQO and MMS, while the ΔveA mutant conidia were more resistant against to NQO. Taken together, we propose that VeA controls protein level of DefA in conidia, which are dormant and equipped with multiple layers of protection against environmental cues.

  16. Foxd3 promotes exit from naïve pluripotency through enhancer decommissioning and inhibits germline specification

    PubMed Central

    Respuela, Patricia; Nikolic, Milos; Tan, Minjia; Frommolt, Peter; Zhao, Yingming; Wysocka, Joanna; Rada-Iglesias, Alvaro

    2016-01-01

    Summary Following implantation, mouse epiblast cells transit from a naïve to a primed state in which they are competent for both somatic and primordial germ cell (PGC) specification. Using mouse embryonic stem cells (mESC) as an in vitro model to study the transcriptional regulatory principles orchestrating peri-implantation development, here we show that the transcription factor Foxd3 is necessary for exit from naïve pluripotency and progression to a primed pluripotent state. During this transition, Foxd3 acts as a repressor that dismantles a significant fraction of the naïve pluripotency expression program through decommissioning of active enhancers associated with key naïve pluripotency and early germline genes. Subsequently, Foxd3 needs to be silenced in primed pluripotent cells to allow reactivation of relevant genes required for proper PGC specification. Our findings therefore uncover a cycle of activation and deactivation of Foxd3 required for exit from naïve pluripotency and subsequent PGC specification. PMID:26748758

  17. Human naïve regulatory T-cells feature high steady-state turnover and are maintained by IL-7.

    PubMed

    Silva, Susana L; Albuquerque, Adriana S; Serra-Caetano, Ana; Foxall, Russell B; Pires, Ana R; Matoso, Paula; Fernandes, Susana M; Ferreira, João; Cheynier, Rémi; Victorino, Rui M M; Caramalho, Iris; Barata, João T; Sousa, Ana E

    2016-03-15

    Naïve FoxP3-expressing regulatory T-cells (Tregs) are essential to control immune responses via continuous replenishment of the activated-Treg pool with thymus-committed suppressor cells. The mechanisms underlying naïve-Treg maintenance throughout life in face of the age-associated thymic involution remain unclear. We found that in adults thymectomized early in infancy the naïve-Treg pool is remarkably well preserved, in contrast to conventional naïve CD4 T-cells. Naïve-Tregs featured high levels of cycling and pro-survival markers, even in healthy individuals, and contrasted with other circulating naïve/memory CD4 T-cell subsets in terms of their strong γc-cytokine-dependent signaling, particularly in response to IL-7. Accordingly, ex-vivo stimulation of naïve-Tregs with IL-7 induced robust cytokine-dependent signaling, Bcl-2 expression, and phosphatidylinositol 3-kinase (PI3K)-dependent proliferation, whilst preserving naïve phenotype and suppressive capacity. Altogether, our data strongly implicate IL-7 in the thymus-independent long-term survival of functional naïve-Tregs, and highlight the potential of targeting the IL-7 pathway to modulate Tregs in different clinical settings.

  18. The Late-Type Extension to MoVeRS (LaTE-MoVeRS): Proper Motion Verified Low-mass Stars and Brown Dwarfs from SDSS, 2MASS, and WISE

    NASA Astrophysics Data System (ADS)

    Theissen, Christopher A.; West, Andrew A.; Shippee, Guillaume; Burgasser, Adam J.; Schmidt, Sarah J.

    2017-03-01

    We present the Late-Type Extension to the Motion Verified Red Stars (LaTE-MoVeRS) catalog, containing 46,463 photometric late-type (>M5) dwarfs within the Sloan Digital Sky Survey (SDSS) footprint. Proper motions were computed for objects combining astrometry from the SDSS Data Release 12 (DR12), the Two-micron All-Sky Survey (2MASS) Point Source Catalog, and the Wide-field Infrared Survey Explorer (WISE) AllWISE data sets. LaTE-MoVeRS objects were required to have significant proper motion ({μ }{tot}≥slant 2{σ }{μ {tot}}). Using the LaTE-MoVeRS sample and Gaia Data Release 1, we estimate Gaia will be ∼64% complete for very low-mass objects (>M5) in comparison to the combined SDSS+2MASS+WISE data set (i< 21.3). We computed photometric distances and estimated stellar effective temperatures for the LaTE-MoVeRS catalog. The majority of the dwarfs in the sample have distances < 150 pc and {T}{eff}< 3000 K. Thirteen objects that have not been previously identified as nearby objects were identified within LaTE-MoVeRS with estimated photometric distances within 25 pc. We also identified one new object that has not been previously identified with a large amount of excess mid-infrared flux (2MASS J11151597+1937266). This object appears to be an L2γ at ∼50 pc showing spectroscopic signs of a flaring event (e.g., strong hydrogen Balmer emission lines). This object does not exhibit kinematics similar to any known kinematic association. The LaTE-MoVeRS catalog is available through SDSS CasJobs and VizieR.

  19. Plasma cytokine abnormalities in drug-naïve, comorbidity-free obsessive-compulsive disorder.

    PubMed

    Rao, Naren P; Venkatasubramanian, Ganesan; Ravi, Vasanthapuram; Kalmady, Sunil; Cherian, Anish; Yc, Janardhan Reddy

    2015-10-30

    Growing evidence in the last decade suggest significant role of immune alterations in the pathogenesis of obsessive-compulsive disorder (OCD). Cytokines, mediators of inflammation, alter the neurotransmitter concentration and result in a hyposerotonergic and hyperglutamatergic state implicated in pathogenesis of OCD. However, only few studies have examined cytokine abnormalities in OCD with inconsistent results possibly due to confounding effects of medications and comorbid anxiety-depression. We examined 20 comorbidity free, drug free OCD patients and 20 age and sex matched healthy controls. Clinical severity was assessed using Yale Brown Obsessive Compulsive Scale, Hamilton anxiety rating scale, Hamilton depression rating scale and Clinical Global Impression. Levels of different cytokines, Interleukin (IL)-2, IL-4, IL-6, IL-10, Tumor necrosis factor (TNF)-α and Interferon (IFN)-γ were assessed using Cytometric Bead Array. OCD patients had significantly greater plasma levels of IL-2, IL-4, IL-6, IL-10 and TNF-α levels than controls but not IFN-γ. Reanalysis of data with only drug naïve patients (excluding 4 drug free patients) did not alter the results. Presence of these abnormalities in drug-naïve patients suggests the possible role of cytokines in the pathogenesis of OCD. Study findings have potential clinical utility in development of novel therapeutic options targeting cytokine aberrations in OCD. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  20. Cerebellar volume deficits in medication-naïve obsessive compulsive disorder.

    PubMed

    Narayanaswamy, Janardhanan C; Jose, Dania; Kalmady, Sunil V; Agarwal, Sri Mahavir; Venkatasubramanian, Ganesan; Janardhan Reddy, Y C

    2016-08-30

    Even though conventional neurobiological models of obsessive compulsive disorder (OCD) commonly demonstrate abnormalities involving fronto-striatal circuits, there is emerging evidence regarding the role of posterior brain structures such as cerebellum. In this study, we examined the cerebellar regional volume in a large sample of medication-naïve OCD patients compared to matched healthy controls (HC). In 49 medication naïve right handed OCD patients and 39 age and sex matched HC, sub-region wise volume of cerebellum was extracted from the T1 weighted images using Spatially Unbiased Infra tentorial Template (SUIT) toolbox and compared using hypothesis driven, region of interest approach after clinical assessment with standard scales. After controlling for age, sex and ICV, the subjects with OCD had significantly smaller cerebellum compared to HC, especially in the posterior lobe sub-regions - lobule VI and left crus 1. This study gives preliminary evidence for region specific cerebellar volumetric deficits in the pathophysiological of OCD. Regional cerebellar volume deficits conform to the abnormal connectivity of cerebellum to specific cortical regions and it is indicative of involvement of regions outside the conventional fronto-striatal circuitry. This might be important in the context of cognitive deficits seen in OCD. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  1. Clinical correlates of hippocampus volume and shape in antipsychotic-naïve schizophrenia.

    PubMed

    Kalmady, Sunil Vasu; Shivakumar, Venkataram; Arasappa, Rashmi; Subramaniam, Aditi; Gautham, S; Venkatasubramanian, Ganesan; Gangadhar, Bangalore N

    2017-05-30

    While volume deficit of hippocampus is an established finding in schizophrenia, very few studies have examined large sample of patients without the confounding effect of antipsychotic treatment. Concurrent evaluation of hippocampus shape will offer additional information on the hippocampal aberrations in schizophrenia. In this study, we analyzed the volume and shape of hippocampus in antipsychotic-naïve schizophrenia patients (N=71) in comparison to healthy controls (N=82). Using 3-T MRI data, gray matter (GM) volume (anterior and posterior sub-divisions) and shape of the hippocampus were analyzed. Schizophrenia patients had significant hippocampal GM volume deficits (specifically the anterior sub-division) in comparison to healthy controls. There were significant positive correlations between anterior hippocampus volume and psychopathology scores of positive syndrome. Shape analyses revealed significant inward deformation of bilateral hippocampal surface in patients. In conclusion, our study findings add robust support for volume deficit in hippocampus in antipsychotic-naïve schizophrenia. Hippocampal shape deficits in schizophrenia observed in this study map to anterior CA1 sub-region. The differential relationship of anterior hippocampus (but not posterior hippocampus) with clinical symptoms is in tune with the findings in animal models. Further systematic studies are needed to evaluate the relationship between these hippocampal gray matter deficits with white matter and functional connectivity to facilitate understanding the hippocampal network abnormalities in schizophrenia. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

  2. Morbidity and nutrition status of rural drug-naïve Kenyan women living with HIV.

    PubMed

    Neumann, Charlotte G; Nyandiko, Winstone; Siika, Abraham; Drorbaugh, Natalie; Samari, Goleen; Ettyang, Grace; Ernst, Judith A

    2016-09-01

    This paper describes morbidity in a group of HIV-positive drug-naïve rural women in western Kenya. A total of 226 drug-naïve HIV-positive women were evaluated for baseline morbidity, immune function, and anthropometry before a food-based nutrition intervention. Kenyan nurses visited women in their homes and conducted semi-structured interviews regarding symptoms and physical signs experienced at the time of the visit and during the previous week and physical inspection. Blood and urine samples were examined for determination of immune function (CD4, CD8, and total lymphocyte counts), anaemia, malaria, and pregnancy status. Intradermal skin testing with tuberculin (PPD), candida, and tetanus toxoid antigens was also performed to evaluate cell-mediated immunity. Anthropometry was measured, and body mass index (BMI) was calculated. Seventy-six per cent of the women reported being sick on the day of the interview or within the previous week. Illnesses considered serious were reported by 13.7% of women. The most frequent morbidity episodes reported were upper respiratory tract infections (13.3%), suspected malaria (5.85%), skeletal pain (4.87%), and stomach pain (4.42%). The most common morbidity signs on physical inspection were respiratory symptoms, most commonly rhinorrhea and coughing. Confirmed malaria and severe diarrhea were significantly associated with a higher BMI.

  3. Predicting drug-induced liver injury in human with Naïve Bayes classifier approach

    NASA Astrophysics Data System (ADS)

    Zhang, Hui; Ding, Lan; Zou, Yi; Hu, Shui-Qing; Huang, Hai-Guo; Kong, Wei-Bao; Zhang, Ji

    2016-10-01

    Drug-induced liver injury (DILI) is one of the major safety concerns in drug development. Although various toxicological studies assessing DILI risk have been developed, these methods were not sufficient in predicting DILI in humans. Thus, developing new tools and approaches to better predict DILI risk in humans has become an important and urgent task. In this study, we aimed to develop a computational model for assessment of the DILI risk with using a larger scale human dataset and Naïve Bayes classifier. The established Naïve Bayes prediction model was evaluated by 5-fold cross validation and an external test set. For the training set, the overall prediction accuracy of the 5-fold cross validation was 94.0 %. The sensitivity, specificity, positive predictive value and negative predictive value were 97.1, 89.2, 93.5 and 95.1 %, respectively. The test set with the concordance of 72.6 %, sensitivity of 72.5 %, specificity of 72.7 %, positive predictive value of 80.4 %, negative predictive value of 63.2 %. Furthermore, some important molecular descriptors related to DILI risk and some toxic/non-toxic fragments were identified. Thus, we hope the prediction model established here would be employed for the assessment of human DILI risk, and the obtained molecular descriptors and substructures should be taken into consideration in the design of new candidate compounds to help medicinal chemists rationally select the chemicals with the best prospects to be effective and safe.

  4. Caffeine Toxicity Due to Supplement Use in Caffeine--Naïve Individual: A Cautionary Tale.

    PubMed

    Lystrup, Robert M; Leggit, Jeffery C

    2015-08-01

    Thousands of military members self-medicate with dietary supplements containing unknown quantities of pharmacologically active compounds. These poorly regulated substances can cause real harm to the military population, especially when they contain stimulants such as caffeine. When taken regularly, caffeine has several performance-enhancing benefits. However, when used excessively or in vulnerable populations, caffeine can cause several unwanted side effects such as nervousness, sensory disturbances, insomnia, arrhythmia, excitability, inattentiveness, restlessness, mood changes, gastrointestinal disturbances, and even psychosis. Vulnerable patients include the caffeine-naïve, physiologically stressed, young, and mentally ill patients. One such case describes a caffeine-naïve service member who suffered an adverse reaction after taking an allegedly moderate dose of caffeine from a pill he obtained from a teammate. This case highlights the importance of supplement awareness among service members, increased provider vigilance, third party verification, and enhanced regulation on the approval and marketing of dietary supplements. Reprint & Copyright © 2015 Association of Military Surgeons of the U.S.

  5. Neonatal and prospective follow-up study of infants delivered by vacuum extraction (VE).

    PubMed

    Blennow, G; Svenningsen, N W; Gustafson, B; Sundén, B; Cronquist, S

    1977-01-01

    Forty infants delivered by vacuum extraction have been studied in the neonatal period--neurological examination, neonatal CSF-examinations, skull X-ray examination, transillumination and sonoencephalography --and at 14 months of age--developmental and behavioural evaluation, neurological examination, skull X-ray examination, sonoencephalography and electroencephalography. Two infants died in the neonatal period but in both cases a life-threatening situation of the fetus required immediate delivery. CSF cytological signs of haemorrhage were observed in 42% of the 26 infants who had a successful lumbar tap, compared to 10% found in normal deliveries. The result of the neonatal neurological study did not differ from that in a control group. The result of the skull X-ray examination and sonoencephalography were also within normal limits. In the follow-up study behavioural problems were found in 25%, but otherwise very few abnormalities were found. The deviatiosn found do not for the present indicate any later signs of brain lesions. It is concluded that this prospective study has shown that VE-delivery in fullterm babies seem to imply no risk fo serious cerebral sequelae. Further follow-up studies at a later age in order to evaluate the incidence of so-called minimal brain damage in VE-delivered children are required.

  6. Using Drama to Promote Argumentation in Science Education. The Case of "Should've"

    NASA Astrophysics Data System (ADS)

    Archila, Pablo Antonio

    2017-05-01

    The purpose of this study was to use drama as a springboard for promoting argumentation among 91 first-semester undergraduate medical students (56 females and 35 males, 16-30 years old) in Colombia during a complete teaching-learning sequence (TLS) supervised by the same teacher. The drama used was the play Should've, written by Nobel laureate Roald Hoffmann. The data was derived from students' written responses, audio and video recordings, and written field notes. This investigation provides evidence that an approach combining drama and argumentation could increase students' awareness of the relevance of ethics in science as one of the features of science (FOS). The findings show that the play Should've can be useful for promoting students' argumentation and is also appropriate for medical students. Future studies could include other science disciplines (e.g., astronomy, biology, chemistry, earth science, ecology, physics); students of other ages; and other plays and experiments in other parts of the world.

  7. A Naïve Bayes Approach to Classifying Topics in Suicide Notes

    PubMed Central

    Spasić, Irena; Burnap, Pete; Greenwood, Mark; Arribas-Ayllon, Michael

    2012-01-01

    The authors present a system developed for the 2011 i2b2 Challenge on Sentiment Classification, whose aim was to automatically classify sentences in suicide notes using a scheme of 15 topics, mostly emotions. The system combines machine learning with a rule-based methodology. The features used to represent a problem were based on lexico–semantic properties of individual words in addition to regular expressions used to represent patterns of word usage across different topics. A naïve Bayes classifier was trained using the features extracted from the training data consisting of 600 manually annotated suicide notes. Classification was then performed using the naïve Bayes classifier as well as a set of pattern–matching rules. The classification performance was evaluated against a manually prepared gold standard consisting of 300 suicide notes, in which 1,091 out of a total of 2,037 sentences were associated with a total of 1,272 annotations. The competing systems were ranked using the micro-averaged F-measure as the primary evaluation metric. Our system achieved the F-measure of 53% (with 55% precision and 52% recall), which was significantly better than the average performance of 48.75% achieved by the 26 participating teams. PMID:22879764

  8. Towards the Integration of APECS and VE-Suite for Virtual Power Plant Co-Simulation

    SciTech Connect

    Zitney, S.E.; McCorkle, D.; Yang, C.; Jordan, T.; Swensen, D.; Bryden, M.

    2007-05-01

    Process modeling and simulation tools are widely used for the design and operation of advanced power generation systems. These tools enable engineers to solve the critical process systems engineering problems that arise throughout the lifecycle of a power plant, such as designing a new process, troubleshooting a process unit or optimizing operations of the full process. To analyze the impact of complex thermal and fluid flow phenomena on overall power plant performance, the Department of Energy’s (DOE) National Energy Technology Laboratory (NETL) has developed the Advanced Process Engineering Co-Simulator (APECS). The APECS system is an integrated software suite that combines process simulation (e.g., Aspen Plus) and high-fidelity equipment simulations such as those based on computational fluid dynamics (CFD), together with advanced analysis capabilities including case studies, sensitivity analysis, stochastic simulation for risk/uncertainty analysis, and multi-objective optimization. In this paper we discuss the initial phases of the integration of the APECS system with the immersive and interactive virtual engineering software, VE-Suite, developed at Iowa State University and Ames Laboratory. VE-Suite uses the ActiveX (OLE Automation) controls in the Aspen Plus process simulator wrapped by the CASI library developed by Reaction Engineering International to run process/CFD co-simulations and query for results. This integration represents a necessary step in the development of virtual power plant co-simulations that will ultimately reduce the time, cost, and technical risk of developing advanced power generation systems.

  9. Safety and Antitumour Activity of ODM-201 (BAY-1841788) in Chemotherapy-naïve and CYP17 Inhibitor-naïve Patients: Follow-up from the ARADES and ARAFOR Trials.

    PubMed

    Shore, Neal D; Tammela, Teuvo L; Massard, Christophe; Bono, Petri; Aspegren, John; Mustonen, Mika; Fizazi, Karim

    2017-02-14

    ODM-201, a new androgen receptor antagonist for treatment of metastatic castration-resistant prostate cancer (mCRPC), demonstrated antitumour activity and acceptable tolerability in phase 1/2 trials. To determine the antitumour activity and safety profile of extended treatment with ODM-201 in men with mCRPC. ARADES and ARAFOR trials with ODM-201 enrolled chemotherapy-naïve and CYP17 inhibitor (CYP17i)-naïve mCRPC patients. Both trials had extended follow-up. Here we report results for chemotherapy-naïve and CYP17i-naïve patients from both trials (data cutoff October 2014 for ARADES and April 2015 for ARAFOR) after extended follow-up. A total of 41 chemotherapy-naïve and CYP17i-naïve patients received oral ODM-201 twice daily (total daily dose of 1200, 1400 or 1800mg). Antitumour activity was assessed in terms of prostate-specific antigen (PSA) declines and PSA/radiographic progression. Safety was assessed until disease progression and/or drug discontinuation due to any intolerable adverse event (AE). ODM-201 safety data after a median treatment time of 13.5 mo (95% confidence interval [CI] 9.7-15.6, interquartile range [IQR] 7.5-22.0) were similar to those reported in the main ARADES and ARAFOR trials. The overall AE incidence was 80.5% (n=33/41), with 58.5% (n=24/41) of patients experiencing only grade 1-2 AEs. The most common AEs were fatigue, back pain, diarrhoea, nausea, and pain in extremity. The median times to PSA and radiological progression were 12.4 mo (95% CI 6.3-18.2, IQR 5.5-22.0) and 15.3 mo (95% CI 9.5-not reached [NR], IQR 6.3-NR), respectively. Extended treatment with ODM-201 (1200-1800mg/d) was well tolerated, with no new safety concerns, and provided evidence of sustained antitumour activity in chemotherapy-naïve and CYP17i-naïve patients with mCRPC. Prolonged treatment with high doses of ODM-201 was well tolerated and provided long-lasting disease control in patients with mCRPC. ODM-201 represents a therapeutic treatment option for m

  10. [Efficacy of dolutegravir in treatment-naïve patients. The SPRING-1, SPRING-2, SINGLE and FLAMINGO trials].

    PubMed

    Bernardino, José I; Antela, Antonio

    2015-03-01

    The efficacy of dolutegravir (DTG) in treatment-naïve patients has been analyzed in the SPRING 1 and 2, SINGLE and FLAMINGO trials, which compared dolutegravir with the agents currently recommended as the drugs of choice in clinical practice guidelines in treatment-naïve patients: efavirenz, raltegravir and darunavir/ritonavir. These trials confirmed the superiority (SINGLE and FLAMINGO) or the non-inferiority (SPRING-2) of dolutegravir. More than 2,000 patients were included in these 4 studies, lending value to their results and reinforcing the view of dolutegravir as the drug of choice in treatment-naïve patients, accompanied either by abacavir/lamivudine (Kivexa(®)) or tenofovir/emtricitabine (Truvada®).

  11. The metabolome regulates the epigenetic landscape during naïve to primed human embryonic stem cell transition

    PubMed Central

    Sperber, Henrik; Mathieu, Julie; Wang, Yuliang; Ferreccio, Amy; Hesson, Jennifer; Xu, Zhuojin; Fischer, Karin A.; Devi, Arikketh; Detraux, Damien; Gu, Haiwei; Battle, Stephanie L.; Showalter, Megan; Valensisi, Cristina; Bielas, Jason H.; Ericson, Nolan G.; Margaretha, Lilyana; Robitaille, Aaron M.; Margineantu, Daciana; Fiehn, Oliver; Hockenbery, David; Blau, C. Anthony; Raftery, Daniel; Margolin, Adam; Hawkins, R. David; Moon, Randall T.; Ware, Carol B.; Ruohola-Baker, Hannele

    2015-01-01

    For nearly a century developmental biologists have recognized that cells from embryos can differ in their potential to differentiate into distinct cell types. Recently, it has been recognized that embryonic stem cells derived from both mice and humans display two stable yet epigenetically distinct states of pluripotency, naïve and primed. We now show that nicotinamide-N-methyl transferase (NNMT) and metabolic state regulate pluripotency in hESCs. Specifically, in naïve hESCs NNMT and its enzymatic product 1-methylnicotinamide (1-MNA) are highly upregulated, and NNMT is required for low SAM levels and H3K27me3 repressive state. NNMT consumes SAM in naïve cells, making it unavailable for histone methylation that represses Wnt and activates HIF pathway in primed hESCs. These data support the hypothesis that the metabolome regulates the epigenetic landscape of the earliest steps in human development. PMID:26571212

  12. Alterations in Polysomnographic (PSG) profile in drug-naïve Parkinson's disease

    PubMed Central

    Joy, Sanju P.; Sinha, Sanjib; Pal, Pramod Kumar; Panda, Samhita; Philip, Mariamma; Taly, Arun B.

    2014-01-01

    Objective: We studied the changes in Polysomnographic (PSG) profile in drug-naïve patients of Parkinson's disease (PD) who underwent evaluation with sleep overnight PSG. Materials and Methods: This prospective study included 30 with newly diagnosed levodopa-naïve patients with PD, fulfilling the UK-PD society brain bank clinical diagnostic criteria (M:F = 25:5; age: 57.2 ± 10.7 years). The disease severity scales and sleep related questionnaires were administered, and then patients were subjected to overnight PSG. Results: The mean duration of illness was 9.7 ± 9.5 months. The mean Hoehn and Yahr stage was 1.8 ± 0.4. The mean Unified Parkinson's Disease Rating Scale (UPDRS) motor score improved from 27.7 ± 9.2 to 17.5 ± 8.9 with sustained usage of levodopa. Nocturnal sleep as assessed by Pittsburgh Sleep Quality Index (PSQI) was impaired in 10 (33.3%) patients (mean PSQI score: 5.1 ± 3.1). Excessive day time somnolence was recorded in three patients with Epworth Sleepiness Scale (ESS) score ≥ 10 (mean ESS score: 4.0 ± 3.4). PSG analysis revealed that poor sleep efficiency of <85% was present in 86.7% of patients (mean: 68.3 ± 21.3%). The latencies to sleep onset (mean: 49.8 ± 67.0 minutes) and stage 2 sleep (36.5 ± 13.1%) were prolonged while slow wave sleep was shortened. Respiration during sleep was significantly impaired in which 43.3% had impaired apnoea hyperpnoea index (AHI) ≥5, mean AHI: 8.3 ± 12.1). Apnoeic episodes were predominantly obstructive (obstructive sleep apnea, OSA index = 2.2 ± 5.1). These patients had periodic leg movement (PLM) disorder (56.7% had PLM index of 5 or more, mean PLMI: 27.53 ± 4 9.05) that resulted in excessive daytime somnolence. Conclusions: To conclude, sleep macro-architecture is altered in frequently and variably in levodopa-naïve patients of PD and the alterations are possibly due to disease process per se. PMID:25221397

  13. miRNA Profiling of Naïve, Effector and Memory CD8 T Cells

    PubMed Central

    Wu, Haoquan; Neilson, Joel R.; Kumar, Priti; Manocha, Monika; Shankar, Premlata; Sharp, Phillip A.; Manjunath, N.

    2007-01-01

    microRNAs have recently emerged as master regulators of gene expression during development and cell differentiation. Although profound changes in gene expression also occur during antigen-induced T cell differentiation, the role of miRNAs in the process is not known. We compared the miRNA expression profiles between antigen-specific naïve, effector and memory CD8+ T cells using 3 different methods-small RNA cloning, miRNA microarray analysis and real-time PCR. Although many miRNAs were expressed in all the T cell subsets, the frequency of 7 miRNAs (miR-16, miR-21, miR-142-3p, miR-142-5p, miR-150, miR-15b and let-7f) alone accounted for ∼60% of all miRNAs, and their expression was several fold higher than the other expressed miRNAs. Global downregulation of miRNAs (including 6/7 dominantly expressed miRNAs) was observed in effector T cells compared to naïve cells and the miRNA expression levels tended to come back up in memory T cells. However, a few miRNAs, notably miR-21 were higher in effector and memory T cells compared to naïve T cells. These results suggest that concomitant with profound changes in gene expression, miRNA profile also changes dynamically during T cell differentiation. Sequence analysis of the cloned mature miRNAs revealed an extensive degree of end polymorphism. While 3′end polymorphisms dominated, heterogeneity at both ends, resembling drosha/dicer processing shift was also seen in miR-142, suggesting a possible novel mechanism to generate new miRNA and/or to diversify miRNA target selection. Overall, our results suggest that dynamic changes in the expression of miRNAs may be important for the regulation of gene expression during antigen-induced T cell differentiation. Our study also suggests possible novel mechanisms for miRNA biogenesis and function. PMID:17925868

  14. p120-catenin regulates VE-cadherin endocytosis and degradation induced by the Kaposi sarcoma–associated ubiquitin ligase K5

    PubMed Central

    Nanes, Benjamin A.; Grimsley-Myers, Cynthia M.; Cadwell, Chantel M.; Robinson, Brian S.; Lowery, Anthony M.; Vincent, Peter A.; Mosunjac, Marina; Früh, Klaus; Kowalczyk, Andrew P.

    2017-01-01

    Vascular endothelial (VE)-cadherin undergoes constitutive internalization driven by a unique endocytic motif that also serves as a p120-catenin (p120) binding site. p120 binding masks the motif, stabilizing the cadherin at cell junctions. This mechanism allows constitutive VE-cadherin endocytosis and recycling to contribute to adherens junction dynamics without resulting in junction disassembly. Here we identify an additional motif that drives VE-cadherin endocytosis and pathological junction disassembly associated with the endothelial-derived tumor Kaposi sarcoma. Human herpesvirus 8, which causes Kaposi sarcoma, expresses the MARCH family ubiquitin ligase K5. We report that K5 targets two membrane-proximal VE-cadherin lysine residues for ubiquitination, driving endocytosis and down-regulation of the cadherin. K5-induced VE-cadherin endocytosis does not require the constitutive endocytic motif. However, K5-induced VE-cadherin endocytosis is associated with displacement of p120 from the cadherin, and p120 protects VE-cadherin from K5. Thus multiple context-dependent signals drive VE-cadherin endocytosis, but p120 binding to the cadherin juxtamembrane domain acts as a master regulator guarding cadherin stability. PMID:27798235

  15. p120-catenin regulates VE-cadherin endocytosis and degradation induced by the Kaposi sarcoma-associated ubiquitin ligase K5.

    PubMed

    Nanes, Benjamin A; Grimsley-Myers, Cynthia M; Cadwell, Chantel M; Robinson, Brian S; Lowery, Anthony M; Vincent, Peter A; Mosunjac, Marina; Früh, Klaus; Kowalczyk, Andrew P

    2017-01-01

    Vascular endothelial (VE)-cadherin undergoes constitutive internalization driven by a unique endocytic motif that also serves as a p120-catenin (p120) binding site. p120 binding masks the motif, stabilizing the cadherin at cell junctions. This mechanism allows constitutive VE-cadherin endocytosis and recycling to contribute to adherens junction dynamics without resulting in junction disassembly. Here we identify an additional motif that drives VE-cadherin endocytosis and pathological junction disassembly associated with the endothelial-derived tumor Kaposi sarcoma. Human herpesvirus 8, which causes Kaposi sarcoma, expresses the MARCH family ubiquitin ligase K5. We report that K5 targets two membrane-proximal VE-cadherin lysine residues for ubiquitination, driving endocytosis and down-regulation of the cadherin. K5-induced VE-cadherin endocytosis does not require the constitutive endocytic motif. However, K5-induced VE-cadherin endocytosis is associated with displacement of p120 from the cadherin, and p120 protects VE-cadherin from K5. Thus multiple context-dependent signals drive VE-cadherin endocytosis, but p120 binding to the cadherin juxtamembrane domain acts as a master regulator guarding cadherin stability. © 2017 Nanes et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

  16. Naïve conceptions about multimedia learning: a study on primary school textbooks

    PubMed Central

    Colombo, Barbara; Antonietti, Alessandro

    2013-01-01

    HIGHLIGHTS This interview study explores beliefs about the instructional role of illustrationsWe compared illustrators', teachers', students' and common people's ideasParticipants' responses were internally coherent and close to multimedia learning theoryWe propose and discuss an integrated multimedia learning model An interview study, based on specific pictures taken from textbooks used in primary schools, was carried out to investigate illustrators', teachers', students', and common people's beliefs about the role that illustrations play in facilitating learning. Participants' responses were internally coherent, indicating a systematic nature of the underlying naïve conceptions. Findings disprove Mayer's pessimistic claim that laypersons' conceptions of multimedia learning fail to match experimentally supported principles and theories. On the contrary, interviewees spontaneously came very close to the multimedia learning theory, which states that students learn better from pictures, which fit specific cognitive principles. Implications for school instruction are highlighted. PMID:23908636

  17. Naïve conceptions about multimedia learning: a study on primary school textbooks.

    PubMed

    Colombo, Barbara; Antonietti, Alessandro

    2013-01-01

    HIGHLIGHTSThis interview study explores beliefs about the instructional role of illustrationsWe compared illustrators', teachers', students' and common people's ideasParticipants' responses were internally coherent and close to multimedia learning theoryWe propose and discuss an integrated multimedia learning model An interview study, based on specific pictures taken from textbooks used in primary schools, was carried out to investigate illustrators', teachers', students', and common people's beliefs about the role that illustrations play in facilitating learning. Participants' responses were internally coherent, indicating a systematic nature of the underlying naïve conceptions. Findings disprove Mayer's pessimistic claim that laypersons' conceptions of multimedia learning fail to match experimentally supported principles and theories. On the contrary, interviewees spontaneously came very close to the multimedia learning theory, which states that students learn better from pictures, which fit specific cognitive principles. Implications for school instruction are highlighted.

  18. Influenza-like illness surveillance on Twitter through automated learning of naïve language.

    PubMed

    Gesualdo, Francesco; Stilo, Giovanni; Agricola, Eleonora; Gonfiantini, Michaela V; Pandolfi, Elisabetta; Velardi, Paola; Tozzi, Alberto E

    2013-01-01

    Twitter has the potential to be a timely and cost-effective source of data for syndromic surveillance. When speaking of an illness, Twitter users often report a combination of symptoms, rather than a suspected or final diagnosis, using naïve, everyday language. We developed a minimally trained algorithm that exploits the abundance of health-related web pages to identify all jargon expressions related to a specific technical term. We then translated an influenza case definition into a Boolean query, each symptom being described by a technical term and all related jargon expressions, as identified by the algorithm. Subsequently, we monitored all tweets that reported a combination of symptoms satisfying the case definition query. In order to geolocalize messages, we defined 3 localization strategies based on codes associated with each tweet. We found a high correlation coefficient between the trend of our influenza-positive tweets and ILI trends identified by US traditional surveillance systems.

  19. Taking Stock: where WE’VE been, where we are, where WE’RE Going

    NASA Astrophysics Data System (ADS)

    Clewell, Beatriz Chu; Campbell, Patricia B.

    Focusing on “where we’ve been, where we are, and where we’re going,” the authors examine minority women’s and White women’s progress in science, mathematics, engineering, and technology (SMET) over the past decade. Starting from an exploration of participation and achievement data, the authors move on to cover the theories behind SMET gender differences, including those based on testing, biology, social-psychology, and cognitive sciences. Looking at practice as well as theory, the authors explore the impacts that interventions and contextual influences, such as societal change and education reform, have had on efforts to achieve gender parity in SMET. The article concludes with the recommendation of logical next steps to preserve and expand the gains made by women in these fields.

  20. Learning accurate and concise naïve Bayes classifiers from attribute value taxonomies and data

    PubMed Central

    Kang, D.-K.; Silvescu, A.; Honavar, V.

    2009-01-01

    In many application domains, there is a need for learning algorithms that can effectively exploit attribute value taxonomies (AVT)—hierarchical groupings of attribute values—to learn compact, comprehensible and accurate classifiers from data—including data that are partially specified. This paper describes AVT-NBL, a natural generalization of the naïve Bayes learner (NBL), for learning classifiers from AVT and data. Our experimental results show that AVT-NBL is able to generate classifiers that are substantially more compact and more accurate than those produced by NBL on a broad range of data sets with different percentages of partially specified values. We also show that AVT-NBL is more efficient in its use of training data: AVT-NBL produces classifiers that outperform those produced by NBL using substantially fewer training examples. PMID:20351793

  1. Characterization of naïve, memory and effector T cells in progressive multiple sclerosis.

    PubMed

    Nielsen, Birgitte Romme; Ratzer, Rikke; Börnsen, Lars; von Essen, Marina Rode; Christensen, Jeppe Romme; Sellebjerg, Finn

    2017-09-15

    We characterized naïve, central memory (CM), effector memory (EM) and terminally differentiated effector memory (TEMRA) CD4(+) and CD8(+) T cells and their expression of CD49d and CD26 in peripheral blood in patients with multiple sclerosis (MS) and healthy controls. CD26(+) CD28(+) CD4(+) TEMRA T cells were increased in all subtypes of MS, and CD26(+) CD28(+) CD8(+) TEMRA T cells were increased in relapsing-remitting and secondary progressive MS. Conversely, in progressive MS, CD49d(+) CM T cells were decreased and natalizumab increased the circulating number of all six subsets but reduced the frequency of most subsets expressing CD49d and CD26. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. Investigation of Blue Bedding in Cages Housing Treatment-Naïve Hamsters.

    PubMed

    Shah, Vishal D; Walton, Betsy J; Culp, Amanda G; Castellino, Stephen

    2015-11-01

    During the acclimation phase of a preclinical safety study involving Syrian golden hamsters, some of the cages of treatment-naïve animals were noted to contain blue-tinged bedding; the urine of these hamsters was not discolored. We sought to understand the underlying cause of this unusual finding to ensure that the study animals were healthy and free from factors that might confound the interpretation of the study. Analysis of extracts from the blue bedding by using HPLC with inline UV detection and high-resolution mass spectrometry indicated that the color was due to the presence of indigo blue. Furthermore, the indigo blue likely was formed through a series of biochemical events initiated by the intestinal metabolism of tryptophan to an indoxyl metabolite. We offer 2 hypotheses regarding the fate of the indoxyl metabolite: indigo blue formation through oxidative coupling in the liver or through urinary bacterial metabolism.

  3. Influenza-Like Illness Surveillance on Twitter through Automated Learning of Naïve Language

    PubMed Central

    Gesualdo, Francesco; Stilo, Giovanni; Agricola, Eleonora; Gonfiantini, Michaela V.; Pandolfi, Elisabetta; Velardi, Paola; Tozzi, Alberto E.

    2013-01-01

    Twitter has the potential to be a timely and cost-effective source of data for syndromic surveillance. When speaking of an illness, Twitter users often report a combination of symptoms, rather than a suspected or final diagnosis, using naïve, everyday language. We developed a minimally trained algorithm that exploits the abundance of health-related web pages to identify all jargon expressions related to a specific technical term. We then translated an influenza case definition into a Boolean query, each symptom being described by a technical term and all related jargon expressions, as identified by the algorithm. Subsequently, we monitored all tweets that reported a combination of symptoms satisfying the case definition query. In order to geolocalize messages, we defined 3 localization strategies based on codes associated with each tweet. We found a high correlation coefficient between the trend of our influenza-positive tweets and ILI trends identified by US traditional surveillance systems. PMID:24324799

  4. Investigation of Blue Bedding in Cages Housing Treatment-Naïve Hamsters

    PubMed Central

    Shah, Vishal D; Walton, Betsy J; Culp, Amanda G; Castellino, Stephen

    2015-01-01

    During the acclimation phase of a preclinical safety study involving Syrian golden hamsters, some of the cages of treatment-naïve animals were noted to contain blue-tinged bedding; the urine of these hamsters was not discolored. We sought to understand the underlying cause of this unusual finding to ensure that the study animals were healthy and free from factors that might confound the interpretation of the study. Analysis of extracts from the blue bedding by using HPLC with inline UV detection and high-resolution mass spectrometry indicated that the color was due to the presence of indigo blue. Furthermore, the indigo blue likely was formed through a series of biochemical events initiated by the intestinal metabolism of tryptophan to an indoxyl metabolite. We offer 2 hypotheses regarding the fate of the indoxyl metabolite: indigo blue formation through oxidative coupling in the liver or through urinary bacterial metabolism. PMID:26632791

  5. Safety and efficacy of fingolimod in treatment-naïve multiple sclerosis patients.

    PubMed

    Marriott, James J

    2011-01-01

    Fingolimod was recently approved for use in the United States after two phase III trials confirmed its effectiveness in reducing disease activity in relapsing-remitting multiple sclerosis. These positive results, coupled with the important fact that this is the first oral disease-modifying therapy, has lead to considerable enthusiasm amongst physicians and patients. However, fingolimod is associated with rare but serious adverse events. In addition, unlike conventional disease-modifying therapies, cardiopulmonary, ophthalmological and dermatological safety monitoring unfamiliar to both neurologists and patients is required before and during treatment. This paper will discuss these issues from the perspective of using fingolimod as a first-line disease-modifying therapy in treatment-naïve relapsing-remitting multiple sclerosis patients.

  6. You've Written a Cool Astronomy Code! Now What Do You Do with It?

    NASA Astrophysics Data System (ADS)

    Allen, Alice; Accomazzi, A.; Berriman, G. B.; DuPrie, K.; Hanisch, R. J.; Mink, J. D.; Nemiroff, R. J.; Shamir, L.; Shortridge, K.; Taylor, M. B.; Teuben, P. J.; Wallin, J. F.

    2014-01-01

    Now that you've written a useful astronomy code for your soon-to-be-published research, you have to figure out what you want to do with it. Our suggestion? Share it! This presentation highlights the means and benefits of sharing your code. Make your code citable -- submit it to the Astrophysics Source Code Library and have it indexed by ADS! The Astrophysics Source Code Library (ASCL) is a free online registry of source codes of interest to astronomers and astrophysicists. With over 700 codes, it is continuing its rapid growth, with an average of 17 new codes a month. The editors seek out codes for inclusion; indexing by ADS improves the discoverability of codes and provides a way to cite codes as separate entries, especially codes without papers that describe them.

  7. Aspect-based sentiment analysis to review products using Naïve Bayes

    NASA Astrophysics Data System (ADS)

    Mubarok, Mohamad Syahrul; Adiwijaya, Aldhi, Muhammad Dwi

    2017-08-01

    Product reviews can provide great benefits for consumers and producers. Number of reviews could be ranging from hundreds to thousands and containing various opinions. These make the process of analyzing and extracting information on existing reviews become increasingly difficult. In this research, sentiment analysis was used to analyze and extract sentiment polarity on product reviews based on a specific aspect of the product. This research was conducted in three phases, such as data preprocessing which involves part-of-speech (POS) tagging, feature selection using Chi Square, and classification of sentiment polarity of aspects using Naïve Bayes. Based on evaluation results, it is known that the system is able to perform aspect-based sentiment analysis with its highest F1-Measure of 78.12%.

  8. Pituitary volume in medication-naïve adults with obsessive compulsive disorder.

    PubMed

    Narayanaswamy, Janardhanan C; Jose, Dania; Kalmady, Sunil V; Venkatasubramanian, Ganesan; Reddy, Y C Janardhan

    2015-01-01

    Pituitary volume is considered to reflect hypothalamic-pituitary-adrenal axis dysregulation, and this has been studied in various psychiatric disorders. This study demonstrates that pituitary volume as assessed through the region of interest manual tracing method in 50 medication-naïve adult patients with obsessive-compulsive disorder was not significantly different compared with 40 healthy control subjects (687.80 ± 126.60 versus 694.73 ± 131.59, F=0.55, p=0.46). The authors also compared the patients with obsessive-compulsive disorder without any comorbid axis I conditions (N=35) with healthy control subjects and found no difference in the pituitary volumes (681.62 ± 130.85 versus 694.72 ± 131.59, F=0.90, p=0.35). This emphasizes the need to examine hypothalamo-pituitary axis structures after taking into consideration various potential confounders such as medications and depression.

  9. Corpus callosum abnormalities in medication-naïve adult patients with obsessive compulsive disorder.

    PubMed

    Jose, Dania; Narayanaswamy, Janardhanan C; Agarwal, Sri Mahavir; Kalmady, Sunil V; Venkatasubramanian, Ganesan; Reddy, Y C Janardhan

    2015-03-30

    Emerging evidence demonstrates widespread abnormalities involving white matter (WM) tracts connecting different cortical regions in obsessive-compulsive disorder (OCD). The corpus callosum (CC), the largest inter-hemispheric tract connecting the association cortices, has been shown to be affected in OCD. This study examines CC abnormalities in a large sample of medication-naïve OCD patients in comparison to matched healthy controls (HCs). We examined the mid-sagittal area of the CC in medication-naïve OCD patients (n=49) in comparison with age-, sex-, and handedness-matched HCs (n=38). Witelson's method was used to measure the sub-regions of the CC - namely, the genu, body, isthmus and splenium - with good inter-rater reliability. The area of the body of the CC and total CC area were significantly larger in OCD patients than in HCs after controlling for age, sex and intracranial area. The Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) compulsion score had a significant negative correlation with the areas of the isthmus and splenium of the CC in addition to the total CC area. The region-specific differences in the body of the CC and the region-specific association of severity score with posterior regions of the CC might be indicative of the involvement of additional areas like the dorsolateral prefrontal cortex, posterior parietal areas, occipital and association cortices in OCD that extend beyond the conventional orbito-fronto-striatal circuitry that is often posited to be involved in OCD. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  10. HIV DNA Reservoir Increases Risk for Cognitive Disorders in cART-Naïve Patients

    PubMed Central

    Valcour, Victor G.; Ananworanich, Jintanat; Agsalda, Melissa; Sailasuta, Napapon; Chalermchai, Thep; Schuetz, Alexandra; Shikuma, Cecilia; Liang, Chin-Yuan; Jirajariyavej, Supunee; Sithinamsuwan, Pasiri; Tipsuk, Somporn; Clifford, David B.; Paul, Robert; Fletcher, James L. K.; Marovich, Mary A.; Slike, Bonnie M.; DeGruttola, Victor; Shiramizu, Bruce

    2013-01-01

    Objectives Cognitive impairment remains frequent in HIV, despite combination antiretroviral therapy (cART). Leading theories implicate peripheral monocyte HIV DNA reservoirs as a mechanism for spread of the virus to the brain. These reservoirs remain present despite cART. The objective of this study was to determine if the level of HIV DNA in CD14+ enriched monocytes predicted cognitive impairment and brain injury. Methods We enrolled 61 cART-naïve HIV-infected Thais in a prospective study and measured HIV DNA in CD14+ enriched monocyte samples in a blinded fashion. We determined HAND diagnoses by consensus panel and all participants underwent magnetic resonance spectroscopy (MRS) to measure markers of brain injury. Immune activation was measured via cytokines in cerebrospinal fluid (CSF). Results The mean (SD) age was 35 (6.9) years, CD4 T-lymphocyte count was 236 (139) and log10 plasma HIV RNA was 4.8 (0.73). Twenty-eight of 61 met HAND criteria. The log10 CD14+ HIV DNA was associated with HAND in unadjusted and adjusted models (p = 0.001). There was a 14.5 increased odds ratio for HAND per 1 log-value of HIV DNA (10-fold increase in copy number). Plasma CD14+ HIV DNA was associated with plasma and CSF neopterin (p = 0.023) and with MRS markers of neuronal injury (lower N-acetyl aspartate) and glial dysfunction (higher myoinositol) in multiple brain regions. Interpretation Reservoir burden of HIV DNA in monocyte-enriched (CD14+) peripheral blood cells increases risk for HAND in treatment-naïve HIV+ subjects and is directly associated with CSF immune activation and both brain injury and glial dysfunction by MRS. PMID:23936155

  11. Homotopic connectivity in drug-naïve, first-episode, early-onset schizophrenia

    PubMed Central

    Li, Hui-Jie; Xu, Yong; Zhang, Ke-Rang; Hoptman, Matthew J.; Zuo, Xi-Nian

    2014-01-01

    Background The disconnection hypothesis of schizophrenia has been extensively tested in adults. Recent studies have reported the presence of brain disconnection in younger patients, adding evidence to support the neurodevelopmental hypothesis of schizophrenia. Because of drug confounds in chronic and medicated patients, it has been extremely challenging for researchers to directly investigate abnormalities in the development of connectivity and their role in the pathophysiology of schizophrenia. The present study aimed to examine functional homotopy – a measure of interhemispheric connection – and its relevance to clinical symptoms in first-episode drug-naïve early-onset schizophrenia (EOS) patients. Methods Resting-state functional magnetic resonance imaging was performed in 26 first-episode drug-naïve EOS patients (age: 14.5 ± 1.94, 13 males) and 25 matched typically developing controls (TDCs) (age: 14.4 ± 2.97, 13 males). We were mainly concerned with the functional connectivity between any pair of symmetric inter-hemispheric voxels (i.e., functional homotopy) measured by voxel-mirrored homotopic connectivity (VMHC). Results EOS patients exhibited both global and regional VMHC reductions in comparison with TDCs. Reduced VMHC values were observed within the superior temporal cortex and postcentral gyrus. These interhemispheric synchronization deficits were negatively correlated with negative symptom of the Positive and Negative Syndrome Scale. Moreover, regions of interest analyses based on left and right clusters of temporal cortex and postcentral gyrus revealed abnormal heterotopic connectivity in EOS patients. Conclusions Our findings provide novel neurodevelopmental evidence for the disconnection hypothesis of schizophrenia and suggest that these alterations occur early in the course of the disease and are independent of medication status. PMID:25130214

  12. Bayesian estimation of Karhunen-Loève expansions; A random subspace approach

    NASA Astrophysics Data System (ADS)

    Chowdhary, Kenny; Najm, Habib N.

    2016-08-01

    One of the most widely-used procedures for dimensionality reduction of high dimensional data is Principal Component Analysis (PCA). More broadly, low-dimensional stochastic representation of random fields with finite variance is provided via the well known Karhunen-Loève expansion (KLE). The KLE is analogous to a Fourier series expansion for a random process, where the goal is to find an orthogonal transformation for the data such that the projection of the data onto this orthogonal subspace is optimal in the L2 sense, i.e., which minimizes the mean square error. In practice, this orthogonal transformation is determined by performing an SVD (Singular Value Decomposition) on the sample covariance matrix or on the data matrix itself. Sampling error is typically ignored when quantifying the principal components, or, equivalently, basis functions of the KLE. Furthermore, it is exacerbated when the sample size is much smaller than the dimension of the random field. In this paper, we introduce a Bayesian KLE procedure, allowing one to obtain a probabilistic model on the principal components, which can account for inaccuracies due to limited sample size. The probabilistic model is built via Bayesian inference, from which the posterior becomes the matrix Bingham density over the space of orthonormal matrices. We use a modified Gibbs sampling procedure to sample on this space and then build probabilistic Karhunen-Loève expansions over random subspaces to obtain a set of low-dimensional surrogates of the stochastic process. We illustrate this probabilistic procedure with a finite dimensional stochastic process inspired by Brownian motion.

  13. Characterization of bovine embryos cultured under conditions appropriate for sustaining human naïve pluripotency

    PubMed Central

    van Tol, Helena T. A.; Groot Koerkamp, Marian J. A.; Wubbolts, Richard W.; Haagsman, Henk P.; Roelen, Bernard A. J.

    2017-01-01

    In mammalian preimplantation development, pluripotent cells are set aside from cells that contribute to extra-embryonic tissues. Although the pluripotent cell population of mouse and human embryos can be cultured as embryonic stem cells, little is known about the pathways involved in formation of a bovine pluripotent cell population, nor how to maintain these cells in vitro. The objective of this study was to determine the transcriptomic profile related to bovine pluripotency. Therefore, in vitro derived embryos were cultured in various culture media that recently have been reported capable of maintaining the naïve pluripotent state of human embryonic cells. Gene expression profiles of embryos cultured in these media were compared using microarray analysis and quantitative RT-PCR. Compared to standard culture conditions, embryo culture in ‘naïve’ media reduced mRNA expression levels of the key pluripotency markers NANOG and POU5F1. A relatively high percentage of genes with differential expression levels were located on the X-chromosome. In addition, reduced XIST expression was detected in embryos cultured in naïve media and female embryos contained fewer cells with H3K27me3 foci, indicating a delay in X-chromosome inactivation. Whole embryos cultured in one of the media, 5iLA, could be maintained until 23 days post fertilization. Together these data indicate that ‘naïve’ conditions do not lead to altered expression of known genes involved in pluripotency. Interestingly, X-chromosome inactivation and development of bovine embryos were dependent on the culture conditions. PMID:28241084

  14. Abnormalities of cingulate cortex in antipsychotic-naïve chronic schizophrenia.

    PubMed

    Liu, Xiaoyi; Wang, Xijin; Lai, Yunyao; Hao, Chuanxi; Chen, Lei; Zhou, Zhenyu; Yu, Xin; Hong, Nan

    2016-05-01

    While several morphometric studies have postulated a critical contribution of the cingulate cortex (CC) to the pathophysiology of schizophrenia based on abnormalities in CC volume, other studies have been inconclusive. Most such studies have focused only on changes in cortical volume, whereas other morphometric parameters such as surface area and cortical thickness could be more relevant and possibly account for these discrepancies. Furthermore, factors such as antipsychotic drug use and treatment duration may also influence cortical morphology. To clarify the association between schizophrenia and CC deficits, we investigated morphometric abnormalities of the CC in antipsychotic drug (AD)-naïve chronic schizophrenia patients by comparing T1-weighted magnetic resonance images (T1WI-MRI) from patients (n=17) to healthy controls (n=17) using the surface-based morphometry program FreeSurfer. Partial correlations were examined between abnormal morphometric measures and both clinical variables and cognitive performance scores. Compared to healthy controls, drug-naïve schizophrenia patients exhibited significantly lower volumes in both left rostral anterior CC (rACC) and left posterior CC (PCC). These reductions in CC volume resulted from reduced surface area rather than reduced cortical thickness. There was also a significant relationship between left PCC volume and working memory in patients. No significant correlations were observed between CC volume and clinical variables. The results suggest that abnormalities in the CC as manifested by reduced surface area may contribute to cognitive dysfunction in schizophrenia. This article is part of a Special Issue entitled SI: PSC and the brain.

  15. Lung Microbiome Analysis in Steroid-Naїve Asthma Patients by Using Whole Sputum

    PubMed Central

    Jung, Jae-Woo; Choi, Jae-Chol; Shin, Jong-Wook; Kim, Jae-Yeol; Park, In-Won; Choi, Byoung Whui; Park, Heung-Woo; Cho, Sang-Heon

    2016-01-01

    Background Although recent metagenomic approaches have characterized the distinguished microbial compositions in airways of asthmatics, these results did not reach a consensus due to the small sample size, non-standardization of specimens and medication status. We conducted a metagenomics approach by using terminal restriction fragment length polymorphism (T-RFLP) analysis of the induced whole sputum representing both the cellular and fluid phases in a relative large number of steroid naïve asthmatics. Methods Induced whole sputum samples obtained from 36 healthy subjects and 89 steroid-naїve asthma patients were analyzed through T-RFLP analysis. Results In contrast to previous reports about microbiota in the asthmatic airways, the diversity of microbial composition was not significantly different between the controls and asthma patients (p=0.937). In an analysis of similarities, the global R-value showed a statistically significant difference but a very low separation (0.148, p=0.002). The dissimilarity in the bacterial communities between groups was 28.74%, and operational taxonomic units (OTUs) contributing to this difference were as follows: OTU 789 (Lachnospiraceae), 517 (Comamonadaceae, Acetobacteraceae , and Chloroplast), 633 (Prevotella), 645 (Actinobacteria and Propionibacterium acnes), 607 (Lactobacillus buchneri, Lactobacillus otakiensis, Lactobacillus sunkii, and Rhodobacteraceae), and 661 (Acinetobacter, Pseudomonas, and Leptotrichiaceae), and they were significantly more prevalent in the sputum of asthma patients than in the sputum of the controls. Conclusion Before starting anti-asthmatic treatment, the microbiota in the whole sputum of patients with asthma showed a marginal difference from the microbiota in the whole sputum of the controls. PMID:27433177

  16. Evaluation of acute effects of melatonin on ethanol drinking in ethanol naïve rats

    PubMed Central

    Rather, Zahoor Ahmad; Chowta, Mukta N.; Bolumbu, Ganaraja; Rakesh, K. B.

    2015-01-01

    Objective: The objective was to evaluate the acute effect of melatonin on ethanol drinking in ethanol naïve rats and to determine the specificity of the effect of melatonin on ethanol intake as compared to an intake of plain tap water or sugar water. Materials and Methods: A total of three experiments (2 weeks duration each) using different drinking solutions (ethanol, plain tap water, sugar water) was conducted in individually housed male wistar rats of 5 weeks age. Each animal had access to bottles containing drinking solutions for 2 h a day. In each experiment, on day 1, day 2, day 4, day 5, day 8, day 9, day 11, day 12 rats received drinking solutions. Each individual rat received single doses of saline, melatonin (50 mg and 100 mg/kg), and naltrexone on day 2, 5, 9, and 12, 1-h before receiving drinking solution. The order of drug administration is permuted such a way that each animal received the drugs in a different order in different experiments. Results: Melatonin has significantly decreased ethanol consumption by the rats and effect is dose-dependent. Naltrexone also has caused a significant reduction in the ethanol consumption. The maximum reduction in ethanol consumption was seen with melatonin 100 mg/kg dose compared to melatonin 50 mg/kg and naltrexone. There was no statistically significant effect of melatonin on plain water and sugar solution intake. Conclusions: Melatonin decreases ethanol consumption in ethanol naïve rats. The effect of melatonin is similar to naltrexone affecting selectively ethanol consumption, but not plain water and sugar water consumption. PMID:26288469

  17. sLORETA intracortical lagged coherence during breath counting in meditation-naïve participants

    PubMed Central

    Milz, Patricia; Faber, Pascal L.; Lehmann, Dietrich; Kochi, Kieko; Pascual-Marqui, Roberto D.

    2013-01-01

    We investigated brain functional connectivity comparing no-task resting to breath counting (a meditation exercise but given as task without referring to meditation). Functional connectivity computed as EEG coherence between head-surface data suffers from localization ambiguity, reference dependence, and overestimation due to volume conduction. Lagged coherence between intracortical model sources addresses these criticisms. With this analysis approach, experienced meditators reportedly showed reduced coherence during meditation, meditation-naïve participants have not yet been investigated. 58-channel EEG from 23 healthy, right-handed, meditation-naïve males during resting [3 runs] and breath counting [2 runs] was computed into sLORETA time series of intracortical electrical activity in 19 regions of interest (ROI) corresponding to the cortex underlying 19 scalp electrode sites, for each of the eight independent EEG frequency bands covering 1.5–44 Hz. Intracortical lagged coherences and head-surface conventional coherences were computed between the 19 regions/sites. During breath counting compared to resting, paired t-tests corrected for multiple testing revealed four significantly lower intracortical lagged coherences, but four significantly higher head-surface conventional coherences. Lowered intracortical lagged coherences involved left BA 10 and right BAs 3, 10, 17, 40. In conclusion, intracortical lagged coherence can yield results that are inverted to those of head-surface conventional coherence. The lowered functional connectivity between cognitive control areas and sensory perception areas during meditation-type breath counting compared to resting conceivably reflects the attention to a bodily percept without cognitive reasoning. The reductions in functional connectivity were similar but not as widespread as the reductions reported during meditation in experienced meditators. PMID:24860483

  18. Prolactin levels in drug-naïve patients with schizophrenia and other psychotic disorders.

    PubMed

    Petrikis, Petros; Tigas, Stelios; Tzallas, Alexandros T; Archimandriti, Dimitra T; Skapinakis, Petros; Mavreas, Venetsanos

    2016-09-01

    Hyperprolactinaemia as a side effect of dopamine receptor blockers is common in patients with schizophrenia and other psychotic disorders and may lead to amenorrhoea, galactorrhoea, hypogonadism, subfertility and osteoporosis. The aim of our study was to determine whether hyperprolactinaemia occurs also in patients with schizophrenia and other psychotic disorders prior to any antipsychotic treatment. Serum prolactin, thyroid-stimulating hormone (TSH), triiodothyronine (T3), free tetraiodothyronine (FT4) and cortisol levels were measured in 40 newly diagnosed, drug naïve, patients with schizophrenia and other psychotic disorders and in 40 age and gender matched healthy subjects. The median prolactin value was 12.5 ng/ml (range: 2-38 ng/ml) for patients and 8.6 ng/ml (range: 4-17.6 ng/ml) for healthy subjects (p = 0.011). Patients had lower levels of T3 compared to healthy controls (mean: 1.08 ng/ml, SD: 0.16 vs. 1.18 ng/ml, 0.18, respectively; p = 0.008). Serum TSH, FT4 and cortisol levels were similar between the two groups. Multiple regression analysis revealed that the difference in serum prolactin values was independent of thyroid function (TSH, FT4, T3) and serum cortisol levels. A higher serum prolactin level was found in drug naïve, newly diagnosed patients with schizophrenia and other psychotic disorders compared to healthy controls, prior to starting any antipsychotic treatment.

  19. Predicting drug-induced liver injury in human with Naïve Bayes classifier approach.

    PubMed

    Zhang, Hui; Ding, Lan; Zou, Yi; Hu, Shui-Qing; Huang, Hai-Guo; Kong, Wei-Bao; Zhang, Ji

    2016-10-01

    Drug-induced liver injury (DILI) is one of the major safety concerns in drug development. Although various toxicological studies assessing DILI risk have been developed, these methods were not sufficient in predicting DILI in humans. Thus, developing new tools and approaches to better predict DILI risk in humans has become an important and urgent task. In this study, we aimed to develop a computational model for assessment of the DILI risk with using a larger scale human dataset and Naïve Bayes classifier. The established Naïve Bayes prediction model was evaluated by 5-fold cross validation and an external test set. For the training set, the overall prediction accuracy of the 5-fold cross validation was 94.0 %. The sensitivity, specificity, positive predictive value and negative predictive value were 97.1, 89.2, 93.5 and 95.1 %, respectively. The test set with the concordance of 72.6 %, sensitivity of 72.5 %, specificity of 72.7 %, positive predictive value of 80.4 %, negative predictive value of 63.2 %. Furthermore, some important molecular descriptors related to DILI risk and some toxic/non-toxic fragments were identified. Thus, we hope the prediction model established here would be employed for the assessment of human DILI risk, and the obtained molecular descriptors and substructures should be taken into consideration in the design of new candidate compounds to help medicinal chemists rationally select the chemicals with the best prospects to be effective and safe.

  20. Susceptibility of naïve and differentiated PC12 cells to Japanese encephalitis virus infection.

    PubMed

    Li, Jian-Ri; Wu, Chih-Cheng; Chang, Cheng-Yi; Ou, Yen-Chuan; Lin, Shih-Yi; Wang, Ya-Yu; Chen, Wen-Ying; Raung, Shue-Ling; Liao, Su-Lan; Chen, Chun-Jung

    2017-02-01

    Japanese encephalitis is a mosquito-borne disease caused by Japanese encephalitis virus (JEV) infection. Although JEV infects and replicates in cells with multiple tissue origins, neurons are the preferential cells for JEV infection. Currently, the identities of JEV cell tropism are largely unclear. To gain better insight into the underlying identities of JEV cell tropism, this study was designed to compare the JEV cell tropism with naïve or differentiated PC12 cells. Through nerve growth factor-differentiated PC12 cells, we discovered that JEV efficiently replicated in differentiated PC12 cells rather than naïve cells. Mechanistic studies revealed that viral adsorption/attachment seemed not to be a crucial factor. Supporting data showed that antagonizing postreceptor intracellular signaling of interferons, along with the activation of suppressor of cytokine signaling-3 (SOCS3) expression and protein tyrosine phosphatase activity, were apparent in differentiated PC12 cells after JEV infection. Independent of differentiating inducing agents, the upregulation of SOCS3 expression and protein tyrosine phosphatase activity, as well as preferential JEV tropism, were common in JEV-infected differentiated PC12 cells. Using cultured primary neurons, JEV efficiently replicated in embryonic neurons rather than adult neurons, and the preference was accompanied by higher SOCS3 expression and protein tyrosine phosphatase activity. Given that both SOCS3 and protein tyrosine phosphatases have been implicated in the process of neuronal differentiation, JEV infection seems to not only create an antagonizing strategy to escape host's interferon antiviral response but also takes advantage of cellular machinery to favor its replication. Taken together, current findings imply that dynamic changes within cellular regulators of antiviral machinery could be accompanied by events of neuronal differentiation, thus concurrently playing roles in the control of JEV cell tropism and

  1. Sequential Therapy for Helicobacter pylori Infection in Treatment-naïve Children.

    PubMed

    Schwarzer, Andrea; Bontems, Patrick; Urruzuno, Pedro; Kalach, Nicolas; Iwanczak, Barbara; Roma-Giannikou, Elefteria; Sykora, Josef; Kindermann, Angelika; Casswall, Thomas; Cadranel, Samy; Koletzko, Sibylle

    2016-04-01

    The goal of first-line Helicobacter pylori therapy is to reach an eradication rate of 90% to avoid further investigations, antibiotic use, and spreading of resistant strains. To evaluate the eradication rate of high-dose sequential therapy in treatment-naïve children and to assess factors associated with failure. Prospective data assessed in a registry from nine European centers between October 2009 and December 2011. Children with biopsy-proven Helicobacter pylori infection were prescribed 5 days of esomeprazole and amoxicillin, followed by 5 days of esomeprazole, clarithromycin, and metronidazole according to bodyweight. Eradication was assessed after 8-12 weeks. Primary endpoint was the eradication rate in children who received at least one dose and had follow-up data. Multivariate analysis evaluated potential factors for treatment success including sex, age, center, migrant status, antibiotic resistance, and adherence to therapy. Follow-up was available in 209 of 232 patients (age range 3.1-17.9 years, 118 females). Primary resistance occurred for clarithromycin in 30 of 209 (14.4%), for metronidazole in 32 (15.3%), for both antibiotics in 7 (3.3%), and culture failed in 6 (2.9%). Eradication was achieved in 168 of 209 children (80.4%, 95% CI 75.02-85.78), in 85.8% with no resistance, 72.6% with single resistance, and 28.6% with double resistance. Independent factors affecting eradication rate included resistance to clarithromycin (adjusted ORs 0.27 (0.09-0.84), p = .024), to metronidazole (0.25 (0.009-0.72), p = .010) or to both (0.04 (0.01-0.35), p = .004), and intake of ≤ 90% of prescribed drugs (0.03 (0.01-0.18), p < .001). A high-dose 10-day sequential therapy cannot be recommended in treatment-naïve children. © 2015 John Wiley & Sons Ltd.

  2. Antipsychotics reverse abnormal EEG complexity in drug-naïve schizophrenia: A multiscale entropy analysis

    PubMed Central

    Takahashi, Tetsuya; Cho, Raymond Y.; Mizuno, Tomoyuki; Kikuchi, Mitsuru; Murata, Tetsuhito; Takahashi, Koichi; Wada, Yuji

    2010-01-01

    Multiscale entropy (MSE) analysis is a novel entropy-based approach for measuring dynamical complexity in physiological systems over a range of temporal scales. To evaluate this analytic approach as an aid to elucidating the pathophysiologic mechanisms in schizophrenia, we examined MSE in EEG activity in drug-naïve schizophrenia subjects pre- and post-treatment with antipsychotics in comparison with traditional EEG analysis. We recorded eyes-closed resting state EEG from frontal, temporal, parietal and occipital regions in drug-naïve 22 schizophrenia and 24 age-matched healthy control subjects. Fifteen patients were re-evaluated within 2–8 weeks after the initiation of antipsychotic treatment. For each participant, MSE was calculated on one continuous 60 second epoch for each experimental session. Schizophrenia subjects showed significantly higher complexity at higher time scales (lower frequencies), than that of healthy controls in fronto-centro-temporal, but not in parieto-occipital regions. Post-treatment, this higher complexity decreased to healthy control subject levels selectively in fronto-central regions, while the increased complexity in temporal sites remained higher. Comparative power analysis identified spectral slowing in frontal regions in pre-treatment schizophrenia subjects, consistent with previous findings, whereas no antipsychotic treatment effect was observed. In summary, multiscale entropy measures identified abnormal dynamical EEG signal complexity in anterior brain areas in schizophrenia that normalized selectively in fronto-central areas with antipsychotic treatment. These findings show that entropy-based analytic methods may serve as a novel approach for characterizing and understanding abnormal cortical dynamics in schizophrenia, and elucidating the therapeutic mechanisms of antipsychotics. PMID:20149880

  3. Heterodimeric protein complex identification by naïve Bayes classifiers

    PubMed Central

    2013-01-01

    Background Protein complexes are basic cellular entities that carry out the functions of their components. It can be found that in databases of protein complexes of yeast like CYC2008, the major type of known protein complexes is heterodimeric complexes. Although a number of methods for trying to predict sets of proteins that form arbitrary types of protein complexes simultaneously have been proposed, it can be found that they often fail to predict heterodimeric complexes. Results In this paper, we have designed several features characterizing heterodimeric protein complexes based on genomic data sets, and proposed a supervised-learning method for the prediction of heterodimeric protein complexes. This method learns the parameters of the features, which are embedded in the naïve Bayes classifier. The log-likelihood ratio derived from the naïve Bayes classifier with the parameter values obtained by maximum likelihood estimation gives the score of a given pair of proteins to predict whether the pair is a heterodimeric complex or not. A five-fold cross-validation shows good performance on yeast. The trained classifiers also show higher predictability than various existing algorithms on yeast data sets with approximate and exact matching criteria. Conclusions Heterodimeric protein complex prediction is a rather harder problem than heteromeric protein complex prediction because heterodimeric protein complex is topologically simpler. However, it turns out that by designing features specialized for heterodimeric protein complexes, predictability of them can be improved. Thus, the design of more sophisticate features for heterodimeric protein complexes as well as the accumulation of more accurate and useful genome-wide data sets will lead to higher predictability of heterodimeric protein complexes. Our tool can be downloaded from http://imi.kyushu-u.ac.jp/~om/. PMID:24299017

  4. Is Tetranychus urticae suitable prey for development and reproduction of naïve Coleomegilla maculata?

    PubMed

    Riddick, Eric W; Wu, Zhixin; Rojas, M Guadalupe

    2014-02-01

    The lady beetle Coleomegilla maculata De Geer is an omnivorous predator that could help suppress aphid and spider mite populations on plants in greenhouses, plantscapes or interiorscapes. We are assessing the nutritional requirements and feeding behavior of C. maculata on target prey (spider mites) and factitious (unnatural) food. Our ultimate goal is to develop an efficacious diet to mass produce C. maculata. In this study, we tested the hypothesis that Tetranychus urticae Koch (two-spotted spider mite) is not suitable prey for development and reproduction of naïve C. maculata (i.e., with no prior exposure to T. urticae). Our objectives were to (i) provide baseline data on the effects of consuming T. urticae on C. maculata life history, (ii) to compare the effects of consuming all stages of T. urticae versus eggs of Musca domestica L. (common housefly), and (iii) to determine if the consumption of plant products was beneficial. We used C. maculata from a colony reared only on Ephestia kuehniella Zeller (Mediterranean flour moth) eggs. In experiments, C. maculata larvae were reared from the first instar to adult stage with prey/food in replicated arenas; adult females were paired with a single male with prey/food. The results showed that naïve C. maculata readily attacked and consumed T. urticae. Nevertheless, T. urticae was less suitable than M. domestica eggs for C. maculata development and reproduction. Applying a synthetic pollen-Chlorella alga powder (SPCA) in arenas containing T. urticae appeared to boost C. maculata female development and reproduction.

  5. Differential effects of modafinil on memory in naïve and memory-impaired rats.

    PubMed

    Garcia, Vanessa Athaíde; Souza de Freitas, Betânia; Busato, Stefano Boemler; D'avila Portal, Bernardo Chaves; Piazza, Francisco Correa; Schröder, Nadja

    2013-12-01

    Modafinil is a wake-promoting drug and has been approved for the treatment of excessive daytime sleepiness in narcolepsy and obstructive sleep apnea. Modafinil was shown to improve learning and memory in rodents, and to reverse memory deficits induced by sleep deprivation or stress. However, depending on the memory paradigm used, modafinil might also impair memory. We aimed to investigate the effects of modafinil on memory consolidation and retrieval for object recognition and inhibitory avoidance in naïve adult rats. We also investigated whether acute or chronic administration of modafinil would reverse memory deficits induced by iron overload, a model of memory impairment related to neurodegenerative disorders. Adult naïve rats received modafinil (0.0, 0.75, 7.5 or 75 mg/kg) either immediately after training or 1 h prior to testing in object recognition or inhibitory avoidance. Iron-treated rats received modafinil immediately after training in object recognition. In order to investigate the effects of chronic modafinil, iron-treated rats received daily injections of modafinil for 17 days, and 24 h later they were trained in object recognition or inhibitory avoidance. Acute modafinil does not affect memory consolidation or retrieval in naive rats. A single injection of modafinil at the highest dose was able to recover recognition memory in iron-treated rats. Chronic modafinil completely recovered iron-induced recognition memory and emotional memory deficits. Additional preclinical and clinical studies are necessary in order to support the applicability of modafinil in recovering memory impairment associated with neurodegenerative disorders.

  6. The Public's View of Agricultural Education: We've Come a Long Way--Or Have We?

    ERIC Educational Resources Information Center

    Krueger, David E.; And Others

    1995-01-01

    Includes "We've Come a Long Way--Or Have We?" (Krueger); "If Agricultural Education Were a Coca-Cola" (Doerfert); "Agriculture Is Taught? In High School?" (Elliot); "Let's Tell Our Story" (Davis); "Perception, Reality or Idealism" (Powers, Bull); "Agricultural Education under the Bright Lights" (Foster); and "The Changing Face of Agricultural…

  7. Coordination. A Follow-up of 1987-1988 Suggestions and Recommendations. ICoVE's 1989-1990-1991 Report.

    ERIC Educational Resources Information Center

    Illinois State Council on Vocational Education, Springfield.

    This 3-year follow-up report describes actions taken by the Illinois Council on Vocational Education (ICoVE) during 1989, 1990, and 1991. It addresses the 31 suggestions and 23 recommendations of 5 technical reports (spanning 1987 and 1988) related to coordination. Recommendations from 1987-88 and follow-up actions are reported on the following…

  8. Do organizational strategies mediate nonverbal memory impairment in drug-naïve patients with obsessive-compulsive disorder?

    PubMed

    Shin, Na Young; Kang, Do-Hyung; Choi, Jung-Seok; Jung, Myung Hun; Jang, Joon Hwan; Kwon, Jun Soo

    2010-07-01

    The present study aimed to examine nonverbal memory and organizational skill functions in psychotropic-naïve patients with OCD. Forty-one drug-naïve, 41 medicated OCD patients and 41 healthy controls, all of whom were matched for gender, age, education and intelligence, were included in the study. The Rey-Osterrieth Complex Figure Test (RCFT) was administered to evaluate nonverbal memory ability and organizational skill. OCD patients demonstrated impaired nonverbal memory irrespective of medication status (F = 6.54, p < .01, eta(2)p = .098 for immediate recall; F = 7.76, p < .01, eta(2)p = .114 for delayed recall). Medicated patients showed deficits in organizational strategies (eta(2)p = .079), which mediated nonverbal memory impairment (Z = -2.20, p = .027). The difference of organizational skill between drug-naïve and control groups did not reach statistical significance (eta(2)p = .054) and the association between organization and nonverbal memory was weak in the drug-naïve sample (Z = -1.74, = .081). There was no significant difference between the patient groups in RCFT indices. Our findings suggest that the organizational strategies may not be an effective mediator of nonverbal memory impairment in OCD and indicate that the clinical characteristics may be important to be considered in future research. Further studies are needed to improve understanding of the nature of nonverbal memory dysfunction in OCD.

  9. DNA methylation-associated colonic mucosal immune and defense responses in treatment-naïve pediatric ulcerative colitis.

    PubMed

    Harris, R Alan; Nagy-Szakal, Dorottya; Mir, Sabina A V; Frank, Eibe; Szigeti, Reka; Kaplan, Jess L; Bronsky, Jiri; Opekun, Antone; Ferry, George D; Winter, Harland; Kellermayer, Richard

    2014-08-01

    Inflammatory bowel diseases (IBD) are emerging globally, indicating that environmental factors may be important in their pathogenesis. Colonic mucosal epigenetic changes, such as DNA methylation, can occur in response to the environment and have been implicated in IBD pathology. However, mucosal DNA methylation has not been examined in treatment-naïve patients. We studied DNA methylation in untreated, left sided colonic biopsy specimens using the Infinium HumanMethylation450 BeadChip array. We analyzed 22 control (C) patients, 15 untreated Crohn's disease (CD) patients, and 9 untreated ulcerative colitis (UC) patients from two cohorts. Samples obtained at the time of clinical remission from two of the treatment-naïve UC patients were also included into the analysis. UC-specific gene expression was interrogated in a subset of adjacent samples (5 C and 5 UC) using the Affymetrix GeneChip PrimeView Human Gene Expression Arrays. Only treatment-naïve UC separated from control. One-hundred-and-twenty genes with significant expression change in UC (> 2-fold, P<0.05) were associated with differentially methylated regions (DMRs). Epigenetically associated gene expression changes (including gene expression changes in the IFITM1, ITGB2, S100A9, SLPI, SAA1, and STAT3 genes) were linked to colonic mucosal immune and defense responses. These findings underscore the relationship between epigenetic changes and inflammation in pediatric treatment-naïve UC and may have potential etiologic, diagnostic, and therapeutic relevance for IBD.

  10. The Communication of Naïve Theories of the Social World in Parent-Child Conversation

    ERIC Educational Resources Information Center

    Chalik, Lisa; Rhodes, Marjorie

    2015-01-01

    Three studies examined the communication of naïve theories of social groups in conversations between parents and their 4-year-old children (N = 48). Parent-child dyads read and discussed a storybook in which they either explained why past social interactions had occurred (Study 1) or evaluated whether future social interactions should occur…

  11. Antibody Profiling in Naïve and Semi-immune Individuals Experimentally Challenged with Plasmodium vivax Sporozoites

    PubMed Central

    Arévalo-Herrera, Myriam; Lopez-Perez, Mary; Dotsey, Emmanuel; Jain, Aarti; Rubiano, Kelly; Felgner, Philip L.; Davies, D. Huw; Herrera, Sócrates

    2016-01-01

    Background Acquisition of malaria immunity in low transmission areas usually occurs after relatively few exposures to the parasite. A recent Plasmodium vivax experimental challenge trial in malaria naïve and semi-immune volunteers from Colombia showed that all naïve individuals developed malaria symptoms, whereas semi-immune subjects were asymptomatic or displayed attenuated symptoms. Sera from these individuals were analyzed by protein microarray to identify antibodies associated with clinical protection. Methodology/Principal Findings Serum samples from naïve (n = 7) and semi-immune (n = 9) volunteers exposed to P. vivax sporozoite-infected mosquito bites were probed against a custom protein microarray displaying 515 P. vivax antigens. The array revealed higher serological responses in semi-immune individuals before the challenge, although malaria naïve individuals also had pre-existing antibodies, which were higher in Colombians than US adults (control group). In both experimental groups the response to the P. vivax challenge peaked at day 45 and returned to near baseline at day 145. Additional analysis indicated that semi-immune volunteers without fever displayed a lower response to the challenge, but recognized new antigens afterwards. Conclusion Clinical protection against experimental challenge in volunteers with previous P. vivax exposure was associated with elevated pre-existing antibodies, an attenuated serological response to the challenge and reactivity to new antigens. PMID:27014875

  12. The Communication of Naïve Theories of the Social World in Parent-Child Conversation

    ERIC Educational Resources Information Center

    Chalik, Lisa; Rhodes, Marjorie

    2015-01-01

    Three studies examined the communication of naïve theories of social groups in conversations between parents and their 4-year-old children (N = 48). Parent-child dyads read and discussed a storybook in which they either explained why past social interactions had occurred (Study 1) or evaluated whether future social interactions should occur…

  13. The Public's View of Agricultural Education: We've Come a Long Way--Or Have We?

    ERIC Educational Resources Information Center

    Krueger, David E.; And Others

    1995-01-01

    Includes "We've Come a Long Way--Or Have We?" (Krueger); "If Agricultural Education Were a Coca-Cola" (Doerfert); "Agriculture Is Taught? In High School?" (Elliot); "Let's Tell Our Story" (Davis); "Perception, Reality or Idealism" (Powers, Bull); "Agricultural Education under the Bright Lights" (Foster); and "The Changing Face of Agricultural…

  14. Tomato immune receptor Ve1 recognizes effector of multiple fungal pathogens uncovered by genome and RNA sequencing

    USDA-ARS?s Scientific Manuscript database

    Fungal plant pathogens secrete effector molecules to establish disease on their hosts, while plants in turn utilize immune receptors to intercept these effectors. The tomato immune receptor Ve1 governs resistance to race 1 strains of the soil-borne vascular wilt fungi Verticillium dahliae and V. alb...

  15. Prolactin serum levels correlate with inflammatory status in drug-naïve first-episode schizophrenia.

    PubMed

    Song, Xueqin; Fan, Xiaoduo; Zhang, Jianjiang; Zheng, Hui; Li, Xue; Pang, Lijuan; Chen, Xumei; Zhang, Wei; Harrington, Amy; Ziedonis, Douglas; Lv, Luxian

    2014-09-01

    The present study was to examine the relationship between serum levels of prolactin and the inflammatory status in drug-naïve, first-episode schizophrenia patients with normal weight. Patients with normal weight, drug-naïve, first-episode schizophrenia and healthy controls were enrolled in the study. Serum levels of prolactin (PRL) were measured using electrical chemiluminescence immunoassay. Serum levels of interleukin-1β (IL-1β), tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were examined using enzyme-linked immunosorbent assay (ELISA). Sixty patients with normal weight, drug-naïve, first-episode schizophrenia and 60 healthy controls were enrolled. The schizophrenia group had higher serum levels of PRL, IL-1β, IL-6 and TNF-α compared with the control group. There was a gender difference of hyperprolactinemia in schizophrenia group. There were positive relationships between serum levels of PRL and serum levels of IL-1β, IL-6 and TNF-α within the schizophrenia group. Within the schizophrenia group, TNF-α was the strongest predictor among the three cytokines for serum levels of prolactin after controlling for gender, age, education, smoking status and disease duration. Patients with normal weight, drug-naïve, first-episode schizophrenia present elevated serum levels of PRL, which might be related to the up-regulated inflammatory status in this patient population.

  16. Feeding preferences of experienced and naïve goats and sheep for the toxic plant Ipomoea carnea subsp. fistulosa

    USDA-ARS?s Scientific Manuscript database

    Ipomoea carnea is a toxic plant that grazing goats and cattle may learn to ingest with repeated exposure. The objective of this study was to evaluate the feeding preferences of experienced and non-experienced (naïve) goats and sheep for I. carnea. The study used 3 groups of 5 goats (Group 1, experi...

  17. Enhanced Computational Toolbox Including Multiquantum Vibration-Translation (VT) & Vibration-Electronic (VE) Exchanges, Dissociation and Radiation Effects. Deliverable 4

    DTIC Science & Technology

    2011-04-30

    the following process: MAMA ii  ’,,  , (1) where terms  and i correspond to the electronic and vibrational states of a diatomic molecule A...the detailed balance at the thermal equilibrium. A VE transition can be described as follows: MAMA ii  ’,’,  (25) where the molecule A

  18. Hapten-specific naïve B cells are biomarkers of vaccine efficacy against drugs of abuse.

    PubMed

    Taylor, J J; Laudenbach, M; Tucker, A M; Jenkins, M K; Pravetoni, M

    2014-03-01

    Vaccination against drugs of abuse shows efficacy in animal models, yet few subjects achieve effective serum antibody titers in clinical studies. A barrier to translation is the lack of pre-vaccination screening assays that predict the most effective conjugate vaccines or subjects amenable to vaccination. To address this obstacle, we developed a fluorescent antigen-based enrichment method paired with flow cytometry to characterize hapten-specific B cells. Using this approach, we studied naïve and activated B cells specific for structurally-related model haptens based on derivatization of the morphinan structure at the C6 position on oxycodone or at the C8 position on hydrocodone, and showing different pre-clinical efficacy against the prescription opioid oxycodone. Prior to vaccination, naïve B cells exhibited relatively higher affinity for the more effective C6-derivatized oxycodone-based hapten (6OXY) and the 6OXY-specific naïve B cell population contained a higher number of B cells with greater affinity for free oxycodone. Higher affinity of naïve B cells for hapten or oxycodone reflected greater efficacy of vaccination in blocking oxycodone distribution to brain in mice. Shortly after immunization, activated hapten-specific B cells were detected prior to oxycodone-specific serum antibodies and provided earlier evidence of vaccine failure or success. Analysis of hapten-specific naïve and activated B cells may aid rational vaccine design and provide screening tools to predict vaccine clinical efficacy against drugs of abuse or other small molecules.

  19. Decreased percentage of peripheral naïve T cells is independently associated with ischemic stroke in patients on hemodialysis.

    PubMed

    Chen, Rongyi; Hu, Jiachang; Xiang, Fangfang; Tan, Xiao; Shen, Bo; Liu, Zhonghua; Lv, Wenlv; Ding, Xiaoqiang; Cao, Xuesen; Zou, Jianzhou

    2017-09-15

    Cerebrovascular complications, including ischemic stroke, account for poor outcomes in patients on hemodialysis. T cell responses may be involved in the pathogenesis of ischemic stroke. We aimed to evaluate the role of naïve T cells in development of ischemic stroke in patients on hemodialysis. In this cross-sectional study, 156 patients on hemodialysis in our blood purification center were included. These patients were divided into the ischemic stroke (IS) group (61 cases) and non-ischemic stroke (non-IS) group (95 cases) according to a new diagnosis after initiation of hemodialysis. After being lysed with red blood cell lysis solution, peripheral blood was tested by flow cytometry to detect the expression of CD45RO and CCR7 in CD4 T and CD8 T cells. Correlation analysis and logistic regression analysis were conducted to identify potential independent risk factors for ischemic stroke. The percentage of peripheral naïve T cells was lower in the IS group [median (interquartile range (IQR)) 13.9% (8.6-22.9%)] compared with the non-IS group [median (IQR) 22.7% (15.9-32.2%), P < 0.001]. Spearman correlation analysis showed that naïve T cells were negatively associated with ischemic stroke (r = -0.308, P < 0.001). Multivariate logistic regression analysis showed that CD4 naïve T cells had an independent negative association with ischemic stroke in patients on hemodialysis (odds ratio 0.933, 95% CI 0.883, 0.986; P = 0.013). A decrease in percentage of peripheral CD4 naïve T cells is a risk factor for ischemic stroke in patients on hemodialysis.

  20. A new mechanism shapes the naïve CD8(+) T cell repertoire: the selection for full diversity.

    PubMed

    Gonçalves, Pedro; Ferrarini, Marco; Molina-Paris, Carmen; Lythe, Grant; Vasseur, Florence; Lim, Annik; Rocha, Benedita; Azogui, Orly

    2017-05-01

    During thymic T cell differentiation, TCR repertoires are shaped by negative, positive and agonist selection. In the thymus and in the periphery, repertoires are also shaped by strong inter-clonal and intra-clonal competition to survive death by neglect. Understanding the impact of these events on the T cell repertoire requires direct evaluation of TCR expression in peripheral naïve T cells. Several studies have evaluated TCR diversity, with contradictory results. Some of these studies had intrinsic technical limitations since they used material obtained from T cell pools, preventing the direct evaluation of clonal sizes. Indeed with these approaches, identical TCRs may correspond to different cells expressing the same receptor, or to several amplicons from the same T cell. We here overcame this limitation by evaluating TCRB expression in individual naïve CD8(+) T cells. Of the 2269 Tcrb sequences we obtained from 13 mice, 99% were unique. Mathematical analysis of the data showed that the average number of naïve peripheral CD8(+) T cells expressing the same TCRB is 1.1 cell. Since TCRA co-expression studies could only increase repertoire diversity, these results reveal that the number of naïve T cells with unique TCRs approaches the number of naïve cells. Since thymocytes undergo multiple rounds of divisions after TCRB rearrangement and 3-5% of thymocytes survive thymic selection events the number of cells expressing the same TCRB was expected to be much higher. Thus, these results suggest a new repertoire selection mechanism, which strongly selects for full TCRB diversity.

  1. A reliable model of intravenous MDMA self-administration in naïve mice.

    PubMed

    Trigo, José Manuel; Panayi, Fany; Soria, Guadalupe; Maldonado, Rafael; Robledo, Patricia

    2006-01-01

    MDMA is one of the most widely consumed recreational drugs in Europe. However, the mechanisms involved in the reinforcing properties of MDMA are still unclear. In this sense, the establishment of a reliable model of MDMA self-administration in mice could represent an important approach to study the neuronal substrates associated with MDMA reward by using genetically modified mice. To develop a reliable model of operant intravenous MDMA self-administration in drug-naïve mice. Mice were trained to acquire intravenous self-administration of MDMA at different doses (0, 0.06, 0.125, 0.25, 0.5 and 1.0 mg/kg/infusion) on a FR1 schedule of reinforcement for 15 consecutive days. The motivational value of different doses of MDMA (0.125, 0.25 and 0.5 mg/kg/infusion) was then tested using a progressive ratio paradigm. Finally, [3H]-mazindol autoradiographic studies were carried out in order to quantitatively assess presynaptic dopamine transporter (DAT) binding sites in the striatum of mice trained to self-administer MDMA (0 and 1.0 mg/kg/infusion) during 15 days. The latency for discrimination between the active and inactive holes, as well as the number of animals acquiring stability criteria, varied as a function of the dose of MDMA. The mice responding for intermediate doses (0.125, 0.25 and 0.5 mg/kg/infusion) discriminated earlier than those responding for low (0.06 mg/kg/infusion) or high (1.0 mg/kg/infusion) doses. The percentage of animals achieving stability criteria increased with days of testing and was inversely proportional to the dose of MDMA. The breaking points achieved for doses of 0.125 and 0.25 mg/kg/infusion were significantly higher than for a dose of 0.5 mg/kg/infusion. No significant DAT neurotoxicity was observed in the striatum of animals self-administering MDMA at a dose of 1 mg/kg/infusion. The present results show that MDMA can be reliably self-administered by drug-naïve mice.

  2. The P2Y2 Receptor Interacts with VE-Cadherin and VEGF Receptor-2 to Regulate Rac1 Activity in Endothelial Cells

    PubMed Central

    Liao, Zhongji; Cao, Chen; Wang, Jianjie; Huxley, Virginia H.; Baker, Olga; Weisman, Gary A.

    2015-01-01

    Vascular endothelial cadherin (VE-cadherin) mediates homophylic adhesion between endothelial cells and is an important regulator of angiogenesis, blood vessel permeability and leukocyte trafficking. Rac1, a member of the Rho family of GTPases, controls VE-cadherin adhesion by acting downstream of several growth factors, including angiopoietin-1 and vascular endothelial growth factor (VEGF). Here we show that UTP-induced activation of the Gq protein-coupled P2Y2 nucleotide receptor (P2Y2R) in human coronary artery endothelial cells (HCAECs) activated Rac1 and caused a transient complex to form between P2Y2R, VE-cadherin and VEGF receptor-2 (VEGFR-2). Knockdown of VE-cadherin expression with siRNA did not affect UTP-induced activation of extracellular signal-regulated kinases 1/2 (ERK1/2) but led to a loss of UTP-induced Rac1 activation and tyrosine phosphorylation of p120 catenin, a cytoplasmic protein known to interact with VE-cadherin. Activation of the P2Y2R by UTP also caused a prolonged interaction between p120 catenin and vav2 (a guanine nucleotide exchange factor for Rac) that correlated with the kinetics of UTP-induced tyrosine phosphorylation of p120 catenin and VE-cadherin. Inhibitors of VEGFR-2 (SU1498) or Src (PP2) significantly diminished UTP-induced Rac1 activation, tyrosine phosphorylation of p120 catenin and VE-cadherin, and association of the P2Y2R with VE-cadherin and p120 catenin with vav2. These findings suggest that the P2Y2R uses Src and VEGFR-2 to mediate association of the P2Y2R with VE-cadherin complexes in endothelial adherens junctions to activate Rac1. PMID:25657827

  3. The P2Y2 Receptor Interacts with VE-Cadherin and VEGF Receptor-2 to Regulate Rac1 Activity in Endothelial Cells.

    PubMed

    Liao, Zhongji; Cao, Chen; Wang, Jianjie; Huxley, Virginia H; Baker, Olga; Weisman, Gary A; Erb, Laurie

    2014-12-01

    Vascular endothelial cadherin (VE-cadherin) mediates homophylic adhesion between endothelial cells and is an important regulator of angiogenesis, blood vessel permeability and leukocyte trafficking. Rac1, a member of the Rho family of GTPases, controls VE-cadherin adhesion by acting downstream of several growth factors, including angiopoietin-1 and vascular endothelial growth factor (VEGF). Here we show that UTP-induced activation of the Gq protein-coupled P2Y2 nucleotide receptor (P2Y2R) in human coronary artery endothelial cells (HCAECs) activated Rac1 and caused a transient complex to form between P2Y2R, VE-cadherin and VEGF receptor-2 (VEGFR-2). Knockdown of VE-cadherin expression with siRNA did not affect UTP-induced activation of extracellular signal-regulated kinases 1/2 (ERK1/2) but led to a loss of UTP-induced Rac1 activation and tyrosine phosphorylation of p120 catenin, a cytoplasmic protein known to interact with VE-cadherin. Activation of the P2Y2R by UTP also caused a prolonged interaction between p120 catenin and vav2 (a guanine nucleotide exchange factor for Rac) that correlated with the kinetics of UTP-induced tyrosine phosphorylation of p120 catenin and VE-cadherin. Inhibitors of VEGFR-2 (SU1498) or Src (PP2) significantly diminished UTP-induced Rac1 activation, tyrosine phosphorylation of p120 catenin and VE-cadherin, and association of the P2Y2R with VE-cadherin and p120 catenin with vav2. These findings suggest that the P2Y2R uses Src and VEGFR-2 to mediate association of the P2Y2R with VE-cadherin complexes in endothelial adherens junctions to activate Rac1.

  4. Prevalence of anaemia and immunological markers among ghanaian HAART-naïve HIV-patients and those on HAART.

    PubMed

    Owiredu, W K B A; Quaye, L; Amidu, N; Addai-Mensah, O

    2011-03-01

    Highly active antiretroviral therapy (HAART) for people living with HIV/AIDS (PLWHA) has been generally accepted as the gold standard for the management of HIV patients but conflicting reports about the ability of HAART to improve upon the quality of life of HIV patients has cast doubts over the efficacy and the need for therapy. This study was conducted to assess the efficacy and ability of HAART to resolve immunological and haematological abnormalities in HIV infected patients, existent sex variations in immunological and haematological parameters and CD4 predictive ability of the study parameters. A total of 442 PLWHA consisting of 166 patients on HAART (28 males and 138 females) and 276 HAART-naïve patients (76 males and 200 females) were recruited for this study. Complete haemogram, immunological analysis (CD4 & CD3) and weight were measured for all the patients. HAART patients were older and heavier than their naïve counterparts. The incidence of anaemia (Hb less or equal to 10.5 (63%) and PCV < 30% (37.6%)) and lymphopoenia (16.7%) in HAART-naïve patients was significantly higher compared to their counterparts on HAART (46%, 15.2% and 5.3%) respectively. 70% of HAART-naïve females had anaemia in comparison to 44% in HAART-naïve males (P = 0.0001). The likelihood of developing microcytic hypochromic anaemia in HAART-naïve patients was 5 times more compared to those on HAART (P = 0.0002). Total lymphocyte count, haemoglobin, lymphocyte count and weight were significant predictors of CD4 counts and TLC values between 1.0 - 2.0 k µL(-1) was a significant predictor of CD4 <200 cells mm(-3). HAART has the capability of reducing the incidence of anaemia and lymphopoenia which are associated with disease progression and death in HIV infected patients. Total lymphocyte count, haemoglobin and weight could also serve as useful predictive tools in the management and monitoring of HIV infected patients in resource limited settings.

  5. Effectiveness of adalimumab for the treatment of ulcerative colitis in clinical practice: comparison between anti-tumour necrosis factor-naïve and non-naïve patients.

    PubMed

    Iborra, Marisa; Pérez-Gisbert, Javier; Bosca-Watts, Marta Maia; López-García, Alicia; García-Sánchez, Valle; López-Sanromán, Antonio; Hinojosa, Esther; Márquez, Lucía; García-López, Santiago; Chaparro, María; Aceituno, Montserrat; Calafat, Margalida; Guardiola, Jordi; Belloc, Blanca; Ber, Yolanda; Bujanda, Luis; Beltrán, Belén; Rodríguez-Gutiérrez, Cristina; Barrio, Jesús; Cabriada, José Luis; Rivero, Montserrat; Camargo, Raquel; van Domselaar, Manuel; Villoria, Albert; Schuterman, Hugo Salata; Hervás, David; Nos, Pilar

    2017-07-01

    Ulcerative colitis (UC) treatment is focused to achieve mucosal healing, avoiding disease progression. The study aimed to evaluate the real-world effectiveness of adalimumab (ADA) in UC and to identify predictors of remission to ADA. This cohort study used data from the ENEIDA registry. Clinical response, clinical remission, endoscopic remission, adverse events (AE), colectomy, and hospitalisations were evaluated; baseline characteristics and biological parameters were compared to determine predictors of response. We included 263 patients (87 naïve and 176 previously exposed to anti-tumour necrosis factor alpha, TNF). After 12 weeks, clinical response, clinical remission, and endoscopic remission rates were 51, 26, and 14 %, respectively. The naïve group demonstrated better response to treatment than the anti-TNF-exposed group at short-term. Clinical and endoscopic remission within 1 year of treatment was better in the naïve group (65 vs. 49 and 50 vs. 35 %, respectively). The rates of AE, dose-escalation, hospitalisations, and colectomy during the first year were higher in anti-TNF-exposed patients (40, 43, and 27 % vs. 26, 21, and 11 %, respectively). Patients with primary failure and intolerance to the first anti-TNF and severe disease were associated with worse clinical response. Primary non-response to prior anti-TNF treatment and severe disease were predictive of poorer clinical remission. Low levels of C-reactive protein (CRP) and faecal calprotectin (FC) at baseline were predictors of clinical remission. In clinical practice, ADA was effective in UC, especially in anti-TNF naïve patients. FC and CRP could be predictors of treatment effectiveness.

  6. Metabolic syndrome in drug naïve patients with substance use disorder.

    PubMed

    Bathla, Manish; Singh, Manpreet; Anjum, Shazia; Kulhara, Parmanand; Jangli, Satyarth

    Metabolic syndrome is a combination of insulin resistance, impaired glucose regulation, dyslipidemia, hypertension, microalbuminuria and obesity and this increases the risk for diabetes, myocardial infarction and thus increases the risk of mortality. Substance dependence is considered as a prominent risk factor for metabolic syndrome, but not much work has been done in this field. Thus this study is aimed to know the prevalence of metabolic syndrome in drug naïve substance users. A total of 50 consecutive indoor drug naive patients with substance dependence (as per ICD 10) were included. Metabolic syndrome was assessed as per WHO criteria for metabolic syndrome. Statistical analysis was done using SPSS version 17.0 software and Chi square test was applied. Of the 50 subjects (46% used alcohol; 26% used opioid and 28% were multiple substance users), a total of 20% of the subjects met the WHO criteria for metabolic syndrome and all of them were only alcoholics. Commonest abnormalities were low HDL (48%), raised SBP/DBP (26%/22%) and TG's (18%). Age, weight, height, DBP and BMI were significant predictors of metabolic syndrome. Metabolic syndrome is a common entity seen in patients with substance abuse, especially in patients with alcohol use disorder, as seen in our study. Copyright © 2016 Diabetes India. Published by Elsevier Ltd. All rights reserved.

  7. Methamphetamine activates reward circuitry in drug naïve human subjects.

    PubMed

    Völlm, Birgit A; de Araujo, Ivan E; Cowen, Philip J; Rolls, Edmund T; Kringelbach, Morten L; Smith, Katharine A; Jezzard, Peter; Heal, Ronald J; Matthews, Paul M

    2004-09-01

    Amphetamines are highly addictive drugs that have pronounced effects on emotional and cognitive behavior in humans. These effects are mediated through their potent dopaminergic agonistic properties. Dopamine has also been implicated in the modulation of responses of the 'reward circuit' in animal and human studies. In this study we use functional magnetic resonance imaging (fMRI) to identify the brain circuitry involved in the psychostimulant effect of methamphetamine in psychostimulant-naïve human subjects. Seven healthy volunteers were scanned in a 3T MR imaging system. They received single-blind intravenous infusions of methamphetamine (0.15 mg/kg), and rated their experience of 'mind-racing' on a button press throughout the experiment. Data were analyzed with statistical parametric mapping methods. Amphetamine administration activated the medial orbitofrontal cortex, the rostral part of the anterior cingulate cortex, and the ventral striatum. Ratings of 'mind-racing' after methamphetamine infusion correlated with activations in the rostral part of the anterior cingulate cortex and in the ventral striatum. In addition, activations in the medial orbitofrontal cortex were independent of motor and related responses involved in making the ratings. These findings indicate that the first administration of a psychostimulant to human subjects activates classical reward circuitry. Our data also support recent hypotheses suggesting a central role for the orbitofrontal cortex in drug reinforcement and the development of addiction.

  8. Management of treatment-naïve limited-stage small cell esophagus carcinoma

    PubMed Central

    Tao, Haitao; Li, Fangfang; Wang, Jinliang; Dong, Weiwei; Gao, Jie; Jiao, Shunchang; Hu, Yi

    2015-01-01

    Objectives: To identify the problems and principles of treatment decisions in treatment-naïve limited-stage small cell esophagus carcinoma (LD-SCEC). Methods: Clinical data from 39 patients with LD-SCEC treated in the Chinese People’s Liberation Army General Hospital, Beijing, China between 2000 and 2013 were retrospectively collected with regard to pathologic characteristics, overall survival (OS), and relevant prognostic factors. Results: The median OS was 21.1 months (95% confidence interval [CI]: 12.4-29.7 months). The one-year OS was 76%, 3-year was 25%, and the 5-year OS was 8%. Depth of invasion, lymph metastasis status, and chemotherapy were independent prognostic factors. Of the 39 cases, only 38.4% (15 cases) were diagnosed as SCEC by the biopsy specimen. Eight of the 15 patients (group A) received chemotherapy and/or radiotherapy, while the remaining 7 patients (group B) and the other 24 patients (group C) received surgery as initial treatment. The one-year survival of group A was 87%, of group B was 69%, and of group C was 74% (p=0.037). The accuracy of the biopsy diagnosis influenced the treatment decisions and prognosis. Conclusion: Small cell esophagus carcinoma is a systemic disease, with depth of invasion, lymph metastasis status, and chemotherapy as independent prognostic factors. Systemic therapy based on chemotherapy is recommended. The top priority is to improve the accuracy of diagnosis before deciding on the initial treatment option. PMID:25737171

  9. SHG-specificity of cellular Rootletin filaments enables naïve imaging with universal conservation

    NASA Astrophysics Data System (ADS)

    Akiyama, Toshihiro; Inoko, Akihito; Kaji, Yuichi; Yonemura, Shigenobu; Kakiguchi, Kisa; Segawa, Hiroki; Ishitsuka, Kei; Yoshida, Masaki; Numata, Osamu; Leproux, Philippe; Couderc, Vincent; Oshika, Tetsuro; Kano, Hideaki

    2017-01-01

    Despite growing demand for truly naïve imaging, label-free observation of cilium-related structure remains challenging, and validation of the pertinent molecules is correspondingly difficult. In this study, in retinas and cultured cells, we distinctively visualized Rootletin filaments in rootlets in the second harmonic generation (SHG) channel, integrated in custom coherent nonlinear optical microscopy (CNOM) with a simple, compact, and ultra-broadband supercontinuum light source. This SHG signal was primarily detected on rootlets of connecting cilia in the retinal photoreceptor and was validated by colocalization with anti-Rootletin staining. Transfection of cells with Rootletin fragments revealed that the SHG signal can be ascribed to filaments assembled from the R234 domain, but not to cross-striations assembled from the R123 domain. Consistent with this, Rootletin-depleted cells lacked SHG signal expected as centrosome linker. As a proof of concept, we confirmed that similar fibrous SHG was observed even in unicellular ciliates. These findings have potential for broad applications in clinical diagnosis and biophysical experiments with various organisms.

  10. Meditation-Based Treatment Yielding Immediate Relief for Meditation-Naïve Migraineurs

    PubMed Central

    Tonelli, Makenzie E.; Wachholtz, Amy B.

    2014-01-01

    Meditation is gaining popularity as an effective means of managing and attenuating pain and has been particularly effective for migraines. Meditation additionally addresses the negative emotional states known to exist with migraines. The purpose of this study was to evaluate the effectiveness of meditation as an immediate intervention for reducing migraine pain as well as alleviating emotional tension, examined herein as a negative affect hypothesized to be correlated with pain. Twenty-seven migraineurs, with two to ten migraines per month, reported migraine-related pain and emotional tension ratings on a Likert scale (ranging from 0 to 10) before and after exposure to a brief meditation-based treatment. All participants were meditation-naïve, and attended one 20-minute guided meditation session based on the Buddhist “loving kindness” approach. After the session, participants reported a 33% decrease in pain and a 43% decrease in emotional tension. The data suggest that a single exposure to a brief meditative technique can significantly reduce pain and tension, as well as offer several clinical implications. It can be concluded that single exposure to a meditative technique can significantly reduce pain and tension. The effectiveness and immediacy of this intervention offers several implications for nurses. PMID:24602422

  11. Meditation-based treatment yielding immediate relief for meditation-naïve migraineurs.

    PubMed

    Tonelli, Makenzie E; Wachholtz, Amy B

    2014-03-01

    Meditation is gaining popularity as an effective means of managing and attenuating pain and has been particularly effective for migraines. Meditation additionally addresses the negative emotional states known to exist with migraines. The purpose of this study was to evaluate the effectiveness of meditation as an immediate intervention for reducing migraine pain as well as alleviating emotional tension, examined herein as a negative affect hypothesized to be correlated with pain. Twenty-seven migraineurs, with two to ten migraines per month, reported migraine-related pain and emotional tension ratings on a Likert scale (ranging from 0 to 10) before and after exposure to a brief meditation-based treatment. All participants were meditation- naïve, and attended one 20-minute guided meditation session based on the Buddhist "loving kindness" approach. After the session, participants reported a 33% decrease in pain and a 43% decrease in emotional tension. The data suggest that a single exposure to a brief meditative technique can significantly reduce pain and tension, as well as offer several clinical implications. It can be concluded that single exposure to a meditative technique can significantly reduce pain and tension. The effectiveness and immediacy of this intervention offers several implications for nurses.

  12. Categorization of Natural Whistled Vowels by Naïve Listeners of Different Language Background.

    PubMed

    Meyer, Julien; Dentel, Laure; Meunier, Fanny

    2017-01-01

    Whistled speech in a non-tonal language consists of the natural emulation of vocalic and consonantal qualities in a simple modulated whistled signal. This special speech register represents a natural telecommunication system that enables high levels of sentence intelligibility by trained speakers and is not directly intelligible to naïve listeners. Yet, it is easily learned by speakers of the language that is being whistled, as attested by the current efforts of the revitalization of whistled Spanish in the Canary Islands. To better understand the relation between whistled and spoken speech perception, we look herein at how Spanish, French, and Standard Chinese native speakers, knowing nothing about whistled speech, categorized four Spanish whistled vowels. The results show that the listeners categorized differently depending on their native language. The Standard Chinese speakers demonstrated the worst performance on this task but were still able to associate a tonal whistle to vowel categories. Spanish speakers were the most accurate, and both Spanish and French participants were able to categorize the four vowels, although not as accurately as an expert whistler. These results attest that whistled speech can be used as a natural laboratory to test the perceptual processes of language.

  13. Reduced anterior cingulate gray matter volume in treatment-naïve clinically depressed adolescents☆

    PubMed Central

    Pannekoek, Justine Nienke; van der Werff, Steven J.A.; van den Bulk, Bianca G.; van Lang, Natasja D.J.; Rombouts, Serge A.R.B.; van Buchem, Mark A.; Vermeiren, Robert R.J.M.; van der Wee, Nic J.A.

    2014-01-01

    Adolescent depression is associated with increased risk for suicidality, social and educational impairment, smoking, substance use, obesity, and depression in adulthood. It is of relevance to further our insight in the neurobiological mechanisms underlying this disorder in the developing brain, as this may be essential to optimize treatment and prevention of adolescent depression and its negative clinical trajectories. The equivocal findings of the limited number of studies on neural abnormalities in depressed youth stress the need for further neurobiological investigation of adolescent depression. We therefore performed a voxel-based morphometry study of the hippocampus, amygdala, superior temporal gyrus, and anterior cingulate cortex (ACC) in 26 treatment-naïve, clinically depressed adolescents and 26 pair-wise matched healthy controls. Additionally, an exploratory whole-brain analysis was performed. Clinically depressed adolescents showed a volume reduction of the bilateral dorsal ACC compared to healthy controls. However, no association was found between gray matter volume of the ACC and clinical severity scores for depression or anxiety. Our finding of a smaller ACC in clinically depressed adolescents is consistent with literature on depressed adults. Future research is needed to investigate if gray matter abnormalities precede or follow clinical depression in adolescents. PMID:24501702

  14. The perception of voice pitch by naïve and experienced listeners

    NASA Astrophysics Data System (ADS)

    Fucci, Donald; Schueller, Marianne; Bond, Zinny

    2002-05-01

    Perceptual judgments of a single speaker's voice pitch will be characterized by any given listener along a subjective continuum. Individual listener attributes have been suggested as an explanation for this diversity in categorizing voice pitch. Professionals involved in the evaluation of voice, specifically voice pitch, are expected to possess a level of perceptual skill that reliably quantifies pitch regardless of personal attributes. Two groups of individuals, one naïve and one experienced, were asked to perceptually match voice pitch during two pitch matching tasks. The first task involved matching an audio taped voice pitch produced on the vowel /a/ to a musical note on a keyboard. The second task involved listening to an audio-taped voice producing words, then matching the voice pitch of the word to a musical note on a keyboard. Accuracy of perceptual judgments was measured upon stimuli produced and assigned musical keyboard note by master's level opera music majors. Results indicate that a difference exists between groups in only one of the four variables measured. Individual differences varied, but appeared unrelated to previous musical experience.

  15. Neural correlates of performance monitoring in chronic cannabis users and cannabis-naïve controls

    PubMed Central

    Fridberg, Daniel J; Skosnik, Patrick D; Hetrick, William P; O’Donnell, Brian F

    2014-01-01

    Chronic cannabis use is associated with residual negative effects on measures of executive functioning. However, little previous work has focused specifically on executive processes involved in performance monitoring in frequent cannabis users. The present study investigated event-related potential (ERP) correlates of performance monitoring in chronic cannabis users. The error-related negativity (ERN) and error positivity (Pe), ERPs sensitive to performance monitoring, were recorded from 30 frequent cannabis users (mean usage=5.52 days/week) and 32 cannabis-naïve control participants during a speeded stimulus discrimination task. The “oddball” P3 ERP was recorded as well. Users and controls did not differ on the amplitude or latency of the ERN; however, Pe amplitude was larger among users. Users also showed increased amplitude and reduced latency of the P3 in response to infrequent stimuli presented during the task. Among users, urinary cannabinoid metabolite levels at testing were unrelated to ERP outcomes. However, total years of cannabis use correlated negatively with P3 latency and positively with P3 amplitude, and age of first cannabis use correlated negatively with P3 amplitude. The results of this study suggest that chronic cannabis use is associated with alterations in neural activity related to the processing of motivationally-relevant stimuli (P3) and errors (Pe). PMID:23427191

  16. The Venus Neutral Atmosphere from the Radio Science Experiment VeRa on Venus Express

    NASA Astrophysics Data System (ADS)

    Tellmann, S.; Haeusler, B.; Paetzold, M.; Bird, M. K.; Tyler, G. L.

    2008-12-01

    The Venus Express Radio Science Experiment VeRa is sounding the Venus neutral atmosphere and ionosphere using the spacecraft radio subsystem in the oneway radio link mode at X-band (8.4 GHz) and S- band (2.3 GHz). An Ultrastable Oscillator (USO) provides a high quality onboard frequency reference source for the derivation of electron density profiles in the ionosphere and profiles of pressure, temperature and neutral number density of the neutral atmosphere. Radial profiles of neutral number density derived from the occultations cover the altitude range 40 to 90 km, which are converted to vertical profiles of temperature and pressure. The polar orbit of Venus Express provides the opportunity to study the atmosphere at all planetocentric latitudes under varying illumination conditions. Five occultation seasons could be covered so far during the Venus Express mission resulting in a data set of more than 150 profiles of the neutral atmosphere. The thermal structure is investigated with regard to the latitudinal and temporal variability. A distinct cold collar region could be observed on both hemispheres. The tropopause altitude increases in this latitude region while the tropopause temperature shows a strong decrease. Profiles of static stability are found to be latitude-dependent and nearly adiabatic in the middle cloud region.

  17. SHG-specificity of cellular Rootletin filaments enables naïve imaging with universal conservation

    PubMed Central

    Akiyama, Toshihiro; Inoko, Akihito; Kaji, Yuichi; Yonemura, Shigenobu; Kakiguchi, Kisa; Segawa, Hiroki; Ishitsuka, Kei; Yoshida, Masaki; Numata, Osamu; Leproux, Philippe; Couderc, Vincent; Oshika, Tetsuro; Kano, Hideaki

    2017-01-01

    Despite growing demand for truly naïve imaging, label-free observation of cilium-related structure remains challenging, and validation of the pertinent molecules is correspondingly difficult. In this study, in retinas and cultured cells, we distinctively visualized Rootletin filaments in rootlets in the second harmonic generation (SHG) channel, integrated in custom coherent nonlinear optical microscopy (CNOM) with a simple, compact, and ultra-broadband supercontinuum light source. This SHG signal was primarily detected on rootlets of connecting cilia in the retinal photoreceptor and was validated by colocalization with anti-Rootletin staining. Transfection of cells with Rootletin fragments revealed that the SHG signal can be ascribed to filaments assembled from the R234 domain, but not to cross-striations assembled from the R123 domain. Consistent with this, Rootletin-depleted cells lacked SHG signal expected as centrosome linker. As a proof of concept, we confirmed that similar fibrous SHG was observed even in unicellular ciliates. These findings have potential for broad applications in clinical diagnosis and biophysical experiments with various organisms. PMID:28059168

  18. The Effect of Orthopedic Advertising and Self-Promotion on a Naïve Population.

    PubMed

    Mohney, Stephen; Lee, Daniel J; Elfar, John C

    2016-01-01

    There has been a marked increase in the number of physicians marketing themselves directly to patients and consumers. However, it is unclear how different promotional styles affect patients' perceptions of their physicians. We hypothesized that self-promoting orthopedic surgeons enjoy a more positive impact on nonphysician patients as compared to non-self-promoting surgeons, as well as a corresponding negative impact on their peer-surgeons. Surgeon websites were selected from the 5 largest population centers in the United States. Subjects with varying degrees of familiarity with orthopedic surgery evaluated Internet profiles of surgeons on a forced choice Likert scale to measure the amount of self-promotion. The naïve subjects judged self-promoting surgeons more favorably than the orthopedic surgeons. In contrast, board-certified orthopedic surgeons viewed self-promoting surgeons more negatively than did their nonphysician counterparts. In summary, the present study revealed that the potential for self-promotion to unduly influence potential patients is real and should be a considerable concern to surgeons, patients, and the profession.

  19. Reactions to small pox vaccine in naïve and previously-vaccinated individuals.

    PubMed

    Auckland, Cressida; Cowlishaw, Alexandra; Morgan, Dilys; Miller, Elizabeth

    2005-07-14

    Two hundred health care workers in England and Wales were vaccinated with the Lister/Elstree strain of the vaccinia virus, and completed health diaries for 21 days or until the lesion had scabbed over. Pain and temperature were measured daily, and all other symptoms recorded freehand by the vaccinee. One hundred and forty two (71%) vaccinees reported pain, of which 25% considered it to be moderate or severe; 32 vaccinees (16%) recorded a temperature of >37.7 degrees C, two of which exceeded 39 degrees C. Other, mainly trivial, adverse events were common; itch was reported in 72%, erythema in 27%, axillary pain or lymphadenopathy in 38%, malaise or flu-like symptoms in 40% and headache in 23%. The incidences of minor adverse events were lower in re-vaccinees, compared with naïve vaccine recipients, significantly so in the case of erythema and general malaise (p=0.001 and 0.006, respectively), perhaps reflecting pre-existing immunity. Major adverse events occurred in two vaccinees (hospital admission, one with cellulitis and one with headache and possible encephalitis), and a further five were treated with antibiotics for local cellulitis. This is the first study to report results derived from active follow-up by diaries in recipients of the Lister/Elstree strain of vaccinia, and to document reductions in trivial adverse events in re-vaccinees.

  20. Optimized suppression of coherent noise from seismic data using the Karhunen-Loève transform.

    PubMed

    Montagne, Raúl; Vasconcelos, Giovani L

    2006-07-01

    Signals obtained in land seismic surveys are usually contaminated with coherent noise, among which the ground roll (Rayleigh surface waves) is of major concern for it can severely degrade the quality of the information obtained from the seismic record. This paper presents an optimized filter based on the Karhunen-Loève transform for processing seismic images contaminated with ground roll. In this method, the contaminated region of the seismic record, to be processed by the filter, is selected in such way as to correspond to the maximum of a properly defined coherence index. The main advantages of the method are that the ground roll is suppressed with negligible distortion of the remnant reflection signals and that the filtering procedure can be automated. The image processing technique described in this study should also be relevant for other applications where coherent structures embedded in a complex spatiotemporal pattern need to be identified in a more refined way. In particular, it is argued that the method is appropriate for processing optical coherence tomography images whose quality is often degraded by coherent noise (speckle).

  1. A Pairwise Naïve Bayes Approach to Bayesian Classification

    PubMed Central

    Betensky, Rebecca A.

    2016-01-01

    Despite the relatively high accuracy of the naïve Bayes (NB) classifier, there may be several instances where it is not optimal, i.e. does not have the same classification performance as the Bayes classifier utilizing the joint distribution of the examined attributes. However, the Bayes classifier can be computationally intractable due to its required knowledge of the joint distribution. Therefore, we introduce a “pairwise naïve” Bayes (PNB) classifier that incorporates all pairwise relationships among the examined attributes, but does not require specification of the joint distribution. In this paper, we first describe the necessary and sufficient conditions under which the PNB classifier is optimal. We then discuss sufficient conditions for which the PNB classifier, and not NB, is optimal for normal attributes. Through simulation and actual studies, we evaluate the performance of our proposed classifier relative to the Bayes and NB classifiers, along with the HNB, AODE, LBR and TAN classifiers, using normal density and empirical estimation methods. Our applications show that the PNB classifier using normal density estimation yields the highest accuracy for data sets containing continuous attributes. We conclude that it offers a useful compromise between the Bayes and NB classifiers. PMID:27087730

  2. Movement imagery classification in EMOTIV cap based system by Naïve Bayes.

    PubMed

    Stock, Vinicius N; Balbinot, Alexandre

    2016-08-01

    Brain-computer interfaces (BCI) provide means of communications and control, in assistive technology, which do not require motor activity from the user. The goal of this study is to promote classification of two types of imaginary movements, left and right hands, in an EMOTIV cap based system, using the Naïve Bayes classifier. A preliminary analysis with respect to results obtained by other experiments in this field is also conducted. Processing of the electroencephalography (EEG) signals is done applying Common Spatial Pattern filters. The EPOC electrodes cap is used for EEG acquisition, in two test subjects, for two distinct trial formats. The channels picked are FC5, FC6, P7 and P8 of the 10-20 system, and a discussion about the differences of using C3, C4, P3 and P4 positions is proposed. Dataset 3 of the BCI Competition II is also analyzed using the implemented algorithms. The maximum classification results for the proposed experiment and for the BCI Competition dataset were, respectively, 79% and 85% The conclusion of this study is that the picked positions for electrodes may be applied for BCI systems with satisfactory classification rates.

  3. Decreased Cardiac Vagal Control in Drug-Naïve Patients with Posttraumatic Stress Disorder

    PubMed Central

    Chang, Hsin-An; Chang, Chuan-Chia; Tzeng, Nian-Sheng; Kuo, Terry BJ; Lu, Ru-Band

    2013-01-01

    Objective Decreased cardiac vagal control (CVC) has been proposed in posttraumatic stress disorder (PTSD), but the results are mixed. Analyses with larger sample sizes and better methodology are needed. Methods Thirty-two drug-naïve survivors with current PTSD, 32 survivors without PTSD and 192 matched controls were recruited for a case-control analysis. We used the PTSD checklist-civilian version (PCL-C) to assess posttraumatic symptoms severity. Cardiac autonomic function was evaluated by measuring heart rate variability (HRV) parameters. Frequency-domain indices of HRV were obtained. The obtained results were evaluated in association with personality traits assessed by the Tridimensional Personality Questionnaire (TPQ). Results PTSD patients exhibited decreased LF-HRV and HF-HRV as compared to survivors without PTSD and to matched controls. The PTSD symptoms severity was associated with reduced mean RR intervals, Var-HRV, LF-HRV and HF-HRV. The harm avoidance score (which has been suggested to be associated with serotonergic activity) was negatively correlated with Var-HRV, LF-HRV and HF-HRV. Conclusion These data suggest that PTSD is accompanied by decreased CVC, highlighting the importance of assessing HRV in PTSD patients. In view of the increased risk for cardiovascular diseases in these vulnerable individuals, one might consider the treatment to restore their autonomic function while reducing PTSD symptoms. PMID:23798959

  4. Categorization of Natural Whistled Vowels by Naïve Listeners of Different Language Background

    PubMed Central

    Meyer, Julien; Dentel, Laure; Meunier, Fanny

    2017-01-01

    Whistled speech in a non-tonal language consists of the natural emulation of vocalic and consonantal qualities in a simple modulated whistled signal. This special speech register represents a natural telecommunication system that enables high levels of sentence intelligibility by trained speakers and is not directly intelligible to naïve listeners. Yet, it is easily learned by speakers of the language that is being whistled, as attested by the current efforts of the revitalization of whistled Spanish in the Canary Islands. To better understand the relation between whistled and spoken speech perception, we look herein at how Spanish, French, and Standard Chinese native speakers, knowing nothing about whistled speech, categorized four Spanish whistled vowels. The results show that the listeners categorized differently depending on their native language. The Standard Chinese speakers demonstrated the worst performance on this task but were still able to associate a tonal whistle to vowel categories. Spanish speakers were the most accurate, and both Spanish and French participants were able to categorize the four vowels, although not as accurately as an expert whistler. These results attest that whistled speech can be used as a natural laboratory to test the perceptual processes of language. PMID:28174545

  5. The Ontogeny of Bumblebee Flight Trajectories: From Naïve Explorers to Experienced Foragers

    PubMed Central

    Osborne, Juliet L.; Smith, Alan; Clark, Suzanne J.; Reynolds, Don R.; Barron, Mandy C.; Lim, Ka S.; Reynolds, Andy M.

    2013-01-01

    Understanding strategies used by animals to explore their landscape is essential to predict how they exploit patchy resources, and consequently how they are likely to respond to changes in resource distribution. Social bees provide a good model for this and, whilst there are published descriptions of their behaviour on initial learning flights close to the colony, it is still unclear how bees find floral resources over hundreds of metres and how these flights become directed foraging trips. We investigated the spatial ecology of exploration by radar tracking bumblebees, and comparing the flight trajectories of bees with differing experience. The bees left the colony within a day or two of eclosion and flew in complex loops of ever-increasing size around the colony, exhibiting Lévy-flight characteristics constituting an optimal searching strategy. This mathematical pattern can be used to predict how animals exploring individually might exploit a patchy landscape. The bees’ groundspeed, maximum displacement from the nest and total distance travelled on a trip increased significantly with experience. More experienced bees flew direct paths, predominantly flying upwind on their outward trips although forage was available in all directions. The flights differed from those of naïve honeybees: they occurred at an earlier age, showed more complex looping, and resulted in earlier returns of pollen to the colony. In summary bumblebees learn to find home and food rapidly, though phases of orientation, learning and searching were not easily separable, suggesting some multi-tasking. PMID:24265707

  6. Follower ants in a tandem pair are not always naïve

    PubMed Central

    Schultheiss, Patrick; Raderschall, Chloé A; Narendra, Ajay

    2015-01-01

    In addition to foraging individually several species of ants guide nestmates to a goal by tandem running. We found that the Australian ant, Camponotus consobrinus, forages both individually and by tandem running to head to the same goal, nest-specific native Australian trees on which they forage. While paths of solitary foragers and initial paths of tandem followers showed no differences in heading directions or straightness, tandem followers moved at about half the speed of solitary runs. When leaders were experimentally removed, follower ants initially engaged in a systematic search around the point of interruption, following which they either (a) headed directly towards and successfully reached the foraging trees, or (b) continued searching or (c) returned to the nest. The high incidence of followers that successfully navigated towards the foraging trees on their own provides strong evidence that many tandem followers are in fact experienced foragers. Detailed analysis of the searching behaviour revealed that even seemingly lost followers displayed a directional bias towards the foraging trees in their search path. Our results show that in a foraging context follower ants in a tandem pair are not always naïve. PMID:26021611

  7. VE-cadherin cleavage by ovarian cancer microparticles induces β-catenin phosphorylation in endothelial cells

    PubMed Central

    Thawadi, Hamda Al; Abu-Kaoud, Nadine; Farsi, Haleema Al; Hoarau-Véchot, Jessica; Rafii, Shahin; Rafii, Arash; Pasquier, Jennifer

    2016-01-01

    Microparticles (MPs) are increasingly recognized as important mediators of cell-cell communication in tumour growth and metastasis by facilitating angiogenesis-related processes. While the effects of the MPs on recipient cells are usually well described in the literature, the leading process remains unclear. Here we isolated MPs from ovarian cancer cells and investigated their effect on endothelial cells. First, we demonstrated that ovarian cancer MPs trigger β-catenin activation in endothelial cells, inducing the upregulation of Wnt/β-catenin target genes and an increase of angiogenic properties. We showed that this MPs mediated activation of β-catenin in ECs was Wnt/Frizzled independent; but dependent on VE-cadherin localization disruption, αVβ3 integrin activation and MMP activity. Finally, we revealed that Rac1 and AKT were responsible for β-catenin phosphorylation and translocation to the nucleus. Overall, our results indicate that MPs released from cancer cells could play a major role in neo-angiogenesis through activation of beta catenin pathway in endothelial cells. PMID:26700621

  8. Qualitative differences between naïve and scientific theories of evolution.

    PubMed

    Shtulman, Andrew

    2006-03-01

    Philosophers of biology have long argued that Darwin's theory of evolution was qualitatively different from all earlier theories of evolution. Whereas Darwin's predecessors and contemporaries explained adaptation as the transformation of a species' "essence," Darwin explained adaptation as the selective propagation of randomly occurring mutations within a population. The present study explored the possibility of a parallel between early "transformational" theories of evolution and modern naïve theories. Forty-two high school and college students and three evolutionary biologists were tested on their understanding of six evolutionary phenomena: variation, inheritance, adaptation, domestication, speciation, and extinction. As predicted, a plurality of participants demonstrated transformational reasoning inconsistent with natural selection. Correlational analyses revealed that participants who demonstrated transformational reasoning were as internally consistent as participants who demonstrated an understanding of natural selection, with the exception of one group of participants who appeared to have assimilated two heuristics--"survival of the fittest" and "acquired traits are not inherited"--into an otherwise transformational framework. These findings suggest that the widespread and early-developing tendency to essentialize biological kinds precludes students from conceptualizing species as populations of individuals differentially affected by the environment.

  9. Strong lensing probability in TeVeS (tensor-vector-scalar) theory

    SciTech Connect

    Chen Daming

    2008-01-15

    We recalculate the strong lensing probability as a function of the image separation in TeVeS (tensor-vector-scalar) cosmology, which is a relativistic version of MOND (MOdified Newtonian Dynamics). The lens is modeled by the Hernquist profile. We assume an open cosmology with {Omega}{sub b} = 0.04 and {Omega}{sub {Lambda}} = 0.5 and three different kinds of interpolating functions. Two different galaxy stellar mass functions (GSMF) are adopted: PHJ (Panter, Heavens and Jimenez 2004 Mon. Not. R. Astron. Soc. 355 764) determined from SDSS data release 1 and Fontana (Fontana et al 2006 Astron. Astrophys. 459 745) from GOODS-MUSIC catalog. We compare our results with both the predicted probabilities for lenses from singular isothermal sphere galaxy halos in LCDM (Lambda cold dark matter) with a Schechter-fit velocity function, and the observational results for the well defined combined sample of the Cosmic Lens All-Sky Survey (CLASS) and Jodrell Bank/Very Large Array Astrometric Survey (JVAS). It turns out that the interpolating function {mu}(x) = x/(1+x) combined with Fontana GSMF matches the results from CLASS/JVAS quite well.

  10. Differential expression of FCRLA in naïve and activated mouse B cells

    PubMed Central

    Reshetnikova, Evdokiya S.; Mechetina, Ludmila V.; Volkova, Olga Y.; Guselnikov, Sergey V.; Chikaev, Nikolai A.; Kövesdi, Dorottya; Alabyev, Boris; Sármay, Gabriella; Burrows, Peter D.; Najakshin, Alexander M.; Taranin, Alexander V.

    2011-01-01

    FCRLA is an intracellular B cell protein that belongs to the FcR-like family. Using newly generated FCRLA-specific antibodies, we studied the constitutive expression pattern of mouse FCRLA and monitored changes during an immune response and following in vitro B cell activation. All B cell subpopulations examined expressed FCRLA. However, the level of FCRLA expression is determined by the stage of B cell differentiation. Low expression of FCRLA is characteristic of naïve follicular and marginal zone B cells. High expression was detected in a small fraction of activated B cells scattered along migratory pathways in the lymphoid tissues. FCRLA-bright cells could be subdivided into two subpopulations, with high and low/undetectable level of intracellular immunoglobulins, which phenotypically resemble either plasma or memory B cells. High expression of FCRLA in subset(s) of terminally differentiated B-cells suggests that, being an ER protein, FCRLA may participate in the regulation of immunoglobulin assembly and secretion. PMID:22078318

  11. Social isolation prompts maternal behavior in sexually naïve male ddN mice.

    PubMed

    Orikasa, Chitose; Nagaoka, Kentaro; Katsumata, Harumi; Sato, Manami; Kondo, Yasuhiko; Minami, Shiro; Sakuma, Yasuo

    2015-11-01

    Maternal behavior in mice is considered to be sexually dimorphic; that is, females show maternal care for their offspring, whereas this behavior is rarely shown in males. Here, we examined how social isolation affects the interaction of adult male mice with pups. Three weeks of isolation during puberty (5-8 weeks old) induced retrieving and crouching when exposed to pups, while males with 1 week isolation (7-8 weeks old) also showed such maternal care, but were less responsive to pups. We also examined the effect of isolation during young adulthood (8-11 weeks old), and found an induction of maternal behavior comparable to that in younger male mice. This effect was blocked by exposure to chemosensory and auditory social signals derived from males in an attached compartment separated by doubled opaque barriers. These results demonstrate that social isolation in both puberty and postpuberty facilitates male maternal behavior in sexually naïve mice. The results also indicate that air-borne chemicals and/or sounds of male conspecifics, including ultrasonic vocalization and noise by their movement may be sufficient to interfere with the isolation effect on induction of maternal behavior in male mice.

  12. Infectious diarrhoea in antiretroviral therapy-naïve HIV/AIDS patients in Kenya

    PubMed Central

    Wanyiri, Jane W.; Kanyi, Henry; Maina, Samuel; Wang, David E.; Ngugi, Paul; O'Connor, Roberta; Kamau, Timothy; Waithera, Tabitha; Kimani, Gachuhi; Wamae, Claire N.; Mwamburi, Mkaya; Ward, Honorine D.

    2013-01-01

    Background Diarrhoea is a significant cause of morbidity and mortality in immunocompromised patients. The objectives of this study were to investigate the aetiological agents, risk factors and clinical features associated with diarrhoea in HIV/AIDS patients in Kenya. Methods Sociodemographic, epidemiological and clinical data were obtained for 164 HIV/AIDS patients (70 with and 94 without diarrhoea) recruited from Kenyatta National Hospital, Kenya. Stool samples were examined for enteric pathogens by microscopy and bacteriology. Results Intestinal protozoa and fungi were identified in 70% of patients, more frequently in those with diarrhoea (p<0.001). Helminths were detected in 25.6% of patients overall, and bacterial pathogens were identified in 51% of patients with diarrhoea. Polyparasitism was more common in patients with diarrhoea than those without (p<0.0001). Higher CD4+ T-cell count (OR = 0.995, 95% CI 0.992–0.998) and water treatment (OR = 0.231, 95% CI 0.126–0.830) were associated with a lower risk of diarrhoea, while close contact with cows (OR = 3.200, 95% CI 1.26–8.13) or pigs (OR = 11.176, 95% CI 3.76–43.56) were associated with a higher risk of diarrhoea. Conclusions Multiple enteric pathogens that are causative agents of diarrhoea were isolated from stools of antiretroviral therapy-naïve HIV/AIDS patients, indicating a need for surveillance, treatment and promotion of hygienic practices. PMID:24026463

  13. BIM expression in treatment naïve cancers predicts responsiveness to kinase inhibitors

    PubMed Central

    Faber, Anthony; Corcoran, Ryan B.; Ebi, Hiromichi; Sequist, Lecia V.; Waltman, Belinda A.; Chung, Euiheon; Incio, Joao; Digumarthy, Subba R.; Pollack, Sarah F.; Song, Youngchul; Muzikansky, Alona; Lifshits, Eugene; Roberge, Sylvie; Coffman, Erik J.; Benes, Cyril; Gómez, Henry; Baselga, Jose; Arteaga, Carlos L.; Rivera, Miguel N.; Dias-Santagata, Dora; Jain, Rakesh K.; Engelman, Jeffrey A.

    2011-01-01

    Cancers with specific genetic mutations are susceptible to selective kinase inhibitors. However, there is wide spectrum of benefit among cancers harboring the same sensitizing genetic mutations. Herein, we measured apoptotic rates among cell lines sharing the same driver oncogene following treatment with the corresponding kinase inhibitor. There was a wide range of kinase inhibitor-induced apoptosis despite comparable inhibition of the target and associated downstream signaling pathways. Surprisingly, pre-treatment RNA levels of the BH3-only pro-apoptotic BIM strongly predicted the capacity of EGFR, HER2, and PI3K inhibitors to induce apoptosis in EGFR mutant, HER2 amplified, and PIK3CA mutant cancers, respectively, but BIM levels did not predict responsiveness to standard chemotherapies. Furthermore, BIM RNA levels in EGFR mutant lung cancer specimens predicted response and duration of clinical benefit from EGFR inhibitors. These findings suggest assessment of BIM levels in treatment naïve tumor biopsies may indicate the degree of benefit from single-agent kinase inhibitors in multiple oncogene-addiction paradigms. PMID:22145099

  14. Nonlinear system stochastic response determination via fractional equivalent linearization and Karhunen-Loève expansion

    NASA Astrophysics Data System (ADS)

    Dai, Hongzhe; Zheng, Zhibao; Wang, Wei

    2017-08-01

    In this paper, a novel fractional equivalent linearization (EL) approach is developed by incorporating a fractional derivative term into the classical linearization equation. Due to the introduction of the fractional derivative term, the accuracy of the new linearization is improved, illustrated by a Duffing oscillator that is subjected to a harmonic excitation. Furthermore, a new method for solving stochastic response of nonlinear SDOF system is developed by combining Karhunen-Loève (K-L) expansion and fractional EL. The method firstly decomposes the stochastic excitation in terms of a set of random variables and deterministic sub-excitations using K-L expansion, and then construct sub-fractional equivalent linear system according to each sub-excitation by fractional EL, the response of the original nonlinear system is finally approximated as the weighed summation of the deterministic response of each sub-system multiplied by the corresponding random variable. The random nature of the final response comes from the set of random variables that is obtained in K-L expansion. In this way, the stochastic response computation is converted to a set of deterministic response analysis problems. The effectiveness of the developed method is demonstrated by a Duffing oscillator that is subjected to stochastic excitation modeled by Winner process. The results are compared with the numerical method and Monte Carlo simulation (MCS).

  15. Beyond naïve cue combination: salience and social cues in early word learning.

    PubMed

    Yurovsky, Daniel; Frank, Michael C

    2017-03-01

    Children learn their earliest words through social interaction, but it is unknown how much they rely on social information. Some theories argue that word learning is fundamentally social from its outset, with even the youngest infants understanding intentions and using them to infer a social partner's target of reference. In contrast, other theories argue that early word learning is largely a perceptual process in which young children map words onto salient objects. One way of unifying these accounts is to model word learning as weighted cue combination, in which children attend to many potential cues to reference, but only gradually learn the correct weight to assign each cue. We tested four predictions of this kind of naïve cue combination account, using an eye-tracking paradigm that combines social word teaching and two-alternative forced-choice testing. None of the predictions were supported. We thus propose an alternative unifying account: children are sensitive to social information early, but their ability to gather and deploy this information is constrained by domain-general cognitive processes. Developmental changes in children's use of social cues emerge not from learning the predictive power of social cues, but from the gradual development of attention, memory, and speed of information processing.

  16. Clozapine--a dangerous drug in a clozapine-naïve subject.

    PubMed

    Stanworth, D; Hunt, N C A; Flanagan, R J

    2012-01-10

    Clozapine is a uniquely effective antipsychotic, but is very toxic in clozapine-naïve subjects. A 34-year-old male patient in a mental health facility, who was not prescribed clozapine, took 350 mg clozapine obtained from another patient at night. He was found dead the next morning. The presence of cardiomegaly related to obesity may have increased the risk of suffering an acute cardiac event after ingestion of clozapine. The medication prescribed to the patient was not thought to have contributed to the fatal outcome. Post mortem femoral blood clozapine and norclozapine concentrations were 0.48 and 0.20mg/L, respectively. By way of comparison, audit of 104,127 plasma samples (26,796 patients) assayed for therapeutic drug monitoring purposes 1993-2007, showed plasma clozapine 0.35 mg/L or more in 57.5% samples (8.4% 1mg/L or more). Those involved in the investigation of clozapine-associated deaths need to be aware that that death in an adult may occur after a single 'therapeutic' dose. A diagnosis of fatal clozapine poisoning cannot be made solely on the basis of a post mortem blood clozapine measurement.

  17. Topography of sensory symptoms in patients with drug-naïve restless legs syndrome.

    PubMed

    Koo, Yong Seo; Lee, Gwan-Taek; Lee, Seo Young; Cho, Yong Won; Jung, Ki-Young

    2013-12-01

    We aimed to describe the sensory topography of restless legs syndrome (RLS) sensory symptoms and to identify the relationship between topography and clinical variables. Eighty adult patients with drug-naïve RLS who had symptoms for more than 1year were consecutively recruited. During face-to-face interviews using a structured paper and pencil questionnaire with all participants, we obtained clinical information and also marked the topography of RLS sensory symptoms on a specified body template, all of which were subsequently inputted into our in-house software. The RLS sensory topography patterns were classified according to localization, lateralization, and symmetry. We investigated if these sensory topography patterns differed according to various clinical variables. The lower extremities only (LE) were the most common location (72.5%), and 76.3% of participants exhibited symmetric sensory topography. Late-onset RLS showed more asymmetric sensory distribution compared with early-onset RLS (P=.024). Patients whose sensory symptoms involved the lower extremities in addition to other body parts (LE-PLUS) showed more severe RLS compared with those involving the LE (P=.037). RLS sensory symptoms typically were symmetrically located in the lower extremities. LE-PLUS or an asymmetric distribution more often occurred in patients with more severe RLS symptoms or late-onset RLS. Copyright © 2013 Elsevier B.V. All rights reserved.

  18. Meta-analysis of cognitive performance in drug-naïve patients with schizophrenia.

    PubMed

    Fatouros-Bergman, Helena; Cervenka, Simon; Flyckt, Lena; Edman, Gunnar; Farde, Lars

    2014-09-01

    Cognitive deficits represent a significant characteristic of schizophrenia. However, a majority of the clinical studies have been conducted in antipsychotic drug treated patients. Thus, it remains unclear if significant cognitive impairments exist in the absence of medication. This is the first meta-analysis of cognitive findings in drug-naïve patients with schizophrenia. Cognitive data from 23 studies encompassing 1106 patients and 1385 controls published from 1992 to 2013 were included. Tests were to a large extent ordered in cognitive domains according to the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) battery. Analysis was performed with STATA using the random-effects model and heterogeneity as well as Egger's publication bias was assessed. Overall the results show that patients performed worse than healthy controls in all cognitive domains with medium to large effect sizes. Verbal memory, speed of processing and working memory were three of the domains with the greatest impairments. The pattern of results is in line with previous meta-analytic findings in antipsychotic treated patients. The present meta-analysis confirms the existence of significant cognitive impairments at the early stage of the illness in the absence of antipsychotic medication.

  19. NBA-Palm: prediction of palmitoylation site implemented in Naïve Bayes algorithm

    PubMed Central

    Xue, Yu; Chen, Hu; Jin, Changjiang; Sun, Zhirong; Yao, Xuebiao

    2006-01-01

    Background Protein palmitoylation, an essential and reversible post-translational modification (PTM), has been implicated in cellular dynamics and plasticity. Although numerous experimental studies have been performed to explore the molecular mechanisms underlying palmitoylation processes, the intrinsic feature of substrate specificity has remained elusive. Thus, computational approaches for palmitoylation prediction are much desirable for further experimental design. Results In this work, we present NBA-Palm, a novel computational method based on Naïve Bayes algorithm for prediction of palmitoylation site. The training data is curated from scientific literature (PubMed) and includes 245 palmitoylated sites from 105 distinct proteins after redundancy elimination. The proper window length for a potential palmitoylated peptide is optimized as six. To evaluate the prediction performance of NBA-Palm, 3-fold cross-validation, 8-fold cross-validation and Jack-Knife validation have been carried out. Prediction accuracies reach 85.79% for 3-fold cross-validation, 86.72% for 8-fold cross-validation and 86.74% for Jack-Knife validation. Two more algorithms, RBF network and support vector machine (SVM), also have been employed and compared with NBA-Palm. Conclusion Taken together, our analyses demonstrate that NBA-Palm is a useful computational program that provides insights for further experimentation. The accuracy of NBA-Palm is comparable with our previously described tool CSS-Palm. The NBA-Palm is freely accessible from: . PMID:17044919

  20. NBA-Palm: prediction of palmitoylation site implemented in Naïve Bayes algorithm.

    PubMed

    Xue, Yu; Chen, Hu; Jin, Changjiang; Sun, Zhirong; Yao, Xuebiao

    2006-10-17

    Protein palmitoylation, an essential and reversible post-translational modification (PTM), has been implicated in cellular dynamics and plasticity. Although numerous experimental studies have been performed to explore the molecular mechanisms underlying palmitoylation processes, the intrinsic feature of substrate specificity has remained elusive. Thus, computational approaches for palmitoylation prediction are much desirable for further experimental design. In this work, we present NBA-Palm, a novel computational method based on Naïve Bayes algorithm for prediction of palmitoylation site. The training data is curated from scientific literature (PubMed) and includes 245 palmitoylated sites from 105 distinct proteins after redundancy elimination. The proper window length for a potential palmitoylated peptide is optimized as six. To evaluate the prediction performance of NBA-Palm, 3-fold cross-validation, 8-fold cross-validation and Jack-Knife validation have been carried out. Prediction accuracies reach 85.79% for 3-fold cross-validation, 86.72% for 8-fold cross-validation and 86.74% for Jack-Knife validation. Two more algorithms, RBF network and support vector machine (SVM), also have been employed and compared with NBA-Palm. Taken together, our analyses demonstrate that NBA-Palm is a useful computational program that provides insights for further experimentation. The accuracy of NBA-Palm is comparable with our previously described tool CSS-Palm. The NBA-Palm is freely accessible from: http://www.bioinfo.tsinghua.edu.cn/NBA-Palm.

  1. Metabolomics study of fatigue in patients with rheumatoid arthritis naïve to biological treatment.

    PubMed

    Surowiec, Izabella; Gjesdal, Clara Gram; Jonsson, Grete; Norheim, Katrine Brække; Lundstedt, Torbjörn; Trygg, Johan; Omdal, Roald

    2016-05-01

    Fatigue occurs in all chronic inflammatory diseases, in cancer, and in some neurological conditions. Patients often regard fatigue as one of their most debilitating problems, but currently there is no established treatment and the mechanisms that lead to and regulate fatigue are incompletely understood. Our objective was to more completely understand the physiology of this phenomenon. Twenty-four patients with rheumatoid arthritis (RA) naïve to treatment with biological drugs were enrolled for the study. Fatigue was measured with a fatigue visual analogue scale (fVAS). Ethylenediaminetetraacetic acid (EDTA) plasma samples were subjected to gas chromatography-time-of-flight mass spectrometry (GC/MS-TOF)-based metabolite profiling. Obtained metabolite data were evaluated by multivariate data analysis with orthogonal projections to latent structures (OPLS) method to pinpoint metabolic changes related to fatigue severity. A significant multivariate OPLS model was obtained between the fVAS scores and the measured metabolic levels. Increasing fatigue scores were associated with a metabolic pattern characterized by down-regulation of metabolites from the urea cycle, fatty acids, tocopherols, aromatic amino acids, and hypoxanthine. Uric acid levels were increased. Apart from fatigue, we found no other disease-related variables that might be responsible for these changes. Our MS-based metabolomic approach demonstrated strong associations between fatigue and several biochemical patterns related to oxidative stress.

  2. CD45-mediated control of TCR tuning in naïve and memory CD8+ T cells

    PubMed Central

    Cho, Jae-Ho; Kim, Hee-Ok; Ju, Young-Jun; Kye, Yoon-Chul; Lee, Gil-Woo; Lee, Sung-Woo; Yun, Cheol-Heui; Bottini, Nunzio; Webster, Kylie; Goodnow, Christopher C.; Surh, Charles D.; King, Cecile; Sprent, Jonathan

    2016-01-01

    Continuous contact with self-major histocompatibility complex (MHC) ligands is essential for survival of naïve T cells but not memory cells. This surprising finding implies that T cell subsets may vary in their relative T-cell receptor (TCR) sensitivity. Here we show that in CD8+T cells TCR sensitivity correlates inversely with levels of CD5, a marker for strong self-MHC reactivity. We also show that TCR sensitivity is lower in memory CD8+ T cells than naïve cells. In both situations, TCR hypo-responsiveness applies only to short-term TCR signalling events and not to proliferation, and correlates directly with increased expression of a phosphatase, CD45 and reciprocal decreased expression of activated LCK. Inhibition by high CD45 on CD8+ T cells may protect against overt TCR auto-MHC reactivity, while enhanced sensitivity to cytokines ensures strong responses to foreign antigens. PMID:27841348

  3. New Middle Permian palaeopteran insects from Lodève Basin in southern France (Ephemeroptera, Diaphanopterodea, Megasecoptera)

    PubMed Central

    Prokop, Jakub; Nel, André

    2011-01-01

    Abstract Three new palaeopteran insects are described from the Middle Permian (Guadalupian) of Salagou Formation in the Lodève Basin (South of France), viz. the diaphanopterodean Alexrasnitsyniidae fam. n., based on Alexrasnitsynia permiana gen. et sp. n., the Parelmoidae Permelmoa magnifica gen. et sp. n., and Lodevohymen lapeyriei gen. et sp. n. (in Megasecoptera or Diaphanopterodea, family undetermined). In addition the first record of mayflies attributed to family Syntonopteridae (Ephemeroptera) is reported. These new fossils clearly demonstrate that the present knowledge of the Permian insects remains very incomplete. They also confirm that the Lodève entomofauna was highly diverse providing links to other Permian localities and also rather unique, with several families still not recorded in other contemporaneous outcrops. PMID:22259265

  4. Symmetry is in the eye of the `beeholder': innate preference for bilateral symmetry in flower-naïve bumblebees

    NASA Astrophysics Data System (ADS)

    Rodríguez, Ivana; Gumbert, Andreas; Hempel de Ibarra, Natalie; Kunze, Jan; Giurfa, Martin

    Bilateral symmetry has been considered as an indicator of phenotypic and genotypic quality supporting innate preferences for highly symmetric partners. Insect pollinators preferentially visit flowers of a particular symmetry type, thus leading to the suggestion that they have innate preferences for symmetrical flowers or flower models. Here we show that flower-naïve bumblebees (Bombus terrestris), with no experience of symmetric or asymmetric patterns and whose visual experience was accurately controlled, have innate preferences for bilateral symmetry. The presence of color cues did not influence the bees' original preference. Our results thus show that bilateral symmetry is innately preferred in the context of food search, a fact that supports the selection of symmetry in flower displays. Furthermore, such innate preferences indicate that the nervous system of naïve animals may be primed to respond to relevant sensory cues in the environment.

  5. Effect of inhaled corticosteroids on blood eosinophil count in steroid-naïve patients with COPD

    PubMed Central

    Kreindler, James L; Watkins, Michael L; Lettis, Sally; Tal-Singer, Ruth; Locantore, Nicholas

    2016-01-01

    Introduction Sputum and blood eosinophil counts have attracted attention as potential biomarkers in chronic obstructive pulmonary disease (COPD). One question regarding the use of blood eosinophils as a biomarker in COPD is whether their levels are affected by the use of inhaled corticosteroids (ICS), which are commonly prescribed for COPD. Methods We performed a retrospective analysis of peripheral blood leucocytes from a previously completed clinical trial that examined effects of ICS in steroid-naïve patients with COPD. Results and conclusion The data show that the ICS-containing treatment arms (containing fluticasone propionate) had a small effect on peripheral blood eosinophils in steroid-naïve patients with COPD. Trial registration number NCT00358358; Post-results. PMID:27651909

  6. Overcoming the barrier of narrative adherence in conflicts through awareness of the psychological bias of naïve realism.

    PubMed

    Nasie, Meytal; Bar-Tal, Daniel; Pliskin, Ruthie; Nahhas, Eman; Halperin, Eran

    2014-11-01

    One significant socio-psychological barrier for peaceful resolution of conflicts is each party's adherence to its own collective narrative. We hypothesized that raising awareness to the psychological bias of naïve realism and its identification in oneself would provide a path to overcoming this barrier, thus increasing openness to the adversary's narrative. We conducted three experimental studies in the context of the Israeli-Palestinian conflict. Studies 1 and 2, conducted among Jewish Israelis and Palestinian Israelis, respectively, revealed that participants with hawkish political ideology reported greater openness to the adversary's narrative when they were made aware of naïve realism bias. Study 3 revealed that hawkish participants at the baseline adhered to the ingroup narrative and resisted the adversary's narrative more than dovish participants. They were also more able to identify the bias in themselves upon learning about it. This identification may explain why the manipulation led to bias correction only among hawkish participants.

  7. Neuron-specific enolase levels in drug-naïve young adults with major depressive disorder.

    PubMed

    Wiener, Carolina David; Molina, Mariane Lopez; Passos, Miguel; Moreira, Fernanda Pedrotti; Bittencourt, Guilherme; de Mattos Souza, Luciano Dias; da Silva, Ricardo Azevedo; Jansen, Karen; Oses, Jean Pierre

    2016-05-04

    The aim of this study is to assess neuron-specific enolase (NSE) levels and clinical features in subjects with major depressive disorder (MDD). This is a cross-sectional study with drug-naïve young adults with MDD (aged 18-29 years). Serum levels of NSE were assessed using the electrochemiluminescence method. MDD diagnosis, suicidal ideation, and time of disease were assessed using the Structured Clinical Interview for DSM-IV (SCID). The Hamilton Depression Rating Scale (HDRS) and Hamilton Anxiety Rating Scale (HARS) were used to assess depressive and anxiety symptoms. No relationship was observed between NSE levels and severity of depressive and anxiety symptoms, time of disease, and suicidal ideation. These results suggest that NSE serum levels were not associated with clinical features of MDD among drug-naïve young adults. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  8. CD45-mediated control of TCR tuning in naïve and memory CD8(+) T cells.

    PubMed

    Cho, Jae-Ho; Kim, Hee-Ok; Ju, Young-Jun; Kye, Yoon-Chul; Lee, Gil-Woo; Lee, Sung-Woo; Yun, Cheol-Heui; Bottini, Nunzio; Webster, Kylie; Goodnow, Christopher C; Surh, Charles D; King, Cecile; Sprent, Jonathan

    2016-11-14

    Continuous contact with self-major histocompatibility complex (MHC) ligands is essential for survival of naïve T cells but not memory cells. This surprising finding implies that T cell subsets may vary in their relative T-cell receptor (TCR) sensitivity. Here we show that in CD8(+)T cells TCR sensitivity correlates inversely with levels of CD5, a marker for strong self-MHC reactivity. We also show that TCR sensitivity is lower in memory CD8(+) T cells than naïve cells. In both situations, TCR hypo-responsiveness applies only to short-term TCR signalling events and not to proliferation, and correlates directly with increased expression of a phosphatase, CD45 and reciprocal decreased expression of activated LCK. Inhibition by high CD45 on CD8(+) T cells may protect against overt TCR auto-MHC reactivity, while enhanced sensitivity to cytokines ensures strong responses to foreign antigens.

  9. Pressure distribution on wing ribs of the VE-7 and TS airplanes in flight Part II : pull-ups

    NASA Technical Reports Server (NTRS)

    Rhode, R V

    1928-01-01

    This paper is the second of a series of notes, each of which presents the complete results of pressure distribution tests made at Langley Field by the National Advisory Committee for Aeronautics, on wing and tail ribs of the VE-7 and TS airplanes for a particular maneuver of flight. The results for pull-ups are presented in the form of curves which show the variation of pressure distribution, total loads, normal acceleration and center of pressure with respect to time.

  10. De novo ALK kinase domain mutations are uncommon in kinase inhibitor-naïve ALK rearranged lung cancers.

    PubMed

    Lucena-Araujo, Antonio R; Moran, Jason P; VanderLaan, Paul A; Dias-Santagata, Dora; Folch, Erik; Majid, Adnan; Kent, Michael S; Gangadharan, Sidharta P; Rangachari, Deepa; Huberman, Mark S; Kobayashi, Susumu S; Costa, Daniel B

    2016-09-01

    Anaplastic lymphoma kinase (ALK) rearranged lung adenocarcinomas are responsive to the multitargeted ALK inhibitor crizotinib. One of the common mechanisms of resistance to crizotinib is the acquisition of ALK kinase domain mutations. However, the presence of ALK mutations in crizotinib-naïve tumors has not been widely reported and it is unclear if de novo ALK mutations affect the response to crizotinib. We analyzed preclinical models of ALK rearranged lung cancers that were sensitive/resistant to ALK inhibitors, probed our institutional and other lung cancer databases for tumors with ALK kinase domain mutations, and evaluated tumor response to crizotinib. ALK rearranged cell lines with ALK kinase domain mutations were heterogeneously less inhibited by increasing concentrations of crizotinib than cells driven solely by EML4-ALK fusions. Previous ALK rearranged lung cancer cohorts did not report ALK kinase mutations in inhibitor-naïve tumors. We identified one TKI-naïve ALK rearranged tumor with an ALK kinase domain mutation: ALK-S1206F (mutations at ALK-S1206 shifted crizotinib inhibitory curves only minimally in preclinical models). The never smoker whose tumor harbored de novo EML4-ALK-E5;A20+ALK-S1206F only achieved a 4-month radiographic response to crizotinib 250mg twice daily. Combining data from our and prior cohorts, ALK kinase domain mutations were uncommon events (<3% of cases) in ALK inhibitor-naïve ALK rearranged lung adenocarcinomas but their effect on intrinsic resistance to ALK inhibitors should be better evaluated. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  11. Distribution of HIV-1 Infection in Different T Lymphocyte Subsets: Antiretroviral Therapy-Naïve vs. Experienced Patients

    PubMed Central

    Perez, Raul; Gibson, Sonia; Lopez, Pablo; Koenig, Ellen; De Castro, Marisol

    2011-01-01

    Abstract Memory CD4 T cells are the primary targets of HIV-1 infection, which then subsequently spreads to other T lymphocyte subsets. Antiretroviral therapy (ART) alters the pattern of HIV-1 distribution. Blood samples were collected from ART-naïve or -experienced HIV-1 patients, and the memory and naïve subsets of CD4+ and CD8+ T lymphocytes, respectively, were isolated by cell sorting. DNA was extracted and the HIV-1 env C2/V3 region PCR amplified. Amplicons were cloned and sequenced, and genetic relatedness among different HIV-1 compartments was determined by the phylogenetic analysis of clonal sequences. The viral V3 sequence of HIV-1 in each compartment was analyzed by using webPSSM to determine CCR5 or CXCR4 coreceptor binding property of the virus. The direction of viral migration among involved compartments was determined by using the MacClade program. In ART-naïve patients, HIV-1 was generally confined to the memory CD4 T (mT4) cell compartment, even though in a few cases, naïve CD4 T (nT4) cells were also infected. When this occurred, the HIV-1 gene migrated from nT4 to mT4. In contrast, HIV-1 was detected in nT4 and mT4 as well as in the memory CD8 T (mT8) compartments of ART-experienced patients. However, no clear pattern of directional HIV-1 gene flow among the compartments could be determined because of the small sample size. All HIV-1–infected T cell compartments housed the virus that used either CCR5 or CXCR4 as the coreceptor. PMID:21054214

  12. Restless legs syndrome in Korean patients with drug-naïve Parkinson's disease: a nation-wide study.

    PubMed

    Shin, Hee-Young; Youn, Jinyoung; Yoon, Won Tae; Kim, Ji Sun; Cho, Jin Whan

    2013-03-01

    Restless legs syndrome is a common neurologic disorder, and there is increasing evidence for a dopaminergic link between Parkinson's disease and restless legs syndrome. However, most previous studies did not take into account the effects of dopaminergic medication. We conducted a nation-wide, cross-sectional study to determine the prevalence and clinical characteristics of restless legs syndrome in Korean drug-naïve Parkinson's disease patients. One hundred and fifty-one drug-naïve patients with Parkinson's disease were enrolled from 18 centers in South Korea over the course of one year. Clinical profiles of parkinsonism, restless legs syndrome, psychiatric symptoms, and laboratory data were collected. The findings of subjects with and without restless legs syndrome were compared. The prevalence of restless legs syndrome in drug-naïve patients with Parkinson's disease was 16.5%. Subjects with restless legs syndrome had a higher mean Hoehn and Yahr stage and more severe limb parkinsonism, especially tremor. There was, however, no difference in iron metabolism between patients with and without restless legs syndrome. Analysis demonstrated that Beck's depression inventory score was associated with the severity of restless legs syndrome. Our study demonstrated an increased prevalence of restless leg syndrome in drug-naïve patients with Parkinson's disease than in the general population. Based on the association between parkinsonism and restless legs syndrome, and the unique characteristics of restless legs syndrome in patients with Parkinson's disease, we suggest that the pathophysiology of restless legs syndrome in Parkinson's disease differs from that in patients without Parkinson's disease. Copyright © 2012 Elsevier Ltd. All rights reserved.

  13. Effects of chronic doxepin and amitriptyline administration in naïve mice and in neuropathic pain mice model.

    PubMed

    Mika, J; Jurga, A M; Starnowska, J; Wasylewski, M; Rojewska, E; Makuch, W; Kwiatkowski, K; Malek, N; Przewlocka, B

    2015-05-21

    Neuropathic pain is a severe clinical problem, often appearing as a co-symptom of many diseases or manifesting as a result of damage to the nervous system. Many drugs and agents are currently used for the treatment of neuropathic pain, such as tricyclic antidepressants (TCAs). The aims of this paper were to test the effects of two classic TCAs, doxepin and amitriptyline, in naïve animals and in a model of neuropathic pain and to determine the role of cytokine activation in the effects of these drugs. All experiments were carried out with Albino-Swiss mice using behavioral tests (von Frey test and the cold plate test) and biochemical analyses (qRT-PCR and Western blot). In the mice subjected to chronic constriction injury (CCI), doxepin and amitriptyline attenuated the symptoms of neuropathic pain and diminished the CCI-induced increase in the levels of spinal interleukin (IL)-6 and -1β mRNA, but not the protein levels of these cytokines, measured on day 12. Unexpectedly, chronic administration of doxepin or amitriptyline for 12 days produced allodynia and hyperalgesia in naïve mice. The treatment with these drugs did not influence the spinal levels of IL-1β and IL-6 mRNA, however, the protein levels of these pronociceptive factors were increased. The administration of ondansetron (5-HT3 receptor antagonist) significantly weakened the allodynia and hyperalgesia induced by both antidepressants in naïve mice; in contrast, yohimbine (α2-adrenergic receptors antagonist) did not influence these effects. Allodynia and hyperalgesia induced in naïve animals by amitriptyline and doxepin may be associated with an increase in the levels of pronociceptive cytokines resulting from 5-HT3-induced hypersensitivity. Our results provide new and important information about the possible side effects of antidepressants. Further investigation of these mechanisms may help to guide decisions about the use of classic TCAs for therapy.

  14. Melanocortin-3 receptors expressed in Nkx2.1(+ve) neurons are sufficient for controlling appetitive responses to hypocaloric conditioning

    PubMed Central

    Girardet, Clémence; Mavrikaki, Maria M.; Stevens, Joseph R.; Miller, Courtney A.; Marks, Daniel L.; Butler, Andrew A.

    2017-01-01

    Melanocortin-3 receptors (MC3R) have a contextual role in appetite control that is amplified with hypocaloric conditioning. C57BL/6J (B6) mice subjected to hypocaloric feeding schedules (HFS) exhibit compulsive behavioral responses involving food anticipatory activity (FAA) and caloric loading following food access. These homeostatic responses to calorie-poor environs are attenuated in B6 mice in which Mc3r transcription is suppressed by a lox-stop-lox sequence in the 5’UTR (Mc3rTB/TB). Here, we report that optimization of caloric loading in B6 mice subject to HFS, characterized by increased meal size and duration, is not observed in Mc3rTB/TB mice. Analysis of hypothalamic and neuroendocrine responses to HFS throughout the light-dark cycle suggests uncoupling of hypothalamic responses involving appetite-stimulating fasting-responsive hypothalamic neurons expressing agouti-related peptide (AgRP) and neuropeptide Y (Npy). Rescuing Mc3rs expression in Nkx2.1(+ve) neurons is sufficient to restore normal hypothalamic responses to negative energy balance. In addition, Mc3rs expressed in Nkx2.1(+ve) neurons are also sufficient to restore FAA and caloric loading of B6 mice subjected to HFS. In summary, MC3Rs expressed in Nkx2.1(+ve) neurons are sufficient to coordinate hypothalamic response and expression of compulsive behavioral responses involving meal anticipation and consumption of large meals during situations of prolonged negative energy balance. PMID:28294152

  15. Characterization and genetic manipulation of primed stem cells into a functional naïve state with ESRRB

    PubMed Central

    Rossello, Ricardo Antonio; Pfenning, Andreas; Howard, Jason T; Hochgeschwender, Ute

    2016-01-01

    AIM To identify differences between primed mouse embryonic stem cells (ESCs) and fully functional naive ESCs; to manipulate primed cells into a naive state. METHODS We have cultured 3 lines of cells from different mouse strains that have been shown to be naive or primed as determined by generating germline-transmitting chimeras. Cells were put through a battery of tests to measure the different features. RNA from cells was analyzed using microarrays, to determine a priority list of the differentially expressed genes. These were later validated by quantificational real-time polymerase chain reaction. Viral cassettes were created to induce expression of differentially expressed genes in the primed cells through lentiviral transduction. Primed reprogrammed cells were subjected to in-vivo incorporation studies. RESULTS Most results show that both primed and naive cells have similar features (morphology, proliferation rates, stem cell genes expressed). However, there were some genes that were differentially expressed in the naïve cells relative to the primed cells. Key upregulated genes in naïve cells include ESRRB, ERAS, ATRX, RNF17, KLF-5, and MYC. After over-expressing some of these genes the primed cells were able to incorporate into embryos in-vivo, re-acquiring a feature previously absent in these cells. CONCLUSION Although there are no notable phenotypic differences, there are key differences in gene expression between these naïve and primed stem cells. These differences can be overcome through overexpression. PMID:27822342

  16. Adalimumab Treatment in Biologically Naïve Crohn's Disease: Relationship with Ectopic MUC5AC Expression and Endoscopic Improvement

    PubMed Central

    Mizoshita, Tsutomu; Tanida, Satoshi; Tsukamoto, Hironobu; Ozeki, Keiji; Katano, Takahito; Nishiwaki, Hirotaka; Ebi, Masahide; Mori, Yoshinori; Kubota, Eiji; Kataoka, Hiromi; Kamiya, Takeshi; Joh, Takashi

    2014-01-01

    Background. Adalimumab (ADA) is effective for patients with Crohn's disease (CD). However, there have been few reports on ADA therapy with respect to its relationship with pathologic findings and drug efficacy in biologically naïve CD cases. Methods. Fifteen patients with active biologically naïve CD were treated with ADA. We examined them clinically and pathologically with ectopic MUC5AC expression in the lesions before and after 12 and 52 weeks of ADA therapy, retrospectively. Results. Both mean CD activity index scores and serum C-reactive protein values were significantly lower after ADA therapy (P < 0.001). In the MUC5AC negative group, all cases exhibited clinical remission (CR) and endoscopic improvement at 52 weeks. In MUC5AC positive groups, loss of MUC5AC expression was detected in cases having CR and endoscopic improvement at 52 weeks, while remnant ectopic MUC5AC expression was observed in those exhibiting no endoscopic improvement and flare up after 52 weeks. Conclusions. ADA leads to CR and endoscopic improvement in biologically naïve CD cases. In addition, ectopic MUC5AC expression may be a predictive marker of flare up and endoscopic improvement in the intestines of CD patients. PMID:24829572

  17. HIV co-receptor tropism prediction remains stable over time in treatment-naïve patients.

    PubMed

    Philip, Keir Ej; Macartney, Malcolm J; Conibear, Tim Cr; Smith, Colette J; Marshall, Neal; Johnson, Margaret A; Haque, Tanzina; Webster, Daniel P

    2016-06-01

    HIV co-receptor tropism determination is essential before prescribing the CCR5 antagonist maraviroc. British HIV Association guidelines suggest tropism testing may remain valid for only 90 days in antiretroviral-naïve patients. We aimed to determine the accuracy of this figure. Tropism was assessed in 26 antiretroviral-naïve patients with ongoing viral replication, sampled yearly from first clinic visit. The V3 region of HIV-1 was sequenced in triplicate, then tropism predicted using the Geno2Pheno system. Baseline tropism prediction remained valid for a median of 52 months (range 7-81). For 19/26 individuals baseline tropism remained unchanged throughout a median of 54 months follow-up; 18 R5 tropic and 1 X4 tropic. In seven patients (27%) baseline tropism switched at least once (range 1-4 switches) during follow-up; however, their baseline tropism prediction remained valid for a median of 45 months. Co-receptor tropism in treatment-naïve patients with ongoing viral replication appears highly stable over time, suggesting that baseline genotypic tropism prediction may be valid for a longer duration in patients delaying ART initiation. In this study, baseline tropism prediction remained valid for a median of 52 months, suggesting current guidelines recommending repeat testing after 90 days may be excessively conservative in their assessment of tropism stability. © The Author(s) 2015.

  18. Deadly intentions: naïve introduced foxes show rapid attraction to odour cues of an unfamiliar native prey

    PubMed Central

    Bytheway, Jenna P.; Price, Catherine J.; Banks, Peter B.

    2016-01-01

    Introduced predators have caused declines and extinctions of native species worldwide, seemingly able to find and hunt new, unfamiliar prey from the time of their introduction. Yet, just as native species are often naïve to introduced predators, in theory, introduced predators should initially be naïve in their response to novel native prey. Here we examine the response of free-living introduced red foxes (Vulpes vulpes) to their first encounter with the odour cues of a novel native prey, the long-nosed bandicoot (Perameles nasuta). Despite no experience with bandicoots at the study site, foxes were significantly more interested in bandicoot odour compared to untreated controls and to a co-evolved prey, the black rat (Rattus rattus). So what gives introduced predators a novelty advantage over native prey? Such neophilia towards novel potential food sources carries little costs, however naïve native prey often lack analogous neophobic responses towards novel predators, possibly because predator avoidance is so costly. We propose that this nexus between the costs and benefits of responding to novel information is different for alien predators and native prey, giving alien predators a novelty advantage over native prey. This may explain why some introduced predators have rapid and devastating impacts on native fauna. PMID:27416966

  19. Toward Defining the Neural Substrates of ADHD: A Controlled Structural MRI Study in Medication-Naïve Adults

    PubMed Central

    Makris, Nikos; Liang, Lichen; Biederman, Joseph; Valera, Eve M.; Brown, Ariel B.; Petty, Carter; Spencer, Thomas J.; Faraone, Stephen V.; Seidman, Larry J.

    2014-01-01

    Objective We assessed the neural correlates of adult ADHD in treatment-naïve participants, an approach necessary for identifying neural substrates unconfounded by medication effects. Method The sample consisted of 24 medication-naïve adults with Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV) diagnosed ADHD and 24 healthy controls, comparable on age, sex, handedness, reading achievement, IQ, and psychiatric comorbidity. All participants were assessed with structured diagnostic interviews. Magnetic resonance imaging (MRI)-based regional voxel-based morphometry (r-VBM) was used to assess volumetric differences in a priori defined brain regions of interest. Results VBM analysis revealed group differences in the hypothesized cortical and subcortical areas; however, only cerebellar volume reductions in ADHD retained significance (p < .05) after corrections for multiple comparisons. Conclusion These results support the notion that medication-naïve ADHD as expressed in adulthood, manifests subtle brain volume reductions from normal in the cerebellum, and possibly in other syndrome-congruent gray-matter structures. Larger samples are required to confirm these findings. PMID:24189200

  20. Motion-enhanced, differential interference contrast (MEDIC) microscopy of moving vesicles in live cells: VE-DIC updated

    PubMed Central

    Hill, David B.; Macosko, Jed C.; Holzwarth, George M.

    2009-01-01

    Summary Video-enhanced DIC microscopy (VE-DIC) with background subtraction has made visible many structures and processes in living cells. In VE-DIC, the background image is stored manually by defocusing the microscope before images are acquired. We have updated and improved VE-DIC by adding automatic generation of the background image as a rolling average of the incoming image stream. Subtraction of this continuously updated 12-bit background image from the incoming 12-bit image stream provides a flat background which allows the contrast of moving objects, such as vesicles, to be strongly enhanced while suppressing stationary features such as the overall cell shape. We call our method MEDIC, for motion-enhanced DIC. By carrying out background subtraction with 12-bit images, the number of graylevels in the moving vesicles can be maximized and a single look-up table can be applied to the entire image, enhancing the contrast of all vesicles simultaneously. Contrast is increased by as much as a factor of 13. The method is illustrated with raw, background, and MEDIC images of moving vesicles within a neurite of a live PC12 cell and a live chick motorneuron. PMID:18754997

  1. Toward Defining the Neural Substrates of ADHD: A Controlled Structural MRI Study in Medication-Naïve Adults.

    PubMed

    Makris, Nikos; Liang, Lichen; Biederman, Joseph; Valera, Eve M; Brown, Ariel B; Petty, Carter; Spencer, Thomas J; Faraone, Stephen V; Seidman, Larry J

    2015-11-01

    We assessed the neural correlates of adult ADHD in treatment-naïve participants, an approach necessary for identifying neural substrates unconfounded by medication effects. The sample consisted of 24 medication-naïve adults with Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV) diagnosed ADHD and 24 healthy controls, comparable on age, sex, handedness, reading achievement, IQ, and psychiatric comorbidity. All participants were assessed with structured diagnostic interviews. Magnetic resonance imaging (MRI)-based regional voxel-based morphometry (r-VBM) was used to assess volumetric differences in a priori defined brain regions of interest. VBM analysis revealed group differences in the hypothesized cortical and subcortical areas; however, only cerebellar volume reductions in ADHD retained significance (p < .05) after corrections for multiple comparisons. These results support the notion that medication-naïve ADHD as expressed in adulthood, manifests subtle brain volume reductions from normal in the cerebellum, and possibly in other syndrome-congruent gray-matter structures. Larger samples are required to confirm these findings. © The Author(s) 2013.

  2. Decreased Functional Connectivity of Insular Cortex in Drug Naïve First Episode Schizophrenia: In Relation to Symptom Severity

    PubMed Central

    Pang, Lijuan; Kennedy, David; Wei, Qinling; Lv, Luxian; Gao, Jinsong; Li, Hong; Quan, Meina; Li, Xue; Yang, Yongfeng; Fan, Xiaoduo; Song, Xueqin

    2017-01-01

    Background This study was to examine the insular cortical functional connectivity in drug naïve patients with first episode schizophrenia and to explore the relationship between the connectivity and the severity of clinical symptoms. Methods Thirty-seven drug naïve patients with schizophrenia and 25 healthy controls were enrolled in this study. A seed-based approach was used to analyze the resting-state functional imaging data. Insular cortical connectivity maps were bilaterally extracted for group comparison and validated by voxel-based morphometry (VBM) analysis. Clinical symptoms were measured using the Positive and Negative Syndrome Scale (PANSS). Results There were significant reductions in the right insular cortical connectivity with the Heschl’s gyrus, anterior cingulate cortex (ACC), and caudate (p’s<0.001) in the patient group compared with the healthy control (HC) group. Reduced right insular cortical connectivity with the Heschl’s gyrus was further confirmed in the VBM analysis (FDR corrected p<0.05). Within the patient group, there was a significant positive relationship between the right insula-Heschl’s connectivity and PANSS general psychopathology scores (r = 0.384, p = 0.019). Conclusion Reduced insula-Heschl’s functional connectivity is present in drug naïve patients with first episode schizophrenia, which might be related to the manifestation of clinical symptoms. PMID:28107346

  3. LaeA and VeA are involved in growth morphology, asexual development, and mycotoxin production in Alternaria alternata.

    PubMed

    Estiarte, N; Lawrence, C B; Sanchis, V; Ramos, A J; Crespo-Sempere, A

    2016-12-05

    Alternaria alternata is a common filamentous fungus that contaminates various fruits, grains and vegetables causing important economic losses to farmers and the food industry. A. alternata is a mycotoxigenic mould, which may jeopardize human and animal health. Two of the most common A. alternata mycotoxins found in food and feed are alternariol and alternariol monomethyl ether. In this study we examined the role of LaeA and VeA, two regulatory proteins belonging to the velvet family, which have been described to be involved in several functions in many fungi including secondary metabolism. We found that deletion of laeA and veA genes, respectively, greatly reduced sporulation and strongly compromised mycotoxin production, both in vitro or during pathogenesis of tomato fruits. We have also studied how the loss of laeA and veA may affect expression of genes related to alternariol and alternariol monomethyl ether biosynthesis (pksJ and altR), and to melanin biosynthesis (cmrA, pksA).

  4. The F-BAR protein pacsin2 inhibits asymmetric VE-cadherin internalization from tensile adherens junctions

    PubMed Central

    Dorland, Yvonne L.; Malinova, Tsveta S.; van Stalborch, Anne-Marieke D.; Grieve, Adam G.; van Geemen, Daphne; Jansen, Nicolette S.; de Kreuk, Bart-Jan; Nawaz, Kalim; Kole, Jeroen; Geerts, Dirk; Musters, René J. P.; de Rooij, Johan; Hordijk, Peter L.; Huveneers, Stephan

    2016-01-01

    Vascular homoeostasis, development and disease critically depend on the regulation of endothelial cell–cell junctions. Here we uncover a new role for the F-BAR protein pacsin2 in the control of VE-cadherin-based endothelial adhesion. Pacsin2 concentrates at focal adherens junctions (FAJs) that are experiencing unbalanced actomyosin-based pulling. FAJs move in response to differences in local cytoskeletal geometry and pacsin2 is recruited consistently to the trailing end of fast-moving FAJs via a mechanism that requires an intact F-BAR domain. Photoconversion, photobleaching, immunofluorescence and super-resolution microscopy reveal polarized dynamics, and organization of junctional proteins between the front of FAJs and their trailing ends. Interestingly, pacsin2 recruitment inhibits internalization of the VE-cadherin complex from FAJ trailing ends and is important for endothelial monolayer integrity. Together, these findings reveal a novel junction protective mechanism during polarized trafficking of VE-cadherin, which supports barrier maintenance within dynamic endothelial tissue. PMID:27417273

  5. Frontoparietal connectivity in substance-naïve youth with and without a family history of alcoholism.

    PubMed

    Wetherill, Reagan R; Bava, Sunita; Thompson, Wesley K; Boucquey, Veronique; Pulido, Carmen; Yang, Tony T; Tapert, Susan F

    2012-01-13

    Frontoparietal connections underlie key executive cognitive functions. Abnormalities in the frontoparietal network have been observed in chronic alcoholics and associated with alcohol-related cognitive deficits. It remains unclear whether neurobiological differences in frontoparietal circuitry exist in substance-naïve youth who are at-risk for alcohol use disorders. This study used functional connectivity magnetic resonance imaging and diffusion tensor imaging to examine frontoparietal connectivity and underlying white matter microstructure in 20 substance-naïve youth with a family history of alcohol dependence and 20 well-matched controls without familial substance use disorders. Youth with a family history of alcohol dependence showed significantly less functional connectivity between posterior parietal and dorsolateral prefrontal seed regions (ps<.05), as compared to family history negative controls; however, they did not show differences in white matter architecture within tracts subserving frontoparietal circuitry (ps>.34). Substance-naïve youth with a family history of alcohol dependence show less frontoparietal functional connectivity in the absence of white matter microstructural abnormalities as compared to youth with no familial risk. This may suggest a potential neurobiological marker for the development of substance use disorders.

  6. Nelfinavir monotherapy increases naïve T-cell numbers in HIV-negative healthy young adults.

    PubMed

    Rizza, Stacey R; Tangalos, Eric G; McClees, Mark D; Strausbauch, Michael A; Targonski, Paul V; McKean, David J; Wettstein, Peter J; Badley, Andrew D

    2008-01-01

    Although patients treated with HIV protease inhibitor (PI) containing regimens manifest increases in naïve T cell number, it is unclear whether this is due to reduction in viral replication or a direct drug effect. We questioned whether Nelfinavir monotherapy directly impacted naïve T-cell number in HIV-negative individuals. HIV-negative volunteers received Nelfinavir, 1250 mg orally, BID for 3 weeks, and T-cell receptor recombination excision circles (TREC) content in peripheral blood were assessed. Whereas TREC copies did not change over 3 weeks in untreated controls, TREC copies/copies CCR5 increased following Nelfinavir monotherapy in 8 patients (p < 0.02), and did not change in 7 patients (p = NS). Those patients who responded were younger than those who did not with a median age of 55 years for responders and 71 years for non-responders (p < 0.03). The increase in TREC was most pronounced in those patients less than 40-years old (p < 0.01). Moreover, the patients who did not increase TREC levels were more likely to have suffered a medical illness previously shown to reduce thymic function. In HIV-negative patients, monotherapy with the HIV PI Nelfinavir for 21 days increases TREC-positive naïve T cell number, particularly in individuals who are healthy and young.

  7. Different genome stability proteins underpin primed and naïve adaptation in E. coli CRISPR-Cas immunity.

    PubMed

    Ivančić-Baće, Ivana; Cass, Simon D; Wearne, Stephen J; Bolt, Edward L

    2015-12-15

    CRISPR-Cas is a prokaryotic immune system built from capture and integration of invader DNA into CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) loci, termed 'Adaptation', which is dependent on Cas1 and Cas2 proteins. In Escherichia coli, Cascade-Cas3 degrades invader DNA to effect immunity, termed 'Interference'. Adaptation can interact with interference ('primed'), or is independent of it ('naïve'). We demonstrate that primed adaptation requires the RecG helicase and PriA protein to be present. Genetic analysis of mutant phenotypes suggests that RecG is needed to dissipate R-loops at blocked replication forks. Additionally, we identify that DNA polymerase I is important for both primed and naive adaptation, and that RecB is needed for naïve adaptation. Purified Cas1-Cas2 protein shows specificity for binding to and nicking forked DNA within single strand gaps, and collapsing forks into DNA duplexes. The data suggest that different genome stability systems interact with primed or naïve adaptation when responding to blocked or collapsed invader DNA replication. In this model, RecG and Cas3 proteins respond to invader DNA replication forks that are blocked by Cascade interference, enabling DNA capture. RecBCD targets DNA ends at collapsed forks, enabling DNA capture without interference. DNA polymerase I is proposed to fill DNA gaps during spacer integration.

  8. Structure of the Venus neutral atmosphere as observed by the Radio Science experiment VeRa on Venus Express

    NASA Astrophysics Data System (ADS)

    Tellmann, Silvia; Pätzold, Martin; Häusler, Bernd; Bird, Michael K.; Tyler, G. Leonard

    2009-04-01

    The European Space Agency Venus Express Radio Science experiment (VeRa) obtained 118 radio occultation measurements of the Venusian atmosphere between July 2006 and June 2007. Southern latitudes are uniformly sampled; measurements in the northern hemisphere are concentrated near the pole. Radial profiles of neutral number density derived from the occultations cover the altitude range 40-90 km, which are converted to profiles of temperature (T) and pressure (p) versus height (h). Profiles of static stability are found to be latitude-dependent and nearly adiabatic in the middle cloud region. Below the clouds the stability decreases at high latitudes. At an altitude of 65 km, the VeRa T[p(h)] profiles generally lie between the Venus International Reference Atmosphere (VIRA) and VIRA-2 models; the retrieved temperatures at any given pressure level typically are within 5 K of those derived from the Pioneer Venus Orbiter Radio Occultation experiments. A large equator-to-pole temperature contrast of ˜30 K is found at the 1-bar (1000 hPa) level. The VeRa observations reveal a distinct cold collar region in the southern hemisphere, complementing that in the north. At the latitudes of the cold collars, the tropopause altitude increases relative to higher and lower latitudes by ≈7 km while the temperature drops roughly 60 K. The observations indicate the existence of a wave number 2 structure poleward of ±75° latitude at altitudes of 62 km.

  9. Wnt/β-catenin signaling promotes self-renewal and inhibits the primed state transition in naïve human embryonic stem cells.

    PubMed

    Xu, Zhuojin; Robitaille, Aaron M; Berndt, Jason D; Davidson, Kathryn C; Fischer, Karin A; Mathieu, Julie; Potter, Jennifer C; Ruohola-Baker, Hannele; Moon, Randall T

    2016-10-18

    In both mice and humans, pluripotent stem cells (PSCs) exist in at least two distinct states of pluripotency, known as the naïve and primed states. Our understanding of the intrinsic and extrinsic factors that enable PSCs to self-renew and to transition between different pluripotent states is important for understanding early development. In mouse embryonic stem cells (mESCs), Wnt proteins stimulate mESC self-renewal and support the naïve state. In human embryonic stem cells (hESCs), Wnt/β-catenin signaling is active in naïve-state hESCs and is reduced or absent in primed-state hESCs. However, the role of Wnt/β-catenin signaling in naïve hESCs remains largely unknown. Here, we demonstrate that inhibition of the secretion of Wnts or inhibition of the stabilization of β-catenin in naïve hESCs reduces cell proliferation and colony formation. Moreover, we show that addition of recombinant Wnt3a partially rescues cell proliferation in naïve hESCs caused by inhibition of Wnt secretion. Notably, inhibition of Wnt/β-catenin signaling in naïve hESCs did not cause differentiation. Instead, it induced primed hESC-like proteomic and metabolic profiles. Thus, our results suggest that naïve hESCs secrete Wnts that activate autocrine or paracrine Wnt/β-catenin signaling to promote efficient self-renewal and inhibit the transition to the primed state.

  10. O-GlcNAc is required for the survival of primed pluripotent stem cells and their reversion to the naïve state.

    PubMed

    Miura, Taichi; Nishihara, Shoko

    2016-10-27

    "Naïve" mouse embryonic stem cells (ESCs) are derived from pre-implantation embryos and possess pluripotency, the ability to differentiate into any cell type of the body. "Primed" mouse epiblast stem cells (EpiSCs) are also pluripotent but are derived from post-implantation embryos. ESC-derived EpiSCs (ESD-EpiSCs) are "primed" pluripotent stem cells and can revert to naïve reverted ESCs (rESCs). O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) is a posttranslational modification in the cytoplasm and nucleus. O-GlcNAc is transferred to serine and threonine residues of proteins by O-GlcNAc transferase (Ogt) and removed from them by O-GlcNAcase (Oga). In naïve ESCs, O-GlcNAc contributes to maintain the undifferentiated state. In the transition from naïve state to primed state, Ogt maintains cell survival, whereas Oga has no function. However, the function of O-GlcNAc in primed ESD-EpiSCs and during the reversion from the primed state to naïve rESCs remains unclear. Here, we show that Ogt is required for the survival of primed ESD-EpiSCs. The expression of cytosolic Oga was significantly increased during induction from naïve ESCs to primed ESD-EpiSCs. Furthermore, both Ogt and Oga were required for the reversion from primed ESD-EpiSCs to naïve rESCs. These findings indicate that O-GlcNAcylation plays an important role in the survival of primed ESD-EpiSCs and in their reversion to naïve rESCs.

  11. Volatile profiling reveals intracellular metabolic changes in Aspergillus parasiticus: veA regulates branched chain amino acid and ethanol metabolism

    PubMed Central

    2010-01-01

    Background Filamentous fungi in the genus Aspergillus produce a variety of natural products, including aflatoxin, the most potent naturally occurring carcinogen known. Aflatoxin biosynthesis, one of the most highly characterized secondary metabolic pathways, offers a model system to study secondary metabolism in eukaryotes. To control or customize biosynthesis of natural products we must understand how secondary metabolism integrates into the overall cellular metabolic network. By applying a metabolomics approach we analyzed volatile compounds synthesized by Aspergillus parasiticus in an attempt to define the association of secondary metabolism with other metabolic and cellular processes. Results Volatile compounds were examined using solid phase microextraction - gas chromatography/mass spectrometry. In the wild type strain Aspergillus parasiticus SU-1, the largest group of volatiles included compounds derived from catabolism of branched chain amino acids (leucine, isoleucine, and valine); we also identified alcohols, esters, aldehydes, and lipid-derived volatiles. The number and quantity of the volatiles produced depended on media composition, time of incubation, and light-dark status. A block in aflatoxin biosynthesis or disruption of the global regulator veA affected the volatile profile. In addition to its multiple functions in secondary metabolism and development, VeA negatively regulated catabolism of branched chain amino acids and synthesis of ethanol at the transcriptional level thus playing a role in controlling carbon flow within the cell. Finally, we demonstrated that volatiles generated by a veA disruption mutant are part of the complex regulatory machinery that mediates the effects of VeA on asexual conidiation and sclerotia formation. Conclusions 1) Volatile profiling provides a rapid, effective, and powerful approach to identify changes in intracellular metabolic networks in filamentous fungi. 2) VeA coordinates the biosynthesis of secondary

  12. Cardiovascular-sleep interaction in drug-naïve patients with essential grade I hypertension.

    PubMed

    Grimaldi, Daniela; Provini, Federica; Calandra-Buonaura, Giovanna; Barletta, Giorgio; Cecere, Annagrazia; Pierangeli, Giulia; Cortelli, Pietro

    2013-03-01

    Lack of nighttime blood pressure (BP) reduction by 10-20% from the mean daytime values (dipping) has been described as a distinguishing feature of essential hypertension and associated, also in normotensive subjects, with increased cardiovascular (CV) risk. Mechanisms involved in the loss of the nocturnal dip are still unclear, but involvement of autonomic nervous system (ANS) activity probably plays a crucial role. Sleep is fundamental in modulating ANS activity to maintain the physiological BP circadian rhythm, and for this reason its integrity has been widely investigated in hypertension. We investigated, under controlled conditions, the autonomic control of the CV system through an autonomic reflex screen in the awake condition and by assessment of circadian rhythm-, day-night-, time-, and state-dependent changes of BP and heart rate (HR) and associated sleep parameters in patients with a recent (≤1 yr) diagnosis of essential grade I hypertension naïve of therapy. Fourteen hypertensive patients (6 males, age: 43 ± 11 yrs; body mass index [BMI]: 24 ± 3 kg/m(2)) were compared with 28 healthy controls matched for sex, age, BMI (2 controls/patient) for cardiovascular reflex and to 8 different subjects from previous controls (6 males), comparable for age and BMI, for the day-night and nighttime CV profiles during two consecutive nights. The cardiovascular reflex screen data showed increased sympathetic effect in hypertensive patients, represented by higher overshoot of BP after Valsalva maneuver. Nighttime sleep architecture during the dark period in terms of duration, representation of sleep stages, sleep fragmentation, and incidence of arousals-periodic limb movements in sleep (PLMS) and PLMS arousals-was similar in patients and controls. Hypertensive patients displayed higher 24-h BP and HR values, but their sleep-related BP decrease was significantly reduced compared with controls. The circadian rhythms of BP and HR were intact and similar in

  13. Transcriptome Analysis of Aspergillus flavus Reveals veA-Dependent Regulation of Secondary Metabolite Gene Clusters, Including the Novel Aflavarin Cluster

    PubMed Central

    Cary, J. W.; Han, Z.; Yin, Y.; Lohmar, J. M.; Shantappa, S.; Harris-Coward, P. Y.; Mack, B.; Ehrlich, K. C.; Wei, Q.; Arroyo-Manzanares, N.; Uka, V.; Vanhaecke, L.; Bhatnagar, D.; Yu, J.; Nierman, W. C.; Johns, M. A.; Sorensen, D.; Shen, H.; De Saeger, S.; Diana Di Mavungu, J.

    2015-01-01

    The global regulatory veA gene governs development and secondary metabolism in numerous fungal species, including Aspergillus flavus. This is especially relevant since A. flavus infects crops of agricultural importance worldwide, contaminating them with potent mycotoxins. The most well-known are aflatoxins, which are cytotoxic and carcinogenic polyketide compounds. The production of aflatoxins and the expression of genes implicated in the production of these mycotoxins are veA dependent. The genes responsible for the synthesis of aflatoxins are clustered, a signature common for genes involved in fungal secondary metabolism. Studies of the A. flavus genome revealed many gene clusters possibly connected to the synthesis of secondary metabolites. Many of these metabolites are still unknown, or the association between a known metabolite and a particular gene cluster has not yet been established. In the present transcriptome study, we show that veA is necessary for the expression of a large number of genes. Twenty-eight out of the predicted 56 secondary metabolite gene clusters include at least one gene that is differentially expressed depending on presence or absence of veA. One of the clusters under the influence of veA is cluster 39. The absence of veA results in a downregulation of the five genes found within this cluster. Interestingly, our results indicate that the cluster is expressed mainly in sclerotia. Chemical analysis of sclerotial extracts revealed that cluster 39 is responsible for the production of aflavarin. PMID:26209694

  14. Transcriptome Analysis of Aspergillus flavus Reveals veA-Dependent Regulation of Secondary Metabolite Gene Clusters, Including the Novel Aflavarin Cluster.

    PubMed

    Cary, J W; Han, Z; Yin, Y; Lohmar, J M; Shantappa, S; Harris-Coward, P Y; Mack, B; Ehrlich, K C; Wei, Q; Arroyo-Manzanares, N; Uka, V; Vanhaecke, L; Bhatnagar, D; Yu, J; Nierman, W C; Johns, M A; Sorensen, D; Shen, H; De Saeger, S; Diana Di Mavungu, J; Calvo, A M

    2015-10-01

    The global regulatory veA gene governs development and secondary metabolism in numerous fungal species, including Aspergillus flavus. This is especially relevant since A. flavus infects crops of agricultural importance worldwide, contaminating them with potent mycotoxins. The most well-known are aflatoxins, which are cytotoxic and carcinogenic polyketide compounds. The production of aflatoxins and the expression of genes implicated in the production of these mycotoxins are veA dependent. The genes responsible for the synthesis of aflatoxins are clustered, a signature common for genes involved in fungal secondary metabolism. Studies of the A. flavus genome revealed many gene clusters possibly connected to the synthesis of secondary metabolites. Many of these metabolites are still unknown, or the association between a known metabolite and a particular gene cluster has not yet been established. In the present transcriptome study, we show that veA is necessary for the expression of a large number of genes. Twenty-eight out of the predicted 56 secondary metabolite gene clusters include at least one gene that is differentially expressed depending on presence or absence of veA. One of the clusters under the influence of veA is cluster 39. The absence of veA results in a downregulation of the five genes found within this cluster. Interestingly, our results indicate that the cluster is expressed mainly in sclerotia. Chemical analysis of sclerotial extracts revealed that cluster 39 is responsible for the production of aflavarin. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  15. veA-dependent RNA-pol II transcription elongation factor like protein, RtfA, is associated with secondary metabolism and morphological development in Aspergillus nidulans

    PubMed Central

    Ramamoorthy, Vellaisamy; Shantappa, Sourabha; Dhingra, Sourabh; Calvo, Ana M.

    2012-01-01

    In Aspergillus nidulans the global regulatory gene veA is necessary for the biosynthesis of several secondary metabolites, including the mycotoxin sterigmatocystin (ST). In order to identify additional veA-dependent genetic elements involved in regulating ST production, we performed a mutagenesis on a deletion veA (ΔveA) strain to obtain revertant mutants (RM) that regained the capability to produce toxin. Genetic analysis and molecular characterization of one of the revertant mutants, RM3, revealed that a point mutation occurred at the coding region of the rtfA gene, encoding a RNA-pol II transcription elongation factor like protein, similar to Saccharomyces cerevisiae Rtf1. The A. nidulans rtfA gene product accumulates in nuclei. Deletion of rtfA gene in a ΔveA background restored mycotoxin production in a medium-dependent manner. rtfA also affects the production of other metabolites including penicillin. Biosynthesis of this antibiotic decreased in the absence of rtfA. Furthermore, rtfA is necessary for normal morphological development. Deletion of the rtfA gene in wild-type strains (veA+) resulted in a slight decrease in growth rate, drastic reduction in conidiation, and complete loss of sexual development. This is the first study of an Rtf1 like gene in filamentous fungi. We found rtfA putative orthologs extensively conserved in numerous fungal species. PMID:22783880

  16. VE-cadherin involved in the pulmonary microvascular endothelial cell barrier injury induced by angiotensin II through modulating the cellular apoptosis and skeletal rearrangement

    PubMed Central

    Wu, Zhiyong; Liu, Huagang; Ren, Wei; Dai, Feifeng; Chang, Jinxing; Li, Bowen

    2016-01-01

    Objective: Angiotensin II (AngII) involved in the pathogenesis of pulmonary injury through impairing the integrity of pulmonary microvascular endothelial barrier, but the mechanism is still not clear. We aim to determine the roles of VE-cadherin, playing crucial roles in the adhesion of the vascular endothelial barrier and the barrier function, in the pulmonary microvascular endothelial cell (PMVEC) barrier injury mediated by AngII. Methods: Mice acute lung injury (ALI) model was induced through pumping of AngII. The infiltration of macrophages and neutrophils as well as the PMVEC permeability were determined in order to determine the barrier injury in vivo and in vitro. Knockdown of VE-cadherin was established using siRNA technique, and its roles in the apoptosis and skeletal rearrangement in the PMVECs were evaluated. Results: After AngII interference, the expression of VE-cadherin in the PMVECs and pulmonary tissues in mice was down-regulated. Upon VE-cadherin knockdown through siRNA technique, AngII induced susceptibility of PMVECs to apoptosis. Knockdown of VE-cadherin contributed to the skeletal rearrangement in the endothelial cells, together with increase of permeability. Conclusions: VE-cadherin expression is closely related to the apoptosis and skeletal rearrangement of PMVECs induced by AngII. PMID:27830014

  17. Distinct Toll-like receptor-mediated cytokine production and immunoglobulin secretion in human newborn naïve B cells

    PubMed Central

    Pettengill, Matthew A; van Haren, Simon D; Li, Ning; Dowling, David J; Bergelson, Ilana; Jans, Jop; Ferwerda, Gerben; Levy, Ofer

    2016-01-01

    Neonatal innate immunity is distinct from that of adults, which may contribute to increased susceptibility to infection and limit vaccine responses. B cells play critical roles in protection from infection and detect PAMPs via TLRs, that, when co-activated with CD40, can drive B cell proliferation and antibody production. We characterized the expression of TLRs in circulating B cells from newborns and adults, and evaluated TLR- and CD40-mediated naïve B cell class-switch recombination (CSR) and cytokine production. Gene expression levels of most TLRs was similar between newborn and adult B cells, except newborn naïve B cells expressed more TLR9 than adult naïve B cells. Neonatal naïve B cells demonstrated impaired TLR2- and TLR7- but enhanced TLR9-mediated cytokine production. Significantly fewer newborn naïve B cells underwent CSR to produce IgG, an impairment also noted with IL-21 stimulation. Additionally, co-stimulation via CD40 and TLRs induced greater cytokine production in adult B cells. Thus, while newborn naïve B cells demonstrate adult-level expression of TLRs and CD40, the responses to stimulation of these receptors are distinct. Relatively high expression of TLR9 and impaired CD40-mediated Ig secretion contributes to distinct innate and adaptive immunity of human newborns and may inform novel approaches to early life immunization. PMID:27252169

  18. TAL-1/SCL and its partners E47 and LMO2 up-regulate VE-cadherin expression in endothelial cells.

    PubMed

    Deleuze, Virginie; Chalhoub, Elias; El-Hajj, Rawan; Dohet, Christiane; Le Clech, Mikaël; Couraud, Pierre-Olivier; Huber, Philippe; Mathieu, Danièle

    2007-04-01

    The basic helix-loop-helix TAL-1/SCL essential for hematopoietic development is also required during vascular development for embryonic angiogenesis. We reported that TAL-1 acts positively on postnatal angiogenesis by stimulating endothelial morphogenesis. Here, we investigated the functional consequences of TAL-1 silencing in human primary endothelial cells. We found that TAL-1 knockdown caused the inhibition of in vitro tubulomorphogenesis, which was associated with a dramatic reduction in vascular endothelial cadherin (VE-cadherin) at intercellular junctions. Consistently, silencing of TAL-1 as well as of its cofactors E47 and LMO2 down-regulated VE-cadherin at both the mRNA and the protein level. Endogenous VE-cadherin transcription could be activated in nonendothelial HEK-293 cells by the sole concomitant ectopic expression of TAL-1, E47, and LMO2. Transient transfections in human primary endothelial cells derived from umbilical vein (HUVECs) demonstrated that VE-cadherin promoter activity was dependent on the integrity of a specialized E-box associated with a GATA motif and was maximal with the coexpression of the different components of the TAL-1 complex. Finally, chromatin immunoprecipitation assays showed that TAL-1 and its cofactors occupied the VE-cadherin promoter in HUVECs. Together, these data identify VE-cadherin as a bona fide target gene of the TAL-1 complex in the endothelial lineage, providing a first clue to TAL-1 function in angiogenesis.

  19. The cytotoxic effects of VE-3N, a novel 1,4-dihydropyridine derivative, involve the mitochondrial bioenergetic disruption via uncoupling mechanisms.

    PubMed

    Marín-Prida, Javier; Pardo Andreu, Gilberto L; Rossignoli, Camila Pederiva; Durruthy, Michael González; Rodríguez, Estael Ochoa; Reyes, Yamila Verdecia; Acosta, Roberto Fernández; Uyemura, Sergio A; Alberici, Luciane C

    2017-03-29

    Several 1,4-dihydropyridine derivatives overcome the multidrug resistance in tumors, but their intrinsic cytotoxic mechanisms remain unclear. Here we addressed if mitochondria are involved in the cytotoxicity of the novel 1,4-dihydropyridine derivative VE-3N [ethyl 6-chloro-5-formyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate] towards cancer cells by employing hepatic carcinoma (HepG2) cells and isolated rat liver mitochondria. In HepG2 cells, VE-3N induced mitochondrial membrane potential dissipation, ATP depletion, annexin V/propidium iodide double labeling, and Hoechst staining; events indicating apoptosis induction. In isolated rat liver mitochondria, VE-3N promoted mitochondrial uncoupling by exerting protonophoric actions and by increasing membrane fluidity. Mitochondrial uncoupling was evidenced by an increase in resting respiration, dissipation of mitochondrial membrane potential, inhibition of Ca(2+) uptake, stimulation of Ca(2+) release, decrease in ATP synthesis, and swelling of valinomycin-treated organelles in hyposmotic potassium acetate media. Furthermore, uncoupling concentrations of VE-3N in the presence of Ca(2+) plus ruthenium red induced the mitochondrial permeability transition process. These results indicate that mitochondrial uncoupling is potentially involved in the VE-3N cytotoxic actions towards HepG2 cells. Considering that hepatocellular carcinoma is the most common form of liver cancer, our findings may open a new avenue for the development of VE-3N-based cancer therapies, and help to unravel the cytotoxic mechanisms of 1,4-dihydropyridines towards cancer cells.

  20. Hamiltonian Map to Conformal Modification of Spacetime Metric: Kaluza-Klein and TeVeS

    NASA Astrophysics Data System (ADS)

    Horwitz, Lawrence; Gershon, Avi; Schiffer, Marcelo

    2011-01-01

    It has been shown that the orbits of motion for a wide class of non-relativistic Hamiltonian systems can be described as geodesic flows on a manifold and an associated dual by means of a conformal map. This method can be applied to a four dimensional manifold of orbits in spacetime associated with a relativistic system. We show that a relativistic Hamiltonian which generates Einstein geodesics, with the addition of a world scalar field, can be put into correspondence in this way with another Hamiltonian with conformally modified metric. Such a construction could account for part of the requirements of Bekenstein for achieving the MOND theory of Milgrom in the post-Newtonian limit. The constraints on the MOND theory imposed by the galactic rotation curves, through this correspondence, would then imply constraints on the structure of the world scalar field. We then use the fact that a Hamiltonian with vector gauge fields results, through such a conformal map, in a Kaluza-Klein type theory, and indicate how the TeVeS structure of Bekenstein and Saunders can be put into this framework. We exhibit a class of infinitesimal gauge transformations on the gauge fields {mathcal{U}}_{μ}(x) which preserve the Bekenstein-Sanders condition {mathcal{U}}_{μ}{mathcal{U}}^{μ}=-1. The underlying quantum structure giving rise to these gauge fields is a Hilbert bundle, and the gauge transformations induce a non-commutative behavior to the fields, i.e. they become of Yang-Mills type. Working in the infinitesimal gauge neighborhood of the initial Abelian theory we show that in the Abelian limit the Yang-Mills field equations provide residual nonlinear terms which may avoid the caustic singularity found by Contaldi et al.

  1. Disrupted brain anatomical connectivity in medication-naïve patients with first-episode schizophrenia.

    PubMed

    Zhang, Ruibin; Wei, Qinling; Kang, Zhuang; Zalesky, Andrew; Li, Meng; Xu, Yong; Li, Leijun; Wang, Junjing; Zheng, Liangrong; Wang, Bin; Zhao, Jingping; Zhang, Jinbei; Huang, Ruiwang

    2015-03-01

    Previous studies suggested that the topological properties of brain anatomical networks may be aberrant in schizophrenia (SCZ), and most of them focused on the chronic and antipsychotic-medicated SCZ patients which may introduce various confounding factors due to antipsychotic medication and duration of illness. To avoid those potential confounders, a desirable approach is to select medication-naïve, first-episode schizophrenia (FE-SCZ) patients. In this study, we acquired diffusion tensor imaging datasets from 30 FE-SCZ patients and 34 age- and gender-matched healthy controls. Taking a distinct gray matter region as a node, inter-regional connectivity as edge and the corresponding streamline counts as edge weight, we constructed whole-brain anatomical networks for both groups, calculated their topological parameters using graph theory, and compared their between-group differences using nonparametric permutation tests. In addition, network-based statistic method was utilized to identify inter-regional connections which were impaired in the FE-SCZ patients. We detected only significantly decreased inter-regional connections in the FE-SCZ patients compared to the controls. These connections were primarily located in the frontal, parietal, occipital, and subcortical regions. Although small-worldness was conserved in the FE-SCZ patients, we found that the network strength and global efficiency as well as the degree were significantly decreased, and shortest path length was significantly increased in the FE-SCZ patients compared to the controls. Most of the regions that showed significantly decreased nodal parameters belonged to the top-down control, sensorimotor, basal ganglia, and limbic-visual system systems. Correlation analysis indicated that the nodal efficiency in the sensorimotor system was negatively correlated with the severity of psychosis symptoms in the FE-SCZ patients. Our results suggest that the network organization is changed in the early stages of the

  2. Oxidative stress in drug naïve first episode psychosis and antioxidant effects of risperidone.

    PubMed

    Noto, Cristiano; Ota, Vanessa Kiyomi; Gadelha, Ary; Noto, Mariane Nunes; Barbosa, Décio Sabbatini; Bonifácio, Kamila Landucci; Nunes, Sandra Odebrecht; Cordeiro, Quirino; Belangero, Sintia Iole; Bressan, Rodrigo Affonseca; Maes, Michael; Brietzke, Elisa

    2015-09-01

    Schizophrenia is accompanied by increased lipid peroxidation and nitric oxide (NO) levels and by lowered antioxidant levels. However, the effect of antipsychotic agents on these processes remains unclear. The objective of this study is to determine the oxidative stress (OS) status in drug naïve first-episode psychotic patients (FEP) compared to healthy controls and to delineate the effects of risperidone on these biomarkers. 51 drug naive FEP patients and 61 healthy controls were enrolled; FEP patients were reassessed 11 weeks after risperidone treatment. Three OS biomarkers, i.e. lipid hydroperoxides - LOOH, NO metabolites - NOx, and advanced oxidation protein products - AOPP, and two antioxidant biomarkers, i.e. total radical-trapping antioxidant parameter - TRAP, and paraoxonase 1 - PON1, were measured. The Positive and Negative Syndrome Scale (PANSS) and the Calgary Depression Scale for Schizophrenia (CDSS) were used to measure symptoms severity. Significantly lower PON1 activity and increased TRAP values were found in FEP patients. There were no significant associations between any of the OS/antioxidant biomarkers and clinical data. Risperidone treatment significantly increased PON1 activity and decreased LOOH levels. These effects of risperidone were not significantly associated with the clinical response and risperidone dosage. Changes in antioxidant profile, but not in lipid or protein oxidation or increased NO production, were found in drug-naive FEP. Risperidone may have antioxidant effects by lowering lipid peroxidation and increasing the antioxidant defenses against lipid peroxidation related to PON1. None of the biomarkers predicted treatment outcome. Copyright © 2015 Elsevier Ltd. All rights reserved.

  3. NEUROCOGNITIVE FUNCTIONING IN ANTIRETROVIRAL THERAPY-NAÏVE YOUTH WITH BEHAVIORALLY ACQUIRED HIV

    PubMed Central

    Nichols, Sharon L.; Bethel, James; Garvie, Patricia A.; Patton, Doyle E; Thornton, Sarah; Kapogiannis, Bill G.; Ren, Weijia; Major-Wilson, Hanna; Puga, Ana; Woods, Steven P.

    2013-01-01

    Purpose Youth living with HIV account for over one-third of new HIV infections and are at high risk of adverse psychosocial, everyday living, and health outcomes. HIV-associated neurocognitive disorders (HAND) are known to affect health outcomes of HIV-infected adults even in the era of combination antiretroviral therapy (cART). Thus, the current study aimed to characterize the prevalence and clinical correlates of HAND in youth living with HIV. Here we report baseline neurocognitive data for behaviorally HIV-infected youth enrolled in a prospective study evaluating strategies of antiretroviral treatment initiation and use. Methods Two hundred twenty participants, age 18-24, naïve to treatment (except for prevention of mother to child HIV transmission; n=3), completed a comprehensive neurocognitive, substance use, and behavioral health assessment battery. Results 64.7% of youth met criteria for HAND (96.4% asymptomatic, 3.5% syndromic), with deficits in episodic memory and fine-motor skills emerging as the most commonly affected ability areas. Multivariable models showed that lower CD4 count, longer time since HIV diagnosis, and high risk alcohol use were uniquely associated with neurocognitive deficits. Conclusions Over two-thirds of youth with behaviorally acquired HIV evidence neurocognitive deficits, which have modest associations with more advanced HIV disease as well as other factors. Research is needed to determine the impact of such neuropsychiatric morbidity on mental health and HIV disease treatment outcomes (e.g., non-adherence) and transition to independent living responsibilities in HIV-infected youth, as well as its long-term trajectory and possible responsiveness to cognitive rehabilitation and pharmacotherapy. PMID:23972941

  4. Proceedings of the XXII A.I.VE.LA. National Meeting

    NASA Astrophysics Data System (ADS)

    Primo Tomasini, Enrico

    2015-11-01

    A.I.VE.LA. - the Italian Association of Laser Velocimetry and non-invasive diagnostics - is a non-profit cultural association whose objective is to promote and support research in the field of non-contact or minimally invasive measurement techniques, particularly electromagnetic-based techniques and optical techniques. Through its Annual Meeting, AIVELA aims to create an active and stimulating forum where current research results and technical advances can be exchanged and the development of new systems for laboratory use, field testing and industrial application can be promoted. The techniques covered include Laser Doppler Anemometry - LDA, Phase Doppler Anemometry - PDA, Image Velocimetry - PIV, Flow visualization techniques, Spectroscopic measurement techniques (LIF, Raman, etc.), Laser Doppler Vibrometry - LDV, Speckle Pattern Interferometry - ESPI, Holographic techniques, Shearography, Digital Image Correlation - DIC, Moiré techniques, Structured light techniques, Infrared imaging, Photoelasticity, Image based measurement techniques, Ultrasonic sensing, Acoustic and Aeroacoustic measurements, etc. The first Annual Meeting was held back in October 1992 and since then there has been a large consensus among the research and scientific communities that the papers presented at the event are of a high scientific interest. The XXII AIVELA Annual Meeting was held at the Faculty of Engineering of University of Rome Tor Vergata on 15-16 December 2014 and was organised in collaboration with the International Master Courses in "Protection Against CBRNe Events". This volume contains a selection of the papers presented at the event. The detailed Programme of the Meeting can be found at: http://www.aivela.org/XXII_Convegno/index.html Trusting our Association and its initiatives will meet your interest, I wish to thank you in advance for your kind attention and hope to meet you soon at one of our events.

  5. Serum alkaline phosphatase negatively affects endothelium-dependent vasodilation in naïve hypertensive patients.

    PubMed

    Perticone, Francesco; Perticone, Maria; Maio, Raffaele; Sciacqua, Angela; Andreucci, Michele; Tripepi, Giovanni; Corrao, Salvatore; Mallamaci, Francesca; Sesti, Giorgio; Zoccali, Carmine

    2015-10-01

    Tissue nonspecific alkaline phosphatase, promoting arterial calcification in experimental models, is a powerful predictor of total and cardiovascular mortality in general population and in patients with renal or cardiovascular diseases. For this study, to evaluate a possible correlation between serum alkaline phosphatase levels and endothelial function, assessed by strain gauge plethysmography, we enrolled 500 naïve hypertensives divided into increasing tertiles of alkaline phosphatase. The maximal response to acetylcholine was inversely related to alkaline phosphatase (r=−0.55; P<0.001), and this association was independent (r=−0.61; P<0.001) of demographic and classical risk factors, body mass index, estimated glomerular filtration rate, serum phosphorus and calcium, C-reactive protein, and albuminuria. At multiple logistic regression analysis, the risk of endothelial dysfunction was ≈3-fold higher in patients in the third tertile than that of patients in the first tertile. We also tested the combined role of alkaline phosphatase and serum phosphorus on endothelial function. The steepness of the alkaline phosphatase/vasodilating response to acetylcholine relationship was substantially attenuated (P<0.001) in patients with serum phosphorus above the median value when compared with patients with serum phosphorus below the median (−5.0% versus −10.2% per alkaline phosphatase unit, respectively), and this interaction remained highly significant (P<0.001) after adjustment of all the previously mentioned risk factors. Our data support a strong and significant inverse relationship between alkaline phosphatase and endothelium-dependent vasodilation, which was attenuated by relatively higher serum phosphorus levels.

  6. Bone Tumor Diagnosis Using a Naïve Bayesian Model of Demographic and Radiographic Features.

    PubMed

    Do, Bao H; Langlotz, Curtis; Beaulieu, Christopher F

    2017-07-27

    Because many bone tumors have a variety of appearances and are uncommon, few radiologists develop sufficient expertise to guide optimal management. Bayesian inference can guide decision-making by computing probabilities of multiple diagnoses to generate a differential. We built and validated a naïve Bayes machine (NBM) that processes 18 demographic and radiographic features. We reviewed over 1664 analog radiographic cases of bone tumors and selected 811 cases (66 diagnoses) for annotation using a quantitative imaging platform. Leave-one-out cross validation was performed. Primary accuracy was defined as the correct pathological diagnosis as the top machine prediction. Differential accuracy was defined as whether the correct pathological diagnosis was within the top three predictions. For the 29 most common diagnoses (710 cases), primary accuracy was 44%, and differential accuracy was 60%. For the top 10 most common diagnoses (478 cases), primary accuracy was 62%, and differential accuracy was 80%. The machine returned relevant diagnoses for the majority of unknown test cases and may be a feasible alternative to machine learning approaches such as deep neural networks or support vector machines that typically require larger training data (our model required a minimum of five samples per diagnosis) and are "black boxes" (our model can provide details of probability calculations to identify features that most significantly contribute to truth diagnoses). Finally, our Bayes model was designed to scale and "learn" from external data, enabling incorporation of outside knowledge such as Dahlin's Bone Tumors, a reference of anatomic and demographic statistics of more than 10,000 tumors.

  7. Characterizing the likelihood of dengue emergence and detection in naïve populations

    PubMed Central

    2014-01-01

    Background Vector-borne disease transmission is dependent on the many nuances of the contact event between infectious and susceptible hosts. Virus acquisition from a viremic human to a susceptible mosquito is often assumed to be nearly perfect and almost always uniform across the infectious period. Dengue transmission models that have previously addressed variability in human to vector transmission dynamics do not account for the variation in infectiousness of a single individual, and subsequent infection of naïve mosquitoes. Understanding the contribution of this variability in human infectiousness is especially important in the context of introduction events where an infected individual carries the virus into a population of competent vectors. Furthermore, it could affect the ability to detect an epidemic (and the timing of detection) following introduction. Methods We constructed a stochastic, compartmental model to describe the heterogeneity of human viremia and calculate the probability of a successful introduction, taking into account the viremia level (and thus acquisition potential) of the index case on, and after, the day of introduction into a susceptible population and varying contact rates between the human and mosquito populations. We then compared the results of this model with those generated by a simpler model that has the same average infectiousness but only a single infectious class. Results We found that the infectivity of the index case as well as the contact rate affected the probability of emergence, but that contact rate had the most significant effect. We also found that the interaction between contact rate and the infectiousness of the index case affected the time to detection relative to the peak of the epidemic curve. Additionally, when compared to our model that accounts for variable infectiousness, a model with a single infectious class underestimates the probability of emergence and transmission intensity. Conclusion Understanding the

  8. Mismatched anti-predator behavioral responses in predator-naïve larval anurans

    PubMed Central

    Vance-Chalcraft, Heather D.

    2015-01-01

    Organisms are adept at altering behaviors to balance the tradeoff between foraging and predation risk in spatially and temporally shifting predator environments. In order to optimize this tradeoff, prey need to be able to display an appropriate response based on degree of predation risk. To be most beneficial in the earliest life stages in which many prey are vulnerable to predation, innate anti-predator responses should scale to match the risk imposed by predators until learned anti-predator responses can occur. We conducted an experiment that examined whether tadpoles with no previous exposure to predators (i.e., predator-naive) exhibit innate antipredator behavioral responses (e.g., via refuge use and spatial avoidance) that match the actual risk posed by each predator. Using 7 treatments (6 free-roaming, lethal predators plus no-predator control), we determined the predation rates of each predator on Lithobates sphenocephalus tadpoles. We recorded behavioral observations on an additional 7 nonlethal treatments (6 caged predators plus no-predator control). Tadpoles exhibited innate responses to fish predators, but not non-fish predators, even though two non-fish predators (newt and crayfish) consumed the most tadpoles. Due to a mismatch between innate response and predator consumption, tadpoles may be vulnerable to greater rates of predation at the earliest life stages before learning can occur. Thus, naïve tadpoles in nature may be at a high risk to predation in the presence of a novel predator until learned anti-predator responses provide additional defenses to the surviving tadpoles. PMID:26664805

  9. Effect of blonanserin on cognitive function in antipsychotic-naïve first-episode schizophrenia.

    PubMed

    Tenjin, Tomomi; Miyamoto, Seiya; Miyake, Nobumi; Ogino, Shin; Kitajima, Rei; Ojima, Kazuaki; Arai, Jun; Teramoto, Haruki; Tsukahara, Sachiko; Ito, Yukie; Tadokoro, Masanori; Anai, Kiriko; Funamoto, Yasuyuki; Kaneda, Yasuhiro; Sumiyoshi, Tomiki; Yamaguchi, Noboru

    2012-01-01

    The purpose of this study was to evaluate the effects of blonanserin, a novel antipsychotic, on cognitive function in first-episode schizophrenia. Twenty-four antipsychotic-naïve patients with first-episode schizophrenia participated in the study. Blonanserin was given in an open-label design for 8 weeks. The Brief Assessment of Cognition in Schizophrenia-Japanese language version (BACS-J) was administered as the primary outcome measure at baseline and 8 weeks. Clinical evaluation included the Positive and Negative Syndrome Scale (PANSS), the Schizophrenia Quality of Life Scale-Japanese language version (SQLS-J), and the Clinical Global Impression-Severity of Illness Scale (CGI-S). To exclude the possibility of retest effects on the BACS-J, 10 age-matched patients with chronic schizophrenia treated with blonanserin were tested at baseline and after an 8-week interval. Twenty first-episode patients completed the study. Repeated measures analysis of covariance revealed a significant group-by-time interaction effect on the letter fluency task due to better performance in the first-episode group, but not in the control group. Main effect of time or group-by-time interaction effect on the Tower of London task was not significant; however, the first-episode group, but not the control group, showed substantial improvement with a moderate effect size. All items on the PANSS, SQLS-J, and CGI-S significantly improved after 8 weeks of treatment. These results suggest that blonanserin improves some types of cognitive function associated with prefrontal cortical function. Copyright © 2012 John Wiley & Sons, Ltd.

  10. ERP Correlates of Proactive and Reactive Cognitive Control in Treatment-Naïve Adult ADHD

    PubMed Central

    Endestad, Tor; Aasen, Ida Emilia S.; Kropotov, Juri; Knight, Robert Thomas

    2016-01-01

    This study investigated whether treatment naïve adults with Attention Deficit Hyperactivity Disorder (ADHD; n = 33; 19 female) differed from healthy controls (n = 31; 17 female) in behavioral performance, event-related potential (ERP) indices of preparatory attention (CueP3 and late CNV), and reactive response control (Go P3, NoGo N2, and NoGo P3) derived from a visual cued Go/NoGo task. On several critical measures, Cue P3, late CNV, and NoGo N2, there were no significant differences between the groups. This indicated normal preparatory processes and conflict monitoring in ADHD patients. However, the patients had attenuated Go P3 and NoGoP3 amplitudes relative to controls, suggesting reduced allocation of attentional resources to processes involved in response control. The patients also had a higher rate of Go signal omission errors, but no other performance decrements compared with controls. Reduced Go P3 and NoGo P3 amplitudes were associated with poorer task performance, particularly in the ADHD group. Notably, the ERPs were not associated with self-reported mood or anxiety. The results provide electrophysiological evidence for reduced effortful engagement of attentional resources to both Go and NoGo signals when reactive response control is needed. The absence of group differences in ERP components indexing proactive control points to impairments in specific aspects of cognitive processes in an untreated adult ADHD cohort. The associations between ERPs and task performance provided additional support for the altered electrophysiological responses. PMID:27448275

  11. Subchronic exposures to fungal bioaerosols promotes allergic pulmonary inflammation in naïve mice

    PubMed Central

    Nayak, Ajay P.; Green, Brett J.; Lemons, Angela R.; Marshall, Nikki B.; Goldsmith, W. Travis; Kashon, Michael L.; Anderson, Stacey E.; Germolec, Dori R.; Beezhold, Donald H.

    2016-01-01

    Background Epidemiological surveys indicate that occupants of mold contaminated environments are at increased risk of respiratory symptoms. The immunological mechanisms associated with these responses require further characterization. Objective The aim of this study was to characterize the immunotoxicological outcomes following repeated inhalation of dry Aspergillus fumigatus spores aerosolized at concentrations potentially encountered in contaminated indoor environments. Methods A. fumigatus spores were delivered to the lungs of naïve BALB/cJ mice housed in a multi-animal nose-only chamber twice a week for a period of 13 weeks. Mice were evaluated at 24 and 48 hours post-exposure for histopathological changes in lung architecture, recruitment of specific immune cells to the airways, and serum antibody responses. Result Germinating A. fumigatus spores were observed in lungs along with persistent fungal debris in the perivascular regions of the lungs. Repeated exposures promoted pleocellular infiltration with concomitant epithelial mucus hypersecretion, goblet cell metaplasia, subepithelial fibrosis and enhanced airway hyperreactivity. Cellular infiltration in airways was predominated by CD4+ T cells expressing the pro-allergic cytokine IL-13. Furthermore, our studies show that antifungal T cell responses (IFN-γ+ or IL-17A+) co-expressed IL-13, revealing a novel mechanism for the dysregulated immune response to inhaled fungi. Total IgE production was augmented in animals repeatedly exposed to A. fumigatus. Conclusions & Clinical Relevance Repeated inhalation of fungal aerosols resulted in significant pulmonary pathology mediated by dynamic shifts in specific immune populations and their cytokines. These studies provide novel insights into the immunological mechanisms and targets that govern the health outcomes that result from repeated inhalation of fungal bioaerosols in contaminated environments. PMID:26892490

  12. Naïve Induced Pluripotent Stem Cells Generated From β-Thalassemia Fibroblasts Allow Efficient Gene Correction With CRISPR/Cas9.

    PubMed

    Yang, Yuanyuan; Zhang, Xiaobai; Yi, Li; Hou, Zhenzhen; Chen, Jiayu; Kou, Xiaochen; Zhao, Yanhong; Wang, Hong; Sun, Xiao-Fang; Jiang, Cizhong; Wang, Yixuan; Gao, Shaorong

    2016-01-01

    Conventional primed human embryonic stem cells and induced pluripotent stem cells (iPSCs) exhibit molecular and biological characteristics distinct from pluripotent stem cells in the naïve state. Although naïve pluripotent stem cells show much higher levels of self-renewal ability and multidifferentiation capacity, it is unknown whether naïve iPSCs can be generated directly from patient somatic cells and will be superior to primed iPSCs. In the present study, we used an established 5i/L/FA system to directly reprogram fibroblasts of a patient with β-thalassemia into transgene-free naïve iPSCs with molecular signatures of ground-state pluripotency. Furthermore, these naïve iPSCs can efficiently produce cross-species chimeras. Importantly, using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 nuclease genome editing system, these naïve iPSCs exhibit significantly improved gene-correction efficiencies compared with the corresponding primed iPSCs. Furthermore, human naïve iPSCs could be directly generated from noninvasively collected urinary cells, which are easily acquired and thus represent an excellent cell resource for further clinical trials. Therefore, our findings demonstrate the feasibility and superiority of using patient-specific iPSCs in the naïve state for disease modeling, gene editing, and future clinical therapy. In the present study, transgene-free naïve induced pluripotent stem cells (iPSCs) directly converted from the fibroblasts of a patient with β-thalassemia in a defined culture system were generated. These naïve iPSCs, which show ground-state pluripotency, exhibited significantly improved single-cell cloning ability, recovery capacity, and gene-targeting efficiency compared with conventional primed iPSCs. These results provide an improved strategy for personalized treatment of genetic diseases such as β-thalassemia. ©AlphaMed Press.

  13. Naïve Induced Pluripotent Stem Cells Generated From β-Thalassemia Fibroblasts Allow Efficient Gene Correction With CRISPR/Cas9

    PubMed Central

    Yang, Yuanyuan; Zhang, Xiaobai; Yi, Li; Hou, Zhenzhen; Chen, Jiayu; Kou, Xiaochen; Zhao, Yanhong; Wang, Hong; Sun, Xiao-Fang; Jiang, Cizhong

    2016-01-01

    Conventional primed human embryonic stem cells and induced pluripotent stem cells (iPSCs) exhibit molecular and biological characteristics distinct from pluripotent stem cells in the naïve state. Although naïve pluripotent stem cells show much higher levels of self-renewal ability and multidifferentiation capacity, it is unknown whether naïve iPSCs can be generated directly from patient somatic cells and will be superior to primed iPSCs. In the present study, we used an established 5i/L/FA system to directly reprogram fibroblasts of a patient with β-thalassemia into transgene-free naïve iPSCs with molecular signatures of ground-state pluripotency. Furthermore, these naïve iPSCs can efficiently produce cross-species chimeras. Importantly, using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 nuclease genome editing system, these naïve iPSCs exhibit significantly improved gene-correction efficiencies compared with the corresponding primed iPSCs. Furthermore, human naïve iPSCs could be directly generated from noninvasively collected urinary cells, which are easily acquired and thus represent an excellent cell resource for further clinical trials. Therefore, our findings demonstrate the feasibility and superiority of using patient-specific iPSCs in the naïve state for disease modeling, gene editing, and future clinical therapy. Significance In the present study, transgene-free naïve induced pluripotent stem cells (iPSCs) directly converted from the fibroblasts of a patient with β-thalassemia in a defined culture system were generated. These naïve iPSCs, which show ground-state pluripotency, exhibited significantly improved single-cell cloning ability, recovery capacity, and gene-targeting efficiency compared with conventional primed iPSCs. These results provide an improved strategy for personalized treatment of genetic diseases such as β-thalassemia. PMID:26676643

  14. Privacy-Preserving Patient-Centric Clinical Decision Support System on Naïve Bayesian Classification.

    PubMed

    Liu, Ximeng; Lu, Rongxing; Ma, Jianfeng; Chen, Le; Qin, Baodong

    2016-03-01

    Clinical decision support system, which uses advanced data mining techniques to help clinician make proper decisions, has received considerable attention recently. The advantages of clinical decision support system include not only improving diagnosis accuracy but also reducing diagnosis time. Specifically, with large amounts of clinical data generated everyday, naïve Bayesian classification can be utilized to excavate valuable information to improve a clinical decision support system. Although the clinical decision support system is quite promising, the flourish of the system still faces many challenges including information security and privacy concerns. In this paper, we propose a new privacy-preserving patient-centric clinical decision support system, which helps clinician complementary to diagnose the risk of patients' disease in a privacy-preserving way. In the proposed system, the past patients' historical data are stored in cloud and can be used to train the naïve Bayesian classifier without leaking any individual patient medical data, and then the trained classifier can be applied to compute the disease risk for new coming patients and also allow these patients to retrieve the top- k disease names according to their own preferences. Specifically, to protect the privacy of past patients' historical data, a new cryptographic tool called additive homomorphic proxy aggregation scheme is designed. Moreover, to leverage the leakage of naïve Bayesian classifier, we introduce a privacy-preserving top- k disease names retrieval protocol in our system. Detailed privacy analysis ensures that patient's information is private and will not be leaked out during the disease diagnosis phase. In addition, performance evaluation via extensive simulations also demonstrates that our system can efficiently calculate patient's disease risk with high accuracy in a privacy-preserving way.

  15. Porcine induced pluripotent stem cells analogous to naïve and primed embryonic stem cells of the mouse.

    PubMed

    Telugu, Bhanu Prakash V L; Ezashi, Toshihiko; Roberts, R Michael

    2010-01-01

    Authentic or naïve embryonic stem cells (ESC) have probably never been derived from the inner cell mass (ICM) of pig blastocysts, despite over 25 years of effort. Recently, several groups, including ours, have reported induced pluripotent stem cells (iPSC) from swine by reprogramming somatic cells with a combination of four factors, OCT4 (POU5F1)/SOX2/KLF4/c-MYC delivered by retroviral transduction. The porcine (p) iPSC resembled human (h) ESC and the mouse "Epiblast stem cells" (EpiSC) in their colony morphology and expression of pluripotent genes, and are likely dependent on FGF2/ACTIVIN/NODAL signaling, therefore representing a primed ESC state. These cells are likely to advance swine as a model in biomedical research, since grafts could potentially be matched to the animal that donated the cells for re-programming. The objective of the present work has been to develop naïve piPSC. Employing a combination of seven reprogramming factors assembled on episomal vectors, we successfully reprogrammed porcine embryonic fibroblasts on a modified LIF-medium supplemented with two kinase inhibitors; CHIR99021, which inhibits GSK-3beta, and PD0325901, a MEK inhibitor. The derived piPSC bear a striking resemblance to naïve mESC in colony morphology, are dependent on LIF to maintain an undifferentiated phenotype, and express markers consistent with pluripotency. They exhibit high telomerase activity, a short cell cycle interval, and a normal karyotype, and are able to generate teratomas. Currently, the competence of these lines for contributing to germ-line chimeras is being tested.

  16. Parental substance abuse and function of the motivation and behavioral inhibition systems in drug-naïve youth.

    PubMed

    Ivanov, Iliyan; Liu, Xun; Shulz, Kurt; Fan, Jin; London, Edythe; Friston, Karl; Halperin, Jeffrey M; Newcorn, Jeffrey H

    2012-02-28

    It is hypothesized that the development of substance abuse (SA) may be due to imbalance in functions of the motivation-reward and behavioral inhibition systems in the brain. This speaks to the search for biological risk factors for SA in drug-naïve children who also exhibit motivational and inhibitory control deficits; however, this type of research is currently lacking. The objective of this study was to establish a neurobiological basis for addiction vulnerability using functional magnetic resonance imaging (fMRI) in drug-naïve youth with attention deficit/hyperactivity disorder (ADHD). We hypothesized that children with ADHD alone would show higher activity in regions of the motivation-reward and behavioral inhibition systems than children with ADHD and a parental history of SA. Toward this goal we scanned 20 drug-naïve children with ADHD ages 8-13 while performing an event-related reward task. High (N=10) and low (N=10) risk subjects were identified, based on parental history of SA. The effects of anticipation, conflict, and reward were assessed with appropriate linear contrasts, and between-group differences were assessed using statistical parametric mapping. The two groups did not differ on behavioral measures of the task. The fMRI results show heightened activation in the brain motivational-reward system and reduced activation of the inhibitory control system in high-risk compared to low-risk children. These results suggest that a functional mismatch between these two systems may represent one possible biological underpinning of SA risk, which is conferred by a parental history of addiction. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  17. Clinical correlates of thalamus volume deficits in anti-psychotic-naïve schizophrenia patients: A 3-Tesla MRI study.

    PubMed

    Rao, Naren P; Kalmady, Sunil; Arasappa, Rashmi; Venkatasubramanian, Ganesan

    2010-07-01

    Thalamus, the sensory and motor gateway to the cortex, plays an important role in cognitive and perceptual disturbances in schizophrenia. Studies examining the volume of the thalamus in schizophrenia have reported conflicting findings due to the presence of potential confounding factors such as low-resolution imaging and anti-psychotics. The thalamus volume in anti-psychotic-naïve patients determined using high-resolution 3-Tesla magnetic resonance imaging (MRI) has not yet been examined. Using 3-Tesla MRI, this study for the first time examined anti-psychotic-naïve schizophrenia patients (n=18; M:F:11:7) in comparison with healthy controls (n=19;M:F:9:10) group-matched for age, sex, handedness, education, and socioeconomic status. The volume of the thalamus was measured using a three-dimensional, interactive, semi-automated analysis with good inter-rater and intra-rater reliability. Psychopathology was assessed using the Scale for Assessment of Negative Symptoms (SANS) and the Scale for Assessment of Positive Symptoms (SAPS). Right, left, and total thalamus volumes of patients were significantly smaller than those of controls after controlling for the potential confounding effect of intracranial volume. Thalamus volumes had significant positive correlation with positive symptoms score (SAPS) and significant negative correlation with negative symptoms score (SANS). Thalamus volume deficits in anti-psychotic-naïve schizophrenia patients support a neurodevelopmental pathogenesis. The contrasting correlation of thalamus volume deficits with psychopathology scores suggests that contrasting pruning aberrations underlie symptom genesis in schizophrenia.

  18. The transition from naïve to primed nociceptive state: A novel wind-up protocol in mice.

    PubMed

    Ziv, Nadav Y; Tal, Michael; Shavit, Yehuda

    2016-01-01

    Wind-up (WU) is a progressive, frequency-dependent facilitation of spinal cord neurons in response to repetitive nociceptive stimulation of constant intensity. We identified a new WU-associated phenomenon in naïve mice (not exposed to noxious stimulation immediately prior to WU stimulation), which were subjected to a novel experimental protocol composed of three consecutive trains of WU stimulation. The 1st train produced a typical linear 'wind-up' curve as expected following a repeating series of stimuli; in addition, this 1st train sensitized ('primed') the nociceptive system so that the responses to two subsequent trains (inter-train interval of 10 min) were significantly amplified compared with the response to the 1st train. We named this augmented response potentiation-of-windup, or "PoW". The PoW phenomenon appears to be centrally mediated, as the augmented response was suppressed by administration of an NMDA receptor antagonist (MK-801) and by cutting the spinal cord. Furthermore, the PoW protocol is accompanied by enhanced pain behavior. The 'priming' effect of the 1st train could be mimicked by exposure to natural noxious stimuli prior to the PoW protocol. Presumably, the PoW phenomenon has not been previously reported due to a procedural reason: typically, WU protocols have been executed in 'primed' rather than naïve animals, i.e., animals exposed to nociceptive stimulation prior to the actual WU recording. Our findings indicate that the PoW paradigm can distinguish between 'naïve' and 'primed' states, suggesting its use as a tool for the assessment of central sensitization.

  19. Demonstration of sustained drug-resistant human immunodeficiency virus type 1 lineages circulating among treatment-naïve individuals.

    PubMed

    Hué, Stéphane; Gifford, Robert J; Dunn, David; Fernhill, Esther; Pillay, Deenan

    2009-03-01

    Transmission of human immunodeficiency virus (HIV) drug resistance is well-recognized and compromises response to first-line therapy. However, the population dynamics of transmitted resistance remains unclear, although previous models have assumed that such transmission reflects direct infection from treated individuals. We investigated whether population-based phylogenetic analyses would uncover lineages of resistant viruses circulating in untreated individuals. Through the phylogenetic analysis of 14,061 HIV type 1 (HIV-1) pol gene sequences generated in the United Kingdom from both treatment-naïve and -experienced individuals, we identified five treatment-independent viral clusters containing mutations conferring cross-resistance to antiretroviral drugs prescribed today in the United Kingdom. These viral lineages represent sustainable reservoirs of resistance among new HIV infections, independent of treatment. Dated phylogenies reconstructed through Bayesian Markov chain Monte Carlo inference indicated that these reservoirs originated between 1997 and 2003 and have persisted in the HIV-infected population for up to 8 years. Since our cohort does not represent all infected individuals within the United Kingdom, our results are likely to underestimate the number and size of the resistant reservoirs circulating among drug-naïve patients. The existence of sustained reservoirs of resistance in the absence of treatment has the capacity to threaten the long-term efficacy of antiretroviral therapy and suggests there is a limit to the decline of transmitted drug resistance. Given the current decrease in resistance transmitted from treated individuals, a greater proportion of resistance is likely to come from drug-naïve lineages. These findings provide new insights for the planning and management of treatment programs in resource-rich and developing countries.

  20. Relapse rates in chronic hepatitis B naïve patients after discontinuation of antiviral therapy with entecavir.

    PubMed

    Ridruejo, E; Marciano, S; Galdame, O; Reggiardo, M V; Muñoz, A E; Adrover, R; Cocozzella, D; Fernandez, N; Estepo, C; Mendizábal, M; Romero, G A; Levi, D; Schroder, T; Paz, S; Fainboim, H; Mandó, O G; Gadano, A C; Silva, M O

    2014-08-01

    Registration studies show entecavir (ETV) to be effective and safe in NUC-naïve patients with chronic hepatitis B, but relapse rates after treatment discontinuation have not been well established. Relapse rates and predictors of relapse were evaluated in naïve HBeAg-positive and HBeAg-negative patients treated with ETV. Treatment duration was defined according to international guidelines. Virological relapse was defined as reappearance in serum of hepatitis B virus (HBV) DNA to >2000 IU/mL after discontinuation of treatment. A hundred and sixty-nine consecutive patients were treated for a median 181 weeks. 61% were HBeAg positive, 23% had cirrhosis, and mean HBV DNA level was 6.88 ± 1.74 log10 IU/mL. Ninety-two per cent became HBV DNA negative; 71% of HBeAg+ve patients became HBeAg negative and 68% anti-HBe positive; 14% became HBsAg negative and 13% anti-HBs positive. At the end of the study, 36 patients discontinued treatment: one due to breakthrough associated with resistant variants and 35 (20%) due to sustained virological response; 33 of these patients developed HBeAg seroconversion and 18 HBsAg seroconversion. Median off-treatment time was 69 weeks. Nine patients (26%), all HBeAg positive at baseline, developed virological relapse after a median 48 weeks off-treatment, 3 of them showed HBeAg reversion and 4 lost anti-HBe. No patient with HBsAg seroconversion relapsed. HBeAg clearance after week 48 of treatment was associated with an increase risk of relapse. After ETV discontinuation, HBsAg seroconversion was maintained in 100% of the patients, HBeAg seroconversion maintained in 90%, and virological relapse rate was 24%.

  1. Attention-deficit hyperactivity disorder and suicidality in a treatment naïve sample of children and adolescents.

    PubMed

    Balazs, Judit; Miklósi, Mónika; Keresztény, Agnes; Dallos, Gyöngyvér; Gádoros, Júlia

    2014-01-01

    The aim of the present study was to investigate the possible association between attention-deficit/hyperactivity disorder (ADHD) and suicidality. Using a structured interview (Mini International Neuropsychiatric Interview Kid), the authors examined 418 treatment naïve children/adolescents (aged: 3-18 years). Suicidality was defined by the M.I.N.I. Kid as having any current suicidal ideations and/or suicide attempts. Two hundred and eleven children/adolescents fulfilled the DSM-IV diagnosis of ADHD and a further 105 showed symptoms of ADHD in subthreshold level. Multiple mediation analyses resulted in a moderated meditational model in which the relationship between symptoms of ADHD and current suicidality was fully mediated by the symptoms of comorbid conditions, but this was moderated by age. In children under 12 years, significant mediators were the symptoms of specific anxiety disorders, while in the adolescent group symptoms of major depressive episode and dysthymia and symptoms of substance abuse/dependence approved as significant mediators. As the study was cross-sectional, it did not reveal any causal relationship among the investigated factors. Furthermore, as the study population included a treatment naïve clinical sample, we can assume that adolescents, who and/or whose family seek for help at the first time in this age belonged to the less sever end of the spectrum. ADHD symptoms are associated with an increased risk of suicidality in treatment naïve children/adolescents. The mechanisms of this relationship can be understood only when developmental factors are considered. Our findings suggest that clinicians should screen suicidality and comorbid symptoms routinely in patients with ADHD. © 2013 Published by Elsevier B.V.

  2. Antiretroviral drug resistance among antiretroviral-naïve and treatment experienced patients infected with HIV in Iran.

    PubMed

    Baesi, Kazem; Ravanshad, Mehrdad; Ghanbarisafari, Maryam; Saberfar, Esmaeil; Seyedalinaghi, Seyedahmad; Volk, Jonathan E

    2014-07-01

    Resistance to antiretroviral therapy (ART) threatens the success of programs to reduce HIV morbidity and mortality, particularly in countries with few treatment options. In the present study, genotype and phenotype data from ART-naïve and experienced hospitalized patients infected with HIV in Tehran, Iran were used to assess the prevalence and types of transmitted (TDR) and acquired drug resistance (ADR) mutations. All 30 participants naïve to ART and 62 of 70 (88.6%) participants receiving ART had detectable viral loads. Among participants receiving ART with sequencing data available (n = 62), 36 (58.1%) had at least one drug resistance mutation; the most common mutations were K103N (21.0%), M184V (19.4%), and the thymidine analogue mutations. Seven (11.3%), 27 (43.5%), and two (3.2%) of these participants had resistance to one, two, and three drug classes, respectively. High-level resistance to efavirenz (EFV) was more common among participants on EFV-based regimens than high-level lopinavir/ritonivar (LPV/r) resistance among those on LPV/r-based regimens (55.3% vs. 6.7%, P < 0.0001). Two (6.7%) antiretroviral-naïve participants had K103N mutations. These findings document an alarmingly high frequency of multiple HIV drug class resistance in Iran, confirm the presence of TDR, and highlight the need for systematic viral load monitoring and drug resistance testing, including at diagnosis. Expanded access to new antiretroviral medications from additional drug classes is needed.

  3. Comparison of Serum Lipid Profile in HIV Positive Patients on ART with ART Naïve Patients

    PubMed Central

    V, Vijay; Shekhanawar, M.S.; Rajeshwari; M, Amareshwaras; D, Shantala

    2014-01-01

    Introduction: The widespread use of effective highly active antiretroviral therapy (HAART) in HIV patients has coincided with increasing reports of complications like HIV-associated lipodystrophy syndrome and the metabolic alterations, affecting the lipid and glucose metabolism. Evidences in support of lipodystrophy and dyslipidaemia associated with First- line HAART in our area is scarce. The aim of the present study was 1) to study and compare Lipid profile in HIV positive patients on ART with that of freshly diagnosed HIV positive patients who were yet to be started on ART. 2) To assess lipodystrophy syndrome in patients on ART. Materials and Methods: Hundred newly diagnosed HIV positive patients who were yet to be started on ART were taken as controls (ART-Naïve).Hundred randomly selected HIV+ patients who were already on First-line ART regimen (Stavudine/Zudovudine + Lamivudine + Nevirapine) for more than 12 months were taken as cases (ART). This study was conducted for a period of 12 months at the VIMS ART centre, Bellary, Karnataka, India. Results: There was a significant increase (p<0.001) in serum Total Cholesterol, LDL-C, TG, VLDL, Non-HDL -C & TC/HDL-C ratio in ART patients compared to ART-naïve patients. Of the 100 ART patients 23 had lipodystrophy syndrome (buffalo hump, abnormal fat deposition around neck & back, buccal fat resorption, increase in abdominal fat). Conclusion: To conclude, it is evident from our study that there is increase in lipid profile (except HDL) in ART patients compared to ART Naïve group and 23 ART patients showed lipodystrophy syndrome. Hence it appears reasonable to measure fasting lipid levels before and 3-6 months after antiretroviral therapy is initiated or when ART regimen is changed. PMID:25478335

  4. Microbiota Separation and C-reactive protein Elevation in Treatment Naïve Pediatric Granulomatous Crohn Disease

    PubMed Central

    Kellermayer, Richard; Mir, Sabina A. V.; Nagy-Szakal, Dorottya; Cox, Stephen B.; Dowd, Scot E.; Kaplan, Jess L.; Sun, Yan; Reddy, Sahna; Bronsky, Jiri; Winter, Harland S.

    2012-01-01

    Objectives In patients with inflammatory bowel diseases (IBD), the presence of non-caseating mucosal granuloma is sufficient for diagnosing Crohn disease (CD) and may represent a specific immune response or microbial-host interaction. The cause of granulomas in CD is unknown and their association with the intestinal microbiota has not been addressed with high-throughput methodologies. Methods The mucosal microbiota from three different pediatric centers was studied with 454 pyrosequencing of the bacterial 16S rRNA gene and the fungal small subunit (SSU) ribosomal region in transverse colonic biopsy specimens from 26 controls and 15 treatment naïve pediatric CD cases. Mycobacterium avium subspecies paratuberculosis (MAP) was tested with real-time PCR. The correlation of granulomatous inflammation with C-reactive protein (CRP) was expanded to 86 treatment naïve CD cases. Results The CD microbiota separated from controls by distance based redundancy analysis (dbRDA; p=0.035). Mucosal granulomata found in any portion of the intestinal tract associated with an augmented colonic bacterial microbiota divergence (p=0.013). The granuloma based microbiota separation persisted even when research center bias was eliminated (p=0.04). Decreased Roseburia and Ruminococcus in granulomatous CD were important in this separation. However, principal coordinates analysis (PCoA) did not reveal partitioning of the groups. CRP levels above 1mg/dl predicted the presence of mucosal granulomata (OR: 28 [6–134.32]; 73% sensitivity, 91% specificity). Conclusions Granulomatous CD associates with microbiota separation and CRP elevation in treatment naïve children. However, overall dysbiosis in pediatric CD appears rather limited. Geographical/center bias should be accounted for in future multi-center microbiota studies. PMID:22699834

  5. Immunobiology of naïve and genetically modified HLA-class-I-knockdown human embryonic stem cells.

    PubMed

    Deuse, Tobias; Seifert, Martina; Phillips, Neil; Fire, Andrew; Tyan, Dolly; Kay, Mark; Tsao, Philip S; Hua, Xiaoqin; Velden, Joachim; Eiermann, Thomas; Volk, Hans-Dieter; Reichenspurner, Hermann; Robbins, Robert C; Schrepfer, Sonja

    2011-09-01

    Human embryonic stem cells (hESCs) can serve as a universal cell source for emerging cell or tissue replacement strategies, but immune rejection of hESC derivatives remains an unsolved problem. Here, we sought to describe the mechanisms of rejection for naïve hESCs and upon HLA class I (HLA I) knockdown (hESC(KD)). hESCs were HLA I-positive but negative for HLA II and co-stimulatory molecules. Transplantation of naïve hESC into immunocompetent Balb/c mice induced substantial T helper cell 1 and 2 (Th1 and Th2) responses with rapid cell death, but hESCs survived in immunodeficient SCID-beige recipients. Histology revealed mainly macrophages and T cells, but only scattered natural killer (NK) cells. A surge of hESC-specific antibodies against hESC class I, but not class II antigens, was observed. Using HLA I RNA interference and intrabody technology, HLA I surface expression of hESC(KD) was 88%-99% reduced. T cell activation after hESC(KD) transplantation into Balb/c was significantly diminished, antibody production was substantially alleviated, the levels of graft-infiltrating immune cells were reduced and the survival of hESC(KD) was prolonged. Because of their very low expression of stimulatory NK ligands, NK-susceptibility of naïve hESCs and hESC(KD) was negligible. Thus, HLA I recognition by T cells seems to be the primary mechanism of hESC recognition, and T cells, macrophages and hESC-specific antibodies participate in hESC killing.

  6. Transcription Profiling of Malaria-Naïve and Semi-immune Colombian Volunteers in a Plasmodium vivax Sporozoite Challenge

    PubMed Central

    Rojas-Peña, Monica L.; Vallejo, Andres; Herrera, Sócrates; Gibson, Greg; Arévalo-Herrera, Myriam

    2015-01-01

    Background Continued exposure to malaria-causing parasites in endemic regions of malaria induces significant levels of acquired immunity in adult individuals. A better understanding of the transcriptional basis for this acquired immunological response may provide insight into how the immune system can be boosted during vaccination, and into why infected individuals differ in symptomology. Methodology/Principal Findings Peripheral blood gene expression profiles of 9 semi-immune volunteers from a Plasmodium vivax malaria prevalent region (Buenaventura, Colombia) were compared to those of 7 naïve individuals from a region with no reported transmission of malaria (Cali, Colombia) after a controlled infection mosquito bite challenge with P. vivax. A Fluidigm nanoscale quantitative RT-PCR array was used to survey altered expression of 96 blood informative transcripts at 7 timepoints after controlled infection, and RNASeq was used to contrast pre-infection and early parasitemia timepoints. There was no evidence for transcriptional changes prior to the appearance of blood stage parasites at day 12 or 13, at which time there was a strong interferon response and, unexpectedly, down-regulation of transcripts related to inflammation and innate immunity. This differential expression was confirmed with RNASeq, which also suggested perturbations of aspects of T cell function and erythropoiesis. Despite differences in clinical symptoms between the semi-immune and malaria naïve individuals, only subtle differences in their transcriptomes were observed, although 175 genes showed significantly greater induction or repression in the naïve volunteers from Cali. Conclusion/Significance Gene expression profiling of whole blood reveals the type and duration of the immune response to P. vivax infection, and highlights a subset of genes that may mediate adaptive immunity. PMID:26244760

  7. [Cost-utility analysis of triple therapy with telaprevir in treatment-naïve hepatitis C patients].

    PubMed

    Buti, María; Gros, Blanca; Oyagüez, Itziar; Andrade, Raúl J; Serra, Miguel A; Turnes, Juan; Casado, Miguel A

    2014-09-16

    The prevalence of Hepatitis C (HCV) in Spain is 2,5%, with a high morbimortality rate. Triple therapy based on telaprevir plus peginterferon/ribavirin ([T/PR]) has demonstrated to be an effective approach in treatment-naïve G1-HCV patients. This analysis evaluated, through a Markov model, the incremental cost-effectiveness ratio of triple therapy compared to peginterferon/ ribavirin ([PR]) alone in naïve patients depending on fibrosis stage, from the Spanish Healthcare Authorities perspective. Efficacy results and adverse events incidence were based on the combined results of ADVANCE and OPTIMIZE studies. Adverse events and disease-related costs (€, 2014) were built up from panel expert opinion except from transplant and post-transplant costs, taken from published data. Drug costs were obtained from national databases and adjusted for the mandatory deduction. Outcomes and costs were both discounted at 3%/year. The analysis shows higher costs and improved outcomes associated with [TR/PR] relative to [PR] alone, resulting in an incremental cost-effectiveness ratio (ICER) of €18,288/ QALY for all the cohort, €14,152QALY for moderate fibrosis, €11,364QALY for bridging fibrosis, €15,929/QALY for cirrhosis. Over a lifetime period, the use of [T/PR] could avoid 12 cirrhosis and 4 liver transplants per 1,000 patients compared to [PR] alone. The probabilistic analysis, following 10,000 Montecarlo simulations, demonstrated the probability of an ICER below a €30,000/QALY gained threshold of 69%. At a willingness- to-pay of €30,000/QALY, [T/PR] could be considered as an efficient option compared with [PR] alone for treatment-naïve genotype 1 HCV patients, over a lifetime horizon. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

  8. Memory-improving activity of Melissa officinalis extract in naïve and scopolamine-treated rats

    PubMed Central

    Soodi, M.; Naghdi, N.; Hajimehdipoor, H.; Choopani, S.; Sahraei, E.

    2014-01-01

    Melissa officinalis L. (Labiatae) traditionally used in treating neurological disorders has also been identified as a memory-enhancing herb. The extract of M. officinalis has a cholinergic property. The role of basal forebrain cholinergic neurons, the neurons that are destroyed in Alzheimer's disease (AD), in learning and memory, is also well known. The aim of this study is to investigate the role of cholinergic system on the memory improving activity of M. officinalis extract. The leaves of M. officinalis were extracted with ethanol 80% using the maceration method. Rats received intra-peritoneal injections of M. officinalis extract in different doses (50–400 mg/kg) alone or in combination with scopolamine (1 mg/kg) before being trained in a Morris water maze (MWM) in a single-day training protocol. After training, the acetylcholinesterase enzyme (AChE) activity was measured in the hippocampus. Administration of M. officinalis extract (200 mg/kg) could significantly enhance learning and memory of naïve rats (p<0.001) and significantly ameliorate scopolamine-induced learning deficit, but the effect of the extract was not dose dependent, and doses above 200 mg/kg could neither enhance memory in naïve rats nor reverse scopolamine-induced memory impairment. Also, inhibition of AChE activity was observed in both naïve and scopolamine-induced memory-impaired rats. These results suggest that M. officinalis can improve memory and that the cholinergic property of the extract may contribute to the memory-improving effects observed in this study. Then M. officinalis extract has potential therapeutic value in alleviating certain memory impairment observed in AD. PMID:25657779

  9. FIJI Macro 3D ART VeSElecT: 3D Automated Reconstruction Tool for Vesicle Structures of Electron Tomograms

    PubMed Central

    Kaltdorf, Kristin Verena; Schulze, Katja; Helmprobst, Frederik; Kollmannsberger, Philip; Stigloher, Christian

    2017-01-01

    Automatic image reconstruction is critical to cope with steadily increasing data from advanced microscopy. We describe here the Fiji macro 3D ART VeSElecT which we developed to study synaptic vesicles in electron tomograms. We apply this tool to quantify vesicle properties (i) in embryonic Danio rerio 4 and 8 days past fertilization (dpf) and (ii) to compare Caenorhabditis elegans N2 neuromuscular junctions (NMJ) wild-type and its septin mutant (unc-59(e261)). We demonstrate development-specific and mutant-specific changes in synaptic vesicle pools in both models. We confirm the functionality of our macro by applying our 3D ART VeSElecT on zebrafish NMJ showing smaller vesicles in 8 dpf embryos then 4 dpf, which was validated by manual reconstruction of the vesicle pool. Furthermore, we analyze the impact of C. elegans septin mutant unc-59(e261) on vesicle pool formation and vesicle size. Automated vesicle registration and characterization was implemented in Fiji as two macros (registration and measurement). This flexible arrangement allows in particular reducing false positives by an optional manual revision step. Preprocessing and contrast enhancement work on image-stacks of 1nm/pixel in x and y direction. Semi-automated cell selection was integrated. 3D ART VeSElecT removes interfering components, detects vesicles by 3D segmentation and calculates vesicle volume and diameter (spherical approximation, inner/outer diameter). Results are collected in color using the RoiManager plugin including the possibility of manual removal of non-matching confounder vesicles. Detailed evaluation considered performance (detected vesicles) and specificity (true vesicles) as well as precision and recall. We furthermore show gain in segmentation and morphological filtering compared to learning based methods and a large time gain compared to manual segmentation. 3D ART VeSElecT shows small error rates and its speed gain can be up to 68 times faster in comparison to manual annotation

  10. Olodaterol attenuates citric acid-induced cough in naïve and ovalbumin-sensitized and challenged guinea pigs.

    PubMed

    Wex, Eva; Bouyssou, Thierry

    2015-01-01

    Excessive coughing is a common feature of airway diseases. Different G-protein coupled receptors, including β2-adrenergic receptors (β2-AR), have been implicated in the molecular mechanisms underlying the cough reflex. However, the potential antitussive property of β2-AR agonists in patients with respiratory disease is a matter of ongoing debate. The aim of our study was to test the efficacy of the long-acting β2-AR agonist olodaterol with regard to its antitussive property in a pre-clinical model of citric acid-induced cough in guinea pigs and to compare the results to different clinically relevant β2-AR agonists. In our study β2-AR agonists were intratracheally administered, as dry powder, into the lungs of naïve or ovalbumin-sensitized guinea pigs 15 minutes prior to induction of cough by exposure to citric acid. Cough events were counted over 15 minutes during the citric acid exposure. Olodaterol dose-dependently inhibited the number of cough events in naïve and even more potently and with a greater maximal efficacy in ovalbumin-sensitized guinea pigs (p < 0.01). Formoterol and salmeterol showed a trend towards reducing cough. On the contrary, indacaterol demonstrated pro-tussive properties as it significantly increased the number of coughs, both in naïve and ovalbumin-sensitized animals (p < 0.001). In conclusion, olodaterol, at doses eliciting bronchodilation, showed antitussive properties in a model of citric acid-induced cough in naïve and ovalbumin-sensitized guinea pigs. This is in agreement with pre-clinical and clinical studies showing antitussive efficacy of β2-AR agonists. Indacaterol increased the number of coughs in this model, which concurs with clinical data where a transient cough has been observed after indacaterol inhalation. While the antitussive properties of β2-AR agonists can be explained by their ability to lead to the cAMP-induced hyperpolarization of the neuron membrane thereby inhibiting sensory nerve activation and the

  11. Olodaterol Attenuates Citric Acid-Induced Cough in Naïve and Ovalbumin-Sensitized and Challenged Guinea Pigs

    PubMed Central

    Wex, Eva; Bouyssou, Thierry

    2015-01-01

    Excessive coughing is a common feature of airway diseases. Different G-protein coupled receptors, including β2-adrenergic receptors (β2-AR), have been implicated in the molecular mechanisms underlying the cough reflex. However, the potential antitussive property of β2-AR agonists in patients with respiratory disease is a matter of ongoing debate. The aim of our study was to test the efficacy of the long-acting β2-AR agonist olodaterol with regard to its antitussive property in a pre-clinical model of citric acid-induced cough in guinea pigs and to compare the results to different clinically relevant β2-AR agonists. In our study β2-AR agonists were intratracheally administered, as dry powder, into the lungs of naïve or ovalbumin-sensitized guinea pigs 15 minutes prior to induction of cough by exposure to citric acid. Cough events were counted over 15 minutes during the citric acid exposure. Olodaterol dose-dependently inhibited the number of cough events in naïve and even more potently and with a greater maximal efficacy in ovalbumin-sensitized guinea pigs (p < 0.01). Formoterol and salmeterol showed a trend towards reducing cough. On the contrary, indacaterol demonstrated pro-tussive properties as it significantly increased the number of coughs, both in naïve and ovalbumin-sensitized animals (p < 0.001). In conclusion, olodaterol, at doses eliciting bronchodilation, showed antitussive properties in a model of citric acid-induced cough in naïve and ovalbumin-sensitized guinea pigs. This is in agreement with pre-clinical and clinical studies showing antitussive efficacy of β2-AR agonists. Indacaterol increased the number of coughs in this model, which concurs with clinical data where a transient cough has been observed after indacaterol inhalation. While the antitussive properties of β2-AR agonists can be explained by their ability to lead to the cAMP-induced hyperpolarization of the neuron membrane thereby inhibiting sensory nerve activation and the

  12. Oh What FUN We've Had! Reflections on the Past and a Look to the Future.

    PubMed

    Dickinson, Shelly D

    2012-01-01

    In 2011 FUN celebrated 20 years of training tomorrow's neuroscientists today. Over the past two decades we've become an international organization of members dedicated to excellence in teaching and research at the undergraduate level. FUN has enacted its mission through our flagship journal JUNE, student travel awards, faculty awards, education workshops, and regional conferences. More recent initiatives include the equipment loan program, department/program consulting service, the honor society Nu Rho Psi, and neuroscience study abroad opportunities. FUN is poised to continue enhancing undergraduate neuroscience education and research over the next 20 years.

  13. Advantages of Karhunen Loève transform over fast Fourier transform for planetary radar and space debris detection

    NASA Astrophysics Data System (ADS)

    Maccone, Claudio

    2007-04-01

    The present article describes that the range of any radiotelescope (and radar in general) may be increased by virtue of software, if one replaces the fast Fourier transform by the Karhunen Loève transform. The range increases with the inverse of the fourth root of the signal-to-noise ratio when this ratio decreases. Thus, the range on any radiotelescope (and radar) may be increased without changing the hardware at all, but by changing the software only. This improvement in the range of the radiotelescope is currently implemented at the 32-m antenna located at Medicina, near Bologna, in Italy, for both SETI and general radioastronomy.

  14. Oh What FUN We’ve Had! Reflections on the Past and a Look to the Future

    PubMed Central

    Dickinson, Shelly D.

    2012-01-01

    In 2011 FUN celebrated 20 years of training tomorrow’s neuroscientists today. Over the past two decades we’ve become an international organization of members dedicated to excellence in teaching and research at the undergraduate level. FUN has enacted its mission through our flagship journal JUNE, student travel awards, faculty awards, education workshops, and regional conferences. More recent initiatives include the equipment loan program, department/program consulting service, the honor society Nu Rho Psi, and neuroscience study abroad opportunities. FUN is poised to continue enhancing undergraduate neuroscience education and research over the next 20 years. PMID:23493526

  15. Systemic therapy for metastatic renal cell carcinoma in treatment naïve patients: a risk-based approach.

    PubMed

    Bukowski, Ronald M

    2010-10-01

    Kidney cancer is the ninth most common cancer in the USA, with an annual incidence of approximately 55,000 cases per year. Over 13,000 patients are estimated to die from this disease annually. Cloning of the VHL gene, recognition of the associated abnormalities in sporadic clear-cell carcinoma, and its role as a regulator of the hypoxic response, were important milestones in our understanding of renal-cell carcinoma (RCC) biology and the recognition of the vascular endothelial growth factor (VEGF) dependency of RCC. A variety of clinical features, including histologic features, prognostic factors, and patient history of comorbid illness, provide the framework in which the results of recent clinical trials and regulatory approvals of these agents are utilized to develop treatment recommendations for the largest metastatic patient RCC group, the therapy naïve individual. The rationale for use of VEGF-targeted therapy in advanced RCC patients and the recently developed treatment options for these individuals are reviewed. Regulatory approval of sorafenib for the treatment of metastatic RCC (mRCC), was followed by the approval of sunitinib, temsirolimus, bevacizumab plus interferon (IFNα), everolimus, and--most recently--pazopanib. These licences were granted from late 2005 through late 2009, a very short span of 4 years. In treatment-naïve mRCC patients, sunitinib, sorafenib, pazopanib, bevacizumab + IFNα, and temsirolimus were approved by the Food and Drug Administration (FDA) and/or the European Medicines Agency (EMEA). The clinical trials and data supporting these approvals are reviewed. This review examines these developments and provides the reader an overview and understanding of available current systemic therapy options for treatment-naïve mRCC patients. As multiple treatment options are now available for treatment-naïve mRCC patients, an understanding of how to utilize this group of agents is required. The use of various clinical features allows a

  16. Water-resources reconnaissance of Île de la Gonâve, Haiti

    NASA Astrophysics Data System (ADS)

    Troester, Joseph W.; Turvey, Michael D.

    Île de la Gonâve is a 750-km2 island off the coast of Haiti. The depth to the water table ranges from less than 30 m in the Eocene and Upper Miocene limestones to over 60 m in the 300-m-thick Quaternary limestone. Annual precipitation ranges from 800-1,400 mm. Most precipitation is lost through evapotranspiration and there is virtually no surface water. Roughly estimated from chloride mass balance, about 4% of the precipitation recharges the karst aquifer. Cave pools and springs are a common source for water. Hand-dug wells provide water in coastal areas. Few productive wells have been drilled deeper than 60 m. Reconnaissance field analyses indicate that groundwater in the interior is a calcium-bicarbonate type, whereas water at the coast is a sodium-chloride type that exceeds World Health Organization recommended values for sodium and chloride. Tests for the presence of hydrogen sulfide-producing bacteria were negative in most drilled wells, but positive in cave pools, hand-dug wells, and most springs, indicating bacterial contamination of most water sources. Because of the difficulties in obtaining freshwater, the 110,000 inhabitants use an average of only 7 L per person per day. L'Île de la Gonâve est une île de 750 km2 au large de la côte d'Haïti. La profondeur de la nappe varie entre moins de 30 m dans les calcaires de l'Éocène et du Miocène supérieur à plus de 60 m dans les calcaires quaternaires épais de 300 m. Les précipitations annuelles sont comprises entre 800-1.400 mm. La plus grande partie des précipitations est perdue par évapotranspiration et il n'y a pratiquement pas d'eau de surface. Le bilan de masse des chlorures permet d'estimer à 4% des précipitations le montant de la recharge de l'aquifère karstique. Des bassins dans les grottes et des sources sont la source d'eau courante. Des puits creusés à la main fournissent de l'eau dans les zones côtières. Quelques puits productifs ont été forés dépassant 60 m de profondeur. L

  17. Antigen-Experienced T cells Limit the Priming of Naïve T cells During Infection with Leishmania major1

    PubMed Central

    Gray, Peter M.; Reiner, Steven L.; Smith, Deborah F.; Kaye, Paul M.; Scott, Phillip

    2009-01-01

    One mechanism to control immune responses following infection is to rapidly down regulate antigen presentation, which has been observed in acute viral and bacterial infections. Here we describe experiments designed to address whether antigen presentation is decreased after an initial response to Leishmania major. Naïve α-β-Leishmania-specific (ABLE) T cell receptor transgenic T cells were adoptively transferred into mice at various times after L. major infection to determine the duration of presentation of parasite-derived antigens. ABLE T cells responded vigorously at the initiation of infection, but the ability to prime these cells quickly diminished, independent of IL-10, regulatory T cells or antigen load. However, antigen-experienced clonal and polyclonal T cell populations could respond, indicating that the diminution in naïve ABLE cell responses was not due to lack of antigen presentation. Since naïve T cell priming could be restored by removal of the endogenous T cell population, or adoptive transfer of antigen pulsed dendritic cells, it appears that T cells that have previously encountered antigen during infection compete with naïve antigen-specific T cells. These results suggest that during L. major infection antigen-experienced T cells, rather than naïve T cells, may be primarily responsible for sustaining the immune response. PMID:16818747

  18. Activation of human naïve Th cells increases surface expression of GD3 and induces neoexpression of GD2 that colocalize with TCR clusters.

    PubMed

    Villanueva-Cabello, Tania M; Mollicone, Rosella; Cruz-Muñoz, Mario E; López-Guerrero, Delia V; Martínez-Duncker, Iván

    2015-12-01

    CD4+ T helper lymphocytes (Th) orchestrate the immune response after their activation by antigen-presenting cells. Activation of naïve Th cells is reported to generate the reduction in surface epitopes of sialic acid (Sia) in α2,3 and α2,6 linkages. In this work, we report that in spite of this glycophenotype, anti-CD3/anti-CD28-activated purified human naïve Th cells show a significant increase in surface Sia, as assessed by metabolic labeling, compared with resting naïve Th cells, suggesting an increased flux of Sia toward Siaα2,8 glycoconjugates. To understand this increase as a result of ganglioside up-regulation, we observed that very early after activation, human naïve Th cells show an increased expression in surface GD3 and neoexpression of surface GD2 gangliosides, the latter clustering with the T cell receptor (TCR). Also, we report that in contrast to GM2/GD2 synthase null mice, lentiviral vector-mediated silencing of the GM2/GD2 synthase in activated human naïve Th cells reduced efficient TCR clustering and downstream signaling, as assessed by proliferation assays and IL-2 and IL-2R expression, pointing to an important role of this enzyme in activation of human naive Th cells. © The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  19. MicroRNA-150 modulates intracellular Ca (2+) levels in naïve CD8(+) T cells by targeting TMEM20.

    PubMed

    Kim, Tae-Don; Jung, Hong-Ryul; Seo, Sang-Hwan; Oh, Se-Chan; Ban, Youngho; Tan, Xiaoxia; Min Kim, Jung; Hyun Lee, Sang; Koh, Duk-Su; Jung, Haiyoung; Park, Young-Jun; Ran Yoon, Suk; Doh, Junsang; Ha, Sang-Jun; Choi, Inpyo; Greenberg, Philip D

    2017-06-01

    Regulation of intracellular Ca(2+) signaling is a major determinant of CD8(+) T cell responsiveness, but the mechanisms underlying this regulation of Ca(2+) levels, especially in naïve CD8(+) T cells, are not fully defined. Here, we showed that microRNA-150 (miR-150) controls intracellular Ca(2+) levels in naïve CD8(+) T cells required for activation by suppressing TMEM20, a negative regulator of Ca(2+) extrusion. miR-150 deficiency increased TMEM20 expression, which resulted in increased intracellular Ca(2+) levels in naïve CD8(+) T cells. The subsequent increase in Ca(2+) levels induced expression of anergy-inducing genes, such as Cbl-b, Egr2, and p27, through activation of NFAT1, as well as reduced cell proliferation, cytokine production, and the antitumor activity of CD8(+) T cells upon antigenic stimulation. The anergy-promoting molecular milieu and function induced by miR-150 deficiency were rescued by reinstatement of miR-150. Additionally, knockdown of TMEM20 in miR-150-deficient naïve CD8(+) T cells reduced intracellular Ca(2+) levels. Our findings revealed that miR-150 play essential roles in controlling intracellular Ca(2+) level and activation in naïve CD8(+) T cells, which suggest a mechanism to overcome anergy induction by the regulation of intracellular Ca(2+) levels.

  20. Bim dictates naïve CD4 T cell lifespan and the development of age-associated functional defects1

    PubMed Central

    Tsukamoto, Hirotake; Huston, Gail E.; Dibble, John; Duso, Debra K.; Swain, Susan L.

    2012-01-01

    With age peripheral naïve CD4 T cells become both longer-lived and functionally impaired and they express reduced levels of Bim, a pro-apoptotic Bcl-family member. In this study, we show that reduced Bim expression by naïve CD4 T cells intrinsically mediates their longer lifespan in the periphery. Moreover, using mixed bone marrow chimeras reconstituted with Bim+/+ and Bim+/− bone marrow cells, Bim+/− naïve CD4 T cells exhibit accelerated development of age-associated dysfunctions including reduced proliferation and IL-2 production and defective helper function for B cells, without any increase in their turnover. However, newly generated Bim+/− naïve CD4 T cells in middle aged mice are not defective, indicating an additional requirement for their persistence in the periphery. These age-associated immune defects develop independently of the “aged” host environment and without extensive division, distinguishing them from classic “senescence”. We suggest that the reduction of Bim levels with age in naïve CD4 T cell is the initiating step that leads to increased cellular lifespan and development of age-associated functional defects. PMID:20844198

  1. Green tea catechins inhibit VEGF-induced angiogenesis in vitro through suppression of VE-cadherin phosphorylation and inactivation of Akt molecule.

    PubMed

    Tang, Feng-Yao; Nguyen, Nhan; Meydani, Mohsen

    2003-10-10

    Studies have indicated that the consumption of green tea is associated with a reduced risk of developing certain forms of cancer and angiogenesis. The mechanism of inhibition of angiogenesis by green tea or its catechins, however, has not been well-established. Vascular endothelial (VE)-cadherin, an adhesive molecule located at the site of intercellular contact, is involved in cell-cell recognition during vascular morphogenesis. The extracellular domain of VE-cadherin mediates initial cell adhesion, whereas the cytosolic tail binding with beta-catenin is required for interaction with the cytoskeleton and junctional strength. Therefore, the cadherin-catenin adhesion system is implicated in cell recognition, differentiation, growth and migration of capillary endothelium. Using tube formation of human microvascular endothelial cells (HMVEC) in culture as an in vitro model of angiogenesis, we reported that vascular endothelial growth factor (VEGF)-induced tube formation is inhibited by anti-VE-cadherin antibody and dose-dependently by green tea catechins. We also demonstrated here that inhibition of tube formation by epigallocatechin gallate (EGCG), one of the green tea catechins, is in part mediated through suppression of VE-cadherin tyrosine phosphorylation and inhibition of Akt activation during VEGF-induced tube formation. These findings indicate that VE-cadherin and Akt, known downstream proteins in VEGFR-2-mediated cascade, are the new-targeted proteins by which green tea catechins inhibit angiogenesis.

  2. Retinol and ascorbate drive erasure of epigenetic memory and enhance reprogramming to naïve pluripotency by complementary mechanisms.

    PubMed

    Hore, Timothy Alexander; von Meyenn, Ferdinand; Ravichandran, Mirunalini; Bachman, Martin; Ficz, Gabriella; Oxley, David; Santos, Fátima; Balasubramanian, Shankar; Jurkowski, Tomasz P; Reik, Wolf

    2016-10-25

    Epigenetic memory, in particular DNA methylation, is established during development in differentiating cells and must be erased to create naïve (induced) pluripotent stem cells. The ten-eleven translocation (TET) enzymes can catalyze the oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and further oxidized derivatives, thereby actively removing this memory. Nevertheless, the mechanism by which the TET enzymes are regulated, and the extent to which they can be manipulated, are poorly understood. Here we report that retinoic acid (RA) or retinol (vitamin A) and ascorbate (vitamin C) act as modulators of TET levels and activity. RA or retinol enhances 5hmC production in naïve embryonic stem cells by activation of TET2 and TET3 transcription, whereas ascorbate potentiates TET activity and 5hmC production through enhanced Fe(2+) recycling, and not as a cofactor as reported previously. We find that both ascorbate and RA or retinol promote the derivation of induced pluripotent stem cells synergistically and enhance the erasure of epigenetic memory. This mechanistic insight has significance for the development of cell treatments for regenenerative medicine, and enhances our understanding of how intrinsic and extrinsic signals shape the epigenome.

  3. Dermatoglyphic correlates of hippocampus volume: Evaluation of aberrant neurodevelopmental markers in antipsychotic-naïve schizophrenia.

    PubMed

    Kalmady, Sunil V; Shivakumar, Venkataram; Gautham, S; Arasappa, Rashmi; Jose, Dania A; Venkatasubramanian, Ganesan; Gangadhar, B N

    2015-10-30

    Schizophrenia is a disorder of aberrant neurodevelopment is marked by abnormalities in brain structure and dermatoglyphic traits. However, the link between these two (i.e. dermatoglyphic parameters and brain structure) which share ectodermal origin and common developmental window has not been explored extensively. The current study examined dermatoglyphic correlates of hippocampal volume in antipsychotic-naïve schizophrenia patients in comparison with matched healthy controls. Ridge counts and asymmetry measures for palmar inter-digital areas (a-b, b-c, c-d) were obtained using high resolution digital scans of palms from 89 schizophrenia patients [M:F=48:41] and 48 healthy controls [M:F=30:18]. Brain scans were obtained for subset of subjects including 26 antipsychotic-naïve patients [M:F=13:13] and 29 healthy controls [M:F=19:10] using 3 T-MRI. Hippocampal volume and palmar ridge counts were measured by blinded raters with good inter-rater reliability using valid methods. Directional asymmetry (DA) of b-c and bilateral hippocampal volume were significantly lower in patients than controls. Significant positive correlation was found between DA and ridge count of b-c with bilateral anterior hippocampal volume. Study demonstrates the utility of dermatoglyphic markers in identifying structural changes in the brain which may form the basis for neurodevelopmental pathogenesis in schizophrenia. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  4. Global white matter microstructural abnormalities associated with addiction liability score in drug naïve youth.

    PubMed

    Hulvershorn, Leslie; Hummer, Tom; Wu, Yu-Chien; Tarter, Ralph; Rea, Parker; Anand, Amit; Andrew Chambers, R; Finn, Peter

    2017-03-07

    Abnormalities in brain white matter (WM) structure have been reported in youths having a family history of substance use disorders (SUDs). It was hypothesized that these abnormalities constitute features of the liability for SUDs transmitted across generations. The association between severity of intergenerational risk for SUD, measured by the Transmissible Liability Index (TLI), and white matter microstructure was examined. Diffusion tensor imaging (DTI) measured WM microstructure in forty-four drug-naïve 10-14 year-olds (N = 19 with parental SUD). Metrics of WM microstructure (i.e., fractional anisotropy, radial diffusivity, mean diffusivity and axial diffusivity) were quantified across the whole brain and in four tracts of interest: anterior corona radiata, superior and inferior longitudinal fasciculi and superior fronto-occipital fasciculi. The TLI was completed by the youths, their parents and, when available, their teachers. The relationship between WM structure and TLI score across the entire group was evaluated using linear multiple regression and between group comparisons were also examined. Fractional anisotropy and radial diffusivity in multiple tracts across the brain were significantly associated with TLI scores. Confirming and extending prior research, the findings indicate that global atypicality in WM tracts was linearly related to liability for eventual SUD development in drug naïve youths.

  5. Mental models or methodological artefacts? Adults' 'naïve' responses to a test of children's conceptions of the earth.

    PubMed

    Nobes, Gavin; Panagiotaki, Georgia

    2009-05-01

    Vosniadou and Brewer (1992) claim that children's drawings and answers to questions show that they have naive, theory-like 'mental models' of the earth; for example, they believe it to be flat, or hollow with people inside. However, recent studies that have used different methods have found little or no evidence of these misconceptions. The contrasting accounts, and possible reasons for the inconsistent findings, were tested by giving adults (N = 484) either the original task (designed for 5-year olds) or a new version in which the same drawing instructions and questions were rephrased and clarified. Many adults' responses to the original version were identical to children's 'naïve' drawings and answers. The new version elicited substantially fewer non-scientific responses. These findings indicate that even adults find the original instructions and questions ambiguous and confusing, and that this is the principal reason for their non-scientific drawings and answers. Since children must find the task even more confusing than adults, this explanation very probably applies to many of their non-scientific responses, too, and therefore accounts for the discrepant findings of previous research. 'Naïve' responses result largely from misinterpretation of Vosniadou and Brewer's apparently simple task, rather than from mental models of the earth.

  6. VE-Cadherin Disassembly and Cell Contractility in the Endothelium are Necessary for Barrier Disruption Induced by Tumor Cells

    PubMed Central

    Aragon-Sanabria, Virginia; Pohler, Steven E.; Eswar, Vikram J.; Bierowski, Matthew; Gomez, Esther W.; Dong, Cheng

    2017-01-01

    During metastasis, breakdown of the endothelial barrier is critical for tumor cell extravasation through blood vessel walls and is mediated by a combination of tumor secreted soluble factors and receptor-ligand interactions. However, a complete mechanism governing tumor cell transendothelial migration remains unclear. Here, we investigate the roles of tumor-associated signals in regulating endothelial cell contractility and adherens junction disassembly leading to endothelial barrier breakdown. We show that Src mediates VE-cadherin disassembly in response to metastatic melanoma cells. Through the use of pharmacological inhibitors of cytoskeletal contractility we find that endothelial cell contractility is responsive to interactions with metastatic cancer cells and that reducing endothelial cell contractility abrogates migration of melanoma cells across endothelial monolayers. Furthermore, we find that a combination of tumor secreted soluble factors and receptor-ligand interactions mediate activation of Src within endothelial cells that is necessary for phosphorylation of VE-cadherin and for breakdown of the endothelial barrier. Together, these results provide insight into how tumor cell signals act in concert to modulate cytoskeletal contractility and adherens junctions disassembly during extravasation and may aid in identification of therapeutic targets to block metastasis. PMID:28393886

  7. Altered fronto-cerebellar connectivity in alcohol-naïve youth with a family history of alcoholism

    PubMed Central

    Herting, Megan M.; Fair, Damien; Nagel, Bonnie J.

    2011-01-01

    Fronto-cerebellar connections are thought to be involved in higher-order cognitive functioning. It is suspected that damage to this network may contribute to cognitive deficits in chronic alcoholics. However, it remains to be elucidated if fronto-cerebellar circuitry is altered in high-risk individuals even prior to alcohol use onset. The current study used functional connectivity MRI (fcMRI) to examine fronto-cerebellar circuitry in 13 alcohol-naïve, at-risk youth with a family history of alcoholism (FH+) and 14 age-matched controls. In addition, we examined how white matter microstructure, as evidenced by fractional anisotropy (FA) related to fcMRI. FH+ youth showed significantly reduced functional connectivity between bilateral anterior prefrontal cortices and contralateral cerebellar seed regions compared to controls. We found that this reduction in connectivity significantly correlated with reduced FA in the anterior limb of the internal capsule and the superior longitudinal fasciculus. Taken together, our findings reflect associated aberrant functional and structural connectivity in substance-naïve FH+ adolescents, perhaps suggesting an identifiable neurophenotypic precursor to substance use. Given the role of frontal and cerebellar brain regions in subserving executive functioning, the presence of premorbid abnormalities in fronto-cerebellar circuitry may heighten the risk for developing an alcohol use disorder in FH+ youth through atypical control processing. PMID:20970506

  8. Motor deficits and schizophrenia: the evidence from neuroleptic-naïve patients and populations at risk.

    PubMed Central

    Wolff, A L; O'Driscoll, G A

    1999-01-01

    Patients with schizophrenia and high-risk populations have elevated rates of eye movement abnormalities. However, it is not known whether these abnormalities are specific to eye movements or whether they are also found in more traditional domains of motor control. Most studies examining the motor function of patients with schizophrenia have involved patients treated with medication; abnormalities in motor function could be a result of treatment rather than the disease itself. If motor abnormalities are related to schizophrenia, they should also be found in neuroleptic-naïve patients and possibly in high-risk populations in whom eye movement abnormalities are also observed. We reviewed relevant empirical papers published in the last 35 years. Results suggest that approximately one-fifth of neuroleptic-naïve patients with schizophrenia have increased rates of parkinsonism and neurological soft signs. In high-risk populations, replicated findings include delayed motor development in preschizophrenia subjects, and poor motor skills in the offspring of patients with schizophrenia. In first-degree relatives, increased rates of neurological soft signs were reported. These findings suggest that motor abnormalities are not limited to eye movements and may constitute markers of vulnerability. The literature has several weaknesses that should be addressed in future studies. PMID:10516797

  9. eNOS-derived nitric oxide regulates endothelial barrier function through VE-cadherin and Rho GTPases

    PubMed Central

    Di Lorenzo, Annarita; Lin, Michelle I.; Murata, Takahisa; Landskroner-Eiger, Shira; Schleicher, Michael; Kothiya, Milankumar; Iwakiri, Yasuko; Yu, Jun; Huang, Paul L.; Sessa, William C.

    2013-01-01

    Summary Transient disruption of endothelial adherens junctions and cytoskeletal remodeling are responsible for increases in vascular permeability induced by inflammatory stimuli and vascular endothelial growth factor (VEGF). Nitric oxide (NO) produced by endothelial NO synthase (eNOS) is crucial for VEGF-induced changes in permeability in vivo; however, the molecular mechanism by which endogenous NO modulates endothelial permeability is not clear. Here, we show that the lack of eNOS reduces VEGF-induced permeability, an effect mediated by enhanced activation of the Rac GTPase and stabilization of cortical actin. The loss of NO increased the recruitment of the Rac guanine-nucleotide-exchange factor (GEF) TIAM1 to adherens junctions and VE-cadherin (also known as cadherin 5), and reduced Rho activation and stress fiber formation. In addition, NO deficiency reduced VEGF-induced VE-cadherin phosphorylation and impaired the localization, but not the activation, of c-Src to cell junctions. The physiological role of eNOS activation is clear given that VEGF-, histamine- and inflammation-induced vascular permeability is reduced in mice bearing a non-phosphorylatable knock-in mutation of the key eNOS phosphorylation site S1176. Thus, NO is crucial for Rho GTPase-dependent regulation of cytoskeletal architecture leading to reversible changes in vascular permeability. PMID:24046447

  10. Characterizing the V1 layer in the Venus ionosphere using VeRa observations from Venus Express

    NASA Astrophysics Data System (ADS)

    Girazian, Z.; Withers, P.; Fallows, K.; Tarrh, A.; Paetzold, M.; Tellmann, S.; Haesler, B.

    2013-12-01

    The Venus Radio Science Experiment (VeRa) on the Venus Express spacecraft sounds the Venus atmosphere during Earth occultations to obtain vertical profiles of electron density in the ionosphere. The resultant profiles reveal the vertical structure of the Venus ionosphere from the topside down to below the lower layers (< 115 km). On the dayside, the dominant plasma layer is the V2 layer at ~142 km, which is produced primarily by photoionization of CO2. Embedded on the bottomside of the V2 layer is the less prominent, and much less studied, V1 layer at ~127 km. The V1 layer is also produced by photoionization of CO2, but secondary ionization due to energetic photoelectrons is much more important. Here we investigate properties of the V1 layer using VeRa profiles from 2006 to 2012 during which the Sun went from the deep solar minimum of Solar Cycle 23 to the rising solar activity levels of Solar Cycle 24. We investigate how the peak electron density and peak altitude of the V1 layer depend on solar zenith angle. We also characterize the shapes of the V1 layer and show how they are related to the solar activity level. Solar spectra from the Solar EUV Experiment (SEE) on the Thermosphere Ionosphere Mesosphere Energetics and Dynamics (TIMED) spacecraft are used to characterize the shapes of the V1 layer with solar activity.

  11. Case report of prenatal diagnosis of Stüve-Wiedemann Syndrome in a woman with another child affected too

    PubMed Central

    Catavorello, Anita; Vitale, Salvatore Giovanni; Rossetti, Diego; Caldaci, Lisa; Panella, Marco Marzio

    2013-01-01

    Summary Objective Stüve-Wiedemann Syndrome (SWS; MIM 601 559) is an autosomal-recessive syndrome characterized by myotonia with mask-like face, skeletal dysplasia and intrauterine growth restriction. Other clinical findings are pursed mouth, hypoplastic midface, congenital contractures and muscular hypotonia. We discuss about the importance of prenatal diagnosis in SWS and the possibility of survival after the first year of life in patients suffering from this disease. Methods we report a case of Stüve-Wiedemann Syndrome detected by morphological examination in our Operative Unit. Prenatal presumptive diagnosis was given with two-dimensional and 3-D probe, during the second trimester of pregnancy. Caesarean section was performed at 38th week of gestation. Then diagnosis was genetically performed. Results at birth, clinical examination was concordant with the ultrasound findings. Genetic analysis also confirmed the presumptive diagnosis. Episodes of respiratory distress and hyperthermia decreased until it disappeared altogether at 1 year of age. Conclusion we underline the usefulness of ultrasound study of fetal skeleton in the prenatal diagnosis. It allowed us to do an early detection of birth defects and their appropriate management. PMID:24175015

  12. Different genome stability proteins underpin primed and naïve adaptation in E. coli CRISPR-Cas immunity

    PubMed Central

    Ivančić-Baće, Ivana; Cass, Simon D; Wearne, Stephen J; Bolt, Edward L

    2015-01-01

    CRISPR-Cas is a prokaryotic immune system built from capture and integration of invader DNA into CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) loci, termed ‘Adaptation’, which is dependent on Cas1 and Cas2 proteins. In Escherichia coli, Cascade-Cas3 degrades invader DNA to effect immunity, termed ‘Interference’. Adaptation can interact with interference (‘primed’), or is independent of it (‘naïve’). We demonstrate that primed adaptation requires the RecG helicase and PriA protein to be present. Genetic analysis of mutant phenotypes suggests that RecG is needed to dissipate R-loops at blocked replication forks. Additionally, we identify that DNA polymerase I is important for both primed and naive adaptation, and that RecB is needed for naïve adaptation. Purified Cas1-Cas2 protein shows specificity for binding to and nicking forked DNA within single strand gaps, and collapsing forks into DNA duplexes. The data suggest that different genome stability systems interact with primed or naïve adaptation when responding to blocked or collapsed invader DNA replication. In this model, RecG and Cas3 proteins respond to invader DNA replication forks that are blocked by Cascade interference, enabling DNA capture. RecBCD targets DNA ends at collapsed forks, enabling DNA capture without interference. DNA polymerase I is proposed to fill DNA gaps during spacer integration. PMID:26578567

  13. Isolation of an ES-Derived Cardiovascular Multipotent Cell Population Based on VE-Cadherin Promoter Activity

    PubMed Central

    Maltabe, Violetta A.; Barka, Eleonora; Kontonika, Marianthi; Florou, Dimitra; Kouvara-Pritsouli, Maria; Roumpi, Maria; Agathopoulos, Simeon; Kolettis, Theofilos M.

    2016-01-01

    Embryonic Stem (ES) or induced Pluripotent Stem (iPS) cells are important sources for cardiomyocyte generation, targeted for regenerative therapies. Several in vitro protocols are currently utilized for their differentiation, but the value of cell-based approaches remains unclear. Here, we characterized a cardiovascular progenitor population derived during ES differentiation, after selection based on VE-cadherin promoter (Pvec) activity. ESCs were genetically modified with an episomal vector, allowing the expression of puromycin resistance gene, under Pvec activity. Puromycin-surviving cells displayed cardiac and endothelial progenitor cells characteristics. Expansion and self-renewal of this cardiac and endothelial dual-progenitor population (CEDP) were achieved by Wnt/β-catenin pathway activation. CEDPs express early cardiac developmental stage-specific markers but not markers of differentiated cardiomyocytes. Similarly, CEDPs express endothelial markers. However, CEDPs can undergo differentiation predominantly to cTnT+ (~47%) and VE-cadherin+ (~28%) cells. Transplantation of CEDPs in the left heart ventricle of adult rats showed that CEDPs-derived cells survive and differentiate in vivo for at least 14 days after transplantation. A novel, dual-progenitor population was isolated during ESCs differentiation, based on Pvec activity. This lineage can self-renew, permitting its maintenance as a source of cardiovascular progenitor cells and constitutes a useful source for regenerative approaches. PMID:28101109

  14. Phylogenetic analysis of HIV-1 subtypes and drug resistance profile among treatment-naïve people in Kuwait.

    PubMed

    Chehadeh, Wassim; Albaksami, Osama; Altawalah, Haya; Ahmad, Suhail; Madi, Nada; John, Sonia E; Abraham, Priya S; Al-Nakib, Widad

    2015-09-01

    Mutations associated with resistance to antiretroviral therapy are a major cause of failure to treatment, and surveillance for the emergence of HIV resistance became a component of all antiretroviral treatment programs. As transmission of resistant viruses to newly infected persons is possible, we aimed to determine the prevalence of primary mutations associated with antiretroviral resistance among treatment-naïve patients, with respect to HIV subtype. Viral RNA was extracted from plasma samples of 43 treatment-naïve patients. Protease (PR) and reverse transcriptase (RT) regions were amplified and sequenced using the TRUGENE HIV-1 Genotyping Assay. A phylogenetic analysis was performed for HIV subtype assignment. Complete sequence information could be obtained for 35 patients. A total of ten different HIV-1 subtypes and recombinant forms were found in Kuwait with predominance of subtypes B, C, and CRF01_AE. A62V and A98G were non-polymorphic resistance-associated mutations (RAMs) detected in the RT region of two and three patients, respectively. Non-polymorphic mutations associated with resistance to protease inhibitors were not detected. Our results support continuous surveillance of RAMs in newly infected individuals to assess the effectiveness of first-line antiretroviral regimen available in Kuwait.

  15. Elevated levels of Insulin-like Growth Factor-1 (IGF-1) in drug-naïve patients with psychosis.

    PubMed

    Petrikis, Petros; Boumba, Vassiliki A; Tzallas, Alexandros T; Voulgari, Paraskevi V; Archimandriti, Dimitra T; Skapinakis, Petros; Mavreas, Venetsanos

    2016-12-30

    Insulin-like growth factor 1 (IGF-1) plays an important role in neurogenesis and synaptogenesis and may be implicated in schizophrenia, although data so far have been inconclusive. The aim of our study was to compare levels of IGF-1 in drug-naïve patients with a first episode of schizophrenia and related disorders with matched healthy controls. Forty drug naïve first-episode patients with schizophrenia and related disorders and forty healthy subjects matched for age, gender, body mass index (BMI) and smoking status were enrolled in the study. Serum levels of IGF-1 for each sample were measured in duplicate by the enzyme-linked immunosorbent assay (ELISA) method using human IGF-1. The median IGF-1 levels were significantly higher in drug-naive patients with psychosis compared to healthy controls (109.66ng/ml vs. 86.96ng/ml, respectively p=0.039). Multiple regression analysis revealed that differences in serum IGF-1 values were independent of glucose metabolism (fasting glucose, fasting insulin, insulin resistance) and cortisol. These results show that IGF-1 may be implicated in the pathophysiology of psychosis but confirmation is needed from other studies.

  16. Behavioural responses to photographs by pictorially naïve baboons (Papio anubis), gorillas (Gorilla gorilla) and chimpanzees (Pan troglodytes).

    PubMed

    Parron, Carole; Call, Josep; Fagot, Joël

    2008-07-01

    This study assessed how pictorially naïve nonhuman primates understand pictures. Fifty-five baboons with no prior exposure to pictures were trained to grasp a slice of banana presented against a pebble in a two alternative forced choice task. Post-training testing involved three stimulus pairs: (1) real banana slice vs. its picture, (2) the banana picture vs. a real pebble and (3) banana picture vs. a pebble picture which were presented twice. Preliminary data were also collected on naïve gorillas (n=4) and chimpanzees (n=7) using the same procedure. Baboons revealed a preference for the food picture in (2) and (3) and often ate this stimulus, but the food item and its picture were accurately discriminated in (1). These results suggest that baboons mistook the pictorial stimulus and its referent, but processed the banana pictures as poor exemplars of the real banana category. Among apes, only gorillas ate the banana pictures, suggesting that picture-object confusion may also occur in this species. Findings are discussed as pertaining to the general issue of representational abilities in nonhuman primates, and its evolution.

  17. HIV DNA and Dementia in Treatment-Naïve HIV-1-Infected Individuals in Bangkok, Thailand

    PubMed Central

    Shiramizu, Bruce; Ratto-Kim, Silvia; Sithinamsuwan, Pasiri; Nidhinandana, Samart; Thitivichianlert, Sataporn; Watt, George; deSouza, Mark; Chuenchitra, Thippawan; Sukwit, Suchitra; Chitpatima, Suwicha; Robertson, Kevin; Paul, Robert; Shikuma, Cecilia; Valcour, Victor

    2007-01-01

    High HIV-1 DNA (HIV DNA) levels in peripheral blood mononuclear cells (PBMC) correlate with HIV-1-associated dementia (HAD) in patients on highly active antiretroviral therapy (HAART). If this relationship also exists among HAART-naïve patients, then HIV DNA may be implicated in the pathogenesis of HAD. In this study, we evaluated the relationship between HIV DNA and cognition in subjects naïve to HAART in a neuro AIDS cohort in Bangkok, Thailand. Subjects with and without HAD were recruited and matched for age, gender, education, and CD4 cell count. PBMC and cellular subsets were analyzed for HIV DNA using real-time PCR. The median log10 HIV DNA copies per 106 PBMC for subjects with HAD (n=15) was 4.27, which was higher than that found in subjects without dementia (ND; n=15), 2.28, p<0.001. This finding was unchanged in a multivariate model adjusting for plasma HIV-1 RNA levels. From a small subset of individuals, in which adequate number of cells were available, more HIV DNA was in monocytes/macrophages from those with HAD compared to those with ND. These results are consistent with a previous report among HAART-experienced subjects, thus further implicating HIV DNA in the pathogenesis of HAD. PMID:17211496

  18. Dynamic features of animate motion activate septal and preoptic areas in visually naïve chicks (Gallus gallus).

    PubMed

    Lorenzi, Elena; Mayer, Uwe; Rosa-Salva, Orsola; Vallortigara, Giorgio

    2017-06-23

    The septum is an evolutionarily well-conserved part of the limbic system. It is known to be involved in many aspects of social behavior and is considered a key node of the social behavior network, together with the preoptic area. Involvement of these two brain regions has been recently observed in newly hatched chicks exposed to the natural motion of a living conspecific. However, it is unknown whether these areas respond also to simple motion cues that elicit animacy perception in humans and social predispositions in chicks. For example, naïve chicks are attracted by visual objects that appear to spontaneously change their speed (an index of self-propulsion, typical of animate creatures). Here we show that the right septum and the preoptic area of newly hatched visually naïve chicks exposed to speed changes have higher neuronal activity (revealed by c-Fos expression), compared with that of chicks exposed to constant motion. We thus found an involvement of these two areas in the perception of motion cues associated with animacy in newly hatched chicks without any previous visual experience. This demonstrates their early involvement in processing simple motion cues that allow the detection of animate creatures and elicit social predispositions in this animal model, as well as preferential attention in human infants and the perception of animacy in human adults. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

  19. Hypoxia-induced expression of VE-cadherin and Filamin B in gliomacell cultures and pseudopalisade structures

    PubMed Central

    Nissou, Marie-France; Elatifi, Michèle; Guttin, Audrey; Godfraind, Catherine; Salon, Caroline; Garcion, Emmanuel; Van Der Sanden, Boudewijn; Issartel, Jean-Paul; Berger, François; Wion, Didier

    2013-01-01

    Most of our knowledge regarding glioma cell biology comes from cell culture experiments. For many years the standards for glioma cell culture were the use of cell lines cultured in the presence of serum and 20% O2. However, in vivo, normoxia in many brain areas is in close to 3% O2. Hence, in cell culture, the experimental value referred as the norm is hyperoxic compared to any brain physiological value. Likewise, cells in vivo are not usually exposed to serum, and low-passaged gliomaneurosphere cultures maintained in serum-free medium is emerging as a new standard. A consequence of changing the experimental normoxic standard from 20% O2 to the more brain physiological value of 3% O2, is that a 3% O2 normoxic reference point enabled a more rigorous characterization of the level of regulation of genes by hypoxia. Among the glioma hypoxia-regulated genes characterized using this approach we found VE-cadherin that is required for blood vessel formation, and Filamin B a gene involved in endothelial cell motility. Both VE-Cadherin and Filamin B were found expressed in pseudopalisades, a glioblastoma pathognomonic structure made of hypoxic migrating cancer cells. These results provide additional clues on the role played by hypoxia in the acquisition of endothelial traits by glioma cells and on the functional links existing between pseudopalisades, hypoxia, and tumor progression. PMID:23543272

  20. Retinol and ascorbate drive erasure of epigenetic memory and enhance reprogramming to naïve pluripotency by complementary mechanisms

    PubMed Central

    von Meyenn, Ferdinand; Ravichandran, Mirunalini; Ficz, Gabriella; Oxley, David; Santos, Fátima; Balasubramanian, Shankar; Jurkowski, Tomasz P.; Reik, Wolf

    2016-01-01

    Epigenetic memory, in particular DNA methylation, is established during development in differentiating cells and must be erased to create naïve (induced) pluripotent stem cells. The ten-eleven translocation (TET) enzymes can catalyze the oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and further oxidized derivatives, thereby actively removing this memory. Nevertheless, the mechanism by which the TET enzymes are regulated, and the extent to which they can be manipulated, are poorly understood. Here we report that retinoic acid (RA) or retinol (vitamin A) and ascorbate (vitamin C) act as modulators of TET levels and activity. RA or retinol enhances 5hmC production in naïve embryonic stem cells by activation of TET2 and TET3 transcription, whereas ascorbate potentiates TET activity and 5hmC production through enhanced Fe2+ recycling, and not as a cofactor as reported previously. We find that both ascorbate and RA or retinol promote the derivation of induced pluripotent stem cells synergistically and enhance the erasure of epigenetic memory. This mechanistic insight has significance for the development of cell treatments for regenenerative medicine, and enhances our understanding of how intrinsic and extrinsic signals shape the epigenome. PMID:27729528

  1. Altered fronto-cerebellar connectivity in alcohol-naïve youth with a family history of alcoholism.

    PubMed

    Herting, Megan M; Fair, Damien; Nagel, Bonnie J

    2011-02-14

    Fronto-cerebellar connections are thought to be involved in higher-order cognitive functioning. It is suspected that damage to this network may contribute to cognitive deficits in chronic alcoholics. However, it remains to be elucidated if fronto-cerebellar circuitry is altered in high-risk individuals even prior to alcohol use onset. The current study used functional connectivity MRI (fcMRI) to examine fronto-cerebellar circuitry in 13 alcohol-naïve, at-risk youth with a family history of alcoholism (FH+) and 14 age-matched controls. In addition, we examined how white matter microstructure, as evidenced by fractional anisotropy (FA), related to fcMRI. FH+youth showed significantly reduced functional connectivity between bilateral anterior prefrontal cortices and contralateral cerebellar seed regions compared to controls. We found that this reduction in connectivity significantly correlated with reduced FA in the anterior limb of the internal capsule and the superior longitudinal fasciculus. Taken together, our findings reflect associated aberrant functional and structural connectivity in substance-naïve FH+adolescents, perhaps suggesting an identifiable neurophenotypic precursor to substance use. Given the role of frontal and cerebellar brain regions in subserving executive functioning, the presence of premorbid abnormalities in fronto-cerebellar circuitry may heighten the risk for developing an alcohol use disorder in FH+youth through atypical control processing.

  2. VE-Cadherin Disassembly and Cell Contractility in the Endothelium are Necessary for Barrier Disruption Induced by Tumor Cells.

    PubMed

    Aragon-Sanabria, Virginia; Pohler, Steven E; Eswar, Vikram J; Bierowski, Matthew; Gomez, Esther W; Dong, Cheng

    2017-04-10

    During metastasis, breakdown of the endothelial barrier is critical for tumor cell extravasation through blood vessel walls and is mediated by a combination of tumor secreted soluble factors and receptor-ligand interactions. However, a complete mechanism governing tumor cell transendothelial migration remains unclear. Here, we investigate the roles of tumor-associated signals in regulating endothelial cell contractility and adherens junction disassembly leading to endothelial barrier breakdown. We show that Src mediates VE-cadherin disassembly in response to metastatic melanoma cells. Through the use of pharmacological inhibitors of cytoskeletal contractility we find that endothelial cell contractility is responsive to interactions with metastatic cancer cells and that reducing endothelial cell contractility abrogates migration of melanoma cells across endothelial monolayers. Furthermore, we find that a combination of tumor secreted soluble factors and receptor-ligand interactions mediate activation of Src within endothelial cells that is necessary for phosphorylation of VE-cadherin and for breakdown of the endothelial barrier. Together, these results provide insight into how tumor cell signals act in concert to modulate cytoskeletal contractility and adherens junctions disassembly during extravasation and may aid in identification of therapeutic targets to block metastasis.

  3. Amino acid consumption in naïve and recombinant CHO cell cultures: producers of a monoclonal antibody.

    PubMed

    Carrillo-Cocom, L M; Genel-Rey, T; Araíz-Hernández, D; López-Pacheco, F; López-Meza, J; Rocha-Pizaña, M R; Ramírez-Medrano, A; Alvarez, M M

    2015-10-01

    Most commercial media for mammalian cell culture are designed to satisfy the amino acid requirements for cell growth, but not necessarily those for recombinant protein production. In this study, we analyze the amino acid consumption pattern in naïve and recombinant Chinese hamster ovary (CHO) cell cultures. The recombinant model we chose was a CHO-S cell line engineered to produce a monoclonal antibody. We report the cell concentration, product concentration, and amino acid concentration profiles in naïve and recombinant cell cultures growing in CD OptiCHO™ medium with or without amino acid supplementation with a commercial supplement (CHO CD EfficientFeed™ B). We quantify and discuss the amino acid demands due to cell growth and recombinant protein production during long term fed batch cultivation protocols. We confirmed that a group of five amino acids, constituting the highest mass fraction of the product, shows the highest depletion rates and could become limiting for product expression. In our experiments, alanine, a non-important mass constituent of the product, is in high demand during recombinant protein production. Evaluation of specific amino acid demands could be of great help in the design of feeding/supplementation strategies for recombinant mammalian cell cultures.

  4. Design and construction of a new human naïve single-chain fragment variable antibody library, IORISS1.

    PubMed

    Pasello, Michela; Zamboni, Silvia; Mallano, Alessandra; Flego, Michela; Picci, Piero; Cianfriglia, Maurizio; Scotlandi, Katia

    2016-04-20

    Human monoclonal antibodies are a powerful tool with increasingly successful exploitations and the single chain fragment variable format can be considered the building block for the implementation of more complex and effective antibody-based constructs. Phage display is one of the best and most efficient methods to isolate human antibodies selected from an efficient and variable phage display library. We report a method for the construction of a human naïve single-chain variable fragment library, termed IORISS1. Many different sets of oligonucleotide primers as well as optimized electroporation and ligation reactions were used to generate this library of 1.2×10(9) individual clones. The key difference is the diversity of variable gene templates, which was derived from only 15 non-immunized human donors. The method described here, was used to make a new human naïve single-chain fragment variable phage display library that represents a valuable source of diverse antibodies that can be used as research reagents or as a starting point for the development of therapeutics. Using biopanning, we determined the ability of IORISS1 to yield antibodies. The results we obtained suggest that, by using an optimized protocol, an efficient phage antibody library can be generated. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. Differential Associations between Cortical Thickness and Striatal Dopamine in Treatment-Naïve Adults with ADHD vs. Healthy Controls.

    PubMed

    Cherkasova, Mariya V; Faridi, Nazlie; Casey, Kevin F; Larcher, Kevin; O'Driscoll, Gillian A; Hechtman, Lily; Joober, Ridha; Baker, Glen B; Palmer, Jennifer; Evans, Alan C; Dagher, Alain; Benkelfat, Chawki; Leyton, Marco

    2017-01-01

    Alterations in catecholamine signaling and cortical morphology have both been implicated in the pathophysiology of attention deficit/hyperactivity disorder (ADHD). However, possible links between the two remain unstudied. Here, we report exploratory analyses of cortical thickness and its relation to striatal dopamine transmission in treatment-naïve adults with ADHD and matched healthy controls. All participants had one magnetic resonance imaging (MRI) and two [(11)C]raclopride positron emission tomography scans. Associations between frontal cortical thickness and the magnitude of d-amphetamine-induced [(11)C]raclopride binding changes were observed that were divergent in the two groups. In the healthy controls, a thicker cortex was associated with less dopamine release; in the ADHD participants the converse was seen. The same divergence was seen for baseline D2/3 receptor availability. In healthy volunteers, lower D2/3 receptor availability was associated with a thicker cortex, while in the ADHD group lower baseline D2/3 receptor availability was associated with a thinner cortex. Individual differences in cortical thickness in these regions correlated with ADHD symptom severity. Together, these findings add to the evidence of associations between dopamine transmission and cortical morphology, and suggest that these relationships are altered in treatment-naïve adults with ADHD.

  6. Prediction of drug-induced eosinophilia adverse effect by using SVM and naïve Bayesian approaches.

    PubMed

    Zhang, Hui; Yu, Peng; Xiang, Ming-Li; Li, Xi-Bo; Kong, Wei-Bao; Ma, Jun-Yi; Wang, Jun-Long; Zhang, Jin-Ping; Zhang, Ji

    2016-03-01

    Drug-induced eosinophilia is a potentially life-threatening adverse effect; clinical manifestations, eosinophilia-myalgia syndrome, mainly include severe skin eruption, fever, hematologic abnormalities, and organ system dysfunction. Using experimental methods to evaluate drug-induced eosinophilia is very complicated, time-consuming, and costly in the early stage of drug development. Thus, in this investigation, we established computational prediction models of drug-induced eosinophilia using SVM and naïve Bayesian approaches. For the SVM modeling, the overall prediction accuracy for the training set by means of fivefold cross-validation is 91.6 and for the external test set is 82.9 %. For the naïve Bayesian modeling, the overall prediction accuracy for the training set is 92.5 and for the external test set is 85.4 %. Moreover, some molecular descriptors and substructures considered as important for drug-induced eosinophilia were identified. Thus, we hope the prediction models of drug-induced eosinophilia built in this work should be applied to filter early-stage molecules for potential eosinophilia adverse effect, and the selected molecular descriptors and substructures of toxic compounds should be taken into consideration in the design of new candidate drugs to help medicinal chemists rationally select the chemicals with the best prospects to be effective and safe.

  7. Cardiopulmonary Exercise Testing in Patients with Chronic Heart Failure: Prognostic Comparison from Peak VO2 and VE/VCO2 Slope

    PubMed Central

    Sarullo, Filippo Maria; Fazio, Giovanni; Brusca, Ignazio; Fasullo, Sergio; Paterna, Salvatore; Licata, Pamela; Novo, Giuseppina; Novo, Salvatore; Di Pasquale, Pietro

    2010-01-01

    Background: Cardiopulmonary exercise testing with ventilatory expired gas analysis (CPET) has proven to be a valuable tool for assessing patients with chronic heart failure (CHF). The maximal oxygen uptake (peak V02) is used in risk stratification of patients with CHF. The minute ventilation-carbon dioxide production relationship (VE/VCO2 slope) has recently demonstrated prognostic significance in patients with CHF. Methods: Between January 2006 and December 2007 we performed CPET in 184 pts (146 M, 38 F, mean age 59.8 ± 12.9 years), with stable CHF (96 coronary artery disease, 88 dilated cardiomyopathy), in NYHA functional class II (n.107) - III (n.77), with left ventricular ejection fraction (LVEF) ≤ 45%,. The ability of peak VO2 and VE/VCO2 slope to predict cardiac related mortality and cardiac related hospitalization within 12 months after evaluation was examined. Results: Peak VO2 and VE/VCO2 slope were demonstrated with univariate Cox regression analysis both to be significant predictor of cardiac-related mortality and hospitalization (p < 0.0001, respectively). Non survivors had a lower peak VO2 (10.49 ± 1.70 ml/kg/min vs. 14.41 ± 3.02 ml/kg/min, p < 0.0001), and steeper Ve/VCO2 slope (41.80 ± 8.07 vs. 29.84 ± 6.47, p < 0.0001) than survivors. Multivariate survival analysis revealed that VE/VCO2 slope added additional value to VO2 peak as an independent prognostic factor (χ2: 56.48, relative risk: 1.08, 95% CI: 1.03 – 1.13, p = 0.001). The results from Kaplan-Meier analysis revealed a 1-year cardiac-related mortality of 75% in patients with VE/VCO2 slope ≥ 35.6 and 25% in those with VE/VCO2 slope < 35.6 (log rank χ2: 67.03, p < 0.0001) and 66% in patients with peak VO2 ≤ 12.2 ml/kg/min and 34% in those with peak VO2 > 12.2 ml/kg/min (log rank χ2: 50.98, p < 0.0001). One-year cardiac-related hospitalization was 77% in patients with VE/VCO2 slope ≥ 32.5 and 23% in those with VE/VCO2 slope < 32.5 (log rank χ2: 133.80, p < 0.0001) and 63% in

  8. Cardiopulmonary Exercise Testing in Patients with Chronic Heart Failure: Prognostic Comparison from Peak VO2 and VE/VCO2 Slope.

    PubMed

    Sarullo, Filippo Maria; Fazio, Giovanni; Brusca, Ignazio; Fasullo, Sergio; Paterna, Salvatore; Licata, Pamela; Novo, Giuseppina; Novo, Salvatore; Di Pasquale, Pietro

    2010-05-26

    Cardiopulmonary exercise testing with ventilatory expired gas analysis (CPET) has proven to be a valuable tool for assessing patients with chronic heart failure (CHF). The maximal oxygen uptake (peak V02) is used in risk stratification of patients with CHF. The minute ventilation-carbon dioxide production relationship (VE/VCO2 slope) has recently demonstrated prognostic significance in patients with CHF. Between January 2006 and December 2007 we performed CPET in 184 pts (146 M, 38 F, mean age 59.8 +/- 12.9 years), with stable CHF (96 coronary artery disease, 88 dilated cardiomyopathy), in NYHA functional class II (n.107) - III (n.77), with left ventricular ejection fraction (LVEF) VE/VCO2 slope to predict cardiac related mortality and cardiac related hospitalization within 12 months after evaluation was examined. Peak VO2 and VE/VCO2 slope were demonstrated with univariate Cox regression analysis both to be significant predictor of cardiac-related mortality and hospitalization (p < 0.0001, respectively). Non survivors had a lower peak VO2 (10.49 +/- 1.70 ml/kg/min vs. 14.41 +/- 3.02 ml/kg/min, p < 0.0001), and steeper Ve/VCO2 slope (41.80 +/- 8.07 vs. 29.84 +/- 6.47, p < 0.0001) than survivors. Multivariate survival analysis revealed that VE/VCO2 slope added additional value to VO2 peak as an independent prognostic factor (chi2: 56.48, relative risk: 1.08, 95% CI: 1.03 - 1.13, p = 0.001). The results from Kaplan-Meier analysis revealed a 1-year cardiac-related mortality of 75% in patients with VE/VCO2 slope >/= 35.6 and 25% in those with VE/VCO2 slope < 35.6 (log rank chi2: 67.03, p < 0.0001) and 66% in patients with peak VO2 12.2 ml/kg/min (log rank chi2: 50.98, p < 0.0001). One-year cardiac-related hospitalization was 77% in patients with VE/VCO2 slope >/= 32.5 and 23% in those with VE/VCO2 slope < 32.5 (log rank chi2: 133.80, p < 0.0001) and 63% in patients with peak VO2

  9. Clinical and Hemodynamic Correlates and Prognostic Value of VE/VCO2 Slope in Patients With Heart Failure With Preserved Ejection Fraction and Pulmonary Hypertension.

    PubMed

    Klaassen, Sebastiaan H C; Liu, Licette C Y; Hummel, Yoran M; Damman, Kevin; van der Meer, Peter; Voors, Adriaan A; Hoendermis, Elke S; van Veldhuisen, Dirk J

    2017-07-20

    Impaired exercise capacity is one of the hallmarks of heart failure with preserved ejection fraction (HFpEF), but the clinical and hemodynamic correlates and prognostic value of exercise testing in patients with HFpEF is unknown. Patients with HFpEF (left ventricular ejection fraction [LVEF] ≥45%) and pulmonary hypertension underwent cardiopulmonary exercise test (CPX) to measure maximal (peak VO2) and submaximal (ventilatory equivalent for carbon dioxide [VE/VCO2] slope) exercise capacity. In addition, right heart catheterization was performed. Patients were grouped in tertiles based on the VE/VCO2 slope. Univariate and multivariate regression analyses were performed. A Cox regression analysis was performed to determine the mortality during follow-up. We studied 88 patients: mean age 73 ± 9 years, 67% female, mean LVEF 58%, median N-terminal pro-B-type natriuretic peptide (NT-proBNP) 840 (interquartile range 411-1938) ng/L. Patients in the highest VE/VCO2 tertile had the most severe HF, as reflected in higher New York Heart Association functional class and higher NT-proBNP plasma levels (all P < .05 for trend), whereas LVEF was similar between the groups. Multivariable regression analysis with backward elimination on invasive hemodynamic measurements showed that VE/VCO2 slope was independently associated with pulmonary vascular resistance (PVR). Cox regression analysis showed that increased VE/VCO2 slope (but not peak VO2) was independently associated with increased mortality. Increased VE/VCO2 slope was associated with more severe disease and higher PVR and was independently associated with increased mortality in patients with HFpEF. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Abnormal cortical sources of resting state electroencephalographic rhythms in single treatment-naïve HIV individuals: A statistical z-score index.

    PubMed

    Babiloni, Claudio; Pennica, Alfredo; Del Percio, Claudio; Noce, Giuseppe; Cordone, Susanna; Muratori, Chiara; Ferracuti, Stefano; Donato, Nicole; Di Campli, Francesco; Gianserra, Laura; Teti, Elisabetta; Aceti, Antonio; Soricelli, Andrea; Viscione, Magdalena; Limatola, Cristina; Andreoni, Massimo; Onorati, Paolo

    2016-03-01

    This study tested a simple statistical procedure to recognize single treatment-naïve HIV individuals having abnormal cortical sources of resting state delta (<4 Hz) and alpha (8-13 Hz) electroencephalographic (EEG) rhythms with reference to a control group of sex-, age-, and education-matched healthy individuals. Compared to the HIV individuals with a statistically normal EEG marker, those with abnormal values were expected to show worse cognitive status. Resting state eyes-closed EEG data were recorded in 82 treatment-naïve HIV (39.8 ys.±1.2 standard error mean, SE) and 59 age-matched cognitively healthy subjects (39 ys.±2.2 SE). Low-resolution brain electromagnetic tomography (LORETA) estimated delta and alpha sources in frontal, central, temporal, parietal, and occipital cortical regions. Ratio of the activity of parietal delta and high-frequency alpha sources (EEG marker) showed the maximum difference between the healthy and the treatment-naïve HIV group. Z-score of the EEG marker was statistically abnormal in 47.6% of treatment-naïve HIV individuals with reference to the healthy group (p<0.05). Compared to the HIV individuals with a statistically normal EEG marker, those with abnormal values exhibited lower mini mental state evaluation (MMSE) score, higher CD4 count, and lower viral load (p<0.05). This statistical procedure permitted for the first time to identify single treatment-naïve HIV individuals having abnormal EEG activity. This procedure might enrich the detection and monitoring of effects of HIV on brain function in single treatment-naïve HIV individuals. Copyright © 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

  11. CMTM3 (CKLF-Like Marvel Transmembrane Domain 3) Mediates Angiogenesis by Regulating Cell Surface Availability of VE-Cadherin in Endothelial Adherens Junctions.

    PubMed

    Chrifi, Ihsan; Louzao-Martinez, Laura; Brandt, Maarten; van Dijk, Christian G M; Burgisser, Petra; Zhu, Changbin; Kros, Johan M; Duncker, Dirk J; Cheng, Caroline

    2017-06-01

    Decrease in VE-cadherin adherens junctions reduces vascular stability, whereas disruption of adherens junctions is a requirement for neovessel sprouting during angiogenesis. Endocytosis plays a key role in regulating junctional strength by altering bioavailability of cell surface proteins, including VE-cadherin. Identification of new mediators of endothelial endocytosis could enhance our understanding of angiogenesis. Here, we assessed the function of CMTM3 (CKLF-like MARVEL transmembrane domain 3), which we have previously identified as highly expressed in Flk1(+) endothelial progenitor cells during embryonic development. Using a 3-dimensional coculture of human umbilical vein endothelial cells-GFP (green fluorescent protein) and pericytes-RFP (red fluorescent protein), we demonstrated that siRNA-mediated CMTM3 silencing in human umbilical vein endothelial cells impairs angiogenesis. In vivo CMTM3 inhibition by morpholino injection in developing zebrafish larvae confirmed that CMTM3 expression is required for vascular sprouting. CMTM3 knockdown in human umbilical vein endothelial cells does not affect proliferation or migration. Intracellular staining demonstrated that CMTM3 colocalizes with early endosome markers EEA1 (early endosome marker 1) and Clathrin(+) vesicles and with cytosolic VE-cadherin in human umbilical vein endothelial cells. Adenovirus-mediated CMTM3 overexpression enhances endothelial endocytosis, shown by an increase in Clathrin(+), EEA1(+), Rab11(+), Rab5(+), and Rab7(+) vesicles. CMTM3 overexpression enhances, whereas CMTM3 knockdown decreases internalization of cell surface VE-cadherin in vitro. CMTM3 promotes loss of endothelial barrier function in thrombin-induced responses, shown by transendothelial electric resistance measurements in vitro. In this study, we have identified a new regulatory function for CMTM3 in angiogenesis. CMTM3 is involved in VE-cadherin turnover and is a regulator of the cell surface pool of VE-cadherin. Therefore

  12. İhtimaller Hesabına Dayalı İstanbul ve Çevresindeki Deprem Tehlikesi (Seismic hazard assessment of Istanbul and its surroundings)

    USGS Publications Warehouse

    Gulkan, Polat; Kalkan, E.

    2010-01-01

    Bu yazının amacı, İstanbul ve yakın çevresinin maruz olduğu deprem tehlikesine dair 1999 depremlerinden bu yana devam eden tartışmalara bilimsel verilere ve hesaplara dayanan ve mümkün olduğu ölçüde kolay anlaşılır bir açıklama getirmektir. Depremlerin bir bölgede yaratabileceği tehlike, yani yerin sarsılması yüzünden yapılar üzerinde doğacak deprem etkileri, bölgenin deprem riskine, yani o bölgede olabilecek en yüksek deprem büyüklüğüne ve bölgenin zemin durumuna bağlıdır. Bu çalışmada, deprem oluşturma potansiyeline sahip aktif faylar ve son 500 yılda meydana gelmiş depremler ihtimal hesapları kullanılarak ilişkilendirilmiş ve Marmara Bölgesi’nde deprem sonucu doğacak yer hareketi şiddetinin dağılımı haritalanmıştır. Sunulan yeni deprem tehlike haritaları önceki bölgesel tehlike haritaları ile karşılaştırıldığında, Marmara Bölgesi’nde hissedilebilecek yer hareketi şiddetinde, benzer çalışmalara oranla % 10 ila % 15 arası artış görülmektedir.

  13. Temporary Threshold Shifts in Naïve and Experienced Belugas: Can Dampening of the Effects of Fatiguing Sounds Be Learned?

    PubMed

    Popov, Vladimir; Supin, Alexander; Nechaev, Dmitry; Sysueva, Evgenia; Rozhnov, Viatcheslav

    2016-01-01

    In belugas (Delphinapterus leucas), substantial (10-15 dB) differences in temporary threshold shifts (TTSs) were observed between the first and subsequent experimental sessions in the same subjects. In the first session (naïve subject state), the TTSs produced by exposure to fatiguing noises were larger than the TTSs produced in subsequent sessions (experienced subject state). After one to two sessions, the TTSs stabilized. The baseline hearing thresholds did not differ between the naïve and experienced states. One possible explanation for this effect is that the animals learned to dampen their hearing during exposure to fatiguing noises and thus mitigate the impact of those noises.

  14. The Ve-mediated resistance response of the tomato to Verticillium dahliae involves H2O2, peroxidase and lignins and drives PAL gene expression

    PubMed Central

    2010-01-01

    Background Verticillium dahliae is a fungal pathogen that infects a wide range of hosts. The only known genes for resistance to Verticillium in the Solanaceae are found in the tomato (Solanum lycopersicum) Ve locus, formed by two linked genes, Ve1 and Ve2. To characterize the resistance response mediated by the tomato Ve gene, we inoculated two nearly isogenic tomato lines, LA3030 (ve/ve) and LA3038 (Ve/Ve), with V. dahliae. Results We found induction of H2O2 production in roots of inoculated plants, followed by an increase in peroxidase activity only in roots of inoculated resistant plants. Phenylalanine-ammonia lyase (PAL) activity was also increased in resistant roots 2 hours after inoculation, while induction of PAL activity in susceptible roots was not seen until 48 hours after inoculation. Phenylpropanoid metabolism was also affected, with increases in ferulic acid, p-coumaric acid, vanillin and p-hydroxybenzaldehyde contents in resistant roots after inoculation. Six tomato PAL cDNA sequences (PAL1 - PAL6) were found in the SolGenes tomato EST database. RT-PCR analysis showed that these genes were expressed in all organs of the plant, albeit at different levels. Real-time RT-PCR indicated distinct patterns of expression of the different PAL genes in V. dahliae-inoculated roots. Phylogenetic analysis of 48 partial PAL cDNAs corresponding to 19 plant species grouped angiosperm PAL sequences into four clusters, suggesting functional differences among the six tomato genes, with PAL2 and PAL6 presumably involved in lignification, and the remaining PAL genes implicated in other biological processes. An increase in the synthesis of lignins was found 16 and 28 days after inoculation in both lines; this increase was greater and faster to develop in the resistant line. In both resistant and susceptible inoculated plants, an increase in the ratio of guaiacyl/syringyl units was detected 16 days after inoculation, resulting from the lowered amount of syringyl units in the

  15. Estimation of rate constant for VE excitation of the С2(D1Σ) state in Не-СО-О2 discharge plasma

    NASA Astrophysics Data System (ADS)

    Grigorian, G.; Cenian, Adam

    2013-01-01

    The paper discusses the experimental results pointing to the efficient channel of the CO vibrational to the C2 electronic energy-transfer. The radiation spectra D1Σu - X1Σg , known as Mulliken bands, are investigated and the relation of their kinetics to a vibrational excitation of CO molecules in the He-CO-O2 plasma is discussed. The rate constant for VE process ( CO(v >= 25) + C2 → CO(v - 25) + C2(D1Σu) ) is estimated, kVE ~ 10-14 см3/с.

  16. Antipsychotics associated with the development of type 2 diabetes in antipsychotic-naïve schizophrenia patients.

    PubMed

    Nielsen, Jimmi; Skadhede, Søren; Correll, Christoph U

    2010-08-01

    Diabetes mellitus occurs in schizophrenia patients at higher rates than in the general population. Reasons for this elevated risk are poorly understood and have not been examined prospectively in antipsychotic-naïve, first-episode patients. This study aims to determine which antipsychotics are associated with diabetes development in antipsychotic-naïve schizophrenia patients. All antipsychotic-naïve patients diagnosed with schizophrenia in Denmark between 01 January 1997 and 31 December 2004, followed until 31 December 2007, allowing for >or=3 years follow-up, unless death or diabetes onset occurred. Risk factors for the time to diabetes onset were assessed, including antipsychotics taken for at least 180 defined daily doses in the first year after first antipsychotic prescription ('initial treatment'). Risk factors for diabetes incidence were assessed, including antipsychotic use within 3 months before diabetes onset or study end ('current treatment'). Of 7139 patients, followed for 6.6 years (47,297 patient years), 307 developed diabetes (annual incidence rate: 0.65%). Time to diabetes onset was significantly shorter in patients with higher age (hazard ratio (HR): 1.03, confidence interval (CI): 1.02-1.03) and those with 'initial' treatment of olanzapine (HR: 1.41, CI: 1.09-1.83), mid-potency first-generation antipsychotics (FGAs) (HR: 1.60, CI: 1.07-2.39), antihypertensive (HR: 1.87, CI: 1.13-3.09), or lipid-lowering drugs (HR: 4.67, CI: 2.19-10.00). Significant factors associated with diabetes within 3 month of its development included treatment with low-potency FGAs (odds ratio (OR): 1.52, CI: 1.14-2.02), olanzapine (OR: 1.44, CI: 1.98-1.91), and clozapine (OR: 1.67, CI: 1.14-2.46), whereas aripiprazole was associated with lower diabetes risk (OR: 0.51, CI: 0.33-0.80). In addition to general diabetes risk factors, such as age, hypertension, and dyslipidemia, diabetes is promoted in schizophrenia patients by initial and current treatment with olanzapine and

  17. Sleep disturbances in drug naïve Parkinson's disease (PD) patients and effect of levodopa on sleep

    PubMed Central

    Ferreira, Teresa; Prabhakar, Sudesh; Kharbanda, Parampreet S.

    2014-01-01

    Context: Parkinson's disease (PD) is associated with sleep disturbances, attributed to the neurodegenerative process and therapeutic drugs. Studies have found levodopa to increase wakefulness in some patients while increasing sleepiness in others. Aims: To confirm sleep disturbances in drug naïve PD patients and understand the impact of levodopa on their sleep. Materials and Methods: Twenty-three drug naïve PD patients and 31 age-gender matched controls were compared using the Parkinson's Disease Sleep Scale (PDSS) and Epworth Sleepiness Scale (ESS). A polysomnogram objectively compared sleep quality. Of the 23 patients, the 12 initiated on levodopa were reassessed subjectively and through polysomnography after 2 months of therapy. Statistical Analysis: Data was expressed as mean ± standard deviation, median, and range. Continuous variables were analyzed by Student's T test for normally distributed data and Mann–Whitney U test for skewed data. Discrete variables were compared by Chi Square tests (Pearson Chi square Test or Fisher's Exact Test). Wilcoxon signed ranks test was applied in the analysis of paired data pre- and post-levodopa. A P value < 0.05 was considered as statistically significant. Statistical analysis of the data was done using the Statistical Package for the Social Sciences (SPSS) version 12. Results: Drug naïve PD patients had lower PDSS scores than controls. The sleep architecture changes observed on polysomnogram were reduced NREM Stage III and REM sleep and increased sleep latency and wake after sleep onset time. Following levodopa, improved sleep efficiency with reduced sleep latency and wake after sleep onset time was noted, coupled with improved PDSS scores. However, NREM Stage III and REM sleep duration did not increase. Discussion: PD patients take longer to fall asleep and have difficulty in sleep maintenance. Sleep maintenance is affected by nocturia, REM behavioral disorder, nocturnal cramps, akinesia, and tremors, as observed in

  18. Relationship between Interleukin-6 Gene Polymorphism and Hippocampal Volume in Antipsychotic-Naïve Schizophrenia: Evidence for Differential Susceptibility?

    PubMed Central

    Kalmady, Sunil Vasu; Venkatasubramanian, Ganesan; Shivakumar, Venkataram; Gautham, S.; Subramaniam, Aditi; Jose, Dania Alphonse; Maitra, Arindam; Ravi, Vasanthapuram; Gangadhar, Bangalore N.

    2014-01-01

    Background Various lines of evidence including epidemiological, genetic and foetal pathogenetic models suggest a compelling role for Interleukin-6 (IL-6) in the pathogenesis of schizophrenia. IL-6 mediated inflammatory response triggered by maternal infection or stress induces disruption of prenatal hippocampal development which might contribute towards psychopathology during adulthood. There is a substantial lack of knowledge on how genetic predisposition to elevated IL-6 expression effects hippocampal structure in schizophrenia patients. In this first-time study, we evaluated the relationship between functional polymorphism rs1800795 of IL-6 and hippocampal gray matter volume in antipsychotic-naïve schizophrenia patients in comparison with healthy controls. Methodology We examined antipsychotic-naïve schizophrenia patients [N = 28] in comparison with healthy controls [N = 37] group matched on age, sex and handedness. Using 3 Tesla – MRI, bilateral hippocampi were manually segmented by blinded raters with good inter-rater reliability using a valid method. Additionally, Voxel-based Morphometry (VBM) analysis was performed using hippocampal mask. The IL-6 level was measured in blood plasma using ELISA technique. SNP rs1800795 was genotyped using PCR and DNA sequencing. Psychotic symptoms were assessed using Scale for Assessment of Positive Symptoms and Scale for Assessment of Negative Symptoms. Results Schizophrenia patients had significantly deficient left and right hippocampal volumes after controlling for the potential confounding effects of age, sex and total brain volume. Plasma IL-6 levels were significantly higher in patients than controls. There was a significant diagnosis by rs1800795 genotype interaction involving both right and left hippocampal volumes. Interestingly, this effect was significant only in men but not in women. Conclusion Our first time observations suggest a significant relationship between IL-6 rs1800795 and reduced hippocampal

  19. Relationship between Interleukin-6 gene polymorphism and hippocampal volume in antipsychotic-naïve schizophrenia: evidence for differential susceptibility?

    PubMed

    Kalmady, Sunil Vasu; Venkatasubramanian, Ganesan; Shivakumar, Venkataram; Gautham, S; Subramaniam, Aditi; Jose, Dania Alphonse; Maitra, Arindam; Ravi, Vasanthapuram; Gangadhar, Bangalore N

    2014-01-01

    Various lines of evidence including epidemiological, genetic and foetal pathogenetic models suggest a compelling role for Interleukin-6 (IL-6) in the pathogenesis of schizophrenia. IL-6 mediated inflammatory response triggered by maternal infection or stress induces disruption of prenatal hippocampal development which might contribute towards psychopathology during adulthood. There is a substantial lack of knowledge on how genetic predisposition to elevated IL-6 expression effects hippocampal structure in schizophrenia patients. In this first-time study, we evaluated the relationship between functional polymorphism rs1800795 of IL-6 and hippocampal gray matter volume in antipsychotic-naïve schizophrenia patients in comparison with healthy controls. We examined antipsychotic-naïve schizophrenia patients [N = 28] in comparison with healthy controls [N = 37] group matched on age, sex and handedness. Using 3 Tesla - MRI, bilateral hippocampi were manually segmented by blinded raters with good inter-rater reliability using a valid method. Additionally, Voxel-based Morphometry (VBM) analysis was performed using hippocampal mask. The IL-6 level was measured in blood plasma using ELISA technique. SNP rs1800795 was genotyped using PCR and DNA sequencing. Psychotic symptoms were assessed using Scale for Assessment of Positive Symptoms and Scale for Assessment of Negative Symptoms. Schizophrenia patients had significantly deficient left and right hippocampal volumes after controlling for the potential confounding effects of age, sex and total brain volume. Plasma IL-6 levels were significantly higher in patients than controls. There was a significant diagnosis by rs1800795 genotype interaction involving both right and left hippocampal volumes. Interestingly, this effect was significant only in men but not in women. Our first time observations suggest a significant relationship between IL-6 rs1800795 and reduced hippocampal volume in antipsychotic-naïve schizophrenia

  20. Spontaneous preference for visual cues of animacy in naïve domestic chicks: The case of speed changes.

    PubMed

    Rosa-Salva, O; Grassi, M; Lorenzi, E; Regolin, L; Vallortigara, G

    2016-12-01

    Animacy perception arises in human adults from motion cues implying an internal energy source to the moving object. The internal energy of the object is often represented by a change in speed. The same features cause preferential attention in infants. We investigated whether speed changes affecting adults' animacy ratings elicit spontaneous social preferences in visually-naïve chicks. Human observers evaluated the similarity between the movement of a red blob stimulus and that of a living creature. The stimulus entered the screen and moved along the azimuth; halfway through its trajectory it could either continue to move at a constant speed or linearly increase in speed. The average speed, the distance covered and the overall motion duration were kept constant. Animacy ratings of humans were higher for accelerating stimuli (Exp. 1). Naïve chicks were then tested for their spontaneous preference for approaching the stimulus moving at a constant speed and trajectory or an identical stimulus, which suddenly accelerated and then decelerated again to the original speed. Chicks showed a significant preference for the 'speed-change stimulus' (Exp. 2). Two additional controls (Exp. 3 and 4) showed that matching the variability of the control 'speed-constant' stimulus to that of the 'speed-change stimulus' did not alter chicks' preference for the latter. Chicks' preference was suppressed by adding two occluders on both displays, positioned along the stimulus trajectory in such a way to occlude the moment of the speed change (Exp. 5). This confirms that, for chicks to show a preference, the moments of speed change need to be visible. Finally, chicks' preference extended to stimuli displaying a direction change, another motion cue eliciting animacy perception in human observers, if the speed- and direction-profile were consistent with each other and resembled what expected for biological entities that invert their motion direction (Exp. 6). Overall, this is the first

  1. Modelling Miscible Fluid Displacements in Porous Media Using Karhunen-Loéve Decomposition and Artificial Neural Networks

    NASA Astrophysics Data System (ADS)

    Smaoui, Nejib; Gharbi, Ridha

    2000-11-01

    An approach to model fluid displacements in porous media that combines two powerful techniques, namely Karhunen-Loéve (KL) decomposition and artificial neural networks (ANNs) is descibed. KL decomposition known, for data compression and feature identification, is used to extract coherent structures or eigenfunctions using fluid concentration maps obtained from fine-mesh numerical simulations of miscible fluid displacements of oil by solvent in a two-dimensional vertical cross-section. Twenty KL eigenfunctions that capture 98.8% of the total energy are extracted. Corresponding data coefficients are constructed by projecting the fluid concentration maps of the numerical simulations onto the KL eigenfunctions. Processing these data coefficients through an ANN is found to be a powerful tool in predicting the fluid displacements of the fine-mesh numerical simulations without actually performing these simulations.

  2. Human memory T cells with a naïve phenotype accumulate with aging and respond to persistent viruses

    PubMed Central

    Pulko, Vesna; Davies, John S.; Martinez, Carmine; Lanteri, Marion C.; Busch, Michael P.; Diamond, Michael S.; Knox, Kenneth; Busch, Erin S.; Sims, Peter A.; Sinari, Shripad; Billheimer, Dean; Haddad, Elias K.; Murray, Kristy O.; Wertheimer, Anne M.; Nikolich-Žugich, Janko

    2016-01-01

    The numbers of naive T cells decrease, and the susceptibility to new microbial infections increases with age. Here, we describe a new subset of phenotypically naive human CD8+T cells that rapidly secrete multiple cytokines in response to persistent viral antigens but differ transcriptionally from memory and effector T cells. The frequency of these CD8+T cells, named T memory cells with naïve phenotype (TMNP) increased with age and following severe acute infection and inversely correlated with the residual immune capacity to respond to new infections with age. CD8+TMNP cells represent a new potential target for immunotherapy of persistent infections, and should be accounted for and subtracted from the naive pool if truly naive T cells are needed to respond to antigens. PMID:27270402

  3. Characterization of suppressible mutations in the viomycin phosphotransferase gene of the Streptomyces enteric plasmid pVE138.

    PubMed Central

    Paradiso, M J; Roberts, G; Streicher, S L; Goldberg, R B

    1987-01-01

    The viomycin phosphotransferase gene (vph) is expressed and confers resistance to viomycin in both Streptomyces spp. and members of the family Enterobacteriaceae. We report the isolation of UGA (opal) and UAG (amber) mutations in the vph gene of shuttle plasmid pVE138. We found that the five UGA mutations in vph resulted in a temperature-sensitive phenotype in Salmonella typhimurium. Su- strains are Vior at 28 degrees C and Vios at 37 degrees C, whereas Su+UGA strains are Vior at both 28 and 37 degrees C. The single amber mutation isolated was not temperature sensitive and resulted in the expected Vios phenotype in Su- strains and Vior in Su+UAG strains. PMID:3029035

  4. Delusion of pregnancy in a drug-naïve young woman showing hyperprolactinemia and hypothyroidism: a case report.

    PubMed

    Penta, Elena; Lasalvia, Antonio

    2013-01-01

    The present article reports the case of a delusional pregnancy that developed in a drug-naïve young woman affected by paranoid schizophrenia and Hashimoto-related hyperprolactinemia. The literature in this field has addressed the phenomenon of distorted thoughts of pregnancy being elicited by physical changes due to drug-induced hyperprolactinemia. The present report gives account of a case of delusional pregnancy that developed in a schizophrenic patient with concurrent hyperprolactinemia induced by a primary endocrine disease. In this instance, however, amelioration of delusional beliefs did not ensue from hyperprolactinemia normalization, but was mostly due to cognitive restructuring of distorted thinking (together with the antipsychotic treatment). This finding confirms the importance of considering the key role of the interaction of biological, cognitive and psychological mechanisms in the construction of inaccurate beliefs and feelings about pregnancy.

  5. Indirect activation of naïve CD4+ T cells by dendritic cell-derived exosomes.

    PubMed

    Théry, Clotilde; Duban, Livine; Segura, Elodie; Véron, Philippe; Lantz, Olivier; Amigorena, Sebastian

    2002-12-01

    Dendritic cells (DCs) secrete vesicles of endosomal origin, called exosomes, that bear major histocompatibility complex (MHC) and T cell costimulatory molecules. Here, we found that injection of antigen- or peptide-bearing exosomes induced antigen-specific naïve CD4+ T cell activation in vivo. In vitro, exosomes did not induce antigen-dependent T cell stimulation unless mature CD8alpha- DCs were also present in the cultures. These mature DCs could be MHC class II-negative, but had to bear CD80 and CD86. Therefore, in addition to carrying antigen, exosomes promote the exchange of functional peptide-MHC complexes between DCs. Such a mechanism may increase the number of DCs bearing a particular peptide, thus amplifying the initiation of primary adaptive immune responses.

  6. Retraction: 'Effect of blonanserin on cognitive function in antipsychotic-naïve first-episode schizophrenia'.

    PubMed

    Tenjin, Tomomi; Miyamoto, Seiya; Miyake, Nobumi; Ogino, Shin; Kitajima, Rei; Ojima, Kazuaki; Arai, Jun; Teramoto, Haruki; Tsukahara, Sachiko; Ito, Yukie; Tadokoro, Masanori; Anai, Kiriko; Funamoto, Yasuyuki; Kaneda, Yasuhiro; Sumiyoshi, Tomiki; Yamaguchi, Noboru

    2017-05-01

    The above article from Human Psychopharmacology, first published on 25 January 2012 in Wiley OnlineLibrary (onlinelibrary.wiley.com), and in Volume 90, pp. 90-100, has been retracted by agreement between the authors, the journal Editor in Chief, David Baldwin, and John Wiley & Sons Ltd. The retraction has been agreed following an investigation by the St Marianna University Ethics Committee which determined that the paper was not as originally designed and approved. Tenjin, T., Miyamoto, S., Miyake, N., Ogino, S., Kitajima, R., Ojima, K., … Yamaguchi, N. (2012). Effect of blonanserin on cognitive function in antipsychotic-naïve first-episode schizophrenia. Hum. Psychopharmacol Clin Exp, 27, 90-100. https://doi.org/10.1002/hup.1276. Copyright © 2017 John Wiley & Sons, Ltd.

  7. A revision of the South African riffle beetle genus Leielmis Delève, 1964 (Coleoptera: Elmidae).

    PubMed

    Bilton, David T

    2017-04-12

    The riffle beetle genus Leielmis Delève, 1964 is redescribed and shown to contain three species, all of which are apparently endemic to the South African Cape, where they live in permanent mountain streams with cold running water. A lectotype is designated for Helmis georyssoides Grouvelle, 1890, and two additional species (L. gibbosus sp. nov. and L. hirsutus sp. nov.) are described for the first time. Following study of the type series, L. georyssoides is shown to be endemic to Table Mountain; most specimens previously assigned to this taxon representing an additional species (L. gibbosus sp. nov.), widespread in the interior Cape Fold Mountains. The record of Leielmis from Angola is considered highly doubtful. Comparative notes and a key are provided to allow the identification of known species of the genus.

  8. Retention of antiretroviral naïve patients registered in HIV care in a program clinic in Pune, India.

    PubMed

    Ghate, Manisha V; Zirpe, Sunil S; Gurav, Nilam P; Rewari, Bharat B; Gangakhedkar, Raman R; Paranjape, Ramesh S

    2014-01-01

    Retention in HIV care ensures delivery of services like secondary prevention, timely initiation of treatment, support, and care on a regular basis. The data on retention in pre antiretroviral therapy (ART) care in India is scanty. Antiretroviral naïve HIV-infected adult patients registered between January 2011 and March 2012 in HIV care (pre-ART) were included in the study. The follow-up procedures were done as per the national guidelines. Patients who did not report to the clinic for 1 year were considered as pre-ART lost to follow-up (pre-ART LFU). They were contacted either telephonically or by home visits. Logistic regression analysis was done to find out factors associated with pre-ART loss to follow-up. A total of 689 antiretroviral naïve adult patients were registered in the HIV care. Fourteen (2%) patients died and 76 (11%) were LFU till March 2013. The multivariate analysis showed that baseline CD4 count >350 cells/mm(3) (P < 0.01) and illiteracy (P = 0.044) were significantly associated with LFU. Of the total pre-ART LFUs, 35 (46.1%) informed that they would visit the clinic at their convenient time. NGOs that referred 16 female sex workers (FSWs) who were LFU (21.1%) informed that they would make efforts to refer them to the clinic. Higher CD4 count and illiteracy were significantly associated with lower retention in pre-ART care. Developing effective "retention package" for patients and strengthening linkage strategies between key sub-population such as FSWs and ART programming will help to plug the leaky cascade in HIV care.

  9. Retention of antiretroviral naïve patients registered in HIV care in a program clinic in Pune, India

    PubMed Central

    Ghate, Manisha V.; Zirpe, Sunil S.; Gurav, Nilam P.; Rewari, Bharat B.; Gangakhedkar, Raman R.; Paranjape, Ramesh S.

    2014-01-01

    Background: Retention in HIV care ensures delivery of services like secondary prevention, timely initiation of treatment, support, and care on a regular basis. The data on retention in pre antiretroviral therapy (ART) care in India is scanty. Materials and Methods: Antiretroviral naïve HIV-infected adult patients registered between January 2011 and March 2012 in HIV care (pre-ART) were included in the study. The follow-up procedures were done as per the national guidelines. Patients who did not report to the clinic for 1 year were considered as pre-ART lost to follow-up (pre-ART LFU). They were contacted either telephonically or by home visits. Logistic regression analysis was done to find out factors associated with pre-ART loss to follow-up. Results: A total of 689 antiretroviral naïve adult patients were registered in the HIV care. Fourteen (2%) patients died and 76 (11%) were LFU till March 2013. The multivariate analysis showed that baseline CD4 count >350 cells/mm3 (P < 0.01) and illiteracy (P = 0.044) were significantly associated with LFU. Of the total pre-ART LFUs, 35 (46.1%) informed that they would visit the clinic at their convenient time. NGOs that referred 16 female sex workers (FSWs) who were LFU (21.1%) informed that they would make efforts to refer them to the clinic. Conclusion: Higher CD4 count and illiteracy were significantly associated with lower retention in pre-ART care. Developing effective “retention package” for patients and strengthening linkage strategies between key sub-population such as FSWs and ART programming will help to plug the leaky cascade in HIV care. PMID:26396447

  10. Dissociation in response to methylphenidate on response variability in a group of medication naïve children with ADHD.

    PubMed

    Johnson, Katherine A; Barry, Edwina; Bellgrove, Mark A; Cox, Marie; Kelly, Simon P; Dáibhis, Aoife; Daly, Michael; Keavey, Michelle; Watchorn, Amy; Fitzgerald, Michael; McNicholas, Fiona; Kirley, Aiveen; Robertson, Ian H; Gill, Michael

    2008-04-01

    Increased variability in reaction time (RT) has been proposed as a cardinal feature of attention deficit hyperactivity disorder (ADHD). Increased variability during sustained attention tasks may reflect inefficient fronto-striatal and fronto-parietal circuitry; activity within these circuits is modulated by the catecholamines. A disruption to dopamine signaling is suggested in ADHD that may be ameliorated by methylphenidate (MPH). This study investigated the effects of MPH administration on the variability in RT and error performance on a sustained attention task of a group of 31 medication naïve children with ADHD, compared with 22 non-ADHD, non-medicated, control children. All children performed the fixed-sequence sustained attention to response task (SART) at two time-points: at baseline and after six weeks. The children with ADHD were tested when medication naive at baseline and after six weeks of treatment with MPH and whilst on medication. The medication naïve children with ADHD performed the SART with greater errors of commission and omission when compared with the control group. They demonstrated greater standard deviation of RT and fast moment-to-moment variability. They did not differ significantly from the control group in terms of slow variability in RT. MPH administration resulted in reduced and normalised levels of commission errors and fast, moment-to-moment variability in RT. MPH did not affect the rate of omission errors, standard deviation of RT or slow frequency variability in RT. MPH administration may have a specific effect on those performance components that reflect sustained attention and top-down control rather than arousal.

  11. Selection of cholera toxin specific IgNAR single-domain antibodies from a naïve shark library.

    PubMed

    Liu, Jinny L; Anderson, George P; Delehanty, James B; Baumann, Richard; Hayhurst, Andrew; Goldman, Ellen R

    2007-03-01

    Shark immunoglobulin new antigen receptor (IgNAR, also referred to as NAR) variable domains (Vs) are single-domain antibody (sdAb) fragments containing only two hypervariable loop structures forming 3D topologies for a wide range of antigen recognition and binding. Their small size ( approximately 12kDa) and high solubility, thermostability and binding specificity make IgNARs an exceptional alternative source of engineered antibodies for sensor applications. Here, two new shark NAR V display libraries containing >10(7) unique clones from non-immunized (naïve) adult spiny dogfish (Squalus acanthias) and smooth dogfish (Mustelus canis) sharks were constructed. The most conserved consensus sequences derived from random clone sequence were compared with published nurse shark (Ginglymostoma cirratum) sequences. Cholera toxin (CT) was chosen for panning one of the naïve display libraries due to its severe pathogenicity and commercial availability. Three very similar CT binders were selected and purified soluble monomeric anti-CT sdAbs were characterized using Luminex(100) and traditional ELISA assays. These novel anti-CT sdAbs selected from our newly constructed shark NAR V sdAb library specifically bound to soluble antigen, without cross reacting with other irrelevant antigens. They also showed superior heat stability, exhibiting slow loss of activity over the course of one hour at high temperature (95 degrees C), while conventional antibodies lost all activity in the first 5-10min. The successful isolation of target specific sdAbs from one of our non-biased NAR libraries, demonstrate their ability to provide binders against an unacquainted antigen of interest.

  12. Relationship between Brain-Derived Neurotrophic Factor and Schneiderian First Rank Symptoms in Antipsychotic-Naïve Schizophrenia

    PubMed Central

    Kalmady, Sunil Vasu; Venkatasubramanian, Ganesan; Shivakumar, Venkataram; Jose, Dania; Ravi, Vasanthapuram; Gangadhar, Bangalore N.

    2013-01-01

    Neurodevelopmental aberrations influenced by neurotrophic factors are among the important paradigms to understand schizophrenia pathogenesis. Among various neurotrophic factors, Brain-Derived Neurotrophic Factor (BDNF) is strongly implicated by previous research studies. Evaluating co-morbidity free, antipsychotic-naïve schizophrenia patients for BDNF levels and examining the correlates of this factor with symptoms might facilitate elucidation of its pathogenetic role without confounds of potential influencing factors. In this study, 59 co-morbidity free, antipsychotic-naïve schizophrenia patients were compared with 60 healthy controls for serum BDNF levels. In addition, the relationship between Schneiderian First Rank Symptoms (FRS) and BDNF level in patients was examined. As a group, schizophrenia patients (28.8 ± 11.7 ng/mL) had significantly lower serum BDNF than healthy controls (34.9 ± 8.2 ng/mL) after controlling for the potential confounding effects of age and sex (F = 7.8; p = 0.006). Further analyses revealed FRS status to have significant effect on plasma BDNF after controlling for the potential confounding effects of age and sex (F = 4.5; p = 0.01). Follow-up post hoc analyses revealed FRS(+) patients to have significant deficit in plasma BDNF level in comparison with healthy controls (p = 0.002); however, FRS(−) patients did not differ from healthy controls (p = 0.38). Our study observations add further support to the role for BDNF in schizophrenia pathogenesis and suggest a potential novel link between deficient BDNF and FRS. PMID:23847552

  13. Diabetes mellitus increases the risk of hepatocellular carcinoma in treatment-naïve chronic hepatitis C patients in China

    PubMed Central

    Li, Xu; Xu, Hongqin; Gao, Yang; Pan, Meng; Wang, Le; Gao, Pujun

    2017-01-01

    Abstract We investigated the link between diabetes mellitus (DM) and hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) risk in treatment-naïve chronic hepatitis C (CHC) patients in China. To examine the association between DM and HCC, we conducted a case–control study of 300 Chinese CHC patients with HCC, compared to an age- and sex-matched control group of 517 CHC patients not diagnosed with HCC. We found that DM was more prevalent in the HCC patient group (18.7%) than in the CHC-only patient group (10.8%). We conducted logistic regression analyses adjusting for demographics features and other HCC risk factors and found that DM increased the risk of HCC development nearly 2-fold [adjusted odds ratio (AOR), 95% confidence interval (95% CI), 1.80 (1.17–2.75)]. Meanwhile, the proportion of HCC patients and CHC-only patients with liver cirrhosis were 79.3% and 46.2%, respectively, yielding an AOR of 4.62 (95% CI, 3.31–6.46). Multivariate analyses comparing the risk of HCV-related HCC development in DM patients with and without liver cirrhosis revealed that the estimated AOR (95% CI) for those with liver cirrhosis was 5.60 (2.25–13.96). However, the HCC risk decreased significantly with a later age of diabetes onset (AOR [95% CI], 0.94 [0.89–0.99]). DM was associated with an increased risk for HCC development in treatment-naïve CHC patients in China. Furthermore, liver cirrhosis and an early DM diagnoses further increased the risks of HCC development in patients diagnosed with both CHC and DM. PMID:28353605

  14. Nimotuzumab with chemoradiation confers a survival advantage in treatment-naïve head and neck tumors over expressing EGFR.

    PubMed

    Basavaraj, Chetana; Sierra, Patricia; Shivu, Jatteppanavar; Melarkode, Ramakrishnan; Montero, Enrique; Nair, Pradip

    2010-10-01

    Head and neck cancer associated with the chewing of betel preparations, including tobacco, is common to South East Asia. We report a Phase IIB study in which ninety-two treatment naïve patients with advanced squamous cell carcinoma received standard therapy with or without an anti-Epidermal Growth Factor Receptor (EGFR) monoclonal antibody (Nimotuzumab). In pretreatment samples, the tissue expression of ErbB family proteins and downstream molecules, including their association with clinical response and survival. Marker expression in tumor adjacent sections was evaluated by immunohistochemistry. The clinical benefit of Nimotuzumab (200 mg/dose, once a week for six weeks) in combination with radiotherapy or chemoradiation was assessed with respect to EGFR expression and intensity. Two antibodies, which recognized independent epitopes, were used to assess EGFR expression levels by immunohistochemistry. EGFR detection using mR3, an antibody with similar specificity to Nimotuzumab, correlated significantly with the expression of ErbB3 (p<0.05), PCNA and pMAPK (p<0.001). Although EGFR expression showed a significant relationship to patient survival in patients treated with Nimotuzumab and chemoradiation (p=0.02), pMAPK expression did not (p=0.07). Interestingly, EGFR overexpression (as defined by mR3) correlated directly with overall survival in this group (p=0.01). This data supports a model of basal activation of the EGFR signal transduction pathway in these oropharyngeal tumors. Detection of EGFR by immunohistochemistry could define a subset of treatment naïve Head and Neck cancer patients who may benefit from receiving EGFR targeted therapies in combination with chemoradiation.

  15. Overt and occult hepatitis B virus infection among treatment-naïve HIV-infected patients in Brazil.

    PubMed

    Oliveira, Marina Pedroso; Lemes, Pollyanne Sousa; Matos, Márcia Alves Dias; Del-Rios, Nativa Helena Alves; Carneiro, Megmar Aparecida Santos; Silva, Ágabo Macedo Costa; Lopes, Carmen Luci Rodrigues; Teles, Sheila Araújo; Aires, Rodrigo Sebba; Lago, Bárbara Vieira; Araujo, Natalia Motta; Martins, Regina Maria Bringel

    2016-07-01

    Although hepatitis B virus (HBV) and human immunodeficiency virus (HIV) co-infection is common, only few data are available on HBV among HIV patients including occult hepatitis B infection (OBI), regardless of serological markers. This study aims to determine the prevalence of OBI and overall HBV infection, associated factors, HBV genotypes, and surface (S) gene mutations in a population of treatment-naïve HIV-infected patients in Brazil. A cross-sectional study was conducted in treatment-naïve HIV-infected patients in Central Brazil. All samples were tested for HBV serological markers and HBV DNA. Sequence analysis of the S gene and overlapping polymerase gene was preformed. Overall, 25.1% (127/505) of the patients had markers of current or previous HBV infection, which was associated with age over 40 years, history of injection drug use, and homosexual sex. The hepatitis B surface antigen (HBsAg) seroprevalence was 4.9% (25/505). HBV DNA was detected in 39 out of 505 patients: 20 of them were HBsAg-positive and 19 were HBsAg-negative, resulting in an OBI prevalence of 3.8%. Patients with OBI had significantly higher HCV seropositivity rate compared to HBsAg-positive patients. Sequencing of the S gene revealed Y100C, T131N, and D144A mutations. One patient had the M204I and L180M drug-resistance mutations (polymerase). HBV genotypes A (A1, A2), D (D2, D3), and F (F2) were identified. In conclusion, OBI represented almost half of all HBV infections with detectable HBV DNA, suggesting that hepatitis B diagnosis in HIV patients should include in addition to serological markers the detection of HBV DNA. © 2016 Wiley Periodicals, Inc.

  16. Polymorphisms of HIV RT Gene Among the ART Naïve Native Drug Exposed Rural PLHA

    PubMed Central

    Krishnan, K Mohana; Amsavathani, SK

    2012-01-01

    Background: The number of people living with human immunodeficiency virus (HIV) is increasing day by day in India. The disease has now spread from urban areas to rural areas. The proof reading of the reverse transcriptase enzyme is poor, which may lead to genetic diversity within the HIV strains, which in turn leads to problems like failure or resistance in antiretroviral treatment. This study is designed to find out the polymorphisms of the reverse transcriptase gene of HIV, after the native drug pressure among antiretroviral therapy (ART) naïve rural people living with HIV/AIDS (RPLHA). Materials and Methods: A total of 207 HIV-Reactive patients were allowed to take native drugs from the local area and were advised to attend the center for HIV after six months for a follow-up. At the time of the follow-up visit, a second blood sample was taken from 20 reactive native-drug exposed ART-naïve patients. The plasma was separated and transported at 20°C to the YRG Care Center for genotyping. Results: Among the 20 HIV-reactive samples processed for gene sequencing analysis to detect the genotypic variations, only one sample (5%) showed high-level mutational resistance variations and the predominant polymorphisms detected were V35T (100%), K122E (94.44%), and V60I (88.88%). Conclusions: The presence of drug-resistance mutations, although minimal, was important, as the drug-resistant strains could spread among the RPLHA and to their sexual partners. There was a definite need to generate a drug resistance database and the polymorphic pattern of Indian strains concern to the future clinical management of the disease, and a vaccine design to contain the disease. PMID:22754246

  17. Prediction of cancer rescue p53 mutants in silico using Naïve Bayes learning methodology.

    PubMed

    Ramani, R Geetha; Jacob, Shomona Gracia

    2013-11-01

    This research is focussed on predicting through Naïve Bayes learning, the possible p53 rescue mutants from amino-acid substitutions at the second, third and fourth site recombination that could reinstate normal p53 activity. The Naïve Bayes probability values of the amino-acid substitutions at the respective site-wise recombination were utilized to formulate the proposed Genetic Mutant Marker Extraction (GMME) technique that could unearth the hot spot cancer, strong rescue and weak rescue mutants. The p53 mutation records depicting the amino-acid substitutions obtained by yeast assays comprising of nearly 16,700 records, available at the University of California, Machine Learning Repository, were utilized as the training dataset for the GMME technique. The proposed GMME technique revealed the hot spot cancer mutants, strong rescue and weak rescue mutants leading to the detection of probable genetic markers for Cancer prediction from the surface regions 96-289 constituting the second, third and fourth site recombinations. Thus far, computational approaches have been able to predict rescue markers at region-specific mutations (96-105, 114-123, 130-156 and 223- 232) with respect to the second site recombination for three hot spot cancer mutants only viz, P152L, R158L and G245S. The GMME technique aimed at predicting possible rescue markers for p53 mutants at the second, third and fourth site recombinations revealing novel rescue markers for fourteen hot spot cancer mutants. Moreover, the GMME technique can be extended effectively to increasing number of recombinant sites that can be efficiently utilized to predict novel rescue markers.

  18. Characterization of the psychological, physiological and EEG profile of acute betel quid intoxication in naïve subjects.

    PubMed

    Osborne, Peter G; Chou, Tung-Shan; Shen, Tsu-Wang

    2011-01-01

    Betel quid use and abuse is wide spread in Asia but the physiological basis of intoxication and addiction are unknown. In subjects naïve to the habit of betel quid intoxication, the psychological and physiological profile of intoxication has never been reported. We compared the effect of chewing gum or chewing betel quid, and subsequent betel quid intoxication, on psychological assessment, prospective time interval estimation, numerical and character digit span, computerized 2 choice tests and mental tasks such as reading and mathematics with concurrent monitoring of ECG, EEG and face temperature in healthy, non-sleep deprived, male subjects naïve to the habit of chewing betel quid. Betel quid intoxication, dose dependently induced tachycardia (max 30 bpm) and elevated face temperature (0.7°C) (P<0.001) above the effects observed in response to chewing gum (max 12 bpm and 0.3°C) in 12 subjects. Gross behavioral indices of working memory such as numerical or character digit span in 8 subjects, or simple visual-motor performance such as reaction speed or accuracy in a two choice scenario in 8 subjects were not affected by betel quid intoxication. Betel quid intoxication strongly influenced the psychological aspects of perception such as slowing of the prospective perception of passage of a 1 minute time interval in 8 subjects (P<0.05) and perceived increased arousal (P<0.01) and perceived decreased ability to think (P<0.05) in 31 subjects. The EEG spectral profile recorded from mental states associated with open and closed eyes, and mental tasks such as reading and eyes closed mental arithmetic were significantly modified (P<0.05) relative to chewing gum by betel quid intoxication in 10 subjects. The prevalence of betel quid consumption across a range of social and work settings warrants greater investigation of this widespread but largely under researched drug.

  19. A Highly Diverse and Functional Naïve Ubiquitin Variant Library for Generation of Intracellular Affinity Reagents.

    PubMed

    Leung, Isabel; Jarvik, Nick; Sidhu, Sachdev S

    2017-01-06

    We report the design, construction, and validation of a highly diverse phage-displayed naïve ubiquitin variant (Ubv) library. We first conducted a mutation tolerance scan of 27 residues and confirmed that 24 of these could be substituted by chemically diverse amino acids without compromising the display of Ubvs on phage. Subsequently, we constructed a library containing 6.8×10(10) unique members, in which these 24 positions were diversified with a degenerate codon that encodes for 6 aa that are prevalent in protein interaction sites. To ensure the optimal structural stability of the Ubvs, we constructed the library in a two-step process, whereby 12 positions were randomized first, and following the selection for displayed Ubvs, the resulting pool was further diversified at the other 12 positions. The resulting library was validated by conducting binding selections against a panel of 40 diverse protein antigens and was found to be as functional as a highly validated synthetic antibody library, yielding binders against 30 of the antigens. Detailed characterization of an Ubv that bound to the cell-surface receptor human epidermal growth factor receptor 3 revealed tight binding in the single-digit nanomolar range. Moreover, Ubvs that bound to two distinct sites on the intracellular adapter Grb2 could be combined to generate a potent inhibitor that functioned in cells. These results validate ubiquitin as a robust scaffold for the construction of naïve libraries that can be used to generate Ubvs that target signaling networks both outside and inside the cells.

  20. Characterization of the Psychological, Physiological and EEG Profile of Acute Betel Quid Intoxication in Naïve Subjects

    PubMed Central

    Osborne, Peter G.; Chou, Tung-Shan; Shen, Tsu-Wang

    2011-01-01

    Betel quid use and abuse is wide spread in Asia but the physiological basis of intoxication and addiction are unknown. In subjects naïve to the habit of betel quid intoxication, the psychological and physiological profile of intoxication has never been reported. We compared the effect of chewing gum or chewing betel quid, and subsequent betel quid intoxication, on psychological assessment, prospective time interval estimation, numerical and character digit span, computerized 2 choice tests and mental tasks such as reading and mathematics with concurrent monitoring of ECG, EEG and face temperature in healthy, non-sleep deprived, male subjects naïve to the habit of chewing betel quid. Betel quid intoxication, dose dependently induced tachycardia (max 30 bpm) and elevated face temperature (0.7°C) (P<0.001) above the effects observed in response to chewing gum (max 12 bpm and 0.3°C) in 12 subjects. Gross behavioral indices of working memory such as numerical or character digit span in 8 subjects, or simple visual-motor performance such as reaction speed or accuracy in a two choice scenario in 8 subjects were not affected by betel quid intoxication. Betel quid intoxication strongly influenced the psychological aspects of perception such as slowing of the prospective perception of passage of a 1 minute time interval in 8 subjects (P<0.05) and perceived increased arousal (P<0.01) and perceived decreased ability to think (P<0.05) in 31 subjects. The EEG spectral profile recorded from mental states associated with open and closed eyes, and mental tasks such as reading and eyes closed mental arithmetic were significantly modified (P<0.05) relative to chewing gum by betel quid intoxication in 10 subjects. The prevalence of betel quid consumption across a range of social and work settings warrants greater investigation of this widespread but largely under researched drug. PMID:21909371

  1. Cost-Effectiveness of New Antiviral Regimens for Treatment-Naïve US Veterans with Hepatitis C

    PubMed Central

    Chidi, Alexis P.; Rogal, Shari; Bryce, Cindy L.; Fine, Michael J.; Good, Chester B.; Myaskovsky, Larissa; Rustgi, Vinod K.; Tsung, Allan; Smith, Kenneth J.

    2015-01-01

    Recently approved, interferon-free medication regimens for treating hepatitis C are highly effective but extremely costly. We aimed to identify cost-effective strategies for managing treatment-naïve US Veterans with new hepatitis C medication regimens. We developed a Markov model with 1-year cycle length for a cohort of 60-year old Veterans with untreated genotype 1 hepatitis C seeking treatment in a typical year. We compared using sofosbuvir/ledipasvir or ombitasvir/ritonavir/paritaprevir/dasabuvir to treat: (1) any patient seeking treatment, (2) only patients with advanced fibrosis or cirrhosis, or (3) patients with advanced disease first and healthier patients one year later. The previous standard of care, sofosbuvir/simeprevir or sofosbuvir/pegylated interferon/ribavirin, was included for comparison. Patients could develop progressive fibrosis, cirrhosis, or hepatocellular carcinoma, undergo transplantation, or die. Complications were less likely after sustained virologic response. We calculated the incremental cost per quality-adjusted life year (QALY) and varied model inputs in one-way and probabilistic sensitivity analyses. We used the Veterans Health Administration perspective with a lifetime time horizon and 3% annual discounting. Treating any patient with ombitasvir-based therapy was the preferred strategy ($35,560; 14.0 QALYs). All other strategies were dominated (greater costs/QALY gained than more effective strategies). Varying treatment efficacy, price and/or duration changed the preferred strategy. In probabilistic sensitivity analysis, treating any patient with ombitasvir-based therapy was cost-effective in 70% of iterations at a $50,000/QALY threshold and 65% of iterations at a $100,000/QALY threshold. Conclusion Managing any treatment-naïve genotype 1 hepatitis C patient with ombitasvir-based therapy is the most economically efficient strategy, although price and efficacy can impact cost-effectiveness. It is economically unfavorable to restrict

  2. The differential effects of chronic imipramine or citalopram administration on physiological and behavioral outcomes in naïve mice.

    PubMed

    Strekalova, Tatyana; Anthony, Daniel C; Dolgov, Oleg; Anokhin, Konstantin; Kubatiev, Aslan; Steinbusch, Harry M W; Schroeter, Careen

    2013-05-15

    Tricyclics and selective serotonin reuptake inhibitors (SSRIs) are probably the most widely employed reference antidepressants in animal studies on depression. Using imipramine and citalopram, we sought to assess which drug would be more appropriate as pharmacological reference in paradigms of depression in C57BL6N mice by measuring their effect on liquid consumption, home cage activity, body weight and long-term memory in naïve animals treated with each compound at generally used dose of 15 mg/kg/day. Continuous logging of home cage movement, weekly monitoring of vertical activity in a novel cage, and body weight was recorded during four-week treatment period and for four weeks after discontinuation of the antidepressant; sucrose preference was evaluated at weekly intervals during drug administration. A novel object recognition memory test was performed in mice treated the antidepressants for two weeks. Compared to control, imipramine-treated mice displayed increased sucrose and water intake, as well as enhanced home-cage and novelty exploration activities, and reduced body weight. Imipramine also impaired learning in the object recognition task, but citalopram diminished object exploration sufficiently to invalidate the test. Citalopram-treated animals demonstrated no changes in a sucrose test and had elevated body mass. Thus basic physiological and behavioral outcomes in naïve mice were significantly altered by the chronic administration of imipramine and, to a lesser extent, citalopram. As altered variables are crucial for the evaluation of antidepressant-like effects in mice, our data suggest that, at commonly used doses, both drugs must be applied in mouse models of depression with caution.

  3. Improvement in Language Function Correlates with Gait Improvement in Drug-naïve Parkinson's Disease Patients Taking Dopaminergic Medication.

    PubMed

    Murakami, Hidetomo; Momma, Yutaro; Nohara, Tetsuhito; Mori, Yukiko; Futamura, Akinori; Sugita, Toshihisa; Ishigaki, Seiichiro; Katoh, Hirotaka; Kezuka, Machiko; Ono, Kenjiro; Miller, Michael W; Kawamura, Mitsuru

    2016-01-01

    Dopaminergic drugs, the gold standard for motor symptoms, are known to affect cognitive function in Parkinson's disease (PD) patients. We compared the effects of dopaminergic treatment on motor and cognitive function in drug-naïve patients. Dopaminergic medication (levodopa, dopamine agonist, selegiline) was given to 27 drug-naïve PD patients and increased to a dose optimal for improved motor symptoms. Patients were tested prior to, and 4-7 months after, drug initiation. Motor function was assessed using the Unified Parkinson's Disease Rating Scale (UPDRS). Cognitive function was assessed using both the Japanese version of the Montreal Cognitive Assessment (MoCA-J) and the Neurobehavioral Cognitive Status Examination (COGNISTAT-J). Improvements from baseline for both motor and cognitive assessment were compared. Mean score of all motor assessments (UPDRS total score of Parts II and III, and sub-scores of tremor, rigidity, bradykinesia, gait, and postural instability) and certain cognitive assessments (MoCA-J total score and subscore of delayed recall) significantly improved with dopaminergic medication. Gait score improvement showed significant positive correlation with improvement in MoCA-J language domain and in language-comprehension subtests of COGNISTAT-J using Spearman's correlation coefficients. Furthermore, multiple regression analysis showed gait score improvement significantly correlated with improvements in the subtests of language-comprehension in COGNISTAT-J. There is correlated improvement in both gait and language function in de novo PD patients in response to dopaminergic drugs. Gait and language dysfunction in these patients may share a common pathophysiology linked to dopamine deficits.

  4. In vitro maintenance of Schistosoma japonicum and surgical transfer from donor to naïve recipient pigs.

    PubMed

    Schou, T W; Bøgh, H O; Willingham, A L; Brück, I; Nielsen, C G; Sørensen, E; Eriksen, L; Andreassen, J

    1997-12-15

    An objective of this study was to find a culture medium and a temperature range suitable for in vitro maintenance of adult Schistosoma japonicum during surgical transplantation experiments. Adult S. japonicum were cultivated in four different media (NCTC 135, NCTC 109, RPMI 1640 and 0.85% physiological saline) supplemented with 10% heat-inactivated normal pig serum (hiNPS) at either 4 degrees C, 22-25 degrees C (room temperature) or 37 degrees C. Based on survival and morphologic evaluation, NCTC 135 at room temperature was found to be the best medium/temperature combination for maintenance of worms. An additional objective was to develop a method for transplanting adult S. japonicum from experimentally infected donor pigs to naïve recipient pigs. Six Landrace/Yorkshire crossbred pigs were used as donors to supply worms for two recipient pigs. Worms for transplantation were obtained by perfusion of the mesenteric veins of the donor pigs and maintained for a maximum of 3 h in NCTC 135 + 10% hiNPS at room temperature. A total of 148 and 132 worms were surgically transferred by way of an infusion tube into caecal veins of the two recipients. Six weeks after transplantation, 14% and 36% of the transferred worms were recovered by perfusion and subsequent manual inspection of the mesenteric veins of the two recipient pigs, respectively. The successful results suggest that surgical transfer of S. japonicum worms from donor to naïve recipient pigs may be useful for future studies on population genetics, dynamics and regulation in the pig/S. japonicum model.

  5. Neurocognitive Function in Acromegaly after Surgical Resection of GH-Secreting Adenoma versus Naïve Acromegaly

    PubMed Central

    Martín-Rodríguez, Juan Francisco; Madrazo-Atutxa, Ainara; Venegas-Moreno, Eva; Benito-López, Pedro; Gálvez, María Ángeles; Cano, David A.; Tinahones, Francisco J.; Torres-Vela, Elena; Soto-Moreno, Alfonso; Leal-Cerro, Alfonso

    2013-01-01

    Patients with active untreated acromegaly show mild to moderate neurocognitive disorders that are associated to chronic exposure to growth hormone (GH) and insulin-like growth factor (IGF-I) hypersecretion. However, it is unknown whether these disorders improve after controlling GH/IGF-I hypersecretion. The aim of this study was to compare neurocognitive functions of patients who successfully underwent GH-secreting adenoma transsphenoidal surgery (cured patients) with patients with naive acromegaly. In addition, we wanted to determine the impact of different clinical and biochemical variables on neurocognitive status in patients with active disease and after long-term cure. A battery of six standardized neuropsychological tests assessed attention, memory and executive functioning. In addition, a quantitative electroencephalography with Low-Resolution Electromagnetic Tomography (LORETA) solution was performed to obtain information about the neurophysiological state of the patients. Neurocognitive data was compared to that of a healthy control group. Multiple linear regression analysis was also conducted using clinical and hormonal parameters to obtain a set of independent predictors of neurocognitive state before and after cure. Both groups of patients scored significantly poorer than the healthy controls on memory tests, especially those assessing visual and verbal recall. Patients with cured acromegaly did not obtain better cognitive measures than naïve patients. Furthermore memory deficits were associated with decreased beta activity in left medial temporal cortex in both groups of patients. Regression analysis showed longer duration of untreated acromegaly was associated with more severe neurocognitive complications, regardless of the diagnostic group, whereas GH levels at the time of assessment was related to neurocognitive outcome only in naïve patients. Longer duration of post-operative biochemical remission of acromegaly was associated with better

  6. Education for Employment. A Follow-up of 1987-1988 Suggestions and Recommendations. ICoVE's 1989-1990-1991 Report.

    ERIC Educational Resources Information Center

    Illinois State Council on Vocational Education, Springfield.

    This 3-year follow-up report describes actions taken by the Illinois Council on Vocational Education (ICoVE) during 1989, 1990, and 1991. It addresses the 140 suggestions and 29 recommendations of 12 technical reports (spanning 1987 and 1988) related to education for employment. Recommendations from 1987-88 and follow-up actions are reported on…

  7. Special Populations. A Follow-up of 1987-1988 Suggestions and Recommendations. ICoVE's 1989-1990-1991 Report.

    ERIC Educational Resources Information Center

    Illinois State Council on Vocational Education, Springfield.

    This 3-year follow-up report describes actions taken by the Illinois Council on Vocational Education (ICoVE) during 1989, 1990, and 1991. It addresses the 66 suggestions and 56 recommendations of 9 technical reports (spanning 1987 and 1988) related to special populations. Recommendations from 1987-88 and follow-up actions are reported on the…

  8. Quality Vocational Education. A Follow-up of 1987-1988 Suggestions and Recommendations. ICoVE's 1989-1990-1991 Report.

    ERIC Educational Resources Information Center

    Illinois State Council on Vocational Education, Springfield.

    This 3-year follow-up report describes actions taken by the Illinois Council on Vocational Education (ICoVE) during 1989, 1990, and 1991. It addresses the 124 suggestions and 35 recommendations of 14 technical reports (spanning 1987 and 1988) related to quality in vocational education. Recommendations from 1987-88 and follow-up actions are…

  9. Private-Sector Involvement. A Follow-up of 1987-1988 Suggestions and Recommendations. ICoVE's 1989-1990-1991 Report.

    ERIC Educational Resources Information Center

    Illinois State Council on Vocational Education, Springfield.

    This 3-year follow-up report describes actions taken by the Illinois Council on Vocational Education (ICoVE) during 1989, 1990, and 1991. It addresses the 45 suggestions and 11 recommendations of 4 technical reports (spanning 1987 and 1988) related to private sector involvement. Recommendations from 1987-88 and follow-up actions are reported on…

  10. Mutations in the Reverse Transcriptase and Protease Genes of Human Immunodeficiency Virus-1 from Antiretroviral Naïve and Treated Pediatric Patients

    PubMed Central

    Bure, Dinesh; Makhdoomi, Muzamil A.; Lodha, Rakesh; Prakash, Somi Sankaran; Kumar, Rajesh; Parray, Hilal A.; Singh, Ravinder; Kabra, Sushil K.; Luthra, Kalpana

    2015-01-01

    The success of highly active antiretroviral therapy (HAART) is challenged by the emergence of resistance-associated mutations in human immunodeficiency virus-1 (HIV-1). In this study, resistance associated mutations in the reverse transcriptase (RT) and protease (PR) genes in antiretroviral therapy (ART) naïve and treated HIV-1 infected pediatric patients from North India were evaluated. Genotyping was successfully performed in 46 patients (30 ART naive and 16 treated) for the RT gene and in 53 patients (27 ART naive and 26 treated) for PR gene and mutations were identified using Stanford HIV Drug Resistance Database. A major drug resistant mutation in RT gene, L74I (NRTI), and two such mutations, K101E and G190A (NNRTI), were observed in two ART naïve patients, while M184V was detected in two ART treated patients. Overall, major resistance associated mutations in RT gene were observed in nine (30%) and seven (36%) of ART naïve and treated children respectively. Minor mutations were identified in PR gene in five children. Few non-clade C viral strains (≈30%) were detected, although subtype C was most predominant. The screening of ART naïve children for mutations in HIV-1 RT and protease genes, before and after initiation of ART is desirable for drug efficacy and good prognosis. PMID:25674767

  11. Mutations in the reverse transcriptase and protease genes of human immunodeficiency virus-1 from antiretroviral naïve and treated pediatric patients.

    PubMed

    Bure, Dinesh; Makhdoomi, Muzamil A; Lodha, Rakesh; Prakash, Somi Sankaran; Kumar, Rajesh; Parray, Hilal A; Singh, Ravinder; Kabra, Sushil K; Luthra, Kalpana

    2015-02-10

    The success of highly active antiretroviral therapy (HAART) is challenged by the emergence of resistance-associated mutations in human immunodeficiency virus-1 (HIV-1). In this study, resistance associated mutations in the reverse transcriptase (RT) and protease (PR) genes in antiretroviral therapy (ART) naïve and treated HIV-1 infected pediatric patients from North India were evaluated. Genotyping was successfully performed in 46 patients (30 ART naive and 16 treated) for the RT gene and in 53 patients (27 ART naive and 26 treated) for PR gene and mutations were identified using Stanford HIV Drug Resistance Database. A major drug resistant mutation in RT gene, L74I (NRTI), and two such mutations, K101E and G190A (NNRTI), were observed in two ART naïve patients, while M184V was detected in two ART treated patients. Overall, major resistance associated mutations in RT gene were observed in nine (30%) and seven (36%) of ART naïve and treated children respectively. Minor mutations were identified in PR gene in five children. Few non-clade C viral strains (≈30%) were detected, although subtype C was most predominant. The screening of ART naïve children for mutations in HIV-1 RT and protease genes, before and after initiation of ART is desirable for drug efficacy and good prognosis.

  12. Aspergillus flavus VelB acts distinctly from VeA in conidiation and may coordinate with FluG to modulate sclerotial production

    USDA-ARS?s Scientific Manuscript database

    Asexual and sexual differentiation in Aspergillus nidulans involve complex control by a number of factors and is light-dependent. The velvet protein, VeA, in A. nidulans is a negative regulator of conidiation and a positive regulator of sexual development. It forms a complex with VelB and LaeA to co...

  13. Having Students Create Short Video Clips to Help Transition from Naïve Conceptions about Mechanics to True Newtonian Physics

    ERIC Educational Resources Information Center

    Corten-Gualtieri, Pascale; Ritter, Christian; Plumat, Jim; Keunings, Roland; Lebrun, Marcel; Raucent, Benoit

    2016-01-01

    Most students enter their first university physics course with a system of beliefs and intuitions which are often inconsistent with the Newtonian frame of reference. This article presents an experiment of collaborative learning aiming at helping first-year students in an engineering programme to transition from their naïve intuition about dynamics…

  14. Sustained attention and planning deficits but intact attentional set-shifting in neuroleptic-naïve first-episode schizophrenia patients.

    PubMed

    Hilti, Caroline C; Delko, Tarik; Orosz, Ariane T; Thomann, Kathrin; Ludewig, Stephan; Geyer, Mark A; Vollenweider, Franz X; Feldon, Joram; Cattapan-Ludewig, Katja

    2010-01-01

    The nature of deficits in tests of sustained attention, planning and attentional set-shifting has not been investigated in neuroleptic-naïve first-episode (FE) schizophrenia patients. Based on previous literature of chronic and medicated FE schizophrenia patients, we predicted that the neuroleptic-naïve patients would show deficits in these cognitive processes. Twenty-nine neuroleptic-naïve FE schizophrenia patients and 33 healthy controls - matched by age, gender, and nicotine consumption - performed 3 tests from the Cambridge Automated Neuropsychological Test Battery (CANTAB) thought to measure these cognitive processes: the Rapid Visual Information Processing task (RVIP, sustained attention), the Stockings of Cambridge task (SOC, planning), and the Intradimensional/Extradimensional set-shifting task (IDED, attention shifting). The patients were significantly impaired in the sensitivity index (A') of the RVIP, and in the number of problems solved with minimum moves on the SOC. Nevertheless, the groups did not differ regarding the number of participants who failed at the crucial extradimensional shift stage of the IDED. Sustained attention and planning abilities are already impaired in neuroleptic-naïve FE schizophrenia patients, whereas set-shifting abilities as measured with the IDED task seem to be intact at illness onset. Since chronic schizophrenia patients have been shown to have impaired IDED performance, we tentatively propose that IDED performance deteriorates over time with illness chronicity and/or medication.

  15. Factors associated with acute-phase response of bisphosphonate-naïve or pretreated women with osteoporosis receiving an intravenous first dose of zoledronate or ibandronate.

    PubMed

    Popp, A W; Senn, R; Curkovic, I; Senn, C; Buffat, H; Popp, P F; Lippuner, K

    2017-03-15

    A first intravenous dose of bisphosphonates may be associated with an acute-phase response (APR). In bisphosphonate-naïve women with postmenopausal osteoporosis, the characteristics and frequency of APR may differ by compound. Prior bisphosphonate exposure was predictive of APR risk and severity.

  16. Normalization with Corresponding Naïve Tissue Minimizes Bias Caused by Commercial Reverse Transcription Kits on Quantitative Real-Time PCR Results

    PubMed Central

    Garcia-Bardon, Andreas

    2016-01-01

    Real-time reverse transcription polymerase chain reaction (PCR) is the gold standard for expression analysis. Designed to improve reproducibility and sensitivity, commercial kits are commonly used for the critical step of cDNA synthesis. The present study was designed to determine the impact of these kits. mRNA from mouse brains were pooled to create serial dilutions ranging from 0.0625 μg to 2 μg, which were transcribed into cDNA using four different commercial reverse-transcription kits. Next, we transcribed mRNA from brain tissue after acute brain injury and naïve mice into cDNA for qPCR. Depending on tested genes, some kits failed to show linear results in dilution series and revealed strong variations in cDNA yield. Absolute expression data in naïve and trauma settings varied substantially between these kits. Normalization with a housekeeping gene failed to reduce kit-dependent variations, whereas normalization eliminated differences when naïve samples from the same region were used. The study shows strong evidence that choice of commercial cDNA synthesis kit has a major impact on PCR results and, consequently, on comparability between studies. Additionally, it provides a solution to overcome this limitation by normalization with data from naïve samples. This simple step helps to compare mRNA expression data between different studies and groups. PMID:27898720

  17. A Study of the Education Professions Development Act Training Programs for Higher Education Personnel, Volume III: The EPDA V-E Training Programs. Final Report.

    ERIC Educational Resources Information Center

    Boyle, E.; Carlson, K.

    Volume III of a study of the Education Professions Development Act (EPDA) training programs for higher education personnel presents the second of a three-faceted approach to assess current needs. This document reviews the task of profiling EPDA V-E training programs to produce a small-scale information system. Section one reviews the profiling…

  18. Endothelial tyrosine kinase receptor B prevents VE-cadherin cleavage and protects against atherosclerotic lesion development in ApoE−/− mice

    PubMed Central

    Jiang, Hong; Huang, Shuhong; Li, Xinyun; Li, Xian; Huang, Shanying; Zhang, Yun; Chen, Zhe-Yu

    2015-01-01

    Tyrosine kinase receptor B (TrkB) is a high-affinity receptor for brain-derived neurotrophic factor (BDNF). In addition to its nervous system functions, TrkB is also expressed in the aortic endothelium. However, the effects of endothelial TrkB signaling on atherosclerosis remained unknown. Immunofluorescence analysis revealed that TrkB expression is downregulated in the endothelium of atherosclerotic lesions from ApoE−/− mice compared with the atheroma-free aorta of WT mice. Endothelial TrkB knockdown led to increased lesion size, lipid deposition and inflammatory responses in the atherosclerotic lesions of the ApoE−/− mice compared with the control mice. Mechanistic studies showed that TrkB activation prevented VE-cadherin shedding by enhancing the interaction between vascular endothelial protein tyrosine phosphatase and VE-cadherin, maintaining VE-cadherin in a dephosphorylated state. Our data demonstrate that TrkB is an endothelial injury-response molecule in atherogenesis. Endothelial BDNF/TrkB signaling reduces VE-cadherin shedding and protects against atherosclerotic lesion development in ApoE−/− mice. PMID:26431274

  19. Interferon-α-induced CD100 on naïve CD8(+) T cells enhances antiviral responses to hepatitis C infection through CD72 signal transduction.

    PubMed

    Li, Bing Jie; He, Yu; Zhang, Ying; Guo, Yong Hong; Zhou, Yun; Zhang, Pei Xin; Wang, Wei; Zhao, Jie Ru; Li, Jin Ge; Zuo, Wei Ze; Fan, Chao; Jia, Zhan Sheng

    2017-02-01

    Objectives We investigated the effects of CD100 on naïve CD8(+) T cells during hepatitis C virus (HCV) infection after interferon-α (IFN-α) therapy to clarify the mechanism underlying the effect of IFN-α in enhancing the antiviral response. Methods The CD100 molecules on subsets of CD8(+) T cells were analysed with flow cytometry. The effects of CD100-overexpressing naïve CD8(+) T cells were determined with ELISAs and an MTT cytotoxicity assay. The role of CD100-CD72 signal transduction was analysed with a neutralization and transwell assays. Results HCV infection reduced CD100 expression on CD8(+) T cells, whereas IFN-α treatment significantly increased CD100 expression on naïve CD8(+) T cells. The increased CD100 interacted with the CD72 receptor and enhanced PBMC cytokine secretion (IFN-γ and tumour necrosis factor-α) and cytotoxicity. Conclusions IFN-α-induced CD100 on naïve CD8(+) T cells promotes PBMC cytokine secretion and cytotoxicity through CD100-CD72 signalling during HCV infection.

  20. Having Students Create Short Video Clips to Help Transition from Naïve Conceptions about Mechanics to True Newtonian Physics

    ERIC Educational Resources Information Center

    Corten-Gualtieri, Pascale; Ritter, Christian; Plumat, Jim; Keunings, Roland; Lebrun, Marcel; Raucent, Benoit

    2016-01-01

    Most students enter their first university physics course with a system of beliefs and intuitions which are often inconsistent with the Newtonian frame of reference. This article presents an experiment of collaborative learning aiming at helping first-year students in an engineering programme to transition from their naïve intuition about dynamics…

  1. Antigen-specific naïve CD8+ T cells produce a single pulse of IFNγ in vivo within hours of infection, but without antiviral effect

    PubMed Central

    Hosking, Martin P.; Flynn, Claudia T.; Whitton, J. Lindsay

    2014-01-01

    In vitro studies have shown that naïve CD8+ T cells are unable to express most of their effector proteins until after at least one round of cell division has taken place. We have re-assessed this issue in vivo, and find that naïve CD8+ T cells mount antigen-specific responses within hours of infection, before proliferation has commenced. Newly-activated naïve antigen specific CD8+ T cells produce a rapid pulse of IFNγ in vivo and begin to accumulate granzyme B and perforin. Later, in vivo cytolytic activity is detectable, coincident with the initiation of cell division. Despite the rapid development of these functional attributes, no antiviral effect was observed early during infection, even when the cells are present in numbers similar to those of virus-specific memory cells. The evolutionary reason for the pulse of IFNγ synthesis by naïve T cells is uncertain, but the lack of antiviral impact suggests that it may be regulatory. PMID:25015828

  2. Transcriptome analysis of Aspergillus flavus reveals veA-dependent regulation of secondary metabolite gene clusters, including the novel aflavarin cluster

    USDA-ARS?s Scientific Manuscript database

    The global regulatory veA gene governs development and secondary metabolism in numerous fungal species, including Aspergillus flavus. This is especially relevant since A. flavus infects crops of agricultural importance worldwide, contaminating them with potent mycotoxins. The most well-known are afl...

  3. Naïve subset develops the most important alloreactive response among human CD4+ T lymphocytes in human leukocyte antigen-identical related setting.

    PubMed

    Chérel, Mathilde; Choufi, Bachra; Trauet, Jacques; Cracco, Pascale; Dessaint, Jean-Paul; Yakoub-Agha, Ibrahim; Labalette, Myriam

    2014-06-01

    In longitudinal clinical studies, receiving a high percentage of allogeneic donor-derived CD4(+) CCR7(+) T cells, which include naïve and central memory subsets have been correlated with increased incidence and severity of acute GVHD. Whether naïve and central memory CD4(+) T-cell subsets contribute more or equally to alloimmune responses are still unclear in human. The aim of this study was to investigate in vitro the alloreactive response of purified naïve, central memory, and effector memory CD4(+) T-cell subsets in HLA identical setting. By coculturing monocyte-derived dendritic cells and purified CD4(+) T-cell subsets, from healthy HLA-identical male and female sibling pairs, we found that naïve CD4(+) CCR7(+) CD45RA(+) T cells developed the highest proliferative response upon stimulation by minor histocompatibility antigens and were progressively driven to produce high levels of interferon-γ, tumor necrosis factor, and interleukin-6. Comparatively, the central memory CD4(+) CCR7(+) CD45RA(neg) subset proliferated to a lower extent and produced very low amounts of pro-inflammatory cytokines while the CCR7(neg) effector memory CD4(+) subset was unresponsive. This study demonstrates the superior capacity of naïve CD4(+) T cells to mount a primary alloreactive response as compared to central memory T cells. Their proliferative response associated with a pro-inflammatory differentiation makes them potentially acute GVHD inducers. These in vitro results in line with what we have observed in clinical studies and may also lend support to approaches of partial selective T-cell depletion for GVHD prevention.

  4. Experimental transmission of avian-like swine H1N1 influenza virus between immunologically naïve and vaccinated pigs.

    PubMed

    Lloyd, Lucy E; Jonczyk, Magdalena; Jervis, Carley M; Flack, Deborah J; Lyall, John; Foote, Alasdair; Mumford, Jennifer A; Brown, Ian H; Wood, James L; Elton, Debra M

    2011-09-01

    Infection of pigs with swine influenza has been studied experimentally and in the field; however, little information is available on the natural transmission of this virus in pigs. Two studies in an experimental transmission model are presented here, one in immunologically naïve and one in a combination of vaccinated and naïve pigs. To investigate the transmission of a recent 'avian-like' swine H1N1 influenza virus in naive piglets, to assess the antibody response to a commercially available vaccine and to determine the efficiency of transmission in pigs after vaccination. Transmission chains were initiated by intranasal challenge of two immunologically naïve pigs. Animals were monitored daily for clinical signs and virus shedding. Pairs of pigs were sequentially co-housed, and once virus was detected in recipients, prior donors were removed. In the vaccination study, piglets were vaccinated and circulating antibody levels were monitored by haemagglutination inhibition assay. To study transmission in vaccinates, a pair of infected immunologically naïve animals was co-housed with vaccinated recipient pigs and further pairs of vaccinates were added sequentially as above. The chain was completed by the addition of naive pigs. Transmission of the H1N1 virus was achieved through a chain of six pairs of naïve piglets and through four pairs of vaccinated animals. Transmission occurred with minimal clinical signs and, in vaccinates, at antibody levels higher than previously reported to protect against infection. © 2011 Blackwell Publishing Ltd.

  5. Gene profiling approach to establish the molecular bases for partial versus full activation of naïve CD8 T lymphocytes.

    PubMed

    Verdeil, Gréory; Puthier, Denis; Nguyen, Catherine; Schmitt-Verhulst, Anne-Marie; Auphan-Anezin, Nathalie

    2002-12-01

    When initial antigen encounter involves optimal antigenic and costimulatory stimuli, naïve CD8 T cells undergo a developmental program that leads to their activation, expansion and acquisition of effector functions (including production of IL-2, IFNgamma and expression of cytolytic effector molecules). A subset of the activated CD8 T cells thrives as long-lived memory cells. Encounter of tissue-associated, and in particular tumor-associated antigen, may often be suboptimal in terms of antigenicity and costimulation, however. We previously developed a model of naïve CD8 T cells from transgenic mice expressing an alloreactive TCR for which a mutant alloantigen behaved as a partial agonist, inducing only some of the effector functions induced by the native alloantigen. To ascertain the molecular bases for the establishment of divergent fates within the same naïve CD8 T cells, we have used cDNA microarrays to monitor sequential gene expression patterns in conditions of full or partial response of these naïve CD8 T cells. Of the 5000 different genes monitored on the array, 18% showed changes in expression in activated versus naïve CD8 T cells, independent of whether stimulation was with full or partial agonist. These included antigen-induced upregulated as well as downregulated genes. Clusters of genes that were differentially expressed were also identified, being either (i) weakly versus strongly, or (ii) transiently versus stably expressed in response to partial and full agonist, respectively. They included (i) genes encoding costimulatory molecules and (ii) genes controlling cytolytic function, cytokine production, and chemokines. Therefore, the cDNA microarray approach was a sensitive tool to provide an exhaustive picture of T cell activation as it could discriminate quantitative, qualitative and dynamic differences in mRNA expression profiles between fully or partially activated T cells.

  6. Tenofovir has inferior efficacy in adefovir-experienced chronic hepatitis B patients compared to nucleos(t)ide-naïve patients

    PubMed Central

    Chung, Goh Eun; Cho, Eun Ju; Lee, Jeong-Hoon; Yoo, Jeong-ju; Lee, Minjong; Cho, Yuri; Lee, Dong Hyeon; Kim, Hwi Young; Yu, Su Jong; Kim, Yoon Jun; Yoon, Jung-Hwan; Zoulim, Fabien

    2017-01-01

    Background/Aims A recent study reported that entecavir had inferior efficacy in nucleos(t)ide analogue (NA)-experienced chronic hepatitis B (CHB) patients compared to NA-naïve patients. We sought to compare the efficacy of tenofovir disoproxil fumarate (TDF) in NA-experienced and NA-naïve CHB patients. Methods We retrospectively enrolled 252 consecutive patients who had a serum hepatitis B virus (HBV) DNA level greater than 2,000 IU/mL at the initiation of TDF treatment and who received TDF for at least 6 months. Complete virologic suppression (CVS) was defined as undetectable serum HBV DNA. We generated a multivariate Cox proportional-hazard model to examine predictive factors that were independently associated with time to CVS. Results The mean age of patients was 48.2 years, and the cohort included 181 NA-naïve patients and 71 NA-experienced patients. The median duration of TDF treatment was 14.4 (interquartile range, 9.5-17.8) months. A total of 167 (92.3%) of 181 NA-naïve patients achieved CVS, and 60 (84.5%) of 71 NA-exposed patients achieved CVS. Forty-nine (89.1%) of 55 patients who previously took an NA aside from adefovir and 11 (68.8%) of 16 adefovir-experienced patients achieved CVS. In multivariable analysis, previous adefovir exposure significantly influenced time to CVS (hazard ratio, 0.37; 95% confidence interval, 0.19-0.72; P=0.003), after adjusting for HBeAg positivity, baseline HBV DNA level and cirrhosis. Conclusions Tenofovir had inferior efficacy in adefovir-experienced CHB patients compared to NA-naïve patients. The response of patients with previous adefovir exposure to TDF monotherapy should be monitored closely. PMID:28190329

  7. Segmentation of white blood cells and comparison of cell morphology by linear and naïve Bayes classifiers.

    PubMed

    Prinyakupt, Jaroonrut; Pluempitiwiriyawej, Charnchai

    2015-06-30

    Blood smear microscopic images are routinely investigated by haematologists to diagnose most blood diseases. However, the task is quite tedious and time consuming. An automatic detection and classification of white blood cells within such images can accelerate the process tremendously. In this paper we propose a system to locate white blood cells within microscopic blood smear images, segment them into nucleus and cytoplasm regions, extract suitable features and finally, classify them into five types: basophil, eosinophil, neutrophil, lymphocyte and monocyte. Two sets of blood smear images were used in this study's experiments. Dataset 1, collected from Rangsit University, were normal peripheral blood slides under light microscope with 100× magnification; 555 images with 601 white blood cells were captured by a Nikon DS-Fi2 high-definition color camera and saved in JPG format of size 960 × 1,280 pixels at 15 pixels per 1 μm resolution. In dataset 2, 477 cropped white blood cell images were downloaded from CellaVision.com. They are in JPG format of size 360 × 363 pixels. The resolution is estimated to be 10 pixels per 1 μm. The proposed system comprises a pre-processing step, nucleus segmentation, cell segmentation, feature extraction, feature selection and classification. The main concept of the segmentation algorithm employed uses white blood cell's morphological properties and the calibrated size of a real cell relative to image resolution. The segmentation process combined thresholding, morphological operation and ellipse curve fitting. Consequently, several features were extracted from the segmented nucleus and cytoplasm regions. Prominent features were then chosen by a greedy search algorithm called sequential forward selection. Finally, with a set of selected prominent features, both linear and naïve Bayes classifiers were applied for performance comparison. This system was tested on normal peripheral blood smear slide images from two datasets. Two sets

  8. BioVeL: a virtual laboratory for data analysis and modelling in biodiversity science and ecology.

    PubMed

    Hardisty, Alex R; Bacall, Finn; Beard, Niall; Balcázar-Vargas, Maria-Paula; Balech, Bachir; Barcza, Zoltán; Bourlat, Sarah J; De Giovanni, Renato; de Jong, Yde; De Leo, Francesca; Dobor, Laura; Donvito, Giacinto; Fellows, Donal; Guerra, Antonio Fernandez; Ferreira, Nuno; Fetyukova, Yuliya; Fosso, Bruno; Giddy, Jonathan; Goble, Carole; Güntsch, Anton; Haines, Robert; Ernst, Vera Hernández; Hettling, Hannes; Hidy, Dóra; Horváth, Ferenc; Ittzés, Dóra; Ittzés, Péter; Jones, Andrew; Kottmann, Renzo; Kulawik, Robert; Leidenberger, Sonja; Lyytikäinen-Saarenmaa, Päivi; Mathew, Cherian; Morrison, Norman; Nenadic, Aleksandra; de la Hidalga, Abraham Nieva; Obst, Matthias; Oostermeijer, Gerard; Paymal, Elisabeth; Pesole, Graziano; Pinto, Salvatore; Poigné, Axel; Fernandez, Francisco Quevedo; Santamaria, Monica; Saarenmaa, Hannu; Sipos, Gergely; Sylla, Karl-Heinz; Tähtinen, Marko; Vicario, Saverio; Vos, Rutger Aldo; Williams, Alan R; Yilmaz, Pelin

    2016-10-20

    Making forecasts about biodiversity and giving support to policy relies increasingly on large collections of data held electronically, and on substantial computational capability and capacity to analyse, model, simulate and predict using such data. However, the physically distributed nature of data resources and of expertise in advanced analytical tools creates many challenges for the modern scientist. Across the wider biological sciences, presenting such capabilities on the Internet (as "Web services") and using scientific workflow systems to compose them for particular tasks is a practical way to carry out robust "in silico" science. However, use of this approach in biodiversity science and ecology has thus far been quite limited. BioVeL is a virtual laboratory for data analysis and modelling in biodiversity science and ecology, freely accessible via the Internet. BioVeL includes functions for accessing and analysing data through curated Web services; for performing complex in silico analysis through exposure of R programs, workflows, and batch processing functions; for on-line collaboration through sharing of workflows and workflow runs; for experiment documentation through reproducibility and repeatability; and for computational support via seamless connections to supporting computing infrastructures. We developed and improved more than 60 Web services with significant potential in many different kinds of data analysis and modelling tasks. We composed reusable workflows using these Web services, also incorporating R programs. Deploying these tools into an easy-to-use and accessible 'virtual laboratory', free via the Internet, we applied the workflows in several diverse case studies. We opened the virtual laboratory for public use and through a programme of external engagement we actively encouraged scientists and third party application and tool developers to try out the services and contribute to the activity. Our work shows we can deliver an operational

  9. Integration of Ixodes ricinus genome sequencing with transcriptome and proteome annotation of the naïve midgut.

    PubMed

    Cramaro, Wibke J; Revets, Dominique; Hunewald, Oliver E; Sinner, Regina; Reye, Anna L; Muller, Claude P

    2015-10-28

    In Europe, Ixodes ricinus ticks are the most important vectors of diseases threatening humans, livestock, wildlife and companion animals. Nevertheless, genomic sequence information is missing and functional annotation of transcripts and proteins is limited. This lack of information is restricting studies of the vector and its interactions with pathogens and hosts. Here we present and integrate the first analysis of the I. ricinus genome with the transcriptome and proteome of the unfed I. ricinus midgut. Whole genome sequencing was performed on I. ricinus ticks and the sequences were de novo assembled. In parallel, I. ricinus ticks were dissected and the midgut transcriptome sequenced. Both datasets were integrated by transcript discovery analysis to identify putative genes and genome contigs were screened for homology. An alignment-based and a motif-search-based approach were combined for the annotation of the midgut transcriptome. Additionally, midgut proteins were identified and annotated by mass spectrometry with public databases and the in-house built transcriptome database as references and results were cross-validated. The de novo assembly of 1 billion DNA sequences to a reference genome of 393 Mb length provides an unprecedented insight into the I. ricinus genome. A homology search revealed sequences in the assembled genome contigs homologous to 89% of the I. scapularis genome scaffolds indicating coverage of most genome regions. We identified moreover 6,415 putative genes. More than 10,000 transcripts from naïve midgut were annotated with respect of predicted function and/or cellular localization. By combining an alignment-based with a motif-search-based annotation approach, we doubled the number of annotations throughout all functional categories. In addition, 574 gel spots were significantly identified by mass spectrometry (p<0.05) and 285 distinct proteins expressed in the naïve midgut were annotated functionally and/or for cellular localization. Our

  10. [Data on rilpivirine in treatment-naïve patients. Lessons from ECHO, THRIVE and STaR].

    PubMed

    Domingo, Pere; Ribera, Esteban

    2013-06-01

    Rilpivirine (RPV) is a new, second-generation nonnucleoside reverse transcriptase inhibitor (NNRTI) that has been recently approved for use in the initial antiretroviral therapy (ART) of treatment-naïve HIV-infected patients, combined with two nucleoside/nucleotide reverse transcriptase inhibitors (NRTI). The approved dose is 25mg once daily with food. RPV has been assessed in a phase IIb study (TMC278-C204) and in three phase III trials (ECHO, THRIVE and STaR). In all of them, RPV was compared with the gold standard, efavirenz (EFV); these studies enrolled a large number of patients (n=1,349 on RPV). RPV was non-inferior to EFV at 48 and 96 weeks. In all the studies and study arms, the tolerability of RPV was better than that of EFV, especially for neuropsychiatric adverse effects, rash, and lipid profile. An analysis of the combined data from the ECHO and THRIVE trials showed marked differences, depending on baseline viral load. The therapeutic efficacy of RPV was superior to that of EFV in patients with a baseline viral load ≤ 100,000 copies/mL, due to a similar virological efficacy and a better tolerability profile. However, in patients with a baseline viral load ≥ 100,000 copies/mL, virological failure was more frequent in the RPV arm, especially in patients with a viral load ≥ 500,000 copies/mL. Emerging resistance mutations to RPV were commonly detected in patients with virological failure, especially in those with a higher baseline viral load. In view of these results, the European Medications Agency and the US Food and Drug Administration have approved the use of RPV in treatment-naïve patients with a baseline viral load ≤ 100,000 copies/mL. Some treatment guidelines have already included RPV among their recommendations. The guidelines of the US Department of Health and Human Services (DHSS) and the International Antiviral Society-USA ((IAS-USA), while awaiting additional data, consider RPV-based regimens as an alternative regimen. The Gesida

  11. Historical Incidence of Spontaneous Lesions in Kidneys from Naïve Swine Utilized In Interventional Renal Denervation Studies.

    PubMed

    Rouselle, Serge D; Dillon, Krista N; Rousselle-Sabiac, Theo H; Brady, Dane A; Tunev, Stefan; Tellez, Armando

    2016-08-01

    The use of preclinical animal models is integral to the safety assessment, pathogenesis research, and testing of diagnostic technologies and therapeutic interventions. With inherent similarity to human anatomy and physiology, various porcine models have been the preferred preclinical model in some research areas such as medical devices, wound healing, and skin therapies. The porcine model has been the cornerstone for interventional cardiology for the evaluation and development of this catheter-based renal denervation (RDN) therapy. The porcine model provides similar vascular access and renal neurovascular anatomy to humans. In these preclinical studies, the downstream kidneys from treated arteries are assessed for possible histopathological changes in the vessel dependent territories. In assessing renal safety following RDN, it becomes critical to distinguish treatment-related changes from pre-existing background pathologies. The incidence of background pathological changes in porcine kidneys has not been previously established in normal clinically healthy. Samples from the cranial, middle, and caudal portion of 331 naïve kidneys from 181 swine were processed histologically to slides and evaluated microscopically. The most commonly encountered spontaneous changes were chronic pyelonephritis found in nearly half of the evaluated naïve kidneys (∼40 %; score 1 = 91 %, score 2 = 8.4 %, score 3 = 0.76 %) followed by chronic interstitial inflammation in 9.7 % of the kidneys (score 1 = 90.6 %, score 2 = 9.4 %). Interestingly, there were a few rare spontaneous vascular changes that could potentially affect data interpretation in interventional and toxicology studies: arteritis and arteriolar dissection. The presence of pelvic cysts was a common occurrence (6.3 %) in the kidney. The domestic swine is a widely used preclinical species in interventional research, namely in the emerging field of transcatheter renal denervation. This

  12. Combination antiretroviral therapy improves cognitive performance and functional connectivity in treatment-naïve HIV-infected individuals.

    PubMed

    Zhuang, Yuchuan; Qiu, Xing; Wang, Lu; Ma, Qing; Mapstone, Mark; Luque, Amneris; Weber, Miriam; Tivarus, Madalina; Miller, Eric; Arduino, Roberto C; Zhong, Jianhui; Schifitto, Giovanni

    2017-08-08

    Our study aimed to investigate the short-term effect of combination antiretroviral therapy (cART) on cognitive performance and functional and structural connectivity and their relationship to plasma levels of antiretroviral (ARV) drugs. Seventeen ARV treatment-naïve HIV-infected individuals (baseline mean CD4 cell count, 479 ± 48 cells/mm(3)) were age matched with 17 HIV-uninfected individuals. All subjects underwent a detailed neurocognitive and functional assessment and magnetic resonance imaging. HIV-infected subjects were scanned before starting cART and 12 weeks after initiation of treatment. Uninfected subjects were assessed once at baseline. Functional connectivity (FC) was assessed within the default mode network while structural connectivity was assessed by voxel-wise analysis using tract-based spatial statistics (TBSS) and probabilistic tractography within the DMN. Tenofovir and emtricitabine blood concentration were measured at week 12 of cART. Prior to cART, HIV-infected individuals had significantly lower cognitive performance than control subjects as measured by the total Z-score from the neuropsychological tests assessing six cognitive domains (p = 0.020). After 12 weeks of cART treatment, there remained only a weak cognitive difference between HIV-infected and HIV-uninfected subjects (p = 0.057). Mean FC was lower in HIV-infected individuals compared with those uninfected (p = 0.008), but FC differences became non-significant after treatment (p = 0.197). There were no differences in DTI metrics between HIV-infected and HIV-uninfected individuals using the TBSS approach and limited evidence of decreased structural connectivity within the DMN in HIV-infected individuals. Tenofovir and emtricitabine plasma concentrations did not correlate with either cognitive performance or imaging metrics. Twelve weeks of cART improves cognitive performance and functional connectivity in ARV treatment-naïve HIV-infected individuals with relatively

  13. Transmitted Drug Resistance Mutations in Antiretroviral-Naïve Injection Drug Users with Chronic HIV-1 Infection in Iran

    PubMed Central

    Memarnejadian, Arash; Menbari, Shahoo; Vahabpour, Rouhollah; Aghasadeghi, Mohammad Reza; Mostafavi, Ehsan; Abdi, Mohammad

    2015-01-01

    The growing incidence and transmission of drug resistant HIV-1 strains due to widespread use of antiretroviral therapy (ART) can jeopardize the success of first-line ART. While there is a known moderate prevalence of transmitted drug resistance (TDR) among newly infected Iranians, no data exist about the rate of these primary resistance mutations among the ART-naïve, chronically infected individuals who are, in fact, the main candidates for ART initiation. To address this issue, we collected blood samples from 40 ART-naïve injection drug-users (IDUs) with chronic HIV-1 infection (seroconversion time ranging from 2 to 9 years) living in Sanandaj, Iran, followed by sequencing of the protease and reverse-transcriptase regions from their HIV-1 genome. Phylogenetic analyses of the sequenced regions revealed that all samples were CRF35_AD. Transmitted resistance mutations were interpreted as surveillance drug-resistant mutations (SDRMs) based on the world health organization (WHO) algorithm. The frequency of SDRMs to any class of antiretroviral drugs was 15%, which included mutations to nucleoside reverse transcriptase inhibitors (NRTIs, 10%), with M41L and M184V as the most common (5%), and non-nucleoside reverse transcriptase inhibitors (NNRTIs, 5%), with K103N as the only detected mutation (5%). Although not in the WHO SDRMs list, several minor protease inhibitor resistant mutations listed in the International Antiviral Society-USA panel were identified, of which M36I, H69K, L89M/V/I (each one 100%) and K20R/T (92.5%) can be considered as polymorphic signatures for CRF35_AD.The relatively high rate of TDR mutations in our study raises concerns about the risk of treatment failure in chronically infected IDUs of Sanandaj city. These results suggest that routine resistance testing should be considered before the therapy initiation in this area. Additional surveillance studies are required to generalize this deduction to other cities of Iran. PMID:25962088

  14. Cost-effectiveness of new antiviral regimens for treatment-naïve U.S. veterans with hepatitis C.

    PubMed

    Chidi, Alexis P; Rogal, Shari; Bryce, Cindy L; Fine, Michael J; Good, Chester B; Myaskovsky, Larissa; Rustgi, Vinod K; Tsung, Allan; Smith, Kenneth J

    2016-02-01

    Recently approved, interferon-free medication regimens for treating hepatitis C are highly effective, but extremely costly. We aimed to identify cost-effective strategies for managing treatment-naïve U.S. veterans with new hepatitis C medication regimens. We developed a Markov model with 1-year cycle length for a cohort of 60-year-old veterans with untreated genotype 1 hepatitis C seeking treatment in a typical year. We compared using sofosbuvir/ledipasvir or ombitasvir/ritonavir/paritaprevir/dasabuvir to treat: (1) any patient seeking treatment; (2) only patients with advanced fibrosis or cirrhosis; or (3) patients with advanced disease first and healthier patients 1 year later. The previous standard of care, sofosbuvir/simeprevir or sofosbuvir/pegylated interferon/ribavirin, was included for comparison. Patients could develop progressive fibrosis, cirrhosis, or hepatocellular carcinoma, undergo transplantation, or die. Complications were less likely after sustained virological response. We calculated the incremental cost per quality-adjusted life year (QALY) and varied model inputs in one-way and probabilistic sensitivity analyses. We used the Veterans Health Administration perspective with a lifetime time horizon and 3% annual discounting. Treating any patient with ombitasvir-based therapy was the preferred strategy ($35,560; 14.0 QALYs). All other strategies were dominated (greater costs/QALY gained than more effective strategies). Varying treatment efficacy, price, and/or duration changed the preferred strategy. In probabilistic sensitivity analysis, treating any patient with ombitasvir-based therapy was cost-effective in 70% of iterations at a $50,000/QALY threshold and 65% of iterations at a $100,000/QALY threshold. Managing any treatment-naïve genotype 1 hepatitis C patient with ombitasvir-based therapy is the most economically efficient strategy, although price and efficacy can impact cost-effectiveness. It is economically unfavorable to restrict

  15. Multiple signal propagation at the tropopause of the Venusian atmosphere: new insights from the Radio Science Experiment (VeRa) onboard Venus Express

    NASA Astrophysics Data System (ADS)

    Herrmann, Maren; Oschlisniok, Janusz; Remus, Stefan; Tellmann, Silvia; Häusler, Bernd; Pätzold, Martin

    2016-10-01

    The rapid change of the refractive index over a short altitude range in a planetary atmosphere can lead to multi-path effects when sounding the atmosphere with radio waves. The Radio Science Experiment (VeRa) [1,2] onboard Venus Express sounded the Venusian atmosphere from 90 km downward to 40 km altitude[3,4]. More than 800 profiles of temperature, pressure and neutral number density could be retrieved which cover almost all local times and latitudes. A specially developed analysis method based on the VeRa open loop receiving technique deciphers the multi-path effect and identifies an inversion layer near the tropopause at an altitude of about 60km. This layer is of particular interest - it separates the stratified troposphere from the highly variable mesosphere and can be a likely location for the formation of gravity waves [5]. The new retrieval method shows an inversion layer up to 15 K colder than commonly thought. Local time and latitude dependence including the influence of the spacecraft trajectory on this effect will be discussed. These results will contribute to a consistent picture of the Venus' thermal atmosphere structure and therefore help to improve atmospheric models.[1] Häusler, B. et al: 'Radio science investigations by VeRa onboard the Venus Express spacecraft' Planetary and Space Science 54, 2006[2] Häusler, B. et al, 'Venus Atmospheric, Ionospheric, Surface and Interplanetery Radio-Wave Propagation Studies with the VeRa Radio Science experiment' Eur. Space Agencys, Spec. Publ., ESA SP 1295, 2007[3] Pätzold, M. et al: 'The structure of Venus' middle atmosphere and ionosphere', Nature 450, 2007[4] Tellmann, S. et al : 'Structure of the Venus neutral atmosphere as observed by the Radio Science experiment VeRa on Venus Express', Journal of Geophysical Research 114, 2009[5] Tellmann, S. et al: 'Small-scale temperature fluctuations seen by the VeRa Radio Science Experiment on Venus Express' Icarus 221, 2012.

  16. Generation of Naïve Bovine Induced Pluripotent Stem Cells Using PiggyBac Transposition of Doxycycline-Inducible Transcription Factors.

    PubMed

    Kawaguchi, Takamasa; Tsukiyama, Tomoyuki; Kimura, Koji; Matsuyama, Shuichi; Minami, Naojiro; Yamada, Masayasu; Imai, Hiroshi

    2015-01-01

    Generation of pluripotent stem cells (PSCs) in large domestic animals has achieved only limited success; most of the PSCs obtained to date have been classified as primed PSCs, which possess very little capacity to produce chimeric offspring. By contrast, mouse PSCs have been classified as naïve PSCs that can contribute to most of the tissues of chimeras, including germ cells. Here, we describe the generation of two different types of bovine induced pluripotent stem cells (biPSCs) from amnion cells, achieved through introduction of piggyBac vectors containing doxycycline-inducible transcription factors (Oct3/4, Sox2, Klf4, and c-Myc). One type of biPSCs, cultured in medium supplemented with knockout serum replacement (KSR), FGF2, and bovine leukemia inhibitory factor (bLIF), had a flattened morphology like human PSCs; these were classified as primed-type. The other type biPSCs, cultured in KSR, bLIF, Mek/Erk inhibitor, GSK3 inhibitor and forskolin, had a compact morphology like mouse PSCs; these were classified as naïve-type. Cells could easily be switched between these two types of biPSCs by changing the culture conditions. Both types of biPSCs had strong alkaline phosphatase activity, expressed pluripotent markers (OCT3/4, NANOG, REX1, ESRRβ, STELLA, and SOCS3), and formed embryoid bodies that gave rise to differentiated cells from all three embryonic germ layers. However, only naïve-type biPSCs showed the hallmarks of naïve mouse PSCs, such as LIF-dependent proliferation, lack of FGF5 expression, and active XIST expression with two active X chromosomes. Furthermore, naïve-type biPSCs could contribute to the inner cell mass (ICM) of host blastocysts and most tissues within chimeric embryos. This is the first report of generation of biPSCs with several characteristics similar to those of naïve mouse PSCs and a demonstrated potential to contribute to chimeras.

  17. Generation of Naïve Bovine Induced Pluripotent Stem Cells Using PiggyBac Transposition of Doxycycline-Inducible Transcription Factors

    PubMed Central

    Kawaguchi, Takamasa; Tsukiyama, Tomoyuki; Kimura, Koji; Matsuyama, Shuichi; Minami, Naojiro; Yamada, Masayasu; Imai, Hiroshi

    2015-01-01

    Generation of pluripotent stem cells (PSCs) in large domestic animals has achieved only limited success; most of the PSCs obtained to date have been classified as primed PSCs, which possess very little capacity to produce chimeric offspring. By contrast, mouse PSCs have been classified as naïve PSCs that can contribute to most of the tissues of chimeras, including germ cells. Here, we describe the generation of two different types of bovine induced pluripotent stem cells (biPSCs) from amnion cells, achieved through introduction of piggyBac vectors containing doxycycline-inducible transcription factors (Oct3/4, Sox2, Klf4, and c-Myc). One type of biPSCs, cultured in medium supplemented with knockout serum replacement (KSR), FGF2, and bovine leukemia inhibitory factor (bLIF), had a flattened morphology like human PSCs; these were classified as primed-type. The other type biPSCs, cultured in KSR, bLIF, Mek/Erk inhibitor, GSK3 inhibitor and forskolin, had a compact morphology like mouse PSCs; these were classified as naïve-type. Cells could easily be switched between these two types of biPSCs by changing the culture conditions. Both types of biPSCs had strong alkaline phosphatase activity, expressed pluripotent markers (OCT3/4, NANOG, REX1, ESRRβ, STELLA, and SOCS3), and formed embryoid bodies that gave rise to differentiated cells from all three embryonic germ layers. However, only naïve-type biPSCs showed the hallmarks of naïve mouse PSCs, such as LIF-dependent proliferation, lack of FGF5 expression, and active XIST expression with two active X chromosomes. Furthermore, naïve-type biPSCs could contribute to the inner cell mass (ICM) of host blastocysts and most tissues within chimeric embryos. This is the first report of generation of biPSCs with several characteristics similar to those of naïve mouse PSCs and a demonstrated potential to contribute to chimeras. PMID:26287611

  18. Efficacy of a preservative-free formulation of fixed-combination bimatoprost and timolol (Ganfort PF) in treatment-naïve patients vs previously treated patients

    PubMed Central

    Cordeiro, M Francesca; Goldberg, Ivan; Schiffman, Rhett; Bernstein, Paula; Bejanian, Marina

    2015-01-01

    Purpose To evaluate, using subgroup analysis, the effect of treatment status on the intraocular pressure (IOP)-lowering efficacy of a preservative-free formulation of fixed-combination bimatoprost 0.03%/timolol 0.5% (FCBT PF). Methods A primary, multicenter, randomized, double-masked, 12-week study compared the efficacy and safety of FCBT PF with preserved FCBT (Ganfort®) in 561 patients diagnosed with glaucoma or ocular hypertension. For this analysis, eligible patients were treatment-naïve or had inadequate IOP lowering and underwent a washout of previous treatment. IOP (8 am, 10 am, and 4 pm) was measured at baseline and weeks 2, 6, and 12. Subgroup analysis of the FCBT PF arm assessed changes in average eye IOP from baseline in treatment-naïve vs previously treated patients. To evaluate the effect of treatment status at baseline (treatment-naïve vs previously treated) on IOP reduction in the FCBT PF treatment group, an analysis of covariance model was used with treatment status and investigator as fixed effects, and baseline average eye IOP, age, glaucoma diagnosis, and baseline average eye corneal thickness as covariates. P-values and the 95% confidence intervals were determined using the model. Results In the FCBT PF arm, IOP mean changes from baseline ranged from −8.7 mmHg to −9.8 mmHg in treatment-naïve patients (N=50), compared with −7.3 mmHg to −8.5 mmHg in previously treated patients (N=228). Baseline IOP, age, glaucoma diagnosis, and corneal thickness significantly affected IOP reduction in the FCBT PF group. Adjusting for these covariates, FCBT PF had a greater IOP-lowering effect (0.8–1.7 mmHg) in treatment-naïve patients than previously treated patients, which was statistically significant (P≤0.05) at seven of nine time points. Conclusion In this subgroup analysis, FCBT PF reduced IOP more effectively in treatment-naïve than in previously treated patients possibly due, in part, to altered responsiveness or tachyphylaxis that has

  19. Viral metagenomics in drug-naïve, first-onset schizophrenia patients with prominent negative symptoms.

    PubMed

    Canuti, Marta; van Beveren, Nico J M; Jazaeri Farsani, Seyed Mohammad; de Vries, Michel; Deijs, Martin; Jebbink, Maarten F; Zaaijer, Hans L; van Schaik, Barbera D C; van Kampen, Antoine H C; van der Kuyl, Antoinette C; de Haan, Lieuwe; Storosum, Jitschak G; van der Hoek, Lia

    2015-10-30

    Although several studies suggest a virus or (endogenous) retrovirus involvement at the time of onset of schizophrenia, the unequivocal identification of one or more infectious agents, by means of an undirected catch-all technique, has never been conducted. In this study VIDISCA, a virus discovery method, was used in combination with Roche-454 high-throughput sequencing as a tool to determine the possible presence of viruses (known or unknown) in blood of first-onset drugs-naïve schizophrenic patients with prominent negative symptoms. Two viruses (the Anellovirus Torque Teno virus and GB virus C) were detected. Both viruses are commonly found in healthy individuals and no clear link with disease was ever established. Viruses from the family Anelloviridae were also identified in the control population (4.8%). Besides, one patient sample was positive for human endogenous retroviruses type K (HML-2) RNA but no specific predominant strain was detected, instead 119 different variants were found. In conclusion, these findings indicate no evidence for viral or endogenous retroviral involvement in sera at the time of onset of schizophrenia. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  20. Integrating Entropy-Based Naïve Bayes and GIS for Spatial Evaluation of Flood Hazard.

    PubMed

    Liu, Rui; Chen, Yun; Wu, Jianping; Gao, Lei; Barrett, Damian; Xu, Tingbao; Li, Xiaojuan; Li, Linyi; Huang, Chang; Yu, Jia

    2017-04-01

    Regional flood risk caused by intensive rainfall under extreme climate conditions has increasingly attracted global attention. Mapping and evaluation of flood hazard are vital parts in flood risk assessment. This study develops an integrated framework for estimating spatial likelihood of flood hazard by coupling weighted naïve Bayes (WNB), geographic information system, and remote sensing. The north part of Fitzroy River Basin in Queensland, Australia, was selected as a case study site. The environmental indices, including extreme rainfall, evapotranspiration, net-water index, soil water retention, elevation, slope, drainage proximity, and density, were generated from spatial data representing climate, soil, vegetation, hydrology, and topography. These indices were weighted using the statistics-based entropy method. The weighted indices were input into the WNB-based model to delineate a regional flood risk map that indicates the likelihood of flood occurrence. The resultant map was validated by the maximum inundation extent extracted from moderate resolution imaging spectroradiometer (MODIS) imagery. The evaluation results, including mapping and evaluation of the distribution of flood hazard, are helpful in guiding flood inundation disaster responses for the region. The novel approach presented consists of weighted grid data, image-based sampling and validation, cell-by-cell probability inferring and spatial mapping. It is superior to an existing spatial naive Bayes (NB) method for regional flood hazard assessment. It can also be extended to other likelihood-related environmental hazard studies. © 2016 Society for Risk Analysis.

  1. Recommendations for patient engagement in guideline development panels: A qualitative focus group study of guideline-naïve patients

    PubMed Central

    Mullins, C. Daniel; Gronseth, Gary S.; Gagliardi, Anna R.

    2017-01-01

    Background Patient and consumer engagement in clinical practice guideline development is internationally advocated, but limited research explores mechanisms for successful engagement. Objective To investigate the perspectives of potential patient/consumer guideline representatives on topics pertaining to engagement including guideline development group composition and barriers to and facilitators of engagement. Setting and participants Participants were guideline-naïve volunteers for programs designed to link community members to academic research with diverse ages, gender, race, and degrees of experience interacting with health care professionals. Methods Three focus groups and one key informant interview were conducted and analyzed using a qualitative descriptive approach. Results Participants recommended small, diverse guideline development groups engaging multiple patient/consumer stakeholders with no prior relationships with each other or professional panel members. No consensus was achieved on the ideal balance of patient/consumer and professional stakeholders. Pre-meeting reading/training and an identified contact person were described as keys to successful early engagement; skilled facilitators, understandable speech and language, and established mechanisms for soliciting patient opinions were suggested to enhance engagement at meetings. Conclusions Most suggestions for effective patient/consumer engagement in guidelines require forethought and planning but little additional expense, making these strategies easily accessible to guideline developers desiring to achieve more meaningful patient and consumer engagement. PMID:28319201

  2. Successful sulfonylurea treatment of an insulin-naïve neonate with diabetes mellitus due to a KCNJ11 mutation.

    PubMed

    Wambach, Jennifer A; Marshall, Bess A; Koster, Joseph C; White, Neil H; Nichols, Colin G

    2010-06-01

    Activating mutations in the K(ATP)-channel cause neonatal diabetes mellitus (NDM), and patients have been safely transitioned from insulin to sulfonylureas. We report a male infant with permanent NDM (PNDM), born to a PNDM mother. Blood glucose began to rise on day of life (DOL) 2, and sulfonylurea (glyburide) therapy was initiated on DOL 5. Glucose was subsequently well controlled and normal at 3 months. A K(ATP) mutation (R201H; KCNJ11) was detected in the infant, the mother, and 6-yr-old sister with PNDM; both were also subsequently transitioned off insulin onto glyburide. To our knowledge, this is the youngest NDM patient to receive oral glyburide and, importantly, the only one deliberately initiated on sulfonylureas. Strikingly, the current dose (0.017 mg/kg/d) is below the reported therapeutic range and approximately 75-fold lower than doses required by the affected sister and mother. Pancreatic insulin disappears in an animal model of K(ATP)-induced NDM, unless glycemia is well controlled, thus, a dramatically lower glyburide requirement in the infant may reflect preserved insulin content because of early sulfonylurea intervention. Safe and effective initiation of glyburide in an insulin-naïve neonatal patient with K(ATP)-dependent PNDM argues for early detection and sulfonylurea intervention.

  3. Regulation of naïve fetal T-cell migration by the chemokines Exodus-2 and Exodus-3.

    PubMed

    Christopherson, K; Brahmi, Z; Hromas, R

    1999-08-03

    We and other workers have recently isolated three novel CC chemokines termed Exodus-1/LARC/Mip-3alpha, Exodus-2/6Ckine/SLC/TCA4, and Exodus-3/Mip-3beta/CKbeta11/ELC. These chemokines share an amino terminal Asp-Cys-Cys-Leu sequence, unique among all chemokines. They also selectively regulate migration of adult T cells. Indeed, there is evidence that Exodus-2 and -3 are critical for adult T-cell adhesion to high endothelial venules in lymph nodes, a rate-limiting step for T-cell trafficking through nodal tissue. Less is known of the factors controlling migration of naïve human fetal T cells. We tested whether these chemokines could regulate chemotaxis in cord blood T-cell populations, and compared that efficacy with normal peripheral blood adult T cells. The findings indicated that naive CD45RA+ cord blood T-cell migration is stimulated by Exodus-2 and -3, and CD4+ cord blood T cells are attracted preferentially by Exodus-2 or -3 as compared with CD8+. Exodus-2 and -3 are likely to be critical in regulating the flux of naive CD4 + fetal T-cell population of secondary lymphoid tissue.

  4. Prediction of psychosis using neural oscillations and machine learning in neuroleptic-naïve at-risk patients.

    PubMed

    Ramyead, Avinash; Studerus, Erich; Kometer, Michael; Uttinger, Martina; Gschwandtner, Ute; Fuhr, Peter; Riecher-Rössler, Anita

    2016-06-01

    This study investigates whether abnormal neural oscillations, which have been shown to precede the onset of frank psychosis, could be used towards the individualised prediction of psychosis in clinical high-risk patients. We assessed the individualised prediction of psychosis by detecting specific patterns of beta and gamma oscillations using machine-learning algorithms. Prediction models were trained and tested on 53 neuroleptic-naïve patients with a clinical high-risk for psychosis. Of these, 18 later transitioned to psychosis. All patients were followed up for at least 3 years. For an honest estimation of the generalisation capacity, the predictive performance of the models was assessed in unseen test cases using repeated nested cross-validation. Transition to psychosis could be predicted from current-source density (CSD; area under the curve [AUC] = 0.77), but not from lagged phase synchronicity data (LPS; AUC = 0.56). Combining both modalities did not improve the predictive accuracy (AUC = 0.78). The left superior temporal gyrus, the left inferior parietal lobule and the precuneus most strongly contributed to the prediction of psychosis. Our results suggest that CSD measurements extracted from clinical resting state EEG can help to improve the prediction of psychosis on a single-subject level.

  5. The Structure of the Venus Neutral Atmosphere from the Radio Science Experiment VeRa on Venus Express

    NASA Astrophysics Data System (ADS)

    Tellmann, S. A.; Häusler, B.; Pätzold, M.; Bird, M. K.; Tyler, G. L.

    2007-12-01

    The Venus Express Radio Science Experiment VeRa is sounding the Venus neutral atmosphere and ionosphere using the spacecraft radio subsystem in the oneway radio link mode. An Ultrastable Oscillator (USO) provides a high quality onboard frequency reference source for the derivation of electron density profiles in the ionosphere and profiles of pressure, temperature and neutral number density of the neutral atmosphere. The measurement configuration allows an altitude resolution of only a few hundred metres from the cloud deck at about 40 km to approximately 100 km. Three occultation seasons could be covered in the first two years of the Venus Express mission resulting in a data set of about 140 profiles of the neutral atmosphere. The polar orbit of Venus Express provides the opportunity to study the atmosphere at all planetocentric latitudes under varying illumination conditions. Special attention will be given to day-night variations of the thermal structure and the temperature distribution at high polar latitudes on both hemispheres ("cold collar region") and signal absorption effects caused by the H2SO4 vapour.

  6. Assessing sandy beach macrofaunal patterns along large-scale environmental gradients: A Fuzzy Naïve Bayes approach

    NASA Astrophysics Data System (ADS)

    Bozzeda, Fabio; Zangrilli, Maria Paola; Defeo, Omar

    2016-06-01

    A Fuzzy Naïve Bayes (FNB) classifier was developed to assess large-scale variations in abundance, species richness and diversity of the macrofauna inhabiting fifteen Uruguayan sandy beaches affected by the effects of beach morphodynamics and the estuarine gradient generated by Rio de la Plata. Information from six beaches was used to estimate FNB parameters, while abiotic data of the remaining nine beaches were used to forecast abundance, species richness and diversity. FNB simulations reproduced the general increasing trend of target variables from inner estuarine reflective beaches to marine dissipative ones. The FNB model also identified a threshold value of salinity range beyond which diversity markedly increased towards marine beaches. Salinity range is suggested as an ecological master factor governing distributional patterns in sandy beach macrofauna. However, the model: 1) underestimated abundance and species richness at the innermost estuarine beach, with the lowest salinity, and 2) overestimated species richness in marine beaches with a reflective morphodynamic state, which is strongly linked to low abundance, species richness and diversity. Therefore, future modeling efforts should be refined by giving a dissimilar weigh to the gradients defined by estuarine (estuarine beaches) and morphodynamic (marine beaches) variables, which could improve predictions of target variables. Our modeling approach could be applied to a wide spectrum of issues, ranging from basic ecology to social-ecological systems. This approach seems relevant, given the current challenge to develop predictive methodologies to assess the simultaneous and nonlinear effects of anthropogenic and natural impacts in coastal ecosystems.

  7. Discovery of a ROCK inhibitor, FPND, which prevents cerebral hemorrhage through maintaining vascular integrity by interference with VE-cadherin

    PubMed Central

    Li, Shang; Ai, Nana; Shen, Mingyun; Dang, Yuanye; Chong, Cheong-Meng; Pan, Peichen; Kwan, Yiu Wa; Chan, Shun Wan; Leung, George Pak Heng; Hoi, Maggie Pui Man; Hou, Tingjun; Lee, Simon Ming-Yuen

    2017-01-01

    Hemorrhagic stroke occurs when a weakened vessel ruptures and bleeds into the surrounding brain, leading to high rates of death and disability worldwide. A series of complex pathophysiological cascades contribute to the risk of hemorrhagic stroke, and no therapies have proven effective to prevent hemorrhagic stroke. Stabilization of vascular integrity has been considered as a potential therapeutic target for hemorrhagic stroke. ROCKs, which belong to the serine/threonine protein kinase family and participate in the organization of actin cytoskeleton, have become attractive targets for the treatment of strokes. In this study, in vitro enzyme-based assays revealed that a new compound (FPND) with a novel scaffold identified by docking-based virtual screening could inhibit ROCK1 specifically at low micromolar concentration. Molecular modeling showed that FPND preferentially interacted with ROCK1, and the difference between the binding affinity of FPND toward ROCK1 and ROCK2 primarily resulted from non-polar contributions. Furthermore, FPND significantly prevented statin-induced cerebral hemorrhage in a zebrafish model. In addition, in vitro studies using the xCELLigence RTCA system, immunofluorescence and western blotting revealed that FPND prevented statin-induced cerebral hemorrhage by enhancing endothelial cell–cell junctions through inhibiting the ROCK-mediated VE-cadherin signaling pathway. As indicated by the extremely low toxicity of FPND against mice, it is safe and can potentially prevent vascular integrity loss-related diseases, such as hemorrhagic stroke. PMID:28845297

  8. Testosterone in Newly Diagnosed, Antipsychotic-Naïve Men with Nonaffective Psychosis: A Test of the Accelerated Aging Hypothesis

    PubMed Central

    Fernandez-Egea, Emilio; García-Rizo, Clemente; Miller, Brian; Parellada, Eduard; Justicia, Azucena; Bernardo, Miguel; Kirkpatrick, Brian

    2011-01-01

    Objective Schizophrenia has been associated with age-related abnormalities, including abnormal glucose tolerance, increased pulse pressure, increased inflammation, abnormal stem cell signalling and shorter telomere length. These metabolic abnormalities as well as other findings suggest schizophrenia and related disorders might be associated with accelerated aging. Testosterone activity has a progressive decline with increasing age. Methods We tested the hypothesis that circulating biologically active testosterone is lower in newly diagnosed, antipsychotic-naïve male patients with nonaffective psychosis than in matched control subjects. Results Patients (n=33) were matched to control subjects (n=33) for age, gender, body mass index, socioeconomic status of the family of origin, and smoking. The free androgen index (FAI), a measure of biologically active testosterone, was significantly lower in the psychosis group [mean 57.7%, SD=26.1] than in control subjects [71.6%, 27.0; p=0.04], with an effect size of 0.53. Multivariate analysis also supported the findings. In the psychosis group, FAI had a significant negative correlation with the conceptual disorganization item (r=-0.35, p=0.049), but not with reality distortion (r=-0.21; p=0.24), negative symptoms (r=0.004; p=0.98) or depression (r=-0.014; p=0.94). Conclusion Lower testosterone is consistent with accelerated aging in nonaffective psychosis, but further testing of this hypothesis is needed. PMID:21949421

  9. Insulin-like growth factor-1 and progression of motor symptoms in early, drug-naïve Parkinson's disease.

    PubMed

    Picillo, Marina; Erro, Roberto; Santangelo, Gabriella; Pivonello, Rosario; Longo, Katia; Pivonello, Claudia; Vitale, Carmine; Amboni, Marianna; Moccia, Marcello; Colao, Annamaria; Barone, Paolo; Pellecchia, Maria Teresa

    2013-07-01

    Much pre-clinical evidence show that insulin-like growth factor 1 (IGF-1) provides protection against loss of dopaminergic neurons. Recently, IGF-1 has been proposed as a possible biomarker for early diagnosis of Parkinson's disease (PD). We aimed to assess the relationship between serum IGF-1 levels and progression of motor symptoms in a cohort of drug-naïve PD patients. Serum IGF-1 was measured at baseline in 37 early, drug-naive PD patients; subsequently, patients were evaluated "on drug" by means of UPDRS-III, UPDRS dopa-resistant score and dopaminergic score at 12, 18 and 24 month follow-up. Repeated measures ANOVA was used both to evaluate progression of motor scores within time and differences between serum IGF-1 quartiles, age at onset and motor phenotype. Patients at the highest IGF-1 quartile were found to have significantly higher UPDRS-III (p < 0.001) and dopaminergic score (p < 0.001), as compared to patients at other quartiles. Mean serum IGF-1 level was moderately increased in PD as compared to healthy controls (p < 0.011). IGF-1 levels are related to those symptoms predominantly responsive to dopaminergic treatment. This is the first study to demonstrate a relationship between serum IGF-1 and progression of motor symptoms in the early stage of disease.

  10. Persisting primitive reflexes in medication-naïve girls with attention-deficit and hyperactivity disorder

    PubMed Central

    Konicarova, Jana; Bob, Petr; Raboch, Jiri

    2013-01-01

    Background and objectives Recent and historical findings suggest that later-developed functions during brain ontogenesis related to higher levels of cognitive and motor integration tend to replace the older, more primitive, ones, and the persistence of the older functions may be linked to specific neuropsychiatric disorders. Currently, there is growing evidence to suggest that persisting primitive reflexes may be related to developmental and neurodegenerative disorders. Preliminary data also suggest that persisting primitive reflexes may be specifically linked to attention-deficit and hyperactivity disorder (ADHD). Methods In the study reported here, we tested to what extent the persisting primitive asymmetric tonic neck reflex and symmetric tonic neck reflex are related to ADHD symptoms measured by Conners’ Parent Questionnaire in 35 medication-naïve girls of school age (8–11 years) with ADHD. The results were compared with those of a control group of 30 girls of the same age. Results This study showed that persisting primitive reflexes are closely linked to ADHD symptoms. Conclusion The data suggest that ADHD symptoms may be linked to more primitive neural mechanisms interfering with higher brain functions due to insufficiently developed cognitive and motor integration. PMID:24092983

  11. Karhunen–Loève treatment to remove noise and facilitate data analysis in sensing, spectroscopy and other applications

    SciTech Connect

    Zaharov, Viktor; Farahi, R. H.; Snyder, Patrick J; Davison, Brian H.; Passian, Ali

    2014-09-08

    Resolving weak spectral variations in the dynamic response of materials that are either dominated or excited by stochastic processes remains a challenge. Responses that are thermal in origin are particularly relevant examples due to the delocalized nature of heat. Despite its inherent properties in dealing with stochastic processes, the Karhunen–Loève expansion has not been fully exploited in measurement of systems that are driven solely by random forces or can exhibit large thermally driven random fluctuations. Here in this paper, we present experimental results and analysis of the archetypes (a) the resonant excitation and transient response of an atomic force microscope probe by the ambient random fluctuations and nanoscale photothermal sample response, and (b) the photothermally scattered photons in pump–probe spectroscopy. In each case, the dynamic process is represented as an infinite series with random coefficients to obtain pertinent frequency shifts and spectral peaks and demonstrate spectral enhancement for a set of compounds including the spectrally complex biomass. The considered cases find important applications in nanoscale material characterization, biosensing, and spectral identification of biological and chemical agents.

  12. Pressure Distribution over a Wing and Tail Rib of a VE-7 and of a TS Airplane in Flight

    NASA Technical Reports Server (NTRS)

    Crowley, J W , Jr

    1928-01-01

    This investigation was made to determine the pressure distribution over a rib of the wing and over a rib of the horizontal tail surface of an airplane in flight and to obtain information as to the time correlation of the loads occurring on these ribs. Two airplanes, VE-7 and TS, were selected in order to obtain the information for a thin and a thick wing section. In each case the pressure distribution was recorded for the full range of angle of attack in level flight and throughout violent maneuvers. The results show: (a) that the present rib load specifications in use by the Army Air Corps and the Bureau of Aeronautics, Navy Department, are in fair agreement with the loads actually occurring in flight, but could be slightly improved; (b) that there appears to be no definite sequence in which wing and tail surface ribs reach their respective maximum loads in different maneuvers; (c) that in accelerated flight, at air speeds less than or equal to 60 per cent of the maximum speed, the accelerations measured agree very closely with the theoretically possible maximum accelerations. In maneuvers at higher air speeds the observed accelerations were smaller than those theoretically possible. (author)

  13. Neuropathies of Stüve-Wiedemann Syndrome due to mutations in leukemia inhibitory factor receptor (LIFR) gene

    PubMed Central

    Oxford, Alexandra E.; Jorcyk, Cheryl L.; Oxford, Julia Thom

    2016-01-01

    Stüve-Wiedemann syndrome (STWS; OMIM #610559) is a rare disease that results in dysfunction of the autonomic nervous system, which controls involuntary processes such as breathing rate and body temperature. In infants, this can result in respiratory distress, feeding and swallowing difficulties, and hyperthermic episodes. Individuals may sweat excessively when body temperature is not elevated. Additionally, individuals have reduced ability to feel pain and may lose reflexes such as the corneal reflex that normally causes one to blink, and the patellar reflex resulting in the knee-jerk. STWS usually results in infant mortality, yet some STWS patients survive into early adulthood. STWS is caused by a mutation in the leukemia inhibitory factor receptor (LIFR) gene, which is inherited in an autosomal-recessive pattern. Most LIFR mutations resulting in STWS cause instability of the mRNA due to frameshift mutations leading to premature stop codons, which prevent the formation of LIFR protein. STWS is managed on a symptomatic basis as no treatment is currently available. PMID:28058407

  14. Neuropathies of Stüve-Wiedemann Syndrome due to mutations in leukemia inhibitory factor receptor (LIFR) gene.

    PubMed

    Oxford, Alexandra E; Jorcyk, Cheryl L; Oxford, Julia Thom

    2016-01-01

    Stüve-Wiedemann syndrome (STWS; OMIM #610559) is a rare disease that results in dysfunction of the autonomic nervous system, which controls involuntary processes such as breathing rate and body temperature. In infants, this can result in respiratory distress, feeding and swallowing difficulties, and hyperthermic episodes. Individuals may sweat excessively when body temperature is not elevated. Additionally, individuals have reduced ability to feel pain and may lose reflexes such as the corneal reflex that normally causes one to blink, and the patellar reflex resulting in the knee-jerk. STWS usually results in infant mortality, yet some STWS patients survive into early adulthood. STWS is caused by a mutation in the leukemia inhibitory factor receptor (LIFR) gene, which is inherited in an autosomal-recessive pattern. Most LIFR mutations resulting in STWS cause instability of the mRNA due to frameshift mutations leading to premature stop codons, which prevent the formation of LIFR protein. STWS is managed on a symptomatic basis as no treatment is currently available.

  15. Discovery of a ROCK inhibitor, FPND, which prevents cerebral hemorrhage through maintaining vascular integrity by interference with VE-cadherin.

    PubMed

    Li, Shang; Ai, Nana; Shen, Mingyun; Dang, Yuanye; Chong, Cheong-Meng; Pan, Peichen; Kwan, Yiu Wa; Chan, Shun Wan; Leung, George Pak Heng; Hoi, Maggie Pui Man; Hou, Tingjun; Lee, Simon Ming-Yuen

    2017-01-01

    Hemorrhagic stroke occurs when a weakened vessel ruptures and bleeds into the surrounding brain, leading to high rates of death and disability worldwide. A series of complex pathophysiological cascades contribute to the risk of hemorrhagic stroke, and no therapies have proven effective to prevent hemorrhagic stroke. Stabilization of vascular integrity has been considered as a potential therapeutic target for hemorrhagic stroke. ROCKs, which belong to the serine/threonine protein kinase family and participate in the organization of actin cytoskeleton, have become attractive targets for the treatment of strokes. In this study, in vitro enzyme-based assays revealed that a new compound (FPND) with a novel scaffold identified by docking-based virtual screening could inhibit ROCK1 specifically at low micromolar concentration. Molecular modeling showed that FPND preferentially interacted with ROCK1, and the difference between the binding affinity of FPND toward ROCK1 and ROCK2 primarily resulted from non-polar contributions. Furthermore, FPND significantly prevented statin-induced cerebral hemorrhage in a zebrafish model. In addition, in vitro studies using the xCELLigence RTCA system, immunofluorescence and western blotting revealed that FPND prevented statin-induced cerebral hemorrhage by enhancing endothelial cell-cell junctions through inhibiting the ROCK-mediated VE-cadherin signaling pathway. As indicated by the extremely low toxicity of FPND against mice, it is safe and can potentially prevent vascular integrity loss-related diseases, such as hemorrhagic stroke.

  16. Neutralization resistant HIV-1 primary isolates from antiretroviral naïve chronically infected children in India.

    PubMed

    Makhdoomi, Muzamil Ashraf; Singh, Deepti; Nair Pananghat, Ambili; Lodha, Rakesh; Kabra, Sushil Kumar; Luthra, Kalpana

    2016-12-01

    Anti-HIV-1 broadly neutralizing antibodies (bnAbs) have been extensively tested against pesudoviruses of diverse strains. We generated and characterized HIV-1 primary isolates from antiretroviral naïve infected Indian children, and determined their susceptibility to known NAbs. All the 8 isolates belonged to subtype-C and were R5 tropic. Majority of these viruses were resistant to neutralization by NAbs, suggesting that the bnAbs, known to efficiently neutralize pseudoviruses (adult and pediatric) of different strains, are less effective against pediatric primary isolates. Interestingly, AIIMS_329 isolate displayed high susceptibility to neutralization by PG9 and PG16bnAbs, with IC50 titer of 1.3 and 0.97μg/ml, suggesting exposure of this epitope on this virus. All isolates except AIIMS_506 were neutralized by contemporaneous plasma antibodies. Our findings suggest that primary isolates, due to close resemblance to viruses in natural infection, should be used to evaluate NAbs as effective vaccine candidates in both children and adults. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Abacavir induced T cell reactivity from drug naïve individuals shares features of allo-immune responses.

    PubMed

    Adam, Jacqueline; Wuillemin, Natascha; Watkins, Stephan; Jamin, Heidi; Eriksson, Klara K; Villiger, Peter; Fontana, Stefano; Pichler, Werner J; Yerly, Daniel

    2014-01-01

    Abacavir hypersensitivity is a severe hypersensitivity reaction which occurs exclusively in carriers of the HLA-B*57∶01 allele. In vitro culture of PBMC with abacavir results in the outgrowth of abacavir-reacting CD8+ T cells, which release IFNγ and are cytotoxic. How this immune response is induced and what is recognized by these T cells is still a matter of debate. We analyzed the conditions required to develop an abacavir-dependent T cell response in vitro. The abacavir reactivity was independent of co-stimulatory signals, as neither DC maturation nor release of inflammatory cytokines were observed upon abacavir exposure. Abacavir induced T cells arose in the absence of professional APC and stemmed from naïve and memory compartments. These features are reminiscent of allo-reactivity. Screening for allo-reactivity revealed that about 5% of generated T cell clones (n = 136) from three donors were allo-reactive exclusively to the related HLA-B*58∶01. The addition of peptides which can bind to the HLA-B*57∶01-abacavir complex and to HLA-B*58∶01 during the induction phase increased the proportion of HLA-B*58∶01 allo-reactive T cell clones from 5% to 42%. In conclusion, abacavir can alter the HLA-B*57∶01-peptide complex in a way that mimics an allo-allele ('altered self-allele') and create the potential for robust T cell responses.

  18. Utilizing computerized entertainment education in the development of decision aids for lower literate and naïve computer users.

    PubMed

    Jibaja-Weiss, Maria L; Volk, Robert J

    2007-01-01

    Decision aids have been developed by using various delivery methods, including interactive computer programs. Such programs, however, still rely heavily on written information, health and digital literacy, and reading ease. We describe an approach to overcome these potential barriers for low-literate, underserved populations by making design considerations for poor readers and naïve computer users and by using concepts from entertainment education to engage the user and to contextualize the content for the user. The system design goals are to make the program both didactic and entertaining and the navigation and graphical user interface as simple as possible. One entertainment education strategy, the soap opera, is linked seamlessly to interactive learning modules to enhance the content of the soap opera episodes. The edutainment decision aid model (EDAM) guides developers through the design process. Although designing patient decision aids that are educational, entertaining, and targeted toward poor readers and those with limited computer skills is a complex task, it is a promising strategy for aiding this population. Entertainment education may be a highly effective approach to promoting informed decision making for patients with low health literacy.

  19. Reduction of Caudate Nucleus Volumes in Neuroleptic-Naïve Female Subjects with Schizotypal Personality Disorder

    PubMed Central

    Koo, Min-Seong; Levitt, James J.; McCarley, Robert W.; Seidman, Larry J.; Dickey, Chandlee C.; Niznikiewicz, Margaret A.; Voglmaier, Martina M.; Zamani, Payman; Long, Katherine R.; Kim, Sunnie S.; Shenton, Martha E.

    2009-01-01

    Background The caudate nucleus might contribute to the psychopathological and cognitive deficits observed in schizotypal personality disorder (SPD), a schizophrenia spectrum disorder. Here we focused on female patients, because this group is underrepresented in studies of SPD and schizophrenia, and we might learn more about the caudate and clinical and cognitive impairments that are unique to female patients diagnosed with SPD. Methods Magnetic resonance imaging scans, obtained on a 1.5-T magnet with 1.5-mm contiguous slices, were used to measure the caudate in 32 neuroleptic-naïve women with SPD and in 29 female normal comparison subjects. Subjects were group-matched for age, parental socioeconomic status, and intelligence quotient. Results We found significantly reduced left and right caudate relative volume (8.3%, 7.7%) in female SPD subjects compared with normal comparison subjects. In female SPD subjects, we found significant correlations between smaller total caudate relative volume and worse performance on the Wisconsin Card Sorting test (nonperseverative errors) and on the California Verbal Learning Test (verbal memory and learning), and significant correlations between smaller total caudate relative volume and both positive and negative symptoms on the Structured Interview for Schizotypy. Conclusions These findings demonstrate that, for female SPD subjects, smaller caudate volume is associated with poorer cognitive performance and more schizotypal symptomatology. PMID:16460694

  20. An Automatic Multidocument Text Summarization Approach Based on Naïve Bayesian Classifier Using Timestamp Strategy

    PubMed Central

    Ramanujam, Nedunchelian; Kaliappan, Manivannan

    2016-01-01

    Nowadays, automatic multidocument text summarization systems can successfully retrieve the summary sentences from the input documents. But, it has many limitations such as inaccurate extraction to essential sentences, low coverage, poor coherence among the sentences, and redundancy. This paper introduces a new concept of timestamp approach with Naïve Bayesian Classification approach for multidocument text summarization. The timestamp provides the summary an ordered look, which achieves the coherent looking summary. It extracts the more relevant information from the multiple documents. Here, scoring strategy is also used to calculate the score for the words to obtain the word frequency. The higher linguistic quality is estimated in terms of readability and comprehensibility. In order to show the efficiency of the proposed method, this paper presents the comparison between the proposed methods with the existing MEAD algorithm. The timestamp procedure is also applied on the MEAD algorithm and the results are examined with the proposed method. The results show that the proposed method results in lesser time than the existing MEAD algorithm to execute the summarization process. Moreover, the proposed method results in better precision, recall, and F-score than the existing clustering with lexical chaining approach. PMID:27034971

  1. Karhunen-Loève treatment to remove noise and facilitate data analysis in sensing, spectroscopy and other applications.

    PubMed

    Zaharov, V V; Farahi, R H; Snyder, P J; Davison, B H; Passian, A

    2014-11-21

    Resolving weak spectral variations in the dynamic response of materials that are either dominated or excited by stochastic processes remains a challenge. Responses that are thermal in origin are particularly relevant examples due to the delocalized nature of heat. Despite its inherent properties in dealing with stochastic processes, the Karhunen-Loève expansion has not been fully exploited in measurement of systems that are driven solely by random forces or can exhibit large thermally driven random fluctuations. Here, we present experimental results and analysis of the archetypes (a) the resonant excitation and transient response of an atomic force microscope probe by the ambient random fluctuations and nanoscale photothermal sample response, and (b) the photothermally scattered photons in pump-probe spectroscopy. In each case, the dynamic process is represented as an infinite series with random coefficients to obtain pertinent frequency shifts and spectral peaks and demonstrate spectral enhancement for a set of compounds including the spectrally complex biomass. The considered cases find important applications in nanoscale material characterization, biosensing, and spectral identification of biological and chemical agents.

  2. A Randomized Trial of Pharmacogenetic Warfarin Dosing in Naïve Patients with Non-Valvular Atrial Fibrillation

    PubMed Central

    Fogar, Paola; Padoan, Andrea; Nante, Giovanni; Pelloso, Michela; Moz, Stefania; Frigo, Anna Chiara; Groppa, Francesca; Bozzato, Dania; Tiso, Enrico; Gnatta, Elisa; Denas, Gentian; Padayattil Jose, Seena; Padrini, Roberto; Basso, Daniela; Plebani, Mario

    2015-01-01

    Genotype-guided warfarin dosing have been proposed to improve patient’s management. This study is aimed to determine whether a CYP2C9- VKORC1- CYP4F2-based pharmacogenetic algorithm is superior to a standard, clinically adopted, pharmacodynamic method. Two-hundred naïve patients with non-valvular atrial fibrillation were randomized to trial arms and 180 completed the study. No significant differences were found in the number of out-of-range INRs (INR<2.0 or >3.0) (p = 0.79) and in the mean percentage of time spent in the therapeutic range (TTR) after 19 days in the pharmacogenetic (51.9%) and in the control arm (53.2%, p = 0.71). The percentage of time spent at INR>4.0 was significantly lower in the pharmacogenetic (0.7%) than in the control arm (1.8%) (p = 0.02). Genotype-guided warfarin dosing is not superior in overall anticoagulation control when compared to accurate clinical standard of care. Trial Registration ClinicalTrials.gov NCT01178034 PMID:26710337

  3. Psychological and cardiovascular effects and short-term sequelae of MDMA ("ecstasy") in MDMA-naïve healthy volunteers.

    PubMed

    Vollenweider, F X; Gamma, A; Liechti, M; Huber, T

    1998-10-01

    3, 4-methylenedioxymethamphetamine (MDMA, "Ecstasy") is a recreational drug reported to produce a different psychological profile than that of classic hallucinogens and stimulants. It has, therefore, been tentatively classified into a novel pharmacological class termed entactogens. This double-blind placebo-controlled study examined the effects of a typical recreational dose of MDMA (1.7 mg/kg) in 13 MDMA-naïve healthy volunteers. MDMA produced an effective state of enhanced mood, well-being, and increased emotional sensitiveness, little anxiety, but no hallucinations or panic reactions. Mild depersonalization and derealization phenomena occurred together with moderate thought disorder, first signs of loss of body control, and alterations in the meaning of percepts. Subjects also displayed changes in the sense of space and time, heightened sensory awareness, and increased psychomotor drive. MDMA did not impair selective attention as measured by the Stroop test. MDMA increased blood pressure moderately, with the exception of one subject who showed a transient hypertensive reaction. This severe increase in blood pressure indicates that the hypertensive effects of MDMA, even at recreational doses, should not be underestimated, particularly in subjects with latent cardiovascular problems. Most frequent acute somatic complaints during the MDMA challenge were jaw clenching, lack of appetite, impaired gait, and restless legs. Adverse sequelae during the following 24 hours included lack of energy and appetite, feelings of restlessness, insomnia, jaw clenching, occasional difficulty concentrating, and brooding. The present findings are consistent with the hypothesis that MDMA produces a different psychological profile than classic hallucinogens or psychostimulants.

  4. Age-Related Gray Matter Shrinkage in a Treatment Naïve Actively Drinking Alcohol Dependent Sample

    PubMed Central

    Fein, George; Shimotsu, Ryan; Barakos, Jerome

    2009-01-01

    Background We previously demonstrated, in a small sample, steeper age-related gray matter shrinkage in treatment naïve alcohol dependent (TxN) men compared to non-alcoholic controls, but could not separate out the contributions of age and lifetime duration of alcohol use (which were highly correlated) to this effect. In the current study, we have quadrupled the sample size and expanded it to include both men and women to try to replicate and extend the previous findings and to separate the contributions of age and alcohol use to the phenomenon. Methods In the current study, we examine cortical gray matter volumes in 18-50 year old TxN (n = 84) vs. age and gender comparable controls (n = 67). We used a new Region of Interest Analysis method which accounts for differences in sulcal and gyral enfolding between individuals (Fein et al., In Press). Results We found greater age-related gray matter shrinkage in TxN than in controls. Partial correlation analysis showed that the effect was a function of age and not lifetime alcohol burden. Conclusions Implications of the findings are discussed in terms of their contribution toward our knowledge of differences between different subpopulations of alcoholics and in terms of their implications for the morbidity of alcohol dependence in an aging national population. PMID:19860794

  5. Using symbolic knowledge in the UMLS to disambiguate words in small datasets with a naïve Bayes classifier.

    PubMed

    Leroy, Gondy; Rindflesch, Thomas C

    2004-01-01

    Current approaches to word sense disambiguation use and combine various machine-learning techniques. Most refer to characteristics of the ambiguous word and surrounding words and are based on hundreds of examples. Unfortunately, developing large training sets is time-consuming. We investigate the use of symbolic knowledge to augment machine-learning techniques for small datasets. UMLS semantic types assigned to concepts found in the sentence and relationships between these semantic types form the knowledge base. A naïve Bayes classifier was trained for 15 words with 100 examples for each. The most frequent sense of a word served as the baseline. The effect of increasingly accurate symbolic knowledge was evaluated in eight experimental conditions. Performance was measured by accuracy based on 10-fold cross-validation. The best condition used only the semantic types of the words in the sentence. Accuracy was then on average 10% higher than the baseline; however, it varied from 8% deterioration to 29% improvement. In a follow-up evaluation, we noted a trend that the best disambiguation was found for words that were the least troublesome to the human evaluators.

  6. Janus kinases 1 and 2 regulate chemokine-mediated integrin activation and naïve T-cell homing.

    PubMed

    Pérez-Rivero, Gema; Cascio, Graciela; Soriano, Silvia Fernández; Sanz, Álvaro Gil; de Guinoa, Julia Sáez; Rodríguez-Frade, José Miguel; Gomariz, Rosa P; Holgado, Borja L; Cabañas, Carlos; Carrasco, Yolanda R; Stein, Jens V; Mellado, Mario

    2013-07-01

    Janus kinases (JAKs) are central signaling molecules in cytokine receptor cascades. Although they have also been implicated in chemokine receptor signaling, this function continues to be debated. To address this issue, we established a nucleofection model in primary, nonactivated mouse T lymphocytes to silence JAK expression and to evaluate the ability of these cells to home to lymph nodes. Reduced JAK1 and JAK2 expression impaired naïve T-cell migration in response to gradients of the chemokines CXCL12 and CCL21. In vivo homing of JAK1/JAK2-deficient cells to lymph nodes decreased, whereas intranodal localization and motility were unaffected. JAK1 and JAK2 defects altered CXCL12- and CCL21-triggered ezrin/radixin/moesin (ERM) dephosphorylation and F-actin polymerization, as well as activation of lymphocyte function-associated Ag-1 and very late Ag-4 integrins. As a result, the cells did not adhere firmly to integrin substrates in response to these chemokines. The results demonstrate that JAK1/JAK2 participate in chemokine-induced integrin activation and might be considered a target for modulation of immune cell extravasation and therefore, control of inflammatory reactions. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. Influence of perspective of action observation training on residual limb control in naïve prosthesis usage

    PubMed Central

    Lawson, Delisa T.; Cusack, William F.; Lawson, Regan; Hardy, Ashley; Kistenberg, Robert; Wheaton, Lewis A.

    2017-01-01

    Prior work in amputees and partial limb immobilization have shown improved neural and behavioral outcomes in using their residual limb with prosthesis when undergoing observation-based training with a prosthesis-using actor compared to an intact limb. It was posited that these improvements are due to an alignment of user with the actor. It may be affected by visual angles that allow emphasis of critical joint actions which may promote behavioral changes. The purpose of this study was to examine how viewing perspective of observation-based training effects prosthesis adaptation in naïve device users. Twenty non-amputated prosthesis users (NAPUs) learned how to use an upper extremity prosthetic device while viewing a training video from either a sagittal or coronal perspective. These views were chosen as they place visual emphasis on different aspects of task performance to the device. We found that perspective of actions has a significant role in adaptation of the residual limb while using upper limb prostheses. Perspectives that demonstrate elbow adaptations to prosthesis usage may enhance the functional motor outcomes of action observation therapy. This work has potential implications on how prosthetic device operation is conveyed to persons adapting to prostheses through action observation based therapy. PMID:27253208

  8. Continuation maintenance therapy with S-1 in chemotherapy-naïve patients with advanced squamous cell lung cancer.

    PubMed

    Suzuki, Seiichiro; Karayama, Masato; Inui, Naoki; Fujisawa, Tomoyuki; Enomoto, Noriyuki; Nakamura, Yutaro; Kuroishi, Shigeki; Matsuda, Hiroyuki; Yokomura, Koshi; Koshimizu, Naoki; Toyoshima, Mikio; Imokawa, Shiro; Asada, Kazuhiro; Masuda, Masafumi; Yamada, Takashi; Watanabe, Hiroshi; Suda, Takafumi

    2016-08-01

    Objectives Maintenance therapy is a standard therapeutic strategy in non-squamous non-small-cell lung cancer. However, there is no consensus regarding the benefit of maintenance therapy for patients with squamous cell lung cancer. We assessed maintenance therapy with S-1, an oral fluoropyrimidine agent, following induction therapy with carboplatin and S-1 in patients with squamous cell lung cancer. Methods In this phase II trial, chemotherapy-naïve patients with squamous cell lung cancer were enrolled to induction therapy with four cycles of carboplatin (at an area under the curve of 5 on day 1) and S-1 (80 mg/m(2)/day on days 1-14) in a 28-day cycle. Patients who achieved disease control after induction therapy received maintenance therapy with S-1 in a 21-day cycle until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival after administration of maintenance therapy. Results Fifty-one patients were enrolled in the study. The median progression-free survival from the start of maintenance therapy was 3.0 months (95 % confidence interval, 2.5-3.5). The most common toxicities associated with maintenance therapy were anemia, thrombocytopenia, and fatigue, but they were not severe. Conclusion S-1 maintenance therapy might be a feasible treatment option in patients with squamous cell lung cancer.

  9. Brentuximab Vedotin in Transplant-Naïve Relapsed/Refractory Hodgkin Lymphoma: Experience in 30 Patients.

    PubMed

    Zinzani, Pier Luigi; Pellegrini, Cinzia; Cantonetti, Maria; Re, Alessandro; Pinto, Antonello; Pavone, Vincenzo; Rigacci, Luigi; Celli, Melania; Broccoli, Alessandro; Argnani, Lisa; Pulsoni, Alessandro

    2015-12-01

    Hodgkin lymphoma (HL) is characterized by the presence of CD30-positive Hodgkin Reed-Sternberg cells. Approximately 30%-40% of patients with advanced disease are refractory to frontline therapy or will relapse after first-line treatment. The standard management of these patients is salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplant (ASCT). The best prognostic factor is the status of disease before ASCT; in particular, the normalization of positron emission tomography (PET) scan. Brentuximab vedotin (BV) has shown a high overall response rate in refractory/relapsed HL after ASCT, whereas few data are available regarding its role before ASCT. A multicenter, retrospective, observational study was conducted. The primary endpoint of the study was the effectiveness of BV as single agent in patients with relapsed/refractory, ASCT-naïve HL, determined by the conversion of PET status from positive to negative; secondary endpoints were safety, capacity to proceed to ASCT, survival, and progression-free status. Thirty patients with relapsed/refractory HL- and PET-positive disease after conventional chemotherapy salvage treatments were treated with a median of 4 cycles of BV. Normalization of PET findings (Deauville score ≤2) occurred in 9 of 30 patients (30%). Those nine patients proceeded to ASCT. These data suggest that BV can normalize PET status in a subset of HL patients refractory to conventional chemotherapy salvage treatments, such as ifosfamide-containing regimens, cytarabine- and platinum-containing regimens, prior to ASCT. ©AlphaMed Press.

  10. The Structure of the Venus Neutral Atmosphere from the Radio Science Experiment VeRa on Venus Express

    NASA Astrophysics Data System (ADS)

    Tellmann, S.; Häusler, B.; Pätzold, M.; Bird, M.; Tyler, G. L.

    2008-09-01

    The Venus Express Radio Science Experiment VeRa uses one-way radio signals at X-band (8.4 GHz) and S-band (2.3 GHz) for the sounding of the Venus neutral atmosphere and ionosphere. Three occultation seasons could be covered during the nominal mission of Venus Express resulting in a data set of about 118 profiles of the neutral atmosphere. Another three occultation seasons are planned during the extended mission. The polar orbit of Venus Express provides the opportunity to study the atmosphere at a large range of planetocentric latitudes under varying illumination conditions. Radial profiles of neutral number density derived from the occultations cover the altitude range 40-90 km, which are converted to vertical profiles of temperature and pressure. Profiles of static stability are found to be latitude-dependent and nearly adiabatic in the middle cloud region. Below the clouds the stability decreases at high latitudes. A large equator-to-pole temperature contrast of approximately 30 K is found at the 1-bar level. A distinct cold collar region could be observed on both hemispheres. At the latitudes of the cold collars, the tropopause altitude increases relative to higher and lower latitudes, while the temperature drops roughly 60 K. The observations indicate the existence of a wave number 2 structure polewards of ±75° latitude at altitudes of about 60 km.

  11. Neural correlates of mindful self-awareness in mindfulness meditators and meditation-naïve subjects revisited.

    PubMed

    Lutz, J; Brühl, A B; Scheerer, H; Jäncke, L; Herwig, U

    2016-09-01

    Mindful self-awareness is central to mindfulness meditation and plays a key role in its salutary effects. It has been related to decreased activation in cortical midline structures (CMS) and amygdala, and increased activation in somatosensory regions. However, findings in untrained individuals are contradictory, and scarce in experienced meditators. Using fMRI, we investigated experienced mindfulness meditators (LTM, n=21, average 4652 practice-hours) and matched meditation-naïve participants (MNP, n=19) during short periods of mindful self-awareness (FEEL) and self-referential thinking (THINK). We report somatosensory activations and decreases in CMS during FEEL for both groups, but significantly stronger decreases in prefrontal CMS in LTM. LTM further showed decreases in language-related and amygdala regions, but the latter was not significantly different between groups. Overall, higher activations in amygdala and mid-line regions during FEEL were related to levels of depressiveness. Neural patterns of mindful self-awareness emerge already in MNP but more pronounced in LTM. Specifically, meditation training might reduce self-reference and verbalization during mindful awareness. We further corroborate the suggested link between mindfulness and healthy self-related functions on the neural le