Modelling the effect of structural QSAR parameters on skin penetration using genetic programming

NASA Astrophysics Data System (ADS)

Chung, K. K.; Do, D. Q.

2010-09-01

In order to model relationships between chemical structures and biological effects in quantitative structure-activity relationship (QSAR) data, an alternative technique of artificial intelligence computing—genetic programming (GP)—was investigated and compared to the traditional method—statistical. GP, with the primary advantage of generating mathematical equations, was employed to model QSAR data and to define the most important molecular descriptions in QSAR data. The models predicted by GP agreed with the statistical results, and the most predictive models of GP were significantly improved when compared to the statistical models using ANOVA. Recently, artificial intelligence techniques have been applied widely to analyse QSAR data. With the capability of generating mathematical equations, GP can be considered as an effective and efficient method for modelling QSAR data.

Compatibility of scientific research and specialty training in General Practice. A cross-sectional study

PubMed Central

Kötter, Thomas; Carmienke, Solveig; Herrmann, Wolfram J.

2014-01-01

Objective: In many departments of General Practice (GP) in Germany, young doctors who are trainees also work as researchers. Often these trainees work part time at the university and part time as a trainee in clinical practice. However, little is known about the situation of the actors involved. The aim of the study was to investigate the perspectives of GP trainees, heads of departments and GP trainers regarding the combination of research and GP training. Methods: We conducted a web-based survey with the heads of all German departments of General Practice, GP trainees who also conduct research and their GP trainers. The questionnaires consisted of open and closed questions. The results were analyzed using descriptive statistics and qualitative methods. Results: 28 heads of GP departments and 20 GP trainees responded. The trainees were mostly very satisfied with their situation as a trainee. However, the trainees considered the combination of research and GP training as difficult. The respondents name as problems the coordination of multiple jobs and the lack of credibility given to research in General Practice. They name as solutions research-enabling training programs and uniform requirements in training regarding research. Conclusion: The combination of GP training and scientific research activity is perceived as difficult. However, well-organized and designed programs can improve the quality of the combination. PMID:25228933

Using Genetic Programming with Prior Formula Knowledge to Solve Symbolic Regression Problem.

PubMed

Lu, Qiang; Ren, Jun; Wang, Zhiguang

2016-01-01

A researcher can infer mathematical expressions of functions quickly by using his professional knowledge (called Prior Knowledge). But the results he finds may be biased and restricted to his research field due to limitation of his knowledge. In contrast, Genetic Programming method can discover fitted mathematical expressions from the huge search space through running evolutionary algorithms. And its results can be generalized to accommodate different fields of knowledge. However, since GP has to search a huge space, its speed of finding the results is rather slow. Therefore, in this paper, a framework of connection between Prior Formula Knowledge and GP (PFK-GP) is proposed to reduce the space of GP searching. The PFK is built based on the Deep Belief Network (DBN) which can identify candidate formulas that are consistent with the features of experimental data. By using these candidate formulas as the seed of a randomly generated population, PFK-GP finds the right formulas quickly by exploring the search space of data features. We have compared PFK-GP with Pareto GP on regression of eight benchmark problems. The experimental results confirm that the PFK-GP can reduce the search space and obtain the significant improvement in the quality of SR.

'I still have no idea why this patient was here': An exploration of the difficulties GP trainees experience when gathering information.

PubMed

Giroldi, Esther; Veldhuijzen, Wemke; de Leve, Tijme; van der Weijden, Trudy; Bueving, Herman; van der Vleuten, Cees

2015-07-01

Collecting information during patient encounters is essential for the delivery of patient-centered care. To obtain insight into areas that require more attention in medical communication training, this study explores what difficulties GP trainees encounter when gathering information. In this phenomenological study, we observed a morning clinic of 15 GP trainees. To explore trainees' experiences with information-gathering, we held brief interviews after every consultation and a lengthier interview directly after the morning clinic. The resulting data were analyzed using template analysis. From trainees' reflections, we distilled five difficulties that trainees experience when gathering information: (1) Goal conflicts; (2) Ineffectiveness of trained communication skills in specific situations; (3) Trainees' distress hampers open communication; (4) Untrustworthy information; (5) Tunnel vision. Information-gathering is difficult for GP trainees. Current generic communication skills training does not seem to support trainees sufficiently to handle effectively the challenges they encounter during consultations. Medical communication training needs to support trainees in handling their goal-conflicts and feelings that hamper information-gathering, while also providing them with communication strategies adapted to handling specific challenging situations. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

A genetic programming approach to oral cancer prognosis.

PubMed

Tan, Mei Sze; Tan, Jing Wei; Chang, Siow-Wee; Yap, Hwa Jen; Abdul Kareem, Sameem; Zain, Rosnah Binti

2016-01-01

The potential of genetic programming (GP) on various fields has been attained in recent years. In bio-medical field, many researches in GP are focused on the recognition of cancerous cells and also on gene expression profiling data. In this research, the aim is to study the performance of GP on the survival prediction of a small sample size of oral cancer prognosis dataset, which is the first study in the field of oral cancer prognosis. GP is applied on an oral cancer dataset that contains 31 cases collected from the Malaysia Oral Cancer Database and Tissue Bank System (MOCDTBS). The feature subsets that is automatically selected through GP were noted and the influences of this subset on the results of GP were recorded. In addition, a comparison between the GP performance and that of the Support Vector Machine (SVM) and logistic regression (LR) are also done in order to verify the predictive capabilities of the GP. The result shows that GP performed the best (average accuracy of 83.87% and average AUROC of 0.8341) when the features selected are smoking, drinking, chewing, histological differentiation of SCC, and oncogene p63. In addition, based on the comparison results, we found that the GP outperformed the SVM and LR in oral cancer prognosis. Some of the features in the dataset are found to be statistically co-related. This is because the accuracy of the GP prediction drops when one of the feature in the best feature subset is excluded. Thus, GP provides an automatic feature selection function, which chooses features that are highly correlated to the prognosis of oral cancer. This makes GP an ideal prediction model for cancer clinical and genomic data that can be used to aid physicians in their decision making stage of diagnosis or prognosis.

A survey of application: genomics and genetic programming, a new frontier.

PubMed

Khan, Mohammad Wahab; Alam, Mansaf

2012-08-01

The aim of this paper is to provide an introduction to the rapidly developing field of genetic programming (GP). Particular emphasis is placed on the application of GP to genomics. First, the basic methodology of GP is introduced. This is followed by a review of applications in the areas of gene network inference, gene expression data analysis, SNP analysis, epistasis analysis and gene annotation. Finally this paper concluded by suggesting potential avenues of possible future research on genetic programming, opportunities to extend the technique, and areas for possible practical applications. Copyright © 2012 Elsevier Inc. All rights reserved.

A simple approach to lifetime learning in genetic programming-based symbolic regression.

PubMed

Azad, Raja Muhammad Atif; Ryan, Conor

2014-01-01

Genetic programming (GP) coarsely models natural evolution to evolve computer programs. Unlike in nature, where individuals can often improve their fitness through lifetime experience, the fitness of GP individuals generally does not change during their lifetime, and there is usually no opportunity to pass on acquired knowledge. This paper introduces the Chameleon system to address this discrepancy and augment GP with lifetime learning by adding a simple local search that operates by tuning the internal nodes of individuals. Although not the first attempt to combine local search with GP, its simplicity means that it is easy to understand and cheap to implement. A simple cache is added which leverages the local search to reduce the tuning cost to a small fraction of the expected cost, and we provide a theoretical upper limit on the maximum tuning expense given the average tree size of the population and show that this limit grows very conservatively as the average tree size of the population increases. We show that Chameleon uses available genetic material more efficiently by exploring more actively than with standard GP, and demonstrate that not only does Chameleon outperform standard GP (on both training and test data) over a number of symbolic regression type problems, it does so by producing smaller individuals and it works harmoniously with two other well-known extensions to GP, namely, linear scaling and a diversity-promoting tournament selection method.

Optional part-time and longer GP training modules in GP practices associated with more trainees becoming GPs - a cohort study in Switzerland.

PubMed

Studerus, Lara; Ahrens, Regina; Häuptle, Christian; Goeldlin, Adrian; Streit, Sven

2018-01-05

Switzerland, like many other countries, has a shortage of General Practitioners (GPs). Optional GP training modules in GP practices were offered during the at least 5-year GP training program to increase student and trainee interest in becoming a GP. The training modules had not yet been evaluated. We determined how many Swiss GP trainees became practicing GPs after they completed optional training modules, and if longer modules were associated with higher rates of GP specialization. In this population-based cohort study, we included GP trainees who chose an optional GP training module in GP practice, provided by the Foundation to Promote Training in General Practice (WHM) between 2006 and 2015. GP trainees were invited to complete an online survey to assess the primary outcome (becoming a practicing GP by 2016). Data on non-responders was collected via an internet search. We calculated univariate time-to-event curves to become a practicing GP, stratified by trainee's gender, length, part-time training, and number of years after graduation until training modules were completed. We used a multivariate model to adjust for characteristics of participants, training, and satisfaction with training modules. We assessed primary outcome for 351 (92.1%) of 381 former GP trainees who participated in a WHM program between 2006 and 2015. Of these 218 (57%) were practicing GPs by 2016. When focusing on the trainees who had completed training between 2006 and 2010, the rate of practicing GPs was even 73%. Longer (p = 0.018) and part-time training modules (p = 0.003) were associated with higher rates of being a practicing GP. Most (81%) practicing GPs thought their optional GP training module was (very) important in their choice of specialty. GP trainees who spent more time training in a GP practice, or who trained part-time were more likely to become practicing GPs. Most (80%) rated their training module as (very) important in their choice of career, highlighting that these modules effectively encourage the interests of those already inclined towards the GP specialty. Longer GP training modules and more opportunities for part-time training may attract and retain more interested trainees, and possibly increase the number of practicing GPs.

A genetic programming approach to oral cancer prognosis

PubMed Central

Tan, Mei Sze; Tan, Jing Wei; Yap, Hwa Jen; Abdul Kareem, Sameem; Zain, Rosnah Binti

2016-01-01

Background The potential of genetic programming (GP) on various fields has been attained in recent years. In bio-medical field, many researches in GP are focused on the recognition of cancerous cells and also on gene expression profiling data. In this research, the aim is to study the performance of GP on the survival prediction of a small sample size of oral cancer prognosis dataset, which is the first study in the field of oral cancer prognosis. Method GP is applied on an oral cancer dataset that contains 31 cases collected from the Malaysia Oral Cancer Database and Tissue Bank System (MOCDTBS). The feature subsets that is automatically selected through GP were noted and the influences of this subset on the results of GP were recorded. In addition, a comparison between the GP performance and that of the Support Vector Machine (SVM) and logistic regression (LR) are also done in order to verify the predictive capabilities of the GP. Result The result shows that GP performed the best (average accuracy of 83.87% and average AUROC of 0.8341) when the features selected are smoking, drinking, chewing, histological differentiation of SCC, and oncogene p63. In addition, based on the comparison results, we found that the GP outperformed the SVM and LR in oral cancer prognosis. Discussion Some of the features in the dataset are found to be statistically co-related. This is because the accuracy of the GP prediction drops when one of the feature in the best feature subset is excluded. Thus, GP provides an automatic feature selection function, which chooses features that are highly correlated to the prognosis of oral cancer. This makes GP an ideal prediction model for cancer clinical and genomic data that can be used to aid physicians in their decision making stage of diagnosis or prognosis. PMID:27688975

Depression management within GP-centered health care - A case-control study based on claims data.

PubMed

Freytag, Antje; Krause, Markus; Lehmann, Thomas; Schulz, Sven; Wolf, Florian; Biermann, Janine; Wasem, Jürgen; Gensichen, Jochen

For most patients with depression, GPs are the first and long-term medical providers. GP-centered health care (GPc-HC) programs target patients with chronic diseases. What are the effects of GPc-HC on primary care depression management? An observational retrospective case-control study was conducted using health insurance claims data of patients with depressive disorder from July 2011 to December 2012. From 40,298 patients insured with the largest health plan in Central Germany participating in the GPc-HC program (intervention group, IG), we observed 4645 patients with depression over 18months: 72.2% women; 66.6years (mean); multiple conditions (morbidity-weight 2.50 (mean), 86%>1.0). We compared them with 4013 patients who did not participate (control group). In participants we found lower number of incomplete/non-specified depression diagnoses (4.46vs.4.82;MD-0.36; p<0.01); lower rate of patients consulting more than one GP-practice (49.1%vs.58.0%;PP-8.9;p<0.01); more GP-contacts (18.19vs.15.59;MD+2.60;p<0.01); more GP-initiated referrals to specialists (82.9%vs.79.3%;PP+3.6;p<0.05), more antidepressant pharmacotherapy prescribed by a GP (37.9%vs.35.4%;PP+2.5;p<0.05), more frequent guideline-concordant therapy duration (19.2%vs.13.1%;PP+6.1;p<0.01) and more patients receiving "GP-psychosomatic basic care" (38.2%vs.30.2%;PP+8.0;p<0.01). Depressive patients participating in a GPc-HC program may be more often diagnosed by a GP, receive symptom-monitoring and appropriate depression treatment. Copyright © 2016 Elsevier Inc. All rights reserved.

A comparison of fitness-case sampling methods for genetic programming

NASA Astrophysics Data System (ADS)

Martínez, Yuliana; Naredo, Enrique; Trujillo, Leonardo; Legrand, Pierrick; López, Uriel

2017-11-01

Genetic programming (GP) is an evolutionary computation paradigm for automatic program induction. GP has produced impressive results but it still needs to overcome some practical limitations, particularly its high computational cost, overfitting and excessive code growth. Recently, many researchers have proposed fitness-case sampling methods to overcome some of these problems, with mixed results in several limited tests. This paper presents an extensive comparative study of four fitness-case sampling methods, namely: Interleaved Sampling, Random Interleaved Sampling, Lexicase Selection and Keep-Worst Interleaved Sampling. The algorithms are compared on 11 symbolic regression problems and 11 supervised classification problems, using 10 synthetic benchmarks and 12 real-world data-sets. They are evaluated based on test performance, overfitting and average program size, comparing them with a standard GP search. Comparisons are carried out using non-parametric multigroup tests and post hoc pairwise statistical tests. The experimental results suggest that fitness-case sampling methods are particularly useful for difficult real-world symbolic regression problems, improving performance, reducing overfitting and limiting code growth. On the other hand, it seems that fitness-case sampling cannot improve upon GP performance when considering supervised binary classification.

Liver Full Reference Set Application :Timothy Block - Drexel Univ (2010) — EDRN Public Portal

Cancer.gov

The goal of this application is to determine if the levels of serum GP73 and fucosylated kininogen/acute phase proteins can be used to detect hepatocellular carcinoma (HCC) in the background of liver cirrhosis. The use of the validation set would allow us to directly compare GP73 and fucosylated markers against AFP, AFP-L3 and DCP as well as test them in combination with these markers

Liver Rapid Reference Set Application: Timothy Block - Drexel Univ (2008) — EDRN Public Portal

Cancer.gov

The goal of this application is to determine if the levels of serum GP73 and fucosylated kininogen/acute phase proteins can be used to detect hepatocellular carcinoma (HCC) in the background of liver cirrhosis. The use of the validation set would allow us to directly compare GP73 and fucosylated markers against AFP, AFP-L3 and DCP as well as test them in combination with these markers

Inversion of oceanic constituents in case I and II waters with genetic programming algorithms.

PubMed

Chami, Malik; Robilliard, Denis

2002-10-20

A stochastic inverse technique based on agenetic programming (GP) algorithm was developed toinvert oceanic constituents from simulated data for case I and case II water applications. The simulations were carried out with the Ordre Successifs Ocean Atmosphere (OSOA) radiative transfer model. They include the effects of oceanic substances such as algal-related chlorophyll, nonchlorophyllous suspended matter, and dissolved organic matter. The synthetic data set also takes into account the directional effects of particles through a variation of their phase function that makes the simulated data realistic. It is shown that GP can be successfully applied to the inverse problem with acceptable stability in the presence of realistic noise in the data. GP is compared with neural network methodology for case I waters; GP exhibits similar retrieval accuracy, which is greater than for traditional techniques such as band ratio algorithms. The application of GP to real satellite data [a Sea-viewing Wide Field-of-view Sensor (SeaWiFS)] was also carried out for case I waters as a validation. Good agreement was obtained when GP results were compared with the SeaWiFS empirical algorithm. For case II waters the accuracy of GP is less than 33%, which remains satisfactory, at the present time, for remote-sensing purposes.

Genetic programming applied to RFI mitigation in radio astronomy

NASA Astrophysics Data System (ADS)

Staats, K.

2016-12-01

Genetic Programming is a type of machine learning that employs a stochastic search of a solutions space, genetic operators, a fitness function, and multiple generations of evolved programs to resolve a user-defined task, such as the classification of data. At the time of this research, the application of machine learning to radio astronomy was relatively new, with a limited number of publications on the subject. Genetic Programming had never been applied, and as such, was a novel approach to this challenging arena. Foundational to this body of research, the application Karoo GP was developed in the programming language Python following the fundamentals of tree-based Genetic Programming described in "A Field Guide to Genetic Programming" by Poli, et al. Karoo GP was tasked with the classification of data points as signal or radio frequency interference (RFI) generated by instruments and machinery which makes challenging astronomers' ability to discern the desired targets. The training data was derived from the output of an observation run of the KAT-7 radio telescope array built by the South African Square Kilometre Array (SKA-SA). Karoo GP, kNN, and SVM were comparatively employed, the outcome of which provided noteworthy correlations between input parameters, the complexity of the evolved hypotheses, and performance of raw data versus engineered features. This dissertation includes description of novel approaches to GP, such as upper and lower limits to the size of syntax trees, an auto-scaling multiclass classifier, and a Numpy array element manager. In addition to the research conducted at the SKA-SA, it is described how Karoo GP was applied to fine-tuning parameters of a weather prediction model at the South African Astronomical Observatory (SAAO), to glitch classification at the Laser Interferometer Gravitational-wave Observatory (LIGO), and to astro-particle physics at The Ohio State University.

Effect of the Programmed Nutrition Beef Program on moisture retention of cooked ground beef patties and enhanced strip loins.

PubMed

2015-02-01

This study evaluated the influence of the Programmed Nutrition Beef Program and exogenous growth promotants (ExGP) on water holding capacity characteristics of enhanced beef strip loins. Sixty, frozen strip loins, arranged in a 2 × 2 factorial treatment arrangement with dietary program serving as the first factor and use of ExGP as the second factor, were thawed, injected with an enhancement solution, and stored for 7 days. Loins from ExGP cattle possessed the ability to bind more (P < 0.05) water before pumping and bind less (P < 0.05) water after pumping and storage. Loin pH across treatments was similar (P > 0.10) before injection, but increased post-injection and after storage (P < 0.01). Treatments did not affect loin purge loss, steak cook loss, and expressible moisture (P > 0.10). The Programmed Nutrition Beef Program and use of ExGPs minimally impacted water holding capacity of enhanced frozen/thawed beef strip loins.

Genetic Programming Transforms in Linear Regression Situations

NASA Astrophysics Data System (ADS)

Castillo, Flor; Kordon, Arthur; Villa, Carlos

The chapter summarizes the use of Genetic Programming (GP) inMultiple Linear Regression (MLR) to address multicollinearity and Lack of Fit (LOF). The basis of the proposed method is applying appropriate input transforms (model respecification) that deal with these issues while preserving the information content of the original variables. The transforms are selected from symbolic regression models with optimal trade-off between accuracy of prediction and expressional complexity, generated by multiobjective Pareto-front GP. The chapter includes a comparative study of the GP-generated transforms with Ridge Regression, a variant of ordinary Multiple Linear Regression, which has been a useful and commonly employed approach for reducing multicollinearity. The advantages of GP-generated model respecification are clearly defined and demonstrated. Some recommendations for transforms selection are given as well. The application benefits of the proposed approach are illustrated with a real industrial application in one of the broadest empirical modeling areas in manufacturing - robust inferential sensors. The chapter contributes to increasing the awareness of the potential of GP in statistical model building by MLR.

Evaluation and selection of sustainable suppliers in supply chain using new GP-DEA model with imprecise data

NASA Astrophysics Data System (ADS)

Jafarzadeh Ghoushchi, Saeid; Dodkanloi Milan, Mehran; Jahangoshai Rezaee, Mustafa

2017-11-01

Nowadays, with respect to knowledge growth about enterprise sustainability, sustainable supplier selection is considered a vital factor in sustainable supply chain management. On the other hand, usually in real problems, the data are imprecise. One method that is helpful for the evaluation and selection of the sustainable supplier and has the ability to use a variety of data types is data envelopment analysis (DEA). In the present article, first, the supplier efficiency is measured with respect to all economic, social and environmental dimensions using DEA and applying imprecise data. Then, to have a general evaluation of the suppliers, the DEA model is developed using imprecise data based on goal programming (GP). Integrating the set of criteria changes the new model into a coherent framework for sustainable supplier selection. Moreover, employing this model in a multilateral sustainable supplier selection can be an incentive for the suppliers to move towards environmental, social and economic activities. Improving environmental, economic and social performance will mean improving the supply chain performance. Finally, the application of the proposed approach is presented with a real dataset.

Genuine functions of P-glycoprotein (ABCB1).

PubMed

Mizutani, Takaharu; Masuda, Masatoshi; Nakai, Emi; Furumiya, Kenji; Togawa, Hiroshi; Nakamura, Yutaka; Kawai, Yuko; Nakahira, Keiko; Shinkai, Shigeko; Takahashi, Kazuhiko

2008-02-01

P-glycoprotein (P-gp, ABCB1, MDR1) was recognized as a drug-exporting protein from cancer cells three decade ago. Apart from the multidrug transporter side effects of P-gp, normal physiological functions of P-gp have been reported. P-gp could be responsible for translocating platelet-activating factor (PAF) across the plasma membrane and PAF inhibited drug transport mediated by P-gp in cancer cells. P-gp regulated the translocation of sphingomyelin (SM) and GlcCer, and short chain C(6)-NBD-GlcCer was found in the apical medium of P-gp cells exclusively and not in the basolateral membrane. SM plays an important role in the esterification of cholesterol. High expression of P-gp prevents stem-cell differentiation, leading to the proliferation and amplification of this cell repertoire, and functional P-gp plays a fundamental role in regulating programmed cell death, apoptosis. The transporter function of P-gp is therefore necessary to protect cells from death. P-gp can translocate both C(6)-NBD-PC and C(6)-NBD-PE across the apical membrane. This PC translocation was also confirmed with [(3)H]choline radioactivity. Progesterone is not transported by P-gp, but blocks P-gp-mediated efflux of other drugs and P-gp can mediate the transport of a variety of steroids. Cells transfected with human P-gp esterified more cholesterol. P-gp might also be involved in the transport of cytokines, particularly IL-1beta, IL-2, IL-4 and IFNgamma, out of activated normal lymphocytes into the surrounding medium. P-gp expression is also associated with a volume-activated chloride channel, thus P-gp is bifunctional with both transport and channel regulators. We also present information about P-gp polymorphism and new structural concepts, "gate" and "twist", of the P-gp structure.

Systemic Functional Linguistic Genre Pedagogy ((SFL GP) in a Tertiary EFL Writing Context in Indonesia

ERIC Educational Resources Information Center

Emilia, Emi; Hamied, Fuad Abdul

2015-01-01

This article reports on the results of a study aiming to investigate whether systemic functional linguistic genre pedagogy (SFL GP) can help students develop their writing ability in English and the students' opinions about the teaching program using SFL GP. The study was conducted in one semester with 19 student teachers taking a writing course…

Biosynthesis and processing of the Autographa californica nuclear polyhedrosis virus gp64 protein.

PubMed

Jarvis, D L; Garcia, A

1994-11-15

gp64 is a major virion envelope glycoprotein of the baculovirus Autographa californica multicapsid nuclear polyhedrosis virus (AcMNPV). gp64 plays an important role in AcMNPV infection, probably mediating penetration of one form of the virus into host cells through the endocytic pathway. gp64 also represents an excellent probe for studying the membrane glycoprotein processing capabilities of baculovirus-infected insect cells, which are used widely as a eucaryotic expression system. The goals of this study were to characterize gp64 biosynthesis and processing and determine how N-glycosylation and N-linked oligosaccharide processing influence the fate and function of gp64 in AcMNPV-infected insect cells. We found that gp64 was synthesized in a biphasic fashion, with peaks at 8 and 24 hr postinfection in both the intracellular and extracellular fractions. Interestingly, the first peak preceded detectable budded virus (BV) production, suggesting that gp64 is shed from infected cells early in infection. Transcriptional regulation accounted for the biphasic mode of gp64 protein synthesis, as transcription initiated at a consensus early motif during early times of infection, at a late motif during late times of infection, and there was a lag between the peak of early and the onset of late transcription. In vitro transcription-translation assays showed that the second ATG in the AcMNPV gp64 long open reading frame is used as the translational initiation codon and that downstream sequences encode a functional signal peptide. Pulse-chase analyses, endoglycosidases, and various inhibitors were used to show that some N-linked oligosaccharides on gp64 are processed by glucosidases and alpha-mannosidases in AcMNPV-infected insect cells. These experiments also revealed that at least two differentially processed gp64 glycoforms are produced in these cells and that both can reach the cell surface and assemble into progeny BV. However, N-linked oligosaccharide processing was not required for gp64 cell surface expression, its assembly into infectious BV, or its fusogenic activity. This suggested that any gp64 glycoform produced during infection, regardless of its N-linked carbohydrate structure, can have essentially normal biological properties. By contrast, transport of gp64 to the cell surface, production of infectious BV, and fusogenic activity were reduced in the absence of N-glycosylation, indicating that this modification is necessary for optimal gp64 function.

N-glycan signatures identified in tumor interstitial fluid and serum of breast cancer patients: association with tumor biology and clinical outcome.

PubMed

Terkelsen, Thilde; Haakensen, Vilde D; Saldova, Radka; Gromov, Pavel; Hansen, Merete Kjaer; Stöckmann, Henning; Lingjaerde, Ole Christian; Børresen-Dale, Anne-Lise; Papaleo, Elena; Helland, Åslaug; Rudd, Pauline M; Gromova, Irina

2018-06-01

Particular N-glycan structures are known to be associated with breast malignancies by coordinating various regulatory events within the tumor and corresponding microenvironment, thus implying that N-glycan patterns may be used for cancer stratification and as predictive or prognostic biomarkers. However, the association between N-glycans secreted by breast tumor and corresponding clinical relevance remain to be elucidated. We profiled N-glycans by HILIC UPLC across a discovery dataset composed of tumor interstitial fluids (TIF, n = 85), paired normal interstitial fluids (NIF, n = 54) and serum samples (n = 28) followed by independent evaluation, with the ultimate goal of identifying tumor-related N-glycan patterns in blood of patients with breast cancer. The segregation of N-linked oligosaccharides revealed 33 compositions, which exhibited differential abundances between TIF and NIF. TIFs were depleted of bisecting N-glycans, which are known to play essential roles in tumor suppression. An increased level of simple high mannose N-glycans in TIF strongly correlated with the presence of tumor infiltrating lymphocytes within tumor. At the same time, a low level of highly complex N-glycans in TIF inversely correlated with the presence of infiltrating lymphocytes within tumor. Survival analysis showed that patients exhibiting increased TIF abundance of GP24 had better outcomes, whereas low levels of GP10, GP23, GP38, and coreF were associated with poor prognosis. Levels of GP1, GP8, GP9, GP14, GP23, GP28, GP37, GP38, and coreF were significantly correlated between TIF and paired serum samples. Cross-validation analysis using an independent serum dataset supported the observed correlation between TIF and serum, for five of nine N-glycan groups: GP8, GP9, GP14, GP23, and coreF. Collectively, our results imply that profiling of N-glycans from proximal breast tumor fluids is a promising strategy for determining tumor-derived glyco-signature(s) in the blood. N-glycans structures validated in our study may serve as novel biomarkers to improve the diagnostic and prognostic stratification of patients with breast cancer. © 2018 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

Implementation of chronic illness care in German primary care practices--how do multimorbid older patients view routine care? A cross-sectional study using multilevel hierarchical modeling.

PubMed

Petersen, Juliana J; Paulitsch, Michael A; Mergenthal, Karola; Gensichen, Jochen; Hansen, Heike; Weyerer, Siegfried; Riedel-Heller, Steffi G; Fuchs, Angela; Maier, Wolfgang; Bickel, Horst; König, Hans-Helmut; Wiese, Birgitt; van den Bussche, Hendrik; Scherer, Martin; Dahlhaus, Anne

2014-08-07

In primary care, patients with multiple chronic conditions are the rule rather than the exception. The Chronic Care Model (CCM) is an evidence-based framework for improving chronic illness care, but little is known about the extent to which it has been implemented in routine primary care. The aim of this study was to describe how multimorbid older patients assess the routine chronic care they receive in primary care practices in Germany, and to explore the extent to which factors at both the practice and patient level determine their views. This cross-sectional study used baseline data from an observational cohort study involving 158 general practitioners (GP) and 3189 multimorbid patients. Standardized questionnaires were employed to collect data, and the Patient Assessment of Chronic Illness Care (PACIC) questionnaire used to assess the quality of care received. Multilevel hierarchical modeling was used to identify any existing association between the dependent variable, PACIC, and independent variables at the patient level (socio-economic factors, weighted count of chronic conditions, instrumental activities of daily living, health-related quality of life, graded chronic pain, no. of contacts with GP, existence of a disease management program (DMP) disease, self-efficacy, and social support) and the practice level (age and sex of GP, years in current practice, size and type of practice). The overall mean PACIC score was 2.4 (SD 0.8), with the mean subscale scores ranging from 2.0 (SD 1.0, subscale goal setting/tailoring) to 3.5 (SD 0.7, delivery system design). At the patient level, higher PACIC scores were associated with a DMP disease, more frequent GP contacts, higher social support, and higher autonomy of past occupation. At the practice level, solo practices were associated with higher PACIC values than other types of practice. This study shows that from the perspective of multimorbid patients receiving care in German primary care practices, the implementation of structured care and counseling could be improved, particularly by helping patients set specific goals, coordinating care, and arranging follow-up contacts. Studies evaluating chronic care should take into consideration that a patient's assessment is associated not only with practice-level factors, but also with individual, patient-level factors. Current Controlled Trials ISRCTN89818205.

Aligning incentives in the management of inguinal hernia: the impact of the payment model.

PubMed

Devarajan, Karthik; Rogers, Loni; Smith, Paul; Schwaitzberg, Steven D

2012-09-01

The Affordable Care Act has stimulated discussion to find feasible, alternate payment models. Adopting a global payment (GP) mechanism may dampen the high number of procedures incentivized by the fee-for-service (FFS) system. The evolving payment mechanism should reflect collaboration between surgeon and system goals. Our aim was to model and perform simulation of a GP system for hernia care and its impact on cost, revenue, and physician reimbursement in an integrated health care system. The results of the 2006 Watchful Waiting (WW) vs Repair of Inguinal Hernia in Minimally Symptomatic Men trial was used as a clinical model for the natural history and progression of inguinal hernia disease Simulations were built using 2009 financial and clinical data from the Cambridge Health Alliance to model costs and revenues in managing care for a 4-year cohort of inguinal hernia patients; FFS, FFS-WW, and the GP-WW were modeled. To build this GP model, surgeons were paid a constant $500 per patient whether herniorrhaphy was performed or not. Compared with the actual combined physician and hospital revenue under the current FFS model ($308,820), implementing the FFS-WW system for 4 years for 139 hernia patients decreased hospital and physician revenues by $93,846 and $19,308, respectively. This resulted in a total savings of $113,154 for the payors only. In contrast, when using WW methodology within a GP model, system savings of $69,174 were observed after 4 years, with preservation of physician and hospital income. Collaboration to achieve shared savings can be accomplished by pooling physician and hospital revenue in order to meet the goals of all parties. Copyright © 2012 American College of Surgeons. Published by Elsevier Inc. All rights reserved.

Toward Effective HIV Vaccination INDUCTION OF BINARY EPITOPE REACTIVE ANTIBODIES WITH BROAD HIV NEUTRALIZING ACTIVITY

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

Nishiyama, Yasuhiro; Planque, Stephanie; Mitsuda, Yukie

2009-11-23

We describe murine monoclonal antibodies (mAbs) raised by immunization with an electrophilic gp120 analog (E-gp120) expressing the rare ability to neutralize genetically heterologous human immunodeficiency virus (HIV) strains. Unlike gp120, E-gp120 formed covalent oligomers. The reactivity of gp120 and E-gp120 with mAbs to reference neutralizing epitopes was markedly different, indicating their divergent structures. Epitope mapping with synthetic peptides and electrophilic peptide analogs indicated binary recognition of two distinct gp120 regions by anti-E-gp120 mAbs, the 421-433 and 288-306 peptide regions. Univalent Fab and single chain Fv fragments expressed the ability to recognize both peptides. X-ray crystallography of an anti-E-gp120 Fab fragmentmore » revealed two neighboring cavities, the typical antigen-binding cavity formed by the complementarity determining regions (CDRs) and another cavity dominated by antibody heavy chain variable (VH) domain framework (FR) residues. Substitution of the FR cavity VH Lys-19 residue by an Ala residue resulted in attenuated binding of the 421-433 region peptide probe. The CDRs and VH FR replacement/silent mutation ratios exceeded the ratio for a random mutation process, suggesting adaptive development of both putative binding sites. All mAbs studied were derived from VH1 family genes, suggesting biased recruitment of the V gene germ line repertoire by E-gp120. The conserved 421-433 region of gp120 is essential for HIV binding to host CD4 receptors. This region is recognized weakly by the FR of antibodies produced without exposure to HIV, but it usually fails to induce adaptive synthesis of neutralizing antibodies. We present models accounting for improved CD4-binding site recognition and broad HIV neutralizing activity of the mAbs, long sought goals in HIV vaccine development.« less

On Using Surrogates with Genetic Programming.

PubMed

Hildebrandt, Torsten; Branke, Jürgen

2015-01-01

One way to accelerate evolutionary algorithms with expensive fitness evaluations is to combine them with surrogate models. Surrogate models are efficiently computable approximations of the fitness function, derived by means of statistical or machine learning techniques from samples of fully evaluated solutions. But these models usually require a numerical representation, and therefore cannot be used with the tree representation of genetic programming (GP). In this paper, we present a new way to use surrogate models with GP. Rather than using the genotype directly as input to the surrogate model, we propose using a phenotypic characterization. This phenotypic characterization can be computed efficiently and allows us to define approximate measures of equivalence and similarity. Using a stochastic, dynamic job shop scenario as an example of simulation-based GP with an expensive fitness evaluation, we show how these ideas can be used to construct surrogate models and improve the convergence speed and solution quality of GP.

Texture segmentation by genetic programming.

PubMed

Song, Andy; Ciesielski, Vic

2008-01-01

This paper describes a texture segmentation method using genetic programming (GP), which is one of the most powerful evolutionary computation algorithms. By choosing an appropriate representation texture, classifiers can be evolved without computing texture features. Due to the absence of time-consuming feature extraction, the evolved classifiers enable the development of the proposed texture segmentation algorithm. This GP based method can achieve a segmentation speed that is significantly higher than that of conventional methods. This method does not require a human expert to manually construct models for texture feature extraction. In an analysis of the evolved classifiers, it can be seen that these GP classifiers are not arbitrary. Certain textural regularities are captured by these classifiers to discriminate different textures. GP has been shown in this study as a feasible and a powerful approach for texture classification and segmentation, which are generally considered as complex vision tasks.

Design, synthesis and biological evaluation of (S)-valine thiazole-derived cyclic and non-cyclic peptidomimetic oligomers as modulators of human P-glycoprotein (ABCB1)

PubMed Central

Singh, Satyakam; Prasad, Nagarajan Rajendra; Kapoor, Khyati; Chufan, Eduardo E.; Patel, Bhargav A.; Ambudkar, Suresh V.; Talele, Tanaji T.

2014-01-01

Multidrug resistance (MDR) caused by ATP-binding cassette (ABC) transporter P-glycoprotein (P-gp) through extrusion of anticancer drugs from the cells is a major cause of failure to cancer chemotherapy. Previously, selenazole containing cyclic peptides were reported as P-gp inhibitors and these were also used for co-crystallization with mouse P-gp, which has 87% homology to human P-gp. It has been reported that human P-gp, can simultaneously accommodate 2-3 moderate size molecules at the drug binding pocket. Our in-silico analysis based on the homology model of human P-gp spurred our efforts to investigate the optimal size of (S)-valine-derived thiazole units that can be accommodated at drug-binding pocket. Towards this goal, we synthesized varying lengths of linear and cyclic derivatives of (S)-valine-derived thiazole units to investigate the optimal size, lipophilicity and the structural form (linear and cyclic) of valine-derived thiazole peptides that can accommodate well in the P-gp binding pocket and affects its activity, previously an unexplored concept. Among these oligomers, lipophilic linear- (13) and cyclic-trimer (17) derivatives of QZ59S-SSS were found to be the most and equally potent inhibitors of human P-gp (IC50 = 1.5 μM). Cyclic trimer and linear trimer being equipotent, future studies can be focused on non-cyclic counterparts of cyclic peptides maintaining linear trimer length. Binding model of the linear trimer (13) within the drug-binding site on the homology model of human P-gp represents an opportunity for future optimization, specifically replacing valine and thiazole groups in the non-cyclic form. PMID:24288265

Design, synthesis, and biological evaluation of (S)-valine thiazole-derived cyclic and noncyclic peptidomimetic oligomers as modulators of human P-glycoprotein (ABCB1).

PubMed

Singh, Satyakam; Prasad, Nagarajan Rajendra; Kapoor, Khyati; Chufan, Eduardo E; Patel, Bhargav A; Ambudkar, Suresh V; Talele, Tanaji T

2014-01-03

Multidrug resistance caused by ATP binding cassette transporter P-glycoprotein (P-gp) through extrusion of anticancer drugs from the cells is a major cause of failure in cancer chemotherapy. Previously, selenazole-containing cyclic peptides were reported as P-gp inhibitors and were also used for co-crystallization with mouse P-gp, which has 87 % homology to human P-gp. It has been reported that human P-gp can simultaneously accommodate two to three moderately sized molecules at the drug binding pocket. Our in silico analysis, based on the homology model of human P-gp, spurred our efforts to investigate the optimal size of (S)-valine-derived thiazole units that can be accommodated at the drug binding pocket. Towards this goal, we synthesized varying lengths of linear and cyclic derivatives of (S)-valine-derived thiazole units to investigate the optimal size, lipophilicity, and structural form (linear or cyclic) of valine-derived thiazole peptides that can be accommodated in the P-gp binding pocket and affects its activity, previously an unexplored concept. Among these oligomers, lipophilic linear (13) and cyclic trimer (17) derivatives of QZ59S-SSS were found to be the most and equally potent inhibitors of human P-gp (IC50 =1.5 μM). As the cyclic trimer and linear trimer compounds are equipotent, future studies should focus on noncyclic counterparts of cyclic peptides maintaining linear trimer length. A binding model of the linear trimer 13 within the drug binding site on the homology model of human P-gp represents an opportunity for future optimization, specifically replacing valine and thiazole groups in the noncyclic form. Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Genetic programming assisted stochastic optimization strategies for optimization of glucose to gluconic acid fermentation.

PubMed

Cheema, Jitender Jit Singh; Sankpal, Narendra V; Tambe, Sanjeev S; Kulkarni, Bhaskar D

2002-01-01

This article presents two hybrid strategies for the modeling and optimization of the glucose to gluconic acid batch bioprocess. In the hybrid approaches, first a novel artificial intelligence formalism, namely, genetic programming (GP), is used to develop a process model solely from the historic process input-output data. In the next step, the input space of the GP-based model, representing process operating conditions, is optimized using two stochastic optimization (SO) formalisms, viz., genetic algorithms (GAs) and simultaneous perturbation stochastic approximation (SPSA). These SO formalisms possess certain unique advantages over the commonly used gradient-based optimization techniques. The principal advantage of the GP-GA and GP-SPSA hybrid techniques is that process modeling and optimization can be performed exclusively from the process input-output data without invoking the detailed knowledge of the process phenomenology. The GP-GA and GP-SPSA techniques have been employed for modeling and optimization of the glucose to gluconic acid bioprocess, and the optimized process operating conditions obtained thereby have been compared with those obtained using two other hybrid modeling-optimization paradigms integrating artificial neural networks (ANNs) and GA/SPSA formalisms. Finally, the overall optimized operating conditions given by the GP-GA method, when verified experimentally resulted in a significant improvement in the gluconic acid yield. The hybrid strategies presented here are generic in nature and can be employed for modeling and optimization of a wide variety of batch and continuous bioprocesses.

Mechanistic kinetic modeling generates system-independent P-glycoprotein mediated transport elementary rate constants for inhibition and, in combination with 3D SIM microscopy, elucidates the importance of microvilli morphology on P-glycoprotein mediated efflux activity.

PubMed

Ellens, Harma; Meng, Zhou; Le Marchand, Sylvain J; Bentz, Joe

2018-06-01

In vitro transporter kinetics are typically analyzed by steady-state Michaelis-Menten approximations. However, no clear evidence exists that these approximations, applied to multiple transporters in biological membranes, yield system-independent mechanistic parameters needed for reliable in vivo hypothesis generation and testing. Areas covered: The classical mass action model has been developed for P-glycoprotein (P-gp) mediated transport across confluent polarized cell monolayers. Numerical integration of the mass action equations for transport using a stable global optimization program yields fitted elementary rate constants that are system-independent. The efflux active P-gp was defined by the rate at which P-gp delivers drugs to the apical chamber, since as much as 90% of drugs effluxed by P-gp partition back into nearby microvilli prior to reaching the apical chamber. The efflux active P-gp concentration was 10-fold smaller than the total expressed P-gp for Caco-2 cells, due to their microvilli membrane morphology. The mechanistic insights from this analysis are readily extrapolated to P-gp mediated transport in vivo. Expert opinion: In vitro system-independent elementary rate constants for transporters are essential for the generation and validation of robust mechanistic PBPK models. Our modeling approach and programs have broad application potential. They can be used for any drug transporter with minor adaptations.

SU-E-T-20: A Correlation Study of 2D and 3D Gamma Passing Rates for Prostate IMRT Plans

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

Zhang, D; Sun Yat-sen University Cancer Center, Guangzhou, Guangdong; Wang, B

2015-06-15

Purpose: To investigate the correlation between the two-dimensional gamma passing rate (2D %GP) and three-dimensional gamma passing rate (3D %GP) in prostate IMRT quality assurance. Methods: Eleven prostate IMRT plans were randomly selected from the clinical database and were used to obtain dose distributions in the phantom and patient. Three types of delivery errors (MLC bank sag errors, central MLC errors and monitor unit errors) were intentionally introduced to modify the clinical plans through an in-house Matlab program. This resulted in 187 modified plans. The 2D %GP and 3D %GP were analyzed using different dose-difference and distance-toagreement (1%-1mm, 2%-2mm andmore » 3%-3mm) and 20% dose threshold. The 2D %GP and 3D %GP were then compared not only for the whole region, but also for the PTVs and critical structures using the statistical Pearson’s correlation coefficient (γ). Results: For different delivery errors, the average comparison of 2D %GP and 3D %GP showed different conclusions. The statistical correlation coefficients between 2D %GP and 3D %GP for the whole dose distribution showed that except for 3%/3mm criterion, 2D %GP and 3D %GP of 1%/1mm criterion and 2%/2mm criterion had strong correlations (Pearson’s γ value >0.8). Compared with the whole region, the correlations of 2D %GP and 3D %GP for PTV were better (the γ value for 1%/1mm, 2%/2mm and 3%/3mm criterion was 0.959, 0.931 and 0.855, respectively). However for the rectum, there was no correlation between 2D %GP and 3D %GP. Conclusion: For prostate IMRT, the correlation between 2D %GP and 3D %GP for the PTV is better than that for normal structures. The lower dose-difference and DTA criterion shows less difference between 2D %GP and 3D %GP. Other factors such as the dosimeter characteristics and TPS algorithm bias may also influence the correlation between 2D %GP and 3D %GP.« less

Prediction of laser cutting heat affected zone by extreme learning machine

NASA Astrophysics Data System (ADS)

Anicic, Obrad; Jović, Srđan; Skrijelj, Hivzo; Nedić, Bogdan

2017-01-01

Heat affected zone (HAZ) of the laser cutting process may be developed based on combination of different factors. In this investigation the HAZ forecasting, based on the different laser cutting parameters, was analyzed. The main goal was to predict the HAZ according to three inputs. The purpose of this research was to develop and apply the Extreme Learning Machine (ELM) to predict the HAZ. The ELM results were compared with genetic programming (GP) and artificial neural network (ANN). The reliability of the computational models were accessed based on simulation results and by using several statistical indicators. Based upon simulation results, it was demonstrated that ELM can be utilized effectively in applications of HAZ forecasting.

P-gp Protein Expression and Transport Activity in Rodent Seizure Models and Human Epilepsy.

PubMed

Hartz, Anika M S; Pekcec, Anton; Soldner, Emma L B; Zhong, Yu; Schlichtiger, Juli; Bauer, Bjoern

2017-04-03

A cure for epilepsy is currently not available, and seizure genesis, seizure recurrence, and resistance to antiseizure drugs remain serious clinical problems. Studies show that the blood-brain barrier is altered in animal models of epilepsy and in epileptic patients. In this regard, seizures increase expression of blood-brain barrier efflux transporters such as P-glycoprotein (P-gp), which is thought to reduce brain uptake of antiseizure drugs, and thus, contribute to antiseizure drug resistance. The goal of the current study was to assess the viability of combining in vivo and ex vivo preparations of isolated brain capillaries from animal models of seizures and epilepsy as well as from patients with epilepsy to study P-gp at the blood-brain barrier. Exposing isolated rat brain capillaries to glutamate ex vivo upregulated P-gp expression to levels that were similar to those in capillaries isolated from rats that had status epilepticus or chronic epilepsy. Moreover, the fold-increase in P-gp protein expression seen in animal models is consistent with the fold-increase in P-gp observed in human brain capillaries isolated from patients with epilepsy compared to age-matched control individuals. Overall, the in vivo/ex vivo approach presented here allows detailed analysis of the mechanisms underlying seizure-induced changes of P-gp expression and transport activity at the blood-brain barrier. This approach can be extended to other blood-brain barrier proteins that might contribute to drug-resistant epilepsy or other CNS disorders as well.

The construction of a decision tool to analyse local demand and local supply for GP care using a synthetic estimation model

PubMed Central

2013-01-01

Background This study addresses the growing academic and policy interest in the appropriate provision of local healthcare services to the healthcare needs of local populations to increase health status and decrease healthcare costs. However, for most local areas information on the demand for primary care and supply is missing. The research goal is to examine the construction of a decision tool which enables healthcare planners to analyse local supply and demand in order to arrive at a better match. Methods National sample-based medical record data of general practitioners (GPs) were used to predict the local demand for GP care based on local populations using a synthetic estimation technique. Next, the surplus or deficit in local GP supply were calculated using the national GP registry. Subsequently, a dynamic internet tool was built to present demand, supply and the confrontation between supply and demand regarding GP care for local areas and their surroundings in the Netherlands. Results Regression analysis showed a significant relationship between sociodemographic predictors of postcode areas and GP consultation time (F [14, 269,467] = 2,852.24; P <0.001). The statistical model could estimate GP consultation time for every postcode area with >1,000 inhabitants in the Netherlands covering 97% of the total population. Confronting these estimated demand figures with the actual GP supply resulted in the average GP workload and the number of full-time equivalent (FTE) GP too much/too few for local areas to cover the demand for GP care. An estimated shortage of one FTE GP or more was prevalent in about 19% of the postcode areas with >1,000 inhabitants if the surrounding postcode areas were taken into consideration. Underserved areas were mainly found in rural regions. Conclusions The constructed decision tool is freely accessible on the Internet and can be used as a starting point in the discussion on primary care service provision in local communities and it can make a considerable contribution to a primary care system which provides care when and where people need it. PMID:24161015

General practitioners' perceptions of their ability to identify and refer patients with suspected axial spondyloarthritis: a qualitative study.

PubMed

van Onna, Marloes; Gorter, Simone; van Meerendonk, Aniek; van Tubergen, Astrid

2014-05-01

To explore the knowledge, beliefs, and experiences of general practitioners (GP) about inflammatory back pain (IBP) and axial spondyloarthritis (axSpA) and potential barriers for referral of patients suspected of having axSpA. A qualitative study involving semistructured interviews with GP was conducted. Transcripts of the interviews were independently read and annotated by 2 readers. Illustrative themes were identified and a coding system to categorize the data was developed. Ten GP (all men; mean age 49 yrs) were interviewed. All could adequately describe "classic" ankylosing spondylitis (AS) and mentioned chronic back pain and/or stiffness as key features. All GP thought that AS is almost exclusively diagnosed in men. Six GP knew that there is a difference between mechanical back pain and IBP, but could recall only a limited number of variables indicative of IBP, such as awakening night pain (4 GP), insidious onset of back pain (1 GP), improvement with movement (1 GP), and (morning) stiffness (2 GP). Two GP mentioned peripheral arthritis as other SpA features, none mentioned dactylitis or enthesitis. GP awareness of associated extraarticular manifestations was low. Most GP expressed that (practical) referral measures would be useful. GP are aware of "classic", but longterm features of axSpA. Knowledge about the disease spectrum and early detection is, however, limited. Addressing these issues in training programs may improve recognition of axSpA in primary care. This may ultimately contribute to earlier referral, diagnosis, and initiation of effective treatment in patients with axSpA.

Automated data extraction from general practice records in an Australian setting: trends in influenza-like illness in sentinel general practices and emergency departments.

PubMed

Liljeqvist, Gösta T H; Staff, Michael; Puech, Michele; Blom, Hans; Torvaldsen, Siranda

2011-06-06

Influenza intelligence in New South Wales (NSW), Australia is derived mainly from emergency department (ED) presentations and hospital and intensive care admissions, which represent only a portion of influenza-like illness (ILI) in the population. A substantial amount of the remaining data lies hidden in general practice (GP) records. Previous attempts in Australia to gather ILI data from GPs have given them extra work. We explored the possibility of applying automated data extraction from GP records in sentinel surveillance in an Australian setting.The two research questions asked in designing the study were: Can syndromic ILI data be extracted automatically from routine GP data? How do ILI trends in sentinel general practice compare with ILI trends in EDs? We adapted a software program already capable of automated data extraction to identify records of patients with ILI in routine electronic GP records in two of the most commonly used commercial programs. This tool was applied in sentinel sites to gather retrospective data for May-October 2007-2009 and in real-time for the same interval in 2010. The data were compared with that provided by the Public Health Real-time Emergency Department Surveillance System (PHREDSS) and with ED data for the same periods. The GP surveillance tool identified seasonal trends in ILI both retrospectively and in near real-time. The curve of seasonal ILI was more responsive and less volatile than that of PHREDSS on a local area level. The number of weekly ILI presentations ranged from 8 to 128 at GP sites and from 0 to 18 in EDs in non-pandemic years. Automated data extraction from routine GP records offers a means to gather data without introducing any additional work for the practitioner. Adding this method to current surveillance programs will enhance their ability to monitor ILI and to detect early warning signals of new ILI events.

Evolutionary Data Mining Approach to Creating Digital Logic

DTIC Science & Technology

2010-01-01

To deal with this problem a genetic program (GP) based data mining ( DM ) procedure has been invented (Smith 2005). A genetic program is an algorithm...that can operate on the variables. When a GP was used as a DM function in the past to automatically create fuzzy decision trees, the Report...rules represents an approach to the determining the effect of linguistic imprecision, i.e., the inability of experts to provide crisp rules. The

Comprehensive analog synthesis of (S)-valine thiazole peptidomimetic TTT-28 to understand enigmatic drug-binding sites of P-glycoprotein

NASA Astrophysics Data System (ADS)

Patel, Bhargav A.

P-glycoprotein (P-gp) is considered an important therapeutic target for reversal of multidrug resistance (MDR) in cancer. It recognizes a diverse range of chemically and mechanistically dissimilar drugs. It has been postulated that the efflux by P-gp plays a major role in failure of chemotherapy. Hence, researchers have been trying to obtain a potent inhibitor of P-gp with specificity to tumor sites. In this pursuit, we previously were able to obtain a novel (S)-valine thiazole-derived peptidomimetic compound 1 ( TTT-28), which showed potent reversal of MDR in vitro as well as in vivo compared to verapamil, a well-known MDR modulator. We have also found that compound 1 triggers ATPase stimulation when incubated with P-gp alike verapamil, which implies its mechanism of action as competitive in nature. In this study, we attempted to understand structural requirements of ligands binding to a perplexing drug-binding site of P-gp and affecting its ATPase function. Toward this goal, we prepared a novel set of 64 analogues by fine tuning lead compound 1. These synthesized analogues were tested using ATPase activity assay. During the course of the study, a potent stimulator (1) of ATPase activity was transformed into an ATPase inhibitory leads such as compounds 43 , 57 and 113. The ATPase inhibitory activity of these compounds is predominantly contributed by the presence of a cyclohexyl group in place of the 2-aminobenzophenone moiety of ATPase activity stimulatory lead compound 1. Molecular modeling studies suggested a need for specific interactions with the drug-binding site of P-gp to induce different conformational states of P-gp to produce either stimulation or inhibition of ATPase activity. Collectively, this comprehensive synthesis work will facilitate further research towards P-gp inhibitor development.

Multitask visual learning using genetic programming.

PubMed

Jaśkowski, Wojciech; Krawiec, Krzysztof; Wieloch, Bartosz

2008-01-01

We propose a multitask learning method of visual concepts within the genetic programming (GP) framework. Each GP individual is composed of several trees that process visual primitives derived from input images. Two trees solve two different visual tasks and are allowed to share knowledge with each other by commonly calling the remaining GP trees (subfunctions) included in the same individual. The performance of a particular tree is measured by its ability to reproduce the shapes contained in the training images. We apply this method to visual learning tasks of recognizing simple shapes and compare it to a reference method. The experimental verification demonstrates that such multitask learning often leads to performance improvements in one or both solved tasks, without extra computational effort.

Barcoded microchips for biomolecular assays.

PubMed

Zhang, Yi; Sun, Jiashu; Zou, Yu; Chen, Wenwen; Zhang, Wei; Xi, Jianzhong Jeff; Jiang, Xingyu

2015-01-20

Multiplexed assay of analytes is of great importance for clinical diagnostics and other analytical applications. Barcode-based bioassays with the ability to encode and decode may realize this goal in a straightforward and consistent manner. We present here a microfluidic barcoded chip containing several sets of microchannels with different widths, imitating the commonly used barcode. A single barcoded microchip can carry out tens of individual protein/nucleic acid assays (encode) and immediately yield all assay results by a portable barcode reader or a smartphone (decode). The applicability of a barcoded microchip is demonstrated by human immunodeficiency virus (HIV) immunoassays for simultaneous detection of three targets (anti-gp41 antibody, anti-gp120 antibody, and anti-gp36 antibody) from six human serum samples. We can also determine seven pathogen-specific oligonucleotides by a single chip containing both positive and negative controls.

Recombinant Nonstructural 3 Protein, rNS3, of Hepatitis C Virus Along With Recombinant GP96 Induce IL-12, TNFα and α5integrin Expression in Antigen Presenting Cells

PubMed Central

Hajizadeh, Mohammad Reza; Mokarram, Pooneh; Kamali sarvestani, Eskandar; Bolhassani, Azam; Mostafavi Pour, Zohreh

2013-01-01

Background Hepatitis C virus (HCV) infection is the main cause of chronic liver disease and to date there has been no vaccine development to prevent this infection. Among non-structural HCV proteins, NS3 protein is an excellent goal for a therapeutic vaccine, due to its large size and less variation in conserved regions. The immunogenic properties of heat shock proteins (HSPs) for instance GP96 have prompted investigations into their function as strong adjuvant to improve innate and adaptive immunity. Objectives The aim of this study was to examine additive effects of recombinant GP96 (rGP96) fragments accompanied by rNS3 on expression levels of α5integrin and pro-inflammatory cytokines, IL-12 and TNFα, in Antigen Presenting Cells (APCs). Materials and Methods Recombinant viral proteins (rNS3 and rRGD-NS3), N-terminal and C-terminal fragments of GP96 were produced and purified from E. coli in order to treat the cells; mouse spleen Dendritic Cells (DCs) and THP-1 macrophages. Results Our results showed that rNT-GP96 alone significantly increases the expression level of IL-12, TNFα and α5integrin in THP-1 macrophages and DCs, while IL-12 and TNFα expression levels were unaffected by either rNS3 or rRGD-NS3. Interestingly, the co-addition of these recombinant proteins with rNT-GP96 increased IL-12, TNFα and α5integrin expression. Pearson Correlation showed a direct association between α5integrin with IL-12 and TNF-α expression. Conclusions we have highlighted the role of rNS3 plus rNT-GP96 mediated by α5integrin in producing IL-12 and TNFα. It can be suggested that rNT-GP96 could enhance immunity characteristic of rNS3 protein via production of pro-inflammatory cytokines. PMID:24032046

HIV-1 gp120 and Modified Vaccinia Virus Ankara (MVA) gp140 Boost Immunogens Increase Immunogenicity of a DNA/MVA HIV-1 Vaccine.

PubMed

Shen, Xiaoying; Basu, Rahul; Sawant, Sheetal; Beaumont, David; Kwa, Sue Fen; LaBranche, Celia; Seaton, Kelly E; Yates, Nicole L; Montefiori, David C; Ferrari, Guido; Wyatt, Linda S; Moss, Bernard; Alam, S Munir; Haynes, Barton F; Tomaras, Georgia D; Robinson, Harriet L

2017-12-15

An important goal of human immunodeficiency virus (HIV) vaccine design is identification of strategies that elicit effective antiviral humoral immunity. One novel approach comprises priming with DNA and boosting with modified vaccinia virus Ankara (MVA) expressing HIV-1 Env on virus-like particles. In this study, we evaluated whether the addition of a gp120 protein in alum or MVA-expressed secreted gp140 (MVAgp140) could improve immunogenicity of a DNA prime-MVA boost vaccine. Five rhesus macaques per group received two DNA primes at weeks 0 and 8 followed by three MVA boosts (with or without additional protein or MVAgp140) at weeks 18, 26, and 40. Both boost immunogens enhanced the breadth of HIV-1 gp120 and V1V2 responses, antibody-dependent cellular cytotoxicity (ADCC), and low-titer tier 1B and tier 2 neutralizing antibody responses. However, there were differences in antibody kinetics, linear epitope specificity, and CD4 T cell responses between the groups. The gp120 protein boost elicited earlier and higher peak responses, whereas the MVAgp140 boost resulted in improved antibody durability and comparable peak responses after the final immunization. Linear V3 specific IgG responses were particularly enhanced by the gp120 boost, whereas the MVAgp140 boost also enhanced responses to linear C5 and C2.2 epitopes. Interestingly, gp120, but not the MVAgp140 boost, increased peak CD4 + T cell responses. Thus, both gp120 and MVAgp140 can augment potential protection of a DNA/MVA vaccine by enhancing gp120 and V1/V2 antibody responses, whereas potential protection by gp120, but not MVAgp140 boosts, may be further impacted by increased CD4 + T cell responses. IMPORTANCE Prior immune correlate analyses with humans and nonhuman primates revealed the importance of antibody responses in preventing HIV-1 infection. A DNA prime-modified vaccinia virus Ankara (MVA) boost vaccine has proven to be potent in eliciting antibody responses. Here we explore the ability of boosts with recombinant gp120 protein or MVA-expressed gp140 to enhance antibody responses elicited by the GOVX-B11 DNA prime-MVA boost vaccine. We found that both types of immunogen boosts enhanced potentially protective antibody responses, whereas the gp120 protein boosts also increased CD4 + T cell responses. Our data provide important information for HIV vaccine designs that aim for effective and balanced humoral and T cell responses. Copyright © 2017 Shen et al.

Improving Search Properties in Genetic Programming

NASA Technical Reports Server (NTRS)

Janikow, Cezary Z.; DeWeese, Scott

1997-01-01

With the advancing computer processing capabilities, practical computer applications are mostly limited by the amount of human programming required to accomplish a specific task. This necessary human participation creates many problems, such as dramatically increased cost. To alleviate the problem, computers must become more autonomous. In other words, computers must be capable to program/reprogram themselves to adapt to changing environments/tasks/demands/domains. Evolutionary computation offers potential means, but it must be advanced beyond its current practical limitations. Evolutionary algorithms model nature. They maintain a population of structures representing potential solutions to the problem at hand. These structures undergo a simulated evolution by means of mutation, crossover, and a Darwinian selective pressure. Genetic programming (GP) is the most promising example of an evolutionary algorithm. In GP, the structures that evolve are trees, which is a dramatic departure from previously used representations such as strings in genetic algorithms. The space of potential trees is defined by means of their elements: functions, which label internal nodes, and terminals, which label leaves. By attaching semantic interpretation to those elements, trees can be interpreted as computer programs (given an interpreter), evolved architectures, etc. JSC has begun exploring GP as a potential tool for its long-term project on evolving dextrous robotic capabilities. Last year we identified representation redundancies as the primary source of inefficiency in GP. Subsequently, we proposed a method to use problem constraints to reduce those redundancies, effectively reducing GP complexity. This method was implemented afterwards at the University of Missouri. This summer, we have evaluated the payoff from using problem constraints to reduce search complexity on two classes of problems: learning boolean functions and solving the forward kinematics problem. We have also developed and implemented methods to use additional problem heuristics to fine-tune the searchable space, and to use typing information to further reduce the search space. Additional improvements have been proposed, but they are yet to be explored and implemented.

More than a century of Grain for Green Program is expected to restore soil carbon stock on alpine grassland revealed by field (13)C pulse labeling.

PubMed

Li, Qi; Chen, Dongdong; Zhao, Liang; Yang, Xue; Xu, Shixiao; Zhao, Xinquan

2016-04-15

Anthropogenic changes in land use/cover have altered the vegetation, soil, and carbon (C) cycling on the Qinghai-Tibetan Plateau (QTP) over the last ~50years. As a result, the Grain for Green Program (GfGP) has been widely implemented over the last 10years to mitigate the impacts of cultivation. To quantify the effects of the GfGP on C partitioning and turnover rates at the ecosystem scale, an in situ (13)C pulse labeling experiment was conducted on natural and GfGP grasslands in an agro-pastoral ecotone in the Lake Qinghai region on the QTP. We found that there were significant differences in the C stocks of all the considered pools in both the natural and GfGP grasslands, with higher CO2 uptake rates in the GfGP grassland than that in the natural grassland. Partitioning of photoassimilate (% of recovered (13)C) in C pools of both grasslands was similar 25days after labeling, except in the roots of the 0-15 and 5-15cm soil layer. Soil organic C (SOC) sequestration rate in the GfGP grassland was 11.59±1.89gCm(-2)yr(-1) significantly greater than that in the natural grassland. The results confirmed that the GfGP is an efficient approach for grassland restoration and C sequestration. However, it will take more than a century (119.19±20.26yr) to restore the SOC stock from the current cropland baseline level to the approximate level of natural grassland. We suggest that additional measures are needed in the selection of suitable plant species for vegetation restoration, and in reasonable grazing management. Copyright © 2016 Elsevier B.V. All rights reserved.

From Heuristic to Mathematical Modeling of Drugs Dissolution Profiles: Application of Artificial Neural Networks and Genetic Programming

PubMed Central

Mendyk, Aleksander; Güres, Sinan; Szlęk, Jakub; Wiśniowska, Barbara; Kleinebudde, Peter

2015-01-01

The purpose of this work was to develop a mathematical model of the drug dissolution (Q) from the solid lipid extrudates based on the empirical approach. Artificial neural networks (ANNs) and genetic programming (GP) tools were used. Sensitivity analysis of ANNs provided reduction of the original input vector. GP allowed creation of the mathematical equation in two major approaches: (1) direct modeling of Q versus extrudate diameter (d) and the time variable (t) and (2) indirect modeling through Weibull equation. ANNs provided also information about minimum achievable generalization error and the way to enhance the original dataset used for adjustment of the equations' parameters. Two inputs were found important for the drug dissolution: d and t. The extrudates length (L) was found not important. Both GP modeling approaches allowed creation of relatively simple equations with their predictive performance comparable to the ANNs (root mean squared error (RMSE) from 2.19 to 2.33). The direct mode of GP modeling of Q versus d and t resulted in the most robust model. The idea of how to combine ANNs and GP in order to escape ANNs' black-box drawback without losing their superior predictive performance was demonstrated. Open Source software was used to deliver the state-of-the-art models and modeling strategies. PMID:26101544

From Heuristic to Mathematical Modeling of Drugs Dissolution Profiles: Application of Artificial Neural Networks and Genetic Programming.

PubMed

Mendyk, Aleksander; Güres, Sinan; Jachowicz, Renata; Szlęk, Jakub; Polak, Sebastian; Wiśniowska, Barbara; Kleinebudde, Peter

2015-01-01

The purpose of this work was to develop a mathematical model of the drug dissolution (Q) from the solid lipid extrudates based on the empirical approach. Artificial neural networks (ANNs) and genetic programming (GP) tools were used. Sensitivity analysis of ANNs provided reduction of the original input vector. GP allowed creation of the mathematical equation in two major approaches: (1) direct modeling of Q versus extrudate diameter (d) and the time variable (t) and (2) indirect modeling through Weibull equation. ANNs provided also information about minimum achievable generalization error and the way to enhance the original dataset used for adjustment of the equations' parameters. Two inputs were found important for the drug dissolution: d and t. The extrudates length (L) was found not important. Both GP modeling approaches allowed creation of relatively simple equations with their predictive performance comparable to the ANNs (root mean squared error (RMSE) from 2.19 to 2.33). The direct mode of GP modeling of Q versus d and t resulted in the most robust model. The idea of how to combine ANNs and GP in order to escape ANNs' black-box drawback without losing their superior predictive performance was demonstrated. Open Source software was used to deliver the state-of-the-art models and modeling strategies.

Co-formulation of P-glycoprotein Substrate and Inhibitor in Nanocarriers: An Emerging Strategy for Cancer Chemotherapy.

PubMed

Saneja, Ankit; Dubey, Ravindra Dhar; Alam, Noor; Khare, Vaibhav; Gupta, Prem N

2014-01-01

Scientific community is striving to understand the role of P-glycoprotein (P-gp) in drug discovery programs due to its impact on pharmacokinetic and multi-drug resistance (MDR) of anticancer drugs. A number of efforts to resolve the crystal structure and understanding the mechanism of P-gp mediated efflux have been made. Several generations of Pgp inhibitors have been developed to tackle this multi-specific efflux protein. Unfortunately, these inhibitors lack selectivity, exhibit poor solubility and severe pharmacokinetic interactions restricting their clinical use. The nanocarrier drug delivery systems (NDDS) are receiving increasing attention for P-gp modulating activity of pharmaceutical excipients which are used in their fabrication. In addition, NDDS can enhance the solubility and exhibited ability to bypass P-gp mediated efflux. The co-formulation of P-gp inhibitors and substrate anticancer drugs in single drug delivery system offers the advantage of bypassing P-gp mediated drug efflux as well as inhibiting the P-gp. Moreover, severe pharmacokinetic interactions between P-gp inhibitor and substrate anticancer drugs could be avoided by using this strategy. In this article we describe the co-formulation strategies using nanocarriers for modulation of pharmacokinetics as well as multi-drug resistance of anticancer drugs along with the challenges in this area.

Application of a soft computing technique in predicting the percentage of shear force carried by walls in a rectangular channel with non-homogeneous roughness.

PubMed

Khozani, Zohreh Sheikh; Bonakdari, Hossein; Zaji, Amir Hossein

2016-01-01

Two new soft computing models, namely genetic programming (GP) and genetic artificial algorithm (GAA) neural network (a combination of modified genetic algorithm and artificial neural network methods) were developed in order to predict the percentage of shear force in a rectangular channel with non-homogeneous roughness. The ability of these methods to estimate the percentage of shear force was investigated. Moreover, the independent parameters' effectiveness in predicting the percentage of shear force was determined using sensitivity analysis. According to the results, the GP model demonstrated superior performance to the GAA model. A comparison was also made between the GP program determined as the best model and five equations obtained in prior research. The GP model with the lowest error values (root mean square error ((RMSE) of 0.0515) had the best function compared with the other equations presented for rough and smooth channels as well as smooth ducts. The equation proposed for rectangular channels with rough boundaries (RMSE of 0.0642) outperformed the prior equations for smooth boundaries.

HIV-gp120 and physical dependence to buprenorphine.

PubMed

Palma, J; Abood, M E; Benamar, K

2015-05-01

Opioids are among the most effective and commonly used analgesics in clinical practice for severe pain. However, the use of opioid medications is clinically limited by several adverse properties including dependence. While opioid dependence is a complex health condition, the treatment of HIV-infected individuals with opioid dependence presents additional challenges. The goal of this study was to examine the physical dependence to buprenorphine in the context of HIV. Young adult male rats (Sprague-Dawley) were pretreated with HIV-1 envelope glycoprotein 120 (gp120) injected into the periaqueductal gray area (PAG) and we examined the impact on physical dependence to opioid. It was found that the physical dependence to methadone occurred earlier than that to buprenorphine, and that gp120 did not enhance or precipitate the buprenorphine withdrawal. The results suggest that buprenorphine could be the better therapeutic option to manage opioid dependence in HIV. Copyright © 2015. Published by Elsevier Ireland Ltd.

Genetic algorithms and genetic programming for multiscale modeling: Applications in materials science and chemistry and advances in scalability

NASA Astrophysics Data System (ADS)

Sastry, Kumara Narasimha

2007-03-01

Effective and efficient rnultiscale modeling is essential to advance both the science and synthesis in a, wide array of fields such as physics, chemistry, materials science; biology, biotechnology and pharmacology. This study investigates the efficacy and potential of rising genetic algorithms for rnultiscale materials modeling and addresses some of the challenges involved in designing competent algorithms that solve hard problems quickly, reliably and accurately. In particular, this thesis demonstrates the use of genetic algorithms (GAs) and genetic programming (GP) in multiscale modeling with the help of two non-trivial case studies in materials science and chemistry. The first case study explores the utility of genetic programming (GP) in multi-timescaling alloy kinetics simulations. In essence, GP is used to bridge molecular dynamics and kinetic Monte Carlo methods to span orders-of-magnitude in simulation time. Specifically, GP is used to regress symbolically an inline barrier function from a limited set of molecular dynamics simulations to enable kinetic Monte Carlo that simulate seconds of real time. Results on a non-trivial example of vacancy-assisted migration on a surface of a face-centered cubic (fcc) Copper-Cobalt (CuxCo 1-x) alloy show that GP predicts all barriers with 0.1% error from calculations for less than 3% of active configurations, independent of type of potentials used to obtain the learning set of barriers via molecular dynamics. The resulting method enables 2--9 orders-of-magnitude increase in real-time dynamics simulations taking 4--7 orders-of-magnitude less CPU time. The second case study presents the application of multiobjective genetic algorithms (MOGAs) in multiscaling quantum chemistry simulations. Specifically, MOGAs are used to bridge high-level quantum chemistry and semiempirical methods to provide accurate representation of complex molecular excited-state and ground-state behavior. Results on ethylene and benzene---two common building blocks in organic chemistry---indicate that MOGAs produce High-quality semiempirical methods that (1) are stable to small perturbations, (2) yield accurate configuration energies on untested and critical excited states, and (3) yield ab initio quality excited-state dynamics. The proposed method enables simulations of more complex systems to realistic, multi-picosecond timescales, well beyond previous attempts or expectation of human experts, and 2--3 orders-of-magnitude reduction in computational cost. While the two applications use simple evolutionary operators, in order to tackle more complex systems, their scalability and limitations have to be investigated. The second part of the thesis addresses some of the challenges involved with a successful design of genetic algorithms and genetic programming for multiscale modeling. The first issue addressed is the scalability of genetic programming, where facetwise models are built to assess the population size required by GP to ensure adequate supply of raw building blocks and also to ensure accurate decision-making between competing building blocks. This study also presents a design of competent genetic programming, where traditional fixed recombination operators are replaced by building and sampling probabilistic models of promising candidate programs. The proposed scalable GP, called extended compact GP (eCGP), combines the ideas from extended compact genetic algorithm (eCGA) and probabilistic incremental program evolution (PIPE) and adaptively identifies, propagates and exchanges important subsolutions of a search problem. Results show that eCGP scales cubically with problem size on both GP-easy and GP-hard problems. Finally, facetwise models are developed to explore limitations of scalability of MOGAs, where the scalability of multiobjective algorithms in reliably maintaining Pareto-optimal solutions is addressed. The results show that even when the building blocks are accurately identified, massive multimodality of the search problems can easily overwhelm the nicher (diversity preserving operator) and lead to exponential scale-up. Facetwise models are developed, which incorporate the combined effects of model accuracy, decision making, and sub-structure supply, as well as the effect of niching on the population sizing, to predict a limit on the growth rate of a maximum number of sub-structures that can compete in the two objectives to circumvent the failure of the niching method. The results show that if the number of competing building blocks between multiple objectives is less than the proposed limit, multiobjective GAs scale-up polynomially with the problem size on boundedly-difficult problems.

A Comparison of Genetic Programming Variants for Hyper-Heuristics

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

Harris, Sean

Modern society is faced with ever more complex problems, many of which can be formulated as generate-and-test optimization problems. General-purpose optimization algorithms are not well suited for real-world scenarios where many instances of the same problem class need to be repeatedly and efficiently solved, such as routing vehicles over highways with constantly changing traffic flows, because they are not targeted to a particular scenario. Hyper-heuristics automate the design of algorithms to create a custom algorithm for a particular scenario. Hyper-heuristics typically employ Genetic Programming (GP) and this project has investigated the relationship between the choice of GP and performance inmore » Hyper-heuristics. Results are presented demonstrating the existence of problems for which there is a statistically significant performance differential between the use of different types of GP.« less

Learning Spatio-Temporal Representations for Action Recognition: A Genetic Programming Approach.

PubMed

Liu, Li; Shao, Ling; Li, Xuelong; Lu, Ke

2016-01-01

Extracting discriminative and robust features from video sequences is the first and most critical step in human action recognition. In this paper, instead of using handcrafted features, we automatically learn spatio-temporal motion features for action recognition. This is achieved via an evolutionary method, i.e., genetic programming (GP), which evolves the motion feature descriptor on a population of primitive 3D operators (e.g., 3D-Gabor and wavelet). In this way, the scale and shift invariant features can be effectively extracted from both color and optical flow sequences. We intend to learn data adaptive descriptors for different datasets with multiple layers, which makes fully use of the knowledge to mimic the physical structure of the human visual cortex for action recognition and simultaneously reduce the GP searching space to effectively accelerate the convergence of optimal solutions. In our evolutionary architecture, the average cross-validation classification error, which is calculated by an support-vector-machine classifier on the training set, is adopted as the evaluation criterion for the GP fitness function. After the entire evolution procedure finishes, the best-so-far solution selected by GP is regarded as the (near-)optimal action descriptor obtained. The GP-evolving feature extraction method is evaluated on four popular action datasets, namely KTH, HMDB51, UCF YouTube, and Hollywood2. Experimental results show that our method significantly outperforms other types of features, either hand-designed or machine-learned.

Gravitational Physics Research

NASA Technical Reports Server (NTRS)

Wu, S. T.

2000-01-01

Gravitational physics research at ISPAE is connected with NASA's Relativity Mission (Gravity Probe B (GP-B)) which will perform a test of Einstein's General Relativity Theory. GP-B will measure the geodetic and motional effect predicted by General Relativity Theory with extremely stable and sensitive gyroscopes in an earth orbiting satellite. Both effects cause a very small precession of the gyroscope spin axis. The goal of the GP-B experiment is the measurement of the gyroscope precession with very high precision. GP-B is being developed by a team at Stanford University and is scheduled for launch in the year 2001. The related UAH research is a collaboration with Stanford University and MSFC. This research is focussed primarily on the error analysis and data reduction methods of the experiment but includes other topics concerned with experiment systems and their performance affecting the science measurements. The hydrogen maser is the most accurate and stable clock available. It will be used in future gravitational physics missions to measure relativistic effects such as the second order Doppler effect. The HMC experiment, currently under development at the Smithsonian Astrophysical Observatory (SAO), will test the performance and capability of the hydrogen maser clock for gravitational physics measurements. UAH in collaboration with the SAO science team will study methods to evaluate the behavior and performance of the HMC. The GP-B data analysis developed by the Stanford group involves complicated mathematical operations. This situation led to the idea to investigate alternate and possibly simpler mathematical procedures to extract the GP-B measurements form the data stream. Comparison of different methods would increase the confidence in the selected scheme.

Graph Structured Program Evolution: Evolution of Loop Structures

NASA Astrophysics Data System (ADS)

Shirakawa, Shinichi; Nagao, Tomoharu

Recently, numerous automatic programming techniques have been developed and applied in various fields. A typical example is genetic programming (GP), and various extensions and representations of GP have been proposed thus far. Complex programs and hand-written programs, however, may contain several loops and handle multiple data types. In this chapter, we propose a new method called Graph Structured Program Evolution (GRAPE). The representation of GRAPE is a graph structure; therefore, it can represent branches and loops using this structure. Each programis constructed as an arbitrary directed graph of nodes and a data set. The GRAPE program handles multiple data types using the data set for each type, and the genotype of GRAPE takes the form of a linear string of integers. We apply GRAPE to three test problems, factorial, exponentiation, and list sorting, and demonstrate that the optimum solution in each problem is obtained by the GRAPE system.

Recombinant interleukin-12 and interleukin-18 antitumor therapy in a guinea-pig hepatoma cell implant model.

PubMed

Shiratori, Ikuo; Suzuki, Yasuhiko; Oshiumi, Hiroyuki; Begum, Nasim A; Ebihara, Takashi; Matsumoto, Misako; Hazeki, Kaoru; Kodama, Ken; Kashiwazaki, Yasuo; Seya, Tsukasa

2007-12-01

Interleukin (IL)-12 and IL-18 are secreted by myeloid cells activated with adjuvants such as Bacillus Calmette-Guérin (BCG) cell wall. They induce T-helper 1 polarization in the host immune system and upregulate production of lymphocyte interferon-gamma, which leads to the induction of an antitumor gene program. It has been reported that humans have an immune system that more closely resembles that of the guinea pig in adjuvant-response features rather than the mouse system, which prevents the mouse results being extrapolated to human immunotherapy. Here we have constructed a tumor-implant system in guinea pigs to evaluate the antitumor potential of guinea pig IL-12 (gpIL-12) and guinea pig IL-18 (gpIL-18). Purified recombinant gpIL-12 and gpIL-18 were prepared and applied intraperitoneally to tumor-bearing (line 10 hepatoma) guinea pigs as the basis of the adjuvant immunotherapy. Intraperitoneal administration of gpIL-12 and gpIL-18 led to retardation of primary tumor growth and suppression of lymph-node metastasis in tumor-bearing guinea pigs. The permissible range of IL-12 appeared wider in guinea pigs than in mice. Even at an IL-12 dose higher than that in mice, there was no evidence of side-effects until day 26, when the guinea pigs were killed. gpIL-18 augmented the antitumor effect of gpIL-12 but exerted less ability to suppress lymph-node metastasis. The effects of gpIL-12 and gpIL-18 on the tumors implanted in guinea pigs will encourage us to use IL-12- and IL-18-inducible adjuvants for immunotherapy in human patients with solid cancer.

A Pareto-optimal moving average multigene genetic programming model for daily streamflow prediction

NASA Astrophysics Data System (ADS)

Danandeh Mehr, Ali; Kahya, Ercan

2017-06-01

Genetic programming (GP) is able to systematically explore alternative model structures of different accuracy and complexity from observed input and output data. The effectiveness of GP in hydrological system identification has been recognized in recent studies. However, selecting a parsimonious (accurate and simple) model from such alternatives still remains a question. This paper proposes a Pareto-optimal moving average multigene genetic programming (MA-MGGP) approach to develop a parsimonious model for single-station streamflow prediction. The three main components of the approach that take us from observed data to a validated model are: (1) data pre-processing, (2) system identification and (3) system simplification. The data pre-processing ingredient uses a simple moving average filter to diminish the lagged prediction effect of stand-alone data-driven models. The multigene ingredient of the model tends to identify the underlying nonlinear system with expressions simpler than classical monolithic GP and, eventually simplification component exploits Pareto front plot to select a parsimonious model through an interactive complexity-efficiency trade-off. The approach was tested using the daily streamflow records from a station on Senoz Stream, Turkey. Comparing to the efficiency results of stand-alone GP, MGGP, and conventional multi linear regression prediction models as benchmarks, the proposed Pareto-optimal MA-MGGP model put forward a parsimonious solution, which has a noteworthy importance of being applied in practice. In addition, the approach allows the user to enter human insight into the problem to examine evolved models and pick the best performing programs out for further analysis.

Gene-expression programming for flip-bucket spillway scour.

PubMed

Guven, Aytac; Azamathulla, H Md

2012-01-01

During the last two decades, researchers have noticed that the use of soft computing techniques as an alternative to conventional statistical methods based on controlled laboratory or field data, gave significantly better results. Gene-expression programming (GEP), which is an extension to genetic programming (GP), has nowadays attracted the attention of researchers in prediction of hydraulic data. This study presents GEP as an alternative tool in the prediction of scour downstream of a flip-bucket spillway. Actual field measurements were used to develop GEP models. The proposed GEP models are compared with the earlier conventional GP results of others (Azamathulla et al. 2008b; RMSE = 2.347, δ = 0.377, R = 0.842) and those of commonly used regression-based formulae. The predictions of GEP models were observed to be in strictly good agreement with measured ones, and quite a bit better than conventional GP and the regression-based formulae. The results are tabulated in terms of statistical error measures (GEP1; RMSE = 1.596, δ = 0.109, R = 0.917) and illustrated via scatter plots.

Space Science

NASA Image and Video Library

2004-01-01

In this photo, the Gravity Probe B (GP-B) detector mount assembly is shown in comparison to the size of a dime. The assembly is used to detect exactly how much starlight is coming through different beams from the beam splitter in the telescope. The measurements from the tiny chips inside are what keeps GP-B aimed at the guide star. The GP-B is the relativity experiment developed at Stanford University to test two extraordinary predictions of Albert Einstein’s general theory of relativity. The experiment will measure, very precisely, the expected tiny changes in the direction of the spin axes of four gyroscopes contained in an Earth-orbiting satellite at a 400-mile altitude. So free are the gyroscopes from disturbance that they will provide an almost perfect space-time reference system. They will measure how space and time are very slightly warped by the presence of the Earth, and, more profoundly, how the Earth’s rotation very slightly drags space-time around with it. These effects, though small for the Earth, have far-reaching implications for the nature of matter and the structure of the Universe. GP-B is among the most thoroughly researched programs ever undertaken by NASA. This is the story of a scientific quest in which physicists and engineers have collaborated closely over many years. Inspired by their quest, they have invented a whole range of technologies that are already enlivening other branches of science and engineering. Launched April 20, 2004 , the GP-B program was managed for NASA by the Marshall Space Flight Center. Development of the GP-B is the responsibility of Stanford University along with major subcontractor Lockheed Martin Corporation. (Image credit to Paul Ehrensberger, Stanford University.)

Gravity Probe B Detector Mount Assembly

NASA Technical Reports Server (NTRS)

2004-01-01

In this photo, the Gravity Probe B (GP-B) detector mount assembly is shown in comparison to the size of a dime. The assembly is used to detect exactly how much starlight is coming through different beams from the beam splitter in the telescope. The measurements from the tiny chips inside are what keeps GP-B aimed at the guide star. The GP-B is the relativity experiment developed at Stanford University to test two extraordinary predictions of Albert Einstein's general theory of relativity. The experiment will measure, very precisely, the expected tiny changes in the direction of the spin axes of four gyroscopes contained in an Earth-orbiting satellite at a 400-mile altitude. So free are the gyroscopes from disturbance that they will provide an almost perfect space-time reference system. They will measure how space and time are very slightly warped by the presence of the Earth, and, more profoundly, how the Earth's rotation very slightly drags space-time around with it. These effects, though small for the Earth, have far-reaching implications for the nature of matter and the structure of the Universe. GP-B is among the most thoroughly researched programs ever undertaken by NASA. This is the story of a scientific quest in which physicists and engineers have collaborated closely over many years. Inspired by their quest, they have invented a whole range of technologies that are already enlivening other branches of science and engineering. Launched April 20, 2004 , the GP-B program was managed for NASA by the Marshall Space Flight Center. Development of the GP-B is the responsibility of Stanford University along with major subcontractor Lockheed Martin Corporation. (Image credit to Paul Ehrensberger, Stanford University.)

Genomic Selection in Plant Breeding: Methods, Models, and Perspectives.

PubMed

Crossa, José; Pérez-Rodríguez, Paulino; Cuevas, Jaime; Montesinos-López, Osval; Jarquín, Diego; de Los Campos, Gustavo; Burgueño, Juan; González-Camacho, Juan M; Pérez-Elizalde, Sergio; Beyene, Yoseph; Dreisigacker, Susanne; Singh, Ravi; Zhang, Xuecai; Gowda, Manje; Roorkiwal, Manish; Rutkoski, Jessica; Varshney, Rajeev K

2017-11-01

Genomic selection (GS) facilitates the rapid selection of superior genotypes and accelerates the breeding cycle. In this review, we discuss the history, principles, and basis of GS and genomic-enabled prediction (GP) as well as the genetics and statistical complexities of GP models, including genomic genotype×environment (G×E) interactions. We also examine the accuracy of GP models and methods for two cereal crops and two legume crops based on random cross-validation. GS applied to maize breeding has shown tangible genetic gains. Based on GP results, we speculate how GS in germplasm enhancement (i.e., prebreeding) programs could accelerate the flow of genes from gene bank accessions to elite lines. Recent advances in hyperspectral image technology could be combined with GS and pedigree-assisted breeding. Copyright © 2017 Elsevier Ltd. All rights reserved.

Space Science

NASA Image and Video Library

2001-08-01

The Gravity Probe B (GP-B) payload was hoisted by crane to the transportation truck in the W.W. Hansen Experimental Physics Laboratory in Stanford, California for shipment to the launch site at Vandenburg Air Force Base. GP-B is the relativity experiment being developed at Stanford University to test two extraordinary predictions of Albert Einstein’s general theory of relativity. The experiment will measure, very precisely, the expected tiny changes in the direction of the spin axes of four gyroscopes contained in an Earth-orbiting satellite at a 400-mile altitude. So free are the gyroscopes from disturbance that they will provide an almost perfect space-time reference system. They will measure how space and time are very slightly warped by the presence of the Earth, and, more profoundly, how the Earth’s rotation very slightly drags space-time around with it. These effects, though small for the Earth, have far-reaching implications for the nature of matter and the structure of the Universe. GP-B is among the most thoroughly researched programs ever undertaken by NASA. This is the story of a scientific quest in which physicists and engineers have collaborated closely over many years. Inspired by their quest, they have invented a whole range of technologies that are already enlivening other branches of science and engineering. Launched April 20, 2004, the GP-B program was managed for NASA by the Marshall Space Flight Center. Development of the GP-B is the responsibility of Stanford University, along with major subcontractor Lockheed Martin Corporation. (Photo Credit: Stanford University)

Space Science

NASA Image and Video Library

2000-01-01

In this photo, the Gravity Probe B (GP-B) space vehicle is being assembled at the Sunnyvale, California location of the Lockheed Martin Corporation. The GP-B is the relativity experiment developed at Stanford University to test two extraordinary predictions of Albert Einstein’s general theory of relativity. The experiment will measure, very precisely, the expected tiny changes in the direction of the spin axes of four gyroscopes contained in an Earth-orbiting satellite at a 400-mile altitude. So free are the gyroscopes from disturbance that they will provide an almost perfect space-time reference system. They will measure how space and time are very slightly warped by the presence of the Earth, and, more profoundly, how the Earth’s rotation very slightly drags space-time around with it. These effects, though small for the Earth, have far-reaching implications for the nature of matter and the structure of the Universe. GP-B is among the most thoroughly researched programs ever undertaken by NASA. This is the story of a scientific quest in which physicists and engineers have collaborated closely over many years. Inspired by their quest, they have invented a whole range of technologies that are already enlivening other branches of science and engineering. Launched April 20, 2004 , the GP-B program was managed for NASA by the Marshall Space Flight Center. Development of the GP-B is the responsibility of Stanford University along with major subcontractor Lockheed Martin Corporation. (Image credit to Russ Underwood, Lockheed Martin Corporation).

Space Science

NASA Image and Video Library

2004-01-01

In this photo, the Gravity Probe B (GP-B) space vehicle is being encapsulated atop the Delta II launch vehicle. The GP-B is the relativity experiment developed at Stanford University to test two extraordinary predictions of Albert Einstein’s general theory of relativity. The experiment will measure, very precisely, the expected tiny changes in the direction of the spin axes of four gyroscopes contained in an Earth-orbiting satellite at a 400-mile altitude. So free are the gyroscopes from disturbance that they will provide an almost perfect space-time reference system. They will measure how space and time are very slightly warped by the presence of the Earth, and, more profoundly, how the Earth’s rotation very slightly drags space-time around with it. These effects, though small for the Earth, have far-reaching implications for the nature of matter and the structure of the Universe. GP-B is among the most thoroughly researched programs ever undertaken by NASA. This is the story of a scientific quest in which physicists and engineers have collaborated closely over many years. Inspired by their quest, they have invented a whole range of technologies that are already enlivening other branches of science and engineering. Launched April 20, 2004 , the GP-B program was managed for NASA by the Marshall Space Flight Center. Development of the GP-B is the responsibility of Stanford University along with major subcontractor Lockheed Martin Corporation. (Image credit to Russ Underwood, Lockheed Martin Corporation).

Genetic Programming and Frequent Itemset Mining to Identify Feature Selection Patterns of iEEG and fMRI Epilepsy Data

PubMed Central

Smart, Otis; Burrell, Lauren

2014-01-01

Pattern classification for intracranial electroencephalogram (iEEG) and functional magnetic resonance imaging (fMRI) signals has furthered epilepsy research toward understanding the origin of epileptic seizures and localizing dysfunctional brain tissue for treatment. Prior research has demonstrated that implicitly selecting features with a genetic programming (GP) algorithm more effectively determined the proper features to discern biomarker and non-biomarker interictal iEEG and fMRI activity than conventional feature selection approaches. However for each the iEEG and fMRI modalities, it is still uncertain whether the stochastic properties of indirect feature selection with a GP yield (a) consistent results within a patient data set and (b) features that are specific or universal across multiple patient data sets. We examined the reproducibility of implicitly selecting features to classify interictal activity using a GP algorithm by performing several selection trials and subsequent frequent itemset mining (FIM) for separate iEEG and fMRI epilepsy patient data. We observed within-subject consistency and across-subject variability with some small similarity for selected features, indicating a clear need for patient-specific features and possible need for patient-specific feature selection or/and classification. For the fMRI, using nearest-neighbor classification and 30 GP generations, we obtained over 60% median sensitivity and over 60% median selectivity. For the iEEG, using nearest-neighbor classification and 30 GP generations, we obtained over 65% median sensitivity and over 65% median selectivity except one patient. PMID:25580059

Feature generation using genetic programming with application to fault classification.

PubMed

Guo, Hong; Jack, Lindsay B; Nandi, Asoke K

2005-02-01

One of the major challenges in pattern recognition problems is the feature extraction process which derives new features from existing features, or directly from raw data in order to reduce the cost of computation during the classification process, while improving classifier efficiency. Most current feature extraction techniques transform the original pattern vector into a new vector with increased discrimination capability but lower dimensionality. This is conducted within a predefined feature space, and thus, has limited searching power. Genetic programming (GP) can generate new features from the original dataset without prior knowledge of the probabilistic distribution. In this paper, a GP-based approach is developed for feature extraction from raw vibration data recorded from a rotating machine with six different conditions. The created features are then used as the inputs to a neural classifier for the identification of six bearing conditions. Experimental results demonstrate the ability of GP to discover autimatically the different bearing conditions using features expressed in the form of nonlinear functions. Furthermore, four sets of results--using GP extracted features with artificial neural networks (ANN) and support vector machines (SVM), as well as traditional features with ANN and SVM--have been obtained. This GP-based approach is used for bearing fault classification for the first time and exhibits superior searching power over other techniques. Additionaly, it significantly reduces the time for computation compared with genetic algorithm (GA), therefore, makes a more practical realization of the solution.

Gravity Probe B Encapsulated

NASA Technical Reports Server (NTRS)

2004-01-01

In this photo, the Gravity Probe B (GP-B) space vehicle is being encapsulated atop the Delta II launch vehicle. The GP-B is the relativity experiment developed at Stanford University to test two extraordinary predictions of Albert Einstein's general theory of relativity. The experiment will measure, very precisely, the expected tiny changes in the direction of the spin axes of four gyroscopes contained in an Earth-orbiting satellite at a 400-mile altitude. So free are the gyroscopes from disturbance that they will provide an almost perfect space-time reference system. They will measure how space and time are very slightly warped by the presence of the Earth, and, more profoundly, how the Earth's rotation very slightly drags space-time around with it. These effects, though small for the Earth, have far-reaching implications for the nature of matter and the structure of the Universe. GP-B is among the most thoroughly researched programs ever undertaken by NASA. This is the story of a scientific quest in which physicists and engineers have collaborated closely over many years. Inspired by their quest, they have invented a whole range of technologies that are already enlivening other branches of science and engineering. Launched April 20, 2004 , the GP-B program was managed for NASA by the Marshall Space Flight Center. Development of the GP-B is the responsibility of Stanford University along with major subcontractor Lockheed Martin Corporation. (Image credit to Russ Underwood, Lockheed Martin Corporation).

Gravity Probe B Assembled

NASA Technical Reports Server (NTRS)

2000-01-01

In this photo, the Gravity Probe B (GP-B) space vehicle is being assembled at the Sunnyvale, California location of the Lockheed Martin Corporation. The GP-B is the relativity experiment developed at Stanford University to test two extraordinary predictions of Albert Einstein's general theory of relativity. The experiment will measure, very precisely, the expected tiny changes in the direction of the spin axes of four gyroscopes contained in an Earth-orbiting satellite at a 400-mile altitude. So free are the gyroscopes from disturbance that they will provide an almost perfect space-time reference system. They will measure how space and time are very slightly warped by the presence of the Earth, and, more profoundly, how the Earth's rotation very slightly drags space-time around with it. These effects, though small for the Earth, have far-reaching implications for the nature of matter and the structure of the Universe. GP-B is among the most thoroughly researched programs ever undertaken by NASA. This is the story of a scientific quest in which physicists and engineers have collaborated closely over many years. Inspired by their quest, they have invented a whole range of technologies that are already enlivening other branches of science and engineering. Launched April 20, 2004 , the GP-B program was managed for NASA by the Marshall Space Flight Center. Development of the GP-B is the responsibility of Stanford University along with major subcontractor Lockheed Martin Corporation. (Image credit to Russ Underwood, Lockheed Martin Corporation).

Gp120/CD4 blocking antibodies are frequently elicited in ART-naïve chronically HIV-1 infected individuals.

PubMed

Carrillo, Jorge; Molinos-Albert, Luis Manuel; Rodríguez de la Concepción, Maria Luisa; Marfil, Silvia; García, Elisabet; Derking, Ronald; Sanders, Rogier W; Clotet, Bonaventura; Blanco, Julià

2015-01-01

Antibodies with the ability to block the interaction of HIV-1 envelope glycoprotein (Env) gp120 with CD4, including those overlapping the CD4 binding site (CD4bs antibodies), can protect from infection by HIV-1, and their elicitation may be an interesting goal for any vaccination strategy. To identify gp120/CD4 blocking antibodies in plasma samples from HIV-1 infected individuals we have developed a competitive flow cytometry-based functional assay. In a cohort of treatment-naïve chronically infected patients, we showed that gp120/CD4 blocking antibodies were frequently elicited (detected in 97% plasma samples) and correlated with binding to trimeric HIV-1 envelope glycoproteins. However, no correlation was observed between functional CD4 binding blockade data and titer of CD4bs antibodies determined by ELISA using resurfaced gp120 proteins. Consistently, plasma samples lacking CD4bs antibodies were able to block the interaction between gp120 and its receptor, indicating that antibodies recognizing other epitopes, such as PGT126 and PG16, can also play the same role. Antibodies blocking CD4 binding increased over time and correlated positively with the capacity of plasma samples to neutralize the laboratory-adapted NL4.3 and BaL virus isolates, suggesting their potential contribution to the neutralizing workforce of plasma in vivo. Determining whether this response can be boosted to achieve broadly neutralizing antibodies may provide valuable information for the design of new strategies aimed to improve the anti-HIV-1 humoral response and to develop a successful HIV-1 vaccine.

Gp120/CD4 Blocking Antibodies Are Frequently Elicited in ART-Naïve Chronically HIV-1 Infected Individuals

PubMed Central

Carrillo, Jorge; Molinos-Albert, Luis Manuel; de la Concepción, Maria Luisa Rodríguez; Marfil, Silvia; García, Elisabet; Derking, Ronald; Sanders, Rogier W.; Clotet, Bonaventura; Blanco, Julià

2015-01-01

Antibodies with the ability to block the interaction of HIV-1 envelope glycoprotein (Env) gp120 with CD4, including those overlapping the CD4 binding site (CD4bs antibodies), can protect from infection by HIV-1, and their elicitation may be an interesting goal for any vaccination strategy. To identify gp120/CD4 blocking antibodies in plasma samples from HIV-1 infected individuals we have developed a competitive flow cytometry-based functional assay. In a cohort of treatment-naïve chronically infected patients, we showed that gp120/CD4 blocking antibodies were frequently elicited (detected in 97% plasma samples) and correlated with binding to trimeric HIV-1 envelope glycoproteins. However, no correlation was observed between functional CD4 binding blockade data and titer of CD4bs antibodies determined by ELISA using resurfaced gp120 proteins. Consistently, plasma samples lacking CD4bs antibodies were able to block the interaction between gp120 and its receptor, indicating that antibodies recognizing other epitopes, such as PGT126 and PG16, can also play the same role. Antibodies blocking CD4 binding increased over time and correlated positively with the capacity of plasma samples to neutralize the laboratory-adapted NL4.3 and BaL virus isolates, suggesting their potential contribution to the neutralizing workforce of plasma in vivo. Determining whether this response can be boosted to achieve broadly neutralizing antibodies may provide valuable information for the design of new strategies aimed to improve the anti-HIV-1 humoral response and to develop a successful HIV-1 vaccine. PMID:25803681

Mapping marginal croplands suitable for cellulosic feedstock crops in the Great Plains, United States

USGS Publications Warehouse

Gu, Yingxin; Wylie, Bruce K.

2016-01-01

Growing cellulosic feedstock crops (e.g., switchgrass) for biofuel is more environmentally sustainable than corn-based ethanol. Specifically, this practice can reduce soil erosion and water quality impairment from pesticides and fertilizer, improve ecosystem services and sustainability (e.g., serve as carbon sinks), and minimize impacts on global food supplies. The main goal of this study was to identify high-risk marginal croplands that are potentially suitable for growing cellulosic feedstock crops (e.g., switchgrass) in the US Great Plains (GP). Satellite-derived growing season Normalized Difference Vegetation Index, a switchgrass biomass productivity map obtained from a previous study, US Geological Survey (USGS) irrigation and crop masks, and US Department of Agriculture (USDA) crop indemnity maps for the GP were used in this study. Our hypothesis was that croplands with relatively low crop yield but high productivity potential for switchgrass may be suitable for converting to switchgrass. Areas with relatively low crop indemnity (crop indemnity <$2 157 068) were excluded from the suitable areas based on low probability of crop failures. Results show that approximately 650 000 ha of marginal croplands in the GP are potentially suitable for switchgrass development. The total estimated switchgrass biomass productivity gain from these suitable areas is about 5.9 million metric tons. Switchgrass can be cultivated in either lowland or upland regions in the GP depending on the local soil and environmental conditions. This study improves our understanding of ecosystem services and the sustainability of cropland systems in the GP. Results from this study provide useful information to land managers for making informed decisions regarding switchgrass development in the GP.

Potentiating Effects of MPL on DSPC Bearing Cationic Liposomes Promote Recombinant GP63 Vaccine Efficacy: High Immunogenicity and Protection

PubMed Central

Mazumder, Saumyabrata; Maji, Mithun; Ali, Nahid

2011-01-01

Background Vaccines that activate strong specific Th1-predominant immune responses are critically needed for many intracellular pathogens, including Leishmania. The requirement for sustained and efficient vaccination against leishmaniasis is to formulate the best combination of immunopotentiating adjuvant with the stable antigen (Ag) delivery system. The aim of the present study is to evaluate the effectiveness of an immunomodulator on liposomal Ag through subcutaneous (s.c.) route of immunization, and its usefulness during prime/boost against visceral leishmaniasis (VL) in BALB/c mice. Methodology/Principal Findings Towards this goal, we formulated recombinant GP63 (rGP63)-based vaccines either with monophosphoryl lipid A-trehalose dicorynomycolate (MPL-TDM) or entrapped within cationic liposomes or both. Combinatorial administration of liposomes with MPL-TDM during prime confers activation of dendritic cells, and induces an early robust T cell response. To investigate whether the combined formulation is required for optimum immune response during boost as well, we chose to evaluate the vaccine efficacy in mice primed with combined adjuvant system followed by boosting with either rGP63 alone, in association with MPL-TDM, liposomes or both. We provide evidences that the presence of either liposomal rGP63 or combined formulations during boost is necessary for effective Th1 immune responses (IFN-γ, IL-12, NO) before challenge infection. However, boosting with MPL-TDM in conjugation with liposomal rGP63 resulted in a greater number of IFN-γ producing effector T cells, significantly higher levels of splenocyte proliferation, and Th1 responses compared to mice boosted with liposomal rGP63, after virulent Leishmania donovani (L. donovani) challenge. Moreover, combined formulations offered superior protection against intracellular amastigote replication in macrophages in vitro, and hepatic and splenic parasite load in vivo. Conclusion Our results define the immunopotentiating effect of MPL-TDM on protein Ag encapsulated in a controlled release system against experimental VL. PMID:22206029

Poor Performance Among Trainees in a Dutch Postgraduate GP Training Program.

PubMed

Vermeulen, Margit I; Kuyvenhoven, Marijke M; de Groot, Esther; Zuithoff, Nicolaas Pa; Pieters, Honore M; van der Graaf, Yolanda; Damoiseaux, Roger Amj

2016-06-01

Poor performance among trainees is an important issue, for patient safety and economic reasons. While early identification might enhance remediation measures, we explored the frequency, nature, and risk factors of poor performance in a Dutch postgraduate general practitioner (GP) training program. All trainees who started the GP training between 2005 and 2007 were included. Multivariate logistic regression analysis was applied to examine associations between individual characteristics; early assessments of competencies and knowledge, training process characteristics (eg, illness, maternal leave), and the outcome poor performance; sub-analyses were performed for each year. A total of 215 trainees started the 3-year GP program, and 49 (22.8%) exhibited poor performance (in one or more years). In the first and second years, problem areas among poor performers were equally distributed across the roles of "medical expert," "communicator," and "professional." In the third year, shortcomings in "professionalism" were the most common problem. Increasing age was a risk factor for poor performance as were insufficient scores in communication and knowledge. Poor performance in the previous year was a risk factor for poor performance in the second and third years; OR=4.20 (CI=1.31--13.47) and OR=5.40 (CI=1.58--18.47), respectively. Poor performance is prevalent but primarily occurring within a single training year. This finding suggests that trainees are capable of solving trainee problems. Increasing age, insufficient assessment scores early in the training, and poor performance in a previous year constitute risk factors for poor performance.

Structure-based Design of Cyclically Permuted HIV-1 gp120 Trimers That Elicit Neutralizing Antibodies*

PubMed Central

Kesavardhana, Sannula; Das, Raksha; Citron, Michael; Datta, Rohini; Ecto, Linda; Srilatha, Nonavinakere Seetharam; DiStefano, Daniel; Swoyer, Ryan; Joyce, Joseph G.; Dutta, Somnath; LaBranche, Celia C.; Montefiori, David C.; Flynn, Jessica A.; Varadarajan, Raghavan

2017-01-01

A major goal for HIV-1 vaccine development is an ability to elicit strong and durable broadly neutralizing antibody (bNAb) responses. The trimeric envelope glycoprotein (Env) spikes on HIV-1 are known to contain multiple epitopes that are susceptible to bNAbs isolated from infected individuals. Nonetheless, all trimeric and monomeric Env immunogens designed to date have failed to elicit such antibodies. We report the structure-guided design of HIV-1 cyclically permuted gp120 that forms homogeneous, stable trimers, and displays enhanced binding to multiple bNAbs, including VRC01, VRC03, VRC-PG04, PGT128, and the quaternary epitope-specific bNAbs PGT145 and PGDM1400. Constructs that were cyclically permuted in the V1 loop region and contained an N-terminal trimerization domain to stabilize V1V2-mediated quaternary interactions, showed the highest homogeneity and the best antigenic characteristics. In guinea pigs, a DNA prime-protein boost regimen with these new gp120 trimer immunogens elicited potent neutralizing antibody responses against highly sensitive Tier 1A isolates and weaker neutralizing antibody responses with an average titer of about 115 against a panel of heterologous Tier 2 isolates. A modest fraction of the Tier 2 virus neutralizing activity appeared to target the CD4 binding site on gp120. These results suggest that cyclically permuted HIV-1 gp120 trimers represent a viable platform in which further modifications may be made to eventually achieve protective bNAb responses. PMID:27879316

Peptide ligands specific to the oxidized form of escherichia coli thioredoxin.

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

Scholle, M. D.; Banach, B. S.; Hamdan, S. M.

Thioredoxin (Trx) is a highly conserved redox protein involved in several essential cellular processes. In this study, our goal was to isolate peptide ligands to Escherichia coli Trx that mimic protein-protein interactions, specifically the T7 polymerase-Trx interaction. To do this, we subjected Trx to affinity selection against a panel of linear and cysteine-constrained peptides using M13 phage display. A novel cyclized conserved peptide sequence, with a motif of C(D/N/S/T/G)D(S/T)-hydrophobic-C-X-hydrophobic-P, was isolated to Trx. These peptides bound specifically to the E. coli Trx when compared to the human and spirulina homologs. An alanine substitution of the active site cysteines (CGPC) resultedmore » in a significant loss of peptide binding affinity to the Cys-32 mutant. The peptides were also characterized in the context of Trx's role as a processivity factor of the T7 DNA polymerase (gp5). As the interaction between gp5 and Trx normally takes place under reducing conditions, which might interfere with the conformation of the disulfide-bridged peptides, we made use of a 22 residue deletion mutant of gp5 in the thioredoxin binding domain (gp5{Delta}22) that bypassed the requirements of reducing conditions to interact with Trx. A competition study revealed that the peptide selectively inhibits the interaction of gp5{Delta}22 with Trx, under oxidizing conditions, with an IC50 of {approx} 10 {micro}M.« less

Primary goals, information-giving and men’s understanding: a qualitative study of Australian and UK doctors’ varied communication about PSA screening

PubMed Central

Pickles, Kristen; Rychetnik, Lucie; McCaffery, Kirsten; Entwistle, Vikki A

2018-01-01

Objectives (1) To characterise variation in general practitioners’ (GPs’) accounts of communicating with men about prostate cancer screening using the prostate-specific antigen (PSA) test, (2) to characterise GPs’ reasons for communicating as they do and (3) to explain why and under what conditions GP communication approaches vary. Study design and setting A grounded theory study. We interviewed 69 GPs consulting in primary care practices in Australia (n=40) and the UK (n=29). Results GPs explained their communication practices in relation to their primary goals. In Australia, three different communication goals were reported: to encourage asymptomatic men to either have a PSA test, or not test, or alternatively, to support men to make their own decision. As well as having different primary goals, GPs aimed to provide different information (from comprehensive to strongly filtered) and to support men to develop different kinds of understanding, from population-level to ‘gist’ understanding. Taking into account these three dimensions (goals, information, understanding) and building on Entwistle et al’s Consider an Offer framework, we derived four overarching approaches to communication: Be screened, Do not be screened, Analyse and choose, and As you wish. We also describe ways in which situational and relational factors influenced GPs’ preferred communication approach. Conclusion GPs’ reported approach to communicating about prostate cancer screening varies according to three dimensions—their primary goal, information provision preference and understanding sought—and in response to specific practice situations. If GP communication about PSA screening is to become more standardised in Australia, it is likely that each of these dimensions will require attention in policy and practice support interventions. PMID:29362252

Primary goals, information-giving and men's understanding: a qualitative study of Australian and UK doctors' varied communication about PSA screening.

PubMed

Pickles, Kristen; Carter, Stacy M; Rychetnik, Lucie; McCaffery, Kirsten; Entwistle, Vikki A

2018-01-23

(1) To characterise variation in general practitioners' (GPs') accounts of communicating with men about prostate cancer screening using the prostate-specific antigen (PSA) test, (2) to characterise GPs' reasons for communicating as they do and (3) to explain why and under what conditions GP communication approaches vary. A grounded theory study. We interviewed 69 GPs consulting in primary care practices in Australia (n=40) and the UK (n=29). GPs explained their communication practices in relation to their primary goals. In Australia, three different communication goals were reported: to encourage asymptomatic men to either have a PSA test, or not test, or alternatively, to support men to make their own decision. As well as having different primary goals, GPs aimed to provide different information (from comprehensive to strongly filtered) and to support men to develop different kinds of understanding, from population-level to 'gist' understanding. Taking into account these three dimensions (goals, information, understanding) and building on Entwistle et al' s Consider an Offer framework, we derived four overarching approaches to communication: Be screened , Do not be screened , Analyse and choose , and As you wish . We also describe ways in which situational and relational factors influenced GPs' preferred communication approach. GPs' reported approach to communicating about prostate cancer screening varies according to three dimensions-their primary goal, information provision preference and understanding sought-and in response to specific practice situations. If GP communication about PSA screening is to become more standardised in Australia, it is likely that each of these dimensions will require attention in policy and practice support interventions. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Optimizing Training Population Size and Genotyping Strategy for Genomic Prediction Using Association Study Results and Pedigree Information. A Case of Study in Advanced Wheat Breeding Lines.

PubMed

Cericola, Fabio; Jahoor, Ahmed; Orabi, Jihad; Andersen, Jeppe R; Janss, Luc L; Jensen, Just

2017-01-01

Wheat breeding programs generate a large amount of variation which cannot be completely explored because of limited phenotyping throughput. Genomic prediction (GP) has been proposed as a new tool which provides breeding values estimations without the need of phenotyping all the material produced but only a subset of it named training population (TP). However, genotyping of all the accessions under analysis is needed and, therefore, optimizing TP dimension and genotyping strategy is pivotal to implement GP in commercial breeding schemes. Here, we explored the optimum TP size and we integrated pedigree records and genome wide association studies (GWAS) results to optimize the genotyping strategy. A total of 988 advanced wheat breeding lines were genotyped with the Illumina 15K SNPs wheat chip and phenotyped across several years and locations for yield, lodging, and starch content. Cross-validation using the largest possible TP size and all the SNPs available after editing (~11k), yielded predictive abilities (rGP) ranging between 0.5-0.6. In order to explore the Training population size, rGP were computed using progressively smaller TP. These exercises showed that TP of around 700 lines were enough to yield the highest observed rGP. Moreover, rGP were calculated by randomly reducing the SNPs number. This showed that around 1K markers were enough to reach the highest observed rGP. GWAS was used to identify markers associated with the traits analyzed. A GWAS-based selection of SNPs resulted in increased rGP when compared with random selection and few hundreds SNPs were sufficient to obtain the highest observed rGP. For each of these scenarios, advantages of adding the pedigree information were shown. Our results indicate that moderate TP sizes were enough to yield high rGP and that pedigree information and GWAS results can be used to greatly optimize the genotyping strategy.

Practical implementation of good practice in health, environment and safety management in enterprise in the Lodz region.

PubMed

Michalak, Jacek

2002-10-01

Good practice in health, environment and safety management in enterprise (GP HESME) is the process that aims at continuous improvement in health, environment and safety performance, involving all stakeholders within and outside the enterprise. The GP HESME system is intended to function at different levels: international, national, local community, and enterprise. The most important issues at the first stage of GP HESME implementation in the Lodz region are described. Also, the proposals of future activities in Lodz are presented. Practical implementation of GP HESME requires close co-operation among all stakeholders: local authorities, employers, employees, research institutions, and the state inspectorate. The WHO and the Nofer Institute of Occupational Medicine (NIOM) are initiating implementation, delivering professional consultation, education and training of stakeholders in the NIOM School of Public Health. The implementation of GP HESME in the Lodz region started in 1999 from a WHO meeting on criteria and indicators, followed by close collaboration of NIOM with the city's Department of Public Health. 'Directions of Actions for Health of Lodz Citizens' is now the city's official document that includes GP HESME as an important part of public health policy in Lodz. Several conferences were organized by NIOM together with the Professional Managers' Club, Labor Inspection, and the city's Department of Public Health to assess the most important needs of enterprises. The employers and managerial staff, who predominated among the participants, stated the need for tailored sets of indicators and economic appraisal of GP HESME activities. Special attention is paid to GP HESME in supermarkets and community-owned enterprises, e.g., a local transportation company. A special program for small- and medium-size enterprises will be the next step of GP HESME in the Lodz region. The implementation of GP HESME is possible if the efforts of local authorities; research institutions and state inspectorate are combined with the support of employers' organizations.

Successful technical trading agents using genetic programming.

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

Othling, Andrew S.; Kelly, John A.; Pryor, Richard J.

2004-10-01

Genetic programming (GP) has proved to be a highly versatile and useful tool for identifying relationships in data for which a more precise theoretical construct is unavailable. In this project, we use a GP search to develop trading strategies for agent based economic models. These strategies use stock prices and technical indicators, such as the moving average convergence/divergence and various exponentially weighted moving averages, to generate buy and sell signals. We analyze the effect of complexity constraints on the strategies as well as the relative performance of various indicators. We also present innovations in the classical genetic programming algorithm thatmore » appear to improve convergence for this problem. Technical strategies developed by our GP algorithm can be used to control the behavior of agents in economic simulation packages, such as ASPEN-D, adding variety to the current market fundamentals approach. The exploitation of arbitrage opportunities by technical analysts may help increase the efficiency of the simulated stock market, as it does in the real world. By improving the behavior of simulated stock markets, we can better estimate the effects of shocks to the economy due to terrorism or natural disasters.« less

Cancer patients use hospital-based care until death: a further analysis of the Dutch Bone Metastasis Study.

PubMed

Meeuse, Jan J; van der Linden, Yvette M; Post, Wendy J; Wanders, Rinus; Gans, Rijk O B; Leer, Jan Willem H; Reyners, Anna K L

2011-10-01

To describe health care utilization (HCU) at the end of life in cancer patients. These data are relevant to plan palliative care services, and to develop training programs for involved health care professionals. The Dutch Bone Metastasis Study (DBMS) was a nationwide study proving equal effectiveness of single fraction palliative radiotherapy compared with multiple fractions for painful bone metastases in 1157 patients. The 860 (74%) patients who died during follow-up were included in the current analysis. The main outcome was the frequency of hospital-based (outpatient contact or admission) and/or general practitioner (GP) contact during the last 12 weeks of life. Changes in HCU towards death were related to data on quality of life and pain intensity using a multilevel regression model. Hospital-based HCU was reported in 1801 (63%) returned questionnaires, whereas GP contact was stated in 1246 (43%). In 573 (20%) questionnaires, both types of HCU were reported. In multilevel regression analyses, the frequency of outpatient contacts remained constant during the weeks towards death, whereas the frequency of GP contacts increased. Lower valuation of quality of life was related to both GP- and hospital-based HCU. There was a high consumption of hospital-based HCU in the last 12 weeks of life of cancer patients with bone metastases. Hospital-based HCU did not decrease during the weeks towards death, despite an increase in GP contacts. Future planning of palliative care and training programs should encompass close collaboration between medical specialists and GPs to optimize end-of-life care.

The Gravity Probe B Payload Hoisted by Crane

NASA Technical Reports Server (NTRS)

2001-01-01

The Gravity Probe B (GP-B) payload was hoisted by crane to the transportation truck in the W.W. Hansen Experimental Physics Laboratory in Stanford, California for shipment to the launch site at Vandenburg Air Force Base. GP-B is the relativity experiment being developed at Stanford University to test two extraordinary predictions of Albert Einstein's general theory of relativity. The experiment will measure, very precisely, the expected tiny changes in the direction of the spin axes of four gyroscopes contained in an Earth-orbiting satellite at a 400-mile altitude. So free are the gyroscopes from disturbance that they will provide an almost perfect space-time reference system. They will measure how space and time are very slightly warped by the presence of the Earth, and, more profoundly, how the Earth's rotation very slightly drags space-time around with it. These effects, though small for the Earth, have far-reaching implications for the nature of matter and the structure of the Universe. GP-B is among the most thoroughly researched programs ever undertaken by NASA. This is the story of a scientific quest in which physicists and engineers have collaborated closely over many years. Inspired by their quest, they have invented a whole range of technologies that are already enlivening other branches of science and engineering. Launched April 20, 2004, the GP-B program was managed for NASA by the Marshall Space Flight Center. Development of the GP-B is the responsibility of Stanford University, along with major subcontractor Lockheed Martin Corporation. (Photo Credit: Stanford University)

GP0.4 from bacteriophage T7: in silico characterisation of its structure and interaction with E. coli FtsZ.

PubMed

Simpkin, Adam J; Rigden, Daniel J

2016-07-13

Proteins produced by bacteriophages can have potent antimicrobial activity. The study of phage-host interactions can therefore inform small molecule drug discovery by revealing and characterising new drug targets. Here we characterise in silico the predicted interaction of gene protein 0.4 (GP0.4) from the Escherichia coli (E. coli) phage T7 with E. coli filamenting temperature-sensitive mutant Z division protein (FtsZ). FtsZ is a tubulin homolog which plays a key role in bacterial cell division and that has been proposed as a drug target. Using ab initio, fragment assembly structure modelling, we predicted the structure of GP0.4 with two programs. A structure similarity-based network was used to identify a U-shaped helix-turn-helix candidate fold as being favoured. ClusPro was used to dock this structure prediction to a homology model of E. coli FtsZ resulting in a favourable predicted interaction mode. Alternative docking methods supported the proposed mode which offered an immediate explanation for the anti-filamenting activity of GP0.4. Importantly, further strong support derived from a previously characterised insertion mutation, known to abolish GP0.4 activity, that is positioned in close proximity to the proposed GP0.4/FtsZ interface. The mode of interaction predicted by bioinformatics techniques strongly suggests a mechanism through which GP0.4 inhibits FtsZ and further establishes the latter's druggable intrafilament interface as a potential drug target.

Expression of gp120 in mice evokes anxiety behavior: Co-occurrence with increased dendritic spines and brain-derived neurotrophic factor in the amygdala.

PubMed

Bachis, Alessia; Forcelli, Patrick; Masliah, Eliezer; Campbell, Lee; Mocchetti, Italo

2016-05-01

Human immunodeficiency virus type 1 (HIV) infection of the brain produces cognitive and motor disorders. In addition, HIV positive individuals exhibit behavioral alterations, such as apathy, and a decrease in spontaneity or emotional responses, typically seen in anxiety disorders. Anxiety can lead to psychological stress, which has been shown to influence HIV disease progression. These considerations underscore the importance of determining if anxiety in HIV is purely psychosocial, or if by contrast, there are the molecular cascades associated directly with HIV infection that may mediate anxiety. The present study had two goals: (1) to determine if chronic exposure to viral proteins would induce anxiety-like behavior in an animal model and (2) to determine if this exposure results in anatomical abnormalities that could explain increased anxiety. We have used gp120 transgenic mice, which display behavior and molecular deficiencies similar to HIV positive subjects with cognitive and motor impairments. In comparison to wild type mice, 6 months old gp120 transgenic mice demonstrated an anxiety like behavior measured by open field, light/dark transition task, and prepulse inhibition tests. Moreover, gp120 transgenic mice have an increased number of spines in the amygdala, as well as higher levels of brain-derived neurotrophic factor and tissue plasminogen activator when compared to age-matched wild type. Our data support the hypothesis that HIV, through gp120, may cause structural changes in the amygdala that lead to maladaptive responses to anxiety. Copyright © 2016 Elsevier Inc. All rights reserved.

Gatekeeping versus direct-access when patient information matters.

PubMed

González, Paula

2010-06-01

We develop a principal-agent model in which the health authority acts as a principal for both a patient and a general practitioner (GP). The goal of the paper is to weigh the merits of gatekeeping versus non-gatekeeping approaches to health care when patient self-health information and patient pressure on GPs to provide referrals for specialized care are considered. We find that, when GPs incentives matter, a non-gatekeeping system is preferable only when (i) patient pressure to refer is sufficiently high and (ii) the quality of the patient's self-health information is neither highly inaccurate (in which case the patient's self-referral will be very inefficient) nor highly accurate (in which case the GP's agency problem will be very costly).

Genetic programming based quantitative structure-retention relationships for the prediction of Kovats retention indices.

PubMed

Goel, Purva; Bapat, Sanket; Vyas, Renu; Tambe, Amruta; Tambe, Sanjeev S

2015-11-13

The development of quantitative structure-retention relationships (QSRR) aims at constructing an appropriate linear/nonlinear model for the prediction of the retention behavior (such as Kovats retention index) of a solute on a chromatographic column. Commonly, multi-linear regression and artificial neural networks are used in the QSRR development in the gas chromatography (GC). In this study, an artificial intelligence based data-driven modeling formalism, namely genetic programming (GP), has been introduced for the development of quantitative structure based models predicting Kovats retention indices (KRI). The novelty of the GP formalism is that given an example dataset, it searches and optimizes both the form (structure) and the parameters of an appropriate linear/nonlinear data-fitting model. Thus, it is not necessary to pre-specify the form of the data-fitting model in the GP-based modeling. These models are also less complex, simple to understand, and easy to deploy. The effectiveness of GP in constructing QSRRs has been demonstrated by developing models predicting KRIs of light hydrocarbons (case study-I) and adamantane derivatives (case study-II). In each case study, two-, three- and four-descriptor models have been developed using the KRI data available in the literature. The results of these studies clearly indicate that the GP-based models possess an excellent KRI prediction accuracy and generalization capability. Specifically, the best performing four-descriptor models in both the case studies have yielded high (>0.9) values of the coefficient of determination (R(2)) and low values of root mean squared error (RMSE) and mean absolute percent error (MAPE) for training, test and validation set data. The characteristic feature of this study is that it introduces a practical and an effective GP-based method for developing QSRRs in gas chromatography that can be gainfully utilized for developing other types of data-driven models in chromatography science. Copyright © 2015 Elsevier B.V. All rights reserved.

Novel Percutaneous Epicardial Autonomic Modulation in the Canine for Atrial Fibrillation: Results of an Efficacy and Safety Study

PubMed Central

Madhavan, Malini; Venkatachalam, K. L.; Swale, Matthew J.; DeSimone, Christopher V.; Gard, Joseph J.; Johnson, Susan B.; Suddendorf, Scott H.; Mikell, Susan B.; Ladewig, Dorothy J.; Nosbush, Toni Grabinger; Danielsen, Andrew J.; Knudson, Mark; Asirvatham, Samuel J.

2016-01-01

Background Endocardial ablation of atrial ganglionated plexi (GP) has been described for treatment of atrial fibrillation (AF). Our objective in this study was to develop percutaneous epicardial GP ablation in a canine model using novel energy sources and catheters. Methods Phase 1: The efficacy of several modalities to ablate the GP was tested in an open chest canine model (n=10). Phase 2: Percutaneous epicardial ablation of GP was done in 6 dogs using the most efficacious modality identified in phase 1 using 2 novel catheters. Results Phase 1: DC in varying doses [blocking (7 -12μA), electroporation (300-500μA), ablation (3000- 7500μA)], radiofrequency ablation (25–50 W), ultrasound (1.5MHz), and alcohol (2-5ml) injection were successful at 0/8, 4/12, 5/7, 3/8, 1/5 and 5/7 GP sites. DC (500–5000μA) along with alcohol irrigation was tested in phase 2. Phase 2: Percutaneous epicardial ablation of the right atrium, oblique sinus, vein of Marshall, and transverse sinus GP was successful in 5/6 dogs. One dog died of ventricular fibrillation (VF) during DC ablation at 5000 μA. Programmed stimulation induced AF in 6 dogs pre-ablation and no atrial arrhythmia in 3, flutter in 1 and AF in 1 post-ablation. Heart rate, blood pressure, effective atrial refractory period and local atrial electrogram amplitude did not change significantly post-ablation. Microscopic examination showed elimination of GP, and minimal injury to atrial myocardium. Conclusion Percutaneous epicardial ablation of GP using direct current and novel catheters is safe and feasible and may be used as an adjunct to pulmonary vein isolation in the treatment of atrial fibrillation in order to minimize additional atrial myocardial ablation. PMID:26854009

Examination of level of knowledge in Italian general practitioners attending an education session on diagnosis and management of the early stage of Alzheimer's disease: pass or fail?

PubMed

Veneziani, Federica; Panza, Francesco; Solfrizzi, Vincenzo; Capozzo, Rosa; Barulli, Maria Rosaria; Leo, Antonio; Lozupone, Madia; Fontana, Andrea; Arcuti, Simona; Copetti, Massimiliano; Cardinali, Valentina; Grasso, Alessandra; Tursi, Marianna; Iurillo, Annalisa; Imbimbo, Bruno Pietro; Seripa, Davide; Logroscino, Giancarlo

2016-07-01

We detected the general level of knowledge about the early diagnosis of Alzheimer's disease (AD) and subsequent care in general practitioners (GPs) from Southern Italy. We explored also the GP perception about their knowledge and training on diagnosis and management of AD. On a sample of 131 GPs, we administered two questionnaires: the GP-Knowledge, evaluating GPs' expertise about AD epidemiology, differential diagnosis, and available treatments, and the GP-QUestionnaire on Awareness of Dementia (GP-QUAD), assessing the GPs' attitudes, awareness, and practice regarding early diagnosis of dementia. Specific screening tests or protocols to diagnose and manage dementia were not used by 53% of our GPs. The training on the recognition of early AD signs and symptoms was considered inadequate by 55% of the participants. Females were more likely to consider their training insufficient (58%) compared to males (53%). Female GPs were less likely to prescribe antipsychotic drugs to control neuropsychiatric symptoms (NPS) and suggest specialist advice in late stage of cognitive impairment. Multiple Correspondence Analysis (MCA) performed only on GP-QUAD suggested two dimensions explaining 26.1% ("GP attitude") and 20.1% ("GP knowledge") of the inertia for a total of 46.2%, In our survey on GP clinical practice, several problems in properly recognizing early AD symptoms and subsequently screening patients to be referred to secondary/tertiary care centers for diagnosis confirmation have emerged. In the future, specific training programs and educational projects for GPs should be implemented also in Italy to improve detection rates and management of dementia in primary care.

Exploring resilience in rural GP registrars--implications for training.

PubMed

Walters, Lucie; Laurence, Caroline O; Dollard, Joanne; Elliott, Taryn; Eley, Diann S

2015-07-02

Resilience can be defined as the ability to rebound from adversity and overcome difficult circumstances. General Practice (GP) registrars face many challenges in transitioning into general practice, and additional stressors and pressures apply for those choosing a career in rural practice. At this time of international rural generalist medical workforce shortages, it is important to focus on the needs of rural GP registrars and how to support them to become resilient health care providers. This study sought to explore GP registrars' perceptions of their resilience and strategies they used to maintain resilience in rural general practice. In this qualitative interpretive research, semi-structured interviews were recorded, transcribed and analysed using an inductive approach. Initial coding resulted in a coding framework which was refined using constant comparison and negative case analysis. Authors developed consensus around the final conceptual model. Eighteen GP registrars from: Australian College of Rural and Remote Medicine Independent Pathway, and three GP regional training programs with rural training posts. Six main themes emerged from the data. Firstly, rural GP registrars described four dichotomous tensions they faced: clinical caution versus clinical courage; flexibility versus persistence; reflective practice versus task-focused practice; and personal connections versus professional commitment. Further themes included: personal skills for balance which facilitated resilience including optimistic attitude, self-reflection and metacognition; and finally GP registrars recognised the role of their supervisors in supporting and stretching them to enhance their clinical resilience. Resilience is maintained as on a wobble board by balancing professional tensions within acceptable limits. These limits are unique to each individual, and may be expanded through personal growth and professional development as part of rural general practice training.

Cultural diversity in patient participation: the influence of patients' characteristics and doctors' communicative behaviour.

PubMed

Schouten, Barbara C; Meeuwesen, Ludwien; Tromp, Fred; Harmsen, Hans A M

2007-07-01

The primary goal of this study was to examine the extent to which patient participation during medical visits is influenced by patients' ethnic background, patients' culture-related characteristics (e.g. acculturation, locus of control, cultural views) and features of doctors' communicative behaviour. Furthermore, the mutual influence between patients' participatory behaviour and doctors' communicative behaviour was investigated. An additional goal was to identify the independent contribution of these variables to the degree of patient satisfaction and mutual understanding between GP and patient. Communicative behaviour of patients (n=103) and GPs (n=29) was analysed with Roter's Interaction Analysis System, frequency of patient questions and patients' assertive utterances (e.g. making requests, suggesting alternative treatment options). Additional data were gathered using GP and patient questionnaires after the consultations. Results show that non-Western ethnic minority patients display less participatory behaviour during medical consultations than Dutch patients. GPs' affective verbal behaviour had most effect on degree of patient participation and patient satisfaction. Regression analyses indicate a significant mutual influence between patients' verbal behaviour and GPs' verbal behaviour. Overall, results of this study show some important differences between Dutch and non-Western ethnic minority patients in degree of patient participation. Furthermore, our results indicate that patient participation encompasses several aspects that are not necessarily interrelated. The necessity for continued education of GPs' communicative skills, particularly when dealing with non-Western ethnic minority patients, is reflected in the strong influence of GP's affective verbal behaviour on both patient participation and their satisfaction with the medical encounter.

The impact of walk-in centres and GP co-operatives on emergency department presentations: A systematic review of the literature.

PubMed

Crawford, Jessica; Cooper, Simon; Cant, Robyn; DeSouza, Ruth

2017-09-01

Internationally, non-urgent presentations are increasing the pressure on Emergency Department (ED) staff and resources. This systematic review aims to identify the impact of alternative emergency care pathways on ED presentations - specifically GP cooperatives and walk-in clinics. Based on a structured PICO enquiry with either walk-in clinic or GP cooperative as the intervention, a search was made for peer-reviewed publications in English, between 2000 and 2014. Medline plus, OVID, PubMed, and Google Scholar were searched. The Critical Appraisal Skills Program (CASP) guidelines were used to assess study quality and data was extracted using an adapted JBI Qualitative Assessment and Review Instrument (QARI). Subsequent reporting followed the PRISMA guideline. Eleven high quality quantitative studies met the inclusion criteria. Walk-in clinics do have the potential to reduce non-urgent emergency department presentations, however evidence of this effect is low. GP cooperatives offer an alternative care stream for patients presenting to the ED and do significantly reduce local ED attendances. Community members need to be made aware of these options in order to make informed treatment choices. GP cooperatives in particular do have the potential to reduce ED workload. Further research is required to uncover recent trends and patient outcomes for walk-in clinics and GP cooperatives. Copyright © 2017 Elsevier Ltd. All rights reserved.

Identification of hydrologic indicators related to fish diversity and abundance: A data mining approach for fish community analysis

NASA Astrophysics Data System (ADS)

Yang, Yi-Chen E.; Cai, Ximing; Herricks, Edwin E.

2008-04-01

This paper develops a new approach to identify hydrologic indicators related to fish community and generate a quantitative function between an ecological target index and the identified hydrologic indicators. The approach is based on genetic programming (GP), a data mining method. Using the Shannon Index (a fish community diversity index) or the number of individuals (total abundance) of a fish community, as an ecological target, the GP identified the most ecologically relevant hydrologic indicators (ERHIs) from 32 indicators of hydrologic alteration, for the case study site, the upper Illinois River. Robustness analysis showed that different GP runs found a similar set of ERHIs; each of the identified ERHI from different GP runs had a consistent relationship with the target index. By comparing the GP results with those from principal component analysis and autecology matrix, the three approaches identified a small number (six) of common ERHIs. Particularly, the timing of low flow (Dmin) seems to be more relevant to the diversity of the fish community, while the magnitude of the low flow (Qb) is more relevant to the total fish abundance; large rising rates result in a significant improvement of fish diversity, which is counterintuitive and against previous findings. The quantitative function developed by GP was further used to construct an indicator impact matrix (IIM), which was demonstrated as a potentially useful tool for streamflow restoration design.

Space Science

NASA Image and Video Library

2003-01-01

The Gravity Probe B (GP-B) is the relativity experiment developed at Stanford University to test two extraordinary predictions of Albert Einstein’s general theory of relativity. The experiment will measure, very precisely, the expected tiny changes in the direction of the spin axes of four gyroscopes contained in an Earth-orbiting satellite at a 400-mile altitude. So free are the gyroscopes from disturbance that they will provide an almost perfect space-time reference system. They will measure how space and time are very slightly warped by the presence of the Earth, and, more profoundly, how the Earth’s rotation very slightly drags space-time around with it. These effects, though small for the Earth, have far-reaching implications for the nature of matter and the structure of the Universe. This photograph is a close up of a niobium-coated gyroscope motor and its housing halves. GP-B is among the most thoroughly researched programs ever undertaken by NASA. This is the story of a scientific quest in which physicists and engineers have collaborated closely over many years. Inspired by their quest, they have invented a whole range of technologies that are already enlivening other branches of science and engineering. Launched April 20, 2004 , the GP-B program was managed for NASA by the Marshall Space Flight Center. Development of the GP-B is the responsibility of Stanford University along with major subcontractor Lockheed Martin Corporation. (Image credit to Don Harley.)

Space Science

NASA Image and Video Library

2000-08-01

The Gravity Probe B (GP-B) is the relativity experiment developed at Stanford University to test two extraordinary predictions of Albert Einstein’s general theory of relativity. The experiment will measure, very precisely, the expected tiny changes in the direction of the spin axes of four gyroscopes contained in an Earth-orbiting satellite at a 400-mile altitude. So free are the gyroscopes from disturbance that they will provide an almost perfect space-time reference system. They will measure how space and time are very slightly warped by the presence of the Earth, and, more profoundly, how the Earth’s rotation very slightly drags space-time around with it. These effects, though small for the Earth, have far-reaching implications for the nature of matter and the structure of the Universe. In this photograph, the completed space vehicle is undergoing thermal vacuum environment testing. GP-B is among the most thoroughly researched programs ever undertaken by NASA. This is the story of a scientific quest in which physicists and engineers have collaborated closely over many years. Inspired by their quest, they have invented a whole range of technologies that are already enlivening other branches of science and engineering. Launched April 20, 2004 , the GP-B program was managed for NASA by the Marshall Space Flight Center. Development of the GP-B is the responsibility of Stanford University along with major subcontractor Lockheed Martin Corporation. (Image credit to Russ Underwood, Lockheed Martin Corporation.)

Space Science

NASA Image and Video Library

2000-08-01

The Gravity Probe B (GP-B) is the relativity experiment developed at Stanford University to test two extraordinary predictions of Albert Einstein’s general theory of relativity. The experiment will measure, very precisely, the expected tiny changes in the direction of the spin axes of four gyroscopes contained in an Earth-orbiting satellite at a 400-mile altitude. So free are the gyroscopes from disturbance that they will provide an almost perfect space-time reference system. They will measure how space and time are very slightly warped by the presence of the Earth, and, more profoundly, how the Earth’s rotation very slightly drags space-time around with it. These effects, though small for the Earth, have far-reaching implications for the nature of matter and the structure of the Universe. In this photograph, Stanford engineer, Chris Gray, is inspecting the number 4 gyro under monochromatic light. GP-B is among the most thoroughly researched programs ever undertaken by NASA. This is the story of a scientific quest in which physicists and engineers have collaborated closely over many years. Inspired by their quest, they have invented a whole range of technologies that are already enlivening other branches of science and engineering. Launched April 20, 2004 , the GP-B program was managed for NASA by the Marshall Space Flight Center. Development of the GP-B is the responsibility of Stanford University along with major subcontractor Lockheed Martin Corporation. (Image credit to Russ Leese, Stanford University.)

Do performance and image enhancing drug users in regional Queensland experience difficulty accessing health services?

PubMed

Dunn, Matthew; Henshaw, Richard; McKay, Fiona H

2016-07-01

To understand health service access and needs of people who use performance and image enhancing drugs (PIED) in regional Queensland. Semi-structured interviews were conducted with 21 people (n = 19 men) who reported the use of a range of PIEDs, including anabolic-androgenic steroids, human chorionic gonadotropin, growth hormone, clenbuterol, tamoxifen, insulin and peptides. Participants reported accessing a range of services, including needle and syringe programs and pharmacies, for sterile injecting equipment. While PIEDs users attributed some stigma to needle and syringe programs, they were seen as an important service for injecting equipment. Participants reported receiving either positive care from health-care providers, such as general practitioners (GP), or having negative experiences due to the stigma attached with PIED use. Few participants reported disclosing their PIED use to their GP not only because of the concerns that their GP would no longer see them but also because they felt their GP was not knowledgeable about these substances. Participants in the study reported no difficulty in accessing health services based on living in a regional area, with their concern focused more upon how they were viewed and treated by service staff. [Dunn M, Henshaw R, Mckay F. H. Do performance and image enhancing drug users in regional Queensland experience difficulty accessing health services? Drug Alcohol Rev 2016;35:377-382]. © 2015 Australasian Professional Society on Alcohol and other Drugs.

Gravity Probe B Gyroscope Rotor

NASA Technical Reports Server (NTRS)

2003-01-01

The Gravity Probe B (GP-B) is the relativity experiment developed at Stanford University to test two extraordinary predictions of Albert Einstein's general theory of relativity. The experiment will measure, very precisely, the expected tiny changes in the direction of the spin axes of four gyroscopes contained in an Earth-orbiting satellite at a 400-mile altitude. So free are the gyroscopes from disturbance that they will provide an almost perfect space-time reference system. They will measure how space and time are very slightly warped by the presence of the Earth, and, more profoundly, how the Earth's rotation very slightly drags space-time around with it. These effects, though small for the Earth, have far-reaching implications for the nature of matter and the structure of the Universe. This photograph is a close up of a niobium-coated gyroscope motor and its housing halves. GP-B is among the most thoroughly researched programs ever undertaken by NASA. This is the story of a scientific quest in which physicists and engineers have collaborated closely over many years. Inspired by their quest, they have invented a whole range of technologies that are already enlivening other branches of science and engineering. Launched April 20, 2004 , the GP-B program was managed for NASA by the Marshall Space Flight Center. Development of the GP-B is the responsibility of Stanford University along with major subcontractor Lockheed Martin Corporation. (Image credit to Don Harley.)

HIV-related high risk sexual behaviors and practices among women in Bogotá, Colombia.

PubMed

Míguez-Burbano, M J; Angarita, I; Shultz, J M; Shor-Posner, G; Klaskala, W; Duque, J L; Lai, H; Londoño, B; Baum, M K

2000-01-01

Determinants associated with high-risk sexual behaviors were investigated in 1,133 sexually active women in Bogotá, Colombia. A self-administered questionnaire was completed by two groups of women: 721 representing the general population (GP), and 412 commercial sex workers (CSWs). High-risk sexual behaviors for HIV/AIDS were evident in both groups. Nevertheless, consistent condom use was reported by only 6% of the GP group, as compared to 67% of the CSWs. Failure to recognize high-risk routes for HIV infection was indicated in 69% of the GP women for anal sex, and by the majority of both groups for intercourse during menses (56% GP women and 54% CSWs). Multivariate analysis revealed that education level, actual age, and age of first sex experience were significant predictors of high-risk sexual practices. The necessity for educational programs regarding high-risk sexual practices and risk of HIV/ AIDS is evident for HIV/AIDS prevention.

Feasibility and acceptability of a physician-delivered weight management programme.

PubMed

Sturgiss, Elizabeth A; Elmitt, Nicholas; Haesler, Emily; van Weel, Chris; Douglas, Kirsty

2017-02-01

Primary health care requires new approaches to assist patients with overweight and obesity. This is a particular concern for patients with limited access to specialist or allied health services due to financial cost or location. The Change Program is a toolkit that provides a structured approach for GPs working with patients on weight management. To assess the acceptability and feasibility of a GP-delivered weight management programme. A feasibility trial in five Australian general practices with 12 GPs and 23 patients. Mixed methods were used to assess the objective through participant interviews, online surveys and the NOrmalization MeAsure Development (NoMAD) tool based on Normalization Process Theory. Content analysis of interviews is presented alongside Likert scales, free text and the NoMAD tool. The Change Program was acceptable to most GPs and patients. It was best suited to patient-GP dyads where the patient felt a strong preference for GP involvement. Patients' main concerns were the time and possible cost associated with the programme if run outside a research setting. For sustainable implementation, it would have been preferable to recruit a whole practice rather than single GPs to enable activation of systems to support the programme. A GP-delivered weight management programme is feasible and acceptable for patients with obesity in Australian primary health care. The addition of this structured toolkit to support GPs is particularly important for patients with a strong preference for GP involvement or who are unable to access other resources due to cost or location. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Investing in big ideas: utilisation and cost of Medicare Allied Health services in Australia under the Chronic Disease Management initiative in primary care.

PubMed

Cant, Robyn P; Foster, Michele M

2011-11-01

To critically examine utilisation of the 13 allied health services provided through Medicare Chronic Disease Management program and related general practitioner (GP) care planning initiatives. Statistics generated from national billing data from July 2005 to June 2009 were extracted from Medicare data and compared by profession, State or Territory and population. Most services grew over 4 years although nationally consistent service levels were not found for any allied health provider profession. On referral from GPs, podiatry, physiotherapy and dietetics provided most services (82%) in 2008-09. Professions had unique patterns of referral instanced by age range and sex of clientele. Wide variation was apparent in per capita utilisation of allied health services by State or Territory; some with far less than average national use and others with high use. Annual number of GP Management Plans or Team Care Arrangements was low (mean: ≤22 per GP in 2008-09), indicating low use of care planning. Inequality of accessibility for patients was apparent. Five years into the program, a review of Medicare Allied Health CDM policy is warranted. Implications. Research and evaluation is needed to identify whether the program is meeting the needs of GPs, allied health providers and chronic disease patients.

Advanced Intelligent System Application to Load Forecasting and Control for Hybrid Electric Bus

NASA Technical Reports Server (NTRS)

Momoh, James; Chattopadhyay, Deb; Elfayoumy, Mahmoud

1996-01-01

The primary motivation for this research emanates from providing a decision support system to the electric bus operators in the municipal and urban localities which will guide the operators to maintain an optimal compromise among the noise level, pollution level, fuel usage etc. This study is backed up by our previous studies on study of battery characteristics, permanent magnet DC motor studies and electric traction motor size studies completed in the first year. The operator of the Hybrid Electric Car must determine optimal power management schedule to meet a given load demand for different weather and road conditions. The decision support system for the bus operator comprises three sub-tasks viz. forecast of the electrical load for the route to be traversed divided into specified time periods (few minutes); deriving an optimal 'plan' or 'preschedule' based on the load forecast for the entire time-horizon (i.e., for all time periods) ahead of time; and finally employing corrective control action to monitor and modify the optimal plan in real-time. A fully connected artificial neural network (ANN) model is developed for forecasting the kW requirement for hybrid electric bus based on inputs like climatic conditions, passenger load, road inclination, etc. The ANN model is trained using back-propagation algorithm employing improved optimization techniques like projected Lagrangian technique. The pre-scheduler is based on a Goal-Programming (GP) optimization model with noise, pollution and fuel usage as the three objectives. GP has the capability of analyzing the trade-off among the conflicting objectives and arriving at the optimal activity levels, e.g., throttle settings. The corrective control action or the third sub-task is formulated as an optimal control model with inputs from the real-time data base as well as the GP model to minimize the error (or deviation) from the optimal plan. These three activities linked with the ANN forecaster proving the output to the GP model which in turn produces the pre-schedule of the optimal control model. Some preliminary results based on a hypothetical test case will be presented for the load forecasting module. The computer codes for the three modules will be made available fe adoption by bus operating agencies. Sample results will be provided using these models. The software will be a useful tool for supporting the control systems for the Electric Bus project of NASA.

Development of genetic programming-based model for predicting oyster norovirus outbreak risks.

PubMed

Chenar, Shima Shamkhali; Deng, Zhiqiang

2018-01-01

Oyster norovirus outbreaks pose increasing risks to human health and seafood industry worldwide but exact causes of the outbreaks are rarely identified, making it highly unlikely to reduce the risks. This paper presents a genetic programming (GP) based approach to identifying the primary cause of oyster norovirus outbreaks and predicting oyster norovirus outbreaks in order to reduce the risks. In terms of the primary cause, it was found that oyster norovirus outbreaks were controlled by cumulative effects of antecedent environmental conditions characterized by low solar radiation, low water temperature, low gage height (the height of water above a gage datum), low salinity, heavy rainfall, and strong offshore wind. The six environmental variables were determined by using Random Forest (RF) and Binary Logistic Regression (BLR) methods within the framework of the GP approach. In terms of predicting norovirus outbreaks, a risk-based GP model was developed using the six environmental variables and various combinations of the variables with different time lags. The results of local and global sensitivity analyses showed that gage height, temperature, and solar radiation were by far the three most important environmental predictors for oyster norovirus outbreaks, though other variables were also important. Specifically, very low temperature and gage height significantly increased the risk of norovirus outbreaks while high solar radiation markedly reduced the risk, suggesting that low temperature and gage height were associated with the norovirus source while solar radiation was the primary sink of norovirus. The GP model was utilized to hindcast daily risks of oyster norovirus outbreaks along the Northern Gulf of Mexico coast. The daily hindcasting results indicated that the GP model was capable of hindcasting all historical oyster norovirus outbreaks from January 2002 to June 2014 in the Gulf of Mexico with only two false positive outbreaks for the 12.5-year period. The performance of the GP model was characterized with the area under the Receiver Operating Characteristic curve of 0.86, the true positive rate (sensitivity) of 78.53% and the true negative rate (specificity) of 88.82%, respectively, demonstrating the efficacy of the GP model. The findings and results offered new insights into the oyster norovirus outbreaks in terms of source, sink, cause, and predictors. The GP model provided an efficient and effective tool for predicting potential oyster norovirus outbreaks and implementing management interventions to prevent or at least reduce norovirus risks to both the human health and the seafood industry. Copyright © 2017 Elsevier Ltd. All rights reserved.

Architectural Insight into Inovirus-Associated Vectors (IAVs) and Development of IAV-Based Vaccines Inducing Humoral and Cellular Responses: Implications in HIV-1 Vaccines

PubMed Central

Hassapis, Kyriakos A.; Stylianou, Dora C.; Kostrikis, Leondios G.

2014-01-01

Inovirus-associated vectors (IAVs) are engineered, non-lytic, filamentous bacteriophages that are assembled primarily from thousands of copies of the major coat protein gp8 and just five copies of each of the four minor coat proteins gp3, gp6, gp7 and gp9. Inovirus display studies have shown that the architecture of inoviruses makes all coat proteins of the inoviral particle accessible to the outside. This particular feature of IAVs allows foreign antigenic peptides to be displayed on the outer surface of the virion fused to its coat proteins and for more than two decades has been exploited in many applications including antibody or peptide display libraries, drug design, and vaccine development against infectious and non-infectious diseases. As vaccine carriers, IAVs have been shown to elicit both a cellular and humoral response against various pathogens through the display of antibody epitopes on their coat proteins. Despite their high immunogenicity, the goal of developing an effective vaccine against HIV-1 has not yet materialized. One possible limitation of previous efforts was the use of broadly neutralizing antibodies, which exhibited autoreactivity properties. In the past five years, however, new, more potent broadly neutralizing antibodies that do not exhibit autoreactivity properties have been isolated from HIV-1 infected individuals, suggesting that vaccination strategies aimed at producing such broadly neutralizing antibodies may confer protection against infection. The utilization of these new, broadly neutralizing antibodies in combination with the architectural traits of IAVs have driven the current developments in the design of an inovirus-based vaccine against HIV-1. This article reviews the applications of IAVs in vaccine development, with particular emphasis on the design of inoviral-based vaccines against HIV-1. PMID:25525909

Architectural insight into inovirus-associated vectors (IAVs) and development of IAV-based vaccines inducing humoral and cellular responses: implications in HIV-1 vaccines.

PubMed

Hassapis, Kyriakos A; Stylianou, Dora C; Kostrikis, Leondios G

2014-12-17

Inovirus-associated vectors (IAVs) are engineered, non-lytic, filamentous bacteriophages that are assembled primarily from thousands of copies of the major coat protein gp8 and just five copies of each of the four minor coat proteins gp3, gp6, gp7 and gp9. Inovirus display studies have shown that the architecture of inoviruses makes all coat proteins of the inoviral particle accessible to the outside. This particular feature of IAVs allows foreign antigenic peptides to be displayed on the outer surface of the virion fused to its coat proteins and for more than two decades has been exploited in many applications including antibody or peptide display libraries, drug design, and vaccine development against infectious and non-infectious diseases. As vaccine carriers, IAVs have been shown to elicit both a cellular and humoral response against various pathogens through the display of antibody epitopes on their coat proteins. Despite their high immunogenicity, the goal of developing an effective vaccine against HIV-1 has not yet materialized. One possible limitation of previous efforts was the use of broadly neutralizing antibodies, which exhibited autoreactivity properties. In the past five years, however, new, more potent broadly neutralizing antibodies that do not exhibit autoreactivity properties have been isolated from HIV-1 infected individuals, suggesting that vaccination strategies aimed at producing such broadly neutralizing antibodies may confer protection against infection. The utilization of these new, broadly neutralizing antibodies in combination with the architectural traits of IAVs have driven the current developments in the design of an inovirus-based vaccine against HIV-1. This article reviews the applications of IAVs in vaccine development, with particular emphasis on the design of inoviral-based vaccines against HIV-1.

Free Energy Perturbation Calculation of Relative Binding Free Energy between Broadly Neutralizing Antibodies and the gp120 Glycoprotein of HIV-1.

PubMed

Clark, Anthony J; Gindin, Tatyana; Zhang, Baoshan; Wang, Lingle; Abel, Robert; Murret, Colleen S; Xu, Fang; Bao, Amy; Lu, Nina J; Zhou, Tongqing; Kwong, Peter D; Shapiro, Lawrence; Honig, Barry; Friesner, Richard A

2017-04-07

Direct calculation of relative binding affinities between antibodies and antigens is a long-sought goal. However, despite substantial efforts, no generally applicable computational method has been described. Here, we describe a systematic free energy perturbation (FEP) protocol and calculate the binding affinities between the gp120 envelope glycoprotein of HIV-1 and three broadly neutralizing antibodies (bNAbs) of the VRC01 class. The protocol has been adapted from successful studies of small molecules to address the challenges associated with modeling protein-protein interactions. Specifically, we built homology models of the three antibody-gp120 complexes, extended the sampling times for large bulky residues, incorporated the modeling of glycans on the surface of gp120, and utilized continuum solvent-based loop prediction protocols to improve sampling. We present three experimental surface plasmon resonance data sets, in which antibody residues in the antibody/gp120 interface were systematically mutated to alanine. The RMS error in the large set (55 total cases) of FEP tests as compared to these experiments, 0.68kcal/mol, is near experimental accuracy, and it compares favorably with the results obtained from a simpler, empirical methodology. The correlation coefficient for the combined data set including residues with glycan contacts, R 2 =0.49, should be sufficient to guide the choice of residues for antibody optimization projects, assuming that this level of accuracy can be realized in prospective prediction. More generally, these results are encouraging with regard to the possibility of using an FEP approach to calculate the magnitude of protein-protein binding affinities. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

The MNS glycophorin variant GP.Mur affects differential erythroid expression of Rh/RhAG transcripts.

PubMed

Hsu, K; Kuo, M-S; Yao, C-C; Cheng, H-C; Lin, H-J; Chan, Y-S; Lin, M

2017-10-01

The band 3 macrocomplex (also known as the ankyrin-associated complex) on the red cell membrane comprises two interacting subcomplexes: a band 3/glycophorin A subcomplex, and a Rh/RhAG subcomplex. Glycophorin B (GPB) is a component of the Rh/RhAG subcomplex that is also structurally associated with glycophorin A (GPA). Expression of glycophorin B-A-B hybrid GP.Mur enhances band 3 expression and is associated with lower levels of Rh-associated glycoprotein (RhAG) and Rh polypeptides. The goal of this study was to determine whether GP.Mur influenced erythroid Rh/RhAG expression at the transcript level. GP.Mur was serologically determined in healthy participants from Taitung County, Taiwan. RNA was extracted from the reticulocyte-enriched fraction of peripheral blood, followed by reverse transcription and quantitative PCR for RhAG, RhD and RhCcEe. Quantification by real-time PCR revealed significantly fewer RhAG and RhCcEe transcripts in the reticulocytes from subjects with homozygous GYP*Mur. Independent from GYP.Mur, both RhAG and RhD transcript levels were threefold or higher than that of RhCcEe. Also, in GYP.Mur and the control samples alike, direct quantitative associations were observed between the transcript levels of RhAG and RhD, but not between that of RhAG and RhCcEe. Erythroid RhD and RhCcEe were differentially expressed at the transcript levels, which could be related to their different degrees of interaction or sensitivity to RhAG. Further, the reduction or absence of glycophorin B in GYP.Mur erythroid cells affected transcript expressions of RhAG and RhCcEe. Thus, GPB and GP.Mur differentially influenced Rh/RhAG expressions prior to protein translation. © 2017 International Society of Blood Transfusion.

Design Control Systems of Human Machine Interface in the NTVS-2894 Seat Grinder Machine to Increase the Productivity

NASA Astrophysics Data System (ADS)

Ardi, S.; Ardyansyah, D.

2018-02-01

In the Manufacturing of automotive spare parts, increased sales of vehicles is resulted in increased demand for production of engine valve of the customer. To meet customer demand, we carry out improvement and overhaul of the NTVS-2894 seat grinder machine on a machining line. NTVS-2894 seat grinder machine has been decreased machine productivity, the amount of trouble, and the amount of downtime. To overcome these problems on overhaul the NTVS-2984 seat grinder machine include mechanical and programs, is to do the design and manufacture of HMI (Human Machine Interface) GP-4501T program. Because of the time prior to the overhaul, NTVS-2894 seat grinder machine does not have a backup HMI (Human Machine Interface) program. The goal of the design and manufacture in this program is to improve the achievement of production, and allows an operator to operate beside it easier to troubleshoot the NTVS-2894 seat grinder machine thereby reducing downtime on the NTVS-2894 seat grinder machine. The results after the design are HMI program successfully made it back, machine productivity increased by 34.8%, the amount of trouble, and downtime decreased 40% decrease from 3,160 minutes to 1,700 minutes. The implication of our design, it could facilitate the operator in operating machine and the technician easer to maintain and do the troubleshooting the machine problems.

Downscaling GCM Output with Genetic Programming Model

NASA Astrophysics Data System (ADS)

Shi, X.; Dibike, Y. B.; Coulibaly, P.

2004-05-01

Climate change impact studies on watershed hydrology require reliable data at appropriate spatial and temporal resolution. However, the outputs of the current global climate models (GCMs) cannot be used directly because GCM do not provide hourly or daily precipitation and temperature reliable enough for hydrological modeling. Nevertheless, we can get more reliable data corresponding to future climate scenarios derived from GCM outputs using the so called 'downscaling techniques'. This study applies Genetic Programming (GP) based technique to downscale daily precipitation and temperature values at the Chute-du-Diable basin of the Saguenay watershed in Canada. In applying GP downscaling technique, the objective is to find a relationship between the large-scale predictor variables (NCEP data which provide daily information concerning the observed large-scale state of the atmosphere) and the predictand (meteorological data which describes conditions at the site scale). The selection of the most relevant predictor variables is achieved using the Pearson's coefficient of determination ( R2) (between the large-scale predictor variables and the daily meteorological data). In this case, the period (1961 - 2000) is identified to represent the current climate condition. For the forty years of data, the first 30 years (1961-1990) are considered for calibrating the models while the remaining ten years of data (1991-2000) are used to validate those models. In general, the R2 between the predictor variables and each predictand is very low in case of precipitation compared to that of maximum and minimum temperature. Moreover, the strength of individual predictors varies for every month and for each GP grammar. Therefore, the most appropriate combination of predictors has to be chosen by looking at the output analysis of all the twelve months and the different GP grammars. During the calibration of the GP model for precipitation downscaling, in addition to the mean daily precipitation and daily precipitation variability for each month, monthly average dry and wet-spell lengths are also considered as performance criteria. For the cases of Tmax and Tmin, means and variances of these variables corresponding to each month were considered as performance criteria. The GP downscaling results show satisfactory agreement between the observed daily temperature (Tmax and Tmin) and the simulated temperature. However, the downscaling results for the daily precipitation still require some improvement - suggesting further investigation of other grammars. KEY WORDS: Climate change; GP downscaling; GCM.

Prediction of Thermodynamic Equilibrium Temperature of Cu-Based Shape-Memory Smart Materials

NASA Astrophysics Data System (ADS)

Eskİl, Murat; Aldaş, Kemal; Özkul, İskender

2015-01-01

The thermodynamic equilibrium temperature ( T 0) is an important factor in the austenite and martensitic phases. In this study, the effects of alloying elements and heat treatments on T 0 temperature were investigated using Genetic Programming (GP) which has become one of the tools used in the study of condensed matter. Due to the changes in T 0, it is possible to analyze the changes in the entropy of the phase transitions. The data patterns of the GP formulation are based on well-established experimental results from the literature. The results of the GP-based formulation were compared with experimental results and found to be reliable with a very high correlation ( R 2 = 0.965 for training and R 2 = 0.952 for testing).

The personal computer and GP-B management. [Gravity Probe experiment

NASA Technical Reports Server (NTRS)

Neighbors, A. K.

1986-01-01

The Gravity Probe-B (GP-B) experiment is one of the most sophisticated and challenging developments to be undertaken by NASA. Its objective is to measure the relativistic drift of gyroscopes in orbit about the earth. In this paper, the experiment is described, and the strategy of phased procurements for accomplishing the engineering development of the hardware is discussed. The microcomputer is a very convenient and powerful tool in the management of GP-B. It is used in creating and monitoring such project data as schedules, budgets, hardware procurements and technical and interface requirements. Commercially available software in word processing, database management, communications, spreadsheet, graphics and program management are used. Examples are described of the efficacy of the application of the computer by the management team.

Impact assessment of a pay-for-performance program on breast cancer screening in France using micro data.

PubMed

Sicsic, Jonathan; Franc, Carine

2017-06-01

A voluntary-based pay-for-performance (P4P) program (the CAPI) aimed at general practitioners (GPs) was implemented in France in 2009. The program targeted prevention practices, including breast cancer screening, by offering a maximal amount of €245 for achieving a target screening rate among eligible women enrolled with the GP. Our objective was to evaluate the impact of the French P4P program (CAPI) on the early detection of breast cancer among women between 50 and 74 years old. Based on an administrative database of 50,752 women aged 50-74 years followed between 2007 and 2011, we estimated a difference-in-difference model of breast cancer screening uptake as a function of visit to a CAPI signatory referral GP, while controlling for both supply-side and demand-side determinants (e.g., sociodemographics, health and healthcare use). Breast cancer screening rates have not changed significantly since the P4P program implementation. Overall, visiting a CAPI signatory referral GP at least once in the pre-CAPI period increased the probability of undergoing breast cancer screening by 1.38 % [95 % CI (0.41-2.35 %)], but the effect was not significantly different following the implementation of the contract. The French P4P program had a nonsignificant impact on breast cancer screening uptake. This result may reflect the fact that the low-powered incentives implemented in France through the CAPI might not provide sufficient leverage to generate better practices, thus inviting regulators to seek additional tools beyond P4P in the field of prevention and screening.

Cultural and communication awareness for general practice registrars who are international medical graduates: a project of CoastCityCountry Training.

PubMed

Duncan, Geraldine F; Gilbey, David

2007-02-01

(1) To generate discussion about Australian culture and language with GP registrars using the medium of poetry; and (2) to introduce discussion about language and communication skills in a role-play format that GP registrars would embrace as part of their clinical training. (1) A variety of Australian poems was selected to reflect six themes: men, women, the Bush, ANZACS, Aboriginal Australia and migrants, which would provide a basis for discussion on a range of cultural issues to aid a medical professional trained overseas in developing further understanding of aspects of Australian culture. (2) A series of role plays was developed to reflect the clinical themes of each Day Release education program. These were enacted in a small group setting by preselected GP registrars with feedback from a medical educator and an English as a Second Language teacher. The Riverina/Murrumbidgee area of New South Wales, one of the three local training groups of CoastCityCountryTraining. GP registrars attached to the Riverina/Murrumbidgee Local Training Group. To show that discussion of poetry and participation in role plays are active language- and cultural-learning environments capable of enhancing understanding of a range of issues about Australia that are relevant to a GP registrar. There was increased participation by GP registrars in accessing the set material prior to each session. It was noted that there was also increased active involvement of all registrars in discussion within the group throughout the year. Discussion allowed clarification of aspects of Australian culture to participants with different international medical backgrounds, as well as providing an opportunity for GP registrars to share their own experiences.

Synthesis of biotinylated glycoconjugates and their use in a novel ELISA for direct comparison of HIV-1 Gp120 recognition of GalCer and related carbohydrate analogues.

PubMed

McReynolds, K D; Hadd, M J; Gervay-Hague, J

1999-01-01

As part of our program directed toward the design and synthesis of high-affinity ligands for the GalCer-binding site on the HIV cell surface glycoprotein, gp120, we required a reliable method for qualitatively assessing relative binding affinities for related analogues. Due to the hydrophilic nature of these synthetic conjugates, difficulties were encountered with typical ELISA methods, which rely upon hydrophobic interactions to anchor the ligand to a microtiter plate. Other types of assays were also problematic due to nonspecific binding of gp120. Therefore, we developed a general method for plating water-soluble ligands on microtiter plates using biotin/NeutrAvidin recognition for adhesion. A water-soluble GalCer analogue was prepared by conjugating psychosine to biotin using a novel tetraethylene glycol linker. In a similar manner, LacCer and GlcCer analogues were prepared and these conjugates were plated into microtiter wells containing NeutrAvidin. Unoccupied sites were blocked using biotin functionalized as a primary amide. Gp120 binding to galactosyl sphingosine, GalSph (19), GlcSph (22), and LacSph (23) conjugates was assessed through incubation with recombinant HRP-gp120. It was determined that LacSph has the strongest interaction with gp120. The binding affinities of GalSph and GlcSph were similar to each other and less strong than LacSph. These data contradict earlier studies where HPTLC showed that LacCer and GlcCer do not significantly bind gp120. They also contradict liposome-based assays that reported psychosine is not recognized by gp120. The extent of plating for each biotinylated molecule was quantified using HRP-biotin, allowing direct comparison of ligand plating efficiencies for the first time. Several other synthetic biotin conjugates were prepared and tested, demonstrating the feasibility of performing ELISA on water-soluble ligands.

Completed Gravity Probe B Undergoes Thermal Vacuum Testing

NASA Technical Reports Server (NTRS)

2000-01-01

The Gravity Probe B (GP-B) is the relativity experiment developed at Stanford University to test two extraordinary predictions of Albert Einstein's general theory of relativity. The experiment will measure, very precisely, the expected tiny changes in the direction of the spin axes of four gyroscopes contained in an Earth-orbiting satellite at a 400-mile altitude. So free are the gyroscopes from disturbance that they will provide an almost perfect space-time reference system. They will measure how space and time are very slightly warped by the presence of the Earth, and, more profoundly, how the Earth's rotation very slightly drags space-time around with it. These effects, though small for the Earth, have far-reaching implications for the nature of matter and the structure of the Universe. In this photograph, the completed space vehicle is undergoing thermal vacuum environment testing. GP-B is among the most thoroughly researched programs ever undertaken by NASA. This is the story of a scientific quest in which physicists and engineers have collaborated closely over many years. Inspired by their quest, they have invented a whole range of technologies that are already enlivening other branches of science and engineering. Launched April 20, 2004 , the GP-B program was managed for NASA by the Marshall Space Flight Center. Development of the GP-B is the responsibility of Stanford University along with major subcontractor Lockheed Martin Corporation. (Image credit to Russ Underwood, Lockheed Martin Corporation.)

Gravity Probe B Number 4 Gyro Inspected

NASA Technical Reports Server (NTRS)

2000-01-01

The Gravity Probe B (GP-B) is the relativity experiment developed at Stanford University to test two extraordinary predictions of Albert Einstein's general theory of relativity. The experiment will measure, very precisely, the expected tiny changes in the direction of the spin axes of four gyroscopes contained in an Earth-orbiting satellite at a 400-mile altitude. So free are the gyroscopes from disturbance that they will provide an almost perfect space-time reference system. They will measure how space and time are very slightly warped by the presence of the Earth, and, more profoundly, how the Earth's rotation very slightly drags space-time around with it. These effects, though small for the Earth, have far-reaching implications for the nature of matter and the structure of the Universe. In this photograph, Stanford engineer, Chris Gray, is inspecting the number 4 gyro under monochromatic light. GP-B is among the most thoroughly researched programs ever undertaken by NASA. This is the story of a scientific quest in which physicists and engineers have collaborated closely over many years. Inspired by their quest, they have invented a whole range of technologies that are already enlivening other branches of science and engineering. Launched April 20, 2004 , the GP-B program was managed for NASA by the Marshall Space Flight Center. Development of the GP-B is the responsibility of Stanford University along with major subcontractor Lockheed Martin Corporation. (Image credit to Russ Leese, Stanford University.)

[A comparative study of social representations of diabetes mellitus and diabetic foot].

PubMed

Mantovani, Alessandra Madia; Fregonesi, Cristina Elena Prado Teles; Pelai, Elisa Bizetti; Mantovani, Aline Madia; Savian, Nathalia Ulices; Pagotto, Priscila

2013-12-01

The study aimed to investigate social representations of the terms "diabetes" and "diabetic foot" in different populations. Participants were divided into groups: diabetics (GD); non- diabetics (GN); and non-diabetic healthcare professionals (GP). Personal data were collected, and subjects answered two questions that were expected to evoke five words that came to mind when they thought of "diabetes" and then "diabetic foot". The evoked material was analyzed with the software Ensemble de Programmes Permettant l'Analyse dês Èvocations. A total of 161 subjects participated, including GD (n = 72) with a mean age of 56.12 ± 5.49 years; GN (n = 38) with a mean age of 54.29 ± 7.91 years; and GP (n = 51) with 34.95 ± 7.52 years. The term "diabetes" evoked 297 words in GD, 172 in GN, and 235 words in GP. The term "diabetic foot" evoked 180 words in GD, 90 in GN, and 236 in GP. The groups proved to be anxious for more information, thus confirming the need for awareness-raising and educational programs on diabetes, covering comprehensive issues concerning the disease.

A binary genetic programing model for teleconnection identification between global sea surface temperature and local maximum monthly rainfall events

NASA Astrophysics Data System (ADS)

Danandeh Mehr, Ali; Nourani, Vahid; Hrnjica, Bahrudin; Molajou, Amir

2017-12-01

The effectiveness of genetic programming (GP) for solving regression problems in hydrology has been recognized in recent studies. However, its capability to solve classification problems has not been sufficiently explored so far. This study develops and applies a novel classification-forecasting model, namely Binary GP (BGP), for teleconnection studies between sea surface temperature (SST) variations and maximum monthly rainfall (MMR) events. The BGP integrates certain types of data pre-processing and post-processing methods with conventional GP engine to enhance its ability to solve both regression and classification problems simultaneously. The model was trained and tested using SST series of Black Sea, Mediterranean Sea, and Red Sea as potential predictors as well as classified MMR events at two locations in Iran as predictand. Skill of the model was measured in regard to different rainfall thresholds and SST lags and compared to that of the hybrid decision tree-association rule (DTAR) model available in the literature. The results indicated that the proposed model can identify potential teleconnection signals of surrounding seas beneficial to long-term forecasting of the occurrence of the classified MMR events.

Genetic programming approach to evaluate complexity of texture images

NASA Astrophysics Data System (ADS)

Ciocca, Gianluigi; Corchs, Silvia; Gasparini, Francesca

2016-11-01

We adopt genetic programming (GP) to define a measure that can predict complexity perception of texture images. We perform psychophysical experiments on three different datasets to collect data on the perceived complexity. The subjective data are used for training, validation, and test of the proposed measure. These data are also used to evaluate several possible candidate measures of texture complexity related to both low level and high level image features. We select four of them (namely roughness, number of regions, chroma variance, and memorability) to be combined in a GP framework. This approach allows a nonlinear combination of the measures and could give hints on how the related image features interact in complexity perception. The proposed complexity measure M exhibits Pearson correlation coefficients of 0.890 on the training set, 0.728 on the validation set, and 0.724 on the test set. M outperforms each of all the single measures considered. From the statistical analysis of different GP candidate solutions, we found that the roughness measure evaluated on the gray level image is the most dominant one, followed by the memorability, the number of regions, and finally the chroma variance.

Comparison between Decision Tree and Genetic Programming to distinguish healthy from stroke postural sway patterns.

PubMed

Marrega, Luiz H G; Silva, Simone M; Manffra, Elisangela F; Nievola, Julio C

2015-01-01

Maintaining balance is a motor task of crucial importance for humans to perform their daily activities safely and independently. Studies in the field of Artificial Intelligence have considered different classification methods in order to distinguish healthy subjects from patients with certain motor disorders based on their postural strategies during the balance control. The main purpose of this paper is to compare the performance between Decision Tree (DT) and Genetic Programming (GP) - both classification methods of easy interpretation by health professionals - to distinguish postural sway patterns produced by healthy and stroke individuals based on 16 widely used posturographic variables. For this purpose, we used a posturographic dataset of time-series of center-of-pressure displacements derived from 19 stroke patients and 19 healthy matched subjects in three quiet standing tasks of balance control. Then, DT and GP models were trained and tested under two different experiments where accuracy, sensitivity and specificity were adopted as performance metrics. The DT method has performed statistically significant (P < 0.05) better in both cases, showing for example an accuracy of 72.8% against 69.2% from GP in the second experiment of this paper.

Evaluation of first-pass cytochrome P4503A (CYP3A) and P-glycoprotein activities using alfentanil and fexofenadine in combination.

PubMed

Kharasch, Evan D; Walker, Alysa; Hoffer, Christine; Sheffels, Pamela

2005-01-01

Cytochrome P4503A (CYP3A) and P-glycoprotein (P-gp) are major determinants of oral bioavailability. Development of in vivo probe(s), for both CYP3A and P-gp, which could be administered in combination, is a current goal. Nevertheless, there is considerable overlap in CYP3A and P-gp substrate selectivities; there are few discrete probes. Alfentanil is a selective CYP3A probe but not a P-gp substrate. Fexofenadine is a P-gp probe but not a CYP3A substrate. This investigation tested the hypothesis that alfentanil and fexofenadine could be administered in combination to probe first-pass CYP3A and P-gp activities in humans. Two 3-way crossover studies were conducted in healthy volunteers. In the first protocol, subjects received oral alfentanil alone, fexofenadine alone, or fexofenadine 1 hour after alfentanil. In the second protocol, subjects abstained from citrus and apple products for 5 days and received fexofenadine alone, fexofenadine 1 hour after alfentanil, or alfentanil 4 hours after fexofenadine. An assay using solid-phase extraction and electrospray liquid chromatography/mass spectrometry was developed for the simultaneous quantification of plasma alfentanil and fexofenadine. In both protocols, alfentanil plasma concentrations and area under the concentration versus time curve (AUC) were unaffected by fexofenadine or meal composition. Fexofenadine given 1 hour after alfentanil and followed 1 hour later by a meal containing orange or apple juice had a somewhat lower AUC compared with fexofenadine alone (geometric mean ratio with and without the interacting drug = 0.73, 90% confidence interval [CI] = 0.59-1.04). Fexofenadine given 1 hour after alfentanil and followed 2 hours later by a meal not containing citrus or apple products had an AUC that was unchanged compared with fexofenadine alone (ratio = 0.91, 90% CI = 0.70-1.35). These results show that alfentanil disposition was not affected by fexofenadine. A dosing regimen was identified in which fexofenadine disposition was not affected by alfentanil. The timing and content of meals after fexofenadine had a significant effect on fexofenadine disposition. Alfentanil and fexofenadine in combination appear to be a useful probe for evaluating both first-pass CYP3A and P-gp activities in humans.

Interactive evolution of camouflage.

PubMed

Reynolds, Craig

2011-01-01

This article presents an abstract computation model of the evolution of camouflage in nature. The 2D model uses evolved textures for prey, a background texture representing the environment, and a visual predator. A human observer, acting as the predator, is shown a cohort of 10 evolved textures overlaid on the background texture. The observer clicks on the five most conspicuous prey to remove ("eat") them. These lower-fitness textures are removed from the population and replaced with newly bred textures. Biological morphogenesis is represented in this model by procedural texture synthesis. Nested expressions of generators and operators form a texture description language. Natural evolution is represented by genetic programming (GP), a variant of the genetic algorithm. GP searches the space of texture description programs for those that appear least conspicuous to the predator.

Surrogate-Assisted Genetic Programming With Simplified Models for Automated Design of Dispatching Rules.

PubMed

Nguyen, Su; Zhang, Mengjie; Tan, Kay Chen

2017-09-01

Automated design of dispatching rules for production systems has been an interesting research topic over the last several years. Machine learning, especially genetic programming (GP), has been a powerful approach to dealing with this design problem. However, intensive computational requirements, accuracy and interpretability are still its limitations. This paper aims at developing a new surrogate assisted GP to help improving the quality of the evolved rules without significant computational costs. The experiments have verified the effectiveness and efficiency of the proposed algorithms as compared to those in the literature. Furthermore, new simplification and visualisation approaches have also been developed to improve the interpretability of the evolved rules. These approaches have shown great potentials and proved to be a critical part of the automated design system.

Constrained Combinatorial Libraries of Gp2 Proteins Enhance Discovery of PD-L1 Binders.

PubMed

Kruziki, Max A; Sarma, Vidur; Hackel, Benjamin J

2018-06-05

Engineered protein ligands are used for molecular therapy, diagnostics, and industrial biotechnology. The Gp2 domain is a 45-amino acid scaffold that has been evolved for specific, high-affinity binding to multiple targets by diversification of two solvent-exposed loops. Inspired by sitewise enrichment of select amino acids, including cysteine pairs, in earlier Gp2 discovery campaigns, we hypothesized that the breadth and efficiency of de novo Gp2 discovery will be aided by sitewise amino acid constraint within combinatorial library design. We systematically constructed eight libraries and comparatively evaluated their efficacy for binder discovery via yeast display against a panel of targets. Conservation of a cysteine pair at the termini of the first diversified paratope loop increased binder discovery 16-fold ( p < 0.001). Yet two other libraries with conserved cysteine pairs, within the second loop or an interloop pair, did not aid discovery thereby indicating site-specific impact. Via a yeast display protease resistance assay, Gp2 variants from the loop one cysteine pair library were 3.3 ± 2.1-fold ( p = 0.005) more stable than nonconstrained variants. Sitewise constraint of noncysteine residues-guided by previously evolved binders, natural Gp2 homology, computed stability, and structural analysis-did not aid discovery. A panel of binders to programmed death ligand 1 (PD-L1), a key target in cancer immunotherapy, were discovered from the loop 1 cysteine constraint library. Affinity maturation via loop walking resulted in strong, specific cellular PD-L1 affinity ( K d = 6-9 nM).

Gender-related differences in general practice preferences: longitudinal evidence from the Netherlands 1982-2001.

PubMed

Mayorova, Tanja; Stevens, Fred; Scherpbier, Albert; van der Velden, Lud; van der Zee, Jouke

2005-04-01

The proportion of female doctors is increasing. Yet, there is little evidence that demonstrates changing career preferences over a long period, nor do we know the long-term impact of changing male-female ratios in medicine. We explored this within the GP profession. By means of a longitudinal cohort study (postal questionnaires) among all graduated GPs in the Netherlands between 1982 and 2001 we explored trends in career preferences and investigated whether practice preferences of men and women differ over the years. Preference of becoming a GP has significantly decreased among men. GPs prefer group practice more than solo practice. Female doctors were more likely to prefer a small practice and to associate. Men prefer to take over an established practice. Main reasons to abstain from practicing as a GP for men were having found another job or not having found a practice according to their preferences. Main reasons for women were having decided for another job and family life. We conclude that male and female GPs select differently on practice setting. Preferences change through the years but tend to converge. Gender differences are likely due to the circumstance that career choices for men are more influenced by fluctuating labour markets, while female choices are more based on family circumstances. We expect that as more women will become a GP the demand for small group practices will increase. Also, as many female GPs abstain from practicing after having finished a vocational GP training program it will be essential to create work facilities to keep them available for the GP labour market.

Improved model reduction and tuning of fractional-order PI(λ)D(μ) controllers for analytical rule extraction with genetic programming.

PubMed

Das, Saptarshi; Pan, Indranil; Das, Shantanu; Gupta, Amitava

2012-03-01

Genetic algorithm (GA) has been used in this study for a new approach of suboptimal model reduction in the Nyquist plane and optimal time domain tuning of proportional-integral-derivative (PID) and fractional-order (FO) PI(λ)D(μ) controllers. Simulation studies show that the new Nyquist-based model reduction technique outperforms the conventional H(2)-norm-based reduced parameter modeling technique. With the tuned controller parameters and reduced-order model parameter dataset, optimum tuning rules have been developed with a test-bench of higher-order processes via genetic programming (GP). The GP performs a symbolic regression on the reduced process parameters to evolve a tuning rule which provides the best analytical expression to map the data. The tuning rules are developed for a minimum time domain integral performance index described by a weighted sum of error index and controller effort. From the reported Pareto optimal front of the GP-based optimal rule extraction technique, a trade-off can be made between the complexity of the tuning formulae and the control performance. The efficacy of the single-gene and multi-gene GP-based tuning rules has been compared with the original GA-based control performance for the PID and PI(λ)D(μ) controllers, handling four different classes of representative higher-order processes. These rules are very useful for process control engineers, as they inherit the power of the GA-based tuning methodology, but can be easily calculated without the requirement for running the computationally intensive GA every time. Three-dimensional plots of the required variation in PID/fractional-order PID (FOPID) controller parameters with reduced process parameters have been shown as a guideline for the operator. Parametric robustness of the reported GP-based tuning rules has also been shown with credible simulation examples. Copyright © 2011 ISA. Published by Elsevier Ltd. All rights reserved.

Atmospheric Downscaling using Genetic Programming

NASA Astrophysics Data System (ADS)

Zerenner, Tanja; Venema, Victor; Simmer, Clemens

2013-04-01

Coupling models for the different components of the Soil-Vegetation-Atmosphere-System requires up-and downscaling procedures. Subject of our work is the downscaling scheme used to derive high resolution forcing data for land-surface and subsurface models from coarser atmospheric model output. The current downscaling scheme [Schomburg et. al. 2010, 2012] combines a bi-quadratic spline interpolation, deterministic rules and autoregressive noise. For the development of the scheme, training and validation data sets have been created by carrying out high-resolution runs of the atmospheric model. The deterministic rules in this scheme are partly based on known physical relations and partly determined by an automated search for linear relationships between the high resolution fields of the atmospheric model output and high resolution data on surface characteristics. Up to now deterministic rules are available for downscaling surface pressure and partially, depending on the prevailing weather conditions, for near surface temperature and radiation. Aim of our work is to improve those rules and to find deterministic rules for the remaining variables, which require downscaling, e.g. precipitation or near surface specifc humidity. To accomplish that, we broaden the search by allowing for interdependencies between different atmospheric parameters, non-linear relations, non-local and time-lagged relations. To cope with the vast number of possible solutions, we use genetic programming, a method from machine learning, which is based on the principles of natural evolution. We are currently working with GPLAB, a Genetic Programming toolbox for Matlab. At first we have tested the GP system to retrieve the known physical rule for downscaling surface pressure, i.e. the hydrostatic equation, from our training data. We have found this to be a simple task to the GP system. Furthermore we have improved accuracy and efficiency of the GP solution by implementing constant variation and optimization as genetic operators. Next we have worked on an improvement of the downscaling rule for the two-meter-temperature. We have added an if-function with four input arguments to the function set. Since this has shown to increase bloat we have additionally modified our fitness function by including penalty terms for both the size of the solutions and the number intron nodes, i.e program parts that are never evaluated. Starting from the known downscaling rule for the two-meter temperature, which linearly exploits the orography anomalies allowed or disallowed by a certain temperature gradient, our GP system has been able to find an improvement. The rule produced by the GP clearly shows a better performance concerning the reproduced small-scale variability.

Improving primary care in British Columbia, Canada: evaluation of a peer-to-peer continuing education program for family physicians.

PubMed

MacCarthy, Dan; Kallstrom, Liza; Kadlec, Helena; Hollander, Marcus

2012-11-09

An innovative program, the Practice Support Program (PSP), for full-service family physicians and their medical office assistants in primary care practices was recently introduced in British Columbia, Canada. The PSP was jointly approved by both government and physician groups, and is a dynamic, interactive, educational and supportive program that offers peer-to-peer training to physicians and their office staff. Topic areas range from clinical tools/skills to office management relevant to General Practitioner (GP) practices and "doable in real GP time". PSP learning modules consist of three half-day learning sessions interspersed with 6-8 week action periods. At the end of the third learning session, all participants were asked to complete a pen-and-paper survey that asked them to rate (a) their satisfaction with the learning module components, including the content and (b) the perceived impact the learning has had on their practices and patients. A total of 887 GPs (response rates ranging from 26.0% to 60.2% across three years) and 405 MOAs (response rates from 21.3% to 49.8%) provided responses on a pen-and-paper survey administered at the last learning session of the learning module. The survey asked respondents to rate (a) their satisfaction with the learning module components, including the content and (b) the perceived impact the learning has had on their practices and patients. The psychometric properties (Chronbach's alphas) of the satisfaction and impact scales ranged from .82 to .94. Evaluation findings from the first three years of the PSP indicated consistently high satisfaction ratings and perceived impact on GP practices and patients, regardless of physician characteristics (gender, age group) or work-related variables (e.g., time worked in family practice). The Advanced Access Learning Module, which offers tools to improve office efficiencies, decreased wait times for urgent, regular and third next available appointments by an average of 1.2, 3.3, and by 3.4 days across all physicians. For the Chronic Disease Management module, over 87% of all GP respondents developed a CDM patient registry and reported being able to take better care of their patients. After attending the Adult Mental Health module: 94.1% of GPs agreed that they felt more comfortable helping patients who required mental health care; over 82% agreed that their skills and their confidence in diagnosing and treating mental health conditions had improved; and 41.0% agreed that their frequency of prescribing medications, if appropriate, had decreased. Additionally for the Adult Mental Health module, a 3-6 month follow-up survey of the GPs indicated that the implemented changes were sustained over time. GP and medical office assistant participant ratings show that the PSP learning modules were consistently successful in providing GPs and their staff with new learning that was relevant and could be implemented and used in "real-GP-time".

GP trainees' in-consultation information-seeking: associations with human, paper and electronic sources.

PubMed

Magin, Parker; Morgan, Simon; Wearne, Susan; Tapley, Amanda; Henderson, Kim; Oldmeadow, Chris; Ball, Jean; Scott, John; Spike, Neil; McArthur, Lawrie; van Driel, Mieke

2015-10-01

Answering clinical questions arising from patient care can improve that care and offers an opportunity for adult learning. It is also a vital component in practising evidence-based medicine. GPs' sources of in-consultation information can be human or non-human (either hard copy or electronic). To establish the prevalence and associations of GP trainees' in-consultation information-seeking, and to establish the prevalence of use of different sources of information (human, hard copy and electronic) and the associations of choosing particular sources. A cross-sectional analysis of data (2010-13) from an ongoing cohort study of Australian GP trainees' consultations. Once each 6-month training term, trainees record detailed data of 60 consecutive consultations. The primary outcome was whether the trainee sought in-consultation information for a problem/diagnosis. Secondary outcomes were whether information-seeking was from a human (GP, other specialist or other health professional) or from a non-human source (electronic or hard copy), and whether a non-human source was electronic or hard copy. Six hundred forty-five trainees (response rate 94.3%) contributed data for 84,723 consultations including 131,583 problems/diagnoses. In-consultation information was sought for 15.4% (95% confidence interval=15.3-15.6) of problems/diagnoses. Sources were: GP in 6.9% of problems/diagnoses, other specialists 0.9%, other health professionals 0.6%, electronic sources 6.5% and hard-copy sources 1.5%. Associations of information-seeking included younger patient age, trainee full-time status and earlier training stage, longer consultation duration, referring the patient, organizing follow-up and generating learning goals. Associations of choosing human information sources (over non-human sources) were similar, but also included the trainee's training organization. Associations of electronic rather than hard-copy information-seeking included the trainee being younger, the training organization and information-seeking for management rather than diagnosis. Trainee information-seeking is mainly from GP colleagues and electronic sources. Human information-sources are preferentially sought for more complex problems, even by these early-career GPs who have trained in the 'internet era'. © The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Space Science

NASA Image and Video Library

2004-01-01

In this photo, the Gravity Probe B (GP-B) space vehicle is completed during the solar array installation. The GP-B is the relativity experiment developed at Stanford University to test two extraordinary predictions of Albert Einstein’s general theory of relativity. The experiment will measure, very precisely, the expected tiny changes in the direction of the spin axes of four gyroscopes contained in an Earth-orbiting satellite at a 400-mile altitude. So free are the gyroscopes from disturbance that they will provide an almost perfect space-time reference system. They will measure how space and time are very slightly warped by the presence of the Earth, and, more profoundly, how the Earth’s rotation very slightly drags space-time around with it. These effects, though small for the Earth, have far-reaching implications for the nature of matter and the structure of the Universe. GP-B is among the most thoroughly researched programs ever undertaken by NASA. This is the story of a scientific quest in which physicists and engineers have collaborated closely over many years. Inspired by their quest, they have invented a whole range of technologies that are already enlivening other branches of science and engineering. GP-B is scheduled for launch in April 2004 and managed for NASA by the Marshall Space Flight Center. Development of the GP-B is the responsibility of Stanford University along with major subcontractor Lockheed Martin Corporation. (Image credit to Russ Underwood, Lockheed Martin Corporation).

CD34+ mesenchymal cells are a major component of the intestinal stem cells niche at homeostasis and after injury.

PubMed

Stzepourginski, Igor; Nigro, Giulia; Jacob, Jean-Marie; Dulauroy, Sophie; Sansonetti, Philippe J; Eberl, Gérard; Peduto, Lucie

2017-01-24

The intestinal epithelium is continuously renewed by intestinal epithelial stem cells (IESCs) positioned at the base of each crypt. Mesenchymal-derived factors are essential to maintain IESCs; however, the cellular composition and development of such mesenchymal niche remains unclear. Here, we identify pericryptal CD34 + Gp38 + αSMA - mesenchymal cells closely associated with Lgr5 + IESCs. We demonstrate that CD34 + Gp38 + cells are the major intestinal producers of the niche factors Wnt2b, Gremlin1, and R-spondin1, and are sufficient to promote maintenance of Lgr5 + IESCs in intestinal organoids, an effect mainly mediated by Gremlin1. CD34 + Gp38 + cells develop after birth in the intestinal submucosa and expand around the crypts during the third week of life in mice, independently of the microbiota. We further show that pericryptal CD34 + gp38 + cells are rapidly activated by intestinal injury, up-regulating niche factors Gremlin1 and R-spondin1 as well as chemokines, proinflammatory cytokines, and growth factors with key roles in gut immunity and tissue repair, including IL-7, Ccl2, Ptgs2, and Amphiregulin. Our results indicate that CD34 + Gp38 + mesenchymal cells are programmed to develop in the intestine after birth to constitute a specialized microenvironment that maintains IESCs at homeostasis and contribute to intestinal inflammation and repair after injury.

Modified directly observed treatment for tuberculosis versus self-administered therapy: an observational study in rural Greece.

PubMed

Charokopos, N; Tsiros, G; Foka, A; Voila, P; Chrysanthopoulos, K; Spiliopoulou, I; Jelastopulu, E

2013-01-01

Directly Observed Treatment (DOT) is the key element of DOTS (directly observed treatment, short course), part of the internationally recommended control strategy for tuberculosis (TB). The evaluation of DOT has not been widely evaluated in rural areas in developed settings. The aim of this pilot study was to evaluate a modified DOT program (MDOT) by a general practitioner (GP) in a rural area of southwest Greece, where there is substantial underreporting of TB cases. Thirteen new TB cases with 30 close contacts were compared with 41 past-treated TB subjects (controls) with 111 close contacts in this observational, case-control study. Home visits by a GP were conducted and comparison of various data (laboratory findings, treatment outcomes, questionnaire-based parameters, on-site recorded conditions) was performed in both newly detected pulmonary TB cases and previously treated TB cases managed without DOT intervention. MDOT by GP implementation revealed that 11 cases (84.6%) were successfully treated, one (7.7%) case died, and one (7.7%) was lost to follow up. None of the close contacts of new TB cases was infected with active TB, while 6.3% of previously-treated TB subjects were infected with active TB and had to receive a complete anti-TB regimen. Chemoprophylaxis was administered to 13.3% of close contacts of new cases; whereas 12.6% of close contacts of previously-treated patients received chemoprophylaxis. This pilot study revealed that a GP is able to implement a program based on DOT resulting in high treatment adherence and prevention of TB compared with the conventional self-administration of treatment.

7 CFR 654.1 - Purpose and scope.

Code of Federal Regulations, 2014 CFR

2014-01-01

...) Federal financially-assisted projects. (i) Watershed Protection and Flood Prevention (WP&FP). See part 622...) Emergency Watershed Protection (EWP). See part 624 of this title. (4) Great Plains Conservation Program (GP...

7 CFR 654.1 - Purpose and scope.

Code of Federal Regulations, 2010 CFR

2010-01-01

...) Federal financially-assisted projects. (i) Watershed Protection and Flood Prevention (WP&FP). See part 622...) Emergency Watershed Protection (EWP). See part 624 of this title. (4) Great Plains Conservation Program (GP...

7 CFR 654.1 - Purpose and scope.

Code of Federal Regulations, 2012 CFR

2012-01-01

...) Federal financially-assisted projects. (i) Watershed Protection and Flood Prevention (WP&FP). See part 622...) Emergency Watershed Protection (EWP). See part 624 of this title. (4) Great Plains Conservation Program (GP...

7 CFR 654.1 - Purpose and scope.

Code of Federal Regulations, 2013 CFR

2013-01-01

...) Federal financially-assisted projects. (i) Watershed Protection and Flood Prevention (WP&FP). See part 622...) Emergency Watershed Protection (EWP). See part 624 of this title. (4) Great Plains Conservation Program (GP...

7 CFR 654.1 - Purpose and scope.

Code of Federal Regulations, 2011 CFR

2011-01-01

...) Federal financially-assisted projects. (i) Watershed Protection and Flood Prevention (WP&FP). See part 622...) Emergency Watershed Protection (EWP). See part 624 of this title. (4) Great Plains Conservation Program (GP...

Template-directed synthesis on the pentanucleotide CpCpGpCpC

NASA Technical Reports Server (NTRS)

Inoue, T.; Joyce, G. F.; Grzeskowiak, K.; Orgel, L. E.; Brown, J. M.; Reese, C. B.

1984-01-01

Experiments in which CpCpGpCpC is used as a template to facilitate the co-oligomerization of 2-MeImpG and 2-MeImpC are described. It is shown that 3' to 5' prime-linked pGpGpCpGpG, whose sequence is complementary to that of the template, is substantially the most adundant pentameric product of the template-directed reaction. The yield of pGpGpCpGpG is never large (less than 20 percent), presumably becauase off-template reactions consume template-directed products. Thus pGpGpCpGpG is converted to the various isomers of G5C and G4C2 by off-template terminal addition of G or C. The 3' to 5' isomer of GpG is elongated on the template to give GpGpC, GpGpCpG, and GpGpCpGpG, while the 2' to 5' isomer does not initiate the synthesis of detectable amounts of longer oligomers.

Expressed wishes and incidence of euthanasia in advanced lung cancer patients.

PubMed

Pardon, Koen; Deschepper, Reginald; Vander Stichele, Robert; Bernheim, Jan L; Mortier, Freddy; Schallier, Denis; Germonpré, Paul; Galdermans, Daniella; Van Kerckhoven, Willem; Deliens, Luc

2012-10-01

This study explores expressed wishes and requests for euthanasia (i.e. administration of lethal drugs at the explicit request of the patient), and incidence of end-of-life decisions with possible life-shortening effects (ELDs) in advanced lung cancer patients in Flanders, Belgium. We performed a prospective, longitudinal, observational study of a consecutive sample of advanced lung cancer patients and selected those who died within 18 months of diagnosis. Immediately after death, the pulmonologist/oncologist and general practitioner (GP) of the patient filled in a questionnaire. Information was available for 105 out of 115 deaths. According to the specialist or GP, one in five patients had expressed a wish for euthanasia; and three in four of these had made an explicit and repeated request. One in two of these received euthanasia. Of the patients who had expressed a wish for euthanasia but had not made an explicit and repeated request, none received euthanasia. Patients with a palliative treatment goal at inclusion were more likely to receive euthanasia. Death was preceded by an ELD in 62.9% of patients. To conclude, advanced lung cancer patients who expressed a euthanasia wish were often determined. Euthanasia was performed significantly more among patients whose treatment goal after diagnosis was exclusively palliative.

The use of genetic programming to develop a predictor of swash excursion on sandy beaches

NASA Astrophysics Data System (ADS)

Passarella, Marinella; Goldstein, Evan B.; De Muro, Sandro; Coco, Giovanni

2018-02-01

We use genetic programming (GP), a type of machine learning (ML) approach, to predict the total and infragravity swash excursion using previously published data sets that have been used extensively in swash prediction studies. Three previously published works with a range of new conditions are added to this data set to extend the range of measured swash conditions. Using this newly compiled data set we demonstrate that a ML approach can reduce the prediction errors compared to well-established parameterizations and therefore it may improve coastal hazards assessment (e.g. coastal inundation). Predictors obtained using GP can also be physically sound and replicate the functionality and dependencies of previous published formulas. Overall, we show that ML techniques are capable of both improving predictability (compared to classical regression approaches) and providing physical insight into coastal processes.

GP and nurses' perceptions of how after hours care for people receiving palliative care at home could be improved: a mixed methods study.

PubMed

Tan, Heather M; O'Connor, Margaret M; Miles, Gail; Klein, Britt; Schattner, Peter

2009-09-14

Primary health care providers play a dominant role in the provision of palliative care (PC) in Australia but many gaps in after hours service remain. In some rural areas only 19% of people receiving palliative care achieve their goal of dying at home. This study, which builds on an earlier qualitative phase of the project, investigates the gaps in care from the perspective of general practitioners (GPs) and PC nurses. Questionnaires, developed from the outcomes of the earlier phase, and containing both structured and open ended questions, were distributed through Divisions of General Practice (1 urban, 1 rural, 1 mixed) to GPs (n = 524) and through a special interest group to palliative care nurses (n = 122) in both rural and urban areas. Questionnaires were returned by 114 GPs (22%) and 52 nurses (43%). The majority of GPs were associated with a practice which provided some after hours services but PC was not a strong focus for most. This was reflected in low levels of PC training, limited awareness of the existence of after hours triage services in their area, and of the availability of Enhanced Primary Care (EPC) Medicare items for care planning for palliative patients. However, more than half of both nurses and GPs were aware of accessible PC resources.Factors such as poor communication and limited availability of after hours services were identified the as most likely to impact negatively on service provision. Strategies considered most likely to improve after hours services were individual patient protocols, palliative care trained respite carers and regular multidisciplinary meetings that included the GP. While some of the identified gaps can only be met by long term funding and policy change, educational tools for use in training programs in PC for health professionals, which focus on the utilisation of EPC Medicare items in palliative care planning, the development of advance care plans and good communication between members of multidisciplinary teams, which include the GP, may enhance after hours service provision for patients receiving palliative care at home. The role of locums in after PC is an area for further research.

The Gravity-Probe-B relativity gyroscope experiment - An update on progress

NASA Technical Reports Server (NTRS)

Parkinson, Bradford W.; Everitt, C. W. Francis; Turneaure, John P.

1987-01-01

The Gravity-Probe-B (GP-B) relativity gyroscope experiment will test two effects of general relativity: (1) the geodetic precession of a gyroscope due to its Fermi-Walker transport around a massive central body; and (2) the motional or gravitomagnetic precession of the gyroscope due to rotation of the central body itself. The experiment will also provide a determination of the deflection of starlight by the sun and an improved determination of the distance to Rigel. In the Shuttle testing phase of the program, prototype hardware is being developed for a full-scale ground model of the GP-B instrument.

Cost Effectiveness of Community Based Strategies for Blood Pressure Control in a Low income Developing Country: Findings from A Cluster Randomized Factorial Controlled Trial

PubMed Central

Jafar, Tazeen H; Islam, Muhammad; Bux, Rasool; Poulter, Neil; Hatcher, Juanita; Chaturvedi, Nish; Ebrahim, Shah; Cosgrove, Peter

2011-01-01

Background Evidence on economically efficient strategies to lower blood pressure (BP) from low- and middle-income countries remains scarce. The Control of Blood Pressure and Risk Attenuation (COBRA) trial randomized 1341 hypertensive subjects in 12 randomly selected communities in Karachi, Pakistan, to three intervention programs: combined home health education (HHE) plus trained general practitioner (GP); 2) HHE only; 3) trained GP only. The comparator was no intervention (or usual care). The reduction in BP was most pronounced in the combined group. The present study examined the cost-effectiveness of these strategies. Methods and Results Total costs were assessed at baseline and 2 years to estimate incremental cost effectiveness ratios (ICER) based on (a) intervention cost; b) cost of physician consultation, medications and diagnostics, changes in lifestyle, and productivity loss and (c) change in systolic BP. Precision of the ICER estimates was assessed by 1000 bootstrapping replications. Bayesian probabilistic sensitivity analysis was also performed. The annual per participant cost associated with the combined HHE plus trained GP, HHE alone, and trained GP alone were $3.99, $3.34, and $0.65, respectively. HHE plus trained GP was the most cost effective intervention with an ICER of $ 23 (6 to 99) per mm Hg reduction in systolic BP compared to usual care and remained so in 97.7% of 1000 bootstrapped replications. Conclusions The combined intervention of HHE plus trained GP is potentially affordable and more cost effective for BP control than usual care or either strategy alone in some communities in Pakistan, and possibly other countries in Indo-China with similar healthcare infrastructure. PMID:21931077

Structures of Ebola virus GP and sGP in complex with therapeutic antibodies.

PubMed

Pallesen, Jesper; Murin, Charles D; de Val, Natalia; Cottrell, Christopher A; Hastie, Kathryn M; Turner, Hannah L; Fusco, Marnie L; Flyak, Andrew I; Zeitlin, Larry; Crowe, James E; Andersen, Kristian G; Saphire, Erica Ollmann; Ward, Andrew B

2016-08-08

The Ebola virus (EBOV) GP gene encodes two glycoproteins. The major product is a soluble, dimeric glycoprotein (sGP) that is secreted abundantly. Despite the abundance of sGP during infection, little is known regarding its structure or functional role. A minor product, resulting from transcriptional editing, is the transmembrane-anchored, trimeric viral surface glycoprotein (GP). GP mediates attachment to and entry into host cells, and is the intended target of antibody therapeutics. Because large portions of sequence are shared between GP and sGP, it has been hypothesized that sGP may potentially subvert the immune response or may contribute to pathogenicity. In this study, we present cryo-electron microscopy structures of GP and sGP in complex with GP-specific and GP/sGP cross-reactive antibodies undergoing human clinical trials. The structure of the sGP dimer presented here, in complex with both an sGP-specific antibody and a GP/sGP cross-reactive antibody, permits us to unambiguously assign the oligomeric arrangement of sGP and compare its structure and epitope presentation to those of GP. We also provide biophysical evaluation of naturally occurring GP/sGP mutations that fall within the footprints identified by our high-resolution structures. Taken together, our data provide a detailed and more complete picture of the accessible Ebolavirus glycoprotein landscape and a structural basis to evaluate patient and vaccine antibody responses towards differently structured products of the GP gene.

Prediction of gas/particle partitioning of polybrominated diphenyl ethers (PBDEs) in global air: A theoretical study

NASA Astrophysics Data System (ADS)

Li, Y.-F.; Ma, W.-L.; Yang, M.

2015-02-01

Gas/particle (G/P) partitioning of semi-volatile organic compounds (SVOCs) is an important process that primarily governs their atmospheric fate, long-range atmospheric transport, and their routes of entering the human body. All previous studies on this issue are hypothetically based on equilibrium conditions, the results of which do not predict results from monitoring studies well in most cases. In this study, a steady-state model instead of an equilibrium-state model for the investigation of the G/P partitioning behavior of polybrominated diphenyl ethers (PBDEs) was established, and an equation for calculating the partition coefficients under steady state (KPS) of PBDEs (log KPS = log KPE + logα) was developed in which an equilibrium term (log KPE = log KOA + logfOM -11.91 where fOM is organic matter content of the particles) and a non-equilibrium term (log α, caused by dry and wet depositions of particles), both being functions of log KOA (octanol-air partition coefficient), are included. It was found that the equilibrium is a special case of steady state when the non-equilibrium term equals zero. A criterion to classify the equilibrium and non-equilibrium status of PBDEs was also established using two threshold values of log KOA, log KOA1, and log KOA2, which divide the range of log KOA into three domains: equilibrium, non-equilibrium, and maximum partition domain. Accordingly, two threshold values of temperature t, tTH1 when log KOA = log KOA1 and tTH2 when log KOA = log KOA2, were identified, which divide the range of temperature also into the same three domains for each PBDE congener. We predicted the existence of the maximum partition domain (the values of log KPS reach a maximum constant of -1.53) that every PBDE congener can reach when log KOA ≥ log KOA2, or t ≤ tTH2. The novel equation developed in this study was applied to predict the G/P partition coefficients of PBDEs for our Chinese persistent organic pollutants (POPs) Soil and Air Monitoring Program, Phase 2 (China-SAMP-II) program and other monitoring programs worldwide, including in Asia, Europe, North America, and the Arctic, and the results matched well with all the monitoring data, except those obtained at e-waste sites due to the unpredictable PBDE emissions at these sites. This study provided evidence that the newly developed steady-state-based equation is superior to the equilibrium-state-based equation that has been used in describing the G/P partitioning behavior over decades. We suggest that the investigation on G/P partitioning behavior for PBDEs should be based onsteady-state, not equilibrium state, and equilibrium is just a special case of steady-state when non-equilibrium factors can be ignored. We also believe that our new equation provides a useful tool for environmental scientists in both monitoring and modeling research on G/P partitioning of PBDEs and can be extended to predict G/P partitioning behavior for other SVOCs as well.

United States Air Force Summer Research Program -- 1993 Summer Research Program Final Reports. Volume 10. Wright Laboratory

DTIC Science & Technology

1993-01-01

LABORATORIES 5800 Uplander Way Culver City, CA 90230-6608 Program Director, RDL Program Manager , AFOSR Gary Moore Col. Hal Rhoades Program Manager , RDL...Laboratory: PL/RK Aerospace Engineering University of Cinc nati Vol-Page No: 8-10 Cincinnati, OH 45221-0000 Burns, Paul Field: Electrical Engineering as...Laboratory: PL/GP Electrical Engineering Boston University Vol-Page No: a- 5 Boston, MA 2215-0000 GSRP Participant Data Stauffer, Joseph Field: Management MS

Financial costs for teaching in rural and urban Australian general practices: is there a difference?

PubMed

Laurence, Caroline O; Coombs, Maryanne; Bell, Janice; Black, Linda

2014-04-01

To determine if the financial costs of teaching GP registrars differs between rural and urban practices. Cost-benefit analysis of teaching activities in private GP for GP vocational training. Data were obtained from a survey of general practitioners in South Australia and Western Australia. General practitioners and practices teaching in association with the Adelaide to Outback General Practice Training Program or the Western Australian General Practice Training. Net financial effect per week per practice. At all the training levels, rural practices experienced a financial loss for teaching GP registrars, while urban practices made a small financial gain. The differences in net benefit between rural and urban teaching practices was significant at the GPT2/PRRT2 (-$515 per week 95% CI -$1578, -$266) and GPT3/PRRT3 training levels (-$396 per week, 95% CI (-$2568, -$175). The variables contributing greatest to the difference were the higher infrastructure costs for a rural practice and higher income to the practice from the GP registrars in urban practices. There were significant differences in the financial costs and benefits for a teaching rural practice compared with an urban teaching practice. With infrastructure costs which include accommodation, being a key contributor to the difference found, it might be time to review the level of incentives paid to practices in this area. If not addressed, this cost difference might be a disincentive for rural practices to participate in teaching. © 2014 National Rural Health Alliance Inc.

Gravity Probe B Completed With Solar Arrays

NASA Technical Reports Server (NTRS)

2004-01-01

In this photo, the Gravity Probe B (GP-B) space vehicle is completed during the solar array installation. The GP-B is the relativity experiment developed at Stanford University to test two extraordinary predictions of Albert Einstein's general theory of relativity. The experiment will measure, very precisely, the expected tiny changes in the direction of the spin axes of four gyroscopes contained in an Earth-orbiting satellite at a 400-mile altitude. So free are the gyroscopes from disturbance that they will provide an almost perfect space-time reference system. They will measure how space and time are very slightly warped by the presence of the Earth, and, more profoundly, how the Earth's rotation very slightly drags space-time around with it. These effects, though small for the Earth, have far-reaching implications for the nature of matter and the structure of the Universe. GP-B is among the most thoroughly researched programs ever undertaken by NASA. This is the story of a scientific quest in which physicists and engineers have collaborated closely over many years. Inspired by their quest, they have invented a whole range of technologies that are already enlivening other branches of science and engineering. GP-B is scheduled for launch in April 2004 and managed for NASA by the Marshall Space Flight Center. Development of the GP-B is the responsibility of Stanford University along with major subcontractor Lockheed Martin Corporation. (Image credit to Russ Underwood, Lockheed Martin Corporation).

Gleason Score 7 Prostate Cancers Emerge through Branched Evolution of Clonal Gleason Pattern 3 and 4.

PubMed

Sowalsky, Adam G; Kissick, Haydn T; Gerrin, Sean J; Schaefer, Rachel J; Xia, Zheng; Russo, Joshua W; Arredouani, M Simo; Bubley, Glenn J; Sanda, Martin G; Li, Wei; Ye, Huihui; Balk, Steven P

2017-07-15

Purpose: The molecular features that account for the distinct histology and aggressive biological behavior of Gleason pattern 4 (Gp4) versus Gp3 prostate cancer, and whether Gp3 tumors progress directly to Gp4, remain to be established. Experimental Design: Whole-exome sequencing and transcriptome profiling of laser capture-microdissected adjacent Gp3 and cribiform Gp4 were used to determine the relationship between these entities. Results: Sequencing confirmed that adjacent Gp3 and Gp4 were clonal based on multiple shared genomic alterations. However, large numbers of unique mutations in the Gp3 and Gp4 tumors showed that the Gp4 were not derived directly from the Gp3. Remarkably, the Gp3 tumors retain their indolent-appearing morphology despite acquisition of multiple genomic alterations, including tumor suppressor losses. Although there were no consistent genomic alterations that distinguished Gp3 from Gp4, pairwise transcriptome analyses identified increased c-Myc and decreased p53 activity in Gp4 versus adjacent clonal Gp3 foci. Conclusions: These findings establish that at least a subset of Gp3 and aggressive Gp4 tumors have a common origin, and support a branched evolution model wherein the Gp3 and Gp4 tumors emerge early from a common precursor and subsequently undergo substantial divergence. Genomic alterations detectable in the Gp3 may distinguish these tumors from truly indolent Gp3. Screening for a panel of these genomic alterations in men who have prostate biopsies showing only Gp3 (Gleason score 6, Gs6) may allow for more precise selection of men who can be safely managed by active surveillance versus those who may benefit from further intervention. Clin Cancer Res; 23(14); 3823-33. ©2017 AACR . ©2017 American Association for Cancer Research.

Saving Space and Time: The Tractor That Einstein Built

NASA Technical Reports Server (NTRS)

2006-01-01

In 1984, NASA initiated the Gravity Probe B (GP-B) program to test two unverified predictions of Albert Einstein s theory of general relativity, hypotheses about the ways space, time, light, and gravity relate to each other. To test these predictions, the Space Agency and researchers at Stanford University developed an experiment that would check, with extreme precision, tiny changes in the spin direction of four gyroscopes contained in an Earth satellite orbiting at a 400-mile altitude directly over the Earth s poles. When the program first began, the researchers assessed using Global Positioning System (GPS) technology to control the attitude of the GP-B spacecraft accurately. At that time, the best GPS receivers could only provide accuracy to nearly 1 meter, but the GP-B spacecraft required a system 100 times more accurate. To address this concern, researchers at Stanford designed high-performance, attitude-determining hardware that used GPS signals, perfecting a high-precision form of GPS called Carrier-Phase Differential GPS that could provide continuous real-time position, velocity, time, and attitude sensor information for all axes of a vehicle. The researchers came to the realization that controlling the GP-B spacecraft with this new system was essentially no different than controlling an airplane. Their thinking took a new direction: If this technology proved successful, the airlines and the Federal Aviation Administration (FAA) were ready commercial markets. They set out to test the new technology, the "Integrity Beacon Landing System," using it to automatically land a commercial Boeing 737 over 100 times successfully through Real-Time Kinematic (RTK) GPS technology. The thinking of the researchers shifted again, from automatically landing aircraft, to automating precision farming and construction equipment.

Modulation of Endoplasmic Reticulum Stress Controls CD4+ T-cell Activation and Antitumor Function.

PubMed

Thaxton, Jessica E; Wallace, Caroline; Riesenberg, Brian; Zhang, Yongliang; Paulos, Chrystal M; Beeson, Craig C; Liu, Bei; Li, Zihai

2017-08-01

The endoplasmic reticulum (ER) is an energy-sensing organelle with intimate ties to programming cell activation and metabolic fate. T-cell receptor (TCR) activation represents a form of acute cell stress and induces mobilization of ER Ca 2+ stores. The role of the ER in programming T-cell activation and metabolic fate remains largely undefined. Gp96 is an ER protein with functions as a molecular chaperone and Ca 2+ buffering protein. We hypothesized that the ER stress response may be important for CD4 + T-cell activation and that gp96 may be integral to this process. To test our hypothesis, we utilized genetic deletion of the gp96 gene Hsp90b1 in a CD4 + T cell-specific manner. We show that gp96-deficient CD4 + T cells cannot undergo activation-induced glycolysis due to defective Ca 2+ mobilization upon TCR engagement. We found that activating naïve CD4 + T cells while inhibiting ER Ca 2+ exchange, through pharmacological blockade of the ER Ca 2+ channel inositol trisphosphate receptor (IP 3 R), led to a reduction in cytosolic Ca 2+ content and generated a pool of CD62L high /CD44 low CD4 + T cells compared with wild-type (WT) matched controls. In vivo IP 3 R-inhibited CD4 + T cells exhibited elevated tumor control above WT T cells. Together, these data show that ER-modulated cytosolic Ca 2+ plays a role in defining CD4 + T-cell phenotype and function. Factors associated with the ER stress response are suitable targets for T cell-based immunotherapies. Cancer Immunol Res; 5(8); 666-75. ©2017 AACR . ©2017 American Association for Cancer Research.

Early predictors of need for remediation in the Australian general practice training program: a retrospective cohort study.

PubMed

Magin, Parker; Stewart, Rebecca; Turnock, Allison; Tapley, Amanda; Holliday, Elizabeth; Cooling, Nick

2017-10-01

Underperforming trainees requiring remediation may threaten patient safety and are challenging for vocational training programs. Decisions to institute remediation are high-stakes-remediation being resource-intensive and emotionally demanding on trainees. Detection of underperformance requiring remediation is particularly problematic in general (family) practice. We sought to establish early-training assessment instruments predictive of general practice (GP) trainees' subsequently requiring formal remediation. We conducted a retrospective cohort study of trainees from a large Australian regionally-based GP training organization. The outcome factor was requirement for formal remediation. Independent variables were demographic factors and a range of formative assessments conducted immediately prior to or during early-stage training. Analyses employed univariate and multivariate logistic regression of each predictor assessment modality with the outcome, adjusting for potential confounders. Of 248 trainees, 26 (10.5 %) required formal remediation. Performance on the Colleague Feedback Evaluation Tool (entailing feedback from a trainee's clinical colleagues on clinical performance, communication and probity) and External Clinical Teaching Visits (half-day sessions of the trainee's clinical consultations observed directly by an experienced GP), along with non-Australian primary medical qualification, were significantly associated with requiring remediation. There was a non-significant trend for association with performance on the Doctors Interpersonal Skills Questionnaire (patient feedback on interpersonal elements of the consultation). There were no significant associations with entry-selection scores or formative exam or assessment scores. Our finding that 'in vivo' assessments of complex behaviour, but not 'in vitro' knowledge-based assessments, predict need for remediation is consistent with theoretical understanding of the nature of remediation decision-making and should inform remediation practice in GP vocational training.

76 FR 70527 - Reporting and Recordkeeping Requirements Under OMB Review

Federal Register 2010, 2011, 2012, 2013, 2014

2011-11-14

...: Title: ``25-Model Corp.Resol.or GP Certif.33-Model Letter to Selling Agent. 34-Bank ID, 1065-Appl.Lic...: ``New Markets Venture Capital Program Application Funding and Reporting''. Form No's: 2216, 2185, 2219...

Consultation sequencing of a hospital with multiple service points using genetic programming

NASA Astrophysics Data System (ADS)

Morikawa, Katsumi; Takahashi, Katsuhiko; Nagasawa, Keisuke

2018-07-01

A hospital with one consultation room operated by a physician and several examination rooms is investigated. Scheduled patients and walk-ins arrive at the hospital, each patient goes to the consultation room first, and some of them visit other service points before consulting the physician again. The objective function consists of the sum of three weighted average waiting times. The problem of sequencing patients for consultation is focused. To alleviate the stress of waiting, the consultation sequence is displayed. A dispatching rule is used to decide the sequence, and best rules are explored by genetic programming (GP). The simulation experiments indicate that the rules produced by GP can be reduced to simple permutations of queues, and the best permutation depends on the weight used in the objective function. This implies that a balanced allocation of waiting times can be achieved by ordering the priority among three queues.

Role of P-glycoprotein inhibitors in ceramide-based therapeutics for treatment of cancer.

PubMed

Morad, Samy A F; Davis, Traci S; MacDougall, Matthew R; Tan, Su-Fern; Feith, David J; Desai, Dhimant H; Amin, Shantu G; Kester, Mark; Loughran, Thomas P; Cabot, Myles C

2017-04-15

The anticancer properties of ceramide, a sphingolipid with potent tumor-suppressor properties, can be dampened via glycosylation, notably in multidrug resistance wherein ceramide glycosylation is characteristically elevated. Earlier works using the ceramide analog, C6-ceramide, demonstrated that the antiestrogen tamoxifen, a first generation P-glycoprotein (P-gp) inhibitor, blocked C6-ceramide glycosylation and magnified apoptotic responses. The present investigation was undertaken with the goal of discovering non-anti-estrogenic alternatives to tamoxifen that could be employed as adjuvants for improving the efficacy of ceramide-centric therapeutics in treatment of cancer. Herein we demonstrate that the tamoxifen metabolites, desmethyltamoxifen and didesmethyltamoxifen, and specific, high-affinity P-gp inhibitors, tariquidar and zosuquidar, synergistically enhanced C6-ceramide cytotoxicity in multidrug resistant HL-60/VCR acute myelogenous leukemia (AML) cells, whereas the selective estrogen receptor antagonist, fulvestrant, was ineffective. Active C6-ceramide-adjuvant combinations elicited mitochondrial ROS production and cytochrome c release, and induced apoptosis. Cytotoxicity was mitigated by introduction of antioxidant. Effective adjuvants markedly inhibited C6-ceramide glycosylation as well as conversion to sphingomyelin. Active regimens were also effective in KG-1a cells, a leukemia stem cell-like line, and in LoVo human colorectal cancer cells, a solid tumor model. In summary, our work details discovery of the link between P-gp inhibitors and the regulation and potentiation of ceramide metabolism in a pro-apoptotic direction in cancer cells. Given the active properties of these adjuvants in synergizing with C6-ceramide, independent of drug resistance status, stemness, or cancer type, our results suggest that the C6-ceramide-containing regimens could provide alternative, promising therapeutic direction, in addition to finding novel, off-label applications for P-gp inhibitors. Copyright © 2017 Elsevier Inc. All rights reserved.

Vaccination with Recombinant Cryptococcus Proteins in Glucan Particles Protects Mice against Cryptococcosis in a Manner Dependent upon Mouse Strain and Cryptococcal Species

PubMed Central

Lee, Chrono K.; Huang, Haibin; Hester, Maureen M.; Liu, Jianhua; Luckie, Bridget A.; Torres Santana, Melanie A.; Mirza, Zeynep; Khoshkenar, Payam; Abraham, Ambily; Shen, Zu T.; Lodge, Jennifer K.; Akalin, Ali; Homan, Jane; Ostroff, Gary R.

2017-01-01

ABSTRACT Development of a vaccine to protect against cryptococcosis is a priority given the enormous global burden of disease in at-risk individuals. Using glucan particles (GPs) as a delivery system, we previously demonstrated that mice vaccinated with crude Cryptococcus-derived alkaline extracts were protected against lethal challenge with Cryptococcus neoformans and Cryptococcus gattii. The goal of the present study was to identify protective protein antigens that could be used in a subunit vaccine. Using biased and unbiased approaches, six candidate antigens (Cda1, Cda2, Cda3, Fpd1, MP88, and Sod1) were selected, recombinantly expressed in Escherichia coli, purified, and loaded into GPs. Three mouse strains (C57BL/6, BALB/c, and DR4) were then vaccinated with the antigen-laden GPs, following which they received a pulmonary challenge with virulent C. neoformans and C. gattii strains. Four candidate vaccines (GP-Cda1, GP-Cda2, GP-Cda3, and GP-Sod1) afforded a significant survival advantage in at least one mouse model; some vaccine combinations provided added protection over that seen with either antigen alone. Vaccine-mediated protection against C. neoformans did not necessarily predict protection against C. gattii. Vaccinated mice developed pulmonary inflammatory responses that effectively contained the infection; many surviving mice developed sterilizing immunity. Predicted T helper cell epitopes differed between mouse strains and in the degree to which they matched epitopes predicted in humans. Thus, we have discovered cryptococcal proteins that make promising candidate vaccine antigens. Protection varied depending on the mouse strain and cryptococcal species, suggesting that a successful human subunit vaccine will need to contain multiple antigens, including ones that are species specific. PMID:29184017

Estimating switchgrass productivity in the Great Plains using satellite vegetation index and site environmental variables

USGS Publications Warehouse

Gu, Yingxin; Wylie, Bruce K.; Howard, Daniel M.

2015-01-01

Switchgrass is being evaluated as a potential feedstock source for cellulosic biofuels and is being cultivated in several regions of the United States. The recent availability of switchgrass land cover maps derived from the National Agricultural Statistics Service cropland data layer for the conterminous United States provides an opportunity to assess the environmental conditions of switchgrass over large areas and across different geographic locations. The main goal of this study is to develop a data-driven multiple regression switchgrass productivity model and identify the optimal climate and environment conditions for the highly productive switchgrass in the Great Plains (GP). Environmental and climate variables used in the study include elevation, soil organic carbon, available water capacity, climate, and seasonal weather. Satellite-derived growing season averaged Normalized Difference Vegetation Index (GSN) was used as a proxy for switchgrass productivity. Multiple regression analyses indicate that there are strong correlations between site environmental variables and switchgrass productivity (r = 0.95). Sufficient precipitation and suitable temperature during the growing season (i.e., not too hot or too cold) are favorable for switchgrass growth. Elevation and soil characteristics (e.g., soil available water capacity) are also an important factor impacting switchgrass productivity. An anticipated switchgrass biomass productivity map for the entire GP based on site environmental and climate conditions and switchgrass productivity model was generated. Highly productive switchgrass areas are mainly located in the eastern part of the GP. Results from this study can help land managers and biofuel plant investors better understand the general environmental and climate conditions influencing switchgrass growth and make optimal land use decisions regarding switchgrass development in the GP.

HBC-Evo: predicting human breast cancer by exploiting amino acid sequence-based feature spaces and evolutionary ensemble system.

PubMed

Majid, Abdul; Ali, Safdar

2015-01-01

We developed genetic programming (GP)-based evolutionary ensemble system for the early diagnosis, prognosis and prediction of human breast cancer. This system has effectively exploited the diversity in feature and decision spaces. First, individual learners are trained in different feature spaces using physicochemical properties of protein amino acids. Their predictions are then stacked to develop the best solution during GP evolution process. Finally, results for HBC-Evo system are obtained with optimal threshold, which is computed using particle swarm optimization. Our novel approach has demonstrated promising results compared to state of the art approaches.

Impact of Ebola mucin-like domain on antiglycoprotein antibody responses induced by Ebola virus-like particles.

PubMed

Martinez, Osvaldo; Tantral, Lee; Mulherkar, Nirupama; Chandran, Kartik; Basler, Christopher F

2011-11-01

Ebola virus (EBOV) glycoprotein (GP), responsible for mediating host-cell attachment and membrane fusion, contains a heavily glycosylated mucin-like domain hypothesized to shield GP from neutralizing antibodies. To test whether the mucin-like domain inhibits the production and function of anti-GP antibodies, we vaccinated mice with Ebola virus-like particles (VLPs) that express vesicular stomatitis virus G, wild-type EBOV GP (EBGP), EBOV GP without its mucin-like domain (ΔMucGP), or EBOV GP with a Crimean-Congo hemorrhagic fever virus mucin-like domain substituted for the EBOV mucin-like domain (CMsubGP). EBGP-VLP immunized mice elicited significantly higher serum antibody titers toward EBGP or its mutants, as detected by western blot analysis, than did VLP-ΔMucGP. However, EBGP-, ΔMucGP- and CMsubGP-VLP immunized mouse sera contained antibodies that bound to cell surface-expressed GP at similar levels. Furthermore, low but similar neutralizing antibody titers, measured against a vesicular stomatitis virus (VSV) expressing EBGP or ΔMucGP, were present in EBGP, ΔMucGP, and CMsubGP sera, although a slightly higher neutralizing titer (2- to 2.5-fold) was detected in ΔMucGP sera. We conclude that the EBOV GP mucin-like domain can increase relative anti-GP titers, however these titers appear to be directed, at least partly, to denatured GP. Furthermore, removing the mucin-like domain from immunizing VLPs has modest impact on neutralizing antibody titers in serum.

[Opinions and attitudes of Flemish pharmacists and general practitioners towards INN prescribing. A survery in Antwerp and East Flanders].

PubMed

Fraeyman, J; De Winter, J; De Loof, H; Van Hal, G; Beutels, P; Remmen, R; De Meyer, G R Y

2013-06-01

Since 2002 in Belgium, physicians are allowed to prescribe by International Non-proprietary Name (INN). In 2005, the conditions for this decree were set. Examples from other countries have shown that INN prescribing can significantly contribute to controlling pharmaceutical expenditures. The share of INN prescriptions remains low in Belgium (7% in 2011). To formulate an answer to the question: what are the opinions and attitudes of pharmacists and general practitioners [GP's] with regards to INN prescribing? In the winter of 2011-2012, a questionnaire with closed-ended questions was send to pharmacists and GP's in the provinces of Antwerp and East-Flanders, through training days and personal visits. Pharmacists and GP's scored a list of statements with a 5-point Likert scale. The themes of the statements related to: delivering INN prescriptions, legislation, impact on expenditures, choices regarding patient concerns and interprofessional relations. In total, 353 questionnaires were completed and returned of which 228 165%1 were by pharmacists and 125 (35%1 by GP's. Although both declared to be sufficiently up to date with regulations to prescribe (84%) or to deliver (95%] a INN prescription, only 13% of the pharmacists said all prescription they receive contain the correct information. Less GP's [36%) than pharmacists (82%] feel aided by their software program when prescribing or delivering an INN prescription. GP's rely mostly on NIHDI (National Institute for Health and Disability Insurance) as the main source for information on INN prescribing, pharmacists rely on the [Local) pharmacists association. The pharmacists and GP's in the study who relied on NIHDI as main information source, were less aware of legislation concerning INN [N2, p<0,05] than those who rely on the local professional association [N2, p<0,0001]. All pharmacists in the study said to consider the patients medication history when delivering an INN prescription for chronic treatment. However, 57% of the GP's preferred not to prescribe by INN for the reason that they are not sure whether the pharmacist will always consider the patients medication history in case of an INN prescription. Although the GP's showed certain motivation to prescribe by INN, it was no greater than for generic prescribing. And INN prescribing has no added value compared to generic prescribing, according to the GP's. For the pharmacists, INN prescribing does contain an opportunity. With the increase in numbers of dosages and sorts of packaging of generic products, it becomes more and more difficult for pharmacists to manage their stock. In case of an INN prescription, the pharmacist can choose between the different packages in his stock. This offers opportunities especially for acute conditions. INN prescribing is a good example of where the collaboration between pharmacists and GP's still contains a lot of opportunities, as well for the two professions, as the government and the patient in terms of controlling the pharmaceutical expenditures. Also the education for pharmacist or GP can further contribute to the sensitization of INN prescribing. In practice, there remain a number of issues and differences in opinions between pharmacists and general practitioners regarding INN prescribing. GP's feel few motivation to prescribe by INN and the government has put no imperative demands towards prescribers. Further evaluation of the practicaL feasibility of the current conditions for prescribing and delivering INN prescriptions is needed.

Using a population-based approach to prevent hepatocellular cancer in New South Wales, Australia: effects on health services utilisation

PubMed Central

2010-01-01

Background Australians born in countries where hepatitis B infection is endemic are 6-12 times more likely to develop hepatocellular cancer (HCC) than Australian-born individuals. However, a program of screening, surveillance and treatment of chronic hepatitis B (CHB) in high risk populations could significantly reduce disease progression and death related to end-stage liver disease and HCC. Consequently we are implementing the B Positive pilot project, aiming to optimise the management of CHB in at-risk populations in south-west Sydney. Program participants receive routine care, enhanced disease surveillance or specialist referral, according to their stage of CHB infection, level of viral load and extent of liver injury. In this paper we examine the program's potential impact on health services utilisation in the study area. Methods Estimated numbers of CHB infections were derived from Australian Bureau of Statistics data and applying estimates of HBV prevalence rates from migrants' countries of birth. These figures were entered into a Markov model of disease progression, constructing a hypothetical cohort of Asian-born adults with CHB infection. We calculated the number of participants in different CHB disease states and estimated the numbers of GP and specialist consultations and liver ultrasound examinations the cohort would require annually over the life of the program. Results Assuming a 25% participation rate among the 5,800 local residents estimated to have chronic hepatitis B infection, approximately 750 people would require routine follow up, 260 enhanced disease surveillance and 210 specialist care during the first year after recruitment is completed. This translates into 5 additional appointments per year for each local GP, 25 for each specialist and 420 additional liver ultrasound examinations. Conclusions While the program will not greatly affect the volume of local GP consultations, it will lead to a significant increase in demand for specialist services. New models of CHB care may be required to aid program implementation and up scaling the program will need to factor in additional demands on health care utilisation in areas of high hepatitis B sero-prevalence. PMID:20663140

Artificial Intelligence Techniques for Predicting and Mapping Daily Pan Evaporation

NASA Astrophysics Data System (ADS)

Arunkumar, R.; Jothiprakash, V.; Sharma, Kirty

2017-09-01

In this study, Artificial Intelligence techniques such as Artificial Neural Network (ANN), Model Tree (MT) and Genetic Programming (GP) are used to develop daily pan evaporation time-series (TS) prediction and cause-effect (CE) mapping models. Ten years of observed daily meteorological data such as maximum temperature, minimum temperature, relative humidity, sunshine hours, dew point temperature and pan evaporation are used for developing the models. For each technique, several models are developed by changing the number of inputs and other model parameters. The performance of each model is evaluated using standard statistical measures such as Mean Square Error, Mean Absolute Error, Normalized Mean Square Error and correlation coefficient (R). The results showed that daily TS-GP (4) model predicted better with a correlation coefficient of 0.959 than other TS models. Among various CE models, CE-ANN (6-10-1) resulted better than MT and GP models with a correlation coefficient of 0.881. Because of the complex non-linear inter-relationship among various meteorological variables, CE mapping models could not achieve the performance of TS models. From this study, it was found that GP performs better for recognizing single pattern (time series modelling), whereas ANN is better for modelling multiple patterns (cause-effect modelling) in the data.

Automated design of image operators that detect interest points.

PubMed

Trujillo, Leonardo; Olague, Gustavo

2008-01-01

This work describes how evolutionary computation can be used to synthesize low-level image operators that detect interesting points on digital images. Interest point detection is an essential part of many modern computer vision systems that solve tasks such as object recognition, stereo correspondence, and image indexing, to name but a few. The design of the specialized operators is posed as an optimization/search problem that is solved with genetic programming (GP), a strategy still mostly unexplored by the computer vision community. The proposed approach automatically synthesizes operators that are competitive with state-of-the-art designs, taking into account an operator's geometric stability and the global separability of detected points during fitness evaluation. The GP search space is defined using simple primitive operations that are commonly found in point detectors proposed by the vision community. The experiments described in this paper extend previous results (Trujillo and Olague, 2006a,b) by presenting 15 new operators that were synthesized through the GP-based search. Some of the synthesized operators can be regarded as improved manmade designs because they employ well-known image processing techniques and achieve highly competitive performance. On the other hand, since the GP search also generates what can be considered as unconventional operators for point detection, these results provide a new perspective to feature extraction research.

Upweighting rare favourable alleles increases long-term genetic gain in genomic selection programs.

PubMed

Liu, Huiming; Meuwissen, Theo H E; Sørensen, Anders C; Berg, Peer

2015-03-21

The short-term impact of using different genomic prediction (GP) models in genomic selection has been intensively studied, but their long-term impact is poorly understood. Furthermore, long-term genetic gain of genomic selection is expected to improve by using Jannink's weighting (JW) method, in which rare favourable marker alleles are upweighted in the selection criterion. In this paper, we extend the JW method by including an additional parameter to decrease the emphasis on rare favourable alleles over the time horizon, with the purpose of further improving the long-term genetic gain. We call this new method dynamic weighting (DW). The paper explores the long-term impact of different GP models with or without weighting methods. Different selection criteria were tested by simulating a population of 500 animals with truncation selection of five males and 50 females. Selection criteria included unweighted and weighted genomic estimated breeding values using the JW or DW methods, for which ridge regression (RR) and Bayesian lasso (BL) were used to estimate marker effects. The impacts of these selection criteria were compared under three genetic architectures, i.e. varying numbers of QTL for the trait and for two time horizons of 15 (TH15) or 40 (TH40) generations. For unweighted GP, BL resulted in up to 21.4% higher long-term genetic gain and 23.5% lower rate of inbreeding under TH40 than RR. For weighted GP, DW resulted in 1.3 to 5.5% higher long-term gain compared to unweighted GP. JW, however, showed a 6.8% lower long-term genetic gain relative to unweighted GP when BL was used to estimate the marker effects. Under TH40, both DW and JW obtained significantly higher genetic gain than unweighted GP. With DW, the long-term genetic gain was increased by up to 30.8% relative to unweighted GP, and also increased by 8% relative to JW, although at the expense of a lower short-term gain. Irrespective of the number of QTL simulated, BL is superior to RR in maintaining genetic variance and therefore results in higher long-term genetic gain. Moreover, DW is a promising method with which high long-term genetic gain can be expected within a fixed time frame.

The Shock and Vibration Bulletin. Part 3. Vibration Testing, Instrumentation and Data Analysis, Loads and Environments.

DTIC Science & Technology

1977-09-01

Ibrahim , Old Dominion University, Norfolk, VA and E.C. Mikulcik, _ 9 The University of Calgary, Calgary, Alberta, Canada LABORATORY IDENTIFICATION OF...existed for a shaker control application. We only had to write a "GP DAP " program to make it a calculator-type program. S S. ". Voice: What are the

Models for the Binary Complex of Bacteriophage T4 Gp59 Helicase Loading Protein. GP32 Single-Stranded DNA-Binding Protein and Ternary Complex with Pseudo-Y Junction DNA

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

Hinerman, Jennifer M.; Dignam, J. David; Mueser, Timothy C.

2012-04-05

The bacteriophage T4 gp59 helicase assembly protein (gp59) is required for loading of gp41 replicative helicase onto DNA protected by gp32 single-stranded DNA-binding protein. The gp59 protein recognizes branched DNA structures found at replication and recombination sites. Binding of gp32 protein (full-length and deletion constructs) to gp59 protein measured by isothermal titration calorimetry demonstrates that the gp32 protein C-terminal A-domain is essential for protein-protein interaction in the absence of DNA. Sedimentation velocity experiments with gp59 protein and gp32ΔB protein (an N-terminal B-domain deletion) show that these proteins are monomers but form a 1:1 complex with a dissociation constant comparable withmore » that determined by isothermal titration calorimetry. Small angle x-ray scattering (SAXS) studies indicate that the gp59 protein is a prolate monomer, consistent with the crystal structure and hydrodynamic properties determined from sedimentation velocity experiments. SAXS experiments also demonstrate that gp32ΔB protein is a prolate monomer with an elongated A-domain protruding from the core. Moreover, fitting structures of gp59 protein and the gp32 core into the SAXS-derived molecular envelope supports a model for the gp59 protein-gp32ΔB protein complex. Our earlier work demonstrated that gp59 protein attracts full-length gp32 protein to pseudo-Y junctions. A model of the gp59 protein-DNA complex, modified to accommodate new SAXS data for the binary complex together with mutational analysis of gp59 protein, is presented in the accompanying article (Dolezal, D., Jones, C. E., Lai, X., Brister, J. R., Mueser, T. C., Nossal, N. G., and Hinton, D. M. (2012) J. Biol. Chem. 287, 18596–18607).« less

Improvement of Transmembrane Transport Mechanism Study of Imperatorin on P-Glycoprotein-Mediated Drug Transport.

PubMed

Liao, Zheng-Gen; Tang, Tao; Guan, Xue-Jing; Dong, Wei; Zhang, Jing; Zhao, Guo-Wei; Yang, Ming; Liang, Xin-Li

2016-11-24

P-glycoprotein (P-gp) affects the transport of many drugs; including puerarin and vincristine. Our previous study demonstrated that imperatorin increased the intestinal absorption of puerarin and vincristine by inhibiting P-gp-mediated drug efflux. However; the underlying mechanism was not known. The present study investigated the mechanism by which imperatorin promotes P-gp-mediated drug transport. We used molecular docking to predict the binding force between imperatorin and P-gp and the effect of imperatorin on P-gp activity. P-gp efflux activity and P-gp ATPase activity were measured using a rhodamine 123 (Rh-123) accumulation assay and a Pgp-Glo™ assay; respectively. The fluorescent probe 1,6-diphenyl-1,3,5-hexatriene (DPH) was used to assess cellular membrane fluidity in MDCK-MDR1 cells. Western blotting was used to analyze the effect of imperatorin on P-gp expression; and P-gp mRNA levels were assessed by qRT-PCR. Molecular docking results demonstrated that the binding force between imperatorin and P-gp was much weaker than the force between P-gp and verapamil (a P-gp substrate). Imperatorin activated P-gp ATPase activity; which had a role in the inhibition of P-gp activity. Imperatorin promoted Rh-123 accumulation in MDCK-MDR1 cells and decreased cellular membrane fluidity. Western blotting demonstrated that imperatorin inhibited P-gp expression; and qRT-PCR revealed that imperatorin down-regulated P-gp (MDR1) gene expression. Imperatorin decreased P-gp-mediated drug efflux by inhibiting P-gp activity and the expression of P-gp mRNA and protein. Our results suggest that imperatorin could down-regulate P-gp expression to overcome multidrug resistance in tumors.

The glycan-mediated mechanism on the interactions of gp120 with CD4 and antibody: Insights from molecular dynamics simulation.

PubMed

Zhang, Yan; Niu, Yuzhen; Tian, Jiaqi; Liu, Xuewei; Yao, Xiaojun; Liu, Huanxiang

2017-12-01

N-linked glycans such as 234 and 276 gp 120 glycans are vital components of HIV evasion from humoral immunity and important for HIV-1 neutralization of many broadly neutralizing antibodies (bNAbs). However, it is unknown the action mechanism of two glycans. To investigate the roles of the glycans on the interactions of gp120 with CD4 and antibody, molecular dynamic simulations based on gp120-CD4-8ANC195 complex with 234 and 276 gp 120 glycans, 234 gp 120 glycan, 276 gp 120 glycan, and without glycan were performed. Our results reveal that 276 gp 120 glycan can enhance gp120-CD4 and gp120-antibody interactions through the formation of hydrogen bonds of the glycan with CD4 and antibody and make the binding interface of gp120, CD4 and antibody stable; 234 gp 120 glycan primarily reinforces gp120-antibody interactions and weakly affects gp120-CD4 interactions as it mainly lies between gp120 and antibody. The co-operating of two glycans can enhance gp120-CD4 and gp120-antibody associations. Through the structural analysis, it can be seen that 234 gp 120 glycan leads to moving upward of two glycans and the variable region of heavy chain, which is favorable for the interactions of gp120 with CD4 and antibody. The information obtained in this study can provide the guidance for design vaccines and small molecule inhibitors. © 2017 John Wiley & Sons A/S.

Effective Strategies to Recruit Young Adults Into the TXT2BFiT mHealth Randomized Controlled Trial for Weight Gain Prevention

PubMed Central

Balestracci, Kate; Wong, Annette TY; Hebden, Lana; McGeechan, Kevin; Denney-Wilson, Elizabeth; Harris, Mark F; Phongsavan, Philayrath; Bauman, Adrian; Allman-Farinelli, Margaret

2015-01-01

Background Younger adults are difficult to engage in preventive health, yet in Australia they are gaining more weight and increasing in waist circumference faster than middle-to-older adults. A further challenge to engaging 18- to 35-year-olds in interventions is the limited reporting of outcomes of recruitment strategies. Objective This paper describes the outcomes of strategies used to recruit young adults to a randomized controlled trial (RCT), healthy lifestyle mHealth program, TXT2BFiT, for prevention of weight gain. The progression from enquiry through eligibility check to randomization into the trial and the costs of recruitment strategies are reported. Factors associated with nonparticipation are explored. Methods Participants were recruited either via letters of invitation from general practitioners (GPs) or via electronic or print advertisements, including Facebook and Google—social media and advertising—university electronic newsletters, printed posters, mailbox drops, and newspapers. Participants recruited from GP invitation letters had an appointment booked with their GP for eligibility screening. Those recruited from other methods were sent an information pack to seek approval to participate from their own GP. The total number and source of enquiries were categorized according to eligibility and subsequent completion of steps to enrolment. Cost data and details of recruitment strategies were recorded. Results From 1181 enquiries in total from all strategies, 250 (21.17%) participants were randomized. A total of 5311 invitation letters were sent from 12 GP practices—16 participating GPs. A total of 131 patients enquired with 68 participants randomized (68/74 of those eligible, 92%). The other recruitment methods yielded the remaining 182 randomized participants. Enrolment from print media was 26% of enquiries, from electronic media was 20%, and from other methods was 3%. Across all strategies the average cost of recruitment was Australian Dollar (AUD) $139 per person. The least expensive modality was electronic (AUD $37), largely due to a free feature story on one university Web home page, despite Facebook advertising costing AUD $945 per enrolment. The most expensive was print media at AUD $213 and GP letters at AUD $145 per enrolment. Conclusions The research indicated that free electronic media was the most cost-effective strategy, with GP letters the least expensive of the paid strategies in comparison to the other strategies. This study is an important contribution for future research into efficacy, translation, and implementation of cost-effective programs for the prevention of weight gain in young adults. Procedural frameworks for recruitment protocols are required, along with systematic reporting of recruitment strategies to reduce unnecessary expenditure and allow for valuable public health prevention programs to go beyond the research setting. Trial Registration Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12612000924853; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=362872 (Archived by WebCite at http://www.webcitation.org/6YpNfv1gI). PMID:26048581

Effective Strategies to Recruit Young Adults Into the TXT2BFiT mHealth Randomized Controlled Trial for Weight Gain Prevention.

PubMed

Partridge, Stephanie R; Balestracci, Kate; Wong, Annette Ty; Hebden, Lana; McGeechan, Kevin; Denney-Wilson, Elizabeth; Harris, Mark F; Phongsavan, Philayrath; Bauman, Adrian; Allman-Farinelli, Margaret

2015-06-05

Younger adults are difficult to engage in preventive health, yet in Australia they are gaining more weight and increasing in waist circumference faster than middle-to-older adults. A further challenge to engaging 18- to 35-year-olds in interventions is the limited reporting of outcomes of recruitment strategies. This paper describes the outcomes of strategies used to recruit young adults to a randomized controlled trial (RCT), healthy lifestyle mHealth program, TXT2BFiT, for prevention of weight gain. The progression from enquiry through eligibility check to randomization into the trial and the costs of recruitment strategies are reported. Factors associated with nonparticipation are explored. Participants were recruited either via letters of invitation from general practitioners (GPs) or via electronic or print advertisements, including Facebook and Google-social media and advertising-university electronic newsletters, printed posters, mailbox drops, and newspapers. Participants recruited from GP invitation letters had an appointment booked with their GP for eligibility screening. Those recruited from other methods were sent an information pack to seek approval to participate from their own GP. The total number and source of enquiries were categorized according to eligibility and subsequent completion of steps to enrolment. Cost data and details of recruitment strategies were recorded. From 1181 enquiries in total from all strategies, 250 (21.17%) participants were randomized. A total of 5311 invitation letters were sent from 12 GP practices-16 participating GPs. A total of 131 patients enquired with 68 participants randomized (68/74 of those eligible, 92%). The other recruitment methods yielded the remaining 182 randomized participants. Enrolment from print media was 26% of enquiries, from electronic media was 20%, and from other methods was 3%. Across all strategies the average cost of recruitment was Australian Dollar (AUD) $139 per person. The least expensive modality was electronic (AUD $37), largely due to a free feature story on one university Web home page, despite Facebook advertising costing AUD $945 per enrolment. The most expensive was print media at AUD $213 and GP letters at AUD $145 per enrolment. The research indicated that free electronic media was the most cost-effective strategy, with GP letters the least expensive of the paid strategies in comparison to the other strategies. This study is an important contribution for future research into efficacy, translation, and implementation of cost-effective programs for the prevention of weight gain in young adults. Procedural frameworks for recruitment protocols are required, along with systematic reporting of recruitment strategies to reduce unnecessary expenditure and allow for valuable public health prevention programs to go beyond the research setting. Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12612000924853; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=362872 (Archived by WebCite at http://www.webcitation.org/6YpNfv1gI).

Gastric Polyp Growth during Endoscopic Surveillance for Esophageal Varices or Barrett's Esophagus.

PubMed

Livovsky, Dan M; Pappo, Orit; Skarzhinsky, Galina; Peretz, Asaf; Turvall, Elliot; Ackerman, Zvi

2016-05-01

We recently observed patients with chronic liver disease (CLD) or chronic reflux symptoms (CRS) who developed gastric polyps (GPs) while undergoing surveillance gastroscopies for the detection of esophageal varices or Barrett's esophagus, respectively. To identify risk factors for GP growth and estimate its growth rate. GP growth rate was defined as the number of days since the first gastroscopy (without polyps) in the surveillance program, until the gastroscopy when a GP was discovered. Gastric polyp growth rates in CLD and CRS patients were similar. However, hyperplastic gastric polyps (HGPs) were detected more often (87.5% vs. 60.5%, P = 0.051) and at a higher number (2.57 ± 1.33 vs. 1.65 ± 0.93, P = 0.021) in the CLD patients. Subgroup analysis revealed the following findings only in CLD patients with HGPs: (i) a positive correlation between the GP growth rate and the patient's age; the older the patient, the higher the GP growth rate (r = 0.7, P = 0.004). (ii) A negative correlation between the patient's age and the Ki-67 proliferation index value; the older the patient, the lower the Ki-67 value (r = -0.64, P = 0.02). No correlation was detected between Ki-67 values of HGPs in CLD patients and the presence of portal hypertension, infection with Helicobacter pylori, or proton pump inhibitor use. In comparison with CRS patients, CLD patients developed HGPs more often and at a greater number. Young CLD patients may have a tendency to develop HGPs at a faster rate than elderly CLD patients.

Correlation between structure, protein composition, morphogenesis and cytopathology of Glossina pallidipes salivary gland hypertrophy virus.

PubMed

Kariithi, Henry M; van Lent, Jan W M; Boeren, Sjef; Abd-Alla, Adly M M; Ince, Ikbal Agah; van Oers, Monique M; Vlak, Just M

2013-01-01

The Glossina pallidipes salivary gland hypertrophy virus (GpSGHV) is a dsDNA virus with rod-shaped, enveloped virions. Its 190 kb genome contains 160 putative protein-coding ORFs. Here, the structural components, protein composition and associated aspects of GpSGHV morphogenesis and cytopathology were investigated. Four morphologically distinct structures: the nucleocapsid, tegument, envelope and helical surface projections, were observed in purified GpSGHV virions by electron microscopy. Nucleocapsids were present in virogenic stroma within the nuclei of infected salivary gland cells, whereas enveloped virions were located in the cytoplasm. The cytoplasm of infected cells appeared disordered and the plasma membranes disintegrated. Treatment of virions with 1 % NP-40 efficiently partitioned the virions into envelope and nucleocapsid fractions. The fractions were separated by SDS-PAGE followed by in-gel trypsin digestion and analysis of the tryptic peptides by liquid chromatography coupled to electrospray and tandem mass spectrometry. Using the MaxQuant program with Andromeda as a database search engine, a total of 45 viral proteins were identified. Of these, ten and 15 were associated with the envelope and the nucleocapsid fractions, respectively, whilst 20 were detected in both fractions, most likely representing tegument proteins. In addition, 51 host-derived proteins were identified in the proteome of the virus particle, 13 of which were verified to be incorporated into the mature virion using a proteinase K protection assay. This study provides important information about GpSGHV biology and suggests options for the development of future anti-GpSGHV strategies by interfering with virus-host interactions.

The structure of brain glycogen phosphorylase-from allosteric regulation mechanisms to clinical perspectives.

PubMed

Mathieu, Cécile; Dupret, Jean-Marie; Rodrigues Lima, Fernando

2017-02-01

Glycogen phosphorylase (GP) is the key enzyme that regulates glycogen mobilization in cells. GP is a complex allosteric enzyme that comprises a family of three isozymes: muscle GP (mGP), liver GP (lGP), and brain GP (bGP). Although the three isozymes display high similarity and catalyze the same reaction, they differ in their sensitivity to the allosteric activator adenosine monophosphate (AMP). Moreover, inactivating mutations in mGP and lGP have been known to be associated with glycogen storage diseases (McArdle and Hers disease, respectively). The determination, decades ago, of the structure of mGP and lGP have allowed to better understand the allosteric regulation of these two isoforms and the development of specific inhibitors. Despite its important role in brain glycogen metabolism, the structure of the brain GP had remained elusive. Here, we provide an overview of the human brain GP structure and its relationship with the two other members of this key family of the metabolic enzymes. We also summarize how this structure provides valuable information to understand the regulation of bGP and to design specific ligands of potential pharmacological interest. © 2016 Federation of European Biochemical Societies.

Prediction of cancer class with majority voting genetic programming classifier using gene expression data.

PubMed

Paul, Topon Kumar; Iba, Hitoshi

2009-01-01

In order to get a better understanding of different types of cancers and to find the possible biomarkers for diseases, recently, many researchers are analyzing the gene expression data using various machine learning techniques. However, due to a very small number of training samples compared to the huge number of genes and class imbalance, most of these methods suffer from overfitting. In this paper, we present a majority voting genetic programming classifier (MVGPC) for the classification of microarray data. Instead of a single rule or a single set of rules, we evolve multiple rules with genetic programming (GP) and then apply those rules to test samples to determine their labels with majority voting technique. By performing experiments on four different public cancer data sets, including multiclass data sets, we have found that the test accuracies of MVGPC are better than those of other methods, including AdaBoost with GP. Moreover, some of the more frequently occurring genes in the classification rules are known to be associated with the types of cancers being studied in this paper.

Recognition of similar epitopes on varicella-zoster virus gpI and gpIV by monoclonal antibodies.

PubMed Central

Vafai, A; Wroblewska, Z; Mahalingam, R; Cabirac, G; Wellish, M; Cisco, M; Gilden, D

1988-01-01

Two monoclonal antibodies, MAb43.2 and MAb79.0, prepared against varicella-zoster virus (VZV) proteins were selected to analyze VZV gpIV and gpI, respectively. MAb43.2 reacted only with cytoplasmic antigens, whereas MAb79.0 recognized both cytoplasmic and membrane antigens in VZV-infected cells. Immunoprecipitation of in vitro translation products with MAb43.2 revealed only proteins encoded by the gpIV gene, whereas MAb79.0 precipitated proteins encoded by the gpIV and gpI genes. Pulse-chase analysis followed by immunoprecipitation of VZV-infected cells indicated reactivity of MAb43.2 with three phosphorylated precursor species of gpIV and reactivity of MAb79.0 with the precursor and mature forms of gpI and gpIV. These results indicated that (i) MAb43.2 and MAb79.0 recognize different epitopes on VZV gpIV, (ii) glycosylation of gpIV ablates recognition by MAb43.2, and (iii) gpIV is phosphorylated. To map the binding site of MAb79.0 on gpI, the pGEM transcription vector, containing the coding region of the gpI gene, was linearized, and three truncated gpI DNA fragments were generated. RNA was transcribed from each truncated fragment by using SP6 RNA polymerase, translated in vitro in a rabbit reticulocyte lysate, and immunoprecipitated with MAb79.0 and human sera. The results revealed the existence of an antibody-binding site within 14 amino acid residues located between residues 109 to 123 on the predicted amino acid sequences of gpI. From the predicted amino acid sequences, 14 residues on gpI (residues 107 to 121) displayed a degree of similarity (36%) to two regions (residues 55 to 69 and 245 to 259) of gp IV. Such similarities may account for the binding of MAb79.0 to both VZV gpI and gpIV. Images PMID:2455814

Solid dispersions in the development of a nimodipine floating tablet formulation and optimization by artificial neural networks and genetic programming.

PubMed

Barmpalexis, Panagiotis; Kachrimanis, Kyriakos; Georgarakis, Emanouil

2011-01-01

The present study investigates the use of nimodipine-polyethylene glycol solid dispersions for the development of effervescent controlled release floating tablet formulations. The physical state of the dispersed nimodipine in the polymer matrix was characterized by differential scanning calorimetry, powder X-ray diffraction, FT-IR spectroscopy and polarized light microscopy, and the mixture proportions of polyethylene glycol (PEG), polyvinyl-pyrrolidone (PVP), hydroxypropylmethylcellulose (HPMC), effervescent agents (EFF) and nimodipine were optimized in relation to drug release (% release at 60 min, and time at which the 90% of the drug was dissolved) and floating properties (tablet's floating strength and duration), employing a 25-run D-optimal mixture design combined with artificial neural networks (ANNs) and genetic programming (GP). It was found that nimodipine exists as mod I microcrystals in the solid dispersions and is stable for at least a three-month period. The tablets showed good floating properties and controlled release profiles, with drug release proceeding via the concomitant operation of swelling and erosion of the polymer matrix. ANNs and GP both proved to be efficient tools in the optimization of the tablet formulation, and the global optimum formulation suggested by the GP equations consisted of PEG=9%, PVP=30%, HPMC=36%, EFF=11%, nimodipine=14%. Copyright © 2010 Elsevier B.V. All rights reserved.

Development of GP and GEP models to estimate an environmental issue induced by blasting operation.

PubMed

Faradonbeh, Roohollah Shirani; Hasanipanah, Mahdi; Amnieh, Hassan Bakhshandeh; Armaghani, Danial Jahed; Monjezi, Masoud

2018-05-21

Air overpressure (AOp) is one of the most adverse effects induced by blasting in the surface mines and civil projects. So, proper evaluation and estimation of the AOp is important for minimizing the environmental problems resulting from blasting. The main aim of this study is to estimate AOp produced by blasting operation in Miduk copper mine, Iran, developing two artificial intelligence models, i.e., genetic programming (GP) and gene expression programming (GEP). Then, the accuracy of the GP and GEP models has been compared to multiple linear regression (MLR) and three empirical models. For this purpose, 92 blasting events were investigated, and subsequently, the AOp values were carefully measured. Moreover, in each operation, the values of maximum charge per delay and distance from blast points, as two effective parameters on the AOp, were measured. After predicting by the predictive models, their performance prediction was checked in terms of variance account for (VAF), coefficient of determination (CoD), and root mean square error (RMSE). Finally, it was found that the GEP with VAF of 94.12%, CoD of 0.941, and RMSE of 0.06 is a more precise model than other predictive models for the AOp prediction in the Miduk copper mine, and it can be introduced as a new powerful tool for estimating the AOp resulting from blasting.

A critical incident study of general practice trainees in their basic general practice term.

PubMed

Diamond, M R; Kamien, M; Sim, M G; Davis, J

1995-03-20

To obtain information on the experiences of general practice (GP) trainees during their first general practice (GP) attachment. Critical incident technique--a qualitative analysis of open-ended interviews about incidents which describe competent or poor professional practice. Thirty-nine Western Australian doctors from the Royal Australian College of General Practitioners' (RACGP) Family Medicine Program who were completing their first six months of general practice in 1992. Doctors reported 180 critical incidents, of which just over 50% involved problems (and sometimes successes) with: difficult patients; paediatrics; the doctor-patient relationship; counselling skills; obstetrics and gynaecology; relationships with other health professionals and practice staff; and cardiovascular disorders. The major skills associated with both positive and negative critical incidents were: the interpersonal skills of rapport and listening; the diagnostic skills of thorough clinical assessment and the appropriate use of investigations; and the management skills of knowing when and how to obtain help from supervisors, hospitals and specialists. Doctors reported high levels of anxiety over difficult management decisions and feelings of guilt over missed diagnoses and inadequate management. The initial GP term is a crucial transition period in the development of the future general practitioner. An analysis of commonly recurring positive and negative critical incidents can be used by the RACGP Training Program to accelerate the learning process of doctors in vocational training and has implications for the planning of undergraduate curricula.

In vitro evaluation of microleakage under a glass ionomer surface protector cement after different enamel treatment procedures.

PubMed

Haznedaroglu, Eda; Mentes, Ali R; Tanboga, Iknur

2012-03-01

The aim of this in vitrostudy was to evaluate the microleakage of a glass-ionomer surface-protector cement (GC Fuji Triage) placed onto the fissure surfaces of extracted human molars prepared using six different treatment procedures. Ninety-six extracted non-carious human molar teeth were divided into five enamel treatment groups: (Gp1) air-abraded (Micadent II, Medidenta); (Gp2) air-abraded and conditioned with 10% polyacrylic acid (GC dentin conditioner); (Gp3) prepared by a bur designed for enameloplasty (#8833 Komet); (Gp4) prepared with a bur and conditioned; (Gp5) conditioned; and (Gp6) no treatment (control). The teeth were then sealed with GC Fuji Triage. The teeth were thermocycled and left in distilled water or artificial saliva for one week, coated twice with nail varnish, and stained in a dye. They were sectioned and scored for microleakage. All groups showed microleakage. Samples that were kept in saliva had better results than those that were kept in distilled water (P<0.05). Samples conditioned before the treatment were also better than non-conditioned groups (P<0.05). In distilled water and artificial saliva, the range of the groups was, from the best, Gp2

The Genital Tract Virulence Factor pGP3 Is Essential for Chlamydia muridarum Colonization in the Gastrointestinal Tract.

PubMed

Shao, Lili; Zhang, Tianyuan; Melero, Jose; Huang, Yumeng; Liu, Yuanjun; Liu, Quanzhong; He, Cheng; Nelson, David E; Zhong, Guangming

2018-01-01

The cryptic plasmid is essential for Chlamydia muridarum dissemination from the genital tract to the gastrointestinal (GI) tract. Following intravaginal inoculation, a C. muridarum strain deficient in plasmid-encoded pGP3 or pGP4 but not pGP5, pGP7, or pGP8 failed to spread to the mouse gastrointestinal tract, although mice infected with these strains developed productive genital tract infections. pGP3- or pGP4-deficient strains also failed to colonize the gastrointestinal tract when delivered intragastrically. pGP4 regulates pGP3, while pGP3 does not affect pGP4 expression, indicating that pGP3 is critical for C. muridarum colonization of the gastrointestinal tract. Mutants deficient in GlgA, a chromosome-encoded protein regulated by pGP4, also consistently colonized the mouse gastrointestinal tract. Interestingly, C. muridarum colonization of the gastrointestinal tract positively correlated with pathogenicity in the upper genital tract. pGP3-deficient C. muridarum strains did not induce hydrosalpinx or spread to the GI tract even when delivered to the oviduct by intrabursal inoculation. Thus, the current study not only has revealed that pGP3 is a novel chlamydial colonization factor in the gastrointestinal tract but also has laid a foundation for investigating the significance of gastrointestinal Chlamydia . Copyright © 2017 American Society for Microbiology.

Identification and characterization of calcium transporter gene family in finger millet in relation to grain calcium content.

PubMed

Singh, Uma M; Metwal, Mamta; Singh, Manoj; Taj, Gohar; Kumar, Anil

2015-07-15

Calcium (Ca) is an essential mineral for proper growth and development of plants as well as animals. In plants including cereals, calcium is deposited in seed during its development which is mediated by specialized Ca transporters. Common cereal seeds contain very low amounts of Ca while the finger millet (Eleusine coracana) contains exceptionally high amounts of Ca in seed. In order to understand the role of Ca transporters in grain Ca accumulation, developing seed transcriptome of two finger millet genotypes (GP-1, low Ca and GP-45 high Ca) differing in seed Ca content was sequenced using Illumina paired-end sequencing technology and members of Ca transporter gene family were identified. Out of 109,218 and 120,130 contigs, 86 and 81 contigs encoding Ca transporters were identified in GP-1 and GP-45, respectively. After removal of redundant sequences, a total of 19 sequences were confirmed as Ca transporter genes, which includes 11 Ca(2+) ATPases, 07 Ca(2+)/cation exchangers and 01 Ca(2+) channel. The differential expressions of all genes were analyzed from transcriptome data and it was observed that 9 and 3 genes were highly expressed in GP-45 and GP-1 genotypes respectively. Validation of transcriptome expression data of selected Ca transporter genes was performed on different stages of developing spikes of both genotypes grown under different concentrations of exogenous Ca. In both genotypes, significant correlation was observed between the expression of these genes, especially EcCaX3, and on the amount of Ca accumulated in seed. The positive correlation of seed mass with the amount of Ca concentration was also observed. The efficient Ca transport property and responsiveness of EcCAX3 towards exogenous Ca could be utilized in future biofortification program. Copyright © 2015 Elsevier B.V. All rights reserved.

Registration of Seven Sugarbeet Germplasms Selected from Crosses between Cultivated Sugarbeet and Wild Beta Species

USDA-ARS?s Scientific Manuscript database

Seven sugarbeet (Beta vulgaris L.) germplasm lines, F1017 (GP-xxx, PIxxxxxx), F1018 (GP-xxx, PIxxxxxx), F1019 (GP-xxx, PIxxxxxx), F1020 (GP-xxx, PIxxxxxx), F1021 (GP-xxx, PIxxxxxx), F1022 (GP-xxx, PIxxxxxx), and F1023 (GP-xxx, PIxxxxxx) were released 23 February 2009 by the USDA-ARS and the North Da...

Evolving rule-based systems in two medical domains using genetic programming.

PubMed

Tsakonas, Athanasios; Dounias, Georgios; Jantzen, Jan; Axer, Hubertus; Bjerregaard, Beth; von Keyserlingk, Diedrich Graf

2004-11-01

To demonstrate and compare the application of different genetic programming (GP) based intelligent methodologies for the construction of rule-based systems in two medical domains: the diagnosis of aphasia's subtypes and the classification of pap-smear examinations. Past data representing (a) successful diagnosis of aphasia's subtypes from collaborating medical experts through a free interview per patient, and (b) correctly classified smears (images of cells) by cyto-technologists, previously stained using the Papanicolaou method. Initially a hybrid approach is proposed, which combines standard genetic programming and heuristic hierarchical crisp rule-base construction. Then, genetic programming for the production of crisp rule based systems is attempted. Finally, another hybrid intelligent model is composed by a grammar driven genetic programming system for the generation of fuzzy rule-based systems. Results denote the effectiveness of the proposed systems, while they are also compared for their efficiency, accuracy and comprehensibility, to those of an inductive machine learning approach as well as to those of a standard genetic programming symbolic expression approach. The proposed GP-based intelligent methodologies are able to produce accurate and comprehensible results for medical experts performing competitive to other intelligent approaches. The aim of the authors was the production of accurate but also sensible decision rules that could potentially help medical doctors to extract conclusions, even at the expense of a higher classification score achievement.

Comparative cellular processing of the human immunodeficiency virus (HIV-1) envelope glycoprotein gp160 by the mammalian subtilisin/kexin-like convertases.

PubMed

Vollenweider, F; Benjannet, S; Decroly, E; Savaria, D; Lazure, C; Thomas, G; Chrétien, M; Seidah, N G

1996-03-01

We present here the pulse and pulse-chase analysis of the biosynthesis of the envelope glycoprotein gp160 and its intracellular processing by the subtilisin/kexin-like convertases furin, PACE4, PC1, PC5 and its isoform PC5/6-B. We demonstrate that furin and to a much lesser extent PACE4, PC5/6-B and PC1 are candidate enzymes capable of processing gp160 intracellularly. Furthermore we show that furin can also process gp160/gp120 into gp77/gp53 products by cleavage at the sequence RIQR/GPGR just preceding the conserved GPGR structure found at the tip of the hypervariable V3 loop. The results show that processing into gp120 could occur at or before the trans-Golgi network (TGN) where sulphation of the oligosaccharide moieties of gp160 was detected. In contrast, the formation of gp77/gp53 by furin is a late event occurring after exit from the TGN. Our data also revealed that the alpha glucosidase I inhibitor N-butyldeoxynojirimycin, although affecting the oligosaccharide composition of gp160, does not impair the processing of either gp160 or gp120 by either furin or PACE4. Finally, the co-expression of the [Arg355, Arg358]-alpha-1-antitrypsin Portland variant was shown to potently inhibit the processing of both gp160 and gp120 by these convertases.

Refinements to the Graves and Pitarka (2010) Broadband Ground Motion Simulation Method

USGS Publications Warehouse

Graves, Robert; Arben Pitarka,

2015-01-01

This brief article describes refinements to the Graves and Pitarka (2010) broadband ground motion simulation methodology (GP2010 hereafter) that have been implemented in version 14.3 of the SCEC Broadband Platform (BBP). The updated version of our method on the current SCEC BBP is referred to as GP14.3. Our simulation technique is a hybrid approach that combines low-­‐frequency and high-­‐frequency motions computed with different methods into a single broadband response. The separate low-­‐ and high-­‐frequency components have traditionally been called “deterministic” and “stochastic”, respectively; however, this nomenclature is an oversimplification. In reality, the low-­‐frequency approach includes many stochastic elements, and likewise, the high-­‐frequency approach includes many deterministic elements (e.g., Pulido and Kubo, 2004; Hartzell et al., 2005; Liu et al., 2006; Frankel, 2009; Graves and Pitarka, 2010; Mai et al., 2010). While the traditional terminology will likely remain in use by the broader modeling community, in this paper we will refer to these using the generic terminology “low-­‐frequency” and “high-­‐ frequency” approaches. Furthermore, one of the primary goals in refining our methodology is to provide a smoother and more consistent transition between the low-­‐ and high-­‐ frequency calculations, with the ultimate objective being the development of a single unified modeling approach that can be applied over a broad frequency band. GP2010 was validated by modeling recorded strong motions from four California earthquakes. While the method performed well overall, several issues were identified including the tendency to over-­‐predict the level of longer period (2-­‐5 sec) motions and the effects of rupture directivity. The refinements incorporated in GP14.3 are aimed at addressing these issues with application to the simulation of earthquakes in Western US (WUS). These refinements include the addition of a deep weak zone (details in following section) to the rupture characterization and allowing perturbations in the correlation of rise time and rupture speed with the specified slip distribution. Additionally, we have extended the parameterization of GP14.3 so that it is also applicable for simulating Eastern North America (ENA) earthquakes. This work has been guided by the comprehensive set of validation studies described in Goulet and Abrahamson (2014) and Dreger et al. (2014). The GP14.3 method shows improved performance relative to GP2010, and we direct the interested reader to Dreger et al. (2014) for a detailed assessment of the current methodology. In this paper, we concentrate on describing the modifications in more detail, and also discussing additional refinements that are currently being developed.

Evaluation of P-Glycoprotein Inhibitory Potential Using a Rhodamine 123 Accumulation Assay

PubMed Central

Jouan, Elodie; Le Vée, Marc; Mayati, Abdullah; Denizot, Claire; Parmentier, Yannick; Fardel, Olivier

2016-01-01

In vitro evaluation of P-glycoprotein (P-gp) inhibitory potential is now a regulatory issue during drug development, in order to predict clinical inhibition of P-gp and subsequent drug–drug interactions. Assays for this purpose, commonly based on P-gp-expressing cell lines and digoxin as a reference P-gp substrate probe, unfortunately exhibit high variability, raising thus the question of developing alternative or complementary tests for measuring inhibition of P-gp activity. In this context, the present study was designed to investigate the use of the fluorescent dye rhodamine 123 as a reference P-gp substrate probe for characterizing P-gp inhibitory potential of 16 structurally-unrelated drugs known to interact with P-gp. 14/16 of these P-gp inhibitors were found to increase rhodamine 123 accumulation in P-gp-overexpressing MCF7R cells, thus allowing the determination of their P-gp inhibitory potential, i.e., their half maximal inhibitor concentration (IC50) value towards P-gp-mediated transport of the dye. These IC50 values were in the range of variability of previously reported IC50 for P-gp and can be used for the prediction of clinical P-gp inhibition according to Food and Drug Administration (FDA) criteria, with notable sensitivity (80%). Therefore, the data demonstrated the feasibility of the use of rhodamine 123 for evaluating the P-gp inhibitory potential of drugs. PMID:27077878

Protective effects of naringin against gp120-induced injury mediated by P2X7 receptors in BV2 microglial cells.

PubMed

Chen, Q; Hu, J; Qin, S S; Liu, C L; Wu, H; Wang, J R; Lu, X M; Wang, J; Chen, G Q; Liu, Y; Liu, B Y; Xu, C S; Liang, S D

2016-05-13

This study was aimed at exploring the effects of P2X7 receptors on gp120-induced injury and naringin's protective effects against gp120-induced injury in BV2 microglia. BV2 microglia injury model was established by gp120 treatment and MTS assay was used to verify whether naringin has a cell-protective effect against gp120-induced injury. Changes in P2X7 receptor expression were assayed using RT-PCR, qPCR, and western blot. Results showed that the ODs of the Ctrl, gp120, gp120+naringin, and gp120+BBG groups were 0.91 ± 0.10, 0.71 ± 0.09, 0.83 ± 0.10, and 0.83 ± 0.10, respectively. Compared to the control group, the gp120 group showed a significantly decreased cell survival rate. Cell survival rates of the gp120+naringin group increased significantly compared to those of the gp120 group, while no difference was observed when compared to the gp120+BBG group. The relative P2X7 mRNA expression levels in the Ctrl, gp120, gp120+naringin, and gp120+BBG groups were 0.73 ± 0.06, 1.05 ± 0.06, 0.78 ± 0.05, and 0.81 ± 0.04, respectively. The corresponding P2X7 protein expression levels were 0.46 ± 0.04, 0.79 ± 0.04, 0.38 ± 0.07, and 0.42 ± 0.06. P2X7 mRNA and protein expression in the gp120 group increased significantly compared to those in the control group, and declined in the gp120+naringin group compared to those in the gp120 group. Therefore, P2X7 receptors might be involved in gp120-induced injury in BV2 microglia, and naringin might play a protective role by inhibiting the up-regulated expression of P2X7 receptors.

LEDS Global Partnership in Action: Advancing Climate-Resilient Low Emission Development Around the World (Fact Sheet)

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

Not Available

2013-11-01

Many countries around the globe are designing and implementing low emission development strategies (LEDS). These LEDS seek to achieve social, economic, and environmental development goals while reducing long-term greenhouse gas (GHG) emissions and increasing resiliency to climate change impacts. The LEDS Global Partnership (LEDS GP) harnesses the collective knowledge and resources of more than 120 countries and international donor and technical organizations to strengthen climate-resilient low emission development efforts around the world.

Registration of eight six-rowed feed barley germplasm lines resistant to both Russian wheat aphid and greenbug

USDA-ARS?s Scientific Manuscript database

STARS 1006B (Reg. No. GP- , PI 659760), STARS 1007B (Reg. No. GP- , PI 659761), STARS 1008B (Reg. No. GP- , PI 659762), STARS 1009B (Reg. No. GP- , PI 659763), STARS 1010B (Reg. No. GP- , PI 659764), STARS 1011B (Reg. No. GP- , PI 659765), STARS 1012B (Reg. No. GP- , PI 659766), and STARS 1013B (Reg...

A single amino acid substitution modulates low-pH-triggered membrane fusion of GP64 protein in Autographa californica and Bombyx mori nucleopolyhedroviruses

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

Katou, Yasuhiro; Yamada, Hayato; Ikeda, Motoko

2010-09-01

We have previously shown that budded viruses of Bombyx mori nucleopolyhedrovirus (BmNPV) enter the cell cytoplasm but do not migrate into the nuclei of non-permissive Sf9 cells that support a high titer of Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV) multiplication. Here we show, using the syncytium formation assay, that low-pH-triggered membrane fusion of BmNPV GP64 protein (Bm-GP64) is significantly lower than that of AcMNPV GP64 protein (Ac-GP64). Mutational analyses of GP64 proteins revealed that a single amino acid substitution between Ac-GP64 H155 and Bm-GP64 Y153 can have significant positive or negative effects on membrane fusion activity. Studies using bacmid-based GP64 recombinantmore » AcMNPV harboring point-mutated ac-gp64 and bm-gp64 genes showed that Ac-GP64 H155Y and Bm-GP64 Y153H substitutions decreased and increased, respectively, the multiplication and cell-to-cell spread of progeny viruses. These results indicate that Ac-GP64 H155 facilitates the low-pH-triggered membrane fusion reaction between virus envelopes and endosomal membranes.« less

Structure of HIV-1 gp120 with gp41-interactive region reveals layered envelope architecture and basis of conformational mobility

PubMed Central

Pancera, Marie; Majeed, Shahzad; Ban, Yih-En Andrew; Chen, Lei; Huang, Chih-chin; Kong, Leopold; Stuckey, Jonathan; Zhou, Tongqing; Robinson, James E.; Schief, William R.; Sodroski, Joseph; Wyatt, Richard; Kwong, Peter D.

2009-01-01

The viral spike of HIV-1 is composed of three gp120 envelope glycoproteins attached noncovalently to three gp41 transmembrane molecules. Viral entry is initiated by binding to the CD4 receptor on the cell surface, which induces large conformational changes in gp120. These changes not only provide a model for receptor-triggered entry, but affect spike sensitivity to drug- and antibody-mediated neutralization. Although some of the details of the CD4-induced conformational change have been visualized by crystal structures and cryoelectron tomograms, the critical gp41-interactive region of gp120 was missing from previous atomic-level characterizations. Here we determine the crystal structure of an HIV-1 gp120 core with intact gp41-interactive region in its CD4-bound state, compare this structure to unliganded and antibody-bound forms to identify structurally invariant and plastic components, and use ligand-oriented cryoelectron tomograms to define component mobility in the viral spike context. Newly defined gp120 elements proximal to the gp41 interface complete a 7-stranded β-sandwich, which appeared invariant in conformation. Loop excursions emanating from the sandwich form three topologically separate—and structurally plastic—layers, topped off by the highly glycosylated gp120 outer domain. Crystal structures, cryoelectron tomograms, and interlayer chemistry were consistent with a mechanism in which the layers act as a shape-changing spacer, facilitating movement between outer domain and gp41-associated β-sandwich and providing for conformational diversity used in immune evasion. A “layered” gp120 architecture thus allows movement among alternative glycoprotein conformations required for virus entry and immune evasion, whereas a β-sandwich clamp maintains gp120–gp41 interaction and regulates gp41 transitions. PMID:20080564

Structure of HIV-1 gp120 with gp41-interactive region reveals layered envelope architecture and basis of conformational mobility.

PubMed

Pancera, Marie; Majeed, Shahzad; Ban, Yih-En Andrew; Chen, Lei; Huang, Chih-chin; Kong, Leopold; Kwon, Young Do; Stuckey, Jonathan; Zhou, Tongqing; Robinson, James E; Schief, William R; Sodroski, Joseph; Wyatt, Richard; Kwong, Peter D

2010-01-19

The viral spike of HIV-1 is composed of three gp120 envelope glycoproteins attached noncovalently to three gp41 transmembrane molecules. Viral entry is initiated by binding to the CD4 receptor on the cell surface, which induces large conformational changes in gp120. These changes not only provide a model for receptor-triggered entry, but affect spike sensitivity to drug- and antibody-mediated neutralization. Although some of the details of the CD4-induced conformational change have been visualized by crystal structures and cryoelectron tomograms, the critical gp41-interactive region of gp120 was missing from previous atomic-level characterizations. Here we determine the crystal structure of an HIV-1 gp120 core with intact gp41-interactive region in its CD4-bound state, compare this structure to unliganded and antibody-bound forms to identify structurally invariant and plastic components, and use ligand-oriented cryoelectron tomograms to define component mobility in the viral spike context. Newly defined gp120 elements proximal to the gp41 interface complete a 7-stranded beta-sandwich, which appeared invariant in conformation. Loop excursions emanating from the sandwich form three topologically separate--and structurally plastic--layers, topped off by the highly glycosylated gp120 outer domain. Crystal structures, cryoelectron tomograms, and interlayer chemistry were consistent with a mechanism in which the layers act as a shape-changing spacer, facilitating movement between outer domain and gp41-associated beta-sandwich and providing for conformational diversity used in immune evasion. A "layered" gp120 architecture thus allows movement among alternative glycoprotein conformations required for virus entry and immune evasion, whereas a beta-sandwich clamp maintains gp120-gp41 interaction and regulates gp41 transitions.

Yellow fever 17D-vectored vaccines expressing Lassa virus GP1 and GP2 glycoproteins provide protection against fatal disease in guinea pigs

PubMed Central

Jiang, Xiaohong; Dalebout, Tim J.; Bredenbeek, Peter J.; Carrion, Ricardo; Brasky, Kathleen; Patterson, Jean; Goicochea, Marco; Bryant, Joseph; Salvato, Maria S.; Lukashevich, Igor S.

2010-01-01

Yellow Fever (YF) and Lassa Fever (LF) are two prevalent hemorrhagic fevers co-circulating in West Africa and responsible for thousands of deaths annually. The YF vaccine 17D has been used as a vector for the Lassa virus glycoprotein precursor (LASV-GPC) or their subunits, GP1 (attachment glycoprotein) and GP2 (fusion glycoprotein). Cloning shorter inserts, LASV GP1 and GP2, between YF17D E and NS1 genes enhanced genetic stability of recombinant viruses, YF17D/LASV-GP1 and –GP2, in comparison with YF17D/LASV-GPC recombinant. The recombinant viruses were replication competent and properly processed YF and LASV GP proteins in infected cells. YF17D/LASV-GP1&GP2 induced specific CD8+ T cell responses in mice and protected strain 13 guinea pigs against fatal LF. Unlike immunization with live attenuated reassortant vaccine ML29, immunization with YF17D/LASV-GP1&GP2 did not provide sterilizing immunity. This study demonstrates the feasibility of YF17D-based vaccine to control LF in West Africa. PMID:21145373

The global financial crisis and Australian general practice.

PubMed

McRae, Ian S; Paolucci, Francesco

2011-02-01

To explore the potential effects of the global financial crisis (GFC) on the market for general practitioner (GP) services in Australia. We estimate the impact of changes in unemployment rates on demand for GP services and the impact of lost asset values on GP retirement plans and work patterns. Combining these supply and demand effects, we estimate the potential effect of the GFC on the market for GP services under various scenarios. If deferral of retirement increases GP availability by 2%, and historic trends to reduce GP working hours are halved, at the current level of ~5.2% unemployment average fees would decline by $0.23 per GP consultation and volumes of GP services would rise by 2.53% with almost no change in average GP gross earnings over what would otherwise have occurred. With 8.5% unemployment, as initially predicted by Treasury, GP fees would increase by $0.91 and GP income by nearly 3%. The GFC is likely to increase activity in the GP market and potentially to reduce fee levels relative to the pre-GFC trends. Net effects on average GP incomes are likely to be small at current unemployment levels.

Polyubiquitylation of AMF requires cooperation between the gp78 and TRIM25 ubiquitin ligases.

PubMed

Wang, Ying; Ha, Seung-Wook; Zhang, Tianpeng; Kho, Dhong-Hyo; Raz, Avraham; Xie, Youming

2014-04-30

gp78 is a ubiquitin ligase that plays a vital role in endoplasmic reticulum (ER)-associated degradation (ERAD). Here we report that autocrine motility factor (AMF), also known as phosphoglucose isomerase (PGI), is a novel substrate of gp78. We show that polyubiquitylation of AMF requires cooperative interaction between gp78 and the ubiquitin ligase TRIM25 (tripartite motif-containing protein 25). While TRIM25 mediates the initial round of ubiquitylation, gp78 catalyzes polyubiquitylation of AMF. The E4-like activity of gp78 was illustrated by an in vitro polyubiquitylation assay using Ub-DHFR as a model substrate. We further demonstrate that TRIM25 ubiquitylates gp78 and that overexpression of TRIM25 accelerates the degradation of gp78. Our data suggest that TRIM25 not only cooperates with gp78 in polyubiquitylation of AMF but also gauges the steady-state level of gp78. This study uncovers a previously unknown functional link between gp78 and TRIM25 and provides mechanistic insight into gp78-mediated protein ubiquitylation.

Polyubiquitylation of AMF requires cooperation between the gp78 and TRIM25 ubiquitin ligases

PubMed Central

Kho, Dhong-Hyo; Raz, Avraham; Xie, Youming

2014-01-01

gp78 is a ubiquitin ligase that plays a vital role in endoplasmic reticulum (ER)-associated degradation (ERAD). Here we report that autocrine motility factor (AMF), also known as phosphoglucose isomerase (PGI), is a novel substrate of gp78. We show that polyubiquitylation of AMF requires cooperative interaction between gp78 and the ubiquitin ligase TRIM25 (tripartite motif-containing protein 25). While TRIM25 mediates the initial round of ubiquitylation, gp78 catalyzes polyubiquitylation of AMF. The E4-like activity of gp78 was illustrated by an in vitro polyubiquitylation assay using Ub-DHFR as a model substrate. We further demonstrate that TRIM25 ubiquitylates gp78 and that overexpression of TRIM25 accelerates the degradation of gp78. Our data suggest that TRIM25 not only cooperates with gp78 in polyubiquitylation of AMF but also gauges the steady-state level of gp78. This study uncovers a previously unknown functional link between gp78 and TRIM25 and provides mechanistic insight into gp78-mediated protein ubiquitylation. PMID:24810856

Space Science

NASA Image and Video Library

2003-07-11

The space vehicle for Gravity Probe B (GP-B) arrives at the launch site at Vandenburg Air Force Base. GP-B is the relativity experiment being developed at Stanford University to test two extraordinary predictions of Albert Einstein's general theory of relativity. The experiment will measure, very precisely, the expected tiny changes in the direction of the spin axes of four gyroscopes contained in an Earth-orbiting satellite at a 400-mile altitude. So free are the gyroscopes from disturbance that they will provide an almost perfect space-time reference system. They will measure how space and time are very slightly warped by the presence of the Earth, and, more profoundly, how the Earth's rotation very slightly drags space-time around with it. These effects, though small for the Earth, have far-reaching implications for the nature of matter and the structure of the Universe. GP-B is among the most thoroughly researched programs ever undertaken by NASA. This is the story of a scientific quest in which physicists and engineers have collaborated closely over many years. Inspired by their quest, they have invented a whole range of technologies that are already enlivening other branches of science and engineering. Scheduled for launch in 2003 and managed for NASA by the Marshall Space Flight Center, development of the GP-B is the responsibility of Stanford University, with major subcontractor Lockheed Martin Corporation.

Amplification of the Gp41 gene for detection of mutations conferring resistance to HIV-1 fusion inhibitors on genotypic assay

NASA Astrophysics Data System (ADS)

Tanumihardja, J.; Bela, B.

2017-08-01

Fusion inhibitors have potential for future use in HIV control programs in Indonesia, so the capacity to test resistance to such drugs needs to be developed. Resistance-detection with a genotypic assay began with amplification of the target gene, gp41. Based on the sequence of the two most common HIV subtypes in Indonesia, AE and B, a primer pair was designed. Plasma samples containing both subtypes were extracted to obtain HIV RNA. Using PCR, the primer pair was used to produce the amplification product, the identity of which was checked based on length under electrophoresis. Eleven plasma samples were included in this study. One-step PCR using the primer pair was able to amplify gp41 from 54.5% of the samples, and an unspecific amplification product was seen in 1.1% of the samples. Amplification failed in 36.4% of the samples, which may be due to an inappropriate primer sequence. It was also found that the optimal annealing temperature for producing the single expected band was 57.2 °C. With one-step PCR, the designed primer pair amplified the HIV-1 gp41 gene from subtypes AE and B. However, further research should be done to determine the conditions that will increase the sensitivity and specificity of the amplification process.

Lifestyle intervention in general practice for physical activity, smoking, alcohol consumption and diet in elderly: a randomized controlled trial.

PubMed

Vrdoljak, Davorka; Marković, Biserka Bergman; Puljak, Livia; Lalić, Dragica Ivezić; Kranjčević, Ksenija; Vučak, Jasna

2014-01-01

The purpose of the study was to compare the effectiveness of programmed and intensified intervention on lifestyle changes, including physical activity, cigarette smoking, alcohol consumption and diet, in patients aged ≥ 65 with the usual care of general practitioners (GP). In this multicenter randomized controlled trial, 738 patients aged ≥ 65 were randomly assigned to receive intensified intervention (N = 371) or usual care (N = 367) of a GP for lifestyle changes, with 18-month follow-up. The main outcome measures were physical activity, smoking, alcohol consumption and diet. The study was conducted in 59 general practices in Croatia between May 2008 and May 2010. The patients' mean age was 72.3 ± 5.2 years. Significant diet correction was achieved after 18-month follow-up in the intervention group, comparing to controls. More patients followed strictly Mediterranean diet and consumed healthy foods more frequently. There was no significant difference between the groups in physical activity, tobacco smoking and alcohol consumption or diet after the intervention. In conclusion, an 18-month intensified GP's intervention had limited effect on lifestyle habits. GP intervention managed to change dietary habits in elderly population, which is encouraging since elderly population is very resistant regarding lifestyle habit changes. Clinical trial registration number. ISRCTN31857696. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Gravity Probe B Space Vehicle

NASA Technical Reports Server (NTRS)

2003-01-01

The space vehicle for Gravity Probe B (GP-B) arrives at the launch site at Vandenburg Air Force Base. GP-B is the relativity experiment being developed at Stanford University to test two extraordinary predictions of Albert Einstein's general theory of relativity. The experiment will measure, very precisely, the expected tiny changes in the direction of the spin axes of four gyroscopes contained in an Earth-orbiting satellite at a 400-mile altitude. So free are the gyroscopes from disturbance that they will provide an almost perfect space-time reference system. They will measure how space and time are very slightly warped by the presence of the Earth, and, more profoundly, how the Earth's rotation very slightly drags space-time around with it. These effects, though small for the Earth, have far-reaching implications for the nature of matter and the structure of the Universe. GP-B is among the most thoroughly researched programs ever undertaken by NASA. This is the story of a scientific quest in which physicists and engineers have collaborated closely over many years. Inspired by their quest, they have invented a whole range of technologies that are already enlivening other branches of science and engineering. Scheduled for launch in 2003 and managed for NASA by the Marshall Space Flight Center, development of the GP-B is the responsibility of Stanford University, with major subcontractor Lockheed Martin Corporation.

Cleavage strongly influences whether soluble HIV-1 envelope glycoprotein trimers adopt a native-like conformation

PubMed Central

Ringe, Rajesh P.; Sanders, Rogier W.; Yasmeen, Anila; Kim, Helen J.; Lee, Jeong Hyun; Cupo, Albert; Korzun, Jacob; Derking, Ronald; van Montfort, Thijs; Julien, Jean-Philippe; Wilson, Ian A.; Klasse, Per Johan; Ward, Andrew B.; Moore, John P.

2013-01-01

We compare the antigenicity and conformation of soluble, cleaved vs. uncleaved envelope glycoprotein (Env gp)140 trimers from the subtype A HIV type 1 (HIV-1) strain BG505. The impact of gp120–gp41 cleavage on trimer structure, in the presence or absence of trimer-stabilizing modifications (i.e., a gp120–gp41 disulfide bond and an I559P gp41 change, together designated SOSIP), was assessed. Without SOSIP changes, cleaved trimers disintegrate into their gp120 and gp41-ectodomain (gp41ECTO) components; when only the disulfide bond is present, they dissociate into gp140 monomers. Uncleaved gp140s remain trimeric whether SOSIP substitutions are present or not. However, negative-stain electron microscopy reveals that only cleaved trimers form homogeneous structures resembling native Env spikes on virus particles. In contrast, uncleaved trimers are highly heterogeneous, adopting a variety of irregular shapes, many of which appear to be gp120 subunits dangling from a central core that is presumably a trimeric form of gp41ECTO. Antigenicity studies with neutralizing and nonneutralizing antibodies are consistent with the EM images; cleaved, SOSIP-stabilized trimers express quaternary structure-dependent epitopes, whereas uncleaved trimers expose nonneutralizing gp120 and gp41ECTO epitopes that are occluded on cleaved trimers. These findings have adverse implications for using soluble, uncleaved trimers for structural studies, and the rationale for testing uncleaved trimers as vaccine candidates also needs to be reevaluated. PMID:24145402

Crystallogenesis of bacteriophage P22 tail accessory factor gp26 at acidic and neutral pH

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

Cingolani, Gino, E-mail: cingolag@upstate.edu; Andrews, Dewan; Casjens, Sherwood

2006-05-01

The crystallogenesis of bacteriophage P22 tail-fiber gp26 is described. To study possible pH-induced conformational changes in gp26 structure, native trimeric gp26 has been crystallized at acidic pH (4.6) and a chimera of gp26 fused to maltose-binding protein (MBP-gp26) has been crystallized at neutral and alkaline pH (7-10). Gp26 is one of three phage P22-encoded tail accessory factors essential for stabilization of viral DNA within the mature capsid. In solution, gp26 exists as an extended triple-stranded coiled-coil protein which shares profound structural similarities with class I viral membrane-fusion protein. In the cryo-EM reconstruction of P22 tail extracted from mature virions, gp26more » forms an ∼220 Å extended needle structure emanating from the neck of the tail, which is likely to be brought into contact with the cell’s outer membrane when the viral DNA-injection process is initiated. To shed light on the potential role of gp26 in cell-wall penetration and DNA injection, gp26 has been crystallized at acidic, neutral and alkaline pH. Crystals of native gp26 grown at pH 4.6 diffract X-rays to 2.0 Å resolution and belong to space group P2{sub 1}, with a dimer of trimeric gp26 molecules in the asymmetric unit. To study potential pH-induced conformational changes in the gp26 structure, a chimera of gp26 fused to maltose-binding protein (MBP-gp26) was generated. Hexagonal crystals of MBP-gp26 were obtained at neutral and alkaline pH using the high-throughput crystallization robot at the Hauptman–Woodward Medical Research Institute, Buffalo, NY, USA. These crystals diffract X-rays to beyond 2.0 Å resolution. Structural analysis of gp26 crystallized at acidic, neutral and alkaline pH is in progress.« less

Comprehensive annotation of Glossina pallidipes salivary gland hypertrophy virus from Ethiopian tsetse flies: a proteogenomics approach

PubMed Central

Kariithi, Henry M.; Cousserans, François; Parker, Nicolas J.; İnce, İkbal Agah; Scully, Erin D.; Boeren, Sjef; Geib, Scott M.; Mekonnen, Solomon; Vlak, Just M.; Parker, Andrew G.; Vreysen, Marc J. B.; Bergoin, Max

2016-01-01

Glossina pallidipes salivary gland hypertrophy virus (GpSGHV; family Hytrosaviridae) can establish asymptomatic and symptomatic infection in its tsetse fly host. Here, we present a comprehensive annotation of the genome of an Ethiopian GpSGHV isolate (GpSGHV-Eth) compared with the reference Ugandan GpSGHV isolate (GpSGHV-Uga; GenBank accession number EF568108). GpSGHV-Eth has higher salivary gland hypertrophy syndrome prevalence than GpSGHV-Uga. We show that the GpSGHV-Eth genome has 190 291 nt, a low G+C content (27.9 %) and encodes 174 putative ORFs. Using proteogenomic and transcriptome mapping, 141 and 86 ORFs were mapped by transcripts and peptides, respectively. Furthermore, of the 174 ORFs, 132 had putative transcriptional signals [TATA-like box and poly(A) signals]. Sixty ORFs had both TATA-like box promoter and poly(A) signals, and mapped by both transcripts and peptides, implying that these ORFs encode functional proteins. Of the 60 ORFs, 10 ORFs are homologues to baculovirus and nudivirus core genes, including three per os infectivity factors and four RNA polymerase subunits (LEF4, 5, 8 and 9). Whereas GpSGHV-Eth and GpSGHV-Uga are 98.1 % similar at the nucleotide level, 37 ORFs in the GpSGHV-Eth genome had nucleotide insertions (n = 17) and deletions (n = 20) compared with their homologues in GpSGHV-Uga. Furthermore, compared with the GpSGHV-Uga genome, 11 and 24 GpSGHV ORFs were deleted and novel, respectively. Further, 13 GpSGHV-Eth ORFs were non-canonical; they had either CTG or TTG start codons instead of ATG. Taken together, these data suggest that GpSGHV-Eth and GpSGHV-Uga represent two different lineages of the same virus. Genetic differences combined with host and environmental factors possibly explain the differential GpSGHV pathogenesis observed in different G. pallidipes colonies. PMID:26801744

In vitro and in vivo evaluations of the P-glycoprotein-mediated efflux of dibenzoylhydrazines

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

Miyata, Ken-ichi, E-mail: Miyata.Kenichi@otsuka.jp; Otsuka Pharmaceutical Co., Ltd., Tokushima 771-0182; Nakagawa, Yoshiaki

2016-05-01

P-glycoprotein (P-gp) is a member of the ATP-binding cassette transporter family. It actively transports a wide variety of compounds out of cells to protect humans from xenobiotics. Thus, determining whether chemicals are substrates and/or inhibitors of P-gp is important in risk assessments of pharmacokinetic interactions among chemicals because P-gp-mediated transport processes play a significant role in their absorption and disposition. We previously reported that dibenzoylhydrazines (DBHs) such as tebufenozide and methoxyfenozide (agrochemicals) stimulated P-gp ATPase activity. However, it currently remains unclear whether these derivatives are transport substrates of P-gp and inhibit transport of other chemicals by P-gp. In the presentmore » study, in order to evaluate the interactions of DBHs with other chemicals in humans, we determined whether DBHs are P-gp transport substrates using both the in vitro bidirectional transport assay and the in vivo study of rats. In the in vivo study, we investigated the influence of P-gp inhibitors on the brain to plasma ratio of methoxyfenozide in rats. We also examined the inhibitory effects of DBHs on quinidine (a P-gp substrate) transport by P-gp in order to ascertain whether these derivatives are inhibitors of P-gp. Based on the results, DBHs were concluded to be weak P-gp transport substrates and moderate P-gp inhibitors. However, the risk of DBHs caused by interaction with other chemicals including drugs was considered to be low by considering the DBHs' potential as the substrates and inhibitors of P-gp as well as their plasma concentrations as long as DBHs are properly used. - Highlights: • Transport of DBHs by P-gp was not detected in in vitro bidirectional transport assay. • DBHs were weak P-gp transport substrates based on in vivo studies in rats. • The in vivo studies are useful methods for evaluating P-gp transport substrates. • DBHs inhibit quinidine transport by P-gp in in vitro bidirectional transport assay.« less

Genetic programming based ensemble system for microarray data classification.

PubMed

Liu, Kun-Hong; Tong, Muchenxuan; Xie, Shu-Tong; Yee Ng, Vincent To

2015-01-01

Recently, more and more machine learning techniques have been applied to microarray data analysis. The aim of this study is to propose a genetic programming (GP) based new ensemble system (named GPES), which can be used to effectively classify different types of cancers. Decision trees are deployed as base classifiers in this ensemble framework with three operators: Min, Max, and Average. Each individual of the GP is an ensemble system, and they become more and more accurate in the evolutionary process. The feature selection technique and balanced subsampling technique are applied to increase the diversity in each ensemble system. The final ensemble committee is selected by a forward search algorithm, which is shown to be capable of fitting data automatically. The performance of GPES is evaluated using five binary class and six multiclass microarray datasets, and results show that the algorithm can achieve better results in most cases compared with some other ensemble systems. By using elaborate base classifiers or applying other sampling techniques, the performance of GPES may be further improved.

Genetic Programming Based Ensemble System for Microarray Data Classification

PubMed Central

Liu, Kun-Hong; Tong, Muchenxuan; Xie, Shu-Tong; Yee Ng, Vincent To

2015-01-01

Recently, more and more machine learning techniques have been applied to microarray data analysis. The aim of this study is to propose a genetic programming (GP) based new ensemble system (named GPES), which can be used to effectively classify different types of cancers. Decision trees are deployed as base classifiers in this ensemble framework with three operators: Min, Max, and Average. Each individual of the GP is an ensemble system, and they become more and more accurate in the evolutionary process. The feature selection technique and balanced subsampling technique are applied to increase the diversity in each ensemble system. The final ensemble committee is selected by a forward search algorithm, which is shown to be capable of fitting data automatically. The performance of GPES is evaluated using five binary class and six multiclass microarray datasets, and results show that the algorithm can achieve better results in most cases compared with some other ensemble systems. By using elaborate base classifiers or applying other sampling techniques, the performance of GPES may be further improved. PMID:25810748

GP and nurses' perceptions of how after hours care for people receiving palliative care at home could be improved: a mixed methods study

PubMed Central

Tan, Heather M; O'Connor, Margaret M; Miles, Gail; Klein, Britt; Schattner, Peter

2009-01-01

Background Primary health care providers play a dominant role in the provision of palliative care (PC) in Australia but many gaps in after hours service remain. In some rural areas only 19% of people receiving palliative care achieve their goal of dying at home. This study, which builds on an earlier qualitative phase of the project, investigates the gaps in care from the perspective of general practitioners (GPs) and PC nurses. Methods Questionnaires, developed from the outcomes of the earlier phase, and containing both structured and open ended questions, were distributed through Divisions of General Practice (1 urban, 1 rural, 1 mixed) to GPs (n = 524) and through a special interest group to palliative care nurses (n = 122) in both rural and urban areas. Results Questionnaires were returned by 114 GPs (22%) and 52 nurses (43%). The majority of GPs were associated with a practice which provided some after hours services but PC was not a strong focus for most. This was reflected in low levels of PC training, limited awareness of the existence of after hours triage services in their area, and of the availability of Enhanced Primary Care (EPC) Medicare items for care planning for palliative patients. However, more than half of both nurses and GPs were aware of accessible PC resources. Factors such as poor communication and limited availability of after hours services were identified the as most likely to impact negatively on service provision. Strategies considered most likely to improve after hours services were individual patient protocols, palliative care trained respite carers and regular multidisciplinary meetings that included the GP. Conclusion While some of the identified gaps can only be met by long term funding and policy change, educational tools for use in training programs in PC for health professionals, which focus on the utilisation of EPC Medicare items in palliative care planning, the development of advance care plans and good communication between members of multidisciplinary teams, which include the GP, may enhance after hours service provision for patients receiving palliative care at home. The role of locums in after PC is an area for further research PMID:19751527

Critical review and hydrologic application of threshold detection methods for the generalized Pareto (GP) distribution

NASA Astrophysics Data System (ADS)

Mamalakis, Antonios; Langousis, Andreas; Deidda, Roberto

2016-04-01

Estimation of extreme rainfall from data constitutes one of the most important issues in statistical hydrology, as it is associated with the design of hydraulic structures and flood water management. To that extent, based on asymptotic arguments from Extreme Excess (EE) theory, several studies have focused on developing new, or improving existing methods to fit a generalized Pareto (GP) distribution model to rainfall excesses above a properly selected threshold u. The latter is generally determined using various approaches, such as non-parametric methods that are intended to locate the changing point between extreme and non-extreme regions of the data, graphical methods where one studies the dependence of GP distribution parameters (or related metrics) on the threshold level u, and Goodness of Fit (GoF) metrics that, for a certain level of significance, locate the lowest threshold u that a GP distribution model is applicable. In this work, we review representative methods for GP threshold detection, discuss fundamental differences in their theoretical bases, and apply them to 1714 daily rainfall records from the NOAA-NCDC open-access database, with more than 110 years of data. We find that non-parametric methods that are intended to locate the changing point between extreme and non-extreme regions of the data are generally not reliable, while methods that are based on asymptotic properties of the upper distribution tail lead to unrealistically high threshold and shape parameter estimates. The latter is justified by theoretical arguments, and it is especially the case in rainfall applications, where the shape parameter of the GP distribution is low; i.e. on the order of 0.1 ÷ 0.2. Better performance is demonstrated by graphical methods and GoF metrics that rely on pre-asymptotic properties of the GP distribution. For daily rainfall, we find that GP threshold estimates range between 2÷12 mm/d with a mean value of 6.5 mm/d, while the existence of quantization in the empirical records, as well as variations in their size, constitute the two most important factors that may significantly affect the accuracy of the obtained results. Acknowledgments The research project was implemented within the framework of the Action «Supporting Postdoctoral Researchers» of the Operational Program "Education and Lifelong Learning" (Action's Beneficiary: General Secretariat for Research and Technology), and co-financed by the European Social Fund (ESF) and the Greek State. The work conducted by Roberto Deidda was funded under the Sardinian Regional Law 7/2007 (funding call 2013).

Investigation of a geodesy coexperiment to the Gravity Probe B relativity gyroscope program

NASA Technical Reports Server (NTRS)

Everitt, C. W. F.; Parkinson, Bradford W.; Tapley, Mark

1993-01-01

Geodesy is the science of measuring the gravitational field of and positions on the Earth. Estimation of the gravitational field via gravitation gradiometry, the measurement of variations in the direction and magnitude of gravitation with respect to position, is this dissertation's focus. Gravity Probe B (GP-B) is a Stanford satellite experiment in gravitational physics. GP-B will measure the precession the rotating Earth causes on the space time around it by observing the precessions of four gyroscopes in a circular, polar, drag-free orbit at 650 km altitude. The gyroscopes are nearly perfect niobium-coated spheres of quartz, operating at 1.8 K to permit observations with extremely low thermal noise. The permissible gyroscope drift rate is miniscule, so the torques on the gyros must be tiny. A drag-free control system, by canceling accelerations caused by nongravitational forces, minimizes the support forces and hence torques. The GP-B system offers two main possibilities for geodesy. One is as a drag-free satellite to be used in trajectory-based estimates of the Earth's gravity field. We described calculations involving that approach in our previous reports, including comparison of laser only, GPS only, and combined tracking and a preliminary estimate of the possibility of estimating relativistic effects on the orbit. The second possibility is gradiometry. This technique has received a more cursory examination in previous reports, so we concentrate on it here. We explore the feasibility of using the residual suspension forces centering the GP-B gyros as gradiometer signals for geodesy. The objective of this work is a statistical prediction of the formal uncertainty in an estimate of the Earth's gravitation field using data from GP-B. We perform an instrument analysis and apply two mathematical techniques to predict uncertainty. One is an analytical approach using a flat-Earth approximation to predict geopotential information quality as a function of spatial wavelength. The second estimates the covariance matrix arising in a least-squares estimate of a spherical harmonic representation of the geopotential using GP-B gradiometer data. The results show that the GP-B data set can be used to create a consistent estimate of the geopotential up to spherical harmonic degree and order 60. The formal uncertainty of all coefficients between degrees 5 and 50 is reduced by factors of up to 30 over current satellite-only estimates and up to 7 over estimates which include surface data. The primary conclusion resulting from this study is that the gravitation gradiometer geodesy coexperiment to GP-B is both feasible and attractive.

Differential role of gp130-dependent STAT and Ras signalling for haematopoiesis following bone-marrow transplantation.

PubMed

Kroy, Daniela C; Hebing, Lisa; Sander, Leif E; Gassler, Nikolaus; Erschfeld, Stephanie; Sackett, Sara; Galm, Oliver; Trautwein, Christian; Streetz, Konrad L

2012-01-01

Bone marrow transplantation (BMT) is a complex process regulated by different cytokines and growth factors. The pleiotropic cytokine IL-6 (Interleukin-6) and related cytokines of the same family acting on the common signal transducer gp130 are known to play a key role in bone marrow (BM) engraftment. In contrast, the exact signalling events that control IL-6/gp130-driven haematopoietic stem cell development during BMT remain unresolved. Conditional gp130 knockout and knockin mice were used to delete gp130 expression (gp130(ΔMx)), or to selectively disrupt gp130-dependent Ras (gp130(ΔMxRas)) or STAT signalling (gp130(ΔMxSTAT)) in BM cells. BM derived from the respective strains was transplanted into irradiated wildtype hosts and repopulation of various haematopoietic lineages was monitored by flow cytometry. BM derived from gp130 deficient donor mice (gp130(ΔMx)) displayed a delayed engraftment, as evidenced by reduced total white blood cells (WBC), marked thrombocytopenia and anaemia in the early phase after BMT. Lineage analysis unravelled a restricted development of CD4(+) and CD8(+) T-cells, CD19(+) B-cells and CD11b(+) myeloid cells after transplantation of gp130-deficient BM grafts. To further delineate the two major gp130-induced signalling cascades, Ras-MAPK and STAT1/3-signalling respectively, we used gp130(ΔMxRas) and gp130(ΔMxSTAT) donor BM. BMT of gp130(ΔMxSTAT) cells significantly impaired engraftment of CD4(+), CD8(+), CD19(+) and CD11b(+) cells, whereas gp130(ΔMxRas) BM displayed a selective impairment in early thrombopoiesis. Importantly, gp130-STAT1/3 signalling deficiency in BM grafts severely impaired survival of transplanted mice, thus demonstrating a pivotal role for this pathway in BM graft survival and function. Our data unravel a vital function of IL-6/gp130-STAT1/3 signals for BM engraftment and haematopoiesis, as well as for host survival after transplantation. STAT1/3 and ras-dependent pathways thereby exert distinct functions on individual bone-marrow-lineages.

A GXXXA motif in the transmembrane domain of the Ebola virus glycoprotein is required for tetherin antagonism.

PubMed

González-Hernández, Mariana; Hoffmann, Markus; Brinkmann, Constantin; Nehls, Julia; Winkler, Michael; Schindler, Michael; Pöhlmann, Stefan

2018-04-18

The interferon-induced antiviral host cell protein tetherin can inhibit the release of several enveloped viruses from infected cells. The Ebola virus (EBOV) glycoprotein (GP) antagonizes tetherin but the domains and amino acids in GP that are required for tetherin antagonism have not been fully defined. A GXXXA motif within the transmembrane domain (TMD) of EBOV-GP was previously shown to be important for GP-mediated cellular detachment. Here, we investigated whether this motif also contributes to tetherin antagonism. Mutation of the GXXXA motif did not impact GP expression or particle incorporation and only modestly reduced EBOV-GP-driven entry. In contrast, the GXXXA motif was required for tetherin antagonism in transfected cells. Moreover, alteration of the GXXXA motif increased tetherin-sensitivity of a replication-competent vesicular stomatitis virus (VSV) chimera encoding EBOV-GP. Although these results await confirmation with authentic EBOV, they indicate that a GXXXA motif in the TMD of EBOV-GP is important for tetherin antagonism. Moreover, they provide the first evidence that GP can antagonize tetherin in the context of an infectious EBOV surrogate. IMPORTANCE The glycoprotein (GP) of Ebola virus (EBOV) inhibits the antiviral host cell protein tetherin and may promote viral spread in tetherin-positive cells. However, tetherin antagonism by GP has so far only been demonstrated using virus-like particles and it is unknown whether GP can block tetherin in infected cells. Moreover, a mutation in GP that selectively abrogates tetherin antagonism is unknown. Here, we show that a GXXXA motif in the transmembrane domain of EBOV-GP, which was previously reported to be required for GP-mediated cell rounding, is also important for tetherin counteraction. Moreover, analysis of this mutation in the context of vesicular stomatitis virus chimeras encoding EBOV-GP revealed that GP-mediated tetherin counteraction is operative in infected cells. To our knowledge, these findings demonstrate for the first time that GP can antagonize tetherin in infected cells and provide a tool to study the impact of GP-dependent tetherin counteraction on EBOV spread. Copyright © 2018 American Society for Microbiology.

Glycoprotein 5 of porcine reproductive and respiratory syndrome virus strain SD16 inhibits viral replication and causes G2/M cell cycle arrest, but does not induce cellular apoptosis in Marc-145 cells

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

Mu, Yang, E-mail: muyang@nwsuaf.edu.cn; Experimental Station of Veterinary Pharmacology and Veterinary Biotechnology, Ministry of Agriculture of the People's Republic of China, No. 22 Xinong Road, Yangling, Shaanxi 712100; Li, Liangliang, E-mail: lifeiyang2007@126.com

Cell apoptosis is common after infection with porcine reproductive and respiratory syndrome virus (PRRSV). PRRSV GP5 has been reported to induce cell apoptosis. To further understand the role of GP5 in PRRSV induced cell apoptosis, we established Marc-145 cell lines stably expressing full-length GP5, GP5{sup Δ84-96} (aa 84-96 deletion), and GP5{sup Δ97-119} (aa 97-119 deletion). Cell proliferation, cell cycle progression, cell apoptosis and virus replication in these cell lines were evaluated. Neither truncated nor full-length GP5 induced cell apoptosis in Marc-145 cells. However, GP5{sup Δ97-119}, but not full-length or GP5{sup Δ84-96}, induced a cell cycle arrest at the G2/M phasemore » resulting in a reduction in the growth of Marc-145 cells. Additionally, GP5{sup Δ84-96} inhibited the replication of PRRSV in Marc-145 cells through induction of IFN-β. These findings suggest that PRRSV GP5 is not responsible for inducing cell apoptosis in Marc-145 cells under these experimental conditions; however it has other important roles in virus/host cell biology. - Highlights: • Marc-145 cell lines stable expression PRRSV GP5 or truncated GP5 were constructed. • GP5{sup Δ97-119} expression in Marc-145 cell induced cell cycle arrest at G2/M phase. • Expression of GP5 and truncated GP5 could not induce Marc-145 cells apoptosis. • PRRSV replication in Marc-145-GP5{sup Δ84-96} was significantly inhibited.« less

Platelet adhesion via glycoprotein IIb integrin is critical for atheroprogression and focal cerebral ischemia: an in vivo study in mice lacking glycoprotein IIb.

PubMed

Massberg, Steffen; Schürzinger, Katrin; Lorenz, Michael; Konrad, Ildiko; Schulz, Christian; Plesnila, Nikolaus; Kennerknecht, Elisabeth; Rudelius, Martina; Sauer, Susanne; Braun, Siegmund; Kremmer, Elisabeth; Emambokus, Nikla R; Frampton, Jon; Gawaz, Meinrad

2005-08-23

The platelet glycoprotein (GP) IIb/IIIa integrin binds to fibrinogen and thereby mediates platelet aggregation. Here, we addressed the role of GP IIb for platelet adhesion and determined the relevance of platelet GP IIb for the processes of atherosclerosis and cerebral ischemia-reperfusion (I/R) injury. GP IIb(-/-) mice were generated and bred with ApoE(-/-) animals to create GP IIb(-/-)ApoE(-/-) mice. Platelet adhesion to the mechanically injured or atherosclerotic vessel wall was monitored by in vivo video fluorescence microscopy. In the presence of GP IIb, vascular injury and early atherosclerosis induced platelet adhesion in the carotid artery (CA). In contrast, platelet adhesion was significantly reduced in the absence of GP IIb integrin (P<0.05). To address the contribution of platelet GP IIb to atheroprogression, we determined atherosclerotic lesion formation in the CA and aortic arch (AA) of GP IIb(+/+)ApoE(-/-) or GP IIb(-/-)ApoE(-/-) mice. Interestingly, the absence of GP IIb attenuated lesion formation in CA and AA, indicating that platelets, via GP IIb, contribute substantially to atherosclerosis. Next, we assessed the implication of GP IIb for cerebral I/R injury. We observed that after occlusion of the middle cerebral artery, the cerebral infarct size was drastically reduced in mice lacking GP IIb compared with wild-types. These findings show for the first time in vivo that GP IIb not only mediates platelet aggregation but also triggers platelet adhesion to exposed extracellular matrices and dysfunctional endothelial cells. In a process strictly involving GP IIb, platelets, which are among the first blood cells to arrive at the scene of endothelial dysfunction, contribute essentially to atherosclerosis and cerebral I/R injury.

Membrane insertion and assembly of epitope-tagged gp9 at the tip of the M13 phage.

PubMed

Ploss, Martin; Kuhn, Andreas

2011-09-26

Filamentous M13 phage extrude from infected Escherichia coli with a tip structure composed of gp7 and gp9. This tip structure is extended by the assembly of the filament composed of the major coat protein gp8. Finally, gp3 and gp6 terminate the phage structure at the proximal end. Up to now, gp3 has been the primary tool for phage display technology. However, gp7, gp8 and gp9 could also be used for phage display and these phage particles should bind to two different or more surfaces when the modified coat proteins are combined. Therefore, we tested here if the amino-terminal end of gp9 can be modified and whether the modified portion is exposed and detectable on the M13 phage particles. The amino-terminal region of gp9 was modified by inserting short sequences that encode antigenic epitopes. We show here that the modified gp9 proteins correctly integrate into the membrane using the membrane insertase YidC exposing the modified epitope into the periplasm. The proteins are then efficiently assembled onto the phage particles. Also extensions up to 36 amino acid residues at the amino-terminal end of gp9 did not interfere with membrane integration and phage assembly. The exposure of the antigenic tags on the phage was visualised with immunogold labelling by electron microscopy and verified by dot blotting with antibodies to the tags. Our results suggest that gp9 at the phage tip is suitable for the phage display technology. The modified gp9 can be supplied in trans from a plasmid and fully complements M13 phage with an amber mutation in gene 9. The modified phage tip is very well accessible to antibodies.

Membrane insertion and assembly of epitope-tagged gp9 at the tip of the M13 phage

PubMed Central

2011-01-01

Background Filamentous M13 phage extrude from infected Escherichia coli with a tip structure composed of gp7 and gp9. This tip structure is extended by the assembly of the filament composed of the major coat protein gp8. Finally, gp3 and gp6 terminate the phage structure at the proximal end. Up to now, gp3 has been the primary tool for phage display technology. However, gp7, gp8 and gp9 could also be used for phage display and these phage particles should bind to two different or more surfaces when the modified coat proteins are combined. Therefore, we tested here if the amino-terminal end of gp9 can be modified and whether the modified portion is exposed and detectable on the M13 phage particles. Results The amino-terminal region of gp9 was modified by inserting short sequences that encode antigenic epitopes. We show here that the modified gp9 proteins correctly integrate into the membrane using the membrane insertase YidC exposing the modified epitope into the periplasm. The proteins are then efficiently assembled onto the phage particles. Also extensions up to 36 amino acid residues at the amino-terminal end of gp9 did not interfere with membrane integration and phage assembly. The exposure of the antigenic tags on the phage was visualised with immunogold labelling by electron microscopy and verified by dot blotting with antibodies to the tags. Conclusions Our results suggest that gp9 at the phage tip is suitable for the phage display technology. The modified gp9 can be supplied in trans from a plasmid and fully complements M13 phage with an amber mutation in gene 9. The modified phage tip is very well accessible to antibodies. PMID:21943062

Yellow fever 17D-vectored vaccines expressing Lassa virus GP1 and GP2 glycoproteins provide protection against fatal disease in guinea pigs.

PubMed

Jiang, Xiaohong; Dalebout, Tim J; Bredenbeek, Peter J; Carrion, Ricardo; Brasky, Kathleen; Patterson, Jean; Goicochea, Marco; Bryant, Joseph; Salvato, Maria S; Lukashevich, Igor S

2011-02-01

Yellow Fever (YF) and Lassa Fever (LF) are two prevalent hemorrhagic fevers co-circulating in West Africa and responsible for thousands of deaths annually. The YF vaccine 17D has been used as a vector for the Lassa virus glycoprotein precursor (LASV-GPC) or their subunits, GP1 (attachment glycoprotein) and GP2 (fusion glycoprotein). Cloning shorter inserts, LASV-GP1 and -GP2, between YF17D E and NS1 genes enhanced genetic stability of recombinant viruses, YF17D/LASV-GP1 and -GP2, in comparison with YF17D/LASV-GPC recombinant. The recombinant viruses were replication competent and properly processed YF proteins and LASV GP antigens in infected cells. YF17D/LASV-GP1 and -GP2 induced specific CD8+ T cell responses in mice and protected strain 13 guinea pigs against fatal LF. Unlike immunization with live attenuated reassortant vaccine ML29, immunization with YF17D/LASV-GP1 and -GP2 did not provide sterilizing immunity. This study demonstrates the feasibility of YF17D-based vaccine to control LF in West Africa. Copyright © 2010 Elsevier Ltd. All rights reserved.

Asthma control in general practice -- GP and patient perspectives compared.

PubMed

Henderson, Joan; Hancock, Kerry L; Armour, Carol; Harrison, Christopher; Miller, Graeme

2013-10-01

How general practitioners (GPs) and patients perceive asthma control, and concordance between these perceptions, may influence asthma management and medication adherence. The aims of this study were to determine asthma prevalence in adult patients, measure patient asthma control and the correlation between GP and patient perceptions of asthma control or impact. A Supplementary Analysis of Nominated Data (SAND) sub-study of the Bettering the Evaluation and Care of Health (BEACH) program surveyed 2563 patients from 103 GPs. Asthma control was measured using the Asthma Control Questionnaire 5-item version (ACQ-5), and medication adherence by patient self-report. Survey procedures in SAS software and Pearson's correlation statistics were used. Asthma prevalence was 12.7% (95% confidence interval: 10.9-14.5), with good correlation between GP and patient perceptions of asthma control/impact, and with raw ACQ-5 scores. Grouped ACQ-5 scores showed higher levels of uncontrolled asthma. Medication adherence was sub-optimal. The ACQ-5 questions are useful for assessing asthma control, for prompting medication reviews, and for reinforcing benefits of medication compliance to improve long-term asthma control.

Prediction of maize phenotype based on whole-genome single nucleotide polymorphisms using deep belief networks

NASA Astrophysics Data System (ADS)

Rachmatia, H.; Kusuma, W. A.; Hasibuan, L. S.

2017-05-01

Selection in plant breeding could be more effective and more efficient if it is based on genomic data. Genomic selection (GS) is a new approach for plant-breeding selection that exploits genomic data through a mechanism called genomic prediction (GP). Most of GP models used linear methods that ignore effects of interaction among genes and effects of higher order nonlinearities. Deep belief network (DBN), one of the architectural in deep learning methods, is able to model data in high level of abstraction that involves nonlinearities effects of the data. This study implemented DBN for developing a GP model utilizing whole-genome Single Nucleotide Polymorphisms (SNPs) as data for training and testing. The case study was a set of traits in maize. The maize dataset was acquisitioned from CIMMYT’s (International Maize and Wheat Improvement Center) Global Maize program. Based on Pearson correlation, DBN is outperformed than other methods, kernel Hilbert space (RKHS) regression, Bayesian LASSO (BL), best linear unbiased predictor (BLUP), in case allegedly non-additive traits. DBN achieves correlation of 0.579 within -1 to 1 range.

Crosslinking CD4 by human immunodeficiency virus gp120 primes T cells for activation-induced apoptosis

PubMed Central

1992-01-01

During human immunodeficiency virus (HIV) infection there is a profound and selective decrease in the CD4+ population of T lymphocytes. The mechanism of this depletion is not understood, as only a small fraction of all CD4+ cells appear to be productively infected with HIV-1 in seropositive individuals. In the present study, crosslinking of bound gp120 on human CD4+ T cells followed by signaling through the T cell receptor for antigen was found to result in activation-dependent cell death by a form of cell suicide termed apoptosis, or programmed cell death. The data indicate that even picomolar concentrations of gp120 prime T cells for activation-induced cell death, suggesting a mechanism for CD4+ T cell depletion in acquired immune deficiency syndrome (AIDS), particularly in the face of concurrent infection and antigenic challenge with other organisms. These results also provide an explanation for the enhancement of infection by certain antibodies against HIV, and for the paradox that HIV appears to cause AIDS after the onset of antiviral immunity. PMID:1402655

A Virtual Community of Practice for General Practice Training: A Preimplementation Survey.

PubMed

Barnett, Stephen; Jones, Sandra C; Bennett, Sue; Iverson, Don; Robinson, Laura

2016-08-18

Professional isolation is an important factor in low rural health workforce retention. The aim of this study was to gain insights to inform the development of an implementation plan for a virtual community of practice (VCoP) for general practice (GP) training in regional Australia. The study also aimed to assess the applicability of the findings of an existing framework in developing this plan. This included ascertaining the main drivers of usage, or usefulness, of the VCoP for users and establishing the different priorities between user groups. A survey study, based on the seven-step health VCoP framework, was conducted with general practice supervisors and registrars-133 usable responses; 40% estimated response rate. Data was analyzed using the t test and the chi-square test for comparisons between groups. Factor analysis and generalized linear regression modeling were used to ascertain factors which may independently predict intention to use the VCoP. In establishing a VCoP, facilitation was seen as important. Regarding stakeholders, the GP training provider was an important sponsor. Factor analysis showed a single goal of usefulness. Registrars had a higher intention to use the VCoP (P<.001) and to perceive it as useful (P<.001) than supervisors. Usefulness independently predicted intention to actively use the VCoP (P<.001). Regarding engagement of a broad church of users, registrars were more likely than supervisors to want allied health professional and specialist involvement (P<.001). A supportive environment was deemed important, but most important was the quality of the content. Participants wanted regular feedback about site activity. Regarding technology and community, training can be online, but trust is better built face-to-face. Supervisors were significantly more likely than registrars to perceive that registrars needed help with knowledge (P=.01) and implementation of knowledge (P<.001). Important factors for a GP training VCoP include the following: facilitation covering administration and expertise, the perceived usefulness of the community, focusing usefulness around knowledge sharing, and overcoming professional isolation with high-quality content. Knowledge needs of different users should be acknowledged and help can be provided online, but trust is better built face-to-face. In conclusion, the findings of the health framework for VCoPs are relevant when developing an implementation plan for a VCoP for GP training. The main driver of success for a GP training VCoP is the perception of its usefulness by participants. Overcoming professional isolation for GP registrars using a VCoP has implications for training and retention of health workers in rural areas.

'Just a GP': a mixed method study of undermining of general practice as a career choice in the UK.

PubMed

Alberti, Hugh; Banner, Kimberley; Collingwood, Helen; Merritt, Kymberlee

2017-11-03

Failure to recruit sufficient applicants to general practice (GP) training has been a problem both nationally and internationally for many years and undermining of GP is one possible contributing factor. The aim of our study was to ascertain what comments, both negative and positive, are being made in UK clinical settings to GP trainees about GP and to further explore these comments and their influence on career choice. We conducted a mixed methods study. We surveyed all foundation doctors and GP trainees within one region of Health Education England regarding any comments they experienced relating to a career in GP. We also conducted six focus groups with early GP trainees to discuss any comments that they experienced and whether these comments had any influence on their or others career choice. Positive comments reported by trainees centred around the concept that choosing GP is a positive, family-focused choice which facilities a good work-life balance. Workload was the most common negative comment, alongside the notion of being 'just a GP'; the belief that GP is boring, a waste of training and a second-class career choice. The reasons for and origin of the comments are multifactorial in nature. Thematic analysis of the focus groups identified key factors such as previous exposure to and experience of GP, family members who were GPs, GP role models, demographics of the clinician and referral behaviour. Trainees perceived that negative comments may be discouraging others from choosing GP as a career. Our study demonstrates that negative comments towards GP as a career do exist within clinical settings and are having a potential impact on poor recruitment rates to GP training. We have identified areas in which further negative comments could be prevented by changing perceptions of GP as a career. Additional time spent in GP as undergraduates and postgraduates, and positive GP role models, could particularly benefit recruitment. We recommend that undermining of GP as a career choice be approached with a zero-tolerance policy. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Lack of gp130 expression in hepatocytes attenuates tumor progression in the DEN model.

PubMed

Hatting, M; Spannbauer, M; Peng, J; Al Masaoudi, M; Sellge, G; Nevzorova, Y A; Gassler, N; Liedtke, C; Cubero, F J; Trautwein, C

2015-03-05

Chronic liver inflammation is a crucial event in the development and growth of hepatocellular carcinoma (HCC). Compelling evidence has shown that interleukin-6 (IL-6)/gp130-dependent signaling has a fundamental role in liver carcinogenesis. Thus, in the present study we aimed to investigate the role of gp130 in hepatocytes for the initiation and progression of HCC. Hepatocyte-specific gp130 knockout mice (gp130(Δhepa)) and control animals (gp130(f/f)) were treated with diethylnitrosamine (DEN). The role of gp130 for acute injury (0-144 h post treatment), tumor initiation (24 weeks) and progression (40 weeks) was analyzed. After acute DEN-induced liver injury we observed a reduction in the inflammatory response in gp130(Δhepa) animals as reflected by decreased levels of IL-6 and oncostatin M. The loss of gp130 slightly attenuated the initiation of HCC 24 weeks after DEN treatment. In contrast, 40 weeks after DEN treatment, male and female gp130(Δhepa) mice showed smaller tumors and reduced tumor burden, indicating a role for hepatocyte-specific gp130 expression during HCC progression. Oxidative stress and DNA damage were substantially and similarly increased by DEN in both gp130(f/f) and gp130(Δhepa) animals. However, gp130(Δhepa) livers revealed aberrant STAT5 activation and decreased levels of transforming growth factor-β (TGFβ), pSMAD2/3 and SMAD2, whereas phosphorylation of STAT3 at Tyr705 and Ser727 was absent. Our results indicate that gp130 deletion in hepatocytes reduces progression, but not HCC initiation in the DEN model. Gp130 deletion resulted in STAT3 inhibition but increased STAT5 activation and diminished TGF-dependent signaling. Hence, blocking gp130 in hepatocytes might be an interesting therapeutic target to inhibit the growth of HCC.

Serological diagnosis and prognosis of severe acute pancreatitis by analysis of serum glycoprotein 2.

PubMed

Roggenbuck, Dirk; Goihl, Alexander; Hanack, Katja; Holzlöhner, Pamela; Hentschel, Christian; Veiczi, Miklos; Schierack, Peter; Reinhold, Dirk; Schulz, Hans-Ulrich

2017-05-01

Glycoprotein 2 (GP2), the pancreatic major zymogen granule membrane glycoprotein, was reported to be elevated in acute pancreatitis in animal models. Enzyme-linked immunosorbent assays (ELISAs) were developed to evaluate human glycoprotein 2 isoform alpha (GP2a) and total GP2 (GP2t) as specific markers for acute pancreatitis in sera of 153 patients with acute pancreatitis, 26 with chronic pancreatitis, 125 with pancreatic neoplasms, 324 with non-pancreatic neoplasms, 109 patients with liver/biliary disease, 67 with gastrointestinal disease, and 101 healthy subjects. GP2a and GP2t levels were correlated with procalcitonin and C-reactive protein in 152 and 146 follow-up samples of acute pancreatitis patients, respectively. The GP2a ELISA revealed a significantly higher assay accuracy in contrast to the GP2t assay (sensitivity ≤3 disease days: 91.7%, specificity: 96.7%, positive likelihood ratio [LR+]: 24.6, LR-: 0.09). GP2a and GP2t levels as well as prevalences were significantly elevated in early acute pancreatitis (≤3 disease days) compared to all control cohorts (p<0.05, respectively). GP2a and GP2t levels were significantly higher in patients with severe acute pancreatitis at admission compared with mild cases (p<0.05, respectively). Odds ratio for GP2a regarding mild vs. severe acute pancreatitis with lethal outcome was 7.8 on admission (p=0.0222). GP2a and GP2t levels were significantly correlated with procalcitonin [Spearman's rank coefficient of correlation (ρ)=0.21, 0.26; p=0.0110, 0.0012; respectively] and C-reactive protein (ρ=0.37, 0.40; p<0.0001; respectively). Serum GP2a is a specific marker of acute pancreatitis and analysis of GP2a can aid in the differential diagnosis of acute upper abdominal pain and prognosis of severe acute pancreatitis.

Chemical synthesis of 5'-pyrophosphate and triphosphate derivatives of 3'-5' ApA, ApG, GpA and GpG. CD study of the effect of 5'-phosphate groups on the conformation of 3'-5' GpG.

PubMed Central

Tomasz, J; Simoncsits, A; Kajtár, M; Krug, R M; Shatkin, A J

1978-01-01

A simple, two-step method is described for the synthesis of the 5'-pyro- and triphosphate derivatives of 3'-5' ApA, ApG, GpA and GpG. The readily accessible 2'(3')-5' ApA, ApG, GpA and GpG were converted in one step to the corresponding 5'-phosphoramidate derivatives which were then transformed to the 5'-pyro- and triphosphates. CD spectra of 3'-5' pn GpG (n = 0,1,2 or 3) derivatives, measured at pH 1, indicated stabilization of the (syn) G+p (anti)G conformation by the 5'-phosphate groups. PMID:211490

Comparison of cloned Kir2 channels with native inward rectifier K+ channels from guinea-pig cardiomyocytes

PubMed Central

Xin Liu, Gong; Derst, Christian; Schlichthörl, Günter; Heinen, Steffen; Seebohm, Guiscard; Brüggemann, Andrea; Kummer, Wolfgang; Veh, Rüdiger W; Daut, Jürgen; Preisig-Müller, Regina

2001-01-01

The aim of the study was to compare the properties of cloned Kir2 channels with the properties of native rectifier channels in guinea-pig (gp) cardiac muscle. The cDNAs of gpKir2.1, gpKir2.2, gpKir2.3 and gpKir2.4 were obtained by screening a cDNA library from guinea-pig cardiac ventricle. A partial genomic structure of all gpKir2 genes was deduced by comparison of the cDNAs with the nucleotide sequences derived from a guinea-pig genomic library. The cell-specific expression of Kir2 channel subunits was studied in isolated cardiomyocytes using a multi-cell RT-PCR approach. It was found that gpKir2.1, gpKir2.2 and gpKir2.3, but not gpKir2.4, are expressed in cardiomyocytes. Immunocytochemical analysis with polyclonal antibodies showed that expression of Kir2.4 is restricted to neuronal cells in the heart. After transfection in human embryonic kidney cells (HEK293) the mean single-channel conductance with symmetrical K+ was found to be 30.6 pS for gpKir2.1, 40.0 pS for gpKir2.2 and 14.2 pS for Kir2.3. Cell-attached measurements in isolated guinea-pig cardiomyocytes (n = 351) revealed three populations of inwardly rectifying K+ channels with mean conductances of 34.0, 23.8 and 10.7 pS. Expression of the gpKir2 subunits in Xenopus oocytes showed inwardly rectifying currents. The Ba2+ concentrations required for half-maximum block at -100 mV were 3.24 μm for gpKir2.1, 0.51 μm for gpKir2.2, 10.26 μm for gpKir2.3 and 235 μm for gpKir2.4. Ba2+ block of inward rectifier channels of cardiomyocytes was studied in cell-attached recordings. The concentration and voltage dependence of Ba2+ block of the large-conductance inward rectifier channels was virtually identical to that of gpKir2.2 expressed in Xenopus oocytes. Our results suggest that the large-conductance inward rectifier channels found in guinea-pig cardiomyocytes (34.0 pS) correspond to gpKir2.2. The intermediate-conductance (23.8 pS) and low-conductance (10.7 pS) channels described here may correspond to gpKir2.1 and gpKir2.3, respectively. PMID:11283229

Molecular cloning and sequence analysis of the Anticarsia gemmatalis multicapsid nuclear polyhedrosis virus GP64 glycoprotein.

PubMed

Pilloff, Marcela Gabriela; Bilen, Marcos Fabián; Belaich, Mariano Nicolás; Lozano, Mario Enrique; Ghiringhelli, Pablo Daniel

2003-01-01

The gp64 locus of Anticarsia gemmatalis multicapsid nucleopolyhedrovirus isolate Santa Fe (AgMNPV-SF) was characterised molecularly in our laboratory. To this end, we have located and cloned a AgMNPV-SF genomic DNA fragment containing the gp64 gene and sequenced the complete gp64 locus. Nucleotide sequence analysis indicated that the AgMNPV gp64 gene consists of a 1500 nucleotide open reading frame (ORF), encoding a protein of 499 amino acids. Of the seven gp64 homologues identified to date, the AgMNPV gp64 ORF shared most sequence similarity with the gp64 gene of Orgyia pseudotsugata MNPV. The GP64 from AgMNPV is the smallest baculoviral envelope glycoprotein found to date, differing in 10 or more residues from the other group I nucleopolyhedroviruses. The biological activity of AgMNPV GP64 protein was assessed by cell fusion assays in UFL-AG-286 cells using the obtained recombinant plasmids. In the upstream and downstream regions, relative to the gp64 ORF, we found different conserved transcriptional and post-transcriptional regulatory elements, respectively.

‘Just a GP’: a mixed method study of undermining of general practice as a career choice in the UK

PubMed Central

Alberti, Hugh; Collingwood, Helen; Merritt, Kymberlee

2017-01-01

Objectives Failure to recruit sufficient applicants to general practice (GP) training has been a problem both nationally and internationally for many years and undermining of GP is one possible contributing factor. The aim of our study was to ascertain what comments, both negative and positive, are being made in UK clinical settings to GP trainees about GP and to further explore these comments and their influence on career choice. Methodology We conducted a mixed methods study. We surveyed all foundation doctors and GP trainees within one region of Health Education England regarding any comments they experienced relating to a career in GP. We also conducted six focus groups with early GP trainees to discuss any comments that they experienced and whether these comments had any influence on their or others career choice. Results Positive comments reported by trainees centred around the concept that choosing GP is a positive, family-focused choice which facilities a good work–life balance. Workload was the most common negative comment, alongside the notion of being ‘just a GP’; the belief that GP is boring, a waste of training and a second-class career choice. The reasons for and origin of the comments are multifactorial in nature. Thematic analysis of the focus groups identified key factors such as previous exposure to and experience of GP, family members who were GPs, GP role models, demographics of the clinician and referral behaviour. Trainees perceived that negative comments may be discouraging others from choosing GP as a career. Conclusion Our study demonstrates that negative comments towards GP as a career do exist within clinical settings and are having a potential impact on poor recruitment rates to GP training. We have identified areas in which further negative comments could be prevented by changing perceptions of GP as a career. Additional time spent in GP as undergraduates and postgraduates, and positive GP role models, could particularly benefit recruitment. We recommend that undermining of GP as a career choice be approached with a zero-tolerance policy. PMID:29102997

Role of the E2 Hypervariable Region (HVR1) in the Immunogenicity of a Recombinant Hepatitis C Virus Vaccine

PubMed Central

2018-01-01

ABSTRACT Current evidence supports a protective role for virus-neutralizing antibodies in immunity against hepatitis C virus (HCV) infection. Many cross-neutralizing monoclonal antibodies have been identified. These antibodies have been shown to provide protection or to clear infection in animal models. Previous clinical trials have shown that a gpE1/gpE2 vaccine can induce antibodies that neutralize the in vitro infectivity of all the major cell culture-derived HCV (HCVcc) genotypes around the world. However, cross-neutralization appeared to favor certain genotypes, with significant but lower neutralization against others. HCV may employ epitope masking to avoid antibody-mediated neutralization. Hypervariable region 1 (HVR1) at the amino terminus of glycoprotein E2 has been shown to restrict access to many neutralizing antibodies. Consistent with this, other groups have reported that recombinant viruses lacking HVR1 are hypersensitive to neutralization. It has been proposed that gpE1/gpE2 lacking this domain could be a better vaccine antigen to induce broadly neutralizing antibodies. In this study, we examined the immunogenicity of recombinant gpE1/gpE2 lacking HVR1 (ΔHVR1). Our results indicate that wild-type (WT) and ΔHVR1 gpE1/gpE2 antigens induced antibodies targeting many well-characterized cross-genotype-neutralizing epitopes. However, while the WT gpE1/gpE2 vaccine can induce cross-genotype protection against various genotypes of HCVcc and/or HCV-pseudotyped virus (HCVpp), antisera from ΔHVR1 gpE1/gpE2-immunized animals exhibited either reduced homologous neutralization activity compared to that of the WT or heterologous neutralization activity similar to that of the WT. These data suggest that ΔHVR1 gpE1/gpE2 is not a superior vaccine antigen. Based on previously reported chimpanzee protection data using WT gpE1/gpE2 and our current findings, we are preparing a combination vaccine including wild-type recombinant gpE1/gpE2 for clinical testing in the future. IMPORTANCE An HCV vaccine is an unmet medical need. Current evidence suggests that neutralizing antibodies play an important role in virus clearance, along with cellular immune responses. Previous clinical data showed that gpE1/gpE2 can effectively induce cross-neutralizing antibodies, although they favor certain genotypes. HCV employs HVR1 within gpE2 to evade host immune control. It has been hypothesized that the removal of this domain would improve the production of cross-neutralizing antibodies. In this study, we compared the immunogenicities of WT and ΔHVR1 gpE1/gpE2 antigens as vaccine candidates. Our results indicate that the ΔHVR1 gpE1/gpE2 antigen confers no advantages in the neutralization of HCV compared with the WT antigen. Previously, we showed that this WT antigen remains the only vaccine candidate to protect chimpanzees from chronic infection, contains multiple cross-neutralizing epitopes, and is well tolerated and immunogenic in humans. The current data support the further clinical development of this vaccine antigen component. PMID:29540595

Functional characterization of Autographa californica multiple nucleopolyhedrovirus gp16 (ac130)

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

Yang, Ming; Huang, Cui; Qian, Duo-Duo

2014-09-15

To investigate the function of Autographa californica multiple nucleopolyhedrovirus (AcMNPV) gp16, multiple gp16-knockout and repair mutants were constructed and characterized. No obvious difference in productivity of budded virus, DNA synthesis, late gene expression and morphogenesis was observed between gp16-knockout and repair viruses, but gp16 deletion resulted in six hours of lengthening in ST{sub 50} to the third instar Spodoptera exigua larvae in bioassays. GP16 was fractionated mainly in the light membrane fraction, by subcellular fractionation. A GP16-EGFP fusion protein was predominantly localized close around the nuclear membrane in infected cells, being coincident with formation of the vesicles associated with themore » nuclear membrane, which hosted nucleocapsids released from the nucleus. These data suggest that gp16 is not required for viral replication, but may be involved in membrane trafficking associated with the envelopment/de-envelopment of budded viruses when they cross over the nuclear membrane and pass through cytoplasm. - Highlights: • gp16 knockout and repair mutants of AcMNPV were constructed and characterized. • AcMNPV gp16 is not essential to virus replication. • Deletion of gp16 resulted in time lengthening to kill S. exigua larvae. • GP16 was localized close around the nuclear membrane of infected cells. • GP16 was fractionated in the light membrane fraction in subcellular fractionation.« less

Energetics of dendrimer binding to HIV-1 gp120-CD4 complex and mechanismic aspects of its role as an entry-inhibitor

NASA Astrophysics Data System (ADS)

Saurabh, Suman; Sahoo, Anil Kumar; Maiti, Prabal K.

2016-10-01

Experiments and computational studies have established that de-protonated dendrimers (SPL7013 and PAMAM) act as entry-inhibitors of HIV. SPL7013 based Vivagel is currently under clinical development. The dendrimer binds to gp120 in the gp120-CD4 complex, destabilizes it by breaking key contacts between gp120 and CD4 and prevents viral entry into target cells. In this work, we provide molecular details and energetics of the formation of the SPL7013-gp120-CD4 ternary complex and decipher modes of action of the dendrimer in preventing viral entry. It is also known from experiments that the dendrimer binds weakly to gp120 that is not bound to CD4. It binds even more weakly to the CD4-binding region of gp120 and thus cannot directly block gp120-CD4 complexation. In this work, we examine the feasibility of dendrimer binding to the gp120-binding region of CD4 and directly blocking gp120-CD4 complex formation. We find that the process of the dendrimer binding to CD4 can compete with gp120-CD4 binding due to comparable free energy change for the two processes, thus creating a possibility for the dendrimer to directly block gp120-CD4 complexation by binding to the gp120-binding region of CD4.

Investigating intermolecular forces associated with thrombus initiation using optical tweezers

NASA Astrophysics Data System (ADS)

Arya, Maneesh; Lopez, Jose A.; Romo, Gabriel M.; Dong, Jing-Fei; McIntire, Larry V.; Moake, Joel L.; Anvari, Bahman

2002-05-01

Thrombus formation occurs when a platelet membrane receptor, glycoprotein (GP) Ib-IX-V complex, binds to its ligand, von Willebrand factor (vWf), in the subendothelium or plasma. To determine which GP Ib-IX-V amino acid sequences are critical for bond formation, we have used optical tweezers to measure forces involved in the binding of vWf to GP Ib-IX-V variants. Inasmuch as GP Ib(alpha) subunit is the primary component in human GP Ib-IX-V complex that binds to vWf, and that canine GP Ib(alpha) , on the other hand, does not bind to human vWf, we progressively replaced human GP Ib(alpha) amino acid sequences with canine GP Ib(alpha) sequences to determine the sequences essential for vWf/GP Ib(alpha) binding. After measuring the adhesive forces between optically trapped, vWf-coated beads and GP Ib(alpha) variants expressed on mammalian cells, we determined that leucine- rich repeat 2 of GP Ib(alpha) was necessary for vWf/GP Ib-IX- V bond formation. We also found that deletion of the N- terminal flanking sequence and leucine-rich repeat 1 reduced adhesion strength to vWf but did not abolish binding. While divalent cations are known to influence binding of vWf, addition of 1mM CaCl2 had no effect on measured vWf/GP Ib(alpha) bond strengths.

Pathway and rate-limiting step of glyphosate degradation by Aspergillus oryzae A-F02.

PubMed

Fu, Gui-Ming; Chen, Yan; Li, Ru-Yi; Yuan, Xiao-Qiang; Liu, Cheng-Mei; Li, Bin; Wan, Yin

2017-09-14

Aspergillus oryzae A-F02, a glyphosate-degrading fungus, was isolated from an aeration tank in a pesticide factory. The pathway and rate-limiting step of glyphosate (GP) degradation were investigated through metabolite analysis. GP, aminomethylphosphonic acid (AMPA), and methylamine were detected in the fermentation liquid of A. oryzae A-F02, whereas sarcosine and glycine were not. The pathway of GP degradation in A. oryzae A-F02 was revealed: GP was first degraded into AMPA, which was then degraded into methylamine. Finally, methylamine was further degraded into other products. Investigating the effects of the exogenous addition of substrates and metabolites showed that the degradation of GP to AMPA is the rate-limiting step of GP degradation by A. oryzae A-F02. In addition, the accumulation of AMPA and methylamine did not cause feedback inhibition in GP degradation. Results showed that degrading GP to AMPA was a crucial step in the degradation of GP, which determines the degradation rate of GP by A. oryzae A-F02.

Ensilage and bioconversion of grape pomace into fuel ethanol.

PubMed

Zheng, Yi; Lee, Christopher; Yu, Chaowei; Cheng, Yu-Shen; Simmons, Christopher W; Zhang, Ruihong; Jenkins, Bryan M; VanderGheynst, Jean S

2012-11-07

Two types of grape pomace were ensiled with eight strains of lactic acid bacteria (LAB). Both fresh grape pomace (FrGP) and fermented grape pomace (FeGP) were preserved through alcoholic fermentation but not malolactic conversion. Water leaching prior to storage was used to reduce water-soluble carbohydrates and ethanol from FrGP and FeGP, respectively, to increase malolactic conversion. Leached FeGP had spoilage after 28 days of ensilage, whereas FrGP was preserved. Dilute acid pretreatment was examined for increasing the conversion of pomace to ethanol via Escherichia coli KO11 fermentation. Dilute acid pretreatment doubled the ethanol yield from FeGP, but it did not improve the ethanol yield from FrGP. The ethanol yields from raw pomace were nearly double the yields from the ensiled pomace. For this reason, the recovery of ethanol produced during winemaking from FeGP and ethanol produced during storage of FrGP is critical for the economical conversion of grape pomace to biofuel.

Structure of the Ebola Virus Glycoprotein Bound to An Antibody From a Human Survivor

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

Lee, J.E.; Fusco, M.L.; Hessell, A.J.

2009-05-20

Ebola virus (EBOV) entry requires the surface glycoprotein (GP) to initiate attachment and fusion of viral and host membranes. Here we report the crystal structure of EBOV GP in its trimeric, pre-fusion conformation (GP1+GP2) bound to a neutralizing antibody, KZ52, derived from a human survivor of the 1995 Kikwit outbreak. Three GP1 viral attachment subunits assemble to form a chalice, cradled by the GP2 fusion subunits, while a novel glycan cap and projected mucin-like domain restrict access to the conserved receptor-binding site sequestered in the chalice bowl. The glycocalyx surrounding GP is likely central to immune evasion and may explainmore » why survivors have insignificant neutralizing antibody titres. KZ52 recognizes a protein epitope at the chalice base where it clamps several regions of the pre-fusion GP2 to the amino terminus of GP1. This structure provides a template for unraveling the mechanism of EBOV GP-mediated fusion and for future immunotherapeutic development.« less

Evaluation of the immunogenicity of a transgenic tobacco plant expressing the recombinant fusion protein of GP5 of porcine reproductive and respiratory syndrome virus and B subunit of Escherichia coli heat-labile enterotoxin in pigs.

PubMed

Chia, Min-Yuan; Hsiao, Shih-Hsuan; Chan, Hui-Ting; Do, Yi-Yin; Huang, Pung-Ling; Chang, Hui-Wen; Tsai, Yi-Chieh; Lin, Chun-Ming; Pang, Victor Fei; Jeng, Chian-Ren

2011-04-15

Escherichia coli heat-labile enterotoxin B subunit (LTB) can be used as an adjuvant for co-administered antigens. Our previous study showed that the expression of neutralizing epitope GP5 of porcine reproductive and respiratory syndrome virus (PRRSV) in transgenic tobacco plant (GP5-T) could induce PRRSV-specific immune responses in pigs. A transgenic tobacco plant co-expressing LTB and PRRSV GP5 as a fusion protein (LTB-GP5-T) was further constructed and its immunogenicity was evaluated. Pigs were given orally three consecutive doses of equal concentration of recombinant GP5 protein expressed in leaves of LTB-GP5-T or GP5-T at a 2-week interval and challenged with PRRSV at 7 weeks post-initial immunization. Pigs receiving LTB-GP5-T or GP5-T developed PRRSV-specific antibody- and cell-mediated immunity and showed significantly lower viremia and tissue viral load and milder lung lesions than wild type tobacco plant (W-T). The LTB-GP5-T-treated group had relatively higher immune responses than the GP5-T-treated group, although the differences were not statistically significant. Copyright © 2011 Elsevier B.V. All rights reserved.

Engineering and exploitation of a fluorescent HIV-1 gp120 for live cell CD4 binding assays

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

Costantini, Lindsey M.; Irvin, Susan C.; Department of Microbiology and Immunology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461

The HIV-1 envelope glycoprotein, gp120, binds the host cell receptor, CD4, in the initial step of HIV viral entry and infection. This process is an appealing target for the development of inhibitory drugs and neutralizing antibodies. To study gp120 binding and intracellular trafficking, we engineered a fluorescent fusion of the humanized gp120 JRFL HIV-1 variant and GFP. Gp120-sfGFP is glycosylated with human sugars, robustly expressed, and secreted from cultured human cells. Protein dynamics, quality control, and trafficking can be visualized in live cells. The fusion protein can be readily modified with different gp120 variants or fluorescent proteins. Finally, secreted gp120-sfGFPmore » enables a sensitive and easy binding assay that can quantitatively screen potential inhibitors of gp120-CD4 binding on live cells via fluorescence imaging or laser scanning cytometry. This adaptable research tool should aid in studies of gp120 cell biology and the development of novel anti-HIV drugs. - Highlights: • Development of fluorescent protein labeled HIV-1 envelope gp120. • Imaging of gp120 dynamics and trafficking in live cells. • Quantitative visual assay of antibody-mediated inhibition of gp120 binding to CD4 on live cells.« less

gp160 of HIV-I synthesized by persistently infected Molt-3 cells is terminally glycosylated: evidence that cleavage of gp160 occurs subsequent to oligosaccharide processing.

PubMed

Merkle, R K; Helland, D E; Welles, J L; Shilatifard, A; Haseltine, W A; Cummings, R D

1991-10-01

The envelope glycoprotein of HIV-I in infected, cultured human T cells is synthesized as a precursor of apparent Mr 160 kDa (gp160) and is cleaved to two glycoproteins, gp120 and gp41, which are the mature envelope glycoproteins in the virus. Neither the temporal and spatial features of glycosylation nor the oligosaccharide processing and proteolytic cleavage of the envelope glycoprotein are well understood. To understand more about these events, we investigated the glycosylation and cleavage of the envelope glycoproteins in the CD4+ human cell line, Molt-3, persistently infected with HIV-I (HTLV IIIB). The carbohydrate analysis of gp160 and gp120 and the behavior of the glycoproteins and glycopeptides derived from them on immobilized lectins demonstrate that both of these glycoproteins contain complex- and high-mannose-type Asn-linked oligosaccharides. In addition, the N-glycanase-resistant oligosaccharides of gp120 were found to contain N-acetyl-galactosamine, a common constituent of Ser/Thr-linked oligosaccharides. Pulse-chase analysis of the conversion of [35S]cysteine-labeled gp160 showed that in Molt-3 cells it takes about 2 h for gp120 to arise with a half-time of conversion of about 5 h. At its earliest detectable occurrence, gp120 was found to contain complex-type Asn-linked oligosaccharides. Taken together, these results indicate that proteolytic cleavage of gp160 to gp120 and gp41 occurs either within the trans-Golgi or in a distal compartment.

Antigenicity and Immunogenicity of RV144 Vaccine AIDSVAX Clade E Envelope Immunogen Is Enhanced by a gp120 N-Terminal Deletion

PubMed Central

Liao, Hua-Xin; Tomaras, Georgia D.; Bonsignori, Mattia; Tsao, Chun-Yen; Hwang, Kwan-Ki; Chen, Haiyan; Lloyd, Krissey E.; Bowman, Cindy; Sutherland, Laura; Jeffries, Thomas L.; Kozink, Daniel M.; Stewart, Shelley; Anasti, Kara; Jaeger, Frederick H.; Parks, Robert; Yates, Nicole L.; Overman, R. Glenn; Sinangil, Faruk; Berman, Phillip W.; Pitisuttithum, Punnee; Kaewkungwal, Jaranit; Nitayaphan, Sorachai; Karasavva, Nicos; Rerks-Ngarm, Supachai; Kim, Jerome H.; Michael, Nelson L.; Zolla-Pazner, Susan; Santra, Sampa; Letvin, Norman L.; Harrison, Stephen C.

2013-01-01

An immune correlates analysis of the RV144 HIV-1 vaccine trial revealed that antibody responses to the gp120 V1/V2 region correlated inversely with infection risk. The RV144 protein immunogens (A244-rp120 and MN-rgp120) were modified by an N-terminal 11-amino-acid deletion (Δ11) and addition of a herpes simplex virus (HSV) gD protein-derived tag (gD). We investigated the effects of these modifications on gp120 expression, antigenicity, and immunogenicity by comparing unmodified A244 gp120 with both Δ11 deletion and gD tag and with Δ11 only. Analysis of A244 gp120, with or without Δ11 or gD, demonstrated that the Δ11 deletion, without the addition of gD, was sufficient for enhanced antigenicity to gp120 C1 region, conformational V2, and V1/V2 gp120 conformational epitopes. RV144 vaccinee serum IgGs bound more avidly to A244 gp120 Δ11 than to the unmodified gp120, and their binding was blocked by C1, V2, and V1/V2 antibodies. Rhesus macaques immunized with the three different forms of A244 gp120 proteins gave similar levels of gp120 antibody titers, although higher antibody titers developed earlier in A244 Δ11 gp120-immunized animals. Conformational V1/V2 monoclonal antibodies (MAbs) gave significantly higher levels of blocking of plasma IgG from A244 Δ11 gp120-immunized animals than IgG from animals immunized with unmodified A244 gp120, thus indicating a qualitative difference in the V1/V2 antibodies induced by A244 Δ11 gp120. These results demonstrate that deletion of N-terminal residues in the RV144 A244 gp120 immunogen improves both envelope antigenicity and immunogenicity. PMID:23175357

A new synthetic dialyzer with advanced permselectivity for enhanced low-molecular weight protein removal.

PubMed

Krieter, Detlef H; Lemke, Horst-Dieter; Wanner, Christoph

2008-07-01

Optimizing solute removal at minimized albumin loss is a major goal of dialyzer engineering. In a prospective, randomized, crossover study on eight patients (age 63 +/- 14 years) on maintenance hemodialysis, the new Baxter Xenium 170 high-flux dialyzer (BX), which contains a 1.7-m(2) PUREMA H dialysis membrane, was compared with two widely used reference high-flux dialyzers currently available for hemodialysis in North America, the Fresenius Optiflux 180 NR (FO) and the Gambro Polyflux 170 H (GP). Solute removal and biocompatibility were assessed in hemodialysis for 240 min at blood and dialysate flow rates of 300 and 500 mL/min, respectively. Additional ex vivo experiments detecting the interleukin-1beta (IL-1b) generation in recirculated donor blood were performed to demonstrate the pyrogen retention properties of the dialyzers. The instantaneous plasma clearances were similar for the three dialyzers except for cystatin c (cysc), for which a lower clearance was measured with FO as compared with BX and GP after 30 and 180 min of hemodialysis. The reduction ratios (RRs) corrected for the hemoconcentration of beta(2)-microglobulin and cysc were lower in FO (44 +/- 9 and 35 +/- 9%, respectively) versus BX (62 +/- 6 and 59 +/- 7%, respectively) and GP (61 +/- 7 and 56 +/- 8%, respectively). The RRs of the cytokine tumor necrosis factor alpha and interleukin-6 were not different between the dialyzers. The albumin loss was <300 mg for all filters. No differences between the dialyzers were found in the biocompatibility parameters showing very low leukocyte and complement activation. The ex vivo recirculation experiments revealed a significantly higher IL-1b generation for GP (710 +/- 585 pg/mL) versus BX (317 +/- 211 pg/mL) and FO (151 +/- 38 pg/mL). BX is characterized by a steep solute sieving profile with high low-molecular weight protein removal at virtually no albumin loss and an excellent biocompatibility. This improved performance may be regarded as a contribution to optimal dialysis therapy.

Socioeconomic inequity in health care utilization, Iran.

PubMed

Mohammadbeigi, Abolfazl; Hassanzadeh, Jafar; Eshrati, Babak; Rezaianzadeh, Abbas

2013-09-01

Reducing poor-rich inequities in health is one of the priorities of both national and international organizations and is also one of the main challenges of health sectors in Iran. Since, in the view of policy making, quantifying the size of inequity in health care utilization (HCU) is a prerequisite for achieving this goal, the current study aimed to determine and compare the socioeconomic inequity in HCU by concentration (C) index and odds ratio (OR). A total of 758 households, consisting of 2,131 subjects who were aged 15 or older, were involved in this cross-sectional study, and their data were gathered through interviews. Household economic index (HEI) was created by the factor analysis from the asset data. The C index and OR were used as measures to determine the overall inequity in HCU according to sex (male/female), living area (urban/rural), insurance, and types of HCU (general physician [GP], specialist, and Health Workers [HWs]). The overall rate of HCU was 66.4%. The rates of using GP, specialist care, and HW care were 21.4%, 21.6% and 21.8%, respectively. The overall inequity in HCU was equal to 0.05 (95% confidence interval; -0.069 to 0.165). The C indexes in HCU, according to the subgroups of HCU, were measured as 0.11 (0.09-0.12) for GP, 0.115 (0.01-0.13) for specialist and -0.065 (-0.08 to -0.05) for HWs. Although the rate of utilization increased from poor to rich quintiles, the inequity regarding sex and living area was also low and non-significant. People with higher HEI used more specialist and GP care, while people with lower HEI used more HW care. The inequity in HCU was low and non-significant in different quintiles of males, females, urban and rural, as well as those who were insured. Copyright © 2013 Ministry of Health, Saudi Arabia. Published by Elsevier Ltd. All rights reserved.

Structural and immunologic correlates of chemically stabilized HIV-1 envelope glycoproteins

PubMed Central

de Val, Natalia; Montefiori, David; Tomaras, Georgia D.; Shen, Xiaoying; Kalyuzhniy, Oleksandr; Sanders, Rogier W.; McCoy, Laura E.; Moore, John P.; Ward, Andrew B.

2018-01-01

Inducing broad spectrum neutralizing antibodies against challenging pathogens such as HIV-1 is a major vaccine design goal, but may be hindered by conformational instability within viral envelope glycoproteins (Env). Chemical cross-linking is widely used for vaccine antigen stabilization, but how this process affects structure, antigenicity and immunogenicity is poorly understood and its use remains entirely empirical. We have solved the first cryo-EM structure of a cross-linked vaccine antigen. The 4.2 Å structure of HIV-1 BG505 SOSIP soluble recombinant Env in complex with a CD4 binding site-specific broadly neutralizing antibody (bNAb) Fab fragment reveals how cross-linking affects key properties of the trimer. We observed density corresponding to highly specific glutaraldehyde (GLA) cross-links between gp120 monomers at the trimer apex and between gp120 and gp41 at the trimer interface that had strikingly little impact on overall trimer conformation, but critically enhanced trimer stability and improved Env antigenicity. Cross-links were also observed within gp120 at sites associated with the N241/N289 glycan hole that locally modified trimer antigenicity. In immunogenicity studies, the neutralizing antibody response to cross-linked trimers showed modest but significantly greater breadth against a global panel of difficult-to-neutralize Tier-2 heterologous viruses. Moreover, the specificity of autologous Tier-2 neutralization was modified away from the N241/N289 glycan hole, implying a novel specificity. Finally, we have investigated for the first time T helper cell responses to next-generation soluble trimers, and report on vaccine-relevant immunodominant responses to epitopes within BG505 that are modified by cross-linking. Elucidation of the structural correlates of a cross-linked viral glycoprotein will allow more rational use of this methodology for vaccine design, and reveals a strategy with promise for eliciting neutralizing antibodies needed for an effective HIV-1 vaccine. PMID:29746590

Designing a Soluble Near Full-Length HIV-1 GP41 Trimer

DTIC Science & Technology

2012-11-26

envelope; gp41 trimer; bacteriophage T4 display; prehairpin fusion intermediate. Background: The envelope glycoprotein gp41 is a key component of...protein into trimers and defined oligomers. These gp41 trimers were displayed on bacteriophage T4 capsid nanoparticles by attaching to the small...Construction of the Expression Vectors —All the gp41 constructs were generated by splicing-by- overlap extension PCR using wild-type HXB2 gp41 DNA

Rheological, mechanical and degradable properties of injectable chitosan/silk fibroin/hydroxyapatite/glycerophosphate hydrogels.

PubMed

Wu, Jingjing; Liu, Jiaoyan; Shi, Yanmei; Wan, Ying

2016-12-01

Silk fibroin (SF) and hydroxyapatite (HA) were incorporated into chitosan/glycerophosphate (GP) system to prepare new types of hydrogels. The formulated chitosan/SF/GP and chitosan/SF/HA/GP solutions were found to be injectable at room temperature, and able to form into hydrogels at near-physiological temperature and pH. Rheological measurements showed that elastic modulus of certain chitosan/SF/GP and chitosan/SF/HA/GP gels could reach around 1.8 and 15kPa, respectively, and was much higher than their respective viscous modulus. Compressive measurements revealed that some chitosan/SF/GP and chitosan/SF/HA/GP gels had 8 and 20-fold modulus and strength higher than the chitosan/GP gel, respectively, confirming that compressive properties of these gels were greatly improved. Results obtained from in vivo degradation demonstrated that degradation endurance of the optimized chitosan/SF/GP and chitosan/SF/HA/GP gels was significantly enhanced as compared to the chitosan/GP gel, and the degradation rate of the gels could be regulated by the SF component alone or by the combination of SF and HA components. Copyright © 2016 Elsevier Ltd. All rights reserved.

The Effects of IGF-1 on Trk Expressing DRG Neurons with HIV-gp120- Induced Neurotoxicity.

PubMed

Li, Hao; Liu, Zhen; Chi, Heng; Bi, Yanwen; Song, Lijun; Liu, Huaxiang

2016-01-01

HIV envelope glycoprotein gp120 is the main protein that causes HIVassociated sensory neuropathy. However, the underlying mechanisms of gp120-induced neurotoxicity are still unclear. There are lack effective treatments for relieving HIV-related neuropathic symptoms caused by gp120-induced neurotoxicity. In the present study, tyrosine kinase receptor (Trk)A, TrkB, and TrkC expression in primary cultured dorsal root ganglion (DRG) neurons with gp120-induced neurotoxicity was investigated. The effects of IGF-1 on distinct Trk-positive DRG neurons with gp120-induced neurotoxicity were also determined. The results showed that gp120 not only dose-dependently induced DRG neuronal apoptosis and inhibited neuronal survival and neurite outgrowth, but also decreased distinct Trk expression levels. IGF-1 rescued DRG neurons from apoptosis and improved neuronal survival of gp120 neurotoxic DRG neurons in vitro. IGF-1 also improved TrkA and TrkB, but not TrkC, expression in gp120 neurotoxic conditions. The effects of IGF-1 could be blocked by preincubation with the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002. These results suggested that gp120 may have a wide range of neurotoxicity on different subpopulations of DRG neurons, while IGF-1 might only relieve some subpopulations of DRG neurons with gp120-induced neurotoxicity. These data provide novel information of mechanisms of gp120 neurotoxicity on primary sensory neurons and the potential therapeutic effects of IGF-1 on gp120-induced neurotoxicity.

Direct interaction of the bacteriophage SPP1 packaging ATPase with the portal protein.

PubMed

Oliveira, Leonor; Cuervo, Ana; Tavares, Paulo

2010-03-05

DNA packaging in tailed bacteriophages and other viruses requires assembly of a complex molecular machine at a specific vertex of the procapsid. This machine is composed of the portal protein that provides a tunnel for DNA entry, an ATPase that fuels DNA translocation (large terminase subunit), and most frequently, a small terminase subunit. Here we characterized the interaction between the terminase ATPase subunit of bacteriophage SPP1 (gp2) and the procapsid portal vertex. We found, by affinity pulldown assays with purified proteins, that gp2 interacts with the portal protein, gp6, independently of the terminase small subunit gp1, DNA, or ATP. The gp2-procapsid interaction via the portal protein depends on gp2 concentration and requires the presence of divalent cations. Competition experiments showed that isolated gp6 can only inhibit gp2-procapsid interactions and DNA packaging at gp6:procapsid molar ratios above 10-fold. Assays with gp6 carrying mutations in distinct regions of its structure that affect the portal-induced stimulation of ATPase and DNA packaging revealed that none of these mutations impedes gp2-gp6 binding. Our results demonstrate that the SPP1 packaging ATPase binds directly to the portal and that the interaction is stronger with the portal embedded in procapsids. Identification of mutations in gp6 that allow for assembly of the ATPase-portal complex but impair DNA packaging support an intricate cross-talk between the two proteins for activity of the DNA translocation motor.

The Role of Conserved N-Linked Glycans on Ebola Virus Glycoprotein 2.

PubMed

Lennemann, Nicholas J; Walkner, Madeline; Berkebile, Abigail R; Patel, Neil; Maury, Wendy

2015-10-01

N-linked glycosylation is a common posttranslational modification found on viral glycoproteins (GPs) and involved in promoting expression, cellular attachment, protection from proteases, and antibody evasion. The GP subunit GP2 of filoviruses contains 2 completely conserved N-linked glycosylation sites (NGSs) at N563 and N618, suggesting that they have been maintained through selective pressures. We assessed mutants lacking these glycans for expression and function to understand the role of these sites during Ebola virus entry. Elimination of either GP2 glycan individually had a modest effect on GP expression and no impact on antibody neutralization of vesicular stomatitis virus pseudotyped with Ebola virus GP. However, loss of the N563 glycan enhanced entry by 2-fold and eliminated GP detection by a well-characterized monoclonal antibody KZ52. Loss of both sites dramatically decreased GP expression and abolished entry. Surprisingly, a GP that retained a single NGS at N563, eliminating the remaining 16 NGSs from GP1 and GP2, had detectable expression, a modest increase in entry, and pronounced sensitivity to antibody neutralization. Our findings support the importance of the GP2 glycans in GP expression/structure, transduction efficiency, and antibody neutralization, particularly when N-linked glycans are also removed from GP1. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Single-Chain Soluble BG505.SOSIP gp140 Trimers as Structural and Antigenic Mimics of Mature Closed HIV-1 Env.

PubMed

Georgiev, Ivelin S; Joyce, M Gordon; Yang, Yongping; Sastry, Mallika; Zhang, Baoshan; Baxa, Ulrich; Chen, Rita E; Druz, Aliaksandr; Lees, Christopher R; Narpala, Sandeep; Schön, Arne; Van Galen, Joseph; Chuang, Gwo-Yu; Gorman, Jason; Harned, Adam; Pancera, Marie; Stewart-Jones, Guillaume B E; Cheng, Cheng; Freire, Ernesto; McDermott, Adrian B; Mascola, John R; Kwong, Peter D

2015-05-01

Similar to other type I fusion machines, the HIV-1 envelope glycoprotein (Env) requires proteolytic activation; specifically, cleavage of a gp160 precursor into gp120 and gp41 subunits creates an N-terminal gp41 fusion peptide and permits folding from an immature uncleaved state to a mature closed state. While the atomic-level consequences of cleavage for HIV-1 Env are still being determined, the uncleaved state is antigenically distinct from the mature closed state, and cleavage has been reported to be essential for mimicry of the mature viral spike by soluble versions of Env. Here we report the redesign of a current state-of-the-art soluble Env mimic, BG505.SOSIP, to make it cleavage independent. Specifically, we replaced the furin cleavage site between gp120 and gp41 with Gly-Ser linkers of various lengths. The resultant linked gp120-gp41 constructs, termed single-chain gp140 (sc-gp140), exhibited different levels of structural and antigenic mimicry of the parent cleaved BG505.SOSIP. When constructs were subjected to negative selection to remove subspecies recognized by poorly neutralizing antibodies, trimers of high antigenic mimicry of BG505.SOSIP could be obtained; negative-stain electron microscopy indicated these to resemble the mature closed state. Higher proportions of BG505.SOSIP-trimer mimicry were observed in sc-gp140s with linkers of 6 or more residues, with a linker length of 15 residues exhibiting especially promising traits. Overall, flexible linkages between gp120 and gp41 in BG505.SOSIP can thus substitute for cleavage, and sc-gp140s that closely mimicked the vaccine-preferred mature closed state of Env could be obtained. The trimeric HIV-1 envelope glycoprotein (Env) is the sole target of virus-directed neutralizing antibody responses and a primary focus of vaccine design. Soluble mimics of Env have proven challenging to obtain and have been thought to require proteolytic cleavage into two-component subunits, gp120 and gp41, to achieve structural and antigenic mimicry of mature Env spikes on virions. Here we show that replacement of the cleavage site between gp120 and gp41 in a lead soluble gp140 construct, BG505.SOSIP, with flexible linkers can result in molecules that do not require cleavage to fold efficiently into the mature closed state. Our results provide insights into the impact of cleavage on HIV-1 Env folding. In some contexts such as genetic immunization, optimized cleavage-independent soluble gp140 constructs may have utility over the parental BG505.SOSIP, as they would not require furin cleavage to achieve mimicry of mature Env spikes on virions. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Derivative Free Gradient Projection Algorithms for Rotation

ERIC Educational Resources Information Center

Jennrich, Robert I.

2004-01-01

A simple modification substantially simplifies the use of the gradient projection (GP) rotation algorithms of Jennrich (2001, 2002). These algorithms require subroutines to compute the value and gradient of any specific rotation criterion of interest. The gradient can be difficult to derive and program. It is shown that using numerical gradients…

Susceptibility of Tsetse Species to Glossina pallidipes Salivary Gland Hypertrophy Virus (GpSGHV)

PubMed Central

Demirbas-Uzel, Güler; Kariithi, Henry M.; Parker, Andrew G.; Vreysen, Marc J. B.; Mach, Robert L.; Abd-Alla, Adly M. M.

2018-01-01

Salivary gland hytrosaviruses (SGHVs, family Hytrosaviridae) are non-occluded dsDNA viruses that are pathogenic to some dipterans. SGHVs primarily replicate in salivary glands (SG), thereby inducing overt salivary gland hypertrophy (SGH) symptoms in their adult hosts. SGHV infection of non-SG tissues results in distinct pathobiologies, including reproductive dysfunctions in tsetse fly, Glossina pallidipes (Diptera: Glossinidae) and house fly. Infection with the G. pallidipes virus (GpSGHV) resulted in the collapse of several laboratory colonies, which hindered the implementation of area wide integrated pest management (AW-IPM) programs that had a sterile insect technique (SIT) component. Although the impact of GpSGHV infection has been studied in some detail in G. pallidipes, the impact of the virus infection on other tsetse species remains largely unknown. In the current study, we assessed the susceptibility of six Glossina species (G. pallidipes, G. brevipalpis, G. m. morsitans, G. m. centralis, G. f. fuscipes, and G. p. gambiensis) to GpSGHV infections, and the impact of the viral infection on the fly pupation rate, adult emergence, and virus replication and transmission from the larval to adult stages. We also evaluated the ability of the virus to infect conspecific Glossina species through serial passages. The results indicate that the susceptibility of Glossina to GpSGHV varied widely amongst the tested species, with G. pallidipes and G. brevipalpis being the most susceptible and most refractory to the virus, respectively. Further, virus injection into the hemocoel of teneral flies led to increased viral copy number over time, while virus injection into the third instar larvae delayed adult eclosion. Except in G. pallidipes, virus injection either into the larvae or teneral adults did not induce any detectable SGH symptoms, although virus infections were PCR-detectable in the fly carcasses. Taken together, our results indicate that although GpSGHV may only cause minor damage in the mass-rearing of tsetse species other than G. pallidipes, preventive control measures are required to avoid viral contamination and transmission in the fly colonies, particularly in the facilities where multiple tsetse species are reared. PMID:29686664

Impact of rapid identification of positive blood cultures using the Verigene system on antibiotic prescriptions: A prospective study of community-onset bacteremia in a tertiary hospital in Japan.

PubMed

Hayakawa, Kayoko; Mezaki, Kazuhisa; Kobayakawa, Masao; Yamamoto, Kei; Mutoh, Yoshikazu; Tsuboi, Motoyuki; Hasimoto, Takehiro; Nagamatsu, Maki; Kutsuna, Satoshi; Takeshita, Nozomi; Katanami, Yuichi; Ishikane, Masahiro; Ohmagari, Norio

2017-01-01

Rapid identification of positive blood cultures is important for initiation of optimal treatment in septic patients. Effects of automated, microarray-based rapid identification systems on antibiotic prescription against community-onset bacteremia (COB) remain unclear. We prospectively enrolled 177 patients with 185 COB episodes (occurring within 72 h of admission) over 17 months. Bacteremia episodes due to gram-positive bacteria (GP) and gram-negative bacteria (GN) in the same patient were counted separately. For GP bacteremia, patients with ≥2 sets of positive blood cultures were included. The primary study objective was evaluating the rates of antibiotic prescription changes within 2 days of rapid identification using the Verigene system. Bacteremia due to GN and GP included 144/185 (77.8%) and 41/185 (22.2%) episodes, respectively. Antibiotic prescription changes occurred in 51/185 cases (27.6% [95%CI:21.3-34.6%]) after Verigene analysis and 70/185 cases (37.8% [30.8-45.2%]) after conventional identification and susceptibility testing. Prescription changes after Verigene identification were more frequent in GP (17/41[41.5%]) than in GN (34/144[23.5%]). Among bacteremia due to single pathogen targeted by Verigene test, bacterial identification agreement between the two tests was high (GP: 38/39[97.4%], GN: 116/116[100%]). The Verigene test correctly predicted targeted antimicrobial resistance. The durations between the initiation of incubation and reporting of the results for the Verigene system and conventional test was 28.3 h (IQR: 25.8-43.4 h) and 90.6 h (68.3-118.4 h), respectively. In only four of the seven episodes of COB in which two isolates were identified by conventional tests, the Verigene test correctly identified both organisms. We observed a high rate of antibiotic prescription changes after the Verigene test in a population with COB especially in GP. The Verigene test would be a useful tool in antimicrobial stewardship programs among patients with COB.

Targeting HIV-1 gp41-induced fusion and pathogenesis for anti-viral therapy.

PubMed

Garg, Himanshu; Viard, Mathias; Jacobs, Amy; Blumenthal, Robert

2011-12-01

HIV gp41 is a metastable protein whose native conformation is maintained in the form of a heterodimer with gp120. The non-covalently associated gp41/gp120 complex forms a trimer on the virus surface. As gp120 engages with HIV's receptor, CD4, and coreceptor, CXCR4 or CCR5, gp41 undergoes several conformational changes resulting in fusion between the viral and cellular membranes. Several lipophilic and amphiphilic domains have been shown to be critical in that process. While the obvious function of gp41 in viral entry is well-established its role in cellular membrane fusion and the link with pathogenesis are only now beginning to appear. Recent targeting of gp41 via fusion inhibitors has revealed an important role of this protein not only in viral entry but also in bystander apoptosis and HIV pathogenesis. Studies by our group and others have shown that the phenomenon of gp41-mediated hemifusion initiates apoptosis in bystander cells and correlates with virus pathogenesis. More interestingly, recent clinical evidence suggests that gp41 mutants arising after Enfuvirtide therapy are associated with CD4 cell increase and immunological benefits. This has in turn been correlated to a decrease in bystander apoptosis in our in vitro as well as in vivo assays. Although a great deal of work has been done to unravel HIV-1 gp41-mediated fusion mechanisms, the factors that regulate gp41-mediated fusion versus hemifusion and the mechanism by which hemifusion initiates bystander apoptosis are not fully understood. Further insight into these issues will open new avenues for drug development making gp41 a critical anti-HIV target both for neutralization and virus attenuation.

Alphavirus Replicon DNA Vectors Expressing Ebola GP and VP40 Antigens Induce Humoral and Cellular Immune Responses in Mice

PubMed Central

Ren, Shoufeng; Wei, Qimei; Cai, Liya; Yang, Xuejing; Xing, Cuicui; Tan, Feng; Leavenworth, Jianmei W.; Liang, Shaohui; Liu, Wenquan

2018-01-01

Ebola virus (EBOV) causes severe hemorrhagic fevers in humans, and no approved therapeutics or vaccine is currently available. Glycoprotein (GP) is the major protective antigen of EBOV, and can generate virus-like particles (VLPs) by co-expression with matrix protein (VP40). In this study, we constructed a recombinant Alphavirus Semliki Forest virus (SFV) replicon vector DREP to express EBOV GP and matrix viral protein (VP40). EBOV VLPs were successfully generated and achieved budding from 293 cells after co-transfection with DREP-based GP and VP40 vectors (DREP-GP+DREP-VP40). Vaccination of BALB/c mice with DREP-GP, DREP-VP40, or DREP-GP+DREP-VP40 vectors, followed by immediate electroporation resulted in a mixed IgG subclass production, which recognized EBOV GP and/or VP40 proteins. This vaccination regimen also led to the generation of both Th1 and Th2 cellular immune responses in mice. Notably, vaccination with DREP-GP and DREP-VP40, which produces both GP and VP40 antigens, induced a significantly higher level of anti-GP IgG2a antibody and increased IFN-γ secreting CD8+ T-cell responses relative to vaccination with DREP-GP or DREP-VP40 vector alone. Our study indicates that co-expression of GP and VP40 antigens based on the SFV replicon vector generates EBOV VLPs in vitro, and vaccination with recombinant DREP vectors containing GP and VP40 antigens induces Ebola antigen-specific humoral and cellular immune responses in mice. This novel approach provides a simple and efficient vaccine platform for Ebola disease prevention. PMID:29375526

P-glycoprotein induction in Caco-2 cells by newly synthetized thioxanthones prevents paraquat cytotoxicity.

PubMed

Silva, Renata; Palmeira, Andreia; Carmo, Helena; Barbosa, Daniel José; Gameiro, Mariline; Gomes, Ana; Paiva, Ana Mafalda; Sousa, Emília; Pinto, Madalena; Bastos, Maria de Lourdes; Remião, Fernando

2015-10-01

The induction of P-glycoprotein (P-gp), an ATP-dependent efflux pump, has been proposed as a strategy against the toxicity induced by P-gp substrates such as the herbicide paraquat (PQ). The aim of this study was to screen five newly synthetized thioxanthonic derivatives, a group known to interact with P-gp, as potential inducers of the pump's expression and/or activity and to evaluate whether they would afford protection against PQ-induced toxicity in Caco-2 cells. All five thioxanthones (20 µM) caused a significant increase in both P-gp expression and activity as evaluated by flow cytometry using the UIC2 antibody and rhodamine 123, respectively. Additionally, it was demonstrated that the tested compounds, when present only during the efflux of rhodamine 123, rapidly induced an activation of P-gp. The tested compounds also increased P-gp ATPase activity in MDR1-Sf9 membrane vesicles, indicating that all derivatives acted as P-gp substrates. PQ cytotoxicity was significantly reduced in the presence of four thioxanthone derivatives, and this protective effect was reversed upon incubation with a specific P-gp inhibitor. In silico studies showed that all the tested thioxanthones fitted onto a previously described three-feature P-gp induction pharmacophore. Moreover, in silico interactions between thioxanthones and P-gp in the presence of PQ suggested that a co-transport mechanism may be operating. Based on the in vitro activation results, a pharmacophore model for P-gp activation was built, which will be of further use in the screening for new P-gp activators. In conclusion, the study demonstrated the potential of the tested thioxanthonic compounds in protecting against toxic effects induced by P-gp substrates through P-gp induction and activation.

Registration of NE Trailblazer C-1, NE Trailblazer C0, NE Trailblazer C2, NE Trailblazer C3, NE Trailblazer C4, and NE Trailblazer C5 Switchgrass Germplasms

USDA-ARS?s Scientific Manuscript database

NE Trailblazer C-1 (GP-101, PI 672015), NE Trailblazer C0 (GP-100, PI 672014), NE Trailblazer C2 (GP-102, PI 672016), NE Trailblazer C3 (GP-103, PI 672017), NE Trailblazer C4 (GP-104, PI 672018), and NE Trailblazer C5 (GP-105, PI 672019) switchgrass (Panicum virgatum L.) germplasms were released by ...

Abcb1 in Pigs: Molecular cloning, tissues distribution, functional analysis, and its effect on pharmacokinetics of enrofloxacin

PubMed Central

Guo, Tingting; Huang, Jinhu; Zhang, Hongyu; Dong, Lingling; Guo, Dawei; Guo, Li; He, Fang; Bhutto, Zohaib Ahmed; Wang, Liping

2016-01-01

P-glycoprotein (P-gp) is one of the best-known ATP-dependent efflux transporters, contributing to differences in pharmacokinetics and drug-drug interactions. Until now, studies on pig P-gp have been scarce. In our studies, the full-length porcine P-gp cDNA was cloned and expressed in a Madin-Darby Canine Kidney (MDCK) cell line. P-gp expression was then determined in tissues and its role in the pharmacokinetics of oral enrofloxacin in pigs was studied. The coding region of pig Abcb1 gene was 3,861 bp, encoding 1,286 amino acid residues (Mw = 141,966). Phylogenetic analysis indicated a close evolutionary relationship between porcine P-gp and those of cow and sheep. Pig P-gp was successfully stably overexpressed in MDCK cells and had efflux activity for rhodamine 123, a substrate of P-gp. Tissue distribution analysis indicated that P-gp was highly expressed in brain capillaries, small intestine, and liver. In MDCK-pAbcb1 cells, enrofloxacin was transported by P-gp with net efflux ratio of 2.48 and the efflux function was blocked by P-gp inhibitor verapamil. High expression of P-gp in the small intestine could modify the pharmacokinetics of orally administrated enrofloxacin by increasing the Cmax, AUC and Ka, which was demonstrated using verapamil, an inhibitor of P-gp. PMID:27572343

Evaluation of a program to strengthen general practice care for patients with chronic disease in Germany.

PubMed

Wensing, Michel; Szecsenyi, Joachim; Stock, Christian; Kaufmann Kolle, Petra; Laux, Gunter

2017-01-21

A program to strengthen general practice care for patients with chronic disease was offered in Germany. Enrollment was a free individual choice for both patients and physicians. This study aimed to examine the long-term impact of this program. Two comparative evaluations were done, at 4 and 5 years (T1 and T2) after start of the program. In each year, patients in the program were compared with patients in usual care. Measures were based on routinely collected data and concerned 11 aspects of primary care and hospital care. Study groups were compared, using regression analysis adjusted for confounders and clustering. Data on 1.187.597 and 1.591.017 eligible patients were available for the analysis for T1 and T2, respectively. Compared to usual care, the program was associated with more visits to the GP per patient (adjusted difference at T2: +1.98), more drugs prescribed per patient (+0.071), lower percentage of drugs that should be avoided (-0.699), and lower yearly medication costs per patient (-85.39 euro). The number of referrals to ambulatory specialists, either with or without referral from GP, was reduced at T2. In hospital care, the program was associated with fewer hospital admissions per patient per year (-0.017) and fewer avoidable hospital admissions of all admissions (-1.165%). Total hospital costs were slightly higher in T1, but lower in T2. Days in hospital and number of readmissions were lower at T2 only. The program has increased the role of general practice in healthcare for patients who chose to be included in the program of intensified general practice care.

Space Science

NASA Image and Video Library

2000-04-12

The space vehicle Gravity Probe B (GP-B) is the relativity experiment developed at Stanford University to test two extraordinary predictions of Albert Einstein’s general theory of relativity. The experiment will measure, very precisely, the expected tiny changes in the direction of the spin axes of four gyroscopes contained in an Earth-orbiting satellite at a 400-mile altitude. So free are the gyroscopes from disturbance that they will provide an almost perfect space-time reference system. They will measure how space and time are very slightly warped by the presence of the Earth, and, more profoundly, how the Earth’s rotation very slightly drags space-time around with it. These effects, though small for the Earth, have far-reaching implications for the nature of matter and the structure of the Universe. GP-B is among the most thoroughly researched programs ever undertaken by NASA. This is the story of a scientific quest in which physicists and engineers have collaborated closely over many years. Inspired by their quest, they have invented a whole range of technologies that are already enlivening other branches of science and engineering. In this photograph, engineer Gary Reynolds is inspecting the inside of the probe neck during probe thermal repairs. GP-B is scheduled for launch in April 2004 and managed for NASA by the Marshall Space Flight Center. Development of the GP-B is the responsibility of Stanford University along with major subcontractor Lockheed Martin Corporation. (Image credit to Russ Leese, Gravity Probe B, Stanford University)

Identification of an urban fractured-rock aquifer dynamics using an evolutionary self-organizing modelling

NASA Astrophysics Data System (ADS)

Hong, Yoon-Seok; Rosen, Michael R.

2002-03-01

An urban fractured-rock aquifer system, where disposal of storm water is via 'soak holes' drilled directly into the top of fractured-rock basalt, has a highly dynamic nature where theories or knowledge to generate the model are still incomplete and insufficient. Therefore, formulating an accurate mechanistic model, usually based on first principles (physical and chemical laws, mass balance, and diffusion and transport, etc.), requires time- and money-consuming tasks. Instead of a human developing the mechanistic-based model, this paper presents an approach to automatic model evolution in genetic programming (GP) to model dynamic behaviour of groundwater level fluctuations affected by storm water infiltration. This GP evolves mathematical models automatically that have an understandable structure using function tree representation by methods of natural selection ('survival of the fittest') through genetic operators (reproduction, crossover, and mutation). The simulation results have shown that GP is not only capable of predicting the groundwater level fluctuation due to storm water infiltration but also provides insight into the dynamic behaviour of a partially known urban fractured-rock aquifer system by allowing knowledge extraction of the evolved models. Our results show that GP can work as a cost-effective modelling tool, enabling us to create prototype models quickly and inexpensively and assists us in developing accurate models in less time, even if we have limited experience and incomplete knowledge for an urban fractured-rock aquifer system affected by storm water infiltration.

Gravity Probe B Inspection

NASA Technical Reports Server (NTRS)

2000-01-01

The space vehicle Gravity Probe B (GP-B) is the relativity experiment developed at Stanford University to test two extraordinary predictions of Albert Einstein's general theory of relativity. The experiment will measure, very precisely, the expected tiny changes in the direction of the spin axes of four gyroscopes contained in an Earth-orbiting satellite at a 400-mile altitude. So free are the gyroscopes from disturbance that they will provide an almost perfect space-time reference system. They will measure how space and time are very slightly warped by the presence of the Earth, and, more profoundly, how the Earth's rotation very slightly drags space-time around with it. These effects, though small for the Earth, have far-reaching implications for the nature of matter and the structure of the Universe. GP-B is among the most thoroughly researched programs ever undertaken by NASA. This is the story of a scientific quest in which physicists and engineers have collaborated closely over many years. Inspired by their quest, they have invented a whole range of technologies that are already enlivening other branches of science and engineering. In this photograph, engineer Gary Reynolds is inspecting the inside of the probe neck during probe thermal repairs. GP-B is scheduled for launch in April 2004 and managed for NASA by the Marshall Space Flight Center. Development of the GP-B is the responsibility of Stanford University along with major subcontractor Lockheed Martin Corporation. (Image credit to Russ Leese, Gravity Probe B, Stanford University)

Investigation of the function of the putative self-association site of Epstein-Barr virus (EBV) glycoprotein 42 (gp42)

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

Rowe, Cynthia L., E-mail: c-rowe@northwestern.edu; Matsuura, Hisae, E-mail: hisaem@stanford.edu; Interdepartmental Biological Sciences Program, Northwestern University, Evanston, IL 60208

The Epstein-Barr virus (EBV) glycoprotein 42 (gp42) is a type II membrane protein essential for entry into B cells but inhibits entry into epithelial cells. X-ray crystallography suggests that gp42 may form dimers when bound to human leukocyte antigen (HLA) class II receptor (Mullen et al., 2002) or multimerize when not bound to HLA class II (Kirschner et al., 2009). We investigated this self-association of gp42 using several different approaches. We generated soluble mutants of gp42 containing mutations within the self-association site and found that these mutants have a defect in fusion. The gp42 mutants bound to gH/gL and HLAmore » class II, but were unable to bind wild-type gp42 or a cleavage mutant of gp42. Using purified gp42, gH/gL, and HLA, we found these proteins associate 1:1:1 by gel filtration suggesting that gp42 dimerization or multimerization does not occur or is a transient event undetectable by our methods.« less

[NF-kappaB-induced gp96 up-regulation promotes hepatocyte growth, cell cycle progression and transition].

PubMed

Feng, Cong; Wu, Bo; Fan, Hongxia; Li, Changfei; Meng, Songdong

2014-10-04

To investigate the mechanism of gp96 raised during hepatitis B virus (HBV) infection and the pathological mechanism. The mechanism of NF-KB activating gp96 expression was determined by bioinformatics analysis, luciferase reporter assay, real-time PCR and Western blot. The effect of over-expression and knockdown gp96 expression by transfection or RNA interference on hepatocyte proliferation, apoptosis and cell cycle was examined by CCK-8 and flow cytometry. The role of gp96 for HCC development was determined by epithelial-mesenchymal transition (EMT) and colony formation assay. NF-kB significantly increased the gp96 expression by binding to the NF-kappaB binding site. Over-expression and knockdown studies both show that gp96 promoted hepatocyte proliferation, inhibited apoptosis, and induced G0/G1 to S phase cell cycle progression. Moreover, gp96 induced epithelial-mesenchymal transition and increased colony formation ability of hepatocytes. Our results therefore provide insights in chronic HBV infection-induced gp96 expression, and indicate that elevated gp96 may contribute to HCC development during chronic inflammation.

Testing Einstein in Space: The Gravity Probe B Relativity Mission

NASA Astrophysics Data System (ADS)

Mester, John

The Gravity Probe B Relativity Mission was successfully launched on April 20, 2004 from Vandenberg Air Force Base in California, a culmination of 40 years of collaborative development at Stanford University and NASA. The goal of the GP-B experiment is to perform precision tests of two independent predictions of general relativity, the geodetic effect and frame dragging. On-orbit cryogenic operations lasted 17.3 months, exceeding requirements. Analysis of the science data is now in progress with a planned announcement of results scheduled for December 2007.

The Gravity-Probe-B relativity gyroscope experiment - Development of the prototype flight instrument

NASA Technical Reports Server (NTRS)

Turneaure, J. P.; Everitt, C. W. F.; Parkinson, B. W.; Bardas, D.; Breakwell, J. V.

1989-01-01

The Gravity-Probe-B relativity gyroscope experiment (GP-B) will measure the geodetic and frame-dragging precession rates of gyroscopes in a 650 km high polar orbit about the earth. The goal is to measure these two effects, which are predicted by Einstein's General Theory of Relativity, to 0.01 percent (geodetic) and 1 percent (frame-dragging). This paper presents the development progress for full-size prototype flight hardware including the gyroscopes, gyro readout and magnetic shielding system, and an integrated ground test instrument.

Enhanced Immune Responses to HIV-1 Envelope Elicited by a Vaccine Regimen Consisting of Priming with Newcastle Disease Virus Expressing HIV gp160 and Boosting with gp120 and SOSIP gp140 Proteins.

PubMed

Khattar, Sunil K; DeVico, Anthony L; LaBranche, Celia C; Panda, Aruna; Montefiori, David C; Samal, Siba K

2016-02-01

Newcastle disease virus (NDV) expressing HIV-1 BaL gp160 was evaluated either alone or with monomeric BaL gp120 and BaL SOSIP gp140 protein in a prime-boost combination in guinea pigs to enhance envelope (Env)-specific humoral and mucosal immune responses. We showed that a regimen consisting of an NDV prime followed by a protein boost elicited stronger serum and mucosal Th-1-biased IgG responses and neutralizing antibody responses than NDV-only immunizations. Additionally, these responses were higher after the gp120 than after the SOSIP gp140 protein boost. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

GP3 is a structural component of the PRRSV type II (US) virion

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

Lima, M. de; Departamento de Microbiologia e Parasitologia, Universidade Federal Fluminense, Niteroi, RJ; Ansari, I.H.

2009-07-20

Glycoprotein 3 (GP3) is a highly glycosylated PRRSV envelope protein which has been reported as being present in the virions of PRRSV type I, while missing in the type II PRRSV (US) virions. We herein present evidence that GP3 is indeed incorporated in the virus particles of a North American strain of PRRSV (FL12), at a density that is consistent with the minor structural role assigned to GP3 in members of the Arterivirus genus. Two 15aa peptides corresponding to two different immunodominant linear epitopes of GP3 derived from the North American strain of PRRSV (FL12) were used as antigen tomore » generate a rabbit monospecific antiserum to this protein. The specificity of this anti-GP3 antiserum was confirmed by radioimmunoprecipitation (RIP) assay using BHK-21 cells transfected with GP3 expressing plasmid, MARC-145 cells infected with FL12 PRRSV, as well as by confocal microscopy on PRRSV-infected MARC-145 cells. To test if GP3 is a structural component of the virion, {sup 35}S-labelled PRRSV virions were pelleted through a 30% sucrose cushion, followed by a second round of purification on a sucrose gradient (20-60%). Virions were detected in specific gradient fractions by radioactive counts and further confirmed by viral infectivity assay in MARC 145 cells. The GP3 was detected in gradient fractions containing purified virions by RIP using anti-GP3 antiserum. Predictably, the GP3 was less abundant in purified virions than other major structural envelope proteins such as GP5 and M. Further evidence of the presence of GP3 at the level of PRRSV FL12 envelope was obtained by immunogold staining of purified virions from the supernatant of infected cells with anti-GP3 antiserum. Taken together, these results indicate that GP3 is a minor structural component of the PRRSV type II (FL12 strain) virion, as had been previously described for PRRSV type I.« less

Identification and Characterization of a Broadly Cross-Reactive HIV-1 Human Monoclonal Antibody That Binds to Both gp120 and gp41

PubMed Central

Zhang, Mei-Yun; Yuan, Tingting; Li, Jingjing; Rosa Borges, Andrew; Watkins, Jennifer D.; Guenaga, Javier; Yang, Zheng; Wang, Yanping; Wilson, Richard; Li, Yuxing; Polonis, Victoria R.; Pincus, Seth H.; Ruprecht, Ruth M.; Dimitrov, Dimiter S.

2012-01-01

Identification of broadly cross-reactive HIV-1-neutralizing antibodies (bnAbs) may assist vaccine immunogen design. Here we report a novel human monoclonal antibody (mAb), designated m43, which co-targets the gp120 and gp41 subunits of the HIV-1 envelope glycoprotein (Env). M43 bound to recombinant gp140 s from various primary isolates, to membrane-associated Envs on transfected cells and HIV-1 infected cells, as well as to recombinant gp120 s and gp41 fusion intermediate structures containing N-trimer structure, but did not bind to denatured recombinant gp140 s and the CD4 binding site (CD4bs) mutant, gp120 D368R, suggesting that the m43 epitope is conformational and overlaps the CD4bs on gp120 and the N-trimer structure on gp41. M43 neutralized 34% of the HIV-1 primary isolates from different clades and all the SHIVs tested in assays based on infection of peripheral blood mononuclear cells (PBMCs) by replication-competent virus, but was less potent in cell line-based pseudovirus assays. In contrast to CD4, m43 did not induce Env conformational changes upon binding leading to exposure of the coreceptor binding site, enhanced binding of mAbs 2F5 and 4E10 specific for the membrane proximal external region (MPER) of gp41 Envs, or increased gp120 shedding. The overall modest neutralization activity of m43 is likely due to the limited binding of m43 to functional Envs which could be increased by antibody engineering if needed. M43 may represent a new class of bnAbs targeting conformational epitopes overlapping structures on both gp120 and gp41. Its novel epitope and possibly new mechanism(s) of neutralization could helpdesign improved vaccine immunogens and candidate therapeutics. PMID:22970187

Innate immunity glycoprotein gp-340 variants may modulate human susceptibility to dental caries

PubMed Central

Jonasson, Anette; Eriksson, Christer; Jenkinson, Howard F; Källestål, Carina; Johansson, Ingegerd; Strömberg, Nicklas

2007-01-01

Background Bacterial adhesion is an important determinant of colonization and infection, including dental caries. The salivary scavenger receptor cysteine-rich glycoprotein gp-340, which mediates adhesion of Streptococcus mutans (implicated in caries), harbours three major size variants, designated gp-340 I to III, each specific to an individual saliva. Here we have examined the association of the gp-340 I to III polymorphisms with caries experience and adhesion of S. mutans. Methods A case-referent study was performed in 12-year-old Swedish children with high (n = 19) or low (n = 19) caries experiences. We measured the gp-340 I to III saliva phenotypes and correlated those with multiple outcome measures for caries experience and saliva adhesion of S. mutans using the partial least squares (PLS) multivariate projection technique. In addition, we used traditional statistics and 2-year caries increment to verify the established PLS associations, and bacterial adhesion to purified gp-340 I to III proteins to support possible mechanisms. Results All except one subject were typed as gp-340 I to III (10, 23 and 4, respectively). The gp-340 I phenotype correlated positively with caries experience (VIP = 1.37) and saliva adhesion of S. mutans Ingbritt (VIP = 1.47). The gp-340 II and III phenotypes tended to behave in the opposite way. Moreover, the gp-340 I phenotype tended to show an increased 2-year caries increment compared to phenotypes II/III. Purified gp-340 I protein mediated markedly higher adhesion of S. mutans strains Ingbritt and NG8 and Lactococcus lactis expressing AgI/II adhesins (SpaP or PAc) compared to gp-340 II and III proteins. In addition, the gp-340 I protein appeared over represented in subjects positive for Db, an allelic acidic PRP variant associated with caries, and subjects positive for both gp-340 I and Db tended to experience more caries than those negative for both proteins. Conclusion Gp-340 I behaves as a caries susceptibility protein. PMID:17562017

The effect of altitude on breaking seed dormancy and stimulation of seed germination of Persian hogweed (Heracleum persicum).

PubMed

Salehani, M Khajavi; Mahmoudi, J; Mahdavi, S Kh; Habibzadeh, R

2013-01-01

Persian hogweed is a perennial herb and aromatic plant which has pharmaceutical and fodder values, and the main propagation method of this species is seed. The goal of this study was to investigate the effect of altitude on breaking dormancy and stimulate seed germination of this species. The study was designed and carried out using the test of seed analysis. For our purpose, seeds were collected from three different altitudes (1700, 2200, 2700 masl) in Kojoor area. After initial purification, germination percent (GP) and speed (GS) of each elevation were determined by cold stratification compared to control. According to results, control seeds did not germinate, showing that the seeds of this species need to be treated. Statistical analysis of results showed that there are significant differences between GP and GS of each elevation, as seeds of higher elevation had slower and less germination in longer periods. So, changes in elevation are an effective factor on seed germination characteristics of this species and this factor has to be considered in seed preparation and restoration with this species.

Interaction of pyridostigmine bromide and N,N-diethyl-m-toluamide alone and in combination with P-glycoprotein expressed in Escherichia coli leaky mutant.

PubMed

El-Masry, Eman M; Abou-Donia, Mohamed B

2006-05-01

P-glycoprotein (P-gp), the most extensively studied ATP-binding transporter, functions as a biological barrier by extruding toxic substances and xenobiotics out of the cell. This study was carried out to determine the effect of N,N-diethyl-m-toluamide (DEET) and pyridostigmine bromide (PB), alone and in combination, on P-gp expression using Escherichia coli leaky mutant transformed with Mdr1 gene (pT5-7/mdr1), which codes for P-gp or lactose permease (pT5-7/lacY) as negative control. Also, daunomycin (a known P-gp sustrate) was used as a positive control and reserpine (a known P-gp inhibitor) served as a negative control. An in vitro cell-resistant assay was used to monitor the potential of test compounds to interact with P-gp. Following exposure of the cells to pyridostigmine bromide or daunomycin, P-gp conferred significant resistance against both compounds, while reserpine and DEET significantly inhibited the glycoprotein. Cells were grown in the presence of noncytotoxic concentrations of daunomycin, pyridostigmine bromide, reserpine, or DEET, and membrane fractions were examined by Western immunoblotting for expression of P-gp. Daunomycin induced P-gp expression quantitatively more than pyridostigmine bromide, while reserpine and DEET significantly inhibited P-gp expression in cells harboring mdr1. Photoaffinity labeling experiment performed with the P-gp ligand [125I]iodoarylazidoprazosin demonstrated that compounds that induced or inhibited P-gp transport activity also bound to P-gp. DEET was also found to be a potent inhibitor of P-gp-mediated ATPase activity, whereas pyridostigmine bromide increased P-gp ATPase activity. Cells expressing P-gp or lac permease were exposed to pyridostigmine bromide and DEET, alone and in combination. Noncytotoxic concentrations of DEET significantly inhibited P-gp-mediated resistance against pyridostigmine bromide, resulting in a reduction of the number of effective drug interactions with biological targets. An explanation of these results might be that DEET is a third-generation inhibitor of P-gp; it has high potency and specificity for P-gp, it inhibits hydrolysis of ATP, it exerts no appreciable impact on cytochrome P-450 3A4, and it prevents transport of xenobiotics, such as pyridostigmine bromide, out of the cell. This conclusion explains, at least in part, the increased toxicity and bioavailability of pyridostigmine bromide following combined administration with DEET. This study improves our understanding of the basis of chemical interactions with DEET by defining the ability of drugs to interact with P-gp either as inhibitors or substrates, which may in turn lead to altered efficacy or toxicity.

Advances in PET Imaging of P-Glycoprotein Function at the Blood-Brain Barrier

PubMed Central

2012-01-01

Efflux transporter P-glycoprotein (P-gp) at the blood-brain barrier (BBB) restricts substrate compounds from entering the brain and may thus contribute to pharmacoresistance observed in patient groups with refractory epilepsy and HIV. Altered P-gp function has also been implicated in neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. Positron emission tomography (PET), a molecular imaging modality, has become a promising method to study the role of P-gp at the BBB. The first PET study of P-gp function was conducted in 1998, and during the past 15 years two main categories of P-gp PET tracers have been investigated: tracers that are substrates of P-gp efflux and tracers that are inhibitors of P-gp function. PET, as a noninvasive imaging technique, allows translational research. Examples of this are preclinical investigations of P-gp function before and after administering P-gp modulating drugs, investigations in various animal and disease models, and clinical investigations regarding disease and aging. The objective of the present review is to give an overview of available PET radiotracers for studies of P-gp and to discuss how such studies can be designed. Further, the review summarizes results from PET studies of P-gp function in different central nervous system disorders. PMID:23421673

Fusion proteins of HIV-1 envelope glycoprotein gp120 with CD4-induced antibodies showed enhanced binding to CD4 and CD4 binding site antibodies

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

Chen, Weizao, E-mail: chenw3@mail.nih.gov; Feng, Yang; Wang, Yanping

Highlights: Black-Right-Pointing-Pointer Some recombinant HIV-1 gp120s do not preserve their conformations on gp140s. Black-Right-Pointing-Pointer We hypothesize that CD4i antibodies could induce conformational changes in gp120. Black-Right-Pointing-Pointer CD4i antibodies enhance binding of CD4 and CD4bs antibodies to gp120. Black-Right-Pointing-Pointer CD4i antibody-gp120 fusion proteins could have potential as vaccine immunogens. -- Abstract: Development of successful AIDS vaccine immunogens continues to be a major challenge. One of the mechanisms by which HIV-1 evades antibody-mediated neutralizing responses is the remarkable conformational flexibility of its envelope glycoprotein (Env) gp120. Some recombinant gp120s do not preserve their conformations on gp140s and functional viral spikes, and exhibitmore » decreased recognition by CD4 and neutralizing antibodies. CD4 binding induces conformational changes in gp120 leading to exposure of the coreceptor-binding site (CoRbs). In this study, we test our hypothesis that CD4-induced (CD4i) antibodies, which target the CoRbs, could also induce conformational changes in gp120 leading to better exposed conserved neutralizing antibody epitopes including the CD4-binding site (CD4bs). We found that a mixture of CD4i antibodies with gp120 only weakly enhanced CD4 binding. However, such interactions in single-chain fusion proteins resulted in gp120 conformations which bound to CD4 and CD4bs antibodies better than the original or mutagenically stabilized gp120s. Moreover, the two molecules in the fusion proteins synergized with each other in neutralizing HIV-1. Therefore, fusion proteins of gp120 with CD4i antibodies could have potential as components of HIV-1 vaccines and inhibitors of HIV-1 entry, and could be used as reagents to explore the conformational flexibility of gp120 and mechanisms of entry and immune evasion.« less

Evaluation of humoral, mucosal, and cellular immune responses following co-immunization of HIV-1 Gag and Env proteins expressed by Newcastle disease virus

PubMed Central

Khattar, Sunil K; Palaniyandi, Senthilkumar; Samal, Sweety; LaBranche, Celia C; Montefiori, David C; Zhu, Xiaoping; Samal, Siba K

2015-01-01

The combination of multiple HIV antigens in a vaccine can broaden antiviral immune responses. In this study, we used NDV vaccine strain LaSota to generate rNDV (rLaSota/optGag) expressing human codon optimized p55 Gag protein of HIV-1. We examined the effect of co-immunization of rLaSota/optGag with rNDVs expressing different forms of Env protein gp160, gp120, gp140L [a version of gp140 that lacked cytoplasmic tail and contained complete membrane-proximal external region (MPER)] and gp140S (a version of gp140 that lacked cytoplasmic tail and distal half of MPER) on magnitude and breadth of humoral, mucosal and cellular immune responses in guinea pigs and mice. Our results showed that inclusion of rLaSota/optGag with rNDVs expressing different forms of Env HIV Gag did not affect the Env-specific humoral and mucosal immune responses in guinea pigs and that the potent immune responses generated against Env persisted for at least 13 weeks post immunization. The highest Env-specific humoral and mucosal immune responses were observed with gp140S+optGag group. The neutralizing antibody responses against HIV strains BaL.26 and MN.3 induced by gp140S+optGag and gp160+optGag were higher than those elicited by other groups. Inclusion of Gag with gp160, gp140S and gp140L enhanced the level of Env-specific IFN-γ-producing CD8+ T cells in mice. Inclusion of Gag with gp160 and gp140L also resulted in increased Env-specific CD4+ T cells. The level of Gag-specific CD8+ and CD4+ T cells was also enhanced in mice immunized with Gag along with gp140S and gp120. These results indicate lack of antigen interference in a vaccine containing rNDVs expressing Env and Gag proteins. PMID:25695657

Shedding of Ebola Virus Surface Glycoprotein Is a Mechanism of Self-regulation of Cellular Cytotoxicity and Has a Direct Effect on Virus Infectivity.

PubMed

Dolnik, Olga; Volchkova, Valentina A; Escudero-Perez, Beatriz; Lawrence, Philip; Klenk, Hans-Dieter; Volchkov, Viktor E

2015-10-01

The surface glycoprotein (GP) is responsible for Ebola virus (EBOV) attachment and membrane fusion during virus entry. Surface expression of highly glycosylated GP causes marked cytotoxicity via masking of a wide range of cellular surface molecules, including integrins. Considerable amounts of surface GP are shed from virus-infected cells in a soluble truncated form by tumor necrosis factor α-converting enzyme. In this study, the role of GP shedding was investigated using a reverse genetics approach by comparing recombinant viruses possessing amino acid substitutions at the GP shedding site. Virus with an L635V substitution showed a substantial decrease in shedding, whereas a D637V substitution resulted in a striking increase in the release of shed GP. Variations in shedding efficacy correlated with observed differences in the amounts of shed GP in the medium, GP present in virus-infected cells, and GP present on virions. An increase in shedding appeared to be associated with a reduction in viral cytotoxicity, and, vice versa, the virus that shed less was more cytotoxic. An increase in shedding also resulted in a reduction in viral infectivity, whereas a decrease in shedding efficacy enhanced viral growth characteristics in vitro. Differences in shedding efficacy and, as a result, differences in the amount of mature GP available for incorporation into budding virions did not equate to differences in overall release of viral particles. Likewise, data suggest that the resulting differences in the amount of mature GP on the cell surface led to variations in the GP content of released particles and, as a consequence, in infectivity. In conclusion, fine-tuning of the levels of EBOV GP expressed at the surface of virus-infected cells via GP shedding plays an important role in EBOV replication by orchestrating the balance between optimal virion GP content and cytotoxicity caused by GP. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Equitable health services for the young? A decomposition of income-related inequalities in young adults' utilization of health care in Northern Sweden.

PubMed

Mosquera, Paola A; Waenerlund, Anna-Karin; Goicolea, Isabel; Gustafsson, Per E

2017-01-18

Despite the goal of the Swedish health system to offer health care according to the principle of horizontal equity, little is known about the equality in access to health care use among young people. To explore this issue, the present study aimed i) to assess horizontal inequity in health care utilization among young people in Northern Sweden; and ii) to explore the contribution of different factors to explain the observed inequalities. Participants (N = 3016 youths aged 16-25 years) came from the "Health on Equal terms" survey conducted in 2014 in the four northernmost counties in Sweden. Concentration indices (C) and horizontal inequity indices (HI) were calculated to measure inequalities in the utilization of two health care services (general practitioners (GP) and youth clinics). The HI was calculated based on health care utilization and variables representing socioeconomic status (household income), health care needs factors and non-need factors affecting health care use. A decomposition analysis was carried out to explain the income-related inequalities. Results showed a significant positive income-related inequality for youth clinic utilization in women (C = 0.166) and total sample (C = 0.097), indicating that services were concentrated among the better-off. In contrast, general practitioner visits showed inequality pointing toward a higher utilization among less affluent individuals; significant in women (C = -0.079), men (C = -0.101) and pooled sample (C = -0.097). After taking health care needs into consideration, the utilization of youth clinics remained significantly pro-rich in women (HI = 0.121) and total sample (HI = 0.099); and consistently pro-poor for the GP visits in the pooled sample (HI = -0.058). The decomposition analyses suggest that socioeconomic inequalities explain a considerable portion of the pro-rich utilization of youth clinics services among young women. The corresponding analyses for GP visits showed that need factors and socioeconomic conditions accounted for the pro-poor concentration of GP visits. The distribution of GP visits among young people in Northern Sweden slightly favored the low-income group, and thus seems to meet the premises of horizontal equity. In contrast, the findings suggest substantial pro-rich horizontal inequity in the utilization of youth clinics among young women, which are largely rooted in socioeconomic inequalities.

Internalization and Axonal Transport of the HIV Glycoprotein gp120

PubMed Central

Berth, Sarah; Caicedo, Hector Hugo; Sarma, Tulika; Morfini, Gerardo

2015-01-01

The HIV glycoprotein gp120, a neurotoxic HIV glycoprotein that is overproduced and shed by HIV-infected macrophages, is associated with neurological complications of HIV such as distal sensory polyneuropathy, but interactions of gp120 in the peripheral nervous system remain to be characterized. Here, we demonstrate internalization of extracellular gp120 in a manner partially independent of binding to its coreceptor CXCR4 by F11 neuroblastoma cells and cultured dorsal root ganglion neurons. Immunocytochemical and pharmacological experiments indicate that gp120 does not undergo trafficking through the endolysosomal pathway. Instead, gp120 is mainly internalized through lipid rafts in a cholesterol-dependent manner, with a minor fraction being internalized by fluid phase pinocytosis. Experiments using compartmentalized microfluidic chambers further indicate that, after internalization, endocytosed gp120 selectively undergoes retrograde but not anterograde axonal transport from axons to neuronal cell bodies. Collectively, these studies illuminate mechanisms of gp120 internalization and axonal transport in peripheral nervous system neurons, providing a novel framework for mechanisms for gp120 neurotoxicity. PMID:25636314

Fluctuation Dynamics Analysis of gp120 Envelope Protein Reveals a Topologically Based Communication Network

PubMed Central

Shrivastava, Indira; LaLonde, Judith M.

2012-01-01

HIV infection is initiated by binding of the viral glycoprotein gp120, to the cellular receptor CD4. Upon CD4 binding, gp120 undergoes conformational change, permitting binding to the chemokine receptor. Crystal structures of gp120 ternary complex reveal the CD4 bound conformation of gp120. We report here the application of Gaussian Network Model (GNM) to the crystal structures of gp120 bound to CD4 or CD4 mimic and 17b, to study the collective motions of the gp120 core and determine the communication propensities of the residue network. The GNM fluctuation profiles identify residues in the inner domain and outer domain that may facilitate conformational change or stability, respectively. Communication propensities delineate a residue network that is topologically suited for signal propagation from the Phe43 cavity throughout the gp120 outer domain. . These results provide a new context for interpreting gp120 core envelope structure-function relationships. PMID:20718047

DIFFERENT PROTOCOLS OF POSTCONDITIONING DOES NOT ATTENUATE MESENTERIC ISCHEMIA-REPERFUSION INJURY AFTER SHORT-TERM REPERFUSION

PubMed Central

BRITO, Marcus Vinicius Henriques; YASOJIMA, Edson Yuzur; MACHADO, Andressa Abnader; SILVEIRA, Matheus Paiva Pacheco Reis; TEIXEIRA, Renan Kleber Costa; YAMAKI, Vitor Nagai; COSTA, Felipe Lobato da Silva

2017-01-01

ABSTRACT Background: Mesenteric ischemia is a challenging diagnosis. Delay in diagnosis can lead to extent bowel necrosis and poor outcomes. Ischemia and reperfusion syndrome plays an important role in this scenario. Aim: To access effects of different post-conditioning cycles on mesenteric ischemia-reperfusion syndrome. Method: Twenty-five rats were assigned into five groups: Sham, used to establish normal parameters; control group, submitted to mesenteric ischemia for 30 min; in groups GP3, GP1 and GP30, ischemia was followed by post-conditioning protocol, which consisted of 1 cycle of 3 min (GP3), 3 cycles of 1 min (GP1) or 6 cycles of 30 s (GP30), respectively. Ileum samples were harvested after one hour of reperfusion. Intestinal mucosal injury was evaluated through histopathological analysis. Results: The average of mesenteric injury degree was 0 in the sham group, 3.6 in the control group, 3.4 in GP3, 3.2 in GP1, and 3.0 in GP30; villous length average was 161.59 in sham group, 136.27 in control group, 135.89 in GP3, 129.46 in GP1, and 135.18 in GP30. Was found significant difference between sham and other groups (p<0.05); however, there was no difference among post-conditioning groups. Conclusion: Post-conditioning adopted protocols were not able to protect intestinal mucosa integrity after mesenteric ischemia and short term reperfusion. PMID:28489164

Generation and Characterization of Inhibitory Antibodies Specific to Guinea Pig CXCR1 and CXCR2.

PubMed

Tanaka, Kento; Yoshimura, Chigusa; Shiina, Tetsuo; Terauchi, Tomoko; Yoshitomi, Tomomi; Hirahara, Kazuki

2017-04-01

CXCR1 and CXCR2 are chemokine receptors that have different selectivity of chemokine ligands, but the distinct role of each receptor is not clearly understood. This is due to the absence of specific inhibitors in guinea pigs, which are the appropriate species for investigation of CXCR1 and CXCR2 because of their functional similarity to humans. In this study, we generated and evaluated monoclonal antibodies that specifically bound to guinea pig CXCR1 (gpCXCR1) and guinea pig CXCR2 (gpCXCR2) for acquisition of specific inhibitors. To assess the activity of antibodies, we established CHO-K1 cells stably expressing either gpCXCR1 or gpCXCR2 (CHO/gpCXCR1 or CHO/gpCXCR2). CHO/gpCXCR1 showed migration in response to guinea pig interleukin (IL)-8, and CHO/gpCXCR2 showed migration in response to both guinea pig IL-8 and guinea pig growth-regulated oncogene α. The receptor selectivities of the chemokines of guinea pigs were the same as the human orthologs. The inhibitory activities of the anti-gpCXCR1 and anti-gpCXCR2 monoclonal antibodies on cell migration were observed in a concentration-dependent manner. In conclusion, we successfully obtained inhibitory antibodies specific to gpCXCR1 and gpCXCR2. These inhibitory antibodies will be useful to clarify the physiological roles of CXCR1 and CXCR2 in guinea pigs.

The Tetherin Antagonism of the Ebola Virus Glycoprotein Requires an Intact Receptor-Binding Domain and Can Be Blocked by GP1-Specific Antibodies.

PubMed

Brinkmann, Constantin; Nehlmeier, Inga; Walendy-Gnirß, Kerstin; Nehls, Julia; González Hernández, Mariana; Hoffmann, Markus; Qiu, Xiangguo; Takada, Ayato; Schindler, Michael; Pöhlmann, Stefan

2016-12-15

The glycoprotein of Ebola virus (EBOV GP), a member of the family Filoviridae, facilitates viral entry into target cells. In addition, EBOV GP antagonizes the antiviral activity of the host cell protein tetherin, which may otherwise restrict EBOV release from infected cells. However, it is unclear how EBOV GP antagonizes tetherin, and it is unknown whether the GP of Lloviu virus (LLOV), a filovirus found in dead bats in Northern Spain, also counteracts tetherin. Here, we show that LLOV GP antagonizes tetherin, indicating that tetherin may not impede LLOV spread in human cells. Moreover, we demonstrate that appropriate processing of N-glycans in tetherin/GP-coexpressing cells is required for tetherin counteraction by EBOV GP. Furthermore, we show that an intact receptor-binding domain (RBD) in the GP1 subunit of EBOV GP is a prerequisite for tetherin counteraction. In contrast, blockade of Niemann-Pick disease type C1 (NPC1), a cellular binding partner of the RBD, did not interfere with tetherin antagonism. Finally, we provide evidence that an antibody directed against GP1, which protects mice from a lethal EBOV challenge, may block GP-dependent tetherin antagonism. Our data, in conjunction with previous reports, indicate that tetherin antagonism is conserved among the GPs of all known filoviruses and demonstrate that the GP1 subunit of EBOV GP plays a central role in tetherin antagonism. Filoviruses are reemerging pathogens that constitute a public health threat. Understanding how Ebola virus (EBOV), a highly pathogenic filovirus responsible for the 2013-2016 Ebola virus disease epidemic in western Africa, counteracts antiviral effectors of the innate immune system might help to define novel targets for antiviral intervention. Similarly, determining whether Lloviu virus (LLOV), a filovirus detected in bats in northern Spain, is inhibited by innate antiviral effectors in human cells might help to determine whether the virus constitutes a threat to humans. The present study shows that LLOV, like EBOV, counteracts the antiviral effector protein tetherin via its glycoprotein (GP), suggesting that tetherin does not pose a defense against LLOV spread in humans. Moreover, our work identifies the GP1 subunit of EBOV GP, in particular an intact receptor-binding domain, as critical for tetherin counteraction and provides evidence that antibodies directed against GP1 can interfere with tetherin counteraction. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Optimization techniques applied to passive measures for in-orbit spacecraft survivability

NASA Technical Reports Server (NTRS)

Mog, Robert A.; Price, D. Marvin

1987-01-01

Optimization techniques applied to passive measures for in-orbit spacecraft survivability, is a six-month study, designed to evaluate the effectiveness of the geometric programming (GP) optimization technique in determining the optimal design of a meteoroid and space debris protection system for the Space Station Core Module configuration. Geometric Programming was found to be superior to other methods in that it provided maximum protection from impact problems at the lowest weight and cost.

Millstone Angle Calibration 1989

DTIC Science & Technology

1990-09-14

tiltmeter calibration models are examined, ("A A 1 GAccession For NTIS GP\\A&I o DTIC TAB 0] Unannounced 01 Justificatlo By Distribution/ Avnilitb lty...parameters. T. A. Cott kindly added the ability to retrieve tiltmeter data from SATCIT raw data tapes to his program SATSNR and provided the program for my...AZLCAL and Current Method 17 3. THE ELEVATION JUMP PHENOMENON 27 3.1 AZLCAL Modeling 27 3.2 Elevation Rate Dependence 27 4. TILTMETER CALIBRATION 29 5

CGP lil-gp 2.1;1.02 User's Manual

NASA Technical Reports Server (NTRS)

Janikow, Cezary Z.; DeWeese, Scott W.

1997-01-01

This document describes extensions provided to lil-gp facilitating dealing with constraints. This document deals specifically with lil-gp 1.02, and the resulting extension is referred to as CGP lil-gp 2.1; 1.02 (the first version is for the extension, the second for the utilized lil-gp version). Unless explicitly needed to avoid confusion, version numbers are omitted.

9 CFR 85.6 - Interstate movement of pseudorabies vaccinate swine, except swine from qualified negative gene...

Code of Federal Regulations, 2010 CFR

2010-01-01

... enzyme-linked immunosorbent assay (ELISA) or a gpI Particle Concentration Fluorescence Immunoassay (PCFIA... negative; (iv) The date of the gpI ELISA or the gpI PCFIA approved differential pseudorabies test; and (v) The name of the laboratory that conducted the gpI ELISA or the gpI PCFIA approved differential...

9 CFR 85.6 - Interstate movement of pseudorabies vaccinate swine, except swine from qualified negative gene...

Code of Federal Regulations, 2011 CFR

2011-01-01

... enzyme-linked immunosorbent assay (ELISA) or a gpI Particle Concentration Fluorescence Immunoassay (PCFIA... negative; (iv) The date of the gpI ELISA or the gpI PCFIA approved differential pseudorabies test; and (v) The name of the laboratory that conducted the gpI ELISA or the gpI PCFIA approved differential...

9 CFR 85.6 - Interstate movement of pseudorabies vaccinate swine, except swine from qualified negative gene...

Code of Federal Regulations, 2012 CFR

2012-01-01

... enzyme-linked immunosorbent assay (ELISA) or a gpI Particle Concentration Fluorescence Immunoassay (PCFIA... negative; (iv) The date of the gpI ELISA or the gpI PCFIA approved differential pseudorabies test; and (v) The name of the laboratory that conducted the gpI ELISA or the gpI PCFIA approved differential...

9 CFR 85.6 - Interstate movement of pseudorabies vaccinate swine, except swine from qualified negative gene...

Code of Federal Regulations, 2014 CFR

2014-01-01

... enzyme-linked immunosorbent assay (ELISA) or a gpI Particle Concentration Fluorescence Immunoassay (PCFIA... negative; (iv) The date of the gpI ELISA or the gpI PCFIA approved differential pseudorabies test; and (v) The name of the laboratory that conducted the gpI ELISA or the gpI PCFIA approved differential...

9 CFR 85.6 - Interstate movement of pseudorabies vaccinate swine, except swine from qualified negative gene...

Code of Federal Regulations, 2013 CFR

2013-01-01

... enzyme-linked immunosorbent assay (ELISA) or a gpI Particle Concentration Fluorescence Immunoassay (PCFIA... negative; (iv) The date of the gpI ELISA or the gpI PCFIA approved differential pseudorabies test; and (v) The name of the laboratory that conducted the gpI ELISA or the gpI PCFIA approved differential...

HIV-1 gp41 and gp160 are hyperthermostable proteins in a mesophilic environment. Characterization of gp41 mutants.

PubMed

Krell, Tino; Greco, Frédéric; Engel, Olivier; Dubayle, Jean; Dubayle, Joseline; Kennel, Audrey; Charloteaux, Benoit; Brasseur, Robert; Chevalier, Michel; Sodoyer, Regis; El Habib, Raphaëlle

2004-04-01

HIV gp41(24-157) unfolds cooperatively over the pH range of 1.0-4.0 with T(m) values of > 100 degrees C. At pH 2.8, protein unfolding was 80% reversible and the DeltaH(vH)/DeltaH(cal) ratio of 3.7 is indicative of gp41 being trimeric. No evidence for a monomer-trimer equilibrium in the concentration range of 0.3-36 micro m was obtained by DSC and tryptophan fluorescence. Glycosylation of gp41 was found to have only a marginal impact on the thermal stability. Reduction of the disulfide bond or mutation of both cysteine residues had only a marginal impact on protein stability. There was no cooperative unfolding event in the DSC thermogram of gp160 in NaCl/P(i), pH 7.4, over a temperature range of 8-129 degrees C. When the pH was lowered to 5.5-3.4, a single unfolding event at around 120 degrees C was noted, and three unfolding events at 93.3, 106.4 and 111.8 degrees C were observed at pH 2.8. Differences between gp41 and gp160, and hyperthermostable proteins from thermophile organisms are discussed. A series of gp41 mutants containing single, double, triple or quadruple point mutations were analysed by DSC and CD. The impact of mutations on the protein structure, in the context of generating a gp41 based vaccine antigen that resembles a fusion intermediate state, is discussed. A gp41 mutant, in which three hydrophobic amino acids in the gp41 loop were replaced with charged residues, showed an increased solubility at neutral pH.

Differential regulation of glutathione peroxidase by selenomethionine and hyperoxia in endothelial cells.

PubMed Central

Jornot, L; Junod, A F

1995-01-01

We have studied the effect of selenomethionine (SeMet) and hyperoxia on the expression of glutathione peroxidase (GP) in human umbilical vein endothelial cells. Incubation of HUVEC with 1 x 10(-6) M SeMet for 24 h and 48 h caused a 65% and 86% increase in GP activity respectively. The same treatment did not result in significant changes in GP gene transcription and mRNA levels. Pactamycin, a specific inhibitor of the initiation step of translation, prevented the rise in GP activity induced by SeMet and caused an increase in GP mRNA in both cells grown in normal and SeMet-supplemented medium. Interestingly, SeMet supplementation stimulated the recruitment of GP mRNA from an untranslatable pool on to polyribosomes, so that the concentration of GP mRNA in polyribosomal translatable pools was 50% higher in cells grown in SeMet-supplemented medium than in cells grown in normal medium. On the other hand, cells exposed to 95% O2 for 3 days in normal medium showed a 60%, 394% and 81% increase in GP gene transcription rate, mRNA levels and activity respectively. Hyperoxia also stabilized GP mRNA. Hyperoxic cells grown in SeMet-supplemented medium did not show any change in GP gene transcription and mRNA levels, but expressed an 81% and 100% increase in GP activity and amount of GP mRNA associated with polyribosomes respectively, when compared with hyperoxic cells maintained in normal medium. Thus, GP appeared to be regulated post-transcriptionally, most probably co-translationally, in response to selenium availability, and transcriptionally and post-transcriptionally in response to oxygen. Images Figure 1 Figure 2 Figure 4 Figure 7 Figure 8 PMID:7887914

Biliary excretion of technetium-99m-sestamibi in wild-type dogs and in dogs with intrinsic (ABCB1-1Delta mutation) and extrinsic (ketoconazole treated) P-glycoprotein deficiency.

PubMed

Coelho, J C; Tucker, R; Mattoon, J; Roberts, G; Waiting, D K; Mealey, K L

2009-10-01

P-glycoprotein (P-gp), the product of ABCB1 gene, is thought to play a role in the biliary excretion of a variety of drugs, but specific studies in dogs have not been performed. Because a number of endogenous (ABCB1 polymorphisms) and exogenous (pharmacological P-gp inhibition) factors can interfere with normal P-gp function, a better understanding of P-gp's role in biliary drug excretion is crucial in preventing adverse drug reactions and drug-drug interactions in dogs. The objectives of this study were to compare biliary excretion of technetium-99m-sestamibi ((99m)Tc-MIBI), a radio-labelled P-gp substrate, in wild-type dogs (ABCB1 wild/wild), and dogs with intrinsic and extrinsic deficiencies in P-gp function. Dogs with intrinsic P-gp deficiency included ABCB1 mut/mut dogs, and dogs with presumed intermediate P-gp phenotype (ABCB1 mut/wild). Dogs with extrinsic P-gp deficiency were considered to be ABCB1 wild/wild dogs treated with the P-gp inhibitor ketoconazole (5 mg/kg PO q12h x 9 doses). Results from this study indicate that ABCB1 mut/mut dogs have significantly decreased biliary excretion of (99m)Tc-MIBI compared with ABCB1 wild/wild dogs. Treatment with ketoconazole significantly decreased biliary excretion of (99m)Tc-MIBI in ABCB1 wild/wild dogs. P-gp appears to play an important role in the biliary excretion of (99m)Tc-MIBI in dogs. It is likely that concurrent administration of a P-gp inhibitor such as ketoconazole will decrease P-gp-mediated biliary excretion of other substrate drugs as well.

Immunization With Fc-Based Recombinant Epstein–Barr Virus gp350 Elicits Potent Neutralizing Humoral Immune Response in a BALB/c Mice Model

PubMed Central

Zhao, Bingchun; Zhang, Xiao; Krummenacher, Claude; Song, Shuo; Gao, Ling; Zhang, Haojiong; Xu, Miao; Feng, Lin; Feng, Qisheng; Zeng, Musheng; Xu, Yuting; Zeng, Yixin

2018-01-01

Epstein–Barr virus (EBV) was the first human virus proved to be closely associated with tumor development, such as lymphoma, nasopharyngeal carcinoma, and EBV-associated gastric carcinoma. Despite many efforts to develop prophylactic vaccines against EBV infection and diseases, no candidates have succeeded in effectively blocking EBV infection in clinical trials. Previous investigations showed that EBV gp350 plays a pivotal role in the infection of B-lymphocytes. Nevertheless, using monomeric gp350 proteins as antigens has not been effective in preventing infection. Multimeric forms of the antigen are more potently immunogenic than monomers; however, the multimerization elements used in previous constructs are not approved for human clinical trials. To prepare a much-needed EBV prophylactic vaccine that is potent, safe, and applicable, we constructed an Fc-based form of gp350 to serve as a dimeric antigen. Here, we show that the Fc-based gp350 antigen exhibits dramatically enhanced immunogenicity compared with wild-type gp350 protein. The complete or partial gp350 ectodomain was fused with the mouse IgG2a Fc domain. Fusion with the Fc domain did not impair gp350 folding, binding to a conformation-dependent neutralizing antibody (nAb) and binding to its receptor by enzyme-linked immunosorbent assay and surface plasmon resonance. Specific antibody titers against gp350 were notably enhanced by immunization with gp350-Fc dimers compared with gp350 monomers. Furthermore, immunization with gp350-Fc fusion proteins elicited potent nAbs against EBV. Our data strongly suggest that an EBV gp350 vaccine based on Fc fusion proteins may be an efficient candidate to prevent EBV infection in clinical applications. PMID:29765376

The consequence of regional gradients of P-gp and CYP3A4 for drug-drug interactions by P-gp inhibitors and the P-gp/CYP3A4 interplay in the human intestine ex vivo.

PubMed

Li, Ming; de Graaf, Inge A M; van de Steeg, Evita; de Jager, Marina H; Groothuis, Geny M M

2017-04-01

Intestinal P-gp and CYP3A4 work coordinately to reduce the intracellular concentration of drugs, and drug-drug interactions (DDIs) based on this interplay are of clinical importance and require pre-clinical investigation. Using precision-cut intestinal slices (PCIS) of human jejunum, ileum and colon, we investigated the P-gp/CYP3A4 interplay and related DDIs with P-gp inhibitors at the different regions of the human intestine with quinidine (Qi), dual substrate of P-gp and CYP3A4, as probe. All the P-gp inhibitors increased the intracellular concentrations of Qi by 2.1-2.6 fold in jejunum, 2.6-3.8 fold in ileum but only 1.2-1.3 fold in colon, in line with the different P-gp expression in these intestinal regions. The selective P-gp inhibitors (CP100356 and PSC833) enhanced 3-hydroxy-quinidine (3OH-Qi) in jejunum and ileum, while dual inhibitors of P-gp and CYP3A4 (verapamil and ketoconazole) decreased the 3OH-Qi production, despite of the increased intracellular Qi concentration, due to inhibition of CYP3A4. The outcome of DDIs based on P-gp/CYP3A4 interplay, shown as remarkable changes in the intracellular concentration of both the parent drug and the metabolite, varied among the intestinal regions, probably due to the different expression of P-gp and CYP3A4, and were different from those found in rat PCIS, which may have important implications for the disposition and toxicity of drugs and their metabolites. Copyright © 2016 Elsevier Ltd. All rights reserved.

Chiral Thioxanthones as Modulators of P-glycoprotein: Synthesis and Enantioselectivity Studies.

PubMed

Lopes, Ana; Martins, Eva; Silva, Renata; Pinto, Madalena M M; Remião, Fernando; Sousa, Emília; Fernandes, Carla

2018-03-10

Recently, thioxanthone derivatives were found to protect cells against toxic P-glycoprotein (P-gp) substrates, acting as potent inducers/activators of this efflux pump. The study of new P-gp chiral modulators produced from thioxanthone derivatives could clarify the enantioselectivity of this ABC transporter towards this new class of modulators. The aim of this study was to evaluate the P-gp modulatory ability of four enantiomeric pairs of new synthesized chiral aminated thioxanthones (ATxs) 1 - 8 , studying the influence of the stereochemistry on P-gp induction/ activation in cultured Caco-2 cells. The data displayed that all the tested compounds (at 20 μM) significantly decreased the intracellular accumulation of a P-gp fluorescent substrate (rhodamine 123) when incubated simultaneously for 60 min, demonstrating an increased activity of the efflux, when compared to control cells. Additionally, all of them except ATx 3 (+), caused similar results when the accumulation of the P-gp fluorescent substrate was evaluated after pre-incubating cells with the test compounds for 24 h, significantly reducing the rhodamine 123 intracellular accumulation as a result of a significant increase in P-gp activity. However, ATx 2 (-) was the only derivative that, after 24 h of incubation, significantly increased P-gp expression. These results demonstrated a significantly increased P-gp activity, even without an increase in P-gp expression. Therefore, ATxs 1 - 8 were shown to behave as P-gp activators. Furthermore, no significant differences were detected in the activity of the protein when comparing the enantiomeric pairs. Nevertheless, ATx 2 (-) modulates P-gp expression differently from its enantiomer, ATx 1 (+). These results disclosed new activators and inducers of P-gp and highlight the existence of enantioselectivity in the induction mechanism.

Triorganotin Derivatives Induce Cell Death Effects on L1210 Leukemia Cells at Submicromolar Concentrations Independently of P-glycoprotein Expression.

PubMed

Bohacova, Viera; Seres, Mario; Pavlikova, Lucia; Kontar, Szilvia; Cagala, Martin; Bobal, Pavel; Otevrel, Jan; Brtko, Julius; Sulova, Zdena; Breier, Albert

2018-05-01

The acceleration of drug efflux activity realized by plasma membrane transporters in neoplastic cells, particularly by P-glycoprotein (P-gp, ABCB1 member of the ABC transporter family), represents a frequently observed molecular cause of multidrug resistance (MDR). This multiple resistance represents a real obstacle in the effective chemotherapy of neoplastic diseases. Therefore, identifying cytotoxic substances that are also effective in P-gp overexpressing cells may be useful for the rational design of substances for the treatment of malignancies with developed MDR. Here, we showed that triorganotin derivatives—tributyltin-chloride (TBT-Cl), tributyltin-bromide (TBT-Br), tributyltin-iodide (TBT-I) and tributyltin-isothiocyanate (TBT-NCS) or triphenyltin-chloride (TPT-Cl) and triphenyltin-isothiocyanate (TPT-NCS)—could induce the death of L1210 mice leukemia cells at a submicromolar concentration independently of P-gp overexpression. The median lethal concentration obtained for triorganotin derivatives did not exceed 0.5 µM in the induction of cell death of either P-gp negative or P-gp positive L1210 cells. Apoptosis related to regulatory pathway of Bcl-2 family proteins seems to be the predominant mode of cell death in either P-gp negative or P-gp positive L1210 cells. TBT-Cl and TBT-Br were more efficient with L1210 cells overexpressing P-gp than with their counterpart P-gp negative cells. In contrast, TBT-I and TPT-NCS induced a more pronounced cell death effect on P-gp negative cells than on P-gp positive cells. Triorganotin derivatives did not affect P-gp efflux in native cells measured by calcein retention within the cells. Taken together, we assumed that triorganotin derivatives represent substances suitable for suppressing the viability of P-gp positive malignant cells.

Features of intrinsic ganglionated plexi in both atria after extensive pulmonary isolation and their clinical significance after catheter ablation in patients with atrial fibrillation.

PubMed

Kurotobi, Toshiya; Shimada, Yoshihisa; Kino, Naoto; Ito, Kazato; Tonomura, Daisuke; Yano, Kentaro; Tanaka, Chiharu; Yoshida, Masataka; Tsuchida, Takao; Fukumoto, Hitoshi

2015-03-01

The features of intrinsic ganglionated plexi (GP) in both atria after extensive pulmonary vein isolation (PVI) and their clinical implications have not been clarified in patients with atrial fibrillation (AF). The purpose of this study was to assess the features of GP response after extensive PVI and to evaluate the relationship between GP responses and subsequent AF episodes. The study population consisted of 216 consecutive AF patients (104 persistent AF) who underwent an initial ablation. We searched for the GP sites in both atria after an extensive PVI. GP responses were determined in 186 of 216 patients (85.6%). In the left atrium, GP responses were observed around the right inferior GP in 116 of 216 patients (53.7%) and around the left inferior GP in 57 of 216 (26.4%). In the right atrium, GP responses were observed around the posteroseptal area: inside the CS in 64 of 216 patients (29.6%), at the CS ostium in 150 of 216 (69.4%), and in the lower right atrium in 45 of 216 (20.8%). The presence of a positive GP response was an independent risk factor for AF recurrence (hazard ratio 4.04, confidence interval 1.48-11.0) in patients with paroxysmal, but not persistent, AF. The incidence of recurrent atrial tachyarrhythmias in patients with paroxysmal AF with a positive GP response was 51% vs 8% in those without a GP response (P = .002). The presence of GP responses after extensive PVI was significantly associated with increased AF recurrence after ablation in patients with paroxysmal AF. Copyright © 2015 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

A Homolog Pentameric Complex Dictates Viral Epithelial Tropism, Pathogenicity and Congenital Infection Rate in Guinea Pig Cytomegalovirus.

PubMed

Coleman, Stewart; Choi, K Yeon; Root, Matthew; McGregor, Alistair

2016-07-01

In human cytomegalovirus (HCMV), tropism to epithelial and endothelial cells is dependent upon a pentameric complex (PC). Given the structure of the placenta, the PC is potentially an important neutralizing antibody target antigen against congenital infection. The guinea pig is the only small animal model for congenital CMV. Guinea pig cytomegalovirus (GPCMV) potentially encodes a UL128-131 HCMV PC homolog locus (GP128-GP133). In transient expression studies, GPCMV gH and gL glycoproteins interacted with UL128, UL130 and UL131 homolog proteins (designated GP129 and GP131 and GP133 respectively) to form PC or subcomplexes which were determined by immunoprecipitation reactions directed to gH or gL. A natural GP129 C-terminal deletion mutant (aa 107-179) and a chimeric HCMV UL128 C-terminal domain swap GP129 mutant failed to form PC with other components. GPCMV infection of a newly established guinea pig epithelial cell line required a complete PC and a GP129 mutant virus lacked epithelial tropism and was attenuated in the guinea pig for pathogenicity and had a low congenital transmission rate. Individual knockout of GP131 or 133 genes resulted in loss of viral epithelial tropism. A GP128 mutant virus retained epithelial tropism and GP128 was determined not to be a PC component. A series of GPCMV mutants demonstrated that gO was not strictly essential for epithelial infection whereas gB and the PC were essential. Ectopic expression of a GP129 cDNA in a GP129 mutant virus restored epithelial tropism, pathogenicity and congenital infection. Overall, GPCMV forms a PC similar to HCMV which enables evaluation of PC based vaccine strategies in the guinea pig model.

Ebola virus glycoprotein needs an additional trigger, beyond proteolytic priming for membrane fusion.

PubMed

Bale, Shridhar; Liu, Tong; Li, Sheng; Wang, Yuhao; Abelson, Dafna; Fusco, Marnie; Woods, Virgil L; Saphire, Erica Ollmann

2011-11-01

Ebolavirus belongs to the family filoviridae and causes severe hemorrhagic fever in humans with 50-90% lethality. Detailed understanding of how the viruses attach to and enter new host cells is critical to development of medical interventions. The virus displays a trimeric glycoprotein (GP(1,2)) on its surface that is solely responsible for membrane attachment, virus internalization and fusion. GP(1,2) is expressed as a single peptide and is cleaved by furin in the host cells to yield two disulphide-linked fragments termed GP1 and GP2 that remain associated in a GP(1,2) trimeric, viral surface spike. After entry into host endosomes, GP(1,2) is enzymatically cleaved by endosomal cathepsins B and L, a necessary step in infection. However, the functional effects of the cleavage on the glycoprotein are unknown. We demonstrate by antibody binding and Hydrogen-Deuterium Exchange Mass Spectrometry (DXMS) of glycoproteins from two different ebolaviruses that although enzymatic priming of GP(1,2) is required for fusion, the priming itself does not initiate the required conformational changes in the ectodomain of GP(1,2). Further, ELISA binding data of primed GP(1,2) to conformational antibody KZ52 suggests that the low pH inside the endosomes also does not trigger dissociation of GP1 from GP2 to effect membrane fusion. The results reveal that the ebolavirus GP(1,2) ectodomain remains in the prefusion conformation upon enzymatic cleavage in low pH and removal of the glycan cap. The results also suggest that an additional endosomal trigger is necessary to induce the conformational changes in GP(1,2) and effect fusion. Identification of this trigger will provide further mechanistic insights into ebolavirus infection.

A Homolog Pentameric Complex Dictates Viral Epithelial Tropism, Pathogenicity and Congenital Infection Rate in Guinea Pig Cytomegalovirus

PubMed Central

McGregor, Alistair

2016-01-01

In human cytomegalovirus (HCMV), tropism to epithelial and endothelial cells is dependent upon a pentameric complex (PC). Given the structure of the placenta, the PC is potentially an important neutralizing antibody target antigen against congenital infection. The guinea pig is the only small animal model for congenital CMV. Guinea pig cytomegalovirus (GPCMV) potentially encodes a UL128-131 HCMV PC homolog locus (GP128-GP133). In transient expression studies, GPCMV gH and gL glycoproteins interacted with UL128, UL130 and UL131 homolog proteins (designated GP129 and GP131 and GP133 respectively) to form PC or subcomplexes which were determined by immunoprecipitation reactions directed to gH or gL. A natural GP129 C-terminal deletion mutant (aa 107–179) and a chimeric HCMV UL128 C-terminal domain swap GP129 mutant failed to form PC with other components. GPCMV infection of a newly established guinea pig epithelial cell line required a complete PC and a GP129 mutant virus lacked epithelial tropism and was attenuated in the guinea pig for pathogenicity and had a low congenital transmission rate. Individual knockout of GP131 or 133 genes resulted in loss of viral epithelial tropism. A GP128 mutant virus retained epithelial tropism and GP128 was determined not to be a PC component. A series of GPCMV mutants demonstrated that gO was not strictly essential for epithelial infection whereas gB and the PC were essential. Ectopic expression of a GP129 cDNA in a GP129 mutant virus restored epithelial tropism, pathogenicity and congenital infection. Overall, GPCMV forms a PC similar to HCMV which enables evaluation of PC based vaccine strategies in the guinea pig model. PMID:27387220

Short-term streamflow forecasting with global climate change implications A comparative study between genetic programming and neural network models

NASA Astrophysics Data System (ADS)

Makkeasorn, A.; Chang, N. B.; Zhou, X.

2008-05-01

SummarySustainable water resources management is a critically important priority across the globe. While water scarcity limits the uses of water in many ways, floods may also result in property damages and the loss of life. To more efficiently use the limited amount of water under the changing world or to resourcefully provide adequate time for flood warning, the issues have led us to seek advanced techniques for improving streamflow forecasting on a short-term basis. This study emphasizes the inclusion of sea surface temperature (SST) in addition to the spatio-temporal rainfall distribution via the Next Generation Radar (NEXRAD), meteorological data via local weather stations, and historical stream data via USGS gage stations to collectively forecast discharges in a semi-arid watershed in south Texas. Two types of artificial intelligence models, including genetic programming (GP) and neural network (NN) models, were employed comparatively. Four numerical evaluators were used to evaluate the validity of a suite of forecasting models. Research findings indicate that GP-derived streamflow forecasting models were generally favored in the assessment in which both SST and meteorological data significantly improve the accuracy of forecasting. Among several scenarios, NEXRAD rainfall data were proven its most effectiveness for a 3-day forecast, and SST Gulf-to-Atlantic index shows larger impacts than the SST Gulf-to-Pacific index on the streamflow forecasts. The most forward looking GP-derived models can even perform a 30-day streamflow forecast ahead of time with an r-square of 0.84 and RMS error 5.4 in our study.

Diagnostic Potential of Zymogen Granule Glycoprotein 2 Antibodies as Serologic Biomarkers in Chinese Patients With Crohn Disease.

PubMed

Zhang, Shulan; Wu, Ziyan; Luo, Jing; Ding, Xuefeng; Hu, Chaojun; Li, Ping; Deng, Chuiwen; Zhang, Fengchun; Qian, Jiaming; Li, Yongzhe

2015-10-01

The need for reliable biomarkers for distinguishing Crohn disease (CD) from ulcerative colitis (UC) is increasing. This study aimed at evaluating the diagnostic potential of anti-GP2 antibodies as a biomarker in Chinese patients with CD. In addition, a variety of autoantibodies, including anti-saccharomyces cerevisiae antibodies (ASCA), perinuclear anti-neutrophil cytoplasmic antibodies (PANCA), anti-intestinal goblet cell autoantibodies (GAB), and anti-pancreatic autoantibodies (PAB), were evaluated.A total of 91 subjects were prospectively enrolled in this study, including 35 patients with CD, 35 patients with UC, 13 patients with non-IBD gastrointestinal diseases as disease controls (non-IBD DC), and 8 healthy controls (HC). The diagnosis of IBD was determined based on the Lennard-Jones criteria, and the clinical phenotypes of the IBD patients were determined based on the Montreal Classification.Anti-GP2 IgG antibodies were significantly elevated in patients with CD, compared with patients with UC (P = 0.0038), HC (P = 0.0055), and non-IBD DC (P = 0.0063). The prevalence of anti-GP2 IgG, anti-GP2 IgA and anti-GP2 IgA, or IgG antibodies in patients with CD was 40.0%, 37.1%, and 54.3%, respectively, which were higher than those in non-IBD DC (anti-GP2 IgG, 15.4%; anti-GP2 IgA, 7.7%; and anti-GP2 IgA or IgG, 23.1%) and those in patients with UC (anti-GP2 IgG, 11.4%; anti-GP2 IgA, 2.9%; and anti-GP2 IgA or IgG, 14.3%). For distinguishing CD from UC, the sensitivity, specificity, positive predictive value (PPV) and positive likelihood ratios (LR+) were 40%, 88.6%, 77.8%, and 3.51 for anti-GP2 IgG, 37.1%, 97.1%, 92.9%, and 13.0 for anti-GP2 IgA, and 54.3%, 85.3%, 79.2%, and 3.69 for anti-GP2 IgA or IgG. For CD diagnosis, the combination of anti-GP2 antibodies with ASCA IgA increased the sensitivity to 68.6% with moderate loss of specificity to 74.3%. Spearman's rank of order revealed a significantly positive correlation of anti-GP2 IgG with ileocolonic location of disease (L3) (P = 0.043) and a negative correlation of anti-GP2 IgA with biologic therapy (P = 0.012).Our findings suggest that anti-GP2 antibodies could serve as a biomarker for distinguishing patients with CD from patients with UC, and the combination of anti-GP2 antibodies with ASCA IgA may improve the predictive power.

Cellular immune response to β2-glycoprotein-I valine/leucine247 phenotypes in Mexican patients with primary antiphospholipid syndrome.

PubMed

Núñez-Álvarez, Carlos A; Hernández-Ramírez, Diego F; Martinez-Castillo, Araceli; Pascual Ramos, Virginia; Cabiedes, Javier; Ortega, Alicia; Cabral, Antonio R

2017-02-01

Homozygote genotype V 247 of the β 2 -glycoprotein-I (β 2 GP-I) gene has been associated with anti-β 2 GP-I and thrombosis in patients with primary anti-phospholipid syndrome APS (PAPS). However, the cellular immune response to β 2 GP-I 247 has been little studied. To evaluate the immune cellular proliferation in response to native and non-native β 2 GP-I 247 valine/leucine phenotype from Mexican patients with PAPS. We studied 10 patients with PAPS and 10 healthy control subjects (HC). The polymorphism at position 247 of the β 2 GP-I gene was determined by PCR-RFLP and the corresponding β 2 GP-I protein was subsequently purified from normal human plasma by affinity chromatography. PBMC purified from patients and controls were stimulated with β 2 GP-I under native and in non native (reduced) conditions. We also determined the anti-β 2 GP-I production in vitro by B cell clones (EBV) generated in cocultures experiments. Differential Scanning Calorimetry (DSC) was studied to determine the structural differences between the β 2 GP-I 247 valine/leucine isoforms. Cytokine profile (IL-2, IL-4, IL-6, TNFα, INFγ) was evaluated in culture supernatants. PAPS and healthy control PBMCs had a higher proliferative response when stimulated with β 2 GP-I under reduced cultures conditions compared to non-denatured conditions. PBMCs response from PAPS patients was higher. We observed more cell proliferation in response to β 2 GP-I 247 valine/leucine or valine isoforms in non-native conditions. In contrast, this response was not significant against β 2 GP-I 247 leucine. These findings were T CD4 + -dependent. Similar results were obtained with B cell clones derived from PAPS patients, which showed more pronounced proliferation in non native conditions and higher against β 2 GP-I 247 valine. No differences were found in anti-β 2 GP-I production, but high levels of IL-6 in vitro were identified. The structural analysis of both β 2 GP-I 247 isoforms by DSC showed a major conformational change due to a single mutation in the β 2 GP-I variants. PAPS PBMCs had a higher cellular response against β 2 GP-I 247 in non-native culture conditions preferentially to the β 2 GP-I 247 valine phenotype. This effect is T CD4 + dependent and appears to be driven by tertiary structural changes adopted by β 2 GP-I 247 polymorphism. Copyright © 2016 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

Host-Primed Ebola Virus GP Exposes a Hydrophobic NPC1 Receptor-Binding Pocket, Revealing a Target for Broadly Neutralizing Antibodies.

PubMed

Bornholdt, Zachary A; Ndungo, Esther; Fusco, Marnie L; Bale, Shridhar; Flyak, Andrew I; Crowe, James E; Chandran, Kartik; Saphire, Erica Ollmann

2016-02-23

The filovirus surface glycoprotein (GP) mediates viral entry into host cells. Following viral internalization into endosomes, GP is cleaved by host cysteine proteases to expose a receptor-binding site (RBS) that is otherwise hidden from immune surveillance. Here, we present the crystal structure of proteolytically cleaved Ebola virus GP to a resolution of 3.3 Å. We use this structure in conjunction with functional analysis of a large panel of pseudotyped viruses bearing mutant GP proteins to map the Ebola virus GP endosomal RBS at molecular resolution. Our studies indicate that binding of GP to its endosomal receptor Niemann-Pick C1 occurs in two distinct stages: the initial electrostatic interactions are followed by specific interactions with a hydrophobic trough that is exposed on the endosomally cleaved GP1 subunit. Finally, we demonstrate that monoclonal antibodies targeting the filovirus RBS neutralize all known filovirus GPs, making this conserved pocket a promising target for the development of panfilovirus therapeutics. Ebola virus uses its glycoprotein (GP) to enter new host cells. During entry, GP must be cleaved by human enzymes in order for receptor binding to occur. Here, we provide the crystal structure of the cleaved form of Ebola virus GP. We demonstrate that cleavage exposes a site at the top of GP and that this site binds the critical domain C of the receptor, termed Niemann-Pick C1 (NPC1). We perform mutagenesis to find parts of the site essential for binding NPC1 and map distinct roles for an upper, charged crest and lower, hydrophobic trough in cleaved GP. We find that this 3-dimensional site is conserved across the filovirus family and that antibody directed against this site is able to bind cleaved GP from every filovirus tested and neutralize viruses bearing those GPs. Copyright © 2016 Bornholdt et al.

Registration of Katelyn Thlaspi arvense L. (Pennycress) with improved nondormant traits

USDA-ARS?s Scientific Manuscript database

Katelyn (Reg. No. GP-35, PI 673443) pennycress (Thlaspi arvense L.) was publicly released by the USDA-ARS in 2014 as part of a new crop improvement program. Katelyn was developed by two generations of mass selection based on the germination response of freshly harvested pennycress seeds. The origina...

Emodin reverses leukemia multidrug resistance by competitive inhibition and downregulation of P-glycoprotein

PubMed Central

Min, Hongping; Niu, Miaomiao; Zhang, Weilin; Yan, Jia; Li, Jiachang; Tan, Xiying; Li, Bo; Su, Mengxiang; Di, Bin; Yan, Fang

2017-01-01

Development of multidrug resistance (MDR) is a continuous clinical challenge partially due to the overexpression of P-glycoprotein (P-gp) for chronic myelogenous leukemia (CML) patients. Herein, we evaluated the inhibitory potency of emodin, a natural anthraquinone derivative isolated from Rheum palmatum L, on P-gp in P-gp positive K562/ADM cells. Competition experiments combined with molecular docking analysis were utilized to investigate the binding modes between emodin and binding sites of P-gp. Emodin reversed adriamycin resistance in K562/ADM cells accompanied with the decrease of P-gp protein expression, further increasing the uptake of rhodamine123 in both K562/ADM and Caco-2 cells, indicating the inhibition of P-gp efflux function. Moreover, when incubated with emodin under different conditions where P-gp was inhibited, K562/ADM cells displayed increasing intracellular uptake of emodin, suggesting that emodin may be the potential substrate of P-gp. Importantly, rhodamine 123 could increase the Kintrinsic (Ki) value of emodin linearly, whereas, verapamil could not, implying that emodin competitively bound to the R site of P-gp and noncompetition existed between emodin and verapamil at the M site, in a good accordance with the results of molecular docking that emodin bound to the R site of P-gp with higher affinity. Based on our results, we suggest that emodin might be used to modulate P-gp function and expression. PMID:29121121

Emodin reverses leukemia multidrug resistance by competitive inhibition and downregulation of P-glycoprotein.

PubMed

Min, Hongping; Niu, Miaomiao; Zhang, Weilin; Yan, Jia; Li, Jiachang; Tan, Xiying; Li, Bo; Su, Mengxiang; Di, Bin; Yan, Fang

2017-01-01

Development of multidrug resistance (MDR) is a continuous clinical challenge partially due to the overexpression of P-glycoprotein (P-gp) for chronic myelogenous leukemia (CML) patients. Herein, we evaluated the inhibitory potency of emodin, a natural anthraquinone derivative isolated from Rheum palmatum L, on P-gp in P-gp positive K562/ADM cells. Competition experiments combined with molecular docking analysis were utilized to investigate the binding modes between emodin and binding sites of P-gp. Emodin reversed adriamycin resistance in K562/ADM cells accompanied with the decrease of P-gp protein expression, further increasing the uptake of rhodamine123 in both K562/ADM and Caco-2 cells, indicating the inhibition of P-gp efflux function. Moreover, when incubated with emodin under different conditions where P-gp was inhibited, K562/ADM cells displayed increasing intracellular uptake of emodin, suggesting that emodin may be the potential substrate of P-gp. Importantly, rhodamine 123 could increase the Kintrinsic (Ki) value of emodin linearly, whereas, verapamil could not, implying that emodin competitively bound to the R site of P-gp and noncompetition existed between emodin and verapamil at the M site, in a good accordance with the results of molecular docking that emodin bound to the R site of P-gp with higher affinity. Based on our results, we suggest that emodin might be used to modulate P-gp function and expression.

Evaluation of designed ligands by a multiple screening method: Application to glycogen phosphorylase inhibitors constructed with a variety of approaches

NASA Astrophysics Data System (ADS)

So, Sung-Sau; Karplus, Martin

2001-07-01

Glycogen phosphorylase (GP) is an important enzyme that regulates blood glucose level and a key therapeutic target for the treatment of type II diabetes. In this study, a number of potential GP inhibitors are designed with a variety of computational approaches. They include the applications of MCSS, LUDI and CoMFA to identify additional fragments that can be attached to existing lead molecules; the use of 2D and 3D similarity-based QSAR models (HQSAR and SMGNN) and of the LUDI program to identify novel molecules that may bind to the glucose binding site. The designed ligands are evaluated by a multiple screening method, which is a combination of commercial and in-house ligand-receptor binding affinity prediction programs used in a previous study (So and Karplus, J. Comp.-Aid. Mol. Des., 13 (1999), 243-258). Each method is used at an appropriate point in the screening, as determined by both the accuracy of the calculations and the computational cost. A comparison of the strengths and weaknesses of the ligand design approaches is made.

Characterisation of gp34, a GPI-anchored protein expressed by schizonts of Theileria parva and T. annulata

PubMed Central

Xue, Gondga; von Schubert, Conrad; Hermann, Pascal; Peyer, Martina; Maushagen, Regina; Schmuckli-Maurer, Jacqueline; Bütikofer, Peter; Langsley, Gordon; Dobbelaere, Dirk A.E.

2010-01-01

Using bioinformatics tools, we searched the predicted Theileria annulata and T. parva proteomes for putative schizont surface proteins. This led to the identification of gp34, a GPI-anchored protein that is stage-specifically expressed by schizonts of both Theileria species and is downregulated upon induction of merogony. Transfection experiments in HeLa cells showed that the gp34 signal peptide and GPI anchor signal are also functional in higher eukaryotes. Epitope-tagged Tp-gp34, but not Ta-gp34, expressed in the cytosol of COS-7 cells was found to localise to the central spindle and midbody. Overexpression of Tp-gp34 and Ta-gp34 induced cytokinetic defects and resulted in accumulation of binucleated cells. These findings suggest that gp34 could contribute to important parasite–host interactions during host cell division. PMID:20381541

Effectiveness of comprehensive care programs for patients with multiple chronic conditions or frailty: A systematic literature review.

PubMed

Hopman, Petra; de Bruin, Simone R; Forjaz, Maria João; Rodriguez-Blazquez, Carmen; Tonnara, Giuseppe; Lemmens, Lidwien C; Onder, Graziano; Baan, Caroline A; Rijken, Mieke

2016-07-01

To describe comprehensive care programs targeting multimorbid and/or frail patients and to estimate their effectiveness regarding improvement of patient and caregiver related outcomes, healthcare utilization and costs. Systematic search in six electronic databases for scientific papers published between January 2011 and March 2014, supplemented by reference tracking. Wagner's Chronic Care Model (CCM) was used to operationalize comprehensive care. The quality of the included studies was assessed, and a best-evidence synthesis was applied. Nineteen publications were included describing effects of eighteen comprehensive care programs for multimorbid or frail patients, of which only one was implemented in a European country. Programs varied in target groups, settings, interventions and number of CCM components addressed. Providing comprehensive care might result in more patient satisfaction, less depressive symptoms, a better health-related quality of life or functioning of multimorbid or frail patients, but the evidence is insufficient. There is no evidence that comprehensive care reduces the number of primary care or GP visits or healthcare costs. Regarding the use of inpatient care, the evidence was insufficient. No evidence was found for a beneficial effect of comprehensive care on caregiver-related outcomes. Despite the fact that over the years several (good-quality) studies have been performed to estimate the value of comprehensive care for multimorbid and/or frail patients, evidence for their effectiveness remains insufficient. More good-quality studies and/or studies allowing meta-analysis are needed to determine which specific target groups at what moment will benefit from comprehensive care. Moreover, evaluation studies could improve by using more appropriate outcome measures, e.g. measures that relate to patient-defined (personal) goals of care. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Toxoplasma gondii Requires Glycogen Phosphorylase for Balancing Amylopectin Storage and for Efficient Production of Brain Cysts.

PubMed

Sugi, Tatsuki; Tu, Vincent; Ma, Yanfen; Tomita, Tadakimi; Weiss, Louis M

2017-08-29

In immunocompromised hosts, latent infection with Toxoplasma gondii can reactivate from tissue cysts, leading to encephalitis. A characteristic of T. gondii bradyzoites in tissue cysts is the presence of amylopectin granules. The regulatory mechanisms and role of amylopectin accumulation in this organism are not fully understood. The T. gondii genome encodes a putative glycogen phosphorylase (TgGP), and mutants were constructed to manipulate the activity of TgGP and to evaluate the function of TgGP in amylopectin storage. Both a stop codon mutant (Pru/TgGP S25stop [expressing a Ser-to-stop codon change at position 25 in TgGP]) and a phosphorylation null mutant (Pru/TgGP S25A [expressing a Ser-to-Ala change at position 25 in TgGp]) mutated at Ser25 displayed amylopectin accumulation, while the phosphorylation-mimetic mutant (Pru/TgGP S25E [expressing a Ser-to-Glu change at position 25 in TgGp]) had minimal amylopectin accumulation under both tachyzoite and bradyzoite growth conditions. The expression of active TgGP S25S or TgGP S25E restored amylopectin catabolism in Pru/TgGP S25A To understand the relation between GP and calcium-dependent protein kinase 2 (CDPK2), which was recently reported to regulate amylopectin consumption, we knocked out CDPK2 in these mutants. Pru Δcdpk2 /TgGP S25E had minimal amylopectin accumulation, whereas the Δcdpk2 phenotype in the other GP mutants and parental lines displayed amylopectin accumulation. Both the inactive S25A and hyperactive S25E mutant produced brain cysts in infected mice, but the numbers of cysts produced were significantly less than the number produced by the S25S wild-type GP parasite. Complementation that restored amylopectin regulation restored brain cyst production to the control levels seen in infected mice. These data suggest that T. gondii requires tight regulation of amylopectin expression for efficient production of cysts and persistent infections and that GP phosphorylation is a regulatory mechanism involved in amylopectin storage and utilization. IMPORTANCE Toxoplasma gondii is an obligate intracellular parasite that causes disease in immune-suppressed individuals, as well as a fetopathy in pregnant women who acquire infection for the first time during pregnancy. This parasite can differentiate between tachyzoites (seen in acute infection) and bradyzoites (seen in latent infection), and this differentiation is associated with disease relapse. A characteristic of bradyzoites is that they contain cytoplasmic amylopectin granules. The regulatory mechanisms and the roles of amylopectin granules during latent infection remain to be elucidated. We have identified a role of T. gondii glycogen phosphorylase (TgGP) in the regulation of starch digestion and a role of posttranslational modification of TgGP, i.e., phosphorylation of Ser25, in the regulation of amylopectin digestion. By manipulating TgGP activity in the parasite with genome editing, we found that the digestion and storage of amylopectin due to TgGP activity are both important for latency in the brain. Copyright © 2017 Sugi et al.

The Elementary Mass Action Rate Constants of P-gp Transport for a Confluent Monolayer of MDCKII-hMDR1 Cells

PubMed Central

Tran, Thuy Thanh; Mittal, Aditya; Aldinger, Tanya; Polli, Joseph W.; Ayrton, Andrew; Ellens, Harma; Bentz, Joe

2005-01-01

The human multi-drug resistance membrane transporter, P-glycoprotein, or P-gp, has been extensively studied due to its importance to human health and disease. Thus far, the kinetic analysis of P-gp transport has been limited to steady-state Michaelis-Menten approaches or to compartmental models, neither of which can prove molecular mechanisms. Determination of the elementary kinetic rate constants of transport will be essential to understanding how P-gp works. The experimental system we use is a confluent monolayer of MDCKII-hMDR1 cells that overexpress P-gp. It is a physiologically relevant model system, and transport is measured without biochemical manipulations of P-gp. The Michaelis-Menten mass action reaction is used to model P-gp transport. Without imposing the steady-state assumptions, this reaction depends upon several parameters that must be simultaneously fitted. An exhaustive fitting of transport data to find all possible parameter vectors that best fit the data was accomplished with a reasonable computation time using a hierarchical algorithm. For three P-gp substrates (amprenavir, loperamide, and quinidine), we have successfully fitted the elementary rate constants, i.e., drug association to P-gp from the apical membrane inner monolayer, drug dissociation back into the apical membrane inner monolayer, and drug efflux from P-gp into the apical chamber, as well as the density of efflux active P-gp. All three drugs had overlapping ranges for the efflux active P-gp, which was a benchmark for the validity of the fitting process. One novel finding was that the association to P-gp appears to be rate-limited solely by drug lateral diffusion within the inner monolayer of the plasma membrane for all three drugs. This would be expected if P-gp structure were open to the lipids of the apical membrane inner monolayer, as has been suggested by recent structural studies. The fitted kinetic parameters show how P-gp efflux of a wide range of xenobiotics has been maximized. PMID:15501934

Multiple Drug Transport Pathways through human P-Glycoprotein(†)

PubMed Central

McCormick, James W.; Vogel, Pia D.; Wise, John G.

2015-01-01

P-glycoprotein (P-gp) is a plasma membrane efflux pump that is commonly associated with therapy resistances in cancers and infectious diseases. P-gp can lower the intracellular concentrations of many drugs to subtherapeutic levels by translocating them out of the cell. Because of the broad range of substrates transported by P-gp, overexpression of P-gp causes multidrug resistance. We reported previously on dynamic transitions of P-gp as it moved through conformations based on crystal structures of homologous ABCB1 proteins using in silico targeted molecular dynamics techniques. We expanded these studies here by docking transport substrates to drug binding sites of P-gp in conformations open to the cytoplasm, followed by cycling the pump through conformations that opened to the extracellular space. We observed reproducible transport of two substrates, daunorubicin and verapamil, by an average of 11 to 12 Å through the plane of the membrane as P-gp progressed through a catalytic cycle. Methyl-pyrophosphate, a ligand that should not be transported by P-gp, did not show this movement through P-gp. Drug binding to either of two subsites on P-gp appeared to determine the initial pathway used for drug movement through the membrane. The specific side-chain interactions with drugs within each pathway seemed to be, at least in part, stochastic. The docking and transport properties of a P-gp inhibitor, tariquidar, were also studied. A mechanism of inhibition by tariquidar is presented that involves stabilization of an outward open conformation with tariquidar bound in intracellular loops or at the drug binding domain of P-gp. PMID:26125482

Multiple Drug Transport Pathways through Human P-Glycoprotein.

PubMed

McCormick, James W; Vogel, Pia D; Wise, John G

2015-07-21

P-Glycoprotein (P-gp) is a plasma membrane efflux pump that is commonly associated with therapy resistances in cancers and infectious diseases. P-gp can lower the intracellular concentrations of many drugs to subtherapeutic levels by translocating them out of the cell. Because of the broad range of substrates transported by P-gp, overexpression of P-gp causes multidrug resistance. We reported previously on dynamic transitions of P-gp as it moved through conformations based on crystal structures of homologous ABCB1 proteins using in silico targeted molecular dynamics techniques. We expanded these studies here by docking transport substrates to drug binding sites of P-gp in conformations open to the cytoplasm, followed by cycling the pump through conformations that opened to the extracellular space. We observed reproducible transport of two substrates, daunorubicin and verapamil, by an average of 11-12 Å through the plane of the membrane as P-gp progressed through a catalytic cycle. Methylpyrophosphate, a ligand that should not be transported by P-gp, did not show this movement through P-gp. Drug binding to either of two subsites on P-gp appeared to determine the initial pathway used for drug movement through the membrane. The specific side-chain interactions with drugs within each pathway seemed to be, at least in part, stochastic. The docking and transport properties of a P-gp inhibitor, tariquidar, were also studied. A mechanism of inhibition by tariquidar that involves stabilization of an outward open conformation with tariquidar bound in intracellular loops or at the drug binding domain of P-gp is presented.

Participation of the 39-kDa glycoprotein (gp39) of the vitelline envelope of Bufo arenarum eggs in sperm-egg interaction.

PubMed

Barrera, Daniel; Llanos, Ricardo J; Miceli, Dora C

2012-05-01

The acquisition of egg fertilizability in Bufo arenarum takes place during the oviductal transit and during this process the extracellular coelomic envelope (CE) of the eggs is converted into the vitelline envelope (VE). It has been stated that one of the necessary events leading to a fertilizable state is the proteolytic cleavage of CE glycoproteins in the oviductal pars recta by oviductin, a serine protease. Consequently, there is a marked increase in the relative quantity of glycoproteins with 39 (gp39) and 42 kDa (gp42) in the VE. In the present study, sperm-VE binding assays using heat-solubilized biotin-conjugated VE glycoproteins revealed that both gp39 and gp42 have sperm binding capacity. According to this result, our study was focused on gp39, a glycoprotein that we have previously reported as a homologue of mammalian ZPC. For this purpose, rabbit polyclonal antibodies against gp39 were generated at our laboratory. The specificity of the antibodies was confirmed with western blot of VE glycoproteins separated on SDS-PAGE. Immunohistochemical and immunoelectron studies showed gp39 distributed throughout the width of the VE. In addition, immunofluorescence assays probed that gp39 bound to the sperm head. Finally, as an approach to elucidate the possible involvement of gp39 in fertilization, inhibition assays showed that pretreatment of eggs with antibodies against gp39 generated a significant decrease in the fertilization rate. Therefore, our findings suggest that gp39, which is modified by oviductal action, participates as a VE glycoprotein ligand for sperm in Bufo arenarum fertilization.

MHC class II presentation of gp100 epitopes in melanoma cells requires the function of conventional endosomes, and is influenced by melanosomes1

PubMed Central

Robila, Valentina; Ostankovitch, Marina; Altrich-VanLith, Michelle L.; Theos, Alexander C.; Drover, Sheila; Marks, Michael S.; Restifo, Nicholas; Engelhard, Victor H.

2009-01-01

Many human solid tumors express MHC II molecules, and proteins normally localized to melanosomes give rise to MHC II restricted epitopes in melanoma. However, the pathways by which this occurs have not been defined. We analyzed the processing of one such epitope, gp10044-59, derived from gp100/Pmel17. In melanomas that have down-regulated components of the melanosomal pathway, but constitutively express HLA-DR*0401, the majority of gp100 is sorted to LAMP-1hi/MHC II+ late endosomes. Using mutant gp100 molecules with altered intracellular trafficking, we demonstrate that endosomal localization is necessary for gp10044-59 presentation. By depletion of the AP2 adaptor protein using siRNA, we demonstrate that gp100 protein internalized from the plasma membrane to such endosomes is a major source for gp10044-59 epitope production. Gp100 trapped in early endosomes gives rise to epitopes that are indistinguishable from those produced in late endosomes but their production is less sensitive to inhibition of lysosomal proteases. In melanomas containing melanosomes, gp100 is underrepresented in late endosomes, and accumulates in stage II melanosomes devoid of MHC II molecules. Gp10044-59 presentation is dramatically reduced, and processing occurs entirely in early endosomes / stage I melanosomes. This suggests that melanosomes are inefficient antigen processing compartments. Thus, melanoma de-differentiation may be accompanied by increased presentation of MHC II restricted epitopes from gp100 and other melanosome-localized proteins, leading to enhanced immune recognition. PMID:19017974

Student evaluation of a primary care clerkship: quality assurance and identification of potential for improvement.

PubMed

Chenot, Jean-François; Kochen, Michael M; Himmel, Wolfgang

2009-04-15

In Germany, like many other countries, general practice clerkships have only recently become mandatory during medical education. The biggest challenges for the organisation of such clerkships are achieving a minimum level of standardisation, and developing and maintaining a system of quality assurance. The aim of this study is to assess the instructional quality in teaching practices using a benchmark system. Before commencing, students anonymously assessed the importance of core aspects of the mandatory primary care clerkship. After the clerkship, they evaluated learning opportunities and teaching performance. Based on this data, a benchmark system was developed to identify areas of strength and weakness for all practices as well as individual teaching practices. A total of 695 students evaluated 97 general practices belonging to a teaching network. Prior to the clerkship, most students considered recognition of frequent diseases (85%) and communication skills (65%) the most important learning goals. After the clerkship, nearly 90% of students confirmed that the general practitioner (GP) was good or excellent at teaching these two goals but only two-thirds thought the GP's teaching performance good or excellent in preventive medicine and screening. In an exemplary analysis, we identified the 2 best and the 2 worst practices that consistently received scores far above or below average, respectively. We were able to identify areas of weakness in teaching and identified specific GPs who did not meet the students' needs and expectations. This evaluation seems to be a useful quality assurance tool to identify the potential for improvement and faculty development.

Characterization of Sulfolobus islandicus rod-shaped virus 2 gp19, a single-strand specific endonuclease.

PubMed

Gardner, Andrew F; Prangishvili, David; Jack, William E

2011-09-01

The hyperthermophilic Sulfolobus islandicus rod-shaped virus 2 (SIRV2) encodes a 25-kDa protein (SIRV2gp19) annotated as a hypothetical protein with sequence homology to the RecB nuclease superfamily. Even though SIRV2gp19 homologs are conserved throughout the rudivirus family and presumably play a role in the viral life cycle, SIRV2gp19 has not been functionally characterized. To define the minimal requirements for activity, SIRV2gp19 was purified and tested under varying conditions. SIRV2gp19 is a single-strand specific endonuclease that requires Mg(2+) for activity and is inactive on double-stranded DNA. A conserved aspartic acid in RecB nuclease superfamily Motif II (D89) is also essential for SIRV2gp19 activity and mutation to alanine (D89A) abolishes activity. Therefore, the SIRV2gp19 cleavage mechanism is similar to previously described RecB nucleases. Finally, SIRV2gp19 single-stranded DNA endonuclease activity could play a role in host chromosome degradation during SIRV2 lytic infection.

The HIV-1 envelope protein gp120 is captured and displayed for B cell recognition by SIGN-R1+ lymph node macrophages

PubMed Central

Park, Chung; Arthos, James; Cicala, Claudia; Kehrl, John H

2015-01-01

The HIV-1 envelope protein gp120 is both the target of neutralizing antibodies and a major focus of vaccine efforts; however how it is delivered to B cells to elicit an antibody response is unknown. Here, we show that following local gp120 injection lymph node (LN) SIGN-R1+ sinus macrophages located in interfollicular pockets and underlying SIGN-R1+ macrophages form a cellular network that rapidly captures gp120 from the afferent lymph. In contrast, two other antigens, phycoerythrin and hen egg lysozyme, were not captured by these cells. Intravital imaging of mouse LNs revealed persistent, but transient interactions between gp120 bearing interfollicular network cells and both trafficking and LN follicle resident gp120 specific B cells. The gp120 specific, but not the control B cells repetitively extracted gp120 from the network cells. Our findings reveal a specialized LN antigen delivery system poised to deliver gp120 and likely other pathogen derived glycoproteins to B cells. DOI: http://dx.doi.org/10.7554/eLife.06467.001 PMID:26258881

Identification of an immunodominant epitope in the C terminus of glycoprotein 5 of porcine reproductive and respiratory syndrome virus.

PubMed

Rodriguez, M J; Sarraseca, J; Fominaya, J; Cortés, E; Sanz, A; Casal, J I

2001-05-01

Glycoprotein 5 (GP(5)) is the major glycoprotein of porcine reproductive and respiratory syndrome virus (PRRSV). Expression of GP(5) has been improved by removing the transmembrane regions. Vectors were constructed encoding complete GP(5) plus three mutants: GP(5) Ns (residues 28--201), GP(5)[30--67] (residues 30--67) and GP(5)[30--201] (residues 30--67/130--201). The three deletion mutants were expressed at levels 20--30 times higher than complete GP(5). GP(5)[30--201] was well recognized in ELISA or immunoblotting by a collection of pig sera. All the fragments were tested for the generation of MAbs, but only the polyhistidine-tagged fragment GP(5)[30--201]H elicited an antibody response sufficient to produce MABS: The two MAbs were positive for PRRSV in ELISA and immunoblotting, but negative for virus neutralization. MAb 4BE12 reacted with residues 130--170 and MAb 3AH9 recognized residues 170--201. This region was recognized strongly in immunoblotting by a collection of infected-pig sera. These results indicate diagnostic potential for this epitope.

Immunological activation following transcutaneous delivery of HR-gp100 protein

PubMed Central

Frankenburg, Shoshana; Grinberg, Igor; Bazak, Ziva; Fingerut, Lena; Pitcovski, Jacob; Gorodetsky, Raphael; Peretz, Tamar; Spira, Ram M.; Skornik, Yehuda; Goldstein, Ronald S.

2009-01-01

Transcutaneous immunization aims at taking advantage of the skin’s immune system for the purpose of immunoprotection. In the present study we evaluated the potential of topical delivery of a recombinant melanoma protein, HR-gp100, derived from a shorter sequence of the native gp100 gene. The protein was applied on the skin, with and without the addition of two forms of heat labile enterotoxin (nLT and LTB). HR-gp100 fused to Haptide, a cell penetrating 20mer peptide (HR-gp100H) was also tested. Topical HR-gp100 and HR-gp100H application on the ears of mice elicited the production of specific antibodies, and transcutaneous delivery to intact human skin induced dose-dependent LC activation. nLT and LTB also activated LC, but did not further increase the activation induced by HR-gp100. These results show that HR-gp100, an antigenic tumor-derived protein, activates the immune system following transcutaneous delivery, as shown by both Langerhans cell activation and induction of antibody production. PMID:17493711

Initial antibodies binding to HIV-1 gp41 in acutely infected subjects are polyreactive and highly mutated

PubMed Central

Chen, Xi; Munshaw, Supriya; Zhang, Ruijun; Marshall, Dawn J.; Vandergrift, Nathan; Whitesides, John F.; Lu, Xiaozhi; Yu, Jae-Sung; Hwang, Kwan-Ki; Gao, Feng; Markowitz, Martin; Heath, Sonya L.; Bar, Katharine J.; Goepfert, Paul A.; Montefiori, David C.; Shaw, George C.; Alam, S. Munir; Margolis, David M.; Denny, Thomas N.; Boyd, Scott D.; Marshal, Eleanor; Egholm, Michael; Simen, Birgitte B.; Hanczaruk, Bozena; Fire, Andrew Z.; Voss, Gerald; Kelsoe, Garnett; Tomaras, Georgia D.; Moody, M. Anthony; Kepler, Thomas B.

2011-01-01

The initial antibody response to HIV-1 is targeted to envelope (Env) gp41, and is nonneutralizing and ineffective in controlling viremia. To understand the origins and characteristics of gp41-binding antibodies produced shortly after HIV-1 transmission, we isolated and studied gp41-reactive plasma cells from subjects acutely infected with HIV-1. The frequencies of somatic mutations were relatively high in these gp41-reactive antibodies. Reverted unmutated ancestors of gp41-reactive antibodies derived from subjects acutely infected with HIV-1 frequently did not react with autologous HIV-1 Env; however, these antibodies were polyreactive and frequently bound to host or bacterial antigens. In one large clonal lineage of gp41-reactive antibodies, reactivity to HIV-1 Env was acquired only after somatic mutations. Polyreactive gp41-binding antibodies were also isolated from uninfected individuals. These data suggest that the majority of gp41-binding antibodies produced after acute HIV-1 infection are cross-reactive responses generated by stimulating memory B cells that have previously been activated by non–HIV-1 antigens. PMID:21987658

The role of proteolytic processing and the stable signal peptide in expression of the Old World arenavirus envelope glycoprotein ectodomain

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

Burri, Dominique J.; Pasquato, Antonella; Ramos da Palma, Joel

2013-02-05

Maturation of the arenavirus GP precursor (GPC) involves proteolytic processing by cellular signal peptidase and the proprotein convertase subtilisin kexin isozyme 1 (SKI-1)/site 1 protease (S1P), yielding a tripartite complex comprised of a stable signal peptide (SSP), the receptor-binding GP1, and the fusion-active transmembrane GP2. Here we investigated the roles of SKI-1/S1P processing and SSP in the biosynthesis of the recombinant GP ectodomains of lymphocytic choriomeningitis virus (LCMV) and Lassa virus (LASV). When expressed in mammalian cells, the LCMV and LASV GP ectodomains underwent processing by SKI-1/S1P, followed by dissociation of GP1 from GP2. The GP2 ectodomain spontaneously formed trimersmore » as revealed by chemical cross-linking. The endogenous SSP, known to be crucial for maturation and transport of full-length arenavirus GPC was dispensable for processing and secretion of the soluble GP ectodomain, suggesting a specific role of SSP in the stable prefusion conformation and transport of full-length GPC.« less

What part of the total care consumed by type 2 diabetes patients is directly related to diabetes? Implications for disease management programs.

PubMed

van Dijk, Christel E; Verheij, Robert A; Swinkels, Ilse C S; Rijken, Mieke; Schellevis, François G; Groenewegen, Peter P; de Bakker, Dinny H

2011-10-01

Disease management programs (DMP) aim at improving coordination and quality of care and reducing healthcare costs for specific chronic diseases. This paper investigates to what extent total healthcare utilization of type 2 diabetes patients is actually related to diabetes and its implications for diabetes management programs. Healthcare utilization for diabetes patients was analyzed using 2008 self-reported data (n=316) and data from electronic medical records (EMR) (n=9023), and divided whether or not care was described in the Dutch type 2 diabetes multidisciplinary healthcare standard. On average 4.3 different disciplines of healthcare providers were involved in the care for diabetes patients. Ninety-six percent contacted a GP-practice and 63% an ophthalmologist, 24% an internist, 32% a physiotherapist and 23% a dietician. Diabetes patients had on average 9.3 contacts with GP-practice of which 53% were included in the healthcare standard. Only a limited part of total healthcare utilization of diabetes patients was included in the healthcare standard and therefore theoretically included in DMPs. Organizing the care for diabetics in a DMP might harm the coordination and quality of all healthcare for diabetics. DMPs should be integrated in the overall organization of care.

Cross-sectional survey of older patients' views regarding multidisciplinary care for chronic conditions in general practice.

PubMed

Bonney, Andrew; Magee, Christopher; Pearson, Russell

2014-01-01

The ageing population and increasing prevalence of chronic illness have contributed to the need for significant primary care reform, including increased use of multidisciplinary care and task substitution. This cross-sectional study explores conditions under which older patients would accept having health professionals other than their general practitioner (GP) involved in their care for chronic disease management (CDM). Ten practices were randomly sampled from a contiguous major city and inner regional area. Questionnaires were distributed to consecutive patients aged 60 years and over in each practice. Agency theory was used to inform analyses. Statistical analysis was undertaken using Wald's test, growth modelling and linear regression, controlling for the clustered design. The response rate was 53% (n=272). Most respondents (79%) had at least one chronic health condition. Respondents were more comfortable with GP than with practice nurse management in the CDM scenario (Wald's test=105.49, P<0.001). Comfort with practice nurse CDM was positively associated with increased contact with their GP at the time of the visit (β=0.41, P<0.001), negatively associated with the number of the respondent's chronic conditions (β=-0.13, P=0.030) and not associated with the frequency of other health professional visits. Agency theory suggests that patients employ continuity of care to optimise factors important in CDM: information symmetry and goal alignment. Our findings are consistent with the theory and lend support to ensuring that interpersonal continuity of care is not lost in health care reform. Further research exploring patients' acceptance of differing systems of care is required.

Registration of five upland cotton mutant germplasm lines with superior fiber length, strength, and uniformity

USDA-ARS?s Scientific Manuscript database

Mutant germplasm lines MD 15-Mut 13 (Reg. No. GP-1025, PI 681706), MD 15-Mut 31 (Reg. No. GP-1026, PI 681707), MD 15-Mut 61 (Reg. No. GP-1027, PI 681708), MD 15-Mut 89 (Reg. No. GP-1028, PI 681709), and MD 15-Mut 138 (Reg. No. GP-1029, PI 681710) are unique genotypes of upland cotton (Gossypium hirs...

A Bipartite Signal Regulates the Faithful Delivery of Apical Domain Marker Podocalyxin/Gp135

PubMed Central

Yu, Chun-Ying; Chen, Jen-Yau; Lin, Yu-Yu; Shen, Kuo-Fang; Lin, Wei-Ling; Chien, Chung-Liang; ter Beest, Martin B.A.

2007-01-01

Podocalyxin/Gp135 was recently demonstrated to participate in the formation of a preapical complex to set up initial polarity in MDCK cells, a function presumably depending on the apical targeting of Gp135. We show that correct apical sorting of Gp135 depends on a bipartite signal composed of an extracellular O-glycosylation–rich region and the intracellular PDZ domain–binding motif. The function of this PDZ-binding motif could be substituted with a fusion construct of Gp135 with Ezrin-binding phosphoprotein 50 (EBP50). In accordance with this observation, EBP50 binds to newly synthesized Gp135 at the Golgi apparatus and facilitates oligomerization and sorting of Gp135 into a clustering complex. A defective connection between Gp135 and EBP50 or EBP50 knockdown results in a delayed exit from the detergent-resistant microdomain, failure of oligomerization, and basolateral missorting of Gp135. Furthermore, the basolaterally missorted EBP50-binding defective mutant of Gp135 was rapidly retrieved via a PKC-dependent mechanism. According to these findings, we propose a model by which a highly negative charged transmembrane protein could be packed into an apical sorting platform with the aid of its cytoplasmic partner EBP50. PMID:17332505

Synthesis and characterization of macromolecular rhodamine tethers and their interactions with P-glycoprotein.

PubMed

Crawford, Lindsey; Putnam, David

2014-08-20

Rhodamine dyes are well-known P-glycoprotein (P-gp) substrates that have played an important role in the detection of inhibitors and other substrates of P-gp, as well as in the understanding of P-gp function. Macromolecular conjugates of rhodamines could prove useful as tethers for further probing of P-gp structure and function. Two macromolecular derivatives of rhodamine, methoxypolyethylene glycol-rhodamine6G and methoxypolyethylene glycol-rhodamine123, were synthesized through the 2'-position of rhodamine6G and rhodamine123, thoroughly characterized, and then evaluated by inhibition with verapamil for their ability to interact with P-gp and to act as efflux substrates. To put the results into context, the P-gp interactions of the new conjugates were compared to the commercially available methoxypolyethylene glycol-rhodamineB. FACS analysis confirmed that macromolecular tethers of rhodamine6G, rhodamine123, and rhodamineB were accumulated in P-gp expressing cells 5.2 ± 0.3%, 26.2 ± 4%, and 64.2 ± 6%, respectively, compared to a sensitive cell line that does not overexpress P-gp. Along with confocal imaging, the efflux analysis confirmed that the macromolecular rhodamine tethers remain P-gp substrates. These results open potential avenues for new ways to probe the function of P-gp both in vitro and in vivo.

Intracellular Mannose Binding Lectin Mediates Subcellular Trafficking of HIV-1 gp120 in Neurons

PubMed Central

Teodorof, C; Divakar, S; Soontornniyomkij, B; Achim, CL; Kaul, M; Singh, KK

2014-01-01

Human immunodeficiency virus -1 (HIV-1) enters the brain early during infection and leads to severe neuronal damage and central nervous system impairment. HIV-1 envelope glycoprotein 120 (gp120), a neurotoxin, undergoes intracellular trafficking and transport across neurons; however mechanisms of gp120 trafficking in neurons are unclear. Our results show that mannose binding lectin (MBL) that binds to the N-linked mannose residues on gp120, participates in intravesicular packaging of gp120 in neuronal subcellular organelles and also in subcellular trafficking of these vesicles in neuronal cells. Perinuclear MBL:gp120 vesicular complexes were observed and MBL facilitated the subcellular trafficking of gp120 via the endoplasmic reticulum (ER) and Golgi vesicles. The functional carbohydrate recognition domain of MBL was required for perinuclear organization, distribution and subcellular trafficking of MBL:gp120 vesicular complexes. Nocodazole, an agent that depolymerizes the microtubule network, abolished the trafficking of MBL:gp120 vesicles, suggesting that these vesicular complexes were transported along the microtubule network. Live cell imaging confirmed the association of the MBL:gp120 complexes with dynamic subcellular vesicles that underwent trafficking in neuronal soma and along the neurites. Thus, our findings suggest that intracellular MBL mediates subcellular trafficking and transport of viral glycoproteins in a microtubule-dependent mechanism in the neurons. PMID:24825317

Intracellular mannose binding lectin mediates subcellular trafficking of HIV-1 gp120 in neurons.

PubMed

Teodorof, C; Divakar, S; Soontornniyomkij, B; Achim, C L; Kaul, M; Singh, K K

2014-09-01

Human immunodeficiency virus-1 (HIV-1) enters the brain early during infection and leads to severe neuronal damage and central nervous system impairment. HIV-1 envelope glycoprotein 120 (gp120), a neurotoxin, undergoes intracellular trafficking and transport across neurons; however mechanisms of gp120 trafficking in neurons are unclear. Our results show that mannose binding lectin (MBL) that binds to the N-linked mannose residues on gp120, participates in intravesicular packaging of gp120 in neuronal subcellular organelles and also in subcellular trafficking of these vesicles in neuronal cells. Perinuclear MBL:gp120 vesicular complexes were observed and MBL facilitated the subcellular trafficking of gp120 via the endoplasmic reticulum (ER) and Golgi vesicles. The functional carbohydrate recognition domain of MBL was required for perinuclear organization, distribution and subcellular trafficking of MBL:gp120 vesicular complexes. Nocodazole, an agent that depolymerizes the microtubule network, abolished the trafficking of MBL:gp120 vesicles, suggesting that these vesicular complexes were transported along the microtubule network. Live cell imaging confirmed the association of the MBL:gp120 complexes with dynamic subcellular vesicles that underwent trafficking in neuronal soma and along the neurites. Thus, our findings suggest that intracellular MBL mediates subcellular trafficking and transport of viral glycoproteins in a microtubule-dependent mechanism in the neurons. Published by Elsevier Inc.

Mini-P-gp and P-gp Co-Expression in Brown Trout Erythrocytes: A Prospective Blood Biomarker of Aquatic Pollution

PubMed Central

Valton, Emeline; Amblard, Christian; Desmolles, François; Combourieu, Bruno; Penault-Llorca, Frédérique; Bamdad, Mahchid

2015-01-01

In aquatic organisms, such as fish, blood is continually exposed to aquatic contaminants. Multidrug Resistance (MDR) proteins are ubiquitous detoxification membrane pumps, which recognize various xenobiotics. Moreover, their expression is induced by a large class of drugs and pollutants. We have highlighted the co-expression of a mini P-gp of 75 kDa and a P-gp of 140 kDa in the primary culture of brown trout erythrocytes and in the erythrocytes of wild brown trout collected from three rivers in the Auvergne region of France. In vitro experiments showed that benzo[a]pyrene, a highly toxic pollutant model, induced the co-expression of mini-P-gp and P-gp in trout erythrocytes in a dose-dependent manner and relay type response. Similarly, in the erythrocytes of wild brown trout collected from rivers contaminated by a mixture of PAH and other multi-residues of pesticides, mini-P-gp and P-gp were able to modulate their expression, according to the nature of the pollutants. The differential and complementary responses of mini-P-gp and P-gp in trout erythrocytes suggest the existence in blood cells of a real protective network against xenobiotics/drugs. This property could be exploited to develop a blood biomarker of river pollution. PMID:26854141

Peptides designed to spatially depict the Epstein-Barr virus major virion glycoprotein gp350 neutralization epitope elicit antibodies that block virus-neutralizing antibody 72A1 interaction with the native gp350 molecule.

PubMed

Tanner, Jerome E; Coinçon, Mathieu; Leblond, Valérie; Hu, Jing; Fang, Janey M; Sygusch, Jurgen; Alfieri, Caroline

2015-05-01

Epstein-Barr virus (EBV) is the etiologic agent of infectious mononucleosis and the root cause of B-cell lymphoproliferative disease in individuals with a weakened immune system, as well as a principal cofactor in nasopharyngeal carcinoma, various lymphomas, and other cancers. The EBV major virion surface glycoprotein gp350 is viewed as the best vaccine candidate to prevent infectious mononucleosis in healthy EBV-naive persons and EBV-related cancers in at-risk individuals. Previous epitope mapping of gp350 revealed only one dominant neutralizing epitope, which has been shown to be the target of the monoclonal antibody 72A1. Computer modeling of the 72A1 antibody interaction with the gp350 amino terminus was used to identify gp350 amino acids that could form strong ionic, electrostatic, or hydrogen bonds with the 72A1 antibody. Peptide DDRTTLQLAQNPVYIPETYPYIKWDN (designated peptide 2) and peptide GSAKPGNGSYFASVKTEMLGNEID (designated peptide 3) were designed to spatially represent the gp350 amino acids predicted to interact with the 72A1 antibody paratope. Peptide 2 bound to the 72A1 antibody and blocked 72A1 antibody recognition of the native gp350 molecule. Peptide 2 and peptide 3 were recognized by human IgG and shown to elicit murine antibodies that could target gp350 and block its recognition by the 72A1 antibody. This work provides a structural mapping of the interaction between the EBV-neutralizing antibody 72A1 and the major virion surface protein gp350. gp350 mimetic peptides that spatially depict the EBV-neutralizing epitope would be useful as a vaccine to focus the immune system exclusively to this important virus epitope. The production of virus-neutralizing antibodies targeting the Epstein-Barr virus (EBV) major surface glycoprotein gp350 is important for the prevention of infectious mononucleosis and EBV-related cancers. The data presented here provide the first in silico map of the gp350 interaction with a virus-blocking monoclonal antibody. Immunization with gp350 peptides identified by in silico mapping generated antibodies that cross-react with the EBV gp350 molecule and block recognition of the gp350 molecule by a virus-neutralizing antibody. Through its ability to focus the immune system exclusively on the gp350 sequence important for viral entry, these peptides may form the basis of an EBV vaccine candidate. This strategy would sidestep the production of other irrelevant gp350 antibodies that divert the immune system from generating a protective antiviral response or that impede access to the virus-blocking epitope by protective antibodies. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

OpenMP GNU and Intel Fortran programs for solving the time-dependent Gross-Pitaevskii equation

NASA Astrophysics Data System (ADS)

Young-S., Luis E.; Muruganandam, Paulsamy; Adhikari, Sadhan K.; Lončar, Vladimir; Vudragović, Dušan; Balaž, Antun

2017-11-01

We present Open Multi-Processing (OpenMP) version of Fortran 90 programs for solving the Gross-Pitaevskii (GP) equation for a Bose-Einstein condensate in one, two, and three spatial dimensions, optimized for use with GNU and Intel compilers. We use the split-step Crank-Nicolson algorithm for imaginary- and real-time propagation, which enables efficient calculation of stationary and non-stationary solutions, respectively. The present OpenMP programs are designed for computers with multi-core processors and optimized for compiling with both commercially-licensed Intel Fortran and popular free open-source GNU Fortran compiler. The programs are easy to use and are elaborated with helpful comments for the users. All input parameters are listed at the beginning of each program. Different output files provide physical quantities such as energy, chemical potential, root-mean-square sizes, densities, etc. We also present speedup test results for new versions of the programs. Program files doi:http://dx.doi.org/10.17632/y8zk3jgn84.2 Licensing provisions: Apache License 2.0 Programming language: OpenMP GNU and Intel Fortran 90. Computer: Any multi-core personal computer or workstation with the appropriate OpenMP-capable Fortran compiler installed. Number of processors used: All available CPU cores on the executing computer. Journal reference of previous version: Comput. Phys. Commun. 180 (2009) 1888; ibid.204 (2016) 209. Does the new version supersede the previous version?: Not completely. It does supersede previous Fortran programs from both references above, but not OpenMP C programs from Comput. Phys. Commun. 204 (2016) 209. Nature of problem: The present Open Multi-Processing (OpenMP) Fortran programs, optimized for use with commercially-licensed Intel Fortran and free open-source GNU Fortran compilers, solve the time-dependent nonlinear partial differential (GP) equation for a trapped Bose-Einstein condensate in one (1d), two (2d), and three (3d) spatial dimensions for six different trap symmetries: axially and radially symmetric traps in 3d, circularly symmetric traps in 2d, fully isotropic (spherically symmetric) and fully anisotropic traps in 2d and 3d, as well as 1d traps, where no spatial symmetry is considered. Solution method: We employ the split-step Crank-Nicolson algorithm to discretize the time-dependent GP equation in space and time. The discretized equation is then solved by imaginary- or real-time propagation, employing adequately small space and time steps, to yield the solution of stationary and non-stationary problems, respectively. Reasons for the new version: Previously published Fortran programs [1,2] have now become popular tools [3] for solving the GP equation. These programs have been translated to the C programming language [4] and later extended to the more complex scenario of dipolar atoms [5]. Now virtually all computers have multi-core processors and some have motherboards with more than one physical computer processing unit (CPU), which may increase the number of available CPU cores on a single computer to several tens. The C programs have been adopted to be very fast on such multi-core modern computers using general-purpose graphic processing units (GPGPU) with Nvidia CUDA and computer clusters using Message Passing Interface (MPI) [6]. Nevertheless, previously developed Fortran programs are also commonly used for scientific computation and most of them use a single CPU core at a time in modern multi-core laptops, desktops, and workstations. Unless the Fortran programs are made aware and capable of making efficient use of the available CPU cores, the solution of even a realistic dynamical 1d problem, not to mention the more complicated 2d and 3d problems, could be time consuming using the Fortran programs. Previously, we published auto-parallel Fortran programs [2] suitable for Intel (but not GNU) compiler for solving the GP equation. Hence, a need for the full OpenMP version of the Fortran programs to reduce the execution time cannot be overemphasized. To address this issue, we provide here such OpenMP Fortran programs, optimized for both Intel and GNU Fortran compilers and capable of using all available CPU cores, which can significantly reduce the execution time. Summary of revisions: Previous Fortran programs [1] for solving the time-dependent GP equation in 1d, 2d, and 3d with different trap symmetries have been parallelized using the OpenMP interface to reduce the execution time on multi-core processors. There are six different trap symmetries considered, resulting in six programs for imaginary-time propagation and six for real-time propagation, totaling to 12 programs included in BEC-GP-OMP-FOR software package. All input data (number of atoms, scattering length, harmonic oscillator trap length, trap anisotropy, etc.) are conveniently placed at the beginning of each program, as before [2]. Present programs introduce a new input parameter, which is designated by Number_of_Threads and defines the number of CPU cores of the processor to be used in the calculation. If one sets the value 0 for this parameter, all available CPU cores will be used. For the most efficient calculation it is advisable to leave one CPU core unused for the background system's jobs. For example, on a machine with 20 CPU cores such that we used for testing, it is advisable to use up to 19 CPU cores. However, the total number of used CPU cores can be divided into more than one job. For instance, one can run three simulations simultaneously using 10, 4, and 5 CPU cores, respectively, thus totaling to 19 used CPU cores on a 20-core computer. The Fortran source programs are located in the directory src, and can be compiled by the make command using the makefile in the root directory BEC-GP-OMP-FOR of the software package. The examples of produced output files can be found in the directory output, although some large density files are omitted, to save space. The programs calculate the values of actually used dimensionless nonlinearities from the physical input parameters, where the input parameters correspond to the identical nonlinearity values as in the previously published programs [1], so that the output files of the old and new programs can be directly compared. The output files are conveniently named such that their contents can be easily identified, following the naming convention introduced in Ref. [2]. For example, a file named -out.txt, where is a name of the individual program, represents the general output file containing input data, time and space steps, nonlinearity, energy and chemical potential, and was named fort.7 in the old Fortran version of programs [1]. A file named -den.txt is the output file with the condensate density, which had the names fort.3 and fort.4 in the old Fortran version [1] for imaginary- and real-time propagation programs, respectively. Other possible density outputs, such as the initial density, are commented out in the programs to have a simpler set of output files, but users can uncomment and re-enable them, if needed. In addition, there are output files for reduced (integrated) 1d and 2d densities for different programs. In the real-time programs there is also an output file reporting the dynamics of evolution of root-mean-square sizes after a perturbation is introduced. The supplied real-time programs solve the stationary GP equation, and then calculate the dynamics. As the imaginary-time programs are more accurate than the real-time programs for the solution of a stationary problem, one can first solve the stationary problem using the imaginary-time programs, adapt the real-time programs to read the pre-calculated wave function and then study the dynamics. In that case the parameter NSTP in the real-time programs should be set to zero and the space mesh and nonlinearity parameters should be identical in both programs. The reader is advised to consult our previous publication where a complete description of the output files is given [2]. A readme.txt file, included in the root directory, explains the procedure to compile and run the programs. We tested our programs on a workstation with two 10-core Intel Xeon E5-2650 v3 CPUs. The parameters used for testing are given in sample input files, provided in the corresponding directory together with the programs. In Table 1 we present wall-clock execution times for runs on 1, 6, and 19 CPU cores for programs compiled using Intel and GNU Fortran compilers. The corresponding columns "Intel speedup" and "GNU speedup" give the ratio of wall-clock execution times of runs on 1 and 19 CPU cores, and denote the actual measured speedup for 19 CPU cores. In all cases and for all numbers of CPU cores, although the GNU Fortran compiler gives excellent results, the Intel Fortran compiler turns out to be slightly faster. Note that during these tests we always ran only a single simulation on a workstation at a time, to avoid any possible interference issues. Therefore, the obtained wall-clock times are more reliable than the ones that could be measured with two or more jobs running simultaneously. We also studied the speedup of the programs as a function of the number of CPU cores used. The performance of the Intel and GNU Fortran compilers is illustrated in Fig. 1, where we plot the speedup and actual wall-clock times as functions of the number of CPU cores for 2d and 3d programs. We see that the speedup increases monotonically with the number of CPU cores in all cases and has large values (between 10 and 14 for 3d programs) for the maximal number of cores. This fully justifies the development of OpenMP programs, which enable much faster and more efficient solving of the GP equation. However, a slow saturation in the speedup with the further increase in the number of CPU cores is observed in all cases, as expected. The speedup tends to increase for programs in higher dimensions, as they become more complex and have to process more data. This is why the speedups of the supplied 2d and 3d programs are larger than those of 1d programs. Also, for a single program the speedup increases with the size of the spatial grid, i.e., with the number of spatial discretization points, since this increases the amount of calculations performed by the program. To demonstrate this, we tested the supplied real2d-th program and varied the number of spatial discretization points NX=NY from 20 to 1000. The measured speedup obtained when running this program on 19 CPU cores as a function of the number of discretization points is shown in Fig. 2. The speedup first increases rapidly with the number of discretization points and eventually saturates. Additional comments: Example inputs provided with the programs take less than 30 minutes to run on a workstation with two Intel Xeon E5-2650 v3 processors (2 QPI links, 10 CPU cores, 25 MB cache, 2.3 GHz).