Novel Adjuvants and Immunomodulators for Veterinary Vaccines

DEFF Research Database (Denmark)

Heegaard, Peter M. H.; Fang, Yongxiang; Jungersen, Gregers

2016-01-01

Adjuvants are crucial for efficacy of vaccines, especially subunit and recombinant vaccines. Rational vaccine design, including knowledge-based and molecularly defined adjuvants tailored for directing and potentiating specific types of host immune responses towards the antigens included in the va...

Mapping Determinants of Virus Neutralization and Viral Escape for Rational Design of a Hepatitis C Virus Vaccine

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Mei-Le Keck

2018-05-01

Full Text Available Hepatitis C virus (HCV continues to spread worldwide with an annual increase of 1.75 million new infections. The number of HCV cases in the U.S. is now greater than the number of HIV cases and is increasing in young adults because of the opioid epidemic sweeping the country. HCV-related liver disease is the leading indication of liver transplantation. An effective vaccine is of paramount importance to control and prevent HCV infection. While this vaccine will need to induce both cellular and humoral immunity, this review is focused on the required antibody responses. For highly variable viruses, such as HCV, isolation and characterization of monoclonal antibodies mediating broad virus neutralization are an important guide for vaccine design. The viral envelope glycoproteins, E1 and E2, are the main targets of these antibodies. Epitopes on the E2 protein have been studied more extensively than epitopes on E1, due to higher antibody targeting that reflects these epitopes having higher degrees of immunogenicity. E2 epitopes are overall organized in discrete clusters of overlapping epitopes that ranged from high conservation to high variability. Other epitopes on E1 and E1E2 also are targets of neutralizing antibodies. Taken together, these regions are important for vaccine design. Another element in vaccine design is based on information on how the virus escapes from broadly neutralizing antibodies. Escape mutations can occur within the epitopes that are involved in antibody binding and in regions that are not involved in their epitopes, but nonetheless reduce the efficiency of neutralizing antibodies. An understanding on the specificities of a protective B cell response, the molecular locations of these epitopes on E1, E2, and E1E2, and the mechanisms, which enable the virus to negatively modulate neutralizing antibody responses to these regions will provide the necessary guidance for vaccine design.

Bounded rationality alters the dynamics of paediatric immunization acceptance.

Science.gov (United States)

Oraby, Tamer; Bauch, Chris T

2015-06-02

Interactions between disease dynamics and vaccinating behavior have been explored in many coupled behavior-disease models. Cognitive effects such as risk perception, framing, and subjective probabilities of adverse events can be important determinants of the vaccinating behaviour, and represent departures from the pure "rational" decision model that are often described as "bounded rationality". However, the impact of such cognitive effects in the context of paediatric infectious disease vaccines has received relatively little attention. Here, we develop a disease-behavior model that accounts for bounded rationality through prospect theory. We analyze the model and compare its predictions to a reduced model that lacks bounded rationality. We find that, in general, introducing bounded rationality increases the dynamical richness of the model and makes it harder to eliminate a paediatric infectious disease. In contrast, in other cases, a low cost, highly efficacious vaccine can be refused, even when the rational decision model predicts acceptance. Injunctive social norms can prevent vaccine refusal, if vaccine acceptance is sufficiently high in the beginning of the vaccination campaign. Cognitive processes can have major impacts on the predictions of behaviour-disease models, and further study of such processes in the context of vaccination is thus warranted.

Tailoring DNA vaccines: designing strategies against HER2 positive cancers

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Cristina eMarchini

2013-05-01

Full Text Available The crucial role of HER2 in epithelial transformation and its selective overexpression on cancer tissues makes it an ideal target for cancer immunotherapies such as passive immunotherapy with Trastuzumab. There are, however, a number of concerns regarding the use of monoclonal antibodies which include resistance, repeated treatments, considerable costs and side effects that make active immunotherapies against HER2 desirable alternative approaches. The efficacy of anti-HER2 DNA vaccination has been widely demonstrated in transgenic cancer-prone mice, which recapitulate several features of human breast cancers. Nonetheless, the rational design of a cancer vaccine able to trigger a long lasting immunity, and thus prevent tumor recurrence in patients, would require the understanding of how tolerance and immunosuppression regulate antitumor immune responses and, at the same time, the identification of the most immunogenic portions of the target protein. We herein retrace the findings that led to our most promising DNA vaccines that, by encoding human/rat chimeric forms of HER2, are able to circumvent peripheral tolerance. Preclinical data obtained with these chimeric DNA vaccines have provided the rationale for their use in an ongoing phase I clinical trial (EudraCT 2011-001104-34.

Structure-function discrepancy in Clostridium botulinum C3 toxin for its rational prioritization as a subunit vaccine.

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Prathiviraj, R; Prisilla, A; Chellapandi, P

2016-06-01

Clostridium botulinum is anaerobic pathogenic bacterium causing food-born botulism in human and animals by producing botulinum neurotoxins A-H, C2, and C3 cytotoxins. Physiological group III strains (type C and D) of this bacterium are capable of producing C2 and C3 toxins in cattle and avian. Herein, we have revealed the structure-function disparity of C3 toxins from two different C. botulinum type C phage (CboC) and type D phage (CboD) to design avirulent toxins rationally. Structure-function discrepancy of the both toxins was computationally evaluated from their homology models based on the conservation in sequence-structure-function relationships upon covariation and point mutations. It has shown that 8 avirulent mutants were generated from CboC of 34 mutants while 27 avirulent mutants resulted from CboD mutants. No major changes were found in tertiary structure of these toxins; however, some structural variations appeared in the coiled and loop regions. Correlated mutation on the first residue would disorder or revolutionize the hydrogen bonding pattern of the coevolved pairs. It suggested that the residues coupling in the local structural environments were compensated with coevolved pairs so as to preserve a pseudocatalytic function in the avirulent mutants. Avirulent mutants of C3 toxins have shown a stable structure with a common blue print of folding process and also attained a near-native backrub ensemble. Thus, we concluded that selecting the site-directed mutagenesis sites are very important criteria for designing avirulent toxins, in development of rational subunit vaccines, to cattle and avian, but the vaccine specificity can be determined by the C3 toxins of C. botulinum harboring phages.

A Brief Review of Computer-Assisted Approaches to Rational Design of Peptide Vaccines

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Ashesh Nandy

2016-05-01

Full Text Available The growing incidences of new viral diseases and increasingly frequent viral epidemics have strained therapeutic and preventive measures; the high mutability of viral genes puts additional strains on developmental efforts. Given the high cost and time requirements for new drugs development, vaccines remain as a viable alternative, but there too traditional techniques of live-attenuated or inactivated vaccines have the danger of allergenic reactions and others. Peptide vaccines have, over the last several years, begun to be looked on as more appropriate alternatives, which are economically affordable, require less time for development and hold the promise of multi-valent dosages. The developments in bioinformatics, proteomics, immunogenomics, structural biology and other sciences have spurred the growth of vaccinomics where computer assisted approaches serve to identify suitable peptide targets for eventual development of vaccines. In this mini-review we give a brief overview of some of the recent trends in computer assisted vaccine development with emphasis on the primary selection procedures of probable peptide candidates for vaccine development.

Mechanism of action of mRNA-based vaccines.

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Iavarone, Carlo; O'hagan, Derek T; Yu, Dong; Delahaye, Nicolas F; Ulmer, Jeffrey B

2017-09-01

The present review summarizes the growing body of work defining the mechanisms of action of this exciting new vaccine technology that should allow rational approaches in the design of next generation mRNA vaccines. Areas covered: Bio-distribution of mRNA, localization of antigen production, role of the innate immunity, priming of the adaptive immune response, route of administration and effects of mRNA delivery systems. Expert commentary: In the last few years, the development of RNA vaccines had a fast growth, the rising number of proof will enable rational approaches to improving the effectiveness and safety of this modern class of medicine.

Challenges and solutions for a rational vaccine design for TB-endemic regions.

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Gowthaman, Uthaman; Mushtaq, Khurram; Tan, Amabel C; Rai, Pradeep K; Jackson, David C; Agrewala, Javed N

2015-01-01

Vaccines have been successful for global eradication or control of dreaded diseases such as smallpox, diphtheria, tetanus, yellow fever, whooping cough, polio, and measles. Unfortunately, this success has not been achieved for controlling tuberculosis (TB) worldwide. Bacillus Calmette Guérin (BCG) is the only available vaccine against TB. Paradoxically, BCG has deciphered success in the Western world but has failed in TB-endemic areas. In this article, we highlight and discuss the aspects of immunity responsible for controlling Mycobacterium tuberculosis infection and factors responsible for the failure of BCG in TB-endemic countries. In addition, we also suggest strategies that contribute toward the development of successful vaccine in protecting populations where BCG has failed.

Rational design of nanomaterials for water treatment

KAUST Repository

Li, Renyuan

2015-08-26

The ever-increasing human demand for safe and clean water is gradually pushing conventional water treatment technologies to their limits and it is now a popular perception that the solutions to the existing and future water challenges will highly hinge upon the further development of nanomaterial sciences. The concept of rational design emphasizes ‘design-for-purpose’ and it necessitates a scientifically clear problem definition to initiate the nanomaterial design. The field of rational design of nanomaterials for water treatment has experienced a significant growth in the past decade and is poised to make its contribution in creating advanced next-generation water treatment technologies in the years to come. Within the water treatment context, this review offers a comprehensive and in-depth overview of the latest progress of the rational design, synthesis and applications of nanomaterials in adsorption, chemical oxidation and reduction reactions, membrane-based separation, oil/water separation, and synergistic multifunctional all-in-one nanomaterials/nanodevices. Special attention is paid on chemical concepts of the nanomaterial designs throughout the review.

Towards a formal logic of design rationalization

DEFF Research Database (Denmark)

Galle, Per

1997-01-01

Certain extensions to standard predicate logic are proposed and used as a framework for critical logical study of patterns of inference in design reasoning. It is shown that within this framework a modal logic of design rationalization (suggested by an empirical study reported earlier) can...... be formally defined in terms of quantification over a universe of discourse of ‘relevant points of view’. Five basic principles of the extended predicate logic are listed, on the basis of which the validity of ten modal patterns of inference encountered in design rationalization is tested. The basic idea...

Designing and testing broadly-protective filoviral vaccines optimized for cytotoxic T-lymphocyte epitope coverage.

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Paul W Fenimore

Full Text Available We report the rational design and in vivo testing of mosaic proteins for a polyvalent pan-filoviral vaccine using a computational strategy designed for the Human Immunodeficiency Virus type 1 (HIV-1 but also appropriate for Hepatitis C virus (HCV and potentially other diverse viruses. Mosaics are sets of artificial recombinant proteins that are based on natural proteins. The recombinants are computationally selected using a genetic algorithm to optimize the coverage of potential cytotoxic T lymphocyte (CTL epitopes. Because evolutionary history differs markedly between HIV-1 and filoviruses, we devised an adapted computational technique that is effective for sparsely sampled taxa; our first significant result is that the mosaic technique is effective in creating high-quality mosaic filovirus proteins. The resulting coverage of potential epitopes across filovirus species is superior to coverage by any natural variants, including current vaccine strains with demonstrated cross-reactivity. The mosaic cocktails are also robust: mosaics substantially outperformed natural strains when computationally tested against poorly sampled species and more variable genes. Furthermore, in a computational comparison of cross-reactive potential a design constructed prior to the Bundibugyo outbreak performed nearly as well against all species as an updated design that included Bundibugyo. These points suggest that the mosaic designs would be more resilient than natural-variant vaccines against future Ebola outbreaks dominated by novel viral variants. We demonstrate in vivo immunogenicity and protection against a heterologous challenge in a mouse model. This design work delineates the likely requirements and limitations on broadly-protective filoviral CTL vaccines.

Designing and testing broadly-protective filoviral vaccines optimized for cytotoxic T-lymphocyte epitope coverage.

Science.gov (United States)

Fenimore, Paul W; Muhammad, Majidat A; Fischer, William M; Foley, Brian T; Bakken, Russell R; Thurmond, James R; Yusim, Karina; Yoon, Hyejin; Parker, Michael; Hart, Mary Kate; Dye, John M; Korber, Bette; Kuiken, Carla

2012-01-01

We report the rational design and in vivo testing of mosaic proteins for a polyvalent pan-filoviral vaccine using a computational strategy designed for the Human Immunodeficiency Virus type 1 (HIV-1) but also appropriate for Hepatitis C virus (HCV) and potentially other diverse viruses. Mosaics are sets of artificial recombinant proteins that are based on natural proteins. The recombinants are computationally selected using a genetic algorithm to optimize the coverage of potential cytotoxic T lymphocyte (CTL) epitopes. Because evolutionary history differs markedly between HIV-1 and filoviruses, we devised an adapted computational technique that is effective for sparsely sampled taxa; our first significant result is that the mosaic technique is effective in creating high-quality mosaic filovirus proteins. The resulting coverage of potential epitopes across filovirus species is superior to coverage by any natural variants, including current vaccine strains with demonstrated cross-reactivity. The mosaic cocktails are also robust: mosaics substantially outperformed natural strains when computationally tested against poorly sampled species and more variable genes. Furthermore, in a computational comparison of cross-reactive potential a design constructed prior to the Bundibugyo outbreak performed nearly as well against all species as an updated design that included Bundibugyo. These points suggest that the mosaic designs would be more resilient than natural-variant vaccines against future Ebola outbreaks dominated by novel viral variants. We demonstrate in vivo immunogenicity and protection against a heterologous challenge in a mouse model. This design work delineates the likely requirements and limitations on broadly-protective filoviral CTL vaccines.

Virus-Like Particle Engineering: From Rational Design to Versatile Applications.

Science.gov (United States)

Ding, Xuanwei; Liu, Dong; Booth, George; Gao, Wei; Lu, Yuan

2018-05-01

As mimicking natural virus structures, virus-like particles (VLPs) have evolved to become a widely accepted technology used for humans which are safe, highly efficacious, and profitable. Several remarkable advantages have been achieved to revolutionize the molecule delivery for diverse applications in nanotechnology, biotechnology, and medicine. Here, the rational structure design, manufacturing process, functionalization strategy, and emerging applications of VLPs is reviewed. The situation and challenges in the VLP engineering, the key development orientation, and future applications have been discussed. To develop a good VLP design concept, the virus/VLP-host interactions need to be examined and the screening methods of the VLP stabilization factors need to be established. The functionalization toolbox can be expanded to fabricate smart, robust, and multifunctional VLPs. Novel robust VLP manufacturing platforms are required to deliver vaccines in resource-poor regions with a significant reduction in the production time and cost. The future applications of VLPs are always driven by the development of emerging technologies and new requirements of modern life. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Bounded rationality alters the dynamics of paediatric immunization acceptance

Science.gov (United States)

Oraby, Tamer; Bauch, Chris T.

2015-01-01

Interactions between disease dynamics and vaccinating behavior have been explored in many coupled behavior-disease models. Cognitive effects such as risk perception, framing, and subjective probabilities of adverse events can be important determinants of the vaccinating behaviour, and represent departures from the pure “rational” decision model that are often described as “bounded rationality”. However, the impact of such cognitive effects in the context of paediatric infectious disease vaccines has received relatively little attention. Here, we develop a disease-behavior model that accounts for bounded rationality through prospect theory. We analyze the model and compare its predictions to a reduced model that lacks bounded rationality. We find that, in general, introducing bounded rationality increases the dynamical richness of the model and makes it harder to eliminate a paediatric infectious disease. In contrast, in other cases, a low cost, highly efficacious vaccine can be refused, even when the rational decision model predicts acceptance. Injunctive social norms can prevent vaccine refusal, if vaccine acceptance is sufficiently high in the beginning of the vaccination campaign. Cognitive processes can have major impacts on the predictions of behaviour-disease models, and further study of such processes in the context of vaccination is thus warranted. PMID:26035413

Re-designing the Mozambique vaccine supply chain to improve access to vaccines.

Science.gov (United States)

Lee, Bruce Y; Haidari, Leila A; Prosser, Wendy; Connor, Diana L; Bechtel, Ruth; Dipuve, Amelia; Kassim, Hidayat; Khanlawia, Balbina; Brown, Shawn T

2016-09-22

Populations and routine childhood vaccine regimens have changed substantially since supply chains were designed in the 1980s, and introducing new vaccines during the "Decade of Vaccine" may exacerbate existing bottlenecks, further inhibiting the flow of all vaccines. Working with the Mozambique Ministry of Health, our team implemented a new process that integrated HERMES computational simulation modeling and on-the-ground implementers to evaluate and improve the Mozambique vaccine supply chain using a system-re-design that integrated new supply chain structures, information technology, equipment, personnel, and policies. The alternative system design raised vaccine availability (from 66% to 93% in Gaza; from 76% to 84% in Cabo Delgado) and reduced the logistics cost per dose administered (from $0.53 to $0.32 in Gaza; from $0.38 to $0.24 in Cabo Delgado) as compared to the multi-tiered system under the current EPI. The alternative system also produced higher availability at lower costs after new vaccine introductions. Since reviewing scenarios modeling deliveries every two months in the north of Gaza, the provincial directorate has decided to pilot this approach diverging from decades of policies dictating monthly deliveries. Re-design improved not only supply chain efficacy but also efficiency, important since resources to deliver vaccines are limited. The Mozambique experience and process can serve as a model for other countries during the Decade of Vaccines. For the Decade of Vaccines, getting vaccines at affordable prices to the market is not enough. Vaccines must reach the population to be successful. Copyright © 2016. Published by Elsevier Ltd.

Relative Contribution of Th1 and Th17 Cells in Adaptive Immunity to Bordetella pertussis: Towards the Rational Design of an Improved Acellular Pertussis Vaccine

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Ross, Pádraig J.; Allen, Aideen C.; Walsh, Kevin; Misiak, Alicja; Lavelle, Ed C.; McLoughlin, Rachel M.; Mills, Kingston H. G.

2013-01-01

Whooping cough caused by Bordetella pertussis is a re-emerging infectious disease despite the introduction of safer acellular pertussis vaccines (Pa). One explanation for this is that Pa are less protective than the more reactogenic whole cell pertussis vaccines (Pw) that they replaced. Although Pa induce potent antibody responses, and protection has been found to be associated with high concentrations of circulating IgG against vaccine antigens, it has not been firmly established that host protection induced with this vaccine is mediated solely by humoral immunity. The aim of this study was to examine the relative contribution of Th1 and Th17 cells in host immunity to infection with B. pertussis and in immunity induced by immunization with Pw and Pa and to use this information to help rationally design a more effective Pa. Our findings demonstrate that Th1 and Th17 both function in protective immunity induced by infection with B. pertussis or immunization with Pw. In contrast, a current licensed Pa, administered with alum as the adjuvant, induced Th2 and Th17 cells, but weak Th1 responses. We found that IL-1 signalling played a central role in protective immunity induced with alum-adsorbed Pa and this was associated with the induction of Th17 cells. Pa generated strong antibody and Th2 responses, but was fully protective in IL-4-defective mice, suggesting that Th2 cells were dispensable. In contrast, Pa failed to confer protective immunity in IL-17A-defective mice. Bacterial clearance mediated by Pa-induced Th17 cells was associated with cell recruitment to the lungs after challenge. Finally, protective immunity induced by an experimental Pa could be enhanced by substituting alum with a TLR agonist that induces Th1 cells. Our findings demonstrate that alum promotes protective immunity through IL-1β-induced IL-17A production, but also reveal that optimum protection against B. pertussis requires induction of Th1, but not Th2 cells. PMID:23592988

Effect of adding crushed Pimpinella anisum, Nigella sativa seeds and Thymus vulgaris mixture to antibiotics-free rations of vaccinated and non-vaccinated male broilers on growth performance, antibody titer and haematological profile

Directory of Open Access Journals (Sweden)

Mamoun Z. Athamneh

2010-04-01

Full Text Available This research explores an experimental study conducted to investigate the effect of crushed Pimpinella anisum (PA, Nigella sativa (NS seeds and Thymus vulgaris (TV mixture as a feed additive on growth performance and mortality rate (MR, selected antibodies titer (Ab’s and blood hematological profile of vaccinated and non-vaccinated Lohman male broiler chicks fed free-antibiotics ration. A total of 400 one-day old chicks were distributed into 16 groups (4 treatment x 4 replicates x 25chicks. The experiment lasted from one to 42 days of age. The statistical findings of this experiment prove that the use of medicinal plants mixture improves live body weight, body weight gain, feed conversion ratio and MR of vaccinated male broilers at 21 and 42 days of age. antibodies titer against infectious bronchitis and infectious bursal disease of non-vaccinated and vaccinated male broilers were significantly improved at 21 and 42 days as a result of the addition of medicinal plant mixture to the basal ration. Concerning Newcastle disease, the use of PA, NS and TV mixture did not reflect in any additional improvement of Ab's than vaccines did. The addition of medicinal plants mixture increases WBC's, RBC's, thrombocytes count and Hb concentration of vaccinated and non-vaccinated male broilers at 21 days of age. Meanwhile, heterophils, lymphocytes and monocytes of vaccinated male broilers (VMB were significantly improved by adding medicinal plant mixture to their basal diet. Moreover, at 42 days of age the use of PA, NS seeds and TV mixture indicate significant increase in total WBC’s, lymphocytes and monocytes and monocytes count of VMB and non-vaccinated male broiler (NVMB. No significant differences were noticed in RBC’s and Hct as a result of feeding crushed medicinal plants mixture.

Rational design of HIV vaccine and microbicides: report of the EUROPRISE annual conference.

Science.gov (United States)

Wahren, Britta; Biswas, Priscilla; Borggren, Marie; Coleman, Adam; Da Costa, Kelly; De Haes, Winni; Dieltjens, Tessa; Dispinseri, Stefania; Grupping, Katrijn; Hallengärd, David; Hornig, Julia; Klein, Katja; Mainetti, Lara; Palma, Paolo; Reudelsterz, Marc; Seifried, Janna; Selhorst, Philippe; Sköld, Annette; Uchtenhagen, Hannes; van Gils, Marit J; Weber, Caroline; Shattock, Robin; Scarlatti, Gabriella

2010-07-26

EUROPRISE is a Network of Excellence sponsored from 2007 to 2011 by the European Commission within the 6th Framework Program. The Network encompasses a wide portfolio of activities ranging from an integrated research program in the field of HIV vaccines and microbicides to training, dissemination and advocacy. The research program covers the whole pipeline of vaccine and microbicide development from discovery to early clinical trials. The Network is composed of 58 partners representing more than 65 institutions from 13 European countries; it also includes three major pharmaceutical companies (GlaxoSmithKline, Novartis and Sanofi-Pasteur) involved in HIV microbicide and vaccine research. The Network displays a dedicated and informative web page: http://www.europrise.org. Finally, a distinguishing trait of EUROPRISE is its PhD School of students from across Europe, a unique example in the world of science aimed at spreading excellence through training. EUROPRISE held its second annual conference in Budapest in November, 2009. The conference had 143 participants and their presentations covered aspects of vaccine and microbicide research, development and discovery. Since training is a major task of the Network, the students of the EUROPRISE PhD program summarized certain presentations and their view of the conference in this paper.

Rational design of HIV vaccine and microbicides: report of the EUROPRISE annual conference

Directory of Open Access Journals (Sweden)

Mainetti Lara

2010-07-01

Full Text Available Abstract EUROPRISE is a Network of Excellence sponsored from 2007 to 2011 by the European Commission within the 6th Framework Program. The Network encompasses a wide portfolio of activities ranging from an integrated research program in the field of HIV vaccines and microbicides to training, dissemination and advocacy. The research program covers the whole pipeline of vaccine and microbicide development from discovery to early clinical trials. The Network is composed of 58 partners representing more than 65 institutions from 13 European countries; it also includes three major pharmaceutical companies (GlaxoSmithKline, Novartis and Sanofi-Pasteur involved in HIV microbicide and vaccine research. The Network displays a dedicated and informative web page: http://www.europrise.org. Finally, a distinguishing trait of EUROPRISE is its PhD School of students from across Europe, a unique example in the world of science aimed at spreading excellence through training. EUROPRISE held its second annual conference in Budapest in November, 2009. The conference had 143 participants and their presentations covered aspects of vaccine and microbicide research, development and discovery. Since training is a major task of the Network, the students of the EUROPRISE PhD program summarized certain presentations and their view of the conference in this paper.

Rational design of HIV vaccines and microbicides: report of the EUROPRISE annual conference 2011.

Science.gov (United States)

Ruffin, Nicolas; Borggren, Marie; Euler, Zelda; Fiorino, Fabio; Grupping, Katrijn; Hallengärd, David; Javed, Aneele; Mendonca, Kevin; Pollard, Charlotte; Reinhart, David; Saba, Elisa; Sheik-Khalil, Enas; Sköld, Annette; Ziglio, Serena; Scarlatti, Gabriella; Gotch, Frances; Wahren, Britta; Shattock, Robin J

2012-07-11

Europrise is a Network of Excellence supported by the European Commission within the 6th Framework programme from 2007 to 2012. The Network has involved over 50 institutions from 13 European countries together with 3 industrial partners and 6 African countries. The Network encompasses an integrated program of research, training, dissemination and advocacy within the field of HIV vaccines and microbicides. A central and timely theme of the Network is the development of the unique concept of co-usage of vaccines and microbicides. Training of PhD students has been a major task, and some of these post-graduate students have here summarized novel ideas emanating from presentations at the last annual Europrise meeting in Prague. The latest data and ideas concerning HIV vaccine and microbicide studies are included in this review; these studies are so recent that the majority have yet to be published. Data were presented and discussed concerning novel immunisation strategies; microbicides and PrEP (alone and in combination with vaccines); mucosal transmission of HIV/SIV; mucosal vaccination; novel adjuvants; neutralizing antibodies; innate immune responses; HIV/SIV pathogenesis and disease progression; new methods and reagents. These - necessarily overlapping topics - are comprehensively summarised by the Europrise students in the context of other recent exciting data.

Rational design of HIV vaccines and microbicides: report of the EUROPRISE annual conference 2011

Directory of Open Access Journals (Sweden)

Ruffin Nicolas

2012-07-01

Full Text Available Abstract Europrise is a Network of Excellence supported by the European Commission within the 6th Framework programme from 2007 to 2012. The Network has involved over 50 institutions from 13 European countries together with 3 industrial partners and 6 African countries. The Network encompasses an integrated program of research, training, dissemination and advocacy within the field of HIV vaccines and microbicides. A central and timely theme of the Network is the development of the unique concept of co-usage of vaccines and microbicides. Training of PhD students has been a major task, and some of these post-graduate students have here summarized novel ideas emanating from presentations at the last annual Europrise meeting in Prague. The latest data and ideas concerning HIV vaccine and microbicide studies are included in this review; these studies are so recent that the majority have yet to be published. Data were presented and discussed concerning novel immunisation strategies; microbicides and PrEP (alone and in combination with vaccines; mucosal transmission of HIV/SIV; mucosal vaccination; novel adjuvants; neutralizing antibodies; innate immune responses; HIV/SIV pathogenesis and disease progression; new methods and reagents. These – necessarily overlapping topics - are comprehensively summarised by the Europrise students in the context of other recent exciting data.

Developing and Testing Rational Models of Message Design.

Science.gov (United States)

O'Keefe, Barbara J.

1992-01-01

Responds to an article in the same issue regarding research methods for conversational cognition. Argues for a noncognitive view of rational models in communication research. Sets out an analysis of the kinds of claims made by rational models of message design. Discusses the implications of this analysis for studies of the cognitive processes…

Enhancing the role of veterinary vaccines reducing zoonotic diseases of humans: Linking systems biology with vaccine development

Energy Technology Data Exchange (ETDEWEB)

Adams, Leslie G.; Khare, Sangeeta; Lawhon, Sara D.; Rossetti, Carlos A.; Lewin, Harris A.; Lipton, Mary S.; Turse, Joshua E.; Wylie, Dennis C.; Bai, Yu; Drake, Kenneth L.

2011-09-22

The aim of research on infectious diseases is their prevention, and brucellosis and salmonellosis as such are classic examples of worldwide zoonoses for application of a systems biology approach for enhanced rational vaccine development. When used optimally, vaccines prevent disease manifestations, reduce transmission of disease, decrease the need for pharmaceutical intervention, and improve the health and welfare of animals, as well as indirectly protecting against zoonotic diseases of people. Advances in the last decade or so using comprehensive systems biology approaches linking genomics, proteomics, bioinformatics, and biotechnology with immunology, pathogenesis and vaccine formulation and delivery are expected to enable enhanced approaches to vaccine development. The goal of this paper is to evaluate the role of computational systems biology analysis of host:pathogen interactions (the interactome) as a tool for enhanced rational design of vaccines. Systems biology is bringing a new, more robust approach to veterinary vaccine design based upon a deeper understanding of the host pathogen interactions and its impact on the host's molecular network of the immune system. A computational systems biology method was utilized to create interactome models of the host responses to Brucella melitensis (BMEL), Mycobacterium avium paratuberculosis (MAP), Salmonella enterica Typhimurium (STM), and a Salmonella mutant (isogenic *sipA, sopABDE2) and linked to the basis for rational development of vaccines for brucellosis and salmonellosis as reviewed by Adams et al. and Ficht et al. [1,2]. A bovine ligated ileal loop biological model was established to capture the host gene expression response at multiple time points post infection. New methods based on Dynamic Bayesian Network (DBN) machine learning were employed to conduct a comparative pathogenicity analysis of 219 signaling and metabolic pathways and 1620 gene ontology (GO) categories that defined the host

Rational design of protamine nanocapsules as antigen delivery carriers.

Science.gov (United States)

González-Aramundiz, José Vicente; Presas, Elena; Dalmau-Mena, Inmaculada; Martínez-Pulgarín, Susana; Alonso, Covadonga; Escribano, José M; Alonso, María J; Csaba, Noemi Stefánia

2017-01-10

Current challenges in global immunization indicate the demand for new delivery strategies, which could be applied to the development of new vaccines against emerging diseases, as well as to improve safety and efficacy of currently existing vaccine formulations. Here, we report a novel antigen nanocarrier consisting of an oily core and a protamine shell, further stabilized with pegylated surfactants. These nanocarriers, named protamine nanocapsules, were rationally designed to promote the intracellular delivery of antigens to immunocompetent cells and to trigger an efficient and long-lasting immune response. Protamine nanocapsules have nanometric size, positive zeta potential and high association capacity for H1N1 influenza hemagglutinin, a protein that was used here as a model antigen. The new formulation shows an attractive stability profile both, as an aqueous suspension or a freeze-dried powder formulation. In vitro studies showed that protamine nanocapsules were efficiently internalized by macrophages without eliciting significant toxicity. In vivo studies indicate that antigen-loaded nanocapsules trigger immune responses comparable to those achieved with alum, even when using significantly lower antigen doses, thus indicating their adjuvant properties. These promising in vivo data, alongside with their versatility for the loading of different antigens and oily immunomodulators and their excellent stability profile, make these nanocapsules a promising platform for the delivery of antigens. Protamine sulphate (PubChem SID: 7849283), Sodium Cholate (PubChem CID: 23668194), Miglyol (PubChem CID: 53471835), α tocopherol (PubChem CID: 14985), Tween® 20(PubChem CID: 443314), Tween® 80(PubChem CID: 5281955), TPGS (PubChem CID: 71406). Copyright © 2016 Elsevier B.V. All rights reserved.

Guest-responsive structural adaptation of a rationally-designed ...

Indian Academy of Sciences (India)

adaptability of the TB core to undergo subtle structural changes in response to the guest that is included. The structural ... we report the design, synthesis and inclusion behaviour of a novel ..... Based on a rational design, we have shown from ...

Using simulation to aid trial design: Ring-vaccination trials.

Directory of Open Access Journals (Sweden)

Matt David Thomas Hitchings

2017-03-01

Full Text Available The 2014-6 West African Ebola epidemic highlights the need for rigorous, rapid clinical trial methods for vaccines. A challenge for trial design is making sample size calculations based on incidence within the trial, total vaccine effect, and intracluster correlation, when these parameters are uncertain in the presence of indirect effects of vaccination.We present a stochastic, compartmental model for a ring vaccination trial. After identification of an index case, a ring of contacts is recruited and either vaccinated immediately or after 21 days. The primary outcome of the trial is total vaccine effect, counting cases only from a pre-specified window in which the immediate arm is assumed to be fully protected and the delayed arm is not protected. Simulation results are used to calculate necessary sample size and estimated vaccine effect. Under baseline assumptions about vaccine properties, monthly incidence in unvaccinated rings and trial design, a standard sample-size calculation neglecting dynamic effects estimated that 7,100 participants would be needed to achieve 80% power to detect a difference in attack rate between arms, while incorporating dynamic considerations in the model increased the estimate to 8,900. This approach replaces assumptions about parameters at the ring level with assumptions about disease dynamics and vaccine characteristics at the individual level, so within this framework we were able to describe the sensitivity of the trial power and estimated effect to various parameters. We found that both of these quantities are sensitive to properties of the vaccine, to setting-specific parameters over which investigators have little control, and to parameters that are determined by the study design.Incorporating simulation into the trial design process can improve robustness of sample size calculations. For this specific trial design, vaccine effectiveness depends on properties of the ring vaccination design and on the

Evaluation of urban river landscape design rationality based on AHP

Directory of Open Access Journals (Sweden)

Qiao Lifang

2008-12-01

Full Text Available An evaluation model for the rationality of the landscape design of urban rivers was established with the analytic hierarchy process (AHP method so as to provide a foundation for updating the landscape design of urban rivers. The evaluation system was divided into four layers, including the target layer, the comprehensive layer, the element layer, and the index layer. Each layer was made of different indices. The evaluation standards for each index were also given in this paper. This evaluation model was proved tenable through its application to the landscape design rationality evaluation of the Weihe River in Xinxiang City of Henan Province. The results show that the water quality, space, activity, facility, community, width of vegetation, sense of beauty and water content are among the most influential factors and should be considered the main basis for evaluating the rationality of the landscape design of urban rivers.

Rational development of an attenuated recombinant cyprinid herpesvirus 3 vaccine using prokaryotic mutagenesis and in vivo bioluminescent imaging.

Science.gov (United States)

Boutier, Maxime; Ronsmans, Maygane; Ouyang, Ping; Fournier, Guillaume; Reschner, Anca; Rakus, Krzysztof; Wilkie, Gavin S; Farnir, Frédéric; Bayrou, Calixte; Lieffrig, François; Li, Hong; Desmecht, Daniel; Davison, Andrew J; Vanderplasschen, Alain

2015-02-01

Cyprinid herpesvirus 3 (CyHV 3) is causing severe economic losses worldwide in common and koi carp industries, and a safe and efficacious attenuated vaccine compatible with mass vaccination is needed. We produced single deleted recombinants using prokaryotic mutagenesis. When producing a recombinant lacking open reading frame 134 (ORF134), we unexpectedly obtained a clone with additional deletion of ORF56 and ORF57. This triple deleted recombinant replicated efficiently in vitro and expressed an in vivo safety/efficacy profile compatible with use as an attenuated vaccine. To determine the role of the double ORF56-57 deletion in the phenotype and to improve further the quality of the vaccine candidate, a series of deleted recombinants was produced and tested in vivo. These experiments led to the selection of a double deleted recombinant lacking ORF56 and ORF57 as a vaccine candidate. The safety and efficacy of this strain were studied using an in vivo bioluminescent imaging system (IVIS), qPCR, and histopathological examination, which demonstrated that it enters fish via skin infection similar to the wild type strain. However, compared to the parental wild type strain, the vaccine candidate replicated at lower levels and spread less efficiently to secondary sites of infection. Transmission experiments allowing water contamination with or without additional physical contact between fish demonstrated that the vaccine candidate has a reduced ability to spread from vaccinated fish to naïve sentinel cohabitants. Finally, IVIS analyses demonstrated that the vaccine candidate induces a protective mucosal immune response at the portal of entry. Thus, the present study is the first to report the rational development of a recombinant attenuated vaccine against CyHV 3 for mass vaccination of carp. We also demonstrated the relevance of the CyHV 3 carp model for studying alloherpesvirus transmission and mucosal immunity in teleost skin.

Proof of principle for epitope-focused vaccine design

Science.gov (United States)

Correia, Bruno E.; Bates, John T.; Loomis, Rebecca J.; Baneyx, Gretchen; Carrico, Chris; Jardine, Joseph G.; Rupert, Peter; Correnti, Colin; Kalyuzhniy, Oleksandr; Vittal, Vinayak; Connell, Mary J.; Stevens, Eric; Schroeter, Alexandria; Chen, Man; MacPherson, Skye; Serra, Andreia M.; Adachi, Yumiko; Holmes, Margaret A.; Li, Yuxing; Klevit, Rachel E.; Graham, Barney S.; Wyatt, Richard T.; Baker, David; Strong, Roland K.; Crowe, James E.; Johnson, Philip R.; Schief, William R.

2014-03-01

Vaccines prevent infectious disease largely by inducing protective neutralizing antibodies against vulnerable epitopes. Several major pathogens have resisted traditional vaccine development, although vulnerable epitopes targeted by neutralizing antibodies have been identified for several such cases. Hence, new vaccine design methods to induce epitope-specific neutralizing antibodies are needed. Here we show, with a neutralization epitope from respiratory syncytial virus, that computational protein design can generate small, thermally and conformationally stable protein scaffolds that accurately mimic the viral epitope structure and induce potent neutralizing antibodies. These scaffolds represent promising leads for the research and development of a human respiratory syncytial virus vaccine needed to protect infants, young children and the elderly. More generally, the results provide proof of principle for epitope-focused and scaffold-based vaccine design, and encourage the evaluation and further development of these strategies for a variety of other vaccine targets, including antigenically highly variable pathogens such as human immunodeficiency virus and influenza.

Novel Adjuvants and Immunomodulators for Veterinary Vaccines.

Science.gov (United States)

Heegaard, Peter M H; Fang, Yongxiang; Jungersen, Gregers

2016-01-01

Adjuvants are crucial for efficacy of vaccines, especially subunit and recombinant vaccines. Rational vaccine design, including knowledge-based and molecularly defined adjuvants tailored for directing and potentiating specific types of host immune responses towards the antigens included in the vaccine is becoming a reality with our increased understanding of innate and adaptive immune activation. This will allow future vaccines to induce immune reactivity having adequate specificity as well as protective and recallable immune effector mechanisms in appropriate body compartments, including mucosal surfaces. Here we describe these new developments and, when possible, relate new immunological knowledge to the many years of experience with traditional, empirical adjuvants. Finally, some protocols are given for production of emulsion (oil-based) and liposome-based adjuvant/antigen formulations.

Rational design of HIV vaccines and microbicides: report of the EUROPRISE network annual conference 2010

Directory of Open Access Journals (Sweden)

Uchtenhagen Hannes

2011-04-01

Full Text Available Abstract Novel, exciting intervention strategies to prevent infection with HIV have been tested in the past year, and the field is rapidly evolving. EUROPRISE is a network of excellence sponsored by the European Commission and concerned with a wide range of activities including integrated developmental research on HIV vaccines and microbicides from discovery to early clinical trials. A central and timely theme of the network is the development of the unique concept of co-usage of vaccines and microbicides. This review, prepared by the PhD students of the network captures much of the research ongoing between the partners. The network is in its 5th year and involves over 50 institutions from 13 European countries together with 3 industrial partners; GSK, Novartis and Sanofi-Pasteur. EUROPRISE is involved in 31 separate world-wide trials of Vaccines and Microbicides including 6 in African countries (Tanzania, Mozambique, South Africa, Kenya, Malawi, Rwanda, and is directly supporting clinical trials including MABGEL, a gp140-hsp70 conjugate trial and HIVIS, vaccine trials in Europe and Africa.

Rational design of HIV vaccines and microbicides: report of the EUROPRISE network annual conference 2010.

Science.gov (United States)

Brinckmann, Sarah; da Costa, Kelly; van Gils, Marit J; Hallengärd, David; Klein, Katja; Madeira, Luisa; Mainetti, Lara; Palma, Paolo; Raue, Katharina; Reinhart, David; Reudelsterz, Marc; Ruffin, Nicolas; Seifried, Janna; Schäfer, Katrein; Sheik-Khalil, Enas; Sköld, Annette; Uchtenhagen, Hannes; Vabret, Nicolas; Ziglio, Serena; Scarlatti, Gabriella; Shattock, Robin; Wahren, Britta; Gotch, Frances

2011-04-12

Novel, exciting intervention strategies to prevent infection with HIV have been tested in the past year, and the field is rapidly evolving. EUROPRISE is a network of excellence sponsored by the European Commission and concerned with a wide range of activities including integrated developmental research on HIV vaccines and microbicides from discovery to early clinical trials. A central and timely theme of the network is the development of the unique concept of co-usage of vaccines and microbicides. This review, prepared by the PhD students of the network captures much of the research ongoing between the partners. The network is in its 5th year and involves over 50 institutions from 13 European countries together with 3 industrial partners; GSK, Novartis and Sanofi-Pasteur. EUROPRISE is involved in 31 separate world-wide trials of Vaccines and Microbicides including 6 in African countries (Tanzania, Mozambique, South Africa, Kenya, Malawi, Rwanda), and is directly supporting clinical trials including MABGEL, a gp140-hsp70 conjugate trial and HIVIS, vaccine trials in Europe and Africa.

Novel structurally designed vaccine for S. aureus α-hemolysin: protection against bacteremia and pneumonia.

Directory of Open Access Journals (Sweden)

Rajan P Adhikari

Full Text Available Staphylococcus aureus (S. aureus is a human pathogen associated with skin and soft tissue infections (SSTI and life threatening sepsis and pneumonia. Efforts to develop effective vaccines against S. aureus have been largely unsuccessful, in part due to the variety of virulence factors produced by this organism. S. aureus alpha-hemolysin (Hla is a pore-forming toxin expressed by most S. aureus strains and reported to play a key role in the pathogenesis of SSTI and pneumonia. Here we report a novel recombinant subunit vaccine candidate for Hla, rationally designed based on the heptameric crystal structure. This vaccine candidate, denoted AT-62aa, was tested in pneumonia and bacteremia infection models using S. aureus strain Newman and the pandemic strain USA300 (LAC. Significant protection from lethal bacteremia/sepsis and pneumonia was observed upon vaccination with AT-62aa along with a Glucopyranosyl Lipid Adjuvant-Stable Emulsion (GLA-SE that is currently in clinical trials. Passive transfer of rabbit immunoglobulin against AT-62aa (AT62-IgG protected mice against intraperitoneal and intranasal challenge with USA300 and produced significant reduction in bacterial burden in blood, spleen, kidney, and lungs. Our Hla-based vaccine is the first to be reported to reduce bacterial dissemination and to provide protection in a sepsis model of S. aureus infection. AT62-IgG and sera from vaccinated mice effectively neutralized the toxin in vitro and AT62-IgG inhibited the formation of Hla heptamers, suggesting antibody-mediated neutralization as the primary mechanism of action. This remarkable efficacy makes this Hla-based vaccine a prime candidate for inclusion in future multivalent S. aureus vaccine. Furthermore, identification of protective epitopes within AT-62aa could lead to novel immunotherapy for S. aureus infection.

Machine learning in the rational design of antimicrobial peptides.

Science.gov (United States)

Rondón-Villarreal, Paola; Sierra, Daniel A; Torres, Rodrigo

2014-01-01

One of the most important public health issues is the microbial and bacterial resistance to conventional antibiotics by pathogen microorganisms. In recent years, many researches have been focused on the development of new antibiotics. Among these, antimicrobial peptides (AMPs) have raised as a promising alternative to combat antibioticresistant microorganisms. For this reason, many theoretical efforts have been done in the development of new computational tools for the rational design of both better and effective AMPs. In this review, we present an overview of the rational design of AMPs using machine learning techniques and new research fields.

The cancer-immunity cycle as rational design for synthetic cancer drugs: Novel DC vaccines and CAR T-cells.

Science.gov (United States)

Ramachandran, Mohanraj; Dimberg, Anna; Essand, Magnus

2017-08-01

Cell therapy is an advanced form of cancer immunotherapy that has had remarkable clinical progress in the past decade in the search for cure of cancer. Most success has been achieved for chimeric antigen receptor (CAR) T-cells where CAR T-cells targeting CD19 show very high complete response rates for patients with refractory acute B-cell acute lymphoblastic leukemia (ALL) and are close to approval for this indication. CD19 CAR T-cells are also effective against B-cell chronic lymphoblastic leukemia (CLL) and B-cell lymphomas. Although encouraging, CAR T-cells have not yet proven clinically effective for solid tumors. This is mainly due to the lack of specific and homogenously expressed targets to direct the T-cells against and a hostile immunosuppressive tumor microenvironment in solid tumors. Cancer vaccines based on dendritic cells (DC) are also making progress although clinical efficacy is still lacking. The likelihood of success is however increasing now when individual tumors can be sequences and patient-specific neoepitopes identified. Neoepitopes and/or neoantigens can then be included in patient-based DC vaccines. This review discusses recent advancements of DC vaccines and CAR T-cells with emphasis on the cancer-immunity cycle, and current efforts to design novel cell therapies. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Rational Design of an Ultrasensitive Quorum-Sensing Switch.

Science.gov (United States)

Zeng, Weiqian; Du, Pei; Lou, Qiuli; Wu, Lili; Zhang, Haoqian M; Lou, Chunbo; Wang, Hongli; Ouyang, Qi

2017-08-18

One of the purposes of synthetic biology is to develop rational methods that accelerate the design of genetic circuits, saving time and effort spent on experiments and providing reliably predictable circuit performance. We applied a reverse engineering approach to design an ultrasensitive transcriptional quorum-sensing switch. We want to explore how systems biology can guide synthetic biology in the choice of specific DNA sequences and their regulatory relations to achieve a targeted function. The workflow comprises network enumeration that achieves the target function robustly, experimental restriction of the obtained candidate networks, global parameter optimization via mathematical analysis, selection and engineering of parts based on these calculations, and finally, circuit construction based on the principles of standardization and modularization. The performance of realized quorum-sensing switches was in good qualitative agreement with the computational predictions. This study provides practical principles for the rational design of genetic circuits with targeted functions.

From bricolage to BioBricks™: Synthetic biology and rational design.

Science.gov (United States)

Lewens, Tim

2013-12-01

Synthetic biology is often described as a project that applies rational design methods to the organic world. Although humans have influenced organic lineages in many ways, it is nonetheless reasonable to place synthetic biology towards one end of a continuum between purely 'blind' processes of organic modification at one extreme, and wholly rational, design-led processes at the other. An example from evolutionary electronics illustrates some of the constraints imposed by the rational design methodology itself. These constraints reinforce the limitations of the synthetic biology ideal, limitations that are often freely acknowledged by synthetic biology's own practitioners. The synthetic biology methodology reflects a series of constraints imposed on finite human designers who wish, as far as is practicable, to communicate with each other and to intervene in nature in reasonably targeted and well-understood ways. This is better understood as indicative of an underlying awareness of human limitations, rather than as expressive of an objectionable impulse to mastery over nature. Copyright © 2013 Elsevier Ltd. All rights reserved.

a rational approach for predicting the minimum composition of anti ...

African Journals Online (AJOL)

of Cv may deviate from what is predicted by the formula given above are discussed. Extensive literature search on malaria, onchocerciasis and schistosomiasis sub-unit vaccine development ... provides a rational framework for constituting a sub-unit anti-parasite vaccine. ..... vaccine formulation produced greater protection.

Rational design of HIV vaccine and microbicides: report of the EUROPRISE annual conference

NARCIS (Netherlands)

Wahren, Britta; Biswas, Priscilla; Borggren, Marie; Coleman, Adam; Da Costa, Kelly; de Haes, Winni; Dieltjens, Tessa; Dispinseri, Stefania; Grupping, Katrijn; Hallengärd, David; Hornig, Julia; Klein, Katja; Mainetti, Lara; Palma, Paolo; Reudelsterz, Marc; Seifried, Janna; Selhorst, Philippe; Sköld, Annette; Uchtenhagen, Hannes; van Gils, Marit J.; Weber, Caroline; Shattock, Robin; Scarlatti, Gabriella

2010-01-01

EUROPRISE is a Network of Excellence sponsored from 2007 to 2011 by the European Commission within the 6th Framework Program. The Network encompasses a wide portfolio of activities ranging from an integrated research program in the field of HIV vaccines and microbicides to training, dissemination

Accelerating tuberculosis vaccine trials with diagnostic and prognostic biomarkers.

Science.gov (United States)

Kaufmann, Stefan H E; Weiner, January; Maertzdorf, Jeroen

2017-08-01

The most recent estimates on tuberculosis (TB) morbidity and mortality reveal that the global disease burden is even higher than previously assumed. Better drugs, diagnostics and vaccines are major requirements to control the ongoing TB pandemic. The high complexity of the infectious process and the underlying pathology, however, challenge elucidation of protective immune mechanisms at the various stages towards active TB disease, which need to be understood for rational design of novel intervention measures. Areas covered: Next to the more classical approaches, host biomarkers increasingly receive attention as promising tools on our way to control the disease. In the area of diagnosis, host biomarkers are recognized as promising new means because the identification of small biosignatures with high discriminatory and even prognostic potential has stimulated the hope that rapid and easy-to-perform diagnosis and prognosis will become possible in the near future. For rational design of new vaccine candidates, correlates of protection are highly desirable. High-throughput systems-vaccinology will boost the identification of such biomarker profiles. Expert commentary: Considering their potential to accelerate development of better diagnostics and vaccines, host biomarkers should be firmly integrated into future TB research.

Design of 2-D rational digital filters

International Nuclear Information System (INIS)

Harris, D.B

1981-01-01

A novel 2-D rational filter design technique is presented which makes use of a reflection coefficient function (RCF) representation for the filter transfer function. The design problem is formulated in the frequency domain. A least-square error criterion is used though the usual error measure is augmented with barrier functions. These act to restrict the domain of approximation to the set of stable filters. Construction of suitable barrier functions is facilitated by the RCF characterization

SARS CTL vaccine candidates; HLA supertype-, genome-wide scanning and biochemical validation

DEFF Research Database (Denmark)

Sylvester-Hvid, C; Nielsen, M; Lamberth, K

2004-01-01

. Exact knowledge of how the immune system handles protein antigens would allow for the identification of such linear sequences directly from genomic/proteomic sequence information (Lauemoller et al., Rev Immunogenet 2001: 2: 477-91). The latter was recently established when a causative coronavirus (SARS...... of the HLA supertypes and identified almost 100 potential vaccine candidates. These should be further validated in SARS survivors and used for vaccine formulation. We suggest that immunobioinformatics may become a fast and valuable tool in rational vaccine design....

SARS CTL vaccine candidates; HLA supertype-, genome-wide scanning and biochemical validation

DEFF Research Database (Denmark)

Sylvester-Hvid, C.; Nielsen, Morten; Lamberth, K.

2004-01-01

. Exact knowledge of how the immune system handles protein antigens would allow for the identification of such linear sequences directly, from genomic/proteomic sequence information (Lauemoller et al., Rev Immunogenet 2001: 2: 477-91). The latter was recently established when a causative coronavirus (SARS...... of the HLA supertypes and identified almost 100 potential vaccine candidates. These should be further validated in SARS survivors and used for vaccine formulation. We suggest that immunobioinformatics may become a fast and valuable tool in rational vaccine design....

Catalase epitopes vaccine design for Helicobacter pylori : A ...

African Journals Online (AJOL)

Catalase, an important enzyme in the virulence of H. pylori, could be a suitable candidate for vaccine design because it is highly conserved, which is important for the survival of H. pylori; it is expressed in high level and it is exposed on the surface of the bacteria. In this study, we designed epitope-based vaccine for catalase ...

42 CFR 71.3 - Designation of yellow fever vaccination centers; Validation stamps.

Science.gov (United States)

2010-10-01

... safe, potent, and pure yellow fever vaccine. Medical facilities of Federal agencies are authorized to obtain yellow fever vaccine without being designated as a yellow fever vaccination center by the Director..., storage, and administration of yellow fever vaccine. If a designated center fails to comply with such...

Refolding of proteins from inclusion bodies: rational design and recipes.

Science.gov (United States)

Basu, Anindya; Li, Xiang; Leong, Susanna Su Jan

2011-10-01

The need to develop protein biomanufacturing platforms that can deliver proteins quickly and cost-effectively is ever more pressing. The rapid rate at which genomes can now be sequenced demands efficient protein production platforms for gene function identification. There is a continued need for the biotech industry to deliver new and more effective protein-based drugs to address new diseases. Bacterial production platforms have the advantage of high expression yields, but insoluble expression of many proteins necessitates the development of diverse and optimised refolding-based processes. Strategies employed to eliminate insoluble expression are reviewed, where it is concluded that inclusion bodies are difficult to eliminate for various reasons. Rational design of refolding systems and recipes are therefore needed to expedite production of recombinant proteins. This review article discusses efforts towards rational design of refolding systems and recipes, which can be guided by the development of refolding screening platforms that yield both qualitative and quantitative information on the progression of a given refolding process. The new opportunities presented by light scattering technologies for developing rational protein refolding buffer systems which in turn can be used to develop new process designs armed with better monitoring and controlling functionalities are discussed. The coupling of dynamic and static light scattering methodologies for incorporation into future bioprocess designs to ensure delivery of high-quality refolded proteins at faster rates is also discussed.

Standby Gasoline Rationing Plan. Contingency gasoline rationing regulations

Energy Technology Data Exchange (ETDEWEB)

1979-02-01

The Economic Regulatory Administration issues final rules with respect to standby gasoline rationing. The plan is designed for and would be used only in the event of a severe gasoline shortage. The plan provides that eligibility for ration allotments will be primarily on the basis of motor vehicle registrations. DOE will mail government ration checks to the parties named in a national vehicle registration file to be maintained by DOE. Ration recipients may cash these checks for ration coupons at various designated coupon issuance points. Retail outlets and other suppliers will be required to redeem the ration coupons received in exchange for gasoline sold. Supplemental gas will be given to high-priority activities. A ration banking system will be established with two separate and distinct of ration accounts: retail outlets and other suppliers will open redemption accounts for the deposit of redeemed ration rights; and individuals or firms may open ration rights accounts, which will operate in much the same manner as monetary checking accounts. A white market will be permitted for the sale of transfer of ration rights. A percentage of the total ration rights to be issued will be reserved for distribution to the states as a State Ration Reserve, to be used by the states primarily for the relief of hardship. A National Ration Reserave will also be established. All sections of the Standby Gasoline Rationing Regulations are analyzed. (MCW)

Current status and future prospects of yellow fever vaccines.

Science.gov (United States)

Beck, Andrew S; Barrett, Alan D T

2015-01-01

Yellow fever 17D vaccine is one of the oldest live-attenuated vaccines in current use that is recognized historically for its immunogenic and safe properties. These unique properties of 17D are presently exploited in rationally designed recombinant vaccines targeting not only flaviviral antigens but also other pathogens of public health concern. Several candidate vaccines based on 17D have advanced to human trials, and a chimeric recombinant Japanese encephalitis vaccine utilizing the 17D backbone has been licensed. The mechanism(s) of attenuation for 17D are poorly understood; however, recent insights from large in silico studies have indicated particular host genetic determinants contributing to the immune response to the vaccine, which presumably influences the considerable durability of protection, now in many cases considered to be lifelong. The very rare occurrence of severe adverse events for 17D is discussed, including a recent fatal case of vaccine-associated viscerotropic disease.

Current Status and Future Prospects of Yellow Fever Vaccines

Science.gov (United States)

Beck, Andrew S.; Barrett, Alan D.T.

2017-01-01

Summary Yellow fever 17D vaccine is one of the oldest live-attenuated vaccines in current use that is recognized for historically immunogenic and safe properties. These unique properties of 17D are presently exploited in rationally designed recombinant vaccines targeting not only flaviviral antigens but also other pathogens of public health concern. Several candidate vaccines based on 17D have advanced to human trials, and a chimeric recombinant Japanese encephalitis vaccine utilizing the 17D backbone has been licensed. The mechanism(s) of attenuation for 17D are poorly understood; however, recent insights from large in silico studies have indicated particular host genetic determinants contributing to the immune response to the vaccine, which presumably influences the considerable durability of protection, now in many cases considered to be life-long. The very rare occurrence of severe adverse events for 17D is discussed, including a recent fatal case of vaccine-associated viscerotropic disease. PMID:26366673

Epidemiological Studies to Support the Development of Next Generation Influenza Vaccines.

Science.gov (United States)

Petrie, Joshua G; Gordon, Aubree

2018-03-26

The National Institute of Allergy and Infectious Diseases recently published a strategic plan for the development of a universal influenza vaccine. This plan focuses on improving understanding of influenza infection, the development of influenza immunity, and rational design of new vaccines. Epidemiological studies such as prospective, longitudinal cohort studies are essential to the completion of these objectives. In this review, we discuss the contributions of epidemiological studies to our current knowledge of vaccines and correlates of immunity, and how they can contribute to the development and evaluation of the next generation of influenza vaccines. These studies have been critical in monitoring the effectiveness of current influenza vaccines, identifying issues such as low vaccine effectiveness, reduced effectiveness among those who receive repeated vaccination, and issues related to egg adaptation during the manufacturing process. Epidemiological studies have also identified population-level correlates of protection that can inform the design and development of next generation influenza vaccines. Going forward, there is an enduring need for epidemiological studies to continue advancing knowledge of correlates of protection and the development of immunity, to evaluate and monitor the effectiveness of next generation influenza vaccines, and to inform recommendations for their use.

Adversomics: a new paradigm for vaccine safety and design.

Science.gov (United States)

Whitaker, Jennifer A; Ovsyannikova, Inna G; Poland, Gregory A

2015-07-01

Despite the enormous population benefits of routine vaccination, vaccine adverse events (AEs) and reactions, whether real or perceived, have posed one of the greatest barriers to vaccine acceptance--and thus to infectious disease prevention--worldwide. A truly integrated clinical, translational, and basic science approach is required to understand the mechanisms behind vaccine AEs, predict them, and then apply this knowledge to new vaccine design approaches that decrease, or avoid, these events. The term 'adversomics' was first introduced in 2009 and refers to the study of vaccine adverse reactions using immunogenomics and systems biology approaches. In this review, we present the current state of adversomics research, review known associations and mechanisms of vaccine AEs/reactions, and outline a plan for the further development of this emerging research field.

Vaccines for the future: learning from human immunology

Science.gov (United States)

De Gregorio, Ennio; Rappuoli, Rino

2012-01-01

Summary Conventional vaccines have been extremely successful in preventing infections by pathogens expressing relatively conserved antigens through antibody‐mediated effector mechanisms. Thanks to vaccination some diseases have been eradicated and mortality due to infectious diseases has been significantly reduced. However, there are still many infections that are not preventable with vaccination, which represent a major cause of mortality worldwide. Some of these infections are caused by pathogens with a high degree of antigen variability that cannot be controlled only by antibodies, but require a mix of humoral and cellular immune responses. Novel technologies for antigen discovery, expression and formulation allow now for the development of vaccines that can better cope with pathogen diversity and trigger multifunctional immune responses. In addition, the application of new genomic assays and systems biology approaches in human immunology can help to better identify vaccine correlates of protection. The availability of novel vaccine technologies, together with the knowledge of the distinct human immune responses that are required to prevent different types of infection, should help to rationally design effective vaccines where conventional approaches have failed. PMID:21880117

Designing Peptide-Based HIV Vaccine for Chinese

Science.gov (United States)

Fan, Xiaojuan

2014-01-01

CD4+ T cells are central to the induction and maintenance of CD8+ T cell and antibody-producing B cell responses, and the latter are essential for the protection against disease in subjects with HIV infection. How to elicit HIV-specific CD4+ T cell responses in a given population using vaccines is one of the major areas of current HIV vaccine research. To design vaccine that targets specifically Chinese, we assembled a database that is comprised of sequences from 821 Chinese HIV isolates and 46 human leukocyte antigen (HLA) DR alleles identified in Chinese population. We then predicted 20 potential HIV epitopes using bioinformatics approaches. The combination of these 20 epitopes has a theoretical coverage of 98.1% of the population for both the prevalent HIV genotypes and also Chinese HLA-DR types. We suggest that testing this vaccine experimentally will facilitate the development of a CD4+ T cell vaccine especially catered for Chinese. PMID:25136573

RECENT ADVANCES TOWARDS THE RATIONAL DESIGN OF PEPTIDE DRUGS

OpenAIRE

YEŞİLADA, Akgül; ÖZKANLI, Fügen

2004-01-01

In this review, after a short introduction to definition and physiological roles of regulatory peptides, problems faced during the development of peptide drugs, studies directed to solve these problems and rational design of peptide drugs with special emphesis on peptidomimetics are mentioned

Evaluation of peptide selection approaches for epitope‐based vaccine design

DEFF Research Database (Denmark)

Schubert, B.; Lund, Ole; Nielsen, Morten

2013-01-01

A major challenge in epitope-based vaccine (EV) design stems from the vast genomic variation of pathogens and the diversity of the host cellular immune system. Several computational approaches have been published to assist the selection of potential T cell epitopes for EV design. So far, no thoro......A major challenge in epitope-based vaccine (EV) design stems from the vast genomic variation of pathogens and the diversity of the host cellular immune system. Several computational approaches have been published to assist the selection of potential T cell epitopes for EV design. So far...... in terms of in silico measurements simulating important vaccine properties like the ability of inducing protection against a multivariant pathogen in a population; the predicted immunogenicity; pathogen, allele, and population coverage; as well as the conservation of selected epitopes. Additionally, we...... evaluate the use of human leukocyte antigen (HLA) supertypes with regards to their applicability for population-spanning vaccine design. The results showed that in terms of induced protection methods that simultaneously aim to optimize pathogen and HLA coverage significantly outperform methods focusing...

Rationalization of a nanoparticle-based nicotine nanovaccine as an effective next-generation nicotine vaccine: A focus on hapten localization.

Science.gov (United States)

Zhao, Zongmin; Hu, Yun; Harmon, Theresa; Pentel, Paul; Ehrich, Marion; Zhang, Chenming

2017-09-01

A lipid-polymeric hybrid nanoparticle-based next-generation nicotine nanovaccine was rationalized in this study to combat nicotine addiction. A series of nanovaccines, which had nicotine-haptens localized on carrier protein (LPKN), nanoparticle surface (LPNK), or both (LPNKN), were designed to study the impact of hapten localization on their immunological efficacy. All three nanovaccines were efficiently taken up and processed by dendritic cells. LPNKN induced a significantly higher immunogenicity against nicotine and a significantly lower anti-carrier protein antibody level compared to LPKN and LPNK. Meanwhile, it was found that the anti-nicotine antibodies elicited by LPKN and LPNKN bind nicotine stronger than those elicited by LPKN, and LPNK and LPNKN resulted in a more balanced Th1-Th2 immunity than LPKN. Moreover, LPNKN exhibited the best ability to block nicotine from entering the brain of mice. Collectively, the results demonstrated that the immunological efficacy of the hybrid nanoparticle-based nicotine vaccine could be enhanced by modulating hapten localization, providing a promising strategy to combatting nicotine addiction. Copyright © 2017 Elsevier Ltd. All rights reserved.

An overview of adjuvants utilized in prophylactic vaccine formulation as immunomodulators.

Science.gov (United States)

Chauhan, Nidhi; Tiwari, Sukirti; Iype, Tessy; Jain, Utkarsh

2017-05-01

Development of efficient and cost effective vaccines have been recognized as the primary concern to improve the overall healthcare in a country. In order to achieve this goal, more improved and powerful adjuvants need to be developed. Lacking in the self-adjuvanting immuno-modulatory constituents, vaccines exhibit lower immunogenicity. Combining potent adjuvants with vaccines is the most appropriate method to enhance the efficacy of the vaccines. Hence, this review is focussed on the most potent adjuvants for the formulation of vaccines. Areas covered: This review focuses on Oil-based emulsions, Mineral compounds, Liposomes, Bacterial products, ISCOMs and most recently used nanomaterials as adjuvants for enhancing the antigenicity of vaccines. Furthermore, this review explains the immunological response elicited by various particles. Moreover, case studies are incorporated providing an in depth analyses of various adjuvant-containing vaccines which are currently used. Expert commentary: Enhanced fundamental knowledge about the adjuvants and their immuno-stimulatory capabilities and delivery mechanisms will facilitate the rational designing of prophylactic vaccines with better efficacy.

A rational approach for ω-transaminase-catalyzed process design

DEFF Research Database (Denmark)

T. Gundersen, Maria; Lloyd, Richard; Tufvesson, Pär

Herein we describe a novel rational approach to the design of a ω-transaminase process such that it will fulfill criteria necessary for industrial use. By first determining the fundamental properties of the reaction system, it is possible to suggest appropriate process strategies that may be used...

Design rationalization and the logic of design: a case study

DEFF Research Database (Denmark)

Galle, Per

1996-01-01

various ‘sources of credibility’ of premises, items of general background knowledge, and several (abductive and deductive) patterns of inference which suggest a possible ‘logic of design’. Rationalization of decisions is defined, and many decisions are found not to be fully rationalized, despite...... the apparent rationality of the reasoning....

Rational Design of Cancer-Targeted Benzoselenadiazole by RGD Peptide Functionalization for Cancer Theranostics.

Science.gov (United States)

Yang, Liye; Li, Wenying; Huang, Yanyu; Zhou, Yangliang; Chen, Tianfeng

2015-09-01

A cancer-targeted conjugate of the selenadiazole derivative BSeC (benzo[1,2,5] selenadiazole-5-carboxylic acid) with RGD peptide as targeting molecule and PEI (polyethylenimine) as a linker is rationally designed and synthesized in the present study. The results show that RGD-PEI-BSeC forms nanoparticles in aqueous solution with a core-shell nanostructure and high stability under physiological conditions. This rational design effectively enhances the selective cellular uptake and cellular retention of BSeC in human glioma cells, and increases its selectivity between cancer and normal cells. The nanoparticles enter the cells through receptor-mediated endocytosis via clathrin-mediated and nystatin-dependent lipid raft-mediated pathways. Internalized nanoparticles trigger glioma cell apoptosis by activation of ROS-mediated p53 phosphorylation. Therefore, this study provides a strategy for the rational design of selenium-containing cancer-targeted theranostics. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The test-negative design for estimating influenza vaccine effectiveness.

Science.gov (United States)

Jackson, Michael L; Nelson, Jennifer C

2013-04-19

The test-negative design has emerged in recent years as the preferred method for estimating influenza vaccine effectiveness (VE) in observational studies. However, the methodologic basis of this design has not been formally developed. In this paper we develop the rationale and underlying assumptions of the test-negative study. Under the test-negative design for influenza VE, study subjects are all persons who seek care for an acute respiratory illness (ARI). All subjects are tested for influenza infection. Influenza VE is estimated from the ratio of the odds of vaccination among subjects testing positive for influenza to the odds of vaccination among subjects testing negative. With the assumptions that (a) the distribution of non-influenza causes of ARI does not vary by influenza vaccination status, and (b) VE does not vary by health care-seeking behavior, the VE estimate from the sample can generalized to the full source population that gave rise to the study sample. Based on our derivation of this design, we show that test-negative studies of influenza VE can produce biased VE estimates if they include persons seeking care for ARI when influenza is not circulating or do not adjust for calendar time. The test-negative design is less susceptible to bias due to misclassification of infection and to confounding by health care-seeking behavior, relative to traditional case-control or cohort studies. The cost of the test-negative design is the additional, difficult-to-test assumptions that incidence of non-influenza respiratory infections is similar between vaccinated and unvaccinated groups within any stratum of care-seeking behavior, and that influenza VE does not vary across care-seeking strata. Copyright © 2013 Elsevier Ltd. All rights reserved.

MIRATE: MIps RATional dEsign Science Gateway.

Science.gov (United States)

Busato, Mirko; Distefano, Rosario; Bates, Ferdia; Karim, Kal; Bossi, Alessandra Maria; López Vilariño, José Manuel; Piletsky, Sergey; Bombieri, Nicola; Giorgetti, Alejandro

2018-06-13

Molecularly imprinted polymers (MIPs) are high affinity robust synthetic receptors, which can be optimally synthesized and manufactured more economically than their biological equivalents (i.e. antibody). In MIPs production, rational design based on molecular modeling is a commonly employed technique. This mostly aids in (i) virtual screening of functional monomers (FMs), (ii) optimization of monomer-template ratio, and (iii) selectivity analysis. We present MIRATE, an integrated science gateway for the intelligent design of MIPs. By combining and adapting multiple state-of-the-art bioinformatics tools into automated and innovative pipelines, MIRATE guides the user through the entire process of MIPs' design. The platform allows the user to fully customize each stage involved in the MIPs' design, with the main goal to support the synthesis in the wet-laboratory. MIRATE is freely accessible with no login requirement at http://mirate.di.univr.it/. All major browsers are supported.

Structure-based, rational design of T cell receptors

Directory of Open Access Journals (Sweden)

Vincent eZoete

2013-09-01

Full Text Available Adoptive cell transfer using engineered T cells is emerging as a promising treatment for metastatic melanoma. Such an approach allows one to introduce TCR modifications that, while maintaining the specificity for the targeted antigen, can enhance the binding and kinetic parameters for the interaction pMHC. Using the well-characterized 2C TCR/SIYR/H-2K(b structure as a model system, we demonstrated that a binding free energy decomposition based on the MM-GBSA approach provides a detailed and reliable description of the TCR/pMHC interactions at the structural and thermodynamic levels. Starting from this result, we developed a new structure-based approach, to rationally design new TCR sequences, and applied it to the BC1 TCR targeting the HLA-A2 restricted NY-ESO-1157-165 cancer-testis epitope. 54% of the designed sequence replacements exhibited improved pMHC-binding as compared to the native TCR, with up to 150 fold increase in affinity, while preserving specificity. Genetically-engineered CD8+ T cells expressing these modified TCRs showed an improved functional activity compared to those expressing BC1 TCR. We measured maximum levels of activities for TCRs within the upper limit of natural affinity. Beyond the affinity threshold at KD < 1 μM we observed an attenuation in cellular function. We have also developed a homology modeling-based approach, TCRep 3D, to obtain accurate structural models of any TCR-pMHC complexes. We have complemented the approach with a simplified rigid method to predict the TCR orientation over pMHC. These methods potentially extend the use of our TCR engineering method to entire TCR repertoires for which no X-ray structure is available. We have also performed a steered molecular dynamics study of the unbinding of the TCR-pMHC complex to get a better understanding of how TCRs interact with pMHCs. This entire rational TCR design pipeline is now being used to produce rationally optimized TCRs for adoptive cell therapies of

Rationalization of design and construction of buildings for nuclear power plants

Energy Technology Data Exchange (ETDEWEB)

Satoh, Shunsaku; Mitsumatsu, Kazuo

1987-02-01

This article presents various rationalization methods introduced in the past few years for design and construction of BWR nuclear power plant buildings. When the site for a nuclear power plant has been decided, investigation is made on various aspects of possible earthquakes, based on which anti-earthquake design for the plant site is established. The next step is to examine the displacements and stresses that may occur to various parts of the bulding from a postulated earthquake. This is normally called the earthquake response analysis and consists of calculating the behaviors of the buildings using large computers. A seismic controlled structure system has recently proposed, aiming to reduce the displacements and stresses of the building itself by controlling the flexibility of the installed seismic apparatus against the input of external loads. Lately, high strength concrete and high strength reinforcing steel bars (rebars) are being considered for practical application. If advanced computers and related accessories are utilized to the maximum, it will lead not only to efficiency in the design work but to the possibility of optimized design. For rational construction, a combined scaffolding and temporary support has been devised to reduce the time and volume of required temporary work. What have been developed for rationalization of construction work also include robots for heavy weight rebar fabrication, horizontal reed blind type rebars, portable concrete distributor, all weather environment facilities, and construction materials conveyance system. (Nogami, K.).

Rationalization of design and construction of buildings for nuclear power plants

International Nuclear Information System (INIS)

Satoh, Shunsaku; Mitsumatsu, Kazuo

1987-01-01

This article presents various rationalization methods introduced in the past few years for design and construction of BWR nuclear power plant buildings. When the site for a nuclear power plant has been decided, investigation is made on various aspects of possible earthquakes, based on which anti-earthquake design for the plant site is established. The next step is to examine the displacements and stresses that may occur to various parts of the bulding from a postulated earthquake. This is normally called the earthquake response analysis and consists of calculating the behaviors of the buildings using large computers. A seismic controlled structure system has recently proposed, aiming to reduce the displacements and stresses of the building itself by controlling the flexibility of the installed seismic apparatus against the input of external loads. Lately, high strength concrete and high strength reinforcing steel bars (rebars) are being considered for practical application. If advanced computers and related accessories are utilized to the maximum, it will lead not only to efficiency in the design work but to the possibility of optimized design. For rational construction, a combined scaffolding and temporary support has been devised to reduce the time and volume of required temporary work. What have been developed for rationalization of construction work also include robots for heavy weight rebar fabrication, horizontal reed blind type rebars, portable concrete distributor, all weather environment facilities, and construction materials conveyance system. (Nogami, K.)

Viral vaccines and their manufacturing cell substrates: New trends and designs in modern vaccinology.

Science.gov (United States)

Rodrigues, Ana F; Soares, Hugo R; Guerreiro, Miguel R; Alves, Paula M; Coroadinha, Ana S

2015-09-01

Vaccination is one of the most effective interventions in global health. The worldwide vaccination programs significantly reduced the number of deaths caused by infectious agents. A successful example was the eradication of smallpox in 1979 after two centuries of vaccination campaigns. Since the first variolation administrations until today, the knowledge on immunology has increased substantially. This knowledge combined with the introduction of cell culture and DNA recombinant technologies revolutionized vaccine design. This review will focus on vaccines against human viral pathogens, recent developments on vaccine design and cell substrates used for their manufacture. While the production of attenuated and inactivated vaccines requires the use of the respective permissible cell substrates, the production of recombinant antigens, virus-like particles, vectored vaccines and chimeric vaccines requires the use - and often the development - of specific cell lines. Indeed, the development of novel modern viral vaccine designs combined with, the stringent safety requirements for manufacture, and the better understanding on animal cell metabolism and physiology are increasing the awareness on the importance of cell line development and engineering areas. A new era of modern vaccinology is arriving, offering an extensive toolbox to materialize novel and creative ideas in vaccine design and its manufacture. Copyright © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

On rationally supported surfaces

DEFF Research Database (Denmark)

Gravesen, Jens; Juttler, B.; Sir, Z.

2008-01-01

We analyze the class of surfaces which are equipped with rational support functions. Any rational support function can be decomposed into a symmetric (even) and an antisymmetric (odd) part. We analyze certain geometric properties of surfaces with odd and even rational support functions....... In particular it is shown that odd rational support functions correspond to those rational surfaces which can be equipped with a linear field of normal vectors, which were discussed by Sampoli et al. (Sampoli, M.L., Peternell, M., Juttler, B., 2006. Rational surfaces with linear normals and their convolutions...... with rational surfaces. Comput. Aided Geom. Design 23, 179-192). As shown recently, this class of surfaces includes non-developable quadratic triangular Bezier surface patches (Lavicka, M., Bastl, B., 2007. Rational hypersurfaces with rational convolutions. Comput. Aided Geom. Design 24, 410426; Peternell, M...

Evaluating the value proposition for improving vaccine thermostability to increase vaccine impact in low and middle-income countries.

Science.gov (United States)

Karp, Christopher L; Lans, Deborah; Esparza, José; Edson, Eleanore B; Owen, Katey E; Wilson, Christopher B; Heaton, Penny M; Levine, Orin S; Rao, Raja

2015-07-09

The need to keep vaccines cold in the face of high ambient temperatures and unreliable access to electricity is a challenge that limits vaccine coverage in low and middle-income countries (LMICs). Greater vaccine thermostability is generally touted as the obvious solution. Despite conventional wisdom, comprehensive analysis of the value proposition for increasing vaccine thermostability has been lacking. Further, while significant investments have been made in increasing vaccine thermostability in recent years, no vaccine products have been commercialized as a result. We analyzed the value proposition for increasing vaccine thermostability, grounding the analysis in specific vaccine use cases (e.g., use in routine immunization [RI] programs, or in campaigns) and in the broader context of cold chain technology and country level supply chain system design. The results were often surprising. For example, cold chain costs actually represent a relatively small fraction of total vaccine delivery system costs. Further, there are critical, vaccine use case-specific temporal thresholds that need to be overcome for significant benefits to be reaped from increasing vaccine thermostability. We present a number of recommendations deriving from this analysis that suggest a rational path toward unlocking the value (maximizing coverage, minimizing total system costs) of increased vaccine thermostability, including: (1) the full range of thermostability of existing vaccines should be defined and included in their labels; (2) for new vaccines, thermostability goals should be addressed up-front at the level of the target product profile; (3) improving cold chain infrastructure and supply chain system design is likely to have the largest impact on total system costs and coverage in the short term-and will influence the degree of thermostability required in the future; (4) in the long term, there remains value in monitoring the emergence of disruptive technologies that could remove the

Rational assembly of nanoparticle superlattices with designed lattice symmetries

Science.gov (United States)

Gang, Oleg; Lu, Fang; Tagawa, Miho

2017-09-05

A method for lattice design via multivalent linkers (LDML) is disclosed that introduces a rationally designed symmetry of connections between particles in order to achieve control over the morphology of their assembly. The method affords the inclusion of different programmable interactions within one linker that allow an assembly of different types of particles. The designed symmetry of connections is preferably provided utilizing DNA encoding. The linkers may include fabricated "patchy" particles, DNA scaffold constructs and Y-shaped DNA linkers, anisotropic particles, which are preferably functionalized with DNA, multimeric protein-DNA complexes, and particles with finite numbers of DNA linkers.

Rational design of soft mechanical metamaterials : Independent tailoring of elastic properties with randomness

NARCIS (Netherlands)

Mirzaali Mazandarani, M.J.; Hedayati, R.; Vena, P; Vergani, L.; Strano, M.; Zadpoor, A.A.

2017-01-01

The elastic properties of mechanical metamaterials are direct functions of their topological designs. Rational design approaches based on computational models could, therefore, be used to devise topological designs that result in the desired properties. It is of particular importance to

A Large Size Chimeric Highly Immunogenic Peptide Presents Multistage Plasmodium Antigens as a Vaccine Candidate System against Malaria.

Science.gov (United States)

Lozano, José Manuel; Varela, Yahson; Silva, Yolanda; Ardila, Karen; Forero, Martha; Guasca, Laura; Guerrero, Yuly; Bermudez, Adriana; Alba, Patricia; Vanegas, Magnolia; Patarroyo, Manuel Elkin

2017-11-01

Rational strategies for obtaining malaria vaccine candidates should include not only a proper selection of target antigens for antibody stimulation, but also a versatile molecular design based on ordering the right pieces from the complex pathogen molecular puzzle towards more active and functional immunogens. Classical Plasmodium falciparum antigens regarded as vaccine candidates have been selected as model targets in this study. Among all possibilities we have chosen epitopes of Pf CSP, STARP; MSA1 and Pf 155/RESA from pre- and erythrocyte stages respectively for designing a large 82-residue chimeric immunogen. A number of options aimed at diminishing steric hindrance for synthetic procedures were assessed based on standard Fmoc chemistry such as building block orthogonal ligation; pseudo-proline and microwave-assisted procedures, therefore the large-chimeric target was produced, characterized and immunologically tested. Antigenicity and functional in vivo efficacy tests of the large-chimera formulations administered alone or as antigen mixtures have proven the stimulation of high antibody titers, showing strong correlation with protection and parasite clearance of vaccinated BALB/c mice after being lethally challenged with both P. berghei -ANKA and P. yoelii 17XL malaria strains. Besides, 3D structure features shown by the large-chimera encouraged as to propose using these rational designed large synthetic molecules as reliable vaccine candidate-presenting systems.

A Large Size Chimeric Highly Immunogenic Peptide Presents Multistage Plasmodium Antigens as a Vaccine Candidate System against Malaria

Directory of Open Access Journals (Sweden)

José Manuel Lozano

2017-11-01

Full Text Available Rational strategies for obtaining malaria vaccine candidates should include not only a proper selection of target antigens for antibody stimulation, but also a versatile molecular design based on ordering the right pieces from the complex pathogen molecular puzzle towards more active and functional immunogens. Classical Plasmodium falciparum antigens regarded as vaccine candidates have been selected as model targets in this study. Among all possibilities we have chosen epitopes of PfCSP, STARP; MSA1 and Pf155/RESA from pre- and erythrocyte stages respectively for designing a large 82-residue chimeric immunogen. A number of options aimed at diminishing steric hindrance for synthetic procedures were assessed based on standard Fmoc chemistry such as building block orthogonal ligation; pseudo-proline and microwave-assisted procedures, therefore the large-chimeric target was produced, characterized and immunologically tested. Antigenicity and functional in vivo efficacy tests of the large-chimera formulations administered alone or as antigen mixtures have proven the stimulation of high antibody titers, showing strong correlation with protection and parasite clearance of vaccinated BALB/c mice after being lethally challenged with both P. berghei-ANKA and P. yoelii 17XL malaria strains. Besides, 3D structure features shown by the large-chimera encouraged as to propose using these rational designed large synthetic molecules as reliable vaccine candidate-presenting systems.

Decision support in vaccination policies.

Science.gov (United States)

Piso, B; Wild, C

2009-10-09

Looking across boarders reveals that the national immunization programs of various countries differ in their vaccination schedules and decisions regarding the implementation and funding of new vaccines. The aim of this review is to identify decision aids and crucial criteria for a rational decision-making process on vaccine introduction and to develop a theoretical framework for decision-making based on available literature. Systematic literature search supplemented by hand-search. We identified five published decision aids for vaccine introduction and program planning in industrialized countries. Their comparison revealed an overall similarity with some differences in the approach as well as criteria. Burden of disease and vaccine characteristics play a key role in all decision aids, but authors vary in their views on the significance of cost-effectiveness analyses. Other relevant factors that should be considered before vaccine introduction are discussed to highly differing extents. These factors include the immunization program itself as well as its conformity with other programs, its feasibility, acceptability, and equity, as well as ethical, legal and political considerations. Assuming that the most comprehensive framework possible will not provide a feasible tool for decision-makers, we suggest a stepwise procedure. Though even the best rational approach and most comprehensive evaluation is limited by remaining uncertainties, frameworks provide at least a structured approach to evaluate the various aspects of vaccine implementation decision-making. This process is essential in making consistently sound decisions and will facilitate the public's confidence in the decision and its realization.

Metabolic immune restraints: implications for anticancer vaccines.

Science.gov (United States)

Mocellin, Simone

2010-01-01

Metabolic immune restraints belong to a highly complex network of molecular mechanisms underlying the failure of naturally occurring and therapeutically induced immune responses against cancer. In the light of the disappointing results yielded so far with anticancer vaccines in the clinical setting, the dissection of the cascade of molecular events leading to tumor immune escape appears the most promising way to develop more effective immunotherapeutic strategies. Here we review the significant advances recently made in the understanding of the tumor-specific metabolic features that contribute to keep malignant cells from being recognized and destroyed by immune effectors. These mechanistic insights are fostering the development of rationally designed therapeutics aimed to revert the immunosuppressive circuits and thus to enhance the effectiveness of anticancer vaccines.

Rotavirus vaccine effectiveness in low-income settings: An evaluation of the test-negative design.

Science.gov (United States)

Schwartz, Lauren M; Halloran, M Elizabeth; Rowhani-Rahbar, Ali; Neuzil, Kathleen M; Victor, John C

2017-01-03

The test-negative design (TND), an epidemiologic method currently used to measure rotavirus vaccine (RV) effectiveness, compares the vaccination status of rotavirus-positive cases and rotavirus-negative controls meeting a pre-defined case definition for acute gastroenteritis. Despite the use of this study design in low-income settings, the TND has not been evaluated to measure rotavirus vaccine effectiveness. This study builds upon prior methods to evaluate the use of the TND for influenza vaccine using a randomized controlled clinical trial database. Test-negative vaccine effectiveness (VE-TND) estimates were derived from three large randomized placebo-controlled trials (RCTs) of monovalent (RV1) and pentavalent (RV5) rotavirus vaccines in sub-Saharan Africa and Asia. Derived VE-TND estimates were compared to the original RCT vaccine efficacy estimates (VE-RCTs). The core assumption of the TND (i.e., rotavirus vaccine has no effect on rotavirus-negative diarrhea) was also assessed. TND vaccine effectiveness estimates were nearly equivalent to original RCT vaccine efficacy estimates. Neither RV had a substantial effect on rotavirus-negative diarrhea. This study supports the TND as an appropriate epidemiologic study design to measure rotavirus vaccine effectiveness in low-income settings. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Meta-analysis of variables affecting mouse protection efficacy of whole organism Brucella vaccines and vaccine candidates

Science.gov (United States)

2013-01-01

challenge pathogen strain) change. It is suggestive that it is difficult to protect against aerosol challenge. Somewhat counter-intuitively, our results indicate that intraperitoneal and subcutaneous vaccinations are much more effective to protect against aerosol Brucella challenge than intranasal vaccination. Conclusions Literature meta-analysis identified variables that significantly contribute to Brucella vaccine protection efficacy. The results obtained provide critical information for rational vaccine study design. Literature meta-analysis is generic and can be applied to analyze variables critical for vaccine protection against other infectious diseases. PMID:23735014

Adjuvants are key factors for the development of future vaccines: Lessons from the Finlay Adjuvant platform

Directory of Open Access Journals (Sweden)

Oliver ePérez

2013-12-01

Full Text Available The development of effective vaccines against neglected diseases, especially those associated with poverty and social deprivation, is urgently needed. Modern vaccine technologies and a better understanding of the immune response have provided scientists with the tools for rational and safer design of subunit vaccines. Often, however, subunit vaccines do not elicit strong immune responses, highlighting the need to incorporate better adjuvants; this step therefore becomes a key factor for vaccine development. In this review we outline some key features of modern vaccinology that are linked with the development of better adjuvants. In line with the increased desire to obtain novel adjuvants for future vaccines, the Finlay Adjuvant Platform offers a novel approach for the development of new and effective adjuvants. The Finlay Adjuvants (AFs, AFPL (proteoliposome and AFCo (cochleate, were initially designed for parenteral and mucosal applications, and constitute potent adjuvants for the induction of Th1 responses against several antigens. This review summarizes the status of the Finlay technology in producing promising adjuvants for unsolved-vaccine diseases including mucosal approaches and therapeutic vaccines. Ideas related to adjuvant classification, adjuvant selection, and their possible influence on innate recognition via multiple toll-like receptors are also discussed.

Host-Derived Cytokines and Chemokines as Vaccine Adjuvants

NARCIS (Netherlands)

Degen, W.G.J.; Schijns, Virgil E.J.C.

2016-01-01

The increased knowledge about immunological concepts and systems nowadays helps to rationally enhance the performance of, and to overcome some of the problems, that are associated with inactivated vaccines. Because the antigenic component of an inactivated vaccine by itself only gives a limited or

Does decision documentation help junior designers rationalize their decisions? A comparative multiple-case study

NARCIS (Netherlands)

Heesch, U. van; Avgeriou, P.; Tang, A.

Software architecture design is challenging, especially for junior software designers. Lacking practice and experience, junior designers need process support in order to make rational architecture decisions. In this paper, we present the results of a comparative multiple-case study conducted to find

Vaccine development: From concept to early clinical testing.

Science.gov (United States)

Cunningham, Anthony L; Garçon, Nathalie; Leo, Oberdan; Friedland, Leonard R; Strugnell, Richard; Laupèze, Béatrice; Doherty, Mark; Stern, Peter

2016-12-20

In the 21st century, an array of microbiological and molecular allow antigens for new vaccines to be specifically identified, designed, produced and delivered with the aim of optimising the induction of a protective immune response against a well-defined immunogen. New knowledge about the functioning of the immune system and host pathogen interactions has stimulated the rational design of vaccines. The design toolbox includes vaccines made from whole pathogens, protein subunits, polysaccharides, pathogen-like particles, use of viral/bacterial vectors, plus adjuvants and conjugation technology to increase and broaden the immune response. Processes such as recombinant DNA technology can simplify the complexity of manufacturing and facilitate consistent production of large quantities of antigen. Any new vaccine development is greatly enhanced by, and requires integration of information concerning: 1. Pathogen life-cycle & epidemiology. Knowledge of pathogen structure, route of entry, interaction with cellular receptors, subsequent replication sites and disease-causing mechanisms are all important to identify antigens suitable for disease prevention. The demographics of infection, specific risk groups and age-specific infection rates determine which population to immunise, and at what age. 2. Immune control & escape. Interactions between the host and pathogen are explored, with determination of the relative importance of antibodies, T-cells of different types and innate immunity, immune escape strategies during infection, and possible immune correlates of protection. This information guides identification and selection of antigen and the specific immune response required for protection. 3. Antigen selection & vaccine formulation. The selected antigen is formulated to remain suitably immunogenic and stable over time, induce an immune response that is likely to be protective, plus be amenable to eventual scale-up to commercial production. 4. Vaccine preclinical

Fundamental understanding and rational design of high energy structural microbatteries

Energy Technology Data Exchange (ETDEWEB)

Wang, Yuxing; Li, Qiuyan; Cartmell, Samuel; Li, Huidong; Mendoza, Sarah; Zhang, Ji-Guang; Deng, Zhiqun Daniel; Xiao, Jie

2018-01-01

Microbatteries play a critical role in determining the lifetime of downsized sensors, wearable devices and medical applications, etc. More often, structural batteries are required from the perspective of aesthetics and space utilization, which is however rarely explored. Herein, we discuss the fundamental issues associated with the rational design of practically usable high energy microbatteries. The tubular shape of the cell further allows the flexible integration of microelectronics. A functioning acoustic micro-transmitter continuously powered by this tubular battery has been successfully demonstrated. Multiple design features adopted to accommodate large mechanical stress during the rolling process are discussed providing new insights in designing the structural microbatteries for emerging technologies.

A New Approach to a Lyme Disease Vaccine

Energy Technology Data Exchange (ETDEWEB)

Livey, I.; Dunn, J.; O' Rourke, M.; Traweger, A.; Savidis-Dacho, H.; Crowe, B. A.; Barrett, P. N.; Yang, X.; Luft, B. J.

2011-02-01

A single recombinant outer surface protein A (OspA) antigen designed to contain protective elements from 2 different OspA serotypes (1 and 2) is able to induce antibody responses that protect mice against infection with either Borrelia burgdorferi sensu stricto (OspA serotype-1) or Borrelia afzelii (OspA serotype-2). Protection against infection with B burgdorferi ss strain ZS7 was demonstrated in a needle-challenge model. Protection against B. afzelii species was shown in a tick-challenge model using feral ticks. In both models, as little as .03 {micro}g of antigen, when administered in a 2-dose immunization schedule with aluminum hydroxide as adjuvant, was sufficient to provide complete protection against the species targeted. This proof of principle study proves that knowledge of protective epitopes can be used for the rational design of effective, genetically modified vaccines requiring fewer OspA antigens and suggests that this approach may facilitate the development of an OspA vaccine for global use.

Design of clinical trials for therapeutic cancer vaccines development.

Science.gov (United States)

Mackiewicz, Jacek; Mackiewicz, Andrzej

2009-12-25

Advances in molecular and cellular biology as well as biotechnology led to definition of a group of drugs referred to as medicinal products of advanced technologies. It includes gene therapy products, somatic cell therapeutics and tissue engineering. Therapeutic cancer vaccines including whole cell tumor cells vaccines or gene modified whole cells belong to somatic therapeutics and/or gene therapy products category. The drug development is a multistep complex process. It comprises of two phases: preclinical and clinical. Guidelines on preclinical testing of cell based immunotherapy medicinal products have been defined by regulatory agencies and are available. However, clinical testing of therapeutic cancer vaccines is still under debate. It presents a serious problem since recently clinical efficacy of the number of cancer vaccines has been demonstrated that focused a lot of public attention. In general clinical testing in the current form is very expensive, time consuming and poorly designed what may lead to overlooking of products clinically beneficial for patients. Accordingly regulatory authorities and researches including Cancer Vaccine Clinical Trial Working Group proposed three regulatory solutions to facilitate clinical development of cancer vaccines: cost-recovery program, conditional marketing authorization, and a new development paradigm. Paradigm includes a model in which cancer vaccines are investigated in two types of clinical trials: proof-of-principle and efficacy. The proof-of-principle trial objectives are: safety; dose selection and schedule of vaccination; and demonstration of proof-of-principle. Efficacy trials are randomized clinical trials with objectives of demonstrating clinical benefit either directly or through a surrogate. The clinical end points are still under debate.

Case-control vaccine effectiveness studies: Preparation, design, and enrollment of cases and controls.

Science.gov (United States)

Verani, Jennifer R; Baqui, Abdullah H; Broome, Claire V; Cherian, Thomas; Cohen, Cheryl; Farrar, Jennifer L; Feikin, Daniel R; Groome, Michelle J; Hajjeh, Rana A; Johnson, Hope L; Madhi, Shabir A; Mulholland, Kim; O'Brien, Katherine L; Parashar, Umesh D; Patel, Manish M; Rodrigues, Laura C; Santosham, Mathuram; Scott, J Anthony; Smith, Peter G; Sommerfelt, Halvor; Tate, Jacqueline E; Victor, J Chris; Whitney, Cynthia G; Zaidi, Anita K; Zell, Elizabeth R

2017-06-05

Case-control studies are commonly used to evaluate effectiveness of licensed vaccines after deployment in public health programs. Such studies can provide policy-relevant data on vaccine performance under 'real world' conditions, contributing to the evidence base to support and sustain introduction of new vaccines. However, case-control studies do not measure the impact of vaccine introduction on disease at a population level, and are subject to bias and confounding, which may lead to inaccurate results that can misinform policy decisions. In 2012, a group of experts met to review recent experience with case-control studies evaluating the effectiveness of several vaccines; here we summarize the recommendations of that group regarding best practices for planning, design and enrollment of cases and controls. Rigorous planning and preparation should focus on understanding the study context including healthcare-seeking and vaccination practices. Case-control vaccine effectiveness studies are best carried out soon after vaccine introduction because high coverage creates strong potential for confounding. Endpoints specific to the vaccine target are preferable to non-specific clinical syndromes since the proportion of non-specific outcomes preventable through vaccination may vary over time and place, leading to potentially confusing results. Controls should be representative of the source population from which cases arise, and are generally recruited from the community or health facilities where cases are enrolled. Matching of controls to cases for potential confounding factors is commonly used, although should be reserved for a limited number of key variables believed to be linked to both vaccination and disease. Case-control vaccine effectiveness studies can provide information useful to guide policy decisions and vaccine development, however rigorous preparation and design is essential. Published by Elsevier Ltd.

Bioinformatics analysis of Brucella vaccines and vaccine targets using VIOLIN.

Science.gov (United States)

He, Yongqun; Xiang, Zuoshuang

2010-09-27

promotes classification and analysis of existing Brucella vaccines and vaccine candidates. Computational prediction of Brucella vaccine targets provides more candidates for rational vaccine development. The use of VIOLIN provides a general approach that can be applied for analyses of vaccines against other pathogens and infection diseases.

Rotavirus vaccine effectiveness in low-income settings: An evaluation of the test-negative design

OpenAIRE

Schwartz, Lauren M.; Halloran, M. Elizabeth; Rowhani-Rahbar, Ali; Neuzil, Kathleen M.; Victor, John C.

2017-01-01

Background The test-negative design (TND), an epidemiologic method currently used to measure rotavirus vaccine (RV) effectiveness, compares the vaccination status of rotavirus-positive cases and rotavirus-negative controls meeting a pre-defined case definition for acute gastroenteritis. Despite the use of this study design in low-income settings, the TND has not been evaluated to measure rotavirus vaccine effectiveness. Methods This study builds upon prior methods to evaluate the use of the T...

Potency assay design for adjuvanted recombinant proteins as malaria vaccines.

Science.gov (United States)

Giersing, Birgitte K; Dubovsky, Filip; Saul, Allan; Denamur, Francoise; Minor, Philip; Meade, Bruce

2006-05-15

Many licensed vaccines are composed of live, attenuated or inactivated whole-cell microorganisms, or they comprise purified components from whole-cell extracts or culture supernatants. For some diseases, pathology is fairly well understood, and there may be known correlates of protection that provide obvious parameters for assessment of vaccine potency. However, this is not always the case, and some effective vaccines are routinely used even though the mechanisms or correlates of protection are unknown. Some more modern vaccine approaches employ purified recombinant proteins, based on molecules that appear on the surface of the pathogen. This is one of the strategies that has been adopted in the quest to develop a malaria vaccine. Use of these parasite antigens as vaccine candidates is supported by substantial epidemiological data, and some have demonstrated the ability to elicit protective responses in animal models of malaria infection. However, there is as yet no immunological correlate of protection and no functional assays or animal models that have demonstrated the ability to predict efficacy in humans. There is little precedence for the most appropriate and practical method for assessing potency of vaccines based on these recombinant molecules for malaria vaccines. This is likely because the majority of malaria vaccine candidates have only recently entered clinical evaluation. The PATH Malaria Vaccine Initiative (MVI) convened a panel with expertise in potency assay design from industry, governmental institutions, and regulatory bodies to discuss and review the rationale, available methods, and best approaches for assessing the potency of recombinant proteins, specifically for their use as malarial vaccines. The aim of this meeting was to produce a discussion document on the practical potency assessment of recombinant protein malaria vaccines, focusing on early phase potency assay development.

The Cost of Cost-Sharing: The Impact of Medicaid Benefit Design on Influenza Vaccination Uptake

Directory of Open Access Journals (Sweden)

Charles Stoecker

2017-03-01

Full Text Available Prior research indicates that cost-sharing and lack of insurance coverage reduce preventive services use among low-income persons. State Medicaid policy may affect the uptake of recommended adult vaccinations. We examined the impact of three aspects of Medicaid benefit design (coverage for vaccines, prohibiting cost-sharing, and copayment amounts on vaccine uptake in the fee-for-service Medicaid population 19–64 years old. We combined previously published reports to obtain state Medicaid policy information from 2003 and 2012. Data on influenza vaccination uptake were taken from the Behavioral Risk Factor Surveillance System. We used a differences-in-differences framework, controlling for national trends and state differences, to estimate the effect of each benefit design factor on vaccination uptake in different Medicaid-eligible populations. Each additional dollar of copayment for vaccination decreased influenza vaccination coverage 1–6 percentage points. The effects of covering vaccines or prohibiting cost-sharing were mixed. Imposing copayments for vaccination is associated with lower vaccination coverage. These findings have implications for the implementation of Medicaid expansion in states that currently impose copayments.

Frequency of Adverse Events after Vaccination with Different Vaccinia Strains.

NARCIS (Netherlands)

Kretzschmar, Mirjam; Wallinga, Jacco; Teunis, Peter F M; Xing, Shuqin; Mikolajczyk, Rafael

2006-01-01

BACKGROUND: Large quantities of smallpox vaccine have been stockpiled to protect entire nations against a possible reintroduction of smallpox. Planning for an appropriate use of these stockpiled vaccines in response to a smallpox outbreak requires a rational assessment of the risks of

Rational Multiparty Computation

OpenAIRE

Wallrabenstein, John Ross

2014-01-01

The field of rational cryptography considers the design of cryptographic protocols in the presence of rational agents seeking to maximize local utility functions. This departs from the standard secure multiparty computation setting, where players are assumed to be either honest or malicious. ^ We detail the construction of both a two-party and a multiparty game theoretic framework for constructing rational cryptographic protocols. Our framework specifies the utility function assumptions neces...

Designing institutions for climate change: Why rational design involves technology

Energy Technology Data Exchange (ETDEWEB)

Coninck, H. de [Energy Research Centre of the Netherlands, Petten (Netherlands)

2008-09-30

This paper aims to explore how to augment the institutional solutions offered by current political theory for addressing the unprecedented problem of climate change. Although steering directly at emission reductions in an international treaty has benefits in terms of cost-effectiveness, the paper arrives at the conclusion that considerations around technological development should be drawn into the treaty equation in order to generate sufficient reciprocity to have a politically feasible international regime. It then argues that the benefits of technology agreements for climate change mitigation may be larger than commonly assumed, as they - if properly designed - could lead to real emission reductions and provide more flexibility to reach agreement in post-2012 negotiations than proposals modelled exclusively on the Kyoto Protocol or other types of absolute emission targets. Based on rational design of international institutions for environmental governance, and attempting to take into account considerations of technological dynamics and the 'sociotechnical system', contours of a possible environmentally effective and politically feasible international climate change agreements are sketched.

Fundamental understanding and rational design of high energy structural microbatteries

International Nuclear Information System (INIS)

Wang, Yuxing; Li, Qiuyan; Cartmell, Samuel; Li, Huidong; Mendoza, Sarah

2017-01-01

We present that microbatteries play a critical role in determining the lifetime of downsized sensors, wearable devices, medical applications, and animal acoustic telemetry transmitters among others. More often, structural batteries are required from the perspective of aesthetics and space utilization, which is however rarely explored. Herein, we discuss the fundamental issues associated with the rational design of practically usable high energy microbatteries. The tubular shape of the cell further allows the flexible integration of microelectronics. A functioning acoustic micro-transmitter continuously powered by this tubular battery has been successfully demonstrated. Finally, multiple design features adopted to accommodate large mechanical stress during the rolling process are discussed providing new insights in designing the structural microbatteries for emerging technologies.

Multi-Step Usage of in Vivo Models During Rational Drug Design and Discovery

Directory of Open Access Journals (Sweden)

Charles H. Williams

2011-04-01

Full Text Available In this article we propose a systematic development method for rational drug design while reviewing paradigms in industry, emerging techniques and technologies in the field. Although the process of drug development today has been accelerated by emergence of computational methodologies, it is a herculean challenge requiring exorbitant resources; and often fails to yield clinically viable results. The current paradigm of target based drug design is often misguided and tends to yield compounds that have poor absorption, distribution, metabolism, and excretion, toxicology (ADMET properties. Therefore, an in vivo organism based approach allowing for a multidisciplinary inquiry into potent and selective molecules is an excellent place to begin rational drug design. We will review how organisms like the zebrafish and Caenorhabditis elegans can not only be starting points, but can be used at various steps of the drug development process from target identification to pre-clinical trial models. This systems biology based approach paired with the power of computational biology; genetics and developmental biology provide a methodological framework to avoid the pitfalls of traditional target based drug design.

Rational Design of Semiconductor Nanostructures for Functional Subcellular Interfaces.

Science.gov (United States)

Parameswaran, Ramya; Tian, Bozhi

2018-05-15

One of the fundamental questions guiding research in the biological sciences is how cellular systems process complex physical and environmental cues and communicate with each other across multiple length scales. Importantly, aberrant signal processing in these systems can lead to diseases that can have devastating impacts on human lives. Biophysical studies in the past several decades have demonstrated that cells can respond to not only biochemical cues but also mechanical and electrical ones. Thus, the development of new materials that can both sense and modulate all of these pathways is necessary. Semiconducting nanostructures are an emerging class of discovery platforms and tools that can push the limits of our ability to modulate and sense biological behaviors for both fundamental research and clinical applications. These materials are of particular interest for interfacing with cellular systems due to their matched dimension with subcellular components (e.g., cytoskeletal filaments), and easily tunable properties in the electrical, optical and mechanical regimes. Rational design via traditional or new approaches, such as nanocasting and mesoscale chemical lithography, can allow us to control micro- and nanoscale features in nanowires to achieve new biointerfaces. Both processes endogenous to the target cell and properties of the material surface dictate the character of these interfaces. In this Account, we focus on (1) approaches for the rational design of semiconducting nanowires that exhibit unique structures for biointerfaces, (2) recent fundamental discoveries that yield robust biointerfaces at the subcellular level, (3) intracellular electrical and mechanical sensing, and (4) modulation of cellular behaviors through material topography and remote physical stimuli. In the first section, we discuss new approaches for the synthetic control of micro- and nanoscale features of these materials. In the second section, we focus on achieving biointerfaces with

Vaccine development against Leishmania donovani

Directory of Open Access Journals (Sweden)

Amrita eDas

2012-05-01

Full Text Available Visceral leishmaniasis (VL caused by Leishmania donovani and Leishmania infantum/ chagasi represents the second most challenging infectious disease worldwide, affecting nearly 500,000 people and 60,000 deaths annually. Zoonotic VL (ZVL caused by L. infantum is re-emergent canid zoonoses which represents a complex epidemiological cycle in New world where domestic dogs serve as reservoir host responsible for potentially fatal human infection where dog culling is the only control measure for eliminating reservoir host. Lifelong immunity in human against reinfection has motivated several attempts in developing prophylactic vaccines against the disease but very few have progressed beyond experimental stage. Absence of any licensed vaccine along with high toxicity and increasing resistance to the current chemotherapeutic drugs has further complicated the situation in endemic regions of the world. Advances in vaccinology, including recombinant proteins, novel antigen-delivery systems/adjuvants, heterologous prime-boost regimens and strategies for intracellular antigen presentation, have contributed to recent advances in vaccine development against VL. Attempts to develop an effective vaccine for use in domestic dogs in areas of canine VL should be pursued for preventing human infection. Studies in animal models and human patients have revealed the pathogenic mechanisms of disease progression and features of protective immunity. This review will summarize the accumulated knowledge about pathogenesis, immune response and prerequisites for protective immunity against human VL. Authors will discuss promising vaccine targets, their developmental status and future prospects in a quest for rational vaccine development against VL. In addition, several challenges such as safety issues, a renewed and coordinated commitment to basic research, preclinical studies and trial design will be addressed to overcome the problems faced in developing effective vaccines

Essays on the collective action dilemma of vaccination

OpenAIRE

Ahlskog, Rafael

2017-01-01

Vaccines famously possess positive externalities that make them susceptible to the collective action dilemma: when I get vaccinated, I protect not only myself, but also those who I might otherwise have infected. Thus, some people will have an incentive to free ride on the immunity of others. In a population of rational agents, the critical level of vaccination uptake required for herd immunity will therefore be difficult to attain in the long run, which poses difficulties for disease eradicat...

Genetic Diversity Underlying the Envelope Glycoproteins of Hepatitis C Virus: Structural and Functional Consequences and the Implications for Vaccine Design

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Alexander W. Tarr

2015-07-01

Full Text Available In the 26 years since the discovery of Hepatitis C virus (HCV a major global research effort has illuminated many aspects of the viral life cycle, facilitating the development of targeted antivirals. Recently, effective direct-acting antiviral (DAA regimens with >90% cure rates have become available for treatment of chronic HCV infection in developed nations, representing a significant advance towards global eradication. However, the high cost of these treatments results in highly restricted access in developing nations, where the disease burden is greatest. Additionally, the largely asymptomatic nature of infection facilitates continued transmission in at risk groups and resource constrained settings due to limited surveillance. Consequently a prophylactic vaccine is much needed. The HCV envelope glycoproteins E1 and E2 are located on the surface of viral lipid envelope, facilitate viral entry and are the targets for host immunity, in addition to other functions. Unfortunately, the extreme global genetic and antigenic diversity exhibited by the HCV glycoproteins represents a significant obstacle to vaccine development. Here we review current knowledge of HCV envelope protein structure, integrating knowledge of genetic, antigenic and functional diversity to inform rational immunogen design.

Rational design and application of responsive α-helical peptide hydrogels

Science.gov (United States)

Banwell, Eleanor F.; Abelardo, Edgardo S.; Adams, Dave J.; Birchall, Martin A.; Corrigan, Adam; Donald, Athene M.; Kirkland, Mark; Serpell, Louise C.; Butler, Michael F.; Woolfson, Derek N.

2009-01-01

Biocompatible hydrogels have a wide variety of potential applications in biotechnology and medicine, such as the controlled delivery and release of cells, cosmetics and drugs; and as supports for cell growth and tissue engineering1. Rational peptide design and engineering are emerging as promising new routes to such functional biomaterials2-4. Here we present the first examples of rationally designed and fully characterized self-assembling hydrogels based on standard linear peptides with purely α-helical structures, which we call hydrogelating self-assembling fibres (hSAFs). These form spanning networks of α-helical fibrils that interact to give self-supporting physical hydrogels of >99% water content. The peptide sequences can be engineered to alter the underlying mechanism of gelation and, consequently, the hydrogel properties. Interestingly, for example, those with hydrogen-bonded networks melt upon heating, whereas those formed via hydrophobic interactions strengthen when warmed. The hSAFs are dual-peptide systems that only gel on mixing, which gives tight control over assembly5. These properties raise possibilities for using the hSAFs as substrates in cell culture. We have tested this in comparison with the widely used Matrigel substrate, and demonstrate that, like Matrigel, hSAFs support both growth and differentiation of rat adrenal pheochromocytoma cells for sustained periods in culture. PMID:19543314

Geology and Design: Formal and Rational Connections

Science.gov (United States)

Eriksson, S. C.; Brewer, J.

2016-12-01

Geological forms and the manmade environment have always been inextricably linked. From the time that Upper Paleolithic man created drawings in the Lascaux Caves in the southwest of France, geology has provided a critical and dramatic spoil for human creativity. This inspiration has manifested itself in many different ways, and the history of architecture is rife with examples of geologically derived buildings. During the early 20th Century, German Expressionist art and architecture was heavily influenced by the natural and often translucent quality of minerals. Architects like Bruno Taut drew and built crystalline forms that would go on to inspire the more restrained Bauhaus movement. Even within the context of Contemporary architecture, geology has been a fertile source for inspiration. Architectural practices across the globe leverage the rationality and grounding found in geology to inform a process that is otherwise dominated by computer-driven parametric design. The connection between advanced design technology and the beautifully realized geo natural forms insures that geology will be a relevant source of architectural inspiration well into the 21st century. The sometimes hidden relationship of geology to the various sub-disciplines of Design such as Architecture, Interiors, Landscape Architecture, and Historic Preservation is explored in relation to curriculum and the practice of design. Topics such as materials, form, history, the cultural and physical landscape, natural hazards, and global design enrich and inform curriculum across the college. Commonly, these help define place-based education.

Structured morphological modeling as a framework for rational strain design of Streptomyces species

NARCIS (Netherlands)

Celler, K.; Picioreanu, C.; Van Loosdrecht, M.C.M.; Van Wezel, G.P.

2012-01-01

Successful application of a computational model for rational design of industrial Streptomyces exploitation requires a better understanding of the relationship between morphology—dictated by microbial growth, branching, fragmentation and adhesion—and product formation. Here we review the

Nucleic acids for the rational design of reaction circuits.

Science.gov (United States)

Padirac, Adrien; Fujii, Teruo; Rondelez, Yannick

2013-08-01

Nucleic acid-based circuits are rationally designed in vitro assemblies that can perform complex preencoded programs. They can be used to mimic in silico computations. Recent works emphasized the modularity and robustness of these circuits, which allow their scaling-up. Another new development has led to dynamic, time-responsive systems that can display emergent behaviors like oscillations. These are closely related to biological architectures and provide an in vitro model of in vivo information processing. Nucleic acid circuits have already been used to handle various processes for technological or biotechnological purposes. Future applications of these chemical smart systems will benefit from the rapidly growing ability to design, construct, and model nucleic acid circuits of increasing size. Copyright © 2012 Elsevier Ltd. All rights reserved.

Tapping the world wide web for designing vaccines for livestock diseases

International Nuclear Information System (INIS)

Deocaris, C.C.

2005-01-01

Post-genomic approaches in the development of new vaccines will fundamentally change how veterinarians prevent and treat diseases. One type of vaccine that has generated renewed interest is the subunit or synthetic vaccine, which has the advantage of rapid, safe and high-throughput production via chemical (as synthetic peptides) or recombinant approaches (as DNA, purified subunit or multigene vaccines). At the heart of such a vaccine are few but powerful epitopes that confer both the humoral and cell-mediated immune responses. Traditional biochemical assays have been used to map these epitopes; however, they are prohibitively labour and capital intensive. In contrast, in silico development of multivalent subunit vaccines is now possible through the availability of genomic information and the nascence of molecular immunoinformatics as a discipline. Algorithms are described in this paper to aid in identifying B and T cell epitopes for design of vaccines based on published available protein databases. From the mapped epitopes, synthetic mimotopes (or epitope-mimicking sequences) are concatenated using glycine bridges aimed at maintaining at least 90% of the secondary structures while minimizing steric hindrances between adjacent epitopes. (author)

Rational use of water in trickle irrigation design.

Science.gov (United States)

Saad, J. C. C.; da Silva Junior, H. M.

2012-04-01

In trickle irrigation systems, the design is based on the pre-established emission uniformity (EU) which is the combined result of the equipment characteristics and its hydraulic configuration. However, this desired value of the EU may not be confirmed by the final project (in field conditions) and neither by the yield uniformity. However, the most important is to assure yield uniformity with rational use of water. The hypotheses of this research were: a) the EU of a trickle irrigation system at field conditions is equal to the emission uniformity pre-established in the design; b) EU has always the lowest value when compared with other indicators of uniformity; c) the discharge variation coefficient is not equal to production variation coefficient in the operational unit; d) the productivity variation coefficient is more dependent on water depth applied than the EU. This study aimed to evaluate the relationships among EU used in the irrigation system design, water depth applied and the final yield uniformity. The uniformity indicators evaluated were: EU, distribution uniformity (UD) and the index proposed by Barragan & Wu (2005). They were compared estimating the performance of a trickle irrigation system applied in a citrus orchard with dimensions of 400m x 600m. The design of the irrigation system was optimized by a Linear Programming model. The tree rows were leveled in the larger direction and the spacing adopted in the orchard was 7m x 4m. The manifold line was always operating on a slope condition. The sensitivity analysis involved different slopes, 0, 3, 6, 9 and 12%, and different values of emission uniformity, 60, 70, 75, 80, 85, 90 and 94%. The citrus yield uniformity was evaluated by the variation coefficient. The emission uniformity (EU) after design differed from the EU pre-established, more sharply in the initial values lower than 90%. Comparing the uniformity indexes, the EU always generated lower values when compared with the UD and with the index

Envelope exchange for the generation of live-attenuated arenavirus vaccines.

Directory of Open Access Journals (Sweden)

Andreas Bergthaler

2006-06-01

Full Text Available Arenaviruses such as Lassa fever virus cause significant mortality in endemic areas and represent potential bioterrorist weapons. The occurrence of arenaviral hemorrhagic fevers is largely confined to Third World countries with a limited medical infrastructure, and therefore live-attenuated vaccines have long been sought as a method of choice for prevention. Yet their rational design and engineering have been thwarted by technical limitations. In addition, viral genes had not been identified that are needed to cause disease but can be deleted or substituted to generate live-attenuated vaccine strains. Lymphocytic choriomeningitis virus, the prototype arenavirus, induces cell-mediated immunity against Lassa fever virus, but its safety for humans is unclear and untested. Using this virus model, we have developed the necessary methodology to efficiently modify arenavirus genomes and have exploited these techniques to identify an arenaviral Achilles' heel suitable for targeting in vaccine design. Reverse genetic exchange of the viral glycoprotein for foreign glycoproteins created attenuated vaccine strains that remained viable although unable to cause disease in infected mice. This phenotype remained stable even after extensive propagation in immunodeficient hosts. Nevertheless, the engineered viruses induced T cell-mediated immunity protecting against overwhelming systemic infection and severe liver disease upon wild-type virus challenge. Protection was established within 3 to 7 d after immunization and lasted for approximately 300 d. The identification of an arenaviral Achilles' heel demonstrates that the reverse genetic engineering of live-attenuated arenavirus vaccines is feasible. Moreover, our findings offer lymphocytic choriomeningitis virus or other arenaviruses expressing foreign glycoproteins as promising live-attenuated arenavirus vaccine candidates.

Envelope Exchange for the Generation of Live-Attenuated Arenavirus Vaccines.

Directory of Open Access Journals (Sweden)

2006-06-01

Full Text Available Arenaviruses such as Lassa fever virus cause significant mortality in endemic areas and represent potential bioterrorist weapons. The occurrence of arenaviral hemorrhagic fevers is largely confined to Third World countries with a limited medical infrastructure, and therefore live-attenuated vaccines have long been sought as a method of choice for prevention. Yet their rational design and engineering have been thwarted by technical limitations. In addition, viral genes had not been identified that are needed to cause disease but can be deleted or substituted to generate live-attenuated vaccine strains. Lymphocytic choriomeningitis virus, the prototype arenavirus, induces cell-mediated immunity against Lassa fever virus, but its safety for humans is unclear and untested. Using this virus model, we have developed the necessary methodology to efficiently modify arenavirus genomes and have exploited these techniques to identify an arenaviral Achilles' heel suitable for targeting in vaccine design. Reverse genetic exchange of the viral glycoprotein for foreign glycoproteins created attenuated vaccine strains that remained viable although unable to cause disease in infected mice. This phenotype remained stable even after extensive propagation in immunodeficient hosts. Nevertheless, the engineered viruses induced T cell-mediated immunity protecting against overwhelming systemic infection and severe liver disease upon wild-type virus challenge. Protection was established within 3 to 7 d after immunization and lasted for approximately 300 d. The identification of an arenaviral Achilles' heel demonstrates that the reverse genetic engineering of live-attenuated arenavirus vaccines is feasible. Moreover, our findings offer lymphocytic choriomeningitis virus or other arenaviruses expressing foreign glycoproteins as promising live-attenuated arenavirus vaccine candidates.

A Francisella tularensis live vaccine strain that improves stimulation of antigen-presenting cells does not enhance vaccine efficacy.

Directory of Open Access Journals (Sweden)

Deanna M Schmitt

Full Text Available Vaccination is a proven strategy to mitigate morbidity and mortality of infectious diseases. The methodology of identifying and testing new vaccine candidates could be improved with rational design and in vitro testing prior to animal experimentation. The tularemia vaccine, Francisella tularensis live vaccine strain (LVS, does not elicit complete protection against lethal challenge with a virulent type A Francisella strain. One factor that may contribute to this poor performance is limited stimulation of antigen-presenting cells. In this study, we examined whether the interaction of genetically modified LVS strains with human antigen-presenting cells correlated with effectiveness as tularemia vaccine candidates. Human dendritic cells infected with wild-type LVS secrete low levels of proinflammatory cytokines, fail to upregulate costimulatory molecules, and activate human T cells poorly in vitro. One LVS mutant, strain 13B47, stimulated higher levels of proinflammatory cytokines from dendritic cells and macrophages and increased costimulatory molecule expression on dendritic cells compared to wild type. Additionally, 13B47-infected dendritic cells activated T cells more efficiently than LVS-infected cells. A deletion allele of the same gene in LVS displayed similar in vitro characteristics, but vaccination with this strain did not improve survival after challenge with a virulent Francisella strain. In vivo, this mutant was attenuated for growth and did not stimulate T cell responses in the lung comparable to wild type. Therefore, stimulation of antigen-presenting cells in vitro was improved by genetic modification of LVS, but did not correlate with efficacy against challenge in vivo within this model system.

Rational drug design paradigms: the odyssey for designing better drugs.

Science.gov (United States)

Kellici, Tahsin; Ntountaniotis, Dimitrios; Vrontaki, Eleni; Liapakis, George; Moutevelis-Minakakis, Panagiota; Kokotos, George; Hadjikakou, Sotiris; Tzakos, Andreas G; Afantitis, Antreas; Melagraki, Georgia; Bryant, Sharon; Langer, Thierry; Di Marzo, Vincenzo; Mavromoustakos, Thomas

2015-01-01

Due to the time and effort requirements for the development of a new drug, and the high attrition rates associated with this developmental process, there is an intense effort by academic and industrial researchers to find novel ways for more effective drug development schemes. The first step in the discovery process of a new drug is the identification of the lead compound. The modern research tendency is to avoid the synthesis of new molecules based on chemical intuition, which is time and cost consuming, and instead to apply in silico rational drug design. This approach reduces the consumables and human personnel involved in the initial steps of the drug design. In this review real examples from our research activity aiming to discover new leads will be given for various dire warnings diseases. There is no recipe to follow for discovering new leads. The strategy to be followed depends on the knowledge of the studied system and the experience of the researchers. The described examples constitute successful and unsuccessful efforts and reflect the reality which medicinal chemists have to face in drug design and development. The drug stability is also discussed in both organic molecules and metallotherapeutics. This is an important issue in drug discovery as drug metabolism in the body can lead to various toxic and undesired molecules.

Technique on rationalization of using electricity and cases

International Nuclear Information System (INIS)

1988-04-01

This book deals with rationalization of using electric and cases. It is divided into four parts. The first part introduces necessity and of progression rationalization of using electric. The second part describes the technique on rationalization of using electric with management of electric energy. The third part depicts domestic cases of rationalization on using of electric such as substation and motor. The last part also introduces foreign cases of rationalization on using of electric with measure of generator circuit, design of motor, design of lighting and design of other equipment.

Immunology, epidemiology and mathematical modelling towards a better understanding of invasive non-typhoidal Salmonella disease and rational vaccination approaches.

Science.gov (United States)

Mastroeni, Pietro; Rossi, Omar

2016-12-01

Invasive non-typhoidal Salmonella (iNTS) infections cause a high burden of lethal sepsis in young children and HIV patients, often associated with malaria, anaemia, malnutrition and sickle-cell disease. Vaccines against iNTS are urgently needed but none are licensed yet. Areas covered: This review illustrates how immunology, epidemiology and within-host pathogen behaviour affect invasive Salmonella infections and highlights how this knowledge can assist the improvement and choice of vaccines. Expert Commentary: Control of iNTS disease requires approaches that reduce transmission and improve diagnosis and treatment. These are often difficult to implement due to the fragile ecology and economies in endemic countries. Vaccines will be key tools in the fight against iNTS disease. To optimise vaccine design, we need to better define protective antigens and mechanisms of resistance to disease in susceptible populations even in those individuals where innate immunity may be impaired by widespread comorbidities.

Epitope mapping: the first step in developing epitope-based vaccines.

Science.gov (United States)

Gershoni, Jonathan M; Roitburd-Berman, Anna; Siman-Tov, Dror D; Tarnovitski Freund, Natalia; Weiss, Yael

2007-01-01

Antibodies are an effective line of defense in preventing infectious diseases. Highly potent neutralizing antibodies can intercept a virus before it attaches to its target cell and, thus, inactivate it. This ability is based on the antibodies' specific recognition of epitopes, the sites of the antigen to which antibodies bind. Thus, understanding the antibody/epitope interaction provides a basis for the rational design of preventive vaccines. It is assumed that immunization with the precise epitope, corresponding to an effective neutralizing antibody, would elicit the generation of similarly potent antibodies in the vaccinee. Such a vaccine would be a 'B-cell epitope-based vaccine', the implementation of which requires the ability to backtrack from a desired antibody to its corresponding epitope. In this article we discuss a range of methods that enable epitope discovery based on a specific antibody. Such a reversed immunological approach is the first step in the rational design of an epitope-based vaccine. Undoubtedly, the gold standard for epitope definition is x-ray analyses of crystals of antigen:antibody complexes. This method provides atomic resolution of the epitope; however, it is not readily applicable to many antigens and antibodies, and requires a very high degree of sophistication and expertise. Most other methods rely on the ability to monitor the binding of the antibody to antigen fragments or mutated variations. In mutagenesis of the antigen, loss of binding due to point modification of an amino acid residue is often considered an indication of an epitope component. In addition, computational combinatorial methods for epitope mapping are also useful. These methods rely on the ability of the antibody of interest to affinity isolate specific short peptides from combinatorial phage display peptide libraries. The peptides are then regarded as leads for the definition of the epitope corresponding to the antibody used to screen the peptide library. For

Design of therapeutic vaccines as a novel antibody therapy for cardiovascular diseases.

Science.gov (United States)

Nakagami, Hironori

2017-09-01

Vaccines are primarily used worldwide as a preventive medicine for infectious diseases and have recently been applied to cancer. We and others have developed therapeutic vaccines designed for cardiovascular diseases that are notably different from previous vaccines. In the case of cancer vaccines, a specific protein in cancer cells is a target antigen, and the activation of cytotoxic T cells (CTL) is required to kill and remove the antigen-presenting cancer cells. Our therapeutic vaccines work against hypertension by targeting angiotensin II (Ang II) as the antigen, which is an endogenous hormone. Therapeutic vaccines must avoid CTL activation and induce the blocking antibodies for Ang II. The goal of our therapeutic vaccine for cardiovascular diseases is to induce the specific antibody response toward the target protein without inducing T-cell or antibody-mediated inflammation through the careful selection of the target antigen, carrier protein and adjuvants. The goal of our therapeutic vaccine is similar to that of antibody therapy. Recently, multiple antibody-based drugs have been developed for cancer, immune-related diseases, and dyslipidemia, which are efficient but expensive. If the effect of a therapeutic vaccine is nearly equivalent to antibody therapy as an alternative approach, the lower medical cost and improvement in drug adherence can be advantages of therapeutic vaccines. In this review, we will describe our concept of therapeutic vaccines for cardiovascular diseases and the future directions of therapeutic vaccines as novel antibody therapies. Copyright © 2017. Published by Elsevier Ltd.

Structurally designed attenuated subunit vaccines for S. aureus LukS-PV and LukF-PV confer protection in a mouse bacteremia model.

Directory of Open Access Journals (Sweden)

Hatice Karauzum

Full Text Available Previous efforts towards S. aureus vaccine development have largely focused on cell surface antigens to induce opsonophagocytic killing aimed at providing sterile immunity, a concept successfully applied to other Gram-positive pathogens such as Streptococcus pneumoniae. However, these approaches have largely failed, possibly in part due to the remarkable diversity of the staphylococcal virulence factors such as secreted immunosuppressive and tissue destructive toxins. S. aureus produces several pore-forming toxins including the single subunit alpha hemolysin as well as bicomponent leukotoxins such as Panton-Valentine leukocidin (PVL, gamma hemolysins (Hlg, and LukED. Here we report the generation of highly attenuated mutants of PVL subunits LukS-PV and LukF-PV that were rationally designed, based on an octameric structural model of the toxin, to be deficient in oligomerization. The attenuated subunit vaccines were highly immunogenic and showed significant protection in a mouse model of S. aureus USA300 sepsis. Protection against sepsis was also demonstrated by passive transfer of rabbit immunoglobulin raised against LukS-PV. Antibodies to LukS-PV inhibited the homologous oligomerization of LukS-PV with LukF-PV as well heterologous oligomerization with HlgB. Importantly, immune sera from mice vaccinated with the LukS mutant not only inhibited the PMN lytic activity produced by the PVL-positive USA300 but also blocked PMN lysis induced by supernatants of PVL-negative strains suggesting a broad protective activity towards other bicomponent toxins. These findings strongly support the novel concept of an anti-virulence, toxin-based vaccine intended for prevention of clinical S. aureus invasive disease, rather than achieving sterile immunity. Such a multivalent vaccine may include attenuated leukotoxins, alpha hemolysin, and superantigens.

Rational design of the exchange-spring permanent magnet.

Science.gov (United States)

Jiang, J S; Bader, S D

2014-02-12

The development of the optimal exchange-spring permanent magnet balances exchange hardening, magnetization enhancement, and the feasibility of scalable fabrication. These requirements can be met with a rational design of the microstructural characteristics. The magnetization processes in several model exchange-spring structures with different geometries have been analyzed with both micromagnetic simulations and nucleation theory. The multilayer geometry and the soft-cylinders-in-hard-matrix geometry have the highest achievable figure of merit (BH)max, while the soft-spheres-in-hard-matrix geometry has the lowest upper limit for (BH)max. The cylindrical geometry permits the soft phase to be larger and does not require strict size control. Exchange-spring permanent magnets based on the cylindrical geometry may be amenable to scaled-up fabrication.

Rational design of the exchange-spring permanent magnet

International Nuclear Information System (INIS)

Jiang, J S; Bader, S D

2014-01-01

The development of the optimal exchange-spring permanent magnet balances exchange hardening, magnetization enhancement, and the feasibility of scalable fabrication. These requirements can be met with a rational design of the microstructural characteristics. The magnetization processes in several model exchange-spring structures with different geometries have been analyzed with both micromagnetic simulations and nucleation theory. The multilayer geometry and the soft-cylinders-in-hard-matrix geometry have the highest achievable figure of merit (BH) max , while the soft-spheres-in-hard-matrix geometry has the lowest upper limit for (BH) max . The cylindrical geometry permits the soft phase to be larger and does not require strict size control. Exchange-spring permanent magnets based on the cylindrical geometry may be amenable to scaled-up fabrication. (paper)

Does decision documentation help junior designers rationalize their decisions? A comparative multiple-case study

OpenAIRE

Heesch, U. van; Avgeriou, P.; Tang, A.

2013-01-01

Software architecture design is challenging, especially for junior software designers. Lacking practice and experience, junior designers need process support in order to make rational architecture decisions. In this paper, we present the results of a comparative multiple-case study conducted to find out if decision viewpoints from van Heesch et al. (2012, in press) can provide such a support. The case study was conducted with four teams of software engineering students working in industrial s...

Design and rationale for the Influenza vaccination After Myocardial Infarction (IAMI) trial

DEFF Research Database (Denmark)

Fröbert, Ole; Götberg, Matthias; Angerås, Oskar

2017-01-01

BACKGROUND: Registry studies and case-control studies have demonstrated that the risk of acute myocardial infarction (AMI) is increased following influenza infection. Small randomized trials, underpowered for clinical end points, indicate that future cardiovascular events can be reduced following...... influenza vaccination in patients with established cardiovascular disease. Influenza vaccination is recommended by international guidelines for patients with cardiovascular disease, but uptake is varying and vaccination is rarely prioritized during hospitalization for AMI. METHODS/DESIGN: The Influenza...... be assigned either to in-hospital influenza vaccination or to placebo. Baseline information is collected from national heart disease registries, and follow-up will be performed using both registries and a structured telephone interview. The primary end point is a composite of time to all-cause death, a new...

Standby Gasoline Rationing Plan

Energy Technology Data Exchange (ETDEWEB)

None

1980-06-01

The final rules adopted by the President for a Standby Gasoline Rationing Plan are presented. The plan provides that eligibility for ration allotments will be determined primarily on the basis of motor vehicle registrations, taking into account historical differences in the use of gasoline among states. The regulations also provide authority for supplemental allotments to firms so that their allotment will equal a specified percentage of gasoline use during a base period. Priority classifications, i.e., agriculture, defense, etc., are established to assure adequate gasoline supplies for designated essential services. Ration rights must be provided by end-users to their suppliers for each gallon sold. DOE will regulate the distribution of gasoline at the wholesale level according to the transfer by suppliers of redeemed ration rights and the gasoline allocation regulations. Ration rights are transferable. A ration banking system is created to facilitate transfers of ration rights. Each state will be provided with a reserve of ration rights to provide for hardship needs and to alleviate inequities. (DC)

Development of a multicomponent Staphylococcus aureus vaccine designed to counter multiple bacterial virulence factors

Science.gov (United States)

Anderson, Annaliesa S.; Miller, Alita A.; Donald, Robert G.K.; Scully, Ingrid L.; Nanra, Jasdeep S.; Cooper, David; Jansen, Kathrin U.

2012-01-01

Staphylococcus aureus is a major cause of healthcare-associated infections and is responsible for a substantial burden of disease in hospitalized patients. Despite increasingly rigorous infection control guidelines, the prevalence and corresponding negative impact of S. aureus infections remain considerable. Difficulties in controlling S. aureus infections as well as the associated treatment costs are exacerbated by increasing rates of resistance to available antibiotics. Despite ongoing efforts over the past 20 years, no licensed S. aureus vaccine is currently available. However, learnings from past clinical failures of vaccine candidates and a better understanding of the immunopathology of S. aureus colonization and infection have aided in the design of new vaccine candidates based on multiple important bacterial pathogenesis mechanisms. This review outlines important considerations in designing a vaccine for the prevention of S. aureus disease in healthcare settings. PMID:22922765

Advanced manufacturing of microdisk vaccines for uniform control of material properties and immune cell function.

Science.gov (United States)

Zeng, Qin; Zhang, Peipei; Zeng, Xiangbin; Tostanoski, Lisa H; Jewell, Christopher M

2017-12-19

The continued challenges facing vaccines in infectious disease and cancer highlight a need for better control over the features of vaccines and the responses they generate. Biomaterials offer unique advantages to achieve this goal through features such as controlled release and co-delivery of antigens and adjuvants. However, many synthesis strategies lead to particles with heterogeneity in diameter, shape, loading level, or other properties. In contrast, advanced manufacturing techniques allow precision control of material properties at the micro- and nano-scale. These capabilities in vaccines and immunotherapies could allow more rational design to speed efficient design and clinical translation. Here we employed soft lithography to generate polymer microdisk vaccines with uniform structures and tunable compositions of vaccine antigens and toll like receptor agonists (TLRas) that serve as molecular adjuvants. Compared to conventional PLGA particles formed by emulsion, microdisks provided a dramatic improvement in the consistency of properties such as diameter. During culture with primary dendritic cells (DCs) from mice, microdisks were internalized by the cells without toxicity, while promoting co-delivery of antigen and TLRa to the same cell. Analysis of DC surface activation markers by flow cytometry revealed microdisk vaccines activated dendritic cells in a manner that depended on the level of TLRa, while antigen processing and presentation depended on the amount of antigen in the microdisks. Together, this work demonstrates the use of advanced manufacturing techniques to produce uniform vaccines that direct DC function depending on the composition in the disks.

Optimal vaccine stockpile design for an eradicated disease: application to polio.

Science.gov (United States)

Tebbens, Radboud J Duintjer; Pallansch, Mark A; Alexander, James P; Thompson, Kimberly M

2010-06-11

Eradication of a disease promises significant health and financial benefits. Preserving those benefits, hopefully in perpetuity, requires preparing for the possibility that the causal agent could re-emerge (unintentionally or intentionally). In the case of a vaccine-preventable disease, creation and planning for the use of a vaccine stockpile becomes a primary concern. Doing so requires consideration of the dynamics at different levels, including the stockpile supply chain and transmission of the causal agent. This paper develops a mathematical framework for determining the optimal management of a vaccine stockpile over time. We apply the framework to the polio vaccine stockpile for the post-eradication era and present examples of solutions to one possible framing of the optimization problem. We use the framework to discuss issues relevant to the development and use of the polio vaccine stockpile, including capacity constraints, production and filling delays, risks associated with the stockpile, dynamics and uncertainty of vaccine needs, issues of funding, location, and serotype dependent behavior, and the implications of likely changes over time that might occur. This framework serves as a helpful context for discussions and analyses related to the process of designing and maintaining a stockpile for an eradicated disease. (c) 2010 Elsevier Ltd. All rights reserved.

The Ontology of Vaccine Adverse Events (OVAE) and its usage in representing and analyzing adverse events associated with US-licensed human vaccines.

Science.gov (United States)

Marcos, Erica; Zhao, Bin; He, Yongqun

2013-11-26

Licensed human vaccines can induce various adverse events (AE) in vaccinated patients. Due to the involvement of the whole immune system and complex immunological reactions after vaccination, it is difficult to identify the relations among vaccines, adverse events, and human populations in different age groups. Many known vaccine adverse events (VAEs) have been recorded in the package inserts of US-licensed commercial vaccine products. To better represent and analyze VAEs, we developed the Ontology of Vaccine Adverse Events (OVAE) as an extension of the Ontology of Adverse Events (OAE) and the Vaccine Ontology (VO). Like OAE and VO, OVAE is aligned with the Basic Formal Ontology (BFO). The commercial vaccines and adverse events in OVAE are imported from VO and OAE, respectively. A new population term 'human vaccinee population' is generated and used to define VAE occurrence. An OVAE design pattern is developed to link vaccine, adverse event, vaccinee population, age range, and VAE occurrence. OVAE has been used to represent and classify the adverse events recorded in package insert documents of commercial vaccines licensed by the USA Food and Drug Administration (FDA). OVAE currently includes over 1,300 terms, including 87 distinct types of VAEs associated with 63 human vaccines licensed in the USA. For each vaccine, occurrence rates for every VAE in different age groups have been logically represented in OVAE. SPARQL scripts were developed to query and analyze the OVAE knowledge base data. To demonstrate the usage of OVAE, the top 10 vaccines accompanying with the highest numbers of VAEs and the top 10 VAEs most frequently observed among vaccines were identified and analyzed. Asserted and inferred ontology hierarchies classify VAEs in different levels of AE groups. Different VAE occurrences in different age groups were also analyzed. The ontology-based data representation and integration using the FDA-approved information from the vaccine package insert documents

Rationally designed synthetic protein hydrogels with predictable mechanical properties.

Science.gov (United States)

Wu, Junhua; Li, Pengfei; Dong, Chenling; Jiang, Heting; Bin Xue; Gao, Xiang; Qin, Meng; Wang, Wei; Bin Chen; Cao, Yi

2018-02-12

Designing synthetic protein hydrogels with tailored mechanical properties similar to naturally occurring tissues is an eternal pursuit in tissue engineering and stem cell and cancer research. However, it remains challenging to correlate the mechanical properties of protein hydrogels with the nanomechanics of individual building blocks. Here we use single-molecule force spectroscopy, protein engineering and theoretical modeling to prove that the mechanical properties of protein hydrogels are predictable based on the mechanical hierarchy of the cross-linkers and the load-bearing modules at the molecular level. These findings provide a framework for rationally designing protein hydrogels with independently tunable elasticity, extensibility, toughness and self-healing. Using this principle, we demonstrate the engineering of self-healable muscle-mimicking hydrogels that can significantly dissipate energy through protein unfolding. We expect that this principle can be generalized for the construction of protein hydrogels with customized mechanical properties for biomedical applications.

The Capricious Nature of Bacterial Pathogens: Phasevarions and Vaccine Development

Directory of Open Access Journals (Sweden)

Aimee Tan

2016-12-01

Full Text Available Infectious diseases are a leading cause of morbidity and mortality worldwide, and vaccines are one of the most successful and cost-effective tools for disease prevention. One of the key considerations for rational vaccine development is the selection of appropriate antigens. Antigens must induce a protective immune response, and this response should be directed to stably expressed antigens so the target microbe can always be recognized by the immune system. Antigens with variable expression, due to environmental signals or phase variation (i.e., high frequency, random switching of expression, are not ideal vaccine candidates because variable expression could lead to immune evasion. Phase variation is often mediated by the presence of highly mutagenic simple tandem DNA repeats, and genes containing such sequences can be easily identified, and their use discounted as vaccine antigens reconsidered. Recent research has identified phase variably expressed DNA methyltransferases that act as global epigenetic regulators. These phase variable regulons, known as phasevarions, are associated with altered virulence phenotypes and/or expression of vaccine candidates. As such, genes encoding candidate vaccine antigens that have no obvious mechanism of phase variation may be subject to indirect, epigenetic control as part of a phasevarion. Bioinformatic and experimental studies are required to elucidate the distribution and mechanism of action of these DNA methyltransferases, and most importantly, whether they mediate epigenetic regulation of potential and current vaccine candidates. This process is essential to define the stably expressed antigen target profile of bacterial pathogens and thereby facilitate efficient, rational selection of vaccine antigens.

In silico-based vaccine design against Ebola virus glycoprotein

Directory of Open Access Journals (Sweden)

Dash R

2017-03-01

Full Text Available Raju Dash,1 Rasel Das,2 Md Junaid,3 Md Forhad Chowdhury Akash,4 Ashekul Islam,5 SM Zahid Hosen1 1Molecular Modeling and Drug Design Laboratory (MMDDL, Pharmacology Research Division, Bangladesh Council of Scientific and Industrial Research (BCSIR, Chittagong, Bangladesh; 2Nanotechnology and Catalysis Research Center, University of Malaya, Kuala Lumpur, Malaysia; 3Department of Pharmaceutical Sciences, North South University, Dhaka, Bangladesh; 4Department of Pharmacy, BGC Trust University Bangladesh, Chittagong, Bangladesh; 5Department of Biochemistry and Molecular Biology, University of Chittagong, Chittagong, Bangladesh Abstract: Ebola virus (EBOV is one of the lethal viruses, causing more than 24 epidemic outbreaks to date. Despite having available molecular knowledge of this virus, no definite vaccine or other remedial agents have been developed yet for the management and avoidance of EBOV infections in humans. Disclosing this, the present study described an epitope-based peptide vaccine against EBOV, using a combination of B-cell and T-cell epitope predictions, followed by molecular docking and molecular dynamics simulation approach. Here, protein sequences of all glycoproteins of EBOV were collected and examined via in silico methods to determine the most immunogenic protein. From the identified antigenic protein, the peptide region ranging from 186 to 220 and the sequence HKEGAFFLY from the positions of 154–162 were considered the most potential B-cell and T-cell epitopes, correspondingly. Moreover, this peptide (HKEGAFFLY interacted with HLA-A*32:15 with the highest binding energy and stability, and also a good conservancy of 83.85% with maximum population coverage. The results imply that the designed epitopes could manifest vigorous enduring defensive immunity against EBOV. Keywords: Ebola virus, epitope, glycoprotein, vaccine design

User-Centered Design for Developing Interventions to Improve Clinician Recommendation of Human Papillomavirus Vaccination.

Science.gov (United States)

Henninger, Michelle L; Mcmullen, Carmit K; Firemark, Alison J; Naleway, Allison L; Henrikson, Nora B; Turcotte, Joseph A

2017-01-01

Human papillomavirus (HPV) is the most common sexually transmitted infection in the US and is associated with multiple types of cancer. Although effective HPV vaccines have been available since 2006, coverage rates in the US remain much lower than with other adolescent vaccinations. Prior research has shown that a strong recommendation from a clinician is a critical determinant in HPV vaccine uptake and coverage. However, few published studies to date have specifically addressed the issue of helping clinicians communicate more effectively with their patients about the HPV vaccine. To develop one or more novel interventions for helping clinicians make strong and effective recommendations for HPV vaccination. Using principles of user-centered design, we conducted qualitative interviews, interviews with persons from analogous industries, and a data synthesis workshop with multiple stakeholders. Five potential intervention strategies targeted at health care clinicians, youth, and their parents were developed. The two most popular choices to pursue were a values-based communication strategy and a puberty education workbook. User-centered design is a useful strategy for developing potential interventions to improve the rate and success of clinicians recommending the HPV vaccine. Further research is needed to test the effectiveness and acceptability of these interventions in clinical settings.

Rational Design of Adjuvant for Skin Delivery: Conjugation of Synthetic β-Glucan Dectin-1 Agonist to Protein Antigen.

Science.gov (United States)

Donadei, Agnese; Gallorini, Simona; Berti, Francesco; O'Hagan, Derek T; Adamo, Roberto; Baudner, Barbara C

2015-05-04

The potential benefits of skin delivery of vaccines derive from the presence of a densely connected network of antigen presenting cells in the skin layer, most significantly represented by Langerhans cells and dermal dendritic cells. Targeting these cells by adjuvant conjugated to an antigen should result in enhanced immunogenicity of a vaccine. Since one of the most widely used adjuvants is an insoluble salt of aluminum (aluminum hydroxide) that cannot be used for skin delivery due to reactogenicity, we focused our attention on agonists of receptors present on skin dendritic cells, including the Dectin-1 receptor. β-(1-3)-glucans, which are the most abundant components of the fungal surface, are known to activate the innate immune response by interaction with the C-type lectin-like Dectin-1 receptor. In this work we identified by rational design a well-defined synthetic β-(1-3)-glucan hexasaccharide as a Dectin-1 agonist and chemically conjugated it to the genetically detoxified diphtheria toxin (CRM197) protein antigen, as a means to increase the binding to Dectin-1 receptor and to target to skin dendritic cells. We demonstrated that the in vitro activation of the receptor was significantly impacted by the presentation of the glucan on the protein carrier. In vivo results in mice showed that the conjugation of the synthetic β-(1-3)-glucan when delivered intradermally resulted in higher antibody titers in comparison to intramuscular (i.m.) immunization and was not different from subcutaneous (s.c.) delivery. These findings suggest that weak receptor binders can be turned into more potent agonists by the multivalent presentation of many ligands covalently conjugated to the protein core. Moreover, this approach is particularly valuable to increase the immunogenicity of antigens administered via skin delivery.

The Evolution of Poxvirus Vaccines

Science.gov (United States)

Sánchez-Sampedro, Lucas; Perdiguero, Beatriz; Mejías-Pérez, Ernesto; García-Arriaza, Juan; Di Pilato, Mauro; Esteban, Mariano

2015-01-01

After Edward Jenner established human vaccination over 200 years ago, attenuated poxviruses became key players to contain the deadliest virus of its own family: Variola virus (VARV), the causative agent of smallpox. Cowpox virus (CPXV) and horsepox virus (HSPV) were extensively used to this end, passaged in cattle and humans until the appearance of vaccinia virus (VACV), which was used in the final campaigns aimed to eradicate the disease, an endeavor that was accomplished by the World Health Organization (WHO) in 1980. Ever since, naturally evolved strains used for vaccination were introduced into research laboratories where VACV and other poxviruses with improved safety profiles were generated. Recombinant DNA technology along with the DNA genome features of this virus family allowed the generation of vaccines against heterologous diseases, and the specific insertion and deletion of poxvirus genes generated an even broader spectrum of modified viruses with new properties that increase their immunogenicity and safety profile as vaccine vectors. In this review, we highlight the evolution of poxvirus vaccines, from first generation to the current status, pointing out how different vaccines have emerged and approaches that are being followed up in the development of more rational vaccines against a wide range of diseases. PMID:25853483

The Evolution of Poxvirus Vaccines

Directory of Open Access Journals (Sweden)

Lucas Sánchez-Sampedro

2015-04-01

Full Text Available After Edward Jenner established human vaccination over 200 years ago, attenuated poxviruses became key players to contain the deadliest virus of its own family: Variola virus (VARV, the causative agent of smallpox. Cowpox virus (CPXV and horsepox virus (HSPV were extensively used to this end, passaged in cattle and humans until the appearance of vaccinia virus (VACV, which was used in the final campaigns aimed to eradicate the disease, an endeavor that was accomplished by the World Health Organization (WHO in 1980. Ever since, naturally evolved strains used for vaccination were introduced into research laboratories where VACV and other poxviruses with improved safety profiles were generated. Recombinant DNA technology along with the DNA genome features of this virus family allowed the generation of vaccines against heterologous diseases, and the specific insertion and deletion of poxvirus genes generated an even broader spectrum of modified viruses with new properties that increase their immunogenicity and safety profile as vaccine vectors. In this review, we highlight the evolution of poxvirus vaccines, from first generation to the current status, pointing out how different vaccines have emerged and approaches that are being followed up in the development of more rational vaccines against a wide range of diseases.

Residualization Rates of Near Infrared Dyes for the Rational Design of Molecular Imaging Agents

Science.gov (United States)

Cilliers, Cornelius; Liao, Jianshan; Atangcho, Lydia; Thurber, Greg M.

2016-01-01

Purpose Near infrared (NIR) fluorescence imaging is widely used for tracking antibodies and biomolecules in vivo. Clinical and preclinical applications include intraoperative imaging, tracking therapeutics, and fluorescent labeling as a surrogate for subsequent radiolabeling. Despite their extensive use, one of the fundamental properties of NIR dyes, the residualization rate within cells following internalization, has not been systematically studied. This rate is required for the rational design of probes and proper interpretation of in vivo results. Procedures In this brief report, we measure the cellular residualization rate of eight commonly used dyes encompassing three core structures (cyanine, BODIPY, and oxazine/thiazine/carbopyronin). Results We identify residualizing (half-life > 24 hrs) and non-residualizing dyes (half-life < 24 hrs) in both the far red (~650-680 nm) and near infrared (~740-800 nm) regions. Conclusions This data will allow researchers to independently and rationally select the wavelength and residualizing nature of dyes for molecular imaging agent design. PMID:25869081

Residualization Rates of Near-Infrared Dyes for the Rational Design of Molecular Imaging Agents.

Science.gov (United States)

Cilliers, Cornelius; Liao, Jianshan; Atangcho, Lydia; Thurber, Greg M

2015-12-01

Near-infrared (NIR) fluorescence imaging is widely used for tracking antibodies and biomolecules in vivo. Clinical and preclinical applications include intraoperative imaging, tracking therapeutics, and fluorescent labeling as a surrogate for subsequent radiolabeling. Despite their extensive use, one of the fundamental properties of NIR dyes, the residualization rate within cells following internalization, has not been systematically studied. This rate is required for the rational design of probes and proper interpretation of in vivo results. In this brief report, we measure the cellular residualization rate of eight commonly used dyes encompassing three core structures (cyanine, boron-dipyrromethene (BODIPY), and oxazine/thiazine/carbopyronin). We identify residualizing (half-life >24 h) and non-residualizing (half-life <24 h) dyes in both the far-red (~650-680 nm) and near-infrared (~740-800 nm) regions. This data will allow researchers to independently and rationally select the wavelength and residualizing nature of dyes for molecular imaging agent design.

Design for Additive Bio-Manufacturing: From Patient-Specific Medical Devices to Rationally Designed Meta-Biomaterials.

Science.gov (United States)

Zadpoor, Amir A

2017-07-25

Recent advances in additive manufacturing (AM) techniques in terms of accuracy, reliability, the range of processable materials, and commercial availability have made them promising candidates for production of functional parts including those used in the biomedical industry. The complexity-for-free feature offered by AM means that very complex designs become feasible to manufacture, while batch-size-indifference enables fabrication of fully patient-specific medical devices. Design for AM (DfAM) approaches aim to fully utilize those features for development of medical devices with substantially enhanced performance and biomaterials with unprecedented combinations of favorable properties that originate from complex geometrical designs at the micro-scale. This paper reviews the most important approaches in DfAM particularly those applicable to additive bio-manufacturing including image-based design pipelines, parametric and non-parametric designs, metamaterials, rational and computationally enabled design, topology optimization, and bio-inspired design. Areas with limited research have been identified and suggestions have been made for future research. The paper concludes with a brief discussion on the practical aspects of DfAM and the potential of combining AM with subtractive and formative manufacturing processes in so-called hybrid manufacturing processes.

Design for Additive Bio-Manufacturing: From Patient-Specific Medical Devices to Rationally Designed Meta-Biomaterials

Directory of Open Access Journals (Sweden)

Amir A. Zadpoor

2017-07-01

Full Text Available Recent advances in additive manufacturing (AM techniques in terms of accuracy, reliability, the range of processable materials, and commercial availability have made them promising candidates for production of functional parts including those used in the biomedical industry. The complexity-for-free feature offered by AM means that very complex designs become feasible to manufacture, while batch-size-indifference enables fabrication of fully patient-specific medical devices. Design for AM (DfAM approaches aim to fully utilize those features for development of medical devices with substantially enhanced performance and biomaterials with unprecedented combinations of favorable properties that originate from complex geometrical designs at the micro-scale. This paper reviews the most important approaches in DfAM particularly those applicable to additive bio-manufacturing including image-based design pipelines, parametric and non-parametric designs, metamaterials, rational and computationally enabled design, topology optimization, and bio-inspired design. Areas with limited research have been identified and suggestions have been made for future research. The paper concludes with a brief discussion on the practical aspects of DfAM and the potential of combining AM with subtractive and formative manufacturing processes in so-called hybrid manufacturing processes.

One-pot synthesis of water soluble iron nanoparticles using rationally-designed peptides and ligand release.

Science.gov (United States)

Papst, Stefanie; Cheong, Soshan; Banholzer, Moritz J; Brimble, Margaret A; Williams, David E; Tilley, Richard D

2013-05-18

Herein we report the rational design of new phosphopeptides for control of nucleation, growth and aggregation of water-soluble, superparamagnetic iron-iron oxide core-shell nanoparticles. The use of the designed peptides enables a one-pot synthesis that avoids utilizing unstable or toxic iron precursors, organic solvents, and the need for exchange of capping agent after synthesis of the NPs.

Design of different strategies of multivalent DNA-based vaccination against rabies and canine distemper in mice and dogs

Directory of Open Access Journals (Sweden)

Touihri Leila

2012-12-01

Full Text Available Abstract Background During the vaccination campaigns, puppies younger than 3 months old are not targeted and remain unvaccinated for at least the first year of their lives. Almost half of the reported rabid dogs are 6 months or younger. Hence, we should recommend the vaccination against rabies of young puppies. Unfortunately, owing to the exposure of puppies to infections with either canine parvovirus (CPV or distemper virus (CDV after the intervention of the vaccinators, owners are reluctant to vaccinate puppies against rabies. Therefore, it is necessary to include the CPV and CDV valences in the vaccine against rabies. Multivalent DNA-based vaccination in dogs, including rabies and distemper valences, could help in raising vaccine coverage. Methods We have designed monovalent and multivalent DNA-based vaccine candidates for in vitro and in vivo assays. These plasmids encode to the rabies virus glycoprotein and/or the canine distemper virus hemagglutinin. The first strategy of multivalent DNA-based vaccination is by mixing plasmids encoding to a single antigen each. The second is by simply fusing the genes of the antigens together. The third is by adding the foot and mouth disease virus (FMDV 2A oligopeptide gene into the antigen genes. The last strategy is by the design and use of a bicistronic plasmid with an “Internal Ribosome Entry Site” (IRES domain. Results The monovalent construct against canine distemper was efficiently validated by inducing higher humoral immune responses compared to cell-culture-derived vaccine both in mice and dogs. All multivalent plasmids efficiently expressed both valences after in vitro transfection of BHK-21 cells. In BALB/c mice, the bicistronic IRES-dependant construct was the most efficient inducer of virus-neutralizing antibodies against both valences. It was able to induce better humoral immune responses compared to the administration of either cell-culture-derived vaccines or monovalent plasmids. The

Design of different strategies of multivalent DNA-based vaccination against rabies and canine distemper in mice and dogs.

Science.gov (United States)

Touihri, Leila; Ahmed, Sami Belhaj; Chtourou, Yacine; Daoud, Rahma; Bahloul, Chokri

2012-12-27

During the vaccination campaigns, puppies younger than 3 months old are not targeted and remain unvaccinated for at least the first year of their lives. Almost half of the reported rabid dogs are 6 months or younger. Hence, we should recommend the vaccination against rabies of young puppies. Unfortunately, owing to the exposure of puppies to infections with either canine parvovirus (CPV) or distemper virus (CDV) after the intervention of the vaccinators, owners are reluctant to vaccinate puppies against rabies. Therefore, it is necessary to include the CPV and CDV valences in the vaccine against rabies. Multivalent DNA-based vaccination in dogs, including rabies and distemper valences, could help in raising vaccine coverage. We have designed monovalent and multivalent DNA-based vaccine candidates for in vitro and in vivo assays. These plasmids encode to the rabies virus glycoprotein and/or the canine distemper virus hemagglutinin. The first strategy of multivalent DNA-based vaccination is by mixing plasmids encoding to a single antigen each. The second is by simply fusing the genes of the antigens together. The third is by adding the foot and mouth disease virus (FMDV) 2A oligopeptide gene into the antigen genes. The last strategy is by the design and use of a bicistronic plasmid with an "Internal Ribosome Entry Site" (IRES) domain. The monovalent construct against canine distemper was efficiently validated by inducing higher humoral immune responses compared to cell-culture-derived vaccine both in mice and dogs. All multivalent plasmids efficiently expressed both valences after in vitro transfection of BHK-21 cells. In BALB/c mice, the bicistronic IRES-dependant construct was the most efficient inducer of virus-neutralizing antibodies against both valences. It was able to induce better humoral immune responses compared to the administration of either cell-culture-derived vaccines or monovalent plasmids. The FMDV 2A was also efficient in the design of multivalent

Sustainable vaccine development: a vaccine manufacturer's perspective.

Science.gov (United States)

Rappuoli, Rino; Hanon, Emmanuel

2018-05-08

Vaccination remains the most cost-effective public health intervention after clean water, and the benefits impressively outweigh the costs. The efforts needed to fulfill the steadily growing demands for next-generation and novel vaccines designed for emerging pathogens and new indications are only realizable in a sustainable business model. Vaccine development can be fast-tracked through strengthening international collaborations, and the continuous innovation of technologies to accelerate their design, development, and manufacturing. However, these processes should be supported by a balanced project portfolio, and by managing sustainable vaccine procurement strategies for different types of markets. Collectively this will allow a gradual shift to a more streamlined and profitable vaccine production, which can significantly contribute to the worldwide effort to shape global health. Copyright © 2018 GlaxoSmithKine Biologicals SA. Published by Elsevier Ltd.. All rights reserved.

Rational modular design of metabolic network for efficient production of plant polyphenol pinosylvin.

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Wu, Junjun; Zhang, Xia; Zhu, Yingjie; Tan, Qinyu; He, Jiacheng; Dong, Mingsheng

2017-05-03

Efficient biosynthesis of the plant polyphenol pinosylvin, which has numerous applications in nutraceuticals and pharmaceuticals, is necessary to make biological production economically viable. To this end, an efficient Escherichia coli platform for pinosylvin production was developed via a rational modular design approach. Initially, different candidate pathway enzymes were screened to construct de novo pinosylvin pathway directly from D-glucose. A comparative analysis of pathway intermediate pools identified that this initial construct led to the intermediate cinnamic acid accumulation. The pinosylvin synthetic pathway was then divided into two new modules separated at cinnamic acid. Combinatorial optimization of transcriptional and translational levels of these two modules resulted in a 16-fold increase in pinosylvin titer. To further improve the concentration of the limiting precursor malonyl-CoA, the malonyl-CoA synthesis module based on clustered regularly interspaced short palindromic repeats interference was assembled and optimized with other two modules. The final pinosylvin titer was improved to 281 mg/L, which was the highest pinosylvin titer even directly from D-glucose without any additional precursor supplementation. The rational modular design approach described here could bolster our capabilities in synthetic biology for value-added chemical production.

Cofactor specificity switch in Shikimate dehydrogenase by rational design and consensus engineering.

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García-Guevara, Fernando; Bravo, Iris; Martínez-Anaya, Claudia; Segovia, Lorenzo

2017-08-01

Consensus engineering has been used to design more stable variants using the most frequent amino acid at each site of a multiple sequence alignment; sometimes consensus engineering modifies function, but efforts have mainly been focused on studying stability. Here we constructed a consensus Rossmann domain for the Shikimate dehydrogenase enzyme; separately we decided to switch the cofactor specificity through rational design in the Escherichia coli Shikimate dehydrogenase enzyme and then analyzed the effect of consensus mutations on top of our design. We found that consensus mutations closest to the 2' adenine moiety increased the activity in our design. Consensus engineering has been shown to result in more stable proteins and our findings suggest it could also be used as a complementary tool for increasing or modifying enzyme activity during design. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Rational Emotive Education

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Knaus, William

1977-01-01

Rational Emotive Education--an outgrowth of theories developed by Albert Ellis--is a teaching design of mental health concepts and problem-solving activities designed to help students to approach and cope with their problems through experiential learning, via a structured, thematic sequence of emotive education lessons. (MJB)

Circulating CXCR5+PD-1+ response predicts influenza vaccine antibody responses in young adults but not elderly adults.

Science.gov (United States)

Herati, Ramin Sedaghat; Reuter, Morgan A; Dolfi, Douglas V; Mansfield, Kathleen D; Aung, Htin; Badwan, Osama Z; Kurupati, Raj K; Kannan, Senthil; Ertl, Hildegund; Schmader, Kenneth E; Betts, Michael R; Canaday, David H; Wherry, E John

2014-10-01

Although influenza vaccination is recommended for all adults annually, the incidence of vaccine failure, defined as weak or absent increase in neutralizing Ab titers, is increased in the elderly compared with young adults. The T follicular helper cell (Tfh) subset of CD4 T cells provides B cell help in germinal centers and is necessary for class-switched Ab responses. Previous studies suggested a role for circulating Tfh cells (cTfh) following influenza vaccination in adults, but cTfh have not been studied in elderly adults in whom weak vaccine responses are often observed. In this study, we studied cTfh expressing CXCR5 and programmed death-1 (PD-1). cTfh from elderly adults were present at reduced frequency, had decreased in vitro B cell help ability, and had greater expression of ICOS compared with young adults. At 7 d after inactivated influenza vaccination, cTfh correlated with influenza vaccine-specific IgM and IgG responses in young adults but not in elderly adults. In sum, we have identified aging-related changes in cTfh that correlated with reduced influenza vaccine responses. Future rational vaccine design efforts should incorporate Tfh measurement as an immune correlate of protection, particularly in the setting of aging. Copyright © 2014 by The American Association of Immunologists, Inc.

Rational design of capillary-driven flows for paper-based microfluidics.

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Elizalde, Emanuel; Urteaga, Raúl; Berli, Claudio L A

2015-05-21

The design of paper-based assays that integrate passive pumping requires a precise programming of the fluid transport, which has to be encoded in the geometrical shape of the substrate. This requirement becomes critical in multiple-step processes, where fluid handling must be accurate and reproducible for each operation. The present work theoretically investigates the capillary imbibition in paper-like substrates to better understand fluid transport in terms of the macroscopic geometry of the flow domain. A fluid dynamic model was derived for homogeneous porous substrates with arbitrary cross-sectional shapes, which allows one to determine the cross-sectional profile required for a prescribed fluid velocity or mass transport rate. An extension of the model to slit microchannels is also demonstrated. Calculations were validated by experiments with prototypes fabricated in our lab. The proposed method constitutes a valuable tool for the rational design of paper-based assays.

Attenuation of Vibrio fischeri quorum sensing using rationally designed polymers.

Science.gov (United States)

Piletska, Elena V; Stavroulakis, Georgios; Karim, Kal; Whitcombe, Michael J; Chianella, Iva; Sharma, Anant; Eboigbodin, Kevin E; Robinson, Gary K; Piletsky, Sergey A

2010-04-12

A first attempt to attenuate the quorum sensing (QS) of a marine heterotroph microorganism, Vibrio fischeri , using signal molecule-sequestering polymers (SSPs) is presented. A set of rationally designed polymers with affinity toward a signal molecule of V. fischeri , N-(beta-ketocaproyl)-l-homoserine lactone (3-oxo-C6-AHL) was produced. It is reported that computationally designed polymers could sequester a signal molecule of V. fischeri and prevent QS-controlled phenotypes (in this case, bioluminescence) from being up-regulated. It was proven that the attenuation of bioluminescence of V. fischeri was due to sequestration of the signal molecule by specific polymers and not due to the toxicity of polymer or nonspecific depletion of nutrients. The ability to disrupt the bacterial communication using easy to synthesize and chemically inert polymers could provide a new concept for the development of pharmaceuticals and susceptible device coatings such as catheters.

Rational design of nanoparticles towards targeting antigen-presenting cells and improved T cell priming.

Science.gov (United States)

Zupančič, Eva; Curato, Caterina; Paisana, Maria; Rodrigues, Catarina; Porat, Ziv; Viana, Ana S; Afonso, Carlos A M; Pinto, João; Gaspar, Rogério; Moreira, João N; Satchi-Fainaro, Ronit; Jung, Steffen; Florindo, Helena F

2017-07-28

Vaccination is a promising strategy to trigger and boost immune responses against cancer or infectious disease. We have designed, synthesized and characterized aliphatic-polyester (poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NP) to investigate how the nature of protein association (adsorbed versus entrapped) and polymer/surfactant concentrations impact on the generation and modulation of antigen-specific immune responses. The ability of the NP formulations to target dendritic cells (DC), be internalized and activate the T cells was characterized and optimized in vitro and in vivo using markers of DC activation and co-stimulatory molecules. Ovalbumin (OVA) was used as a model antigen in combination with the engraftment of CD4 + and CD8 + T cells, carrying a transgenic OVA-responding T cell receptor (TCR), to trace and characterize the activation of antigen-specific CD4 + and CD8 + lymph node T cells upon NP vaccination. Accordingly, the phenotype and frequency of immune cell stimulation induced by the NP loaded with OVA, isolated or in combination with synthetic unmethylated cytosine-phosphate-guanine (CpG) oligodeoxynucleotide (ODN) motifs, were characterized. DC-NP interactions increased with incubation time, presenting internalization values between 50 and 60% and 30-40%, in vitro and in vivo, respectively. Interestingly, animal immunization with antigen-adsorbed NP up-regulated major histocompatibility complex (MHC) class II (MHCII), while NP entrapping the antigen up-regulated MHCI, suggesting a more efficient cross-presentation. On the other hand, rather surprisingly, the surfactant used in the NP formulation had a major impact on the activation of antigen presenting cells (APC). In fact, DC collected from lymph nodes of animals immunized with NP prepared using poly(vinil alcohol) (PVA), as a surfactant, expressed significantly higher levels of CD86, MHCI and MHCII. In addition, those NP prepared with PVA and co-entrapping OVA and the toll

Polymeric micro/nanoparticles: Particle design and potential vaccine delivery applications.

Science.gov (United States)

Yue, Hua; Ma, Guanghui

2015-11-04

Particle based adjuvant showed promising signs on delivering antigen to immune cells and acting as stimulators to elicit preventive or therapeutic response. Nevertheless, the wide size distribution of available polymeric particles has so far obscured the immunostimulative effects of particle adjuvant, and compromised the progress in pharmacological researches. To conquer this hurdle, our research group has carried out a series of researches regarding the particulate vaccine, by taking advantage of the successful fabrication of polymeric particles with uniform size. In this review, we highlight the insight and practical progress focused on the effects of physiochemical property (e.g. particle size, charge, hydrophobicity, surface chemical group, and particle shape) and antigen loading mode on the resultant biological/immunological outcome. The underlying mechanisms of how the particles-based vaccine functioned in the immune system are also discussed. Based on the knowledge, particles with high antigen payload and optimized attributes could be designed for expected adjuvant purpose, leading to the development of high efficient vaccine candidates. Copyright © 2015 Elsevier Ltd. All rights reserved.

Development of rational design technique for frame steel structure combining seismic resistance and economic performance

International Nuclear Information System (INIS)

Kato, Motoki; Morishita, Kunihiro; Shimono, Masaki; Chuman, Yasuharu; Okafuji, Takashi; Monaka, Toshiaki

2015-01-01

Anti-seismic designs have been applied to plant support steel frames for years. Today, a rational structure that further improves seismic resistance and ensures economic performance is required in response to an increase of seismic load on the assumption of predicted future massive earthquakes. For satisfying this requirement, a steel frame design method that combines a steel frame weight minimizing method, which enables economic design through simultaneous minimization of multiple steel frame materials, and a seismic response control design technology that improves seismic resistance has been established. Its application in the design of real structures has been promoted. This paper gives an overview of this design technology and presents design examples to which this design technology is applied. (author)

A combinatorial approach to the design of vaccines.

Science.gov (United States)

Martínez, Luis; Milanič, Martin; Legarreta, Leire; Medvedev, Paul; Malaina, Iker; de la Fuente, Ildefonso M

2015-05-01

We present two new problems of combinatorial optimization and discuss their applications to the computational design of vaccines. In the shortest λ-superstring problem, given a family S1,...,S(k) of strings over a finite alphabet, a set Τ of "target" strings over that alphabet, and an integer λ, the task is to find a string of minimum length containing, for each i, at least λ target strings as substrings of S(i). In the shortest λ-cover superstring problem, given a collection X1,...,X(n) of finite sets of strings over a finite alphabet and an integer λ, the task is to find a string of minimum length containing, for each i, at least λ elements of X(i) as substrings. The two problems are polynomially equivalent, and the shortest λ-cover superstring problem is a common generalization of two well known combinatorial optimization problems, the shortest common superstring problem and the set cover problem. We present two approaches to obtain exact or approximate solutions to the shortest λ-superstring and λ-cover superstring problems: one based on integer programming, and a hill-climbing algorithm. An application is given to the computational design of vaccines and the algorithms are applied to experimental data taken from patients infected by H5N1 and HIV-1.

Mutation of the N-Terminal Region of Chikungunya Virus Capsid Protein: Implications for Vaccine Design.

Science.gov (United States)

Taylor, Adam; Liu, Xiang; Zaid, Ali; Goh, Lucas Y H; Hobson-Peters, Jody; Hall, Roy A; Merits, Andres; Mahalingam, Suresh

2017-02-21

Mosquito-transmitted chikungunya virus (CHIKV) is an arthritogenic alphavirus of the Togaviridae family responsible for frequent outbreaks of arthritic disease in humans. Capsid protein, a structural protein encoded by the CHIKV RNA genome, is able to translocate to the host cell nucleolus. In encephalitic alphaviruses, nuclear translocation induces host cell transcriptional shutoff; however, the role of capsid protein nucleolar localization in arthritogenic alphaviruses remains unclear. Using recombinant enhanced green fluorescent protein (EGFP)-tagged expression constructs and CHIKV infectious clones, we describe a nucleolar localization sequence (NoLS) in the N-terminal region of capsid protein, previously uncharacterized in CHIKV. Mutation of the NoLS by site-directed mutagenesis reduced efficiency of nuclear import of CHIKV capsid protein. In the virus, mutation of the capsid protein NoLS (CHIKV-NoLS) attenuated replication in mammalian and mosquito cells, producing a small-plaque phenotype. Attenuation of CHIKV-NoLS is likely due to disruption of the viral replication cycle downstream of viral RNA synthesis. In mice, CHIKV-NoLS infection caused no disease signs compared to wild-type CHIKV (CHIKV-WT)-infected mice; lack of disease signs correlated with significantly reduced viremia and decreased expression of proinflammatory factors. Mice immunized with CHIKV-NoLS, challenged with CHIKV-WT at 30 days postimmunization, develop no disease signs and no detectable viremia. Serum from CHIKV-NoLS-immunized mice is able to efficiently neutralize CHIKV infection in vitro Additionally, CHIKV-NoLS-immunized mice challenged with the related alphavirus Ross River virus showed reduced early and peak viremia postchallenge, indicating a cross-protective effect. The high degree of CHIKV-NoLS attenuation may improve CHIKV antiviral and rational vaccine design. IMPORTANCE CHIKV is a mosquito-borne pathogen capable of causing explosive epidemics of incapacitating joint pain

A rationally designed combined treatment with an alphavirus-based cancer vaccine, sunitinib and low-dose tumor irradiation completely blocks tumor development

NARCIS (Netherlands)

Draghiciu, Oana; Boerma, Annemarie; Hoogeboom, Baukje Nynke; Nijman, Hans W.; Daemen, Toos

2015-01-01

The clinical efficacy of therapeutic cancer vaccines remains limited. For effective immunotherapeutic responses in cancer patients, multimodal approaches capable of both inducing antitumor immune responses and bypassing tumor-mediated immune escape seem essential. Here, we report on a combination

Designing and modeling of complex DNA vaccine based on tropomyosin protein of Boophilus genus tick.

Science.gov (United States)

Ranjbar, Mohamamd Mahdi; Gupta, Shishir K; Ghorban, Khodayar; Nabian, Sedigheh; Sazmand, Alireza; Taheri, Mohammad; Esfandyari, Sahar; Taheri, Maryam

2015-01-01

Boophilus tick is a bloodsucking ectoparasite that transfers some pathogens, reducing production and thus leading to economical losses in the cattle industry. Tropomyosin (TPM) protein is a salivary protein, has actin regulator activity, and plays an important role in immune reactions against parasites. In the current study, besides developing a safe, effective, and broad spectrum protective measure against Boophilus genus tick based on TPM protein, we attempted to minimize possible problems occurring in the design of polytopic vaccines. Briefly, the steps that were followed in the present study were as follows: retrieving sequences and finding the mutational/conservative regions, selecting consensus and high immunogenic epitopes of B and CD4(+) T cells by different approaches, three-dimensional structure (3D structure) prediction and representation of epitopes and highly variable/conserve regions, designing vaccinal construct by fusion of B and T cell epitopes by special patterns and improving immunogenicity, evaluation of the constructs' primary structure and posttranslational modification, calculation of hydrophobic regions, reverse translation, codon optimization, open reading frame checking, insertion of start/end codon, Kozak sequence, and finally constructing the DNA vaccine. Variation plot showed some shared epitopes among the ticks' and mites' species that some might be effective only in some species. Finally, by following the steps mentioned above, two constructs for B and T cells were achieved. Checking constructs revealed their reliability and efficacy for in vitro production and utilization. Successful in silico modeling is an essential step of designing vigorous vaccines. We developed a novel protective and therapeutic vaccine against Boophilus genus (based on TPM protein). At the next step, constructed DNA vaccine would be produced in vitro and administrated to cattle, and its potency to induction of immune response and protection against Boophilus

Application of Absorption Modeling in Rational Design of Drug Product Under Quality-by-Design Paradigm.

Science.gov (United States)

Kesisoglou, Filippos; Mitra, Amitava

2015-09-01

Physiologically based absorption models can be an important tool in understanding product performance and hence implementation of Quality by Design (QbD) in drug product development. In this report, we show several case studies to demonstrate the potential application of absorption modeling in rational design of drug product under the QbD paradigm. The examples include application of absorption modeling—(1) prior to first-in-human studies to guide development of a formulation with minimal sensitivity to higher gastric pH and hence reduced interaction when co-administered with PPIs and/or H2RAs, (2) design of a controlled release formulation with optimal release rate to meet trough plasma concentrations and enable QD dosing, (3) understanding the impact of API particle size distribution on tablet bioavailability and guide formulation design in late-stage development, (4) assess impact of API phase change on product performance to guide specification setting, and (5) investigate the effect of dissolution rate changes on formulation bioperformance and enable appropriate specification setting. These case studies are meant to highlight the utility of physiologically based absorption modeling in gaining a thorough understanding of the product performance and the critical factors impacting performance to drive design of a robust drug product that would deliver the optimal benefit to the patients.

Vaccination, herd behavior, and herd immunity.

Science.gov (United States)

Cohen, Matan J; Brezis, Mayer; Block, Colin; Diederich, Adele; Chinitz, David

2013-11-01

During the 2009 outbreak of novel influenza AH1N1, insufficient data were available to adequately inform decision makers about benefits and risks of vaccination and disease. We hypothesized that individuals would opt to mimic their peers, having no better decision anchor. We used Game Theory, decision analysis, and transmission models to simulate the impact of subjective risks and preference estimates on vaccination behavior. We asked 95 students to provide estimates of risk and health state valuations with regard to AH1N1 infection, complications, and expectations of vaccine benefits and risks. These estimates were included in a sequential chain of models: a dynamic epidemic model, a decision tree, and a population-level model. Additionally, participants' intentions to vaccinate or not at varying vaccination rates were documented. The model showed that at low vaccination rates, vaccination dominated. When vaccination rates increased above 78%, nonvaccination was the dominant strategy. We found that vaccination intentions did not correspond to the shift in strategy dominance and segregated to 3 types of intentions: regardless of what others do 29/95 (31%) intended to vaccinate while 27/95 (28%) did not; among 39 of 95 (41%) intention was positively associated with putative vaccination rates. Some people conform to the majority's choice, either shifting epidemic dynamics toward herd immunity or, conversely, limiting societal goals. Policy leaders should use models carefully, noting their limitations and theoretical assumptions. Behavior drivers were not explicitly explored in this study, and the discrepant results beg further investigation. Models including real subjective perceptions with empiric or subjective probabilities can provide insight into deviations from expected rational behavior and suggest interventions in order to provide better population outcomes.

Live attenuated vaccines: Historical successes and current challenges.

Science.gov (United States)

Minor, Philip D

2015-05-01

Live attenuated vaccines against human viral diseases have been amongst the most successful cost effective interventions in medical history. Smallpox was declared eradicated in 1980; poliomyelitis is nearing global eradication and measles has been controlled in most parts of the world. Vaccines function well for acute diseases such as these but chronic infections such as HIV are more challenging for reasons of both likely safety and probable efficacy. The derivation of the vaccines used has in general not been purely rational except in the sense that it has involved careful clinical trials of candidates and subsequent careful follow up in clinical use; the identification of the candidates is reviewed. Copyright © 2015 The Author. Published by Elsevier Inc. All rights reserved.

Translational mini-review series on vaccines: The Edward Jenner Museum and the history of vaccination.

Science.gov (United States)

Morgan, A J; Parker, S

2007-03-01

Edward Jenner's discovery of vaccination must rank as one of the most important medical advances of all time and is a prominent example of the power of rational enquiry being brought to bear during the Age of Enlightenment in 18th century Europe. In the modern era many millions of lives are saved each year by vaccines that work essentially on the same principles that were established by Edward Jenner more than 200 years ago. His country home in Berkeley, Gloucestershire, is where he carried out his work and where he spent most of his life. The building is now a museum in which the life and times of Jenner are commemorated including not only the discovery of smallpox vaccination but also his other important scientific contributions to natural history and medicine. The trustees of the Edward Jenner museum are committed to promoting the museum as a real and "virtual" educational centre that is both entertaining and informative.

An immunologic model for rapid vaccine assessment -- a clinical trial in a test tube.

Science.gov (United States)

Higbee, Russell G; Byers, Anthony M; Dhir, Vipra; Drake, Donald; Fahlenkamp, Heather G; Gangur, Jyoti; Kachurin, Anatoly; Kachurina, Olga; Leistritz, Del; Ma, Yifan; Mehta, Riyaz; Mishkin, Eric; Moser, Janice; Mosquera, Luis; Nguyen, Mike; Parkhill, Robert; Pawar, Santosh; Poisson, Louis; Sanchez-Schmitz, Guzman; Schanen, Brian; Singh, Inderpal; Song, Haifeng; Tapia, Tenekua; Warren, William; Wittman, Vaughan

2009-09-01

While the duration and size of human clinical trials may be difficult to reduce, there are several parameters in pre-clinical vaccine development that may be possible to further optimise. By increasing the accuracy of the models used for pre-clinical vaccine testing, it should be possible to increase the probability that any particular vaccine candidate will be successful in human trials. In addition, an improved model will allow the collection of increasingly more-informative data in pre-clinical tests, thus aiding the rational design and formulation of candidates entered into clinical evaluation. An acceleration and increase in sophistication of pre-clinical vaccine development will thus require the advent of more physiologically-accurate models of the human immune system, coupled with substantial advances in the mechanistic understanding of vaccine efficacy, achieved by using this model. We believe the best viable option available is to use human cells and/or tissues in a functional in vitro model of human physiology. Not only will this more accurately model human diseases, it will also eliminate any ethical, moral and scientific issues involved with use of live humans and animals. An in vitro model, termed "MIMIC" (Modular IMmune In vitro Construct), was designed and developed to reflect the human immune system in a well-based format. The MIMIC System is a laboratory-based methodology that replicates the human immune system response. It is highly automated, and can be used to simulate a clinical trial for a diverse population, without putting human subjects at risk. The MIMIC System uses the circulating immune cells of individual donors to recapitulate each individual human immune response by maintaining the autonomy of the donor. Thus, an in vitro test system has been created that is functionally equivalent to the donor's own immune system and is designed to respond in a similar manner to the in vivo response. 2009 FRAME.

Rational design of hierarchical ZnO@Carbon nanoflower for high performance lithium ion battery anodes

Science.gov (United States)

liu, Huichao; Shi, Ludi; Li, Dongzhi; Yu, Jiali; Zhang, Han-Ming; Ullah, Shahid; Yang, Bo; Li, Cuihua; Zhu, Caizhen; Xu, Jian

2018-05-01

The rational structure design and strong interfacial bonding are crucially desired for high performance zinc oxide (ZnO)/carbon composite electrodes. In this context, micro-nano secondary structure design and strong dopamine coating strategies are adopted for the fabrication of flower-like ZnO/carbon (ZnO@C nanoflowers) composite electrodes. The results show the ZnO@C nanoflowers (2-6 μm) are assembled by hierarchical ZnO nanosheets (∼27 nm) and continuous carbon framework. The micro-nano secondary architecture can facilitate the penetration of electrolyte, shorten lithium ions diffusion length, and hinder the aggregation of the nanosheets. Moreover, the strong chemical interaction between ZnO and coating carbon layer via C-Zn bond improves structure stability as well as the electronic conductivity. As a synergistic result, when evaluated as lithium ion batteries (LIBs) anode, the ZnO@C nanoflower electrodes show high reversible capacity of ca. 1200 mA h g-1 at 0.1 A g-1 after 80 cycles. As well as good long-cycling stability (638 and 420 mA h g-1 at 1 and 5 A g-1 after 500 cycles, respectively) and excellent rate capability. Therefore, this rational design of ZnO@C nanoflowers electrode is a promising anode for high-performance LIBs.

[Clinical effectiveness and economical evaluation of preventive vaccination].

Science.gov (United States)

Vaz Carneiro, António; Belo, Ana Isabel; Gouveia, Miguel; Costa, João; Borges, Margarida

2011-01-01

The value of mass vaccination as a preventive measure for infectious diseases is one of the most important advances of modern Medicine. The impact on incidence of several infectious diseases, until recently responsible for significant morbidity and mortality at world level, is well proved in a series of high quality epidemiological studies. In this scientific review we aimed firstly to briefly resume the history of mass vaccination and its scientists, responsible for synthesis and marketing of these drugs. In second place we present a group of a few disease preventable by vaccines as well as the Portuguese National Vaccination Plan and its benefits. In third place we identified groups of subjects in which a well structured vaccination plan is particularly important, as well as the correspondent diseases to be covered by vaccination. Fourthly, we discussed the ethical considerations of vaccination, and its tensions between subject autonomy and society advantages in com pulsive programs. Fifthly, we analyzed clinical effectiveness of vaccines through the concept of herd immunity, clinical evaluation of immune response to vaccines and some examples of systematic reviews on three relevant diseases (influenza, meningococcal and pneumococcal infections). In sixth place we discussed vaccine safety presenting monitoring methods of vaccination risks, as well as discussing the public myths concerning vaccines. Finally we present a economic analysis of preventive vaccination with a review of some published literature on specific diseases. We conclude that mass vaccination is a efficacious preventive measure, as well as a economic rational choice, and that this public health intervention should be a pillar of a modern preventive system.

A clinically parameterized mathematical model of Shigella immunity to inform vaccine design.

Directory of Open Access Journals (Sweden)

Courtney L Davis

Full Text Available We refine and clinically parameterize a mathematical model of the humoral immune response against Shigella, a diarrheal bacteria that infects 80-165 million people and kills an estimated 600,000 people worldwide each year. Using Latin hypercube sampling and Monte Carlo simulations for parameter estimation, we fit our model to human immune data from two Shigella EcSf2a-2 vaccine trials and a rechallenge study in which antibody and B-cell responses against Shigella's lipopolysaccharide (LPS and O-membrane proteins (OMP were recorded. The clinically grounded model is used to mathematically investigate which key immune mechanisms and bacterial targets confer immunity against Shigella and to predict which humoral immune components should be elicited to create a protective vaccine against Shigella. The model offers insight into why the EcSf2a-2 vaccine had low efficacy and demonstrates that at a group level a humoral immune response induced by EcSf2a-2 vaccine or wild-type challenge against Shigella's LPS or OMP does not appear sufficient for protection. That is, the model predicts an uncontrolled infection of gut epithelial cells that is present across all best-fit model parameterizations when fit to EcSf2a-2 vaccine or wild-type challenge data. Using sensitivity analysis, we explore which model parameter values must be altered to prevent the destructive epithelial invasion by Shigella bacteria and identify four key parameter groups as potential vaccine targets or immune correlates: 1 the rate that Shigella migrates into the lamina propria or epithelium, 2 the rate that memory B cells (BM differentiate into antibody-secreting cells (ASC, 3 the rate at which antibodies are produced by activated ASC, and 4 the Shigella-specific BM carrying capacity. This paper underscores the need for a multifaceted approach in ongoing efforts to design an effective Shigella vaccine.

A clinically parameterized mathematical model of Shigella immunity to inform vaccine design.

Science.gov (United States)

Davis, Courtney L; Wahid, Rezwanul; Toapanta, Franklin R; Simon, Jakub K; Sztein, Marcelo B

2018-01-01

We refine and clinically parameterize a mathematical model of the humoral immune response against Shigella, a diarrheal bacteria that infects 80-165 million people and kills an estimated 600,000 people worldwide each year. Using Latin hypercube sampling and Monte Carlo simulations for parameter estimation, we fit our model to human immune data from two Shigella EcSf2a-2 vaccine trials and a rechallenge study in which antibody and B-cell responses against Shigella's lipopolysaccharide (LPS) and O-membrane proteins (OMP) were recorded. The clinically grounded model is used to mathematically investigate which key immune mechanisms and bacterial targets confer immunity against Shigella and to predict which humoral immune components should be elicited to create a protective vaccine against Shigella. The model offers insight into why the EcSf2a-2 vaccine had low efficacy and demonstrates that at a group level a humoral immune response induced by EcSf2a-2 vaccine or wild-type challenge against Shigella's LPS or OMP does not appear sufficient for protection. That is, the model predicts an uncontrolled infection of gut epithelial cells that is present across all best-fit model parameterizations when fit to EcSf2a-2 vaccine or wild-type challenge data. Using sensitivity analysis, we explore which model parameter values must be altered to prevent the destructive epithelial invasion by Shigella bacteria and identify four key parameter groups as potential vaccine targets or immune correlates: 1) the rate that Shigella migrates into the lamina propria or epithelium, 2) the rate that memory B cells (BM) differentiate into antibody-secreting cells (ASC), 3) the rate at which antibodies are produced by activated ASC, and 4) the Shigella-specific BM carrying capacity. This paper underscores the need for a multifaceted approach in ongoing efforts to design an effective Shigella vaccine.

Bacterial Artificial Chromosome Clones of Viruses Comprising the Towne Cytomegalovirus Vaccine

Directory of Open Access Journals (Sweden)

Xiaohong Cui

2012-01-01

Full Text Available Bacterial artificial chromosome (BAC clones have proven invaluable for genetic manipulation of herpesvirus genomes. BAC cloning can also be useful for capturing representative genomes that comprise a viral stock or mixture. The Towne live attenuated cytomegalovirus vaccine was developed in the 1970s by serial passage in cultured fibroblasts. Although its safety, immunogenicity, and efficacy have been evaluated in nearly a thousand human subjects, the vaccine itself has been little studied. Instead, genetic composition and in vitro growth properties have been inferred from studies of laboratory stocks that may not always accurately represent the viruses that comprise the vaccine. Here we describe the use of BAC cloning to define the genotypic and phenotypic properties of viruses from the Towne vaccine. Given the extensive safety history of the Towne vaccine, these BACs provide a logical starting point for the development of next-generation rationally engineered cytomegalovirus vaccines.

Bacterial artificial chromosome clones of viruses comprising the towne cytomegalovirus vaccine.

Science.gov (United States)

Cui, Xiaohong; Adler, Stuart P; Davison, Andrew J; Smith, Larry; Habib, El-Sayed E; McVoy, Michael A

2012-01-01

Bacterial artificial chromosome (BAC) clones have proven invaluable for genetic manipulation of herpesvirus genomes. BAC cloning can also be useful for capturing representative genomes that comprise a viral stock or mixture. The Towne live attenuated cytomegalovirus vaccine was developed in the 1970s by serial passage in cultured fibroblasts. Although its safety, immunogenicity, and efficacy have been evaluated in nearly a thousand human subjects, the vaccine itself has been little studied. Instead, genetic composition and in vitro growth properties have been inferred from studies of laboratory stocks that may not always accurately represent the viruses that comprise the vaccine. Here we describe the use of BAC cloning to define the genotypic and phenotypic properties of viruses from the Towne vaccine. Given the extensive safety history of the Towne vaccine, these BACs provide a logical starting point for the development of next-generation rationally engineered cytomegalovirus vaccines.

Immune Serum From Sabin Inactivated Poliovirus Vaccine Immunization Neutralizes Multiple Individual Wild and Vaccine-Derived Polioviruses.

Science.gov (United States)

Sun, Mingbo; Li, Changgui; Xu, Wenbo; Liao, Guoyang; Li, Rongcheng; Zhou, Jian; Li, Yanping; Cai, Wei; Yan, Dongmei; Che, Yanchun; Ying, Zhifang; Wang, Jianfeng; Yang, Huijuan; Ma, Yan; Ma, Lei; Ji, Guang; Shi, Li; Jiang, Shude; Li, Qihan

2017-05-15

A Sabin strain-based inactivated poliomyelitis vaccine (Sabin-IPV) is the rational option for completely eradicating poliovirus transmission. The neutralizing capacity of Sabin-IPV immune serum to different strains of poliovirus is a key indicator of the clinical protective efficacy of this vaccine. Sera collected from 500 infants enrolled in a randomized, blinded, positive control, phase 2 clinical trial were randomly divided into 5 groups: Groups A, B, and C received high, medium, and low doses, respectively, of Sabin-IPV, while groups D and E received trivalent oral polio vaccine and Salk strain-based IPV, respectively, all on the same schedule. Immune sera were collected after the third dose of primary immunization, and tested in cross-neutralization assays against 19 poliovirus strains of all 3 types. All immune sera from all 5 groups interacted with the 19 poliovirus strains with various titers and in a dose-dependent manner. One type 2 immunodeficiency-associated vaccine-derived poliovirus strain was not recognized by these immune sera. Sabin-IPV vaccine can induce protective antibodies against currently circulating and reference wild poliovirus strains and most vaccine-derived poliovirus strains, with rare exceptions. NCT01056705. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Rational design of functional and tunable oscillating enzymatic networks

Science.gov (United States)

Semenov, Sergey N.; Wong, Albert S. Y.; van der Made, R. Martijn; Postma, Sjoerd G. J.; Groen, Joost; van Roekel, Hendrik W. H.; de Greef, Tom F. A.; Huck, Wilhelm T. S.

2015-02-01

Life is sustained by complex systems operating far from equilibrium and consisting of a multitude of enzymatic reaction networks. The operating principles of biology's regulatory networks are known, but the in vitro assembly of out-of-equilibrium enzymatic reaction networks has proved challenging, limiting the development of synthetic systems showing autonomous behaviour. Here, we present a strategy for the rational design of programmable functional reaction networks that exhibit dynamic behaviour. We demonstrate that a network built around autoactivation and delayed negative feedback of the enzyme trypsin is capable of producing sustained oscillating concentrations of active trypsin for over 65 h. Other functions, such as amplification, analog-to-digital conversion and periodic control over equilibrium systems, are obtained by linking multiple network modules in microfluidic flow reactors. The methodology developed here provides a general framework to construct dissipative, tunable and robust (bio)chemical reaction networks.

Testing the rationality assumption using a design difference in the TV game show 'Jeopardy'

OpenAIRE

Sjögren Lindquist, Gabriella; Säve-Söderbergh, Jenny

2006-01-01

Abstract This paper empirically investigates the rationality assumption commonly applied in economic modeling by exploiting a design difference in the game-show Jeopardy between the US and Sweden. In particular we address the assumption of individuals’ capabilities to process complex mathematical problems to find optimal strategies. The vital difference is that US contestants are given explicit information before they act, while Swedish contestants individually need to calculate the same info...

Immunological evaluation of lipopeptide group A streptococcus (GAS vaccine: structure-activity relationship.

Directory of Open Access Journals (Sweden)

Mehfuz Zaman

Full Text Available Streptococcus pyogenes (group A streptococcus, GAS is a Gram-positive bacterial pathogen responsible for a wide variety of diseases. To date, GAS vaccine development has focused primarily on the M-protein. The M-protein is highly variable at the amino (N-terminus (determining serotype but is conserved at the carboxyl (C-terminus. Previously a 29 amino acid peptide (named J14 from the conserved region of the M-protein was identified as a potential vaccine candidate. J14 was capable of eliciting protective antibodies that recognized many GAS serotypes when co-administered with immuno-stimulants. This minimal epitope however showed no immunogenicity when administered alone. In an attempt overcome this immunological non-responsiveness, we developed a self-adjuvanting vaccine candidate composed of three components: the B-cell epitope (J14, a universal helper T-cell epitope (P25 and a lipid moiety consisting of lipoamino acids (Laas which target Toll-like receptor 2 (TLR2. Immunological evaluation in B10.BR (H-2k mice demonstrated that the epitope attachment to the point of lipid moiety, and the length of the Laa alkyl chain have a profound effect on vaccine immunogenicity after intranasal administration. It was demonstrated that a vaccine featuring C-terminal lipid moiety containing alkyl chains of 16 carbons, with P25 located at the N-terminus, and J14 attached to the side chain of a central lysine residue was capable of inducing optimal antibody response. These findings have considerable relevance to the development of a broad spectrum J14-based GAS vaccine and in particular provided a rational basis for peptide vaccine design based on this self-adjuvanting lipopeptide technology.

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

Science.gov (United States)

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

2014-03-01

Vaccination against drugs of abuse shows efficacy in animal models, yet few subjects achieve effective serum antibody titers in clinical studies. A barrier to translation is the lack of pre-vaccination screening assays that predict the most effective conjugate vaccines or subjects amenable to vaccination. To address this obstacle, we developed a fluorescent antigen-based enrichment method paired with flow cytometry to characterize hapten-specific B cells. Using this approach, we studied naïve and activated B cells specific for structurally-related model haptens based on derivatization of the morphinan structure at the C6 position on oxycodone or at the C8 position on hydrocodone, and showing different pre-clinical efficacy against the prescription opioid oxycodone. Prior to vaccination, naïve B cells exhibited relatively higher affinity for the more effective C6-derivatized oxycodone-based hapten (6OXY) and the 6OXY-specific naïve B cell population contained a higher number of B cells with greater affinity for free oxycodone. Higher affinity of naïve B cells for hapten or oxycodone reflected greater efficacy of vaccination in blocking oxycodone distribution to brain in mice. Shortly after immunization, activated hapten-specific B cells were detected prior to oxycodone-specific serum antibodies and provided earlier evidence of vaccine failure or success. Analysis of hapten-specific naïve and activated B cells may aid rational vaccine design and provide screening tools to predict vaccine clinical efficacy against drugs of abuse or other small molecules. Copyright © 2014 Elsevier B.V. All rights reserved.

Rationality of limited rationality : some aggregate implications

OpenAIRE

Uri M. Possen; Mikko Puhakka

1994-01-01

In this paper we let economic agents choose whether to become fully rational or stay boundedly rational. Boundedly rational agents are less sophisticated in their information processing abilities. It is costly to acquire information needed to become fully rational, and thus not all agents are willing to incur those costs. We then explore the aggregate effects of endogenizing the decision whether the agent should or should not become fully rational in handling information. Since fully and boun...

Protecting our Khmer daughters: Ghosts of the past, uncertain futures, and the HPV vaccine

Science.gov (United States)

Burke, Nancy J.; Do, Huyen H.; Talbot, Jocelyn; Sos, Channdara; Ros, Srey; Taylor, Victoria M.

2014-01-01

Objectives The FDA approved the first HPV vaccine in 2006. Research into parental decision-making and concerns about HPV vaccination highlight questions about parenting and parents’ role in the crafting of their daughters’ future sexuality. In contrast to much of this literature, we explore narratives from interviews with Cambodian mothers of HPV vaccine age-eligible daughters who experienced genocide and came to the United States as refugees. Design We conducted in-depth, in-person interviews with 25 Cambodian mothers of HPV vaccine-age eligible daughters. Interviews were conducted in Khmer and translated into English for analysis. We followed standard qualitative analysis techniques including iterative data review, multiple coders, and ‘member checking’. Five members of the research team reviewed all transcripts and two members independently coded each transcript for concepts and themes. Results Interview narratives highlight the presence of the past alongside desires for protection from uncertain futures. We turn to Quesada and colleagues’ (2011) concept structural vulnerability to outline the constraints posed by these women’s positionalities as genocide survivors when faced with making decisions in a area with which they have little direct knowledge or background: cervical cancer prevention. Conclusion Our study sheds light on the prioritization of various protective health practices, including but not exclusive to HPV vaccination, for Khmer mothers, as well as the rationalities informing decision-making regarding their daughters’ health. PMID:24905057

Designing Vaccines for the Twenty-First Century Society

OpenAIRE

Finco, Oretta; Rappuoli, Rino

2014-01-01

The history of vaccination clearly demonstrates that vaccines have been highly successful in preventing infectious diseases, reducing significantly the incidence of childhood diseases and mortality. However, many infections are still not preventable with the currently available vaccines and they represent a major cause of mortality worldwide. In the twenty-first century, the innovation brought by novel technologies in antigen discovery and formulation together with a deeper knowledge of the h...

Designing vaccines for the 21st century society

OpenAIRE

Oretta eFinco; Rino eRappuoli

2014-01-01

The history of vaccination clearly demonstrates that vaccines have been highly successful in preventing infectious diseases, reducing significantly the incidence of childhood diseases and mortality. However many infections are still not preventable with the currently available vaccines and they represent a major cause of mortality worldwide. In the 21st century, the innovation brought by novel technologies in antigen discovery and formulation together with a deeper knowledge of the human imm...

Rationalization with ruled surfaces in architecture

DEFF Research Database (Denmark)

Steenstrup, Kasper Hornbak

This thesis addresses the problems of rationalizing and segmenting large scale 3D models, and how to handle difficult production constraints in this area. The design choices when constructing large scale architecture are influenced by the budget. Therefore I strive to minimize the amount of time...... and material needed for production. This makes advanced free form architecture viable for low cost projects, allowing the architects to realize their designs. By pre-cutting building blocks using hot wire robots, the amount of milling necessary can be reduced drastically. I do this by rationalizing...

GREEN: A program package for docking studies in rational drug design

Science.gov (United States)

Tomioka, Nobuo; Itai, Akiko

1994-08-01

A program package, GREEN, has been developed that enables docking studies between ligand molecules and a protein molecule. Based on the structure of the protein molecule, the physical and chemical environment of the ligand-binding site is expressed as three-dimensional grid-point data. The grid-point data are used for the real-time evaluation of the protein-ligand interaction energy, as well as for the graphical representation of the binding-site environment. The interactive docking operation is facilitated by various built-in functions, such as energy minimization, energy contribution analysis and logging of the manipulation trajectory. Interactive modeling functions are incorporated for designing new ligand molecules while considering the binding-site environment and the protein-ligand interaction. As an example of the application of GREEN, a docking study is presented on the complex between trypsin and a synthetic trypsin inhibitor. The program package will be useful for rational drug design, based on the 3D structure of the target protein.

Rational Design Approach for Enhancing Higher-Mode Response of a Microcantilever in Vibro-Impacting Mode

Directory of Open Access Journals (Sweden)

Ieva Migliniene

2017-12-01

Full Text Available This paper proposes an approach for designing an efficient vibration energy harvester based on a vibro-impacting piezoelectric microcantilever with a geometric shape that has been rationally modified in accordance with results of dynamic optimization. The design goal is to increase the amplitudes of higher-order vibration modes induced during the vibro-impact response of the piezoelectric transducer, thereby providing a means to improve the energy conversion efficiency and power output. A rational configuration of the energy harvester is proposed and it is demonstrated that the new design retains essential modal characteristics of the optimal microcantilever structures, further providing the added benefit of less costly fabrication. The effects of structural dynamics associated with advantageous exploitation of higher vibration modes are analyzed experimentally by means of laser vibrometry as well as numerically via transient simulations of microcantilever response to random excitation. Electrical characterization results indicate that the proposed harvester outperforms its conventional counterpart (based on the microcantilever of the constant cross-section in terms of generated electrical output. Reported results may serve for the development of impact-type micropower generators with harvesting performance that is enhanced by virtue of self-excitation of large intensity higher-order mode responses when the piezoelectric transducer is subjected to relatively low-frequency excitation with strongly variable vibration magnitudes.

Rationalization and Design of the Complementarity Determining Region Sequences in an Antibody-Antigen Recognition Interface

Science.gov (United States)

Chen, Ing-Chien; Lee, Yu-Ching; Chen, Jun-Bo; Tsai, Keng-Chang; Chen, Ching-Tai; Chang, Jeng-Yih; Yang, Ei-Wen; Hsu, Po-Chiang; Jian, Jhih-Wei; Hsu, Hung-Ju; Chang, Hung-Ju; Hsu, Wen-Lian; Huang, Kai-Fa; Ma, Alex Che; Yang, An-Suei

2012-01-01

Protein-protein interactions are critical determinants in biological systems. Engineered proteins binding to specific areas on protein surfaces could lead to therapeutics or diagnostics for treating diseases in humans. But designing epitope-specific protein-protein interactions with computational atomistic interaction free energy remains a difficult challenge. Here we show that, with the antibody-VEGF (vascular endothelial growth factor) interaction as a model system, the experimentally observed amino acid preferences in the antibody-antigen interface can be rationalized with 3-dimensional distributions of interacting atoms derived from the database of protein structures. Machine learning models established on the rationalization can be generalized to design amino acid preferences in antibody-antigen interfaces, for which the experimental validations are tractable with current high throughput synthetic antibody display technologies. Leave-one-out cross validation on the benchmark system yielded the accuracy, precision, recall (sensitivity) and specificity of the overall binary predictions to be 0.69, 0.45, 0.63, and 0.71 respectively, and the overall Matthews correlation coefficient of the 20 amino acid types in the 24 interface CDR positions was 0.312. The structure-based computational antibody design methodology was further tested with other antibodies binding to VEGF. The results indicate that the methodology could provide alternatives to the current antibody technologies based on animal immune systems in engineering therapeutic and diagnostic antibodies against predetermined antigen epitopes. PMID:22457753

Rational design of an influenza subunit vaccine powder with sugar glass technology : preventing conformational changes of haemagglutinin during freezing and freeze-drying

NARCIS (Netherlands)

Amorij, J-P; Meulenaar, J; Hinrichs, W L J; Stegmann, T; Huckriede, A; Coenen, F; Frijlink, H W

2007-01-01

The development of a stable influenza subunit vaccine in the dry state was investigated. The influence of various carbohydrates, buffer types and freezing rates on the integrity of haemagglutinin after freeze-thawing or freeze-drying was investigated with a range of analytical and immunological

Therapeutics targeting tumor immune escape: towards the development of new generation anticancer vaccines.

Science.gov (United States)

Mocellin, Simone; Nitti, Donato

2008-05-01

Despite the evidence that immune effectors can play a significant role in controlling tumor growth under natural conditions or in response to therapeutic manipulation, it is clear that malignant cells evade immune surveillance in most cases. Considering that anticancer vaccination has reached a plateau of results and currently no vaccination regimen is indicated as a standard anticancer therapy, the dissection of the molecular events underlying tumor immune escape is the necessary condition to make anticancer vaccines a therapeutic weapon effective enough to be implemented in the routine clinical setting. Recent years have witnessed significant advances in our understanding of the molecular mechanisms underlying tumor immune escape. These mechanistic insights are fostering the development of rationally designed therapeutics aimed at reverting the immunosuppressive circuits that undermine an effective antitumor immune response. In this review, the best characterized mechanisms that allow cancer cells to evade immune surveillance are overviewed and the most debated controversies constellating this complex field are highlighted. In addition, the latest therapeutic strategies devised to overcome tumor immune escape are described, with special regard to those entering clinical phase investigation. Copyright (c) 2007 Wiley-Periodicals, Inc.

Rational design of new materials using recombinant structural proteins: Current state and future challenges.

Science.gov (United States)

Sutherland, Tara D; Huson, Mickey G; Rapson, Trevor D

2018-01-01

Sequence-definable polymers are seen as a prerequisite for design of future materials, with many polymer scientists regarding such polymers as the holy grail of polymer science. Recombinant proteins are sequence-defined polymers. Proteins are dictated by DNA templates and therefore the sequence of amino acids in a protein is defined, and molecular biology provides tools that allow redesign of the DNA as required. Despite this advantage, proteins are underrepresented in materials science. In this publication we investigate the advantages and limitations of using proteins as templates for rational design of new materials. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

Gleaning Insights from Fecal Microbiota Transplantation and Probiotic Studies for the Rational Design of Combination Microbial Therapies

Science.gov (United States)

Hudson, Lauren E.; Anderson, Sarah E.; Corbett, Anita H.

2016-01-01

SUMMARY Beneficial microorganisms hold promise for the treatment of numerous gastrointestinal diseases. The transfer of whole microbiota via fecal transplantation has already been shown to ameliorate the severity of diseases such as Clostridium difficile infection, inflammatory bowel disease, and others. However, the exact mechanisms of fecal microbiota transplant efficacy and the particular strains conferring this benefit are still unclear. Rationally designed combinations of microbial preparations may enable more efficient and effective treatment approaches tailored to particular diseases. Here we use an infectious disease, C. difficile infection, and an inflammatory disorder, the inflammatory bowel disease ulcerative colitis, as examples to facilitate the discussion of how microbial therapy might be rationally designed for specific gastrointestinal diseases. Fecal microbiota transplantation has already shown some efficacy in the treatment of both these disorders; detailed comparisons of studies evaluating commensal and probiotic organisms in the context of these disparate gastrointestinal diseases may shed light on potential protective mechanisms and elucidate how future microbial therapies can be tailored to particular diseases. PMID:27856521

How influenza vaccination policy may affect vaccine logistics.

Science.gov (United States)

Assi, Tina-Marie; Rookkapan, Korngamon; Rajgopal, Jayant; Sornsrivichai, Vorasith; Brown, Shawn T; Welling, Joel S; Norman, Bryan A; Connor, Diana L; Chen, Sheng-I; Slayton, Rachel B; Laosiritaworn, Yongjua; Wateska, Angela R; Wisniewski, Stephen R; Lee, Bruce Y

2012-06-22

When policymakers make decision about the target populations and timing of influenza vaccination, they may not consider the impact on the vaccine supply chains, which may in turn affect vaccine availability. Our goal is to explore the effects on the Thailand vaccine supply chain of introducing influenza vaccines and varying the target populations and immunization time-frames. We Utilized our custom-designed software HERMES (Highly Extensible Resource for Modeling Supply Chains), we developed a detailed, computational discrete-event simulation model of the Thailand's National Immunization Program (NIP) supply chain in Trang Province, Thailand. A suite of experiments simulated introducing influenza vaccines for different target populations and over different time-frames prior to and during the annual influenza season. Introducing influenza vaccines creates bottlenecks that reduce the availability of both influenza vaccines as well as the other NIP vaccines, with provincial to district transport capacity being the primary constraint. Even covering only 25% of the Advisory Committee on Immunization Practice-recommended population while administering the vaccine over six months hinders overall vaccine availability so that only 62% of arriving patients can receive vaccines. Increasing the target population from 25% to 100% progressively worsens these bottlenecks, while increasing influenza vaccination time-frame from 1 to 6 months decreases these bottlenecks. Since the choice of target populations for influenza vaccination and the time-frame to deliver this vaccine can substantially affect the flow of all vaccines, policy-makers may want to consider supply chain effects when choosing target populations for a vaccine. Copyright © 2012 Elsevier Ltd. All rights reserved.

New approaches to design HIV-1 T-cell vaccines.

Science.gov (United States)

Perrin, Hélène; Canderan, Glenda; Sékaly, Rafick-Pierre; Trautmann, Lydie

2010-09-01

Following the evidence that T-cell responses are crucial in the control of HIV-1 infection, vaccines targeting T-cell responses were tested in recent clinical trials. However, these vaccines showed a lack of efficacy. This review attempts to define the qualitative and quantitative features that are desirable for T-cell-induced responses by vaccines. We also describe strategies that could lead to achievement of this goal. Using the yellow fever vaccine as a benchmark of an efficient vaccine, recent studies identified factors of immune protection and more importantly innate immune pathways needed for the establishment of long-term protective adaptive immunity. To prevent or control HIV-1 infection, a vaccine must induce efficient and persistent antigen-specific T cells endowed with mucosal homing capacity. Such cells should have the capability to counteract HIV-1 diversity and its rapid spread from the initial site of infection. To achieve this goal, the activation of a diversified innate immune response is critical. New systems biology approaches will provide more precise correlates of immune protection that will pave the way for new approaches in T-cell-based vaccines.

Methyltransferase-defective avian metapneumovirus vaccines provide complete protection against challenge with the homologous Colorado strain and the heterologous Minnesota strain.

Science.gov (United States)

Sun, Jing; Wei, Yongwei; Rauf, Abdul; Zhang, Yu; Ma, Yuanmei; Zhang, Xiaodong; Shilo, Konstantin; Yu, Qingzhong; Saif, Y M; Lu, Xingmeng; Yu, Lian; Li, Jianrong

2014-11-01

Avian metapneumovirus (aMPV), also known as avian pneumovirus or turkey rhinotracheitis virus, is the causative agent of turkey rhinotracheitis and is associated with swollen head syndrome in chickens. Since its discovery in the 1970s, aMPV has been recognized as an economically important pathogen in the poultry industry worldwide. The conserved region VI (CR VI) of the large (L) polymerase proteins of paramyxoviruses catalyzes methyltransferase (MTase) activities that typically methylate viral mRNAs at guanine N-7 (G-N-7) and ribose 2'-O positions. In this study, we generated a panel of recombinant aMPV (raMPV) Colorado strains carrying mutations in the S-adenosyl methionine (SAM) binding site in the CR VI of L protein. These recombinant viruses were specifically defective in ribose 2'-O, but not G-N-7 methylation and were genetically stable and highly attenuated in cell culture and viral replication in the upper and lower respiratory tracts of specific-pathogen-free (SPF) young turkeys. Importantly, turkeys vaccinated with these MTase-defective raMPVs triggered a high level of neutralizing antibody and were completely protected from challenge with homologous aMPV Colorado strain and heterologous aMPV Minnesota strain. Collectively, our results indicate (i) that aMPV lacking 2'-O methylation is highly attenuated in vitro and in vivo and (ii) that inhibition of mRNA cap MTase can serve as a novel target to rationally design live attenuated vaccines for aMPV and perhaps other paramyxoviruses. Paramyxoviruses include many economically and agriculturally important viruses such as avian metapneumovirus (aMPV), and Newcastle disease virus (NDV), human pathogens such as human respiratory syncytial virus, human metapneumovirus, human parainfluenza virus type 3, and measles virus, and highly lethal emerging pathogens such as Nipah virus and Hendra virus. For many of them, there is no effective vaccine or antiviral drug. These viruses share common strategies for viral gene

Structural characterization by NMR of a double phosphorylated chimeric peptide vaccine for treatment of Alzheimer's disease.

Science.gov (United States)

Ramírez-Gualito, Karla; Richter, Monique; Matzapetakis, Manolis; Singer, David; Berger, Stefan

2013-04-26

Rational design of peptide vaccines becomes important for the treatment of some diseases such as Alzheimer's disease (AD) and related disorders. In this study, as part of a larger effort to explore correlations of structure and activity, we attempt to characterize the doubly phosphorylated chimeric peptide vaccine targeting a hyperphosphorylated epitope of the Tau protein. The 28-mer linear chimeric peptide consists of the double phosphorylated B cell epitope Tau₂₂₉₋₂₃₇[pThr231/pSer235] and the immunomodulatory T cell epitope Ag85B₂₄₁₋₂₅₅ originating from the well-known antigen Ag85B of the Mycobacterium tuberculosis, linked by a four amino acid sequence -GPSL-. NMR chemical shift analysis of our construct demonstrated that the synthesized peptide is essentially unfolded with a tendency to form a β-turn due to the linker. In conclusion, the -GPSL- unit presumably connects the two parts of the vaccine without transferring any structural information from one part to the other. Therefore, the double phosphorylated epitope of the Tau peptide is flexible and accessible.

Rational Design of Coordination Polymers with Flexible Oxyethylene Side Chains

International Nuclear Information System (INIS)

Choi, Eun Young; Gao, Chunji; Lee, Suck Hyun; Kwon, O Pil

2012-01-01

We rationally designed and synthesized metallopolymers with organic 1,4-benzenedicarboxylic acid (BDC) linkers with different lengths of oxyethylene side chains in order to examine the influence of side chains on the coordination characteristics. While in a previous report the BDC linkers with alkyl side chains were found to form three-dimensional (3D) isoreticular metal-organic framework (IRMOF) structures or one-dimensional (1D) coordination polymeric structures with short -O(CH 2 ) 6 CH 3 or long -O(CH 2 ) 9 CH 3 side chains, respectively, new BDC linkers with oxyethylene side chains of the same lengths, -(OCH 2 CH 2 ) 2 CH 3 and -(OCH 2 CH 2 ) 3 CH 3 , form only 3D IRMOF structures. This result is attributed to the higher flexibility and smaller volume of oxyethylene side chains compared to alkyl side chains

Impact of imitation processes on the effectiveness of ring vaccination.

Science.gov (United States)

Wells, Chad R; Tchuenche, Jean M; Meyers, Lauren Ancel; Galvani, Alison P; Bauch, Chris T

2011-11-01

Ring vaccination can be a highly effective control strategy for an emerging disease or in the final phase of disease eradication, as witnessed in the eradication of smallpox. However, the impact of behavioural dynamics on the effectiveness of ring vaccination has not been explored in mathematical models. Here, we analyze a series of stochastic models of voluntary ring vaccination. Contacts of an index case base vaccinating decisions on their own individual payoffs to vaccinate or not vaccinate, and they can also imitate the behaviour of other contacts of the index case. We find that including imitation changes the probability of containment through ring vaccination considerably. Imitation can cause a strong majority of contacts to choose vaccination in some cases, or to choose non-vaccination in other cases-even when the equivalent solution under perfectly rational (non-imitative) behaviour yields mixed choices. Moreover, imitation processes can result in very different outcomes in different stochastic realizations sampled from the same parameter distributions, by magnifying moderate tendencies toward one behaviour or the other: in some realizations, imitation causes a strong majority of contacts not to vaccinate, while in others, imitation promotes vaccination and reduces the number of secondary infections. Hence, the effectiveness of ring vaccination can depend significantly and unpredictably on imitation processes. Therefore, our results suggest that risk communication efforts should be initiated early in an outbreak when ring vaccination is to be applied, especially among subpopulations that are heavily influenced by peer opinions.

Epitope-based peptide vaccine design and target site depiction against Ebola viruses: an immunoinformatics study.

Science.gov (United States)

Khan, M A; Hossain, M U; Rakib-Uz-Zaman, S M; Morshed, M N

2015-07-01

Ebola viruses (EBOVs) have been identified as an emerging threat in recent year as it causes severe haemorrhagic fever in human. Epitope-based vaccine design for EBOVs remains a top priority because a mere progress has been made in this regard. Another reason is the lack of antiviral drug and licensed vaccine although there is a severe outbreak in Central Africa. In this study, we aimed to design an epitope-based vaccine that can trigger a significant immune response as well as to prognosticate inhibitor that can bind with potential drug target sites using various immunoinformatics and docking simulation tools. The capacity to induce both humoral and cell-mediated immunity by T cell and B cell was checked for the selected protein. The peptide region spanning 9 amino acids from 42 to 50 and the sequence TLASIGTAF were found as the most potential B and T cell epitopes, respectively. This peptide could interact with 12 HLAs and showed high population coverage up to 80.99%. Using molecular docking, the epitope was further appraised for binding against HLA molecules to verify the binding cleft interaction. In addition with this, the allergenicity of the epitopes was also evaluated. In the post-therapeutic strategy, docking study of predicted 3D structure identified suitable therapeutic inhibitor against targeted protein. However, this computational epitope-based peptide vaccine designing and target site prediction against EBOVs open up a new horizon which may be the prospective way in Ebola viruses research; the results require validation by in vitro and in vivo experiments. © 2015 John Wiley & Sons Ltd.

Improving specific activity and thermostability of Escherichia coli phytase by structure-based rational design.

Science.gov (United States)

Wu, Tzu-Hui; Chen, Chun-Chi; Cheng, Ya-Shan; Ko, Tzu-Ping; Lin, Cheng-Yen; Lai, Hui-Lin; Huang, Ting-Yung; Liu, Je-Ruei; Guo, Rey-Ting

2014-04-10

Escherichia coli phytase (EcAppA) which hydrolyzes phytate has been widely applied in the feed industry, but the need to improve the enzyme activity and thermostability remains. Here, we conduct rational design with two strategies to enhance the EcAppA performance. First, residues near the substrate binding pocket of EcAppA were modified according to the consensus sequence of two highly active Citrobacter phytases. One out of the eleven mutants, V89T, exhibited 17.5% increase in catalytic activity, which might be a result of stabilized protein folding. Second, the EcAppA glycosylation pattern was modified in accordance with the Citrobacter phytases. An N-glycosylation motif near the substrate binding site was disrupted to remove spatial hindrance for phytate entry and product departure. The de-glycosylated mutants showed 9.6% increase in specific activity. On the other hand, the EcAppA mutants that adopt N-glycosylation motifs from CbAppA showed improved thermostability that three mutants carrying single N-glycosylation motif exhibited 5.6-9.5% residual activity after treatment at 80°C (1.8% for wild type). Furthermore, the mutant carrying all three glycosylation motifs exhibited 27% residual activity. In conclusion, a successful rational design was performed to obtain several useful EcAppA mutants with better properties for further applications. Copyright © 2014 Elsevier B.V. All rights reserved.

Simultaneous inhibition of aberrant cancer kinome using rationally designed polymer-protein core-shell nanomedicine.

Science.gov (United States)

Chandran, Parwathy; Gupta, Neha; Retnakumari, Archana Payickattu; Malarvizhi, Giridharan Loghanathan; Keechilat, Pavithran; Nair, Shantikumar; Koyakutty, Manzoor

2013-11-01

Simultaneous inhibition of deregulated cancer kinome using rationally designed nanomedicine is an advanced therapeutic approach. Herein, we have developed a polymer-protein core-shell nanomedicine to inhibit critically aberrant pro-survival kinases (mTOR, MAPK and STAT5) in primitive (CD34(+)/CD38(-)) Acute Myeloid Leukemia (AML) cells. The nanomedicine consists of poly-lactide-co-glycolide core (~250 nm) loaded with mTOR inhibitor, everolimus, and albumin shell (~25 nm thick) loaded with MAPK/STAT5 inhibitor, sorafenib and the whole construct was surface conjugated with monoclonal antibody against CD33 receptor overexpressed in AML. Electron microscopy confirmed formation of core-shell nanostructure (~290 nm) and flow cytometry and confocal studies showed enhanced cellular uptake of targeted nanomedicine. Simultaneous inhibition of critical kinases causing synergistic lethality against leukemic cells, without affecting healthy blood cells, was demonstrated using immunoblotting, cytotoxicity and apoptosis assays. This cell receptor plus multi-kinase targeted core-shell nanomedicine was found better specific and tolerable compared to current clinical regime of cytarabine and daunorubicin. These authors demonstrate simultaneous inhibition of critical kinases causing synergistic lethality against leukemic cells, without affecting healthy blood cells by using rationally designed polymer-protein core-shell nanomedicine, provoding an advanced method to eliminate cancer cells, with the hope of future therapeutic use. Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical engineering in the electronics industry: progress towards the rational design of organic semiconductor heterojunctions

KAUST Repository

Clancy, Paulette

2012-05-01

We review the current status of heterojunction design for combinations of organic semiconductor materials, given its central role in affecting the device performance for electronic devices and solar cell applications. We provide an emphasis on recent progress towards the rational design of heterojunctions that may lead to higher performance of charge separation and mobility. We also play particular attention to the role played by computational approaches and its potential to help define the best choice of materials for solar cell development in the future. We report the current status of the field with respect to such goals. © 2012 Elsevier Ltd.

Chemical engineering in the electronics industry: progress towards the rational design of organic semiconductor heterojunctions

KAUST Repository

Clancy, Paulette

2012-01-01

We review the current status of heterojunction design for combinations of organic semiconductor materials, given its central role in affecting the device performance for electronic devices and solar cell applications. We provide an emphasis on recent progress towards the rational design of heterojunctions that may lead to higher performance of charge separation and mobility. We also play particular attention to the role played by computational approaches and its potential to help define the best choice of materials for solar cell development in the future. We report the current status of the field with respect to such goals. © 2012 Elsevier Ltd.

Design and implementation of a children vaccination reminder system based on short message service

Directory of Open Access Journals (Sweden)

Marjan Ghazisaeedi

2016-09-01

Full Text Available Background: Most problems related to quality of care and patient safety are related to human negligence. One of the causes of these problems is forgetting to do something. This problem can be avoided with information technology in many cases. Some forgotten are very important. Among these is failure to comply with vaccination schedule by parents that can result in inappropriate outcomes. In this study, we developed and evaluated a SMS reminder system for regular and timely vaccination of children. Methods: In this developmental-applied research, firstly, a child vaccination reminder system was designed and implemented to help parents reduce the forgetfulness. This system based on the child's vaccination history and the date of birth, offer time and type of future vaccines. Then the parents of 27 children, that their vaccination was between 22 June and 21 August 2015, referred to Children's Medical Center, were sent text messages by using this system. We evaluated the accuracy of the system logic by using some scenarios. In addition, we evaluated parents' satisfaction with the system using a questionnaire. Results: In all cases but one, the system proposed the type and date of future children vaccines correctly. All the parents who have received text messages had good perception and satisfaction on the majority of questions (total mean score of 4.15 out of 5. Most parents (4.92 out of 5 stated that using the system to remind their visit for child immunization was helpful and willing to offer the system to their friends and other families. Conclusion: Using the short message system is beneficial for parents to remind their children’s vaccination time and increases their satisfaction. So, it can be considered as an important and essential tool in providing healthcare services. SMS is an easy, cheap and effective way to improve the quality of care services.

Theory and simulation of DNA-coated colloids: a guide for rational design.

Science.gov (United States)

Angioletti-Uberti, Stefano; Mognetti, Bortolo M; Frenkel, Daan

2016-03-07

By exploiting the exquisite selectivity of DNA hybridization, DNA-coated colloids (DNACCs) can be made to self-assemble in a wide variety of structures. The beauty of this system stems largely from its exceptional versatility and from the fact that a proper choice of the grafted DNA sequences yields fine control over the colloidal interactions. Theory and simulations have an important role to play in the optimal design of self assembling DNACCs. At present, the powerful model-based design tools are not widely used, because the theoretical literature is fragmented and the connection between different theories is often not evident. In this Perspective, we aim to discuss the similarities and differences between the different models that have been described in the literature, their underlying assumptions, their strengths and their weaknesses. Using the tools described in the present Review, it should be possible to move towards a more rational design of novel self-assembling structures of DNACCs and, more generally, of systems where ligand-receptor are used to control interactions.

Rational In Silico Design of an Organic Semiconductor with Improved Electron Mobility.

Science.gov (United States)

Friederich, Pascal; Gómez, Verónica; Sprau, Christian; Meded, Velimir; Strunk, Timo; Jenne, Michael; Magri, Andrea; Symalla, Franz; Colsmann, Alexander; Ruben, Mario; Wenzel, Wolfgang

2017-11-01

Organic semiconductors find a wide range of applications, such as in organic light emitting diodes, organic solar cells, and organic field effect transistors. One of their most striking disadvantages in comparison to crystalline inorganic semiconductors is their low charge-carrier mobility, which manifests itself in major device constraints such as limited photoactive layer thicknesses. Trial-and-error attempts to increase charge-carrier mobility are impeded by the complex interplay of the molecular and electronic structure of the material with its morphology. Here, the viability of a multiscale simulation approach to rationally design materials with improved electron mobility is demonstrated. Starting from one of the most widely used electron conducting materials (Alq 3 ), novel organic semiconductors with tailored electronic properties are designed for which an improvement of the electron mobility by three orders of magnitude is predicted and experimentally confirmed. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Design of a Discrete Tracking Controller for a Magnetic Levitation System: A Nonlinear Rational Model Approach

Directory of Open Access Journals (Sweden)

Fernando Gómez-Salas

2015-01-01

Full Text Available This work proposes a discrete-time nonlinear rational approximate model for the unstable magnetic levitation system. Based on this model and as an application of the input-output linearization technique, a discrete-time tracking control design will be derived using the corresponding classical state space representation of the model. A simulation example illustrates the efficiency of the proposed methodology.

Rational design of a bi-layered reduced graphene oxide film on polystyrene foam for solar-driven interfacial water evaporation

KAUST Repository

Shi, Le; Wang, Yuchao; Zhang, Lianbin; Wang, Peng

2016-01-01

Solar-driven water evaporation has been emerging as a highly efficient way for utilizing solar energy for clean water production and wastewater treatment. Here we rationally designed and fabricated a bi-layered photothermal membrane with a porous

Structural Characterization by NMR of a Double Phosphorylated Chimeric Peptide Vaccine for Treatment of Alzheimer’s Disease

Directory of Open Access Journals (Sweden)

Stefan Berger

2013-04-01

Full Text Available Rational design of peptide vaccines becomes important for the treatment of some diseases such as Alzheimer’s disease (AD and related disorders. In this study, as part of a larger effort to explore correlations of structure and activity, we attempt to characterize the doubly phosphorylated chimeric peptide vaccine targeting a hyperphosphorylated epitope of the Tau protein. The 28-mer linear chimeric peptide consists of the double phosphorylated B cell epitope Tau229-237[pThr231/pSer235] and the immunomodulatory T cell epitope Ag85B241-255 originating from the well-known antigen Ag85B of the Mycobacterium tuberculosis, linked by a four amino acid sequence -GPSL-. NMR chemical shift analysis of our construct demonstrated that the synthesized peptide is essentially unfolded with a tendency to form a β-turn due to the linker. In conclusion, the -GPSL- unit presumably connects the two parts of the vaccine without transferring any structural information from one part to the other. Therefore, the double phosphorylated epitope of the Tau peptide is flexible and accessible.

Recent advances in the molecular design of synthetic vaccines

Science.gov (United States)

Jones, Lyn H.

2015-12-01

Vaccines have typically been prepared using whole organisms. These are normally either attenuated bacteria or viruses that are live but have been altered to reduce their virulence, or pathogens that have been inactivated and effectively killed through exposure to heat or formaldehyde. However, using whole organisms to elicit an immune response introduces the potential for infections arising from a reversion to a virulent form in live pathogens, unproductive reactions to vaccine components or batch-to-batch variability. Synthetic vaccines, in which a molecular antigen is conjugated to a carrier protein, offer the opportunity to circumvent these problems. This Perspective will highlight the progress that has been achieved in developing synthetic vaccines using a variety of molecular antigens. In particular, the different approaches used to develop conjugate vaccines using peptide/proteins, carbohydrates and other small molecule haptens as antigens are compared.

Rational Design, Synthesis and Pharmacological Evaluation of the (2R)- and (2S)-Stereoisomers of 3-(2-Carboxypyrrolidinyl)-2-methyl Acetic Acid as Ligands for the Ionotropic Glutamate Receptors

DEFF Research Database (Denmark)

Rasmussen, Julie; Storgaard, Morten; Pickering, Darryl S

2011-01-01

In this paper we describe the rational design, synthesis and pharmacological evaluation of two new stereoisomeric (S)-glutamate (Glu) analogues. The rational design was based on hybrid structures of the natural product kainic acid, a synthetic analogue CPAA and the high-affinity Glu analogue SYM...

Rational design of stealthy hyperuniform two-phase media with tunable order

Science.gov (United States)

DiStasio, Robert A.; Zhang, Ge; Stillinger, Frank H.; Torquato, Salvatore

2018-02-01

Disordered stealthy hyperuniform materials are exotic amorphous states of matter that have attracted recent attention because of their novel structural characteristics (hidden order at large length scales) and physical properties, including desirable photonic and transport properties. It is therefore useful to devise algorithms that enable one to design a wide class of such amorphous configurations at will. In this paper, we present several algorithms enabling the systematic identification and generation of discrete (digitized) stealthy hyperuniform patterns with a tunable degree of order, paving the way towards the rational design of disordered materials endowed with novel thermodynamic and physical properties. To quantify the degree of order or disorder of the stealthy systems, we utilize the discrete version of the τ order metric, which accounts for the underlying spatial correlations that exist across all relevant length scales in a given digitized two-phase (or, equivalently, a two-spin state) system of interest. Our results impinge on a myriad of fields, ranging from physics, materials science and engineering, visual perception, and information theory to modern data science.

Oral vaccination of fish

OpenAIRE

Embregts, Carmen W.E.; Forlenza, Maria

2016-01-01

The limited number of oral vaccines currently approved for use in humans and veterinary species clearly illustrates that development of efficacious and safe oral vaccines has been a challenge not only for fish immunologists. The insufficient efficacy of oral vaccines is partly due to antigen breakdown in the harsh gastric environment, but also to the high tolerogenic gut environment and to inadequate vaccine design. In this review we discuss current approaches used to develop oral vaccines fo...

Live attenuated vaccines: Historical successes and current challenges

Energy Technology Data Exchange (ETDEWEB)

Minor, Philip D., E-mail: Philip.Minor@nibsc.org

2015-05-15

Live attenuated vaccines against human viral diseases have been amongst the most successful cost effective interventions in medical history. Smallpox was declared eradicated in 1980; poliomyelitis is nearing global eradication and measles has been controlled in most parts of the world. Vaccines function well for acute diseases such as these but chronic infections such as HIV are more challenging for reasons of both likely safety and probable efficacy. The derivation of the vaccines used has in general not been purely rational except in the sense that it has involved careful clinical trials of candidates and subsequent careful follow up in clinical use; the identification of the candidates is reviewed. - Highlights: • Live vaccines against human diseases caused by viruses have been very successful. • They have been developed by empirical clinical studies and problems identified in later use. • It can be difficult to balance ability to cause disease and ability to immunise for a strain. • There is currently no reliable basis for predicting success from pure virological studies. • Vaccinia, which eradicated smallpox, is the paradigm for all successes and issues.

Live attenuated vaccines: Historical successes and current challenges

International Nuclear Information System (INIS)

Minor, Philip D.

2015-01-01

Live attenuated vaccines against human viral diseases have been amongst the most successful cost effective interventions in medical history. Smallpox was declared eradicated in 1980; poliomyelitis is nearing global eradication and measles has been controlled in most parts of the world. Vaccines function well for acute diseases such as these but chronic infections such as HIV are more challenging for reasons of both likely safety and probable efficacy. The derivation of the vaccines used has in general not been purely rational except in the sense that it has involved careful clinical trials of candidates and subsequent careful follow up in clinical use; the identification of the candidates is reviewed. - Highlights: • Live vaccines against human diseases caused by viruses have been very successful. • They have been developed by empirical clinical studies and problems identified in later use. • It can be difficult to balance ability to cause disease and ability to immunise for a strain. • There is currently no reliable basis for predicting success from pure virological studies. • Vaccinia, which eradicated smallpox, is the paradigm for all successes and issues

Crystals of Human Serum Albumin for Use in Genetic Engineering and Rational Drug Design

Science.gov (United States)

Carter, Daniel C. (Inventor)

1994-01-01

This invention pertains to crystals of serum albumin and processes for growing them. The purpose of the invention is to provide crystals of serum albumin which can be studied to determine binding sites for drugs. Form 2 crystals grow in the monoclinic space P2(sub 1), and possesses the following unit cell constraints: a = 58.9 +/- 7, b = 88.3 +/- 7, c = 60.7 +/- 7, Beta = 101.0 +/- 2 degrees. One advantage of the invention is that it will allow rational drug design

Cellular based cancer vaccines

DEFF Research Database (Denmark)

Hansen, M; Met, Ö; Svane, I M

2012-01-01

Cancer vaccines designed to re-calibrate the existing host-tumour interaction, tipping the balance from tumor acceptance towards tumor control holds huge potential to complement traditional cancer therapies. In general, limited success has been achieved with vaccines composed of tumor...... to transiently affect in vitro migration via autocrine receptor-mediated endocytosis of CCR7. In the current review, we discuss optimal design of DC maturation focused on pre-clinical as well as clinical results from standard and polarized dendritic cell based cancer vaccines....

Managing uncertainty: healthcare professionals' meanings regarding the HPV vaccine.

Science.gov (United States)

Todorova, Irina; Alexandrova-Karamanova, Anna; Panayotova, Yulia; Dimitrova, Elitsa; Kotzeva, Tatyana

2014-02-01

New preventive technologies such as vaccines offer insight into psychological, social, and cultural landscapes. Providers have a key role in parents' decisions for vaccinating their children. Yet, perspectives from providers regarding the human papillomavirus (HPV) vaccine, or vaccination in general, are rarely sought Our objective in this paper is to understand how the HPV vaccine is perceived by health care providers and the multiple contextual meanings it elicits. We conducted interviews with 20 health care professionals in Bulgaria about their attitudes and practices related to HPV vaccination and their recommendations for policies. The verbatim-transcribed interviews were analyzed through narrative analysis, with a special focus on language. We illustrate providers' contradictory and contextualized constructions of the vaccine and the narrative strategies they use to manage any uncertainty it elicits. These include being advocates and missionaries for preventive health, confirming their trust in the medical profession and professional organizations, challenging patients' concerns with rational explanations, normalizing the risk of medical innovations, and avoiding the sexual nature of HPV transmission. The introduction of a vaccine to prevent HPV infection, and by implication, possibly cervical and other cancers, created hope, and at the same time, intensified confusion and uncertainty. Providers have been frustrated for years with the rising mortality from cervical cancer in Bulgaria, and their perceived powerlessness in affecting this. HPV vaccination, on the other hand, seems relatively simple and "taming uncertainty" positions them as instrumental in limiting (or even eliminating) morbidity and mortality in future generations.

Microneedle array design determines the induction of protective memory CD8+ T cell responses induced by a recombinant live malaria vaccine in mice.

Directory of Open Access Journals (Sweden)

John B Carey

Full Text Available Vaccine delivery into the skin has received renewed interest due to ease of access to the immune system and microvasculature, however the stratum corneum (SC, must be breached for successful vaccination. This has been achieved by removing the SC by abrasion or scarification or by delivering the vaccine intradermally (ID with traditional needle-and-syringes or with long microneedle devices. Microneedle patch-based transdermal vaccine studies have predominantly focused on antibody induction by inactivated or subunit vaccines. Here, our principal aim is to determine if the design of a microneedle patch affects the CD8(+ T cell responses to a malaria antigen induced by a live vaccine.Recombinant modified vaccinia virus Ankara (MVA expressing a malaria antigen was percutaneously administered to mice using a range of silicon microneedle patches, termed ImmuPatch, that differed in microneedle height, density, patch area and total pore volume. We demonstrate that microneedle arrays that have small total pore volumes induce a significantly greater proportion of central memory T cells that vigorously expand to secondary immunization. Microneedle-mediated vaccine priming induced significantly greater T cell immunity post-boost and equivalent protection against malaria challenge compared to ID vaccination. Notably, unlike ID administration, ImmuPatch-mediated vaccination did not induce inflammatory responses at the site of immunization or in draining lymph nodes.This study demonstrates that the design of microneedle patches significantly influences the magnitude and memory of vaccine-induced CD8(+ T cell responses and can be optimised for the induction of desired immune responses. Furthermore, ImmuPatch-mediated delivery may be of benefit to reducing unwanted vaccine reactogenicity. In addition to the advantages of low cost and lack of pain, the development of optimised microneedle array designs for the induction of T cell responses by live vaccines aids

"The Impact of Mycobacterium tuberculosis Immune Evasion on Protective Immunity: Implications for TB Vaccine Design" - Meeting report.

Science.gov (United States)

Boggiano, Cesar; Eichelberg, Katrin; Ramachandra, Lakshmi; Shea, Jaqueline; Ramakrishnan, Lalita; Behar, Samuel; Ernst, Joel D; Porcelli, Steven A; Maeurer, Markus; Kornfeld, Hardy

2017-06-14

Tuberculosis (TB) is the major cause of death from infectious diseases around the world, particularly in HIV infected individuals. TB vaccine design and development have been focused on improving Bacille Calmette-Guérin (BCG) and evaluating recombinant and viral vector expressed Mycobacterium tuberculosis (Mtb) proteins, for boosting BCG-primed immunity, but these approaches have not yet yielded significant improvements over the modest effects of BCG in protecting against infection or disease. On March 7-8, 2016, the National Institute of Allergy and Infectious Diseases (NIAID) convened a workshop on "The Impact of Mtb Immune Evasion on Protective Immunity: Implications for TB Vaccine Design" with the goal of defining immune mechanisms that could be targeted through novel research approaches, to inform vaccine design and immune therapeutic interventions for prevention of TB. The workshop addressed early infection events, the impact of Mtb evolution on the development and maintenance of an adaptive immune response, and the factors that influence protection against and progression to active disease. Scientific gaps and areas of study to revitalize and accelerate TB vaccine design were discussed and prioritized. These included a comprehensive evaluation of innate and Mtb-specific adaptive immune responses in the lung at different stages of disease; determining the role of B cells and antibodies (Abs) during Mtb infection; development of better assays to measure Mtb burden following exposure, infection, during latency and after treatment, and approaches to improving current animal models to study Mtb immunogenicity, TB disease and transmission. Copyright © 2017.

Future of anti-addiction vaccines.

Science.gov (United States)

Kosten, Thomas R

2005-01-01

The medical rational for using anti-drug antibodies in the serum as a treatment is to reduce drug levels in the brain and to bind drug before it enters the brain. Drugs of abuse are small molecules that can readily cross the blood brain barrier, while antibodies are larger molecules that cannot get into the brain. Thus, any drug that is bound to antibody also cannot cross the blood brain barrier and cannot enter the brain. Active anti-drug vaccines stimulate the body to makes its own antibodies, but the small size of abused drugs prevents them from stimulating an immune response. Thus, individuals do not ordinarily produce antibodies to abused drugs, and vaccines to stimulate antibodies are made by chemically linking these abused drugs to toxins such as cholera toxin. Alternatively, passive immunotherapy uses monoclonal antibodies that are generated in a laboratory and then administered via intravenous injection. Antibodies can be used to treat drug overdose; to reduce drug use relapse; or to protect certain at risk populations who have not yet become drug dependent. The advantages of anti-addiction vaccines are that antibodies target the drug, not the drug's sites of action in the brain and antibody binding inactivates the drug. These vaccines can complement behavioral and other medical therapies with minimal side effects and are not addictive like some chemical agonists. Technology advances in manufacturing and delivery systems will improve future anti-addiction vaccines, but social acceptance of anti-addiction vaccines will depend on substance abuse program staff and the families of substance abusers, who have some values that oppose medical solutions to addictive diseases and view addictions as moral problems.

Rationalization: A Bibliography.

Science.gov (United States)

Pedrini, D. T.; Pedrini, Bonnie C.

Rationalization was studied by Sigmund Freud and was specifically labeled by Ernest Jones. Rationalization ought to be differentiated from rational, rationality, logical analysis, etc. On the one hand, rationalization is considered a defense mechanism, on the other hand, rationality is not. Haan has done much work with self-report inventories and…

Peptide Vaccines for Leishmaniasis

Directory of Open Access Journals (Sweden)

Rory C. F. De Brito

2018-05-01

Full Text Available Due to an increase in the incidence of leishmaniases worldwide, the development of new strategies such as prophylactic vaccines to prevent infection and decrease the disease have become a high priority. Classic vaccines against leishmaniases were based on live or attenuated parasites or their subunits. Nevertheless, the use of whole parasite or their subunits for vaccine production has numerous disadvantages. Therefore, the use of Leishmania peptides to design more specific vaccines against leishmaniases seems promising. Moreover, peptides have several benefits in comparison with other kinds of antigens, for instance, good stability, absence of potentially damaging materials, antigen low complexity, and low-cost to scale up. By contrast, peptides are poor immunogenic alone, and they need to be delivered correctly. In this context, several approaches described in this review are useful to solve these drawbacks. Approaches, such as, peptides in combination with potent adjuvants, cellular vaccinations, adenovirus, polyepitopes, or DNA vaccines have been used to develop peptide-based vaccines. Recent advancements in peptide vaccine design, chimeric, or polypeptide vaccines and nanovaccines based on particles attached or formulated with antigenic components or peptides have been increasingly employed to drive a specific immune response. In this review, we briefly summarize the old, current, and future stands on peptide-based vaccines, describing the disadvantages and benefits associated with them. We also propose possible approaches to overcome the related weaknesses of synthetic vaccines and suggest future guidelines for their development.

Peptide Vaccines for Leishmaniasis.

Science.gov (United States)

De Brito, Rory C F; Cardoso, Jamille M De O; Reis, Levi E S; Vieira, Joao F; Mathias, Fernando A S; Roatt, Bruno M; Aguiar-Soares, Rodrigo Dian D O; Ruiz, Jeronimo C; Resende, Daniela de M; Reis, Alexandre B

2018-01-01

Due to an increase in the incidence of leishmaniases worldwide, the development of new strategies such as prophylactic vaccines to prevent infection and decrease the disease have become a high priority. Classic vaccines against leishmaniases were based on live or attenuated parasites or their subunits. Nevertheless, the use of whole parasite or their subunits for vaccine production has numerous disadvantages. Therefore, the use of Leishmania peptides to design more specific vaccines against leishmaniases seems promising. Moreover, peptides have several benefits in comparison with other kinds of antigens, for instance, good stability, absence of potentially damaging materials, antigen low complexity, and low-cost to scale up. By contrast, peptides are poor immunogenic alone, and they need to be delivered correctly. In this context, several approaches described in this review are useful to solve these drawbacks. Approaches, such as, peptides in combination with potent adjuvants, cellular vaccinations, adenovirus, polyepitopes, or DNA vaccines have been used to develop peptide-based vaccines. Recent advancements in peptide vaccine design, chimeric, or polypeptide vaccines and nanovaccines based on particles attached or formulated with antigenic components or peptides have been increasingly employed to drive a specific immune response. In this review, we briefly summarize the old, current, and future stands on peptide-based vaccines, describing the disadvantages and benefits associated with them. We also propose possible approaches to overcome the related weaknesses of synthetic vaccines and suggest future guidelines for their development.

Vaccination Perceptions of College Students: With and without Vaccination Waiver.

Science.gov (United States)

Jadhav, Emmanuel D; Winkler, Danielle L; Anderson, Billie S

2018-01-01

The resurgence of vaccine preventable diseases occurs more often among intentionally unvaccinated individuals, placing at direct risk young adults not caught up on vaccinations. The objectives of this study were to characterize the sociodemographic characteristics of young adults with and without vaccination waivers and identify their perceived benefits, barriers, and influencers of vaccination. Young adults ( n  = 964) from a Midwestern rural university responded to a survey (fall 2015-spring 2016) designed to identify their perception toward vaccination. Instrument consistency was measured using the Cronbach α-scores. The Chi-square test was used to test any sociodemographic differences and Mann-Whitney U -tests results for differences between exempt and non-exempt students. Analysis occurred in spring 2017. A little over one-third of young adults with a vaccination waiver were not up to date on their vaccinations, and think that vaccinations can cause autism. The biggest identifiable benefit was effective control against disease. The surveyed young adults ranked the out of pocket cost associated with vaccination as the most important barrier and safe and easy to use vaccines as the most important influencer of vaccination. Young adults who have had a vaccination waiver appear to not be up to date on their vaccinations. Vaccine administration programs, such as university campus clinics, would benefit from addressing perceptions unique to young adults with and without a vaccine waiver. This would subsequently better provide young adults a second shot for getting appropriately caught up on vaccinations.

Public policy, rationality and reason

Directory of Open Access Journals (Sweden)

Rodolfo Canto Sáenz

2015-07-01

Full Text Available This work suggests the incorporation of practical reason in the design, implementation and evaluation of public policies, alongside instrumental rationality. It takes two proposals that today point in this direction: Rawls distinction between reasonable (practical reason and rational (instrumental reason and what this author calls the CI Procedure (categorical imperative procedure and Habermas model of deliberative democracy. The main conclusion is that the analysis of public policies can not be limited to rather narrow limits of science, but requires the contribution of political and moral philosophy.

Rational Design and Synthesis of Efficient Sunscreens To Boost the Solar Protection Factor.

Science.gov (United States)

Losantos, Raúl; Funes-Ardoiz, Ignacio; Aguilera, José; Herrera-Ceballos, Enrique; García-Iriepa, Cristina; Campos, Pedro J; Sampedro, Diego

2017-03-01

Skin cancer incidence has been increasing in the last decades, but most of the commercial formulations used as sunscreens are designed to protect only against solar erythema. Many of the active components present in sunscreens show critical weaknesses, such as low stability and toxicity. Thus, the development of more efficient components is an urgent health necessity and an attractive industrial target. We have rationally designed core moieties with increased photoprotective capacities and a new energy dissipation mechanism. Using these scaffolds, we have synthesized a series of compounds with tunable properties suitable for their use in sunscreens, and enhanced properties in terms of stability, light energy dissipation, and toxicity. Moreover, some representative compounds were included in final sunscreen formulations and a relevant solar protection factor boost was measured. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Rational Decision Making as Performative Praxis: Explaining Rationality's Éternel Retour

OpenAIRE

Cabantous, L.; Gond, J-P.

2011-01-01

Organizational theorists built their knowledge of decision making through a progressive critique of rational choice theory. Their positioning towards rationality, however, is at odds with the observation of rationality persistence in organizational life. This paper addresses this paradox. It proposes a new perspective on rationality that allows the theorizing of the production of rational decisions by organizations. To account for rationality's éternel retour, we approach rational decision ma...

Approaches and Perspectives for Development of African Swine Fever Virus Vaccines

Directory of Open Access Journals (Sweden)

Marisa Arias

2017-10-01

Full Text Available African swine fever (ASF is a complex disease of swine, caused by a large DNA virus belonging to the family Asfarviridae. The disease shows variable clinical signs, with high case fatality rates, up to 100%, in the acute forms. ASF is currently present in Africa and Europe where it circulates in different scenarios causing a high socio-economic impact. In most affected regions, control has not been effective in part due to lack of a vaccine. The availability of an effective and safe ASFV vaccines would support and enforce control–eradication strategies. Therefore, work leading to the rational development of protective ASF vaccines is a high priority. Several factors have hindered vaccine development, including the complexity of the ASF virus particle and the large number of proteins encoded by its genome. Many of these virus proteins inhibit the host’s immune system thus facilitating virus replication and persistence. We review previous work aimed at understanding ASFV–host interactions, including mechanisms of protective immunity, and approaches for vaccine development. These include live attenuated vaccines, and “subunit” vaccines, based on DNA, proteins, or virus vectors. In the shorter to medium term, live attenuated vaccines are the most promising and best positioned candidates. Gaps and future research directions are evaluated.

Rational Design of a Green-Light-Mediated Unimolecular Platform for Fast Switchable Acidic Sensing.

Science.gov (United States)

Zhou, Yunyun; Zou, Qi; Qiu, Jing; Wang, Linjun; Zhu, Liangliang

2018-02-01

A controllable sensing ability strongly connects to complex and precise events in diagnosis and treatment. However, imposing visible light into the molecular-scale mediation of sensing processes is restricted by the lack of structural relevance. To address this critical challenge, we present the rational design, synthesis, and in vitro studies of a novel cyanostyryl-modified azulene system for green-light-mediated fast switchable acidic sensing. The advantageous features of the design include a highly efficient green-light-driven Z/E-isomerization (a quantum yield up to 61.3%) for fast erasing chromatic and luminescent expressions and a superior compatibility with control of ratiometric protonation. Significantly, these merits of the design enable the development of a microfluidic system to perform a green-light-mediated reusable sensing function toward a gastric acid analyte in a miniaturized platform. The results may provide new insights for building future integrated green materials.

Vaccination Perceptions of College Students: With and without Vaccination Waiver

Directory of Open Access Journals (Sweden)

Emmanuel D. Jadhav

2018-02-01

Full Text Available IntroductionThe resurgence of vaccine preventable diseases occurs more often among intentionally unvaccinated individuals, placing at direct risk young adults not caught up on vaccinations. The objectives of this study were to characterize the sociodemographic characteristics of young adults with and without vaccination waivers and identify their perceived benefits, barriers, and influencers of vaccination.MethodsYoung adults (n = 964 from a Midwestern rural university responded to a survey (fall 2015—spring 2016 designed to identify their perception toward vaccination. Instrument consistency was measured using the Cronbach α-scores. The Chi-square test was used to test any sociodemographic differences and Mann–Whitney U-tests results for differences between exempt and non-exempt students. Analysis occurred in spring 2017.ResultsA little over one-third of young adults with a vaccination waiver were not up to date on their vaccinations, and think that vaccinations can cause autism. The biggest identifiable benefit was effective control against disease. The surveyed young adults ranked the out of pocket cost associated with vaccination as the most important barrier and safe and easy to use vaccines as the most important influencer of vaccination.ConclusionYoung adults who have had a vaccination waiver appear to not be up to date on their vaccinations. Vaccine administration programs, such as university campus clinics, would benefit from addressing perceptions unique to young adults with and without a vaccine waiver. This would subsequently better provide young adults a second shot for getting appropriately caught up on vaccinations.

Plant viral nanoparticles-based HER2 vaccine: Immune response influenced by differential transport, localization and cellular interactions of particulate carriers.

Science.gov (United States)

Shukla, Sourabh; Myers, Jay T; Woods, Sarah E; Gong, Xingjian; Czapar, Anna E; Commandeur, Ulrich; Huang, Alex Y; Levine, Alan D; Steinmetz, Nicole F

2017-03-01

Cancer vaccines are designed to elicit an endogenous adaptive immune response that can successfully recognize and eliminate residual or recurring tumors. Such approaches can potentially overcome shortcomings of passive immunotherapies by generating long-lived therapeutic effects and immune memory while limiting systemic toxicities. A critical determinant of vaccine efficacy is efficient transport and delivery of tumor-associated antigens to professional antigen presenting cells (APCs). Plant viral nanoparticles (VNPs) with natural tropism for APCs and a high payload carrying capacity may be particularly effective vaccine carriers. The applicability of VNP platform technologies is governed by stringent structure-function relationships. We compare two distinct VNP platforms: icosahedral cowpea mosaic virus (CPMV) and filamentous potato virus X (PVX). Specifically, we evaluate in vivo capabilities of engineered VNPs delivering human epidermal growth factor receptor 2 (HER2) epitopes for therapy and prophylaxis of HER2 + malignancies. Our results corroborate the structure-function relationship where icosahedral CPMV particles showed significantly enhanced lymph node transport and retention, and greater uptake by/activation of APCs compared to filamentous PVX particles. These enhanced immune cell interactions and transport properties resulted in elevated HER2-specific antibody titers raised by CPMV- vs. PVX-based peptide vaccine. The 'synthetic virology' field is rapidly expanding with numerous platforms undergoing development and preclinical testing; our studies highlight the need for systematic studies to define rules guiding the design and rational choice of platform, in the context of peptide-vaccine display technologies. Copyright © 2016 Elsevier Ltd. All rights reserved.

Molecular and macro-scale analysis of enzyme-crosslinked silk hydrogels for rational biomaterial design.

Science.gov (United States)

McGill, Meghan; Coburn, Jeannine M; Partlow, Benjamin P; Mu, Xuan; Kaplan, David L

2017-11-01

Silk fibroin-based hydrogels have exciting applications in tissue engineering and therapeutic molecule delivery; however, their utility is dependent on their diffusive properties. The present study describes a molecular and macro-scale investigation of enzymatically-crosslinked silk fibroin hydrogels, and demonstrates that these systems have tunable crosslink density and diffusivity. We developed a liquid chromatography tandem mass spectroscopy (LC-MS/MS) method to assess the quantity and order of covalent tyrosine crosslinks in the hydrogels. This analysis revealed between 28 and 56% conversion of tyrosine to dityrosine, which was dependent on the silk concentration and reactant concentration. The crosslink density was then correlated with storage modulus, revealing that both crosslinking and protein concentration influenced the mechanical properties of the hydrogels. The diffusive properties of the bulk material were studied by fluorescence recovery after photobleaching (FRAP), which revealed a non-linear relationship between silk concentration and diffusivity. As a result of this work, a model for synthesizing hydrogels with known crosslink densities and diffusive properties has been established, enabling the rational design of silk hydrogels for biomedical applications. Hydrogels from naturally-derived silk polymers offer versitile opportunities in the biomedical field, however, their design has largely been an empirical process. We present a fundamental study of the crosslink density, storage modulus, and diffusion behavior of enzymatically-crosslinked silk hydrogels to better inform scaffold design. These studies revealed unexpected non-linear trends in the crosslink density and diffusivity of silk hydrogels with respect to protein concentration and crosslink reagent concentration. This work demonstrates the tunable diffusivity and crosslinking in silk fibroin hydrogels, and enables the rational design of biomaterials. Further, the characterization methods

Basic principles of test-negative design in evaluating influenza vaccine effectiveness.

Science.gov (United States)

Fukushima, Wakaba; Hirota, Yoshio

2017-08-24

Based on the unique characteristics of influenza, the concept of "monitoring" influenza vaccine effectiveness (VE) across the seasons using the same observational study design has been developed. In recent years, there has been a growing number of influenza VE reports using the test-negative design, which can minimize both misclassification of diseases and confounding by health care-seeking behavior. Although the test-negative designs offer considerable advantages, there are some concerns that widespread use of the test-negative design without knowledge of the basic principles of epidemiology could produce invalid findings. In this article, we briefly review the basic concepts of the test-negative design with respect to classic study design such as cohort studies or case-control studies. We also mention selection bias, which may be of concern in some countries where rapid diagnostic testing is frequently used in routine clinical practices, as in Japan. Copyright © 2017. Published by Elsevier Ltd.

[Development of current smallpox vaccines].

Science.gov (United States)

Maksiutov, R A; Gavrilova, E V; Shchelkunov, S N

2011-01-01

The review gives data on the history of smallpox vaccination and shows the high topicality of designing the current safe vaccines against orthopoxviruses. Four generations of live smallpox, protein subunit, and DNA vaccines are considered. Analysis of the data published leads to the conclusion that it is promising to use the up-to-date generations of safe smallpox subunit or DNA vaccines for mass primary immunization with possible further revaccination with classical live vaccine.

Microneedle Array Design Determines the Induction of Protective Memory CD8+ T Cell Responses Induced by a Recombinant Live Malaria Vaccine in Mice

Science.gov (United States)

Carey, John B.; Pearson, Frances E.; Vrdoljak, Anto; McGrath, Marie G.; Crean, Abina M.; Walsh, Patrick T.; Doody, Timothy; O'Mahony, Conor; Hill, Adrian V. S.; Moore, Anne C.

2011-01-01

Background Vaccine delivery into the skin has received renewed interest due to ease of access to the immune system and microvasculature, however the stratum corneum (SC), must be breached for successful vaccination. This has been achieved by removing the SC by abrasion or scarification or by delivering the vaccine intradermally (ID) with traditional needle-and-syringes or with long microneedle devices. Microneedle patch-based transdermal vaccine studies have predominantly focused on antibody induction by inactivated or subunit vaccines. Here, our principal aim is to determine if the design of a microneedle patch affects the CD8+ T cell responses to a malaria antigen induced by a live vaccine. Methodology and Findings Recombinant modified vaccinia virus Ankara (MVA) expressing a malaria antigen was percutaneously administered to mice using a range of silicon microneedle patches, termed ImmuPatch, that differed in microneedle height, density, patch area and total pore volume. We demonstrate that microneedle arrays that have small total pore volumes induce a significantly greater proportion of central memory T cells that vigorously expand to secondary immunization. Microneedle-mediated vaccine priming induced significantly greater T cell immunity post-boost and equivalent protection against malaria challenge compared to ID vaccination. Notably, unlike ID administration, ImmuPatch-mediated vaccination did not induce inflammatory responses at the site of immunization or in draining lymph nodes. Conclusions/Significance This study demonstrates that the design of microneedle patches significantly influences the magnitude and memory of vaccine-induced CD8+ T cell responses and can be optimised for the induction of desired immune responses. Furthermore, ImmuPatch-mediated delivery may be of benefit to reducing unwanted vaccine reactogenicity. In addition to the advantages of low cost and lack of pain, the development of optimised microneedle array designs for the induction

Rational design of carbon and TiO2 assembly materials: covered or strewn, which is better for photocatalysis?

Science.gov (United States)

Cui, Guan-wei; Wang, Wei-liang; Ma, Ming-yue; Zhang, Ming; Xia, Xin-yuan; Han, Feng-yun; Shi, Xi-feng; Zhao, Ying-qiang; Dong, Yu-bin; Tang, Bo

2013-07-21

The rational design of carbonaceous hybrid nanostructures is very important for obtaining high photoactivity. TiO2 particles strewn with an optimal quantity of carbon nanodots have a much higher photoactivity than that of TiO2 covered with a carbon layer, showing the importance of carbon morphology in the photocatalysis of carbonaceous hybrid nanostructures.

THE APPROACHES TO DESIGNING OF NEW GENERATION VACCINES AGAINST THE SHEEP POX DISEASE

Directory of Open Access Journals (Sweden)

E. F. Yilmaz

2016-12-01

Full Text Available In this review the authors analyzed the sheep pox disease, which occurs outbreaks all over the world particularly in Asia and Africa causing substantial losses in trade of animal and animal products. They categorized the sheep pox disease is one of the prioritized groups of diseases against which the World Organization for Animal Health is fighting. Data concerning a sheep poxes’ history, epidemiology, epizootiology, mortality and economic impact, clinical and pathological signs, features of capripoxvirus that forms the disease are given. Diagnosis treatment and vaccine have been investigated as well. The main conclusion is done according which the designing of new vaccine generation against the sheep pox disease could be as an alternative approach against sheep pox.

Laccase engineering: from rational design to directed evolution.

Science.gov (United States)

Mate, Diana M; Alcalde, Miguel

2015-01-01

Laccases are multicopper oxidoreductases considered by many in the biotechonology field as the ultimate "green catalysts". This is mainly due to their broad substrate specificity and relative autonomy (they use molecular oxygen from air as an electron acceptor and they only produce water as by-product), making them suitable for a wide array of applications: biofuel production, bioremediation, organic synthesis, pulp biobleaching, textiles, the beverage and food industries, biosensor and biofuel cell development. Since the beginning of the 21st century, specific features of bacterial and fungal laccases have been exhaustively adapted in order to reach the industrial demands for high catalytic activity and stability in conjunction with reduced production cost. Among the goals established for laccase engineering, heterologous functional expression, improved activity and thermostability, tolerance to non-natural media (organic solvents, ionic liquids, physiological fluids) and resistance to different types of inhibitors are all challenges that have been met, while obtaining a more comprehensive understanding of laccase structure-function relationships. In this review we examine the most significant advances in this exciting research area in which rational, semi-rational and directed evolution approaches have been employed to ultimately convert laccases into high value-added biocatalysts. Copyright © 2014 Elsevier Inc. All rights reserved.

Meningococcal B vaccine. An immunogenic vaccine possibly useful during outbreaks.

Science.gov (United States)

2014-09-01

Invasive meningococcal infections can be life-threatening and cause severe sequelae. Antibiotic therapy is only partially effective. Bexsero is the first meningococcal B vaccine to be approved in the European Union. It contains four capsular antigens from various strains of group B meningococci. Clinical trials of this meningococcal B vaccine did not assess clinical protection. Two immunogenicity studies in adults, one in adolescents and six in infants, are available. They established the immunogenicity of the meningococcal B vaccine, determined age-appropriate vaccination schedules, and verified that concomitant administration of other vaccines did not undermine its immunogenicity. In the absence of relevant clinical trials, an in vitro study showed that sera from vaccinated individuals were likely to have bactericidal activity against 85% of 200 invasive meningococcal B strains isolated in France in 2007-2008. The meningococcal B vaccine provoked local adverse effects in most vaccinees, including local erythema, induration and pain. Fever occurred in about half of vaccinated children. Six cases of Kawasaki syndrome have been reported in children who received the vaccine, compared to only one case in control groups. In practice, the harm-benefit balance of this meningococcal B vaccine justify using it during outbreaks, provided the outbreak strain is covered by the vaccine antigens. Vaccinees should be enrolled in studies designed to evaluate clinical efficacy and to better determine the risk of Kawasaki syndrome.

Computer-Aided Design of an Epitope-Based Vaccine against Epstein-Barr Virus

Directory of Open Access Journals (Sweden)

Julio Alonso-Padilla

2017-01-01

Full Text Available Epstein-Barr virus is a very common human virus that infects 90% of human adults. EBV replicates in epithelial and B cells and causes infectious mononucleosis. EBV infection is also linked to various cancers, including Burkitt’s lymphoma and nasopharyngeal carcinomas, and autoimmune diseases such as multiple sclerosis. Currently, there are no effective drugs or vaccines to treat or prevent EBV infection. Herein, we applied a computer-aided strategy to design a prophylactic epitope vaccine ensemble from experimentally defined T and B cell epitopes. Such strategy relies on identifying conserved epitopes in conjunction with predictions of HLA presentation for T cell epitope selection and calculations of accessibility and flexibility for B cell epitope selection. The T cell component includes 14 CD8 T cell epitopes from early antigens and 4 CD4 T cell epitopes, targeted during the course of a natural infection and providing a population protection coverage of over 95% and 81.8%, respectively. The B cell component consists of 3 experimentally defined B cell epitopes from gp350 plus 4 predicted B cell epitopes from other EBV envelope glycoproteins, all mapping in flexible and solvent accessible regions. We discuss the rationale for the formulation and possible deployment of this epitope vaccine ensemble.

Informing vaccine decision-making: A strategic multi-attribute ranking tool for vaccines-SMART Vaccines 2.0.

Science.gov (United States)

Knobler, Stacey; Bok, Karin; Gellin, Bruce

2017-01-20

SMART Vaccines 2.0 software is being developed to support decision-making among multiple stakeholders in the process of prioritizing investments to optimize the outcomes of vaccine development and deployment. Vaccines and associated vaccination programs are one of the most successful and effective public health interventions to prevent communicable diseases and vaccine researchers are continually working towards expanding targets for communicable and non-communicable diseases through preventive and therapeutic modes. A growing body of evidence on emerging vaccine technologies, trends in disease burden, costs associated with vaccine development and deployment, and benefits derived from disease prevention through vaccination and a range of other factors can inform decision-making and investment in new and improved vaccines and targeted utilization of already existing vaccines. Recognizing that an array of inputs influences these decisions, the strategic multi-attribute ranking method for vaccines (SMART Vaccines 2.0) is in development as a web-based tool-modified from a U.S. Institute of Medicine Committee effort (IOM, 2015)-to highlight data needs and create transparency to facilitate dialogue and information-sharing among decision-makers and to optimize the investment of resources leading to improved health outcomes. Current development efforts of the SMART Vaccines 2.0 framework seek to generate a weighted recommendation on vaccine development or vaccination priorities based on population, disease, economic, and vaccine-specific data in combination with individual preference and weights of user-selected attributes incorporating valuations of health, economics, demographics, public concern, scientific and business, programmatic, and political considerations. Further development of the design and utility of the tool is being carried out by the National Vaccine Program Office of the Department of Health and Human Services and the Fogarty International Center of the

Rationality in Society

NARCIS (Netherlands)

Flache, Andreas; Dijkstra, Jacob; Wright, James D.

2015-01-01

Contemporary theories of rational behavior in human society augment the orthodox model of rationality both by adding various forms of bounded rationality and relaxing the assumptions of self-interest and materialistic preferences. This entry discusses how these extensions of the theory of rational

A Rational Approach to Rational Suicide.

Science.gov (United States)

Richman, Joseph

1992-01-01

Describes suicide as reaction to internal and external sources of stress and the impact of life events. Notes that, in the elderly, these situations are prevalent in many who are not suicidal. Contends that much more is written about rational suicide than its alternative (rational nonsuicide). Reviews reasons for this and suggests rational…

Rational design of competitive electrocatalysts for the oxygen reduction reaction in hydrogen fuel cells

Science.gov (United States)

Stolbov, Sergey; Alcántara Ortigoza, Marisol

2012-02-01

The large-scale application of one of the most promising clean and renewable sources of energy, hydrogen fuel cells, still awaits efficient and cost-effective electrocatalysts for the oxygen reduction reaction (ORR) occurring on the cathode. We demonstrate that truly rational design renders electrocatalysts possessing both qualities. By unifying the knowledge on surface morphology, composition, electronic structure and reactivity, we solve that sandwich-like structures are an excellent choice for optimization. Their constituting species couple synergistically yielding reaction-environment stability, cost-effectiveness and tunable reactivity. This cooperative-action concept enabled us to predict two advantageous ORR electrocatalysts. Density functional theory calculations of the reaction free-energy diagrams confirm that these materials are more active toward ORR than the so far best Pt-based catalysts. Our designing concept advances also a general approach for engineering materials in heterogeneous catalysis.

The HPV Vaccination Crisis

Science.gov (United States)

Following the release of a consensus statement from the NCI-Designated Cancer Centers urging HPV vaccination in the United States, Dr. Noel Brewer discusses the country’s low vaccination rates and how clinicians can help to improve them.

Establishing Correlates of Protection for Vaccine Development: Considerations for the Respiratory Syncytial Virus Vaccine Field.

Science.gov (United States)

Kulkarni, Prasad S; Hurwitz, Julia L; Simões, Eric A F; Piedra, Pedro A

2018-03-01

Correlates of protection (CoPs) can play a significant role in vaccine development by assisting the selection of vaccine candidates for clinical trials, supporting clinical trial design and implementation, and simplifying tests of vaccine modifications. Because of this important role in vaccine development, it is essential that CoPs be defined by well-designed immunogenicity and efficacy studies, with attention paid to benefits and limitations. The respiratory syncytial virus (RSV) field is unique in that a great deal of information about the humoral response is available from basic research and clinical studies. Polyclonal and monoclonal antibodies have been used routinely in the clinic to protect vulnerable infants from infection, providing a wealth of information about correlations between neutralizing antibodies and disease prevention. Considerations for the establishment of future CoPs to support RSV vaccine development in different populations are therefore discussed.

Geometric Rationalization for Freeform Architecture

KAUST Repository

Jiang, Caigui

2016-06-20

The emergence of freeform architecture provides interesting geometric challenges with regards to the design and manufacturing of large-scale structures. To design these architectural structures, we have to consider two types of constraints. First, aesthetic constraints are important because the buildings have to be visually impressive. Sec- ond, functional constraints are important for the performance of a building and its e cient construction. This thesis contributes to the area of architectural geometry. Specifically, we are interested in the geometric rationalization of freeform architec- ture with the goal of combining aesthetic and functional constraints and construction requirements. Aesthetic requirements typically come from designers and architects. To obtain visually pleasing structures, they favor smoothness of the building shape, but also smoothness of the visible patterns on the surface. Functional requirements typically come from the engineers involved in the construction process. For exam- ple, covering freeform structures using planar panels is much cheaper than using non-planar ones. Further, constructed buildings have to be stable and should not collapse. In this thesis, we explore the geometric rationalization of freeform archi- tecture using four specific example problems inspired by real life applications. We achieve our results by developing optimization algorithms and a theoretical study of the underlying geometrical structure of the problems. The four example problems are the following: (1) The design of shading and lighting systems which are torsion-free structures with planar beams based on quad meshes. They satisfy the functionality requirements of preventing light from going inside a building as shad- ing systems or reflecting light into a building as lighting systems. (2) The Design of freeform honeycomb structures that are constructed based on hex-dominant meshes with a planar beam mounted along each edge. The beams intersect without

A Design of Experiment approach to predict product and process parameters for a spray dried influenza vaccine.

Science.gov (United States)

Kanojia, Gaurav; Willems, Geert-Jan; Frijlink, Henderik W; Kersten, Gideon F A; Soema, Peter C; Amorij, Jean-Pierre

2016-09-25

Spray dried vaccine formulations might be an alternative to traditional lyophilized vaccines. Compared to lyophilization, spray drying is a fast and cheap process extensively used for drying biologicals. The current study provides an approach that utilizes Design of Experiments for spray drying process to stabilize whole inactivated influenza virus (WIV) vaccine. The approach included systematically screening and optimizing the spray drying process variables, determining the desired process parameters and predicting product quality parameters. The process parameters inlet air temperature, nozzle gas flow rate and feed flow rate and their effect on WIV vaccine powder characteristics such as particle size, residual moisture content (RMC) and powder yield were investigated. Vaccine powders with a broad range of physical characteristics (RMC 1.2-4.9%, particle size 2.4-8.5μm and powder yield 42-82%) were obtained. WIV showed no significant loss in antigenicity as revealed by hemagglutination test. Furthermore, descriptive models generated by DoE software could be used to determine and select (set) spray drying process parameter. This was used to generate a dried WIV powder with predefined (predicted) characteristics. Moreover, the spray dried vaccine powders retained their antigenic stability even after storage for 3 months at 60°C. The approach used here enabled the generation of a thermostable, antigenic WIV vaccine powder with desired physical characteristics that could be potentially used for pulmonary administration. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Design and application of chitosan microspheres as oral and nasal vaccine carriers: an updated review

Directory of Open Access Journals (Sweden)

Islam MA

2012-12-01

Full Text Available Mohammad Ariful Islam,1–3,* Jannatul Firdous,1–3,* Yun-Jaie Choi,1 Cheol-Heui Yun,1–4 Chong-Su Cho1,21Department of Agricultural Biotechnology, 2Research Institute for Agriculture and Life Sciences, 3Center for Food and Bioconvergence, 4World Class University Biomodulation Program, Seoul National University, Seoul, South Korea*These authors contributed equally to this workAbstract: Chitosan, a natural biodegradable polymer, is of great interest in biomedical research due to its excellent properties including bioavailability, nontoxicity, high charge density, and mucoadhesivity, which creates immense potential for various pharmaceutical applications. It has gelling properties when it interacts with counterions such as sulfates or polyphosphates and when it crosslinks with glutaraldehyde. This characteristic facilitates its usefulness in the coating or entrapment of biochemicals, drugs, antigenic molecules as a vaccine candidate, and microorganisms. Therefore, chitosan together with the advance of nanotechnology can be effectively applied as a carrier system for vaccine delivery. In fact, chitosan microspheres have been studied as a promising carrier system for mucosal vaccination, especially via the oral and nasal route to induce enhanced immune responses. Moreover, the thiolated form of chitosan is of considerable interest due to its improved mucoadhesivity, permeability, stability, and controlled/extended release profile. This review describes the various methods used to design and synthesize chitosan microspheres and recent updates on their potential applications for oral and nasal delivery of vaccines. The potential use of thiolated chitosan microspheres as next-generation mucosal vaccine carriers is also discussed.Keywords: chitosan microspheres, oral, nasal, vaccine delivery, mucosal and systemic immune responses

Rational development of an attenuated recombinant cyprinid herpesvirus 3 vaccine using prokaryotic mutagenesis and in vivo bioluminescent imaging

Science.gov (United States)

Cyprinid herpesvirus 3 (CyHV-3) is causing severe economic losses worldwide in the carp industry, and a safe and efficacious attenuated vaccine compatible with mass vaccination is needed. We produced single deleted recombinants using prokaryotic mutagenesis. When producing a recombinant lacking open...

Vaccination coverage and reasons for non-vaccination in a district of Istanbul

Directory of Open Access Journals (Sweden)

Bakırcı Nadi

2006-05-01

Full Text Available Abstract Background In order to control and eliminate the vaccine preventable diseases it is important to know the vaccination coverage and reasons for non-vaccination. The primary objective of this study was to determine the complete vaccination rate; the reasons for non-vaccination and the predictors that influence vaccination of children. The other objective was to determine coverage of measles vaccination of the Measles Immunization Days (MID 2005 for children aged 9 month to 6 years in a region of Umraniye, Istanbul, Turkey. Methods A '30 × 7' cluster sampling design was used as the sampling method. Thirty streets were selected at random from study area. Survey data were collected by a questionnaire which was applied face to face to parents of 221 children. A Chi-square test and logistic regression was used for the statistical analyses. Content analysis method was used to evaluate the open-ended questions. Results The complete vaccination rate for study population was 84.5% and 3.2% of all children were totally non-vaccinated. The siblings of non-vaccinated children were also non-vaccinated. Reasons for non-vaccination were as follows: being in the village and couldn't reach to health care services; having no knowledge about vaccination; the father of child didn't allow vaccination; intercurrent illness of child during vaccination time; missed opportunities like not to shave off a vial for only one child. In logistic regression analysis, paternal and maternal levels of education and immigration time of both parents to Istanbul were found to influence whether children were completely vaccinated or non-vaccinated. Measles vaccination coverage during MID was 79.3%. Conclusion Efforts to increase vaccination coverage should take reasons for non-vaccination into account.

Guidelines for Rational Cancer Therapeutics

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Byunghee Yoo

2017-12-01

Full Text Available Traditionally, cancer therapy has relied on surgery, radiation therapy, and chemotherapy. In recent years, these interventions have become increasingly replaced or complemented by more targeted approaches that are informed by a deeper understanding of the underlying biology. Still, the implementation of fully rational patient-specific drug design appears to be years away. Here, we present a vision of rational drug design for cancer that is defined by two major components: modularity and image guidance. We suggest that modularity can be achieved by combining a nanocarrier and an oligonucleotide component into the therapeutic. Image guidance can be incorporated into the nanocarrier component by labeling with a specific imaging reporter, such as a radionuclide or contrast agent for magnetic resonance imaging. While limited by the need for additional technological advancement in the areas of cancer biology, nanotechnology, and imaging, this vision for the future of cancer therapy can be used as a guide to future research endeavors.

Rational design of DNA sequences for nanotechnology, microarrays and molecular computers using Eulerian graphs.

Science.gov (United States)

Pancoska, Petr; Moravek, Zdenek; Moll, Ute M

2004-01-01

Nucleic acids are molecules of choice for both established and emerging nanoscale technologies. These technologies benefit from large functional densities of 'DNA processing elements' that can be readily manufactured. To achieve the desired functionality, polynucleotide sequences are currently designed by a process that involves tedious and laborious filtering of potential candidates against a series of requirements and parameters. Here, we present a complete novel methodology for the rapid rational design of large sets of DNA sequences. This method allows for the direct implementation of very complex and detailed requirements for the generated sequences, thus avoiding 'brute force' filtering. At the same time, these sequences have narrow distributions of melting temperatures. The molecular part of the design process can be done without computer assistance, using an efficient 'human engineering' approach by drawing a single blueprint graph that represents all generated sequences. Moreover, the method eliminates the necessity for extensive thermodynamic calculations. Melting temperature can be calculated only once (or not at all). In addition, the isostability of the sequences is independent of the selection of a particular set of thermodynamic parameters. Applications are presented for DNA sequence designs for microarrays, universal microarray zip sequences and electron transfer experiments.

Novel Ordered Stepped-Wedge Cluster Trial Designs for Detecting Ebola Vaccine Efficacy Using a Spatially Structured Mathematical Model.

Directory of Open Access Journals (Sweden)

Ibrahim Diakite

2016-08-01

Full Text Available During the 2014 Ebola virus disease (EVD outbreak, policy-makers were confronted with difficult decisions on how best to test the efficacy of EVD vaccines. On one hand, many were reluctant to withhold a vaccine that might prevent a fatal disease from study participants randomized to a control arm. On the other, regulatory bodies called for rigorous placebo-controlled trials to permit direct measurement of vaccine efficacy prior to approval of the products. A stepped-wedge cluster study (SWCT was proposed as an alternative to a more traditional randomized controlled vaccine trial to address these concerns. Here, we propose novel "ordered stepped-wedge cluster trial" (OSWCT designs to further mitigate tradeoffs between ethical concerns, logistics, and statistical rigor.We constructed a spatially structured mathematical model of the EVD outbreak in Sierra Leone. We used the output of this model to simulate and compare a series of stepped-wedge cluster vaccine studies. Our model reproduced the observed order of first case occurrence within districts of Sierra Leone. Depending on the infection risk within the trial population and the trial start dates, the statistical power to detect a vaccine efficacy of 90% varied from 14% to 32% for standard SWCT, and from 67% to 91% for OSWCTs for an alpha error of 5%. The model's projection of first case occurrence was robust to changes in disease natural history parameters.Ordering clusters in a step-wedge trial based on the cluster's underlying risk of infection as predicted by a spatial model can increase the statistical power of a SWCT. In the event of another hemorrhagic fever outbreak, implementation of our proposed OSWCT designs could improve statistical power when a step-wedge study is desirable based on either ethical concerns or logistical constraints.

Harvesting bioenergy with rationally designed complex functional materials

Science.gov (United States)

Kuang, Liangju

A key challenge in renewable energy is to capture, convert and store solar power with earth-abundant materials and environmentally benign technologies. The goal of this thesis is to develop rationally designed complex functional materials for bio-renewable energy applications. On one hand, photoconversion membrane proteins (MPs) are nature's nanoengineering feats for renewable energy management. Harnessing their functions in synthetic systems could help understand, predict, and ultimately control matter and energy at the nanoscale. This is particularly enticing in the post-genome era as recombinant or cell-free expression of many MPs with high yields becomes possible. However, the labile nature of lipid bilayers renders them unsuitable for use in a broad range of engineered systems. A knowledge gap exists about how to design robust synthetic nanomembranes as lipid-bilayer-mimics to support MP functions and how to direct hierarchical MP reconstitution into those membranes to form 2-D or 3-D ordered proteomembrane arrays. Our studies on proteorhodopsin (PR) and bacterial reaction center (BRC), the two light-harvesting MPs, reveal that a charge-interaction-directed reconstitution (CIDR) mechanism induces spontaneous reconstitution of detergent-solubilized MPs into various amphiphilic block copolymer membranes, many of which have far superior stability than lipid bilayers. Our preliminary data also suggest MPs are not enslaved by the biological membranes they derive from; rather, the chemically nonspecific material properties of MP-supporting membranes may act as allosteric regulators. Versatile chemical designs are possible to modulate the conformational energetics of MPs, hence their transport performance in synthetic systems. On the other hand, microalgae are widely regarded as a sustainable feedstock for biofuel production. Microalgae-derived biofuels have not been commercialized yet because current technologies for microalgae dewatering add a huge cost to the

A rational and economical seismic design of beam columns in steel frames

International Nuclear Information System (INIS)

Gupta, A.K.; Fang, S.-J.; Chu, S.-L.

1977-01-01

In the present study, a new rational procedure is used in which simultaneous variation in various response quantities is predicted. For designing the beam column section according to the AISC Manual of Steel Construction, one has to know the values of the axial force, the moment about x and y axes at the two ends, and the maximum moments about x, y axes near the center of the beam column, which altogether constitutes seven response quantities of interest for each beam column element. Normally, seven equivalent modes will be required to represent the response. However, by designing the two end sections and the intermediate section independently one can consider three equivalent modes for each section, thus simplifying the problem a great deal. An existing computer program is used for the implementation of the proposed method. Results for typical example problems have been presented. It is shown that savings up to 42% in the steel cross-sectional area can be obtained depending upon combination of various forces and moments. The propposed method is 'exact' within the existing assumptions of the SRSS (square root of the sum of the squares) or the double sum method

Rational design of botulinum neurotoxin A1 mutants with improved oxidative stability.

Science.gov (United States)

López de la Paz, Manuela; Scheps, Daniel; Jurk, Marcel; Hofmann, Fred; Frevert, Jürgen

2018-06-01

Botulinum neurotoxins (BoNTs) are the most potent toxic proteins to mankind known but applied in low doses trigger a localized muscle paralysis that is beneficial for the therapy of several neurological disorders and aesthetic treatment. The paralytic effect is generated by the enzymatic activity of the light chain (LC) that cleaves specifically one of the SNARE proteins responsible for neurotransmitter exocytosis. The activity of the LC in a BoNT-containing therapeutic can be compromised by denaturing agents present during manufacturing and/or in the cell. Stabilization of the LC by reducing vulnerability towards denaturants would thus be advantageous for the development of BoNT-based therapeutics. In this work, we focused on increasing the stability of LC of BoNT/A1 (LC/A1) towards oxidative stress. We tackled this task by rational design of mutations at cysteine and methionine LC/A1 sites. Designed mutants showed improved oxidative stability in vitro and equipotency to wildtype toxin in vivo. Our results suggest that suitable modification of the catalytic domain can lead to more stable BoNTs without impairing their therapeutic efficacy. Copyright © 2017 Elsevier Ltd. All rights reserved.

Model-based rational feedback controller design for closed-loop deep brain stimulation of Parkinson's disease

Science.gov (United States)

Gorzelic, P.; Schiff, S. J.; Sinha, A.

2013-04-01

Objective. To explore the use of classical feedback control methods to achieve an improved deep brain stimulation (DBS) algorithm for application to Parkinson's disease (PD). Approach. A computational model of PD dynamics was employed to develop model-based rational feedback controller design. The restoration of thalamocortical relay capabilities to patients suffering from PD is formulated as a feedback control problem with the DBS waveform serving as the control input. Two high-level control strategies are tested: one that is driven by an online estimate of thalamic reliability, and another that acts to eliminate substantial decreases in the inhibition from the globus pallidus interna (GPi) to the thalamus. Control laws inspired by traditional proportional-integral-derivative (PID) methodology are prescribed for each strategy and simulated on this computational model of the basal ganglia network. Main Results. For control based upon thalamic reliability, a strategy of frequency proportional control with proportional bias delivered the optimal control achieved for a given energy expenditure. In comparison, control based upon synaptic inhibitory output from the GPi performed very well in comparison with those of reliability-based control, with considerable further reduction in energy expenditure relative to that of open-loop DBS. The best controller performance was amplitude proportional with derivative control and integral bias, which is full PID control. We demonstrated how optimizing the three components of PID control is feasible in this setting, although the complexity of these optimization functions argues for adaptive methods in implementation. Significance. Our findings point to the potential value of model-based rational design of feedback controllers for Parkinson's disease.

Rational design of peptide affinity ligands for the purification of therapeutic enzymes.

Science.gov (United States)

Trasatti, John P; Woo, James; Ladiwala, Asif; Cramer, Steven; Karande, Pankaj

2018-04-25

Non-mAb biologics represent a growing class of therapeutics under clinical development. Although affinity chromatography is a potentially attractive approach for purification, the development of platform technologies, such as Protein A for mAbs, has been challenging due to the inherent chemical and structural diversity of these molecules. Here, we present our studies on the rapid development of peptide affinity ligands for the purification of biologics using a prototypical enzyme therapeutic in clinical use. Employing a suite of de novo rational and combinatorial design strategies we designed and screened a library of peptides on microarray platforms for their ability to bind to the target with high affinity and selectivity in cell culture fluid. Lead peptides were evaluated on resin in batch conditions and compared with a commercially available resin to evaluate their efficacy. Two lead candidates identified from microarray studies provided high binding capacity to the target while demonstrating high selectivity against culture contaminants and product variants compared to a commercial resin system. These findings provide a proof-of-concept for developing affinity peptide-based bioseparations processes for a target biologic. Peptide affinity ligand design and screening approaches presented in this work can also be easily translated to other biologics of interest. © 2018 American Institute of Chemical Engineers Biotechnol. Prog., 2018. © 2018 American Institute of Chemical Engineers.

A Rapid and Improved Method to Generate Recombinant Dengue Virus Vaccine Candidates.

Science.gov (United States)

Govindarajan, Dhanasekaran; Guan, Liming; Meschino, Steven; Fridman, Arthur; Bagchi, Ansu; Pak, Irene; ter Meulen, Jan; Casimiro, Danilo R; Bett, Andrew J

2016-01-01

Dengue is one of the most important mosquito-borne infections accounting for severe morbidity and mortality worldwide. Recently, the tetravalent chimeric live attenuated Dengue vaccine Dengvaxia® was approved for use in several dengue endemic countries. In general, live attenuated vaccines (LAV) are very efficacious and offer long-lasting immunity against virus-induced disease. Rationally designed LAVs can be generated through reverse genetics technology, a method of generating infectious recombinant viruses from full length cDNA contained in bacterial plasmids. In vitro transcribed (IVT) viral RNA from these infectious clones is transfected into susceptible cells to generate recombinant virus. However, the generation of full-length dengue virus cDNA clones can be difficult due to the genetic instability of viral sequences in bacterial plasmids. To circumvent the need for a single plasmid containing a full length cDNA, in vitro ligation of two or three cDNA fragments contained in separate plasmids can be used to generate a full-length dengue viral cDNA template. However, in vitro ligation of multiple fragments often yields low quality template for IVT reactions, resulting in inconsistent low yield RNA. These technical difficulties make recombinant virus recovery less efficient. In this study, we describe a simple, rapid and efficient method of using LONG-PCR to recover recombinant chimeric Yellow fever dengue (CYD) viruses as potential dengue vaccine candidates. Using this method, we were able to efficiently generate several viable recombinant viruses without introducing any artificial mutations into the viral genomes. We believe that the techniques reported here will enable rapid and efficient recovery of recombinant flaviviruses for evaluation as vaccine candidates and, be applicable to the recovery of other RNA viruses.

Bioinformatics and multiepitope DNA immunization to design rational snake antivenom.

Directory of Open Access Journals (Sweden)

Simon C Wagstaff

2006-06-01

Full Text Available Snake venom is a potentially lethal and complex mixture of hundreds of functionally diverse proteins that are difficult to purify and hence difficult to characterize. These difficulties have inhibited the development of toxin-targeted therapy, and conventional antivenom is still generated from the sera of horses or sheep immunized with whole venom. Although life-saving, antivenoms contain an immunoglobulin pool of unknown antigen specificity and known redundancy, which necessitates the delivery of large volumes of heterologous immunoglobulin to the envenomed victim, thus increasing the risk of anaphylactoid and serum sickness adverse effects. Here we exploit recent molecular sequence analysis and DNA immunization tools to design more rational toxin-targeted antivenom.We developed a novel bioinformatic strategy that identified sequences encoding immunogenic and structurally significant epitopes from an expressed sequence tag database of a venom gland cDNA library of Echis ocellatus, the most medically important viper in Africa. Focusing upon snake venom metalloproteinases (SVMPs that are responsible for the severe and frequently lethal hemorrhage in envenomed victims, we identified seven epitopes that we predicted would be represented in all isomers of this multimeric toxin and that we engineered into a single synthetic multiepitope DNA immunogen (epitope string. We compared the specificity and toxin-neutralizing efficacy of antiserum raised against the string to antisera raised against a single SVMP toxin (or domains or antiserum raised by conventional (whole venom immunization protocols. The SVMP string antiserum, as predicted in silico, contained antibody specificities to numerous SVMPs in E. ocellatus venom and venoms of several other African vipers. More significantly, the antiserum cross-specifically neutralized hemorrhage induced by E. ocellatus and Cerastes cerastes cerastes venoms.These data provide valuable sequence and structure

Vaccines Meet Big Data: State-of-the-Art and Future Prospects. From the Classical 3Is ("Isolate-Inactivate-Inject") Vaccinology 1.0 to Vaccinology 3.0, Vaccinomics, and Beyond: A Historical Overview.

Science.gov (United States)

Bragazzi, Nicola Luigi; Gianfredi, Vincenza; Villarini, Milena; Rosselli, Roberto; Nasr, Ahmed; Hussein, Amr; Martini, Mariano; Behzadifar, Masoud

2018-01-01

Vaccines are public health interventions aimed at preventing infections-related mortality, morbidity, and disability. While vaccines have been successfully designed for those infectious diseases preventable by preexisting neutralizing specific antibodies, for other communicable diseases, additional immunological mechanisms should be elicited to achieve a full protection. "New vaccines" are particularly urgent in the nowadays society, in which economic growth, globalization, and immigration are leading to the emergence/reemergence of old and new infectious agents at the animal-human interface. Conventional vaccinology (the so-called "vaccinology 1.0") was officially born in 1796 thanks to the contribution of Edward Jenner. Entering the twenty-first century, vaccinology has shifted from a classical discipline in which serendipity and the Pasteurian principle of the three I s (isolate, inactivate, and inject) played a major role to a science, characterized by a rational design and plan ("vaccinology 3.0"). This shift has been possible thanks to Big Data, characterized by different dimensions, such as high volume, velocity, and variety of data. Big Data sources include new cutting-edge, high-throughput technologies, electronic registries, social media, and social networks, among others. The current mini-review aims at exploring the potential roles as well as pitfalls and challenges of Big Data in shaping the future vaccinology, moving toward a tailored and personalized vaccine design and administration.

Pragmatics & rationality.

OpenAIRE

Allott, N. E.

2007-01-01

This thesis is about the reconciliation of realistic views of rationality with inferential-intentional theories of communication. Grice (1957 1975) argued that working out what a speaker meant by an utterance is a matter of inferring the speaker's intentions on the presumption that she is acting rationally. This is abductive inference: inference to the best explanation for the utterance. Thus an utterance both rationalises and causes the interpretation the hearer constructs. Human rationality...

Oral vaccination of fish: Lessons from humans and veterinary species.

Science.gov (United States)

Embregts, Carmen W E; Forlenza, Maria

2016-11-01

The limited number of oral vaccines currently approved for use in humans and veterinary species clearly illustrates that development of efficacious and safe oral vaccines has been a challenge not only for fish immunologists. The insufficient efficacy of oral vaccines is partly due to antigen breakdown in the harsh gastric environment, but also to the high tolerogenic gut environment and to inadequate vaccine design. In this review we discuss current approaches used to develop oral vaccines for mass vaccination of farmed fish species. Furthermore, using various examples from the human and veterinary vaccine development, we propose additional approaches to fish vaccine design also considering recent advances in fish mucosal immunology and novel molecular tools. Finally, we discuss the pros and cons of using the zebrafish as a pre-screening animal model to potentially speed up vaccine design and testing for aquaculture fish species. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

A vaccine encoding conserved promiscuous HIV CD4 epitopes induces broad T cell responses in mice transgenic to multiple common HLA class II molecules.

Directory of Open Access Journals (Sweden)

Susan Pereira Ribeiro

Full Text Available Current HIV vaccine approaches are focused on immunogens encoding whole HIV antigenic proteins that mainly elicit cytotoxic CD8+ responses. Mounting evidence points toward a critical role for CD4+ T cells in the control of immunodeficiency virus replication, probably due to cognate help. Vaccine-induced CD4+ T cell responses might, therefore, have a protective effect in HIV replication. In addition, successful vaccines may have to elicit responses to multiple epitopes in a high proportion of vaccinees, to match the highly variable circulating strains of HIV. Using rational vaccine design, we developed a DNA vaccine encoding 18 algorithm-selected conserved, "promiscuous" (multiple HLA-DR-binding B-subtype HIV CD4 epitopes - previously found to be frequently recognized by HIV-infected patients. We assessed the ability of the vaccine to induce broad T cell responses in the context of multiple HLA class II molecules using different strains of HLA class II- transgenic mice (-DR2, -DR4, -DQ6 and -DQ8. Mice displayed CD4+ and CD8+ T cell responses of significant breadth and magnitude, and 16 out of the 18 encoded epitopes were recognized. By virtue of inducing broad responses against conserved CD4+ T cell epitopes that can be recognized in the context of widely diverse, common HLA class II alleles, this vaccine concept may cope both with HIV genetic variability and increased population coverage. The vaccine may thus be a source of cognate help for HIV-specific CD8+ T cells elicited by conventional immunogens, in a wide proportion of vaccinees.

Influenza vaccine effectiveness estimates in the Dutch population from 2003 to 2014: the test-negative design case-control study with different control groups.

NARCIS (Netherlands)

Doorn, E. van; Darvishian, M.; Dijkstra, F.; Donker, G.A.; Overduin, P.; Meijer, A.; Hak, E.

2017-01-01

Information about influenza vaccine effectiveness (IVE) is important for vaccine strain selection and immunization policy decisions. The test-negative design (TND) case-control study is commonly used to obtain IVE estimates. However, the definition of the control patients may influence IVE

Influenza vaccine effectiveness estimates in the Dutch population from 2003 to 2014 : The test-negative design case-control study with different control groups

NARCIS (Netherlands)

van Doorn, Eva; Darvishian, Maryam; Dijkstra, Frederika; Donker, Gé A; Overduin, Pieter; Meijer, Adam; Hak, Eelko

2017-01-01

Information about influenza vaccine effectiveness (IVE) is important for vaccine strain selection and immunization policy decisions. The test-negative design (TND) case-control study is commonly used to obtain IVE estimates. However, the definition of the control patients may influence IVE

Influenza vaccine effectiveness estimates in the Dutch population from 2003 to 2014: The test-negative design case-control study with different control groups.

NARCIS (Netherlands)

van Doorn, Eva; Darvishian, Maryam; Dijkstra, Frederika; Donker, Gé A; Overduin, Pieter; Meijer, Adam; Hak, Eelko

2017-01-01

Information about influenza vaccine effectiveness (IVE) is important for vaccine strain selection and immunization policy decisions. The test-negative design (TND) case-control study is commonly used to obtain IVE estimates. However, the definition of the control patients may influence IVE

Typhoid fever vaccination strategies.

Science.gov (United States)

Date, Kashmira A; Bentsi-Enchill, Adwoa; Marks, Florian; Fox, Kimberley

2015-06-19

Typhoid vaccination is an important component of typhoid fever prevention and control, and is recommended for public health programmatic use in both endemic and outbreak settings. We reviewed experiences with various vaccination strategies using the currently available typhoid vaccines (injectable Vi polysaccharide vaccine [ViPS], oral Ty21a vaccine, and injectable typhoid conjugate vaccine [TCV]). We assessed the rationale, acceptability, effectiveness, impact and implementation lessons of these strategies to inform effective typhoid vaccination strategies for the future. Vaccination strategies were categorized by vaccine disease control strategy (preemptive use for endemic disease or to prevent an outbreak, and reactive use for outbreak control) and vaccine delivery strategy (community-based routine, community-based campaign and school-based). Almost all public health typhoid vaccination programs used ViPS vaccine and have been in countries of Asia, with one example in the Pacific and one experience using the Ty21a vaccine in South America. All vaccination strategies were found to be acceptable, feasible and effective in the settings evaluated; evidence of impact, where available, was strongest in endemic settings and in the short- to medium-term. Vaccination was cost-effective in high-incidence but not low-incidence settings. Experience in disaster and outbreak settings remains limited. TCVs have recently become available and none are WHO-prequalified yet; no program experience with TCVs was found in published literature. Despite the demonstrated success of several typhoid vaccination strategies, typhoid vaccines remain underused. Implementation lessons should be applied to design optimal vaccination strategies using TCVs which have several anticipated advantages, such as potential for use in infant immunization programs and longer duration of protection, over the ViPS and Ty21a vaccines for typhoid prevention and control. Copyright © 2015. Published by

Baseline rationing

DEFF Research Database (Denmark)

Hougaard, Jens Leth; Moreno-Ternero, Juan D.; Østerdal, Lars Peter Raahave

The standard problem of adjudicating conflicting claims describes a situation in which a given amount of a divisible good has to be allocated among agents who hold claims against it exceeding the available amount. This paper considers more general rationing problems in which, in addition to claims...... to international protocols for the reduction of greenhouse emissions, or water distribution in drought periods. We define a family of allocation methods for such general rationing problems - called baseline rationing rules - and provide an axiomatic characterization for it. Any baseline rationing rule within...... the family is associated with a standard rule and we show that if the latter obeys some properties reflecting principles of impartiality, priority and solidarity, the former obeys them too....

LVIF Call 2 - Innovations to improve livestock vaccines

International Development Research Centre (IDRC) Digital Library (Canada)

Musa Mulongo

production, and commercialization of innovative vaccines against livestock ... novel vaccine design/formulations that present significant improvements over ... and which can be transferred to vaccine manufacturers for subsequent registration of.

Rationing with baselines

DEFF Research Database (Denmark)

Hougaard, Jens Leth; Moreno-Ternero, Juan D.; Østerdal, Lars Peter Raahave

2013-01-01

We introduce a new operator for general rationing problems in which, besides conflicting claims, individual baselines play an important role in the rationing process. The operator builds onto ideas of composition, which are not only frequent in rationing, but also in related problems...... such as bargaining, choice, and queuing. We characterize the operator and show how it preserves some standard axioms in the literature on rationing. We also relate it to recent contributions in such literature....

Protein engineering of Bacillus acidopullulyticus pullulanase for enhanced thermostability using in silico data driven rational design methods.

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Chen, Ana; Li, Yamei; Nie, Jianqi; McNeil, Brian; Jeffrey, Laura; Yang, Yankun; Bai, Zhonghu

2015-10-01

Thermostability has been considered as a requirement in the starch processing industry to maintain high catalytic activity of pullulanase under high temperatures. Four data driven rational design methods (B-FITTER, proline theory, PoPMuSiC-2.1, and sequence consensus approach) were adopted to identify the key residue potential links with thermostability, and 39 residues of Bacillus acidopullulyticus pullulanase were chosen as mutagenesis targets. Single mutagenesis followed by combined mutagenesis resulted in the best mutant E518I-S662R-Q706P, which exhibited an 11-fold half-life improvement at 60 °C and a 9.5 °C increase in Tm. The optimum temperature of the mutant increased from 60 to 65 °C. Fluorescence spectroscopy results demonstrated that the tertiary structure of the mutant enzyme was more compact than that of the wild-type (WT) enzyme. Structural change analysis revealed that the increase in thermostability was most probably caused by a combination of lower stability free-energy and higher hydrophobicity of E518I, more hydrogen bonds of S662R, and higher rigidity of Q706P compared with the WT. The findings demonstrated the effectiveness of combined data-driven rational design approaches in engineering an industrial enzyme to improve thermostability. Copyright © 2015 Elsevier Inc. All rights reserved.

Rational design of metal-organic electronic devices: A computational perspective

Science.gov (United States)

Chilukuri, Bhaskar

engineers to choose the appropriate metal electrodes considering the chemical interactions at the interface. Additionally, the calculations performed on the interfaces provided valuable insight into binding energies, charge redistribution, change in the energy levels, dipole formation, etc., which are important parameters to consider while fabricating an electronic device. The research described in this dissertation highlights the application of unique computational modeling methods at different levels of theory to guide the experimental chemists and device engineers toward a rational design of transition metal based electronic devices with low cost and high performance.

Vaccine Hesitancy Among Caregivers and Association with Childhood Vaccination Timeliness in Addis Ababa, Ethiopia.

Science.gov (United States)

Masters, Nina B; Tefera, Yemesrach A; Wagner, Abram L; Boulton, Matthew L

2018-05-24

Vaccines are vital to reducing childhood mortality, and prevent an estimated 2 to 3 million deaths annually which disproportionately occur in the developing world. Overall vaccine coverage is typically used as a metric to evaluate the adequacy of vaccine program performance, though it does not account for untimely administration, which may unnecessarily prolong children's susceptibility to disease. This study explored a hypothesized positive association between increasing vaccine hesitancy and untimeliness of immunizations administered under the Expanded Program on Immunization (EPI) in Addis Ababa, Ethiopia. This cross-sectional survey employed a multistage sampling design, randomly selecting one health center within five sub-cities of Addis Ababa. Caregivers of 3 to 12-month-old infants completed a questionnaire on vaccine hesitancy, and their infants' vaccination cards were examined to assess timeliness of received vaccinations. The sample comprised 350 caregivers. Overall, 82.3% of the surveyed children received all recommended vaccines, although only 55.9% of these vaccinations were timely. Few caregivers (3.4%) reported ever hesitating and 3.7% reported ever refusing a vaccine for their child. Vaccine hesitancy significantly increased the odds of untimely vaccination (AOR 1.94, 95% CI: 1.02, 3.71) in the adjusted analysis. This study found high vaccine coverage among a sample of 350 young children in Addis Ababa, though only half received all recommended vaccines on time. High vaccine hesitancy was strongly associated with infants' untimely vaccination, indicating that increased efforts to educate community members and providers about vaccines may have a beneficial impact on vaccine timeliness in Addis Ababa.

Rational design and optimization of downstream processes of virus particles for biopharmaceutical applications: current advances.

Science.gov (United States)

Vicente, Tiago; Mota, José P B; Peixoto, Cristina; Alves, Paula M; Carrondo, Manuel J T

2011-01-01

The advent of advanced therapies in the pharmaceutical industry has moved the spotlight into virus-like particles and viral vectors produced in cell culture holding great promise in a myriad of clinical targets, including cancer prophylaxis and treatment. Even though a couple of cases have reached the clinic, these products have yet to overcome a number of biological and technological challenges before broad utilization. Concerning the manufacturing processes, there is significant research focusing on the optimization of current cell culture systems and, more recently, on developing scalable downstream processes to generate material for pre-clinical and clinical trials. We review the current options for downstream processing of these complex biopharmaceuticals and underline current advances on knowledge-based toolboxes proposed for rational optimization of their processing. Rational tools developed to increase the yet scarce knowledge on the purification processes of complex biologicals are discussed as alternative to empirical, "black-boxed" based strategies classically used for process development. Innovative methodologies based on surface plasmon resonance, dynamic light scattering, scale-down high-throughput screening and mathematical modeling for supporting ion-exchange chromatography show great potential for a more efficient and cost-effective process design, optimization and equipment prototyping. Copyright © 2011 Elsevier Inc. All rights reserved.

Evolutionary and Comparative Genomics to Drive Rational Drug Design, with Particular Focus on Neuropeptide Seven-Transmembrane Receptors.

Science.gov (United States)

Furlong, Michael; Seong, Jae Young

2017-01-01

Seven transmembrane receptors (7TMRs), also known as G protein-coupled receptors, are popular targets of drug development, particularly 7TMR systems that are activated by peptide ligands. Although many pharmaceutical drugs have been discovered via conventional bulk analysis techniques the increasing availability of structural and evolutionary data are facilitating change to rational, targeted drug design. This article discusses the appeal of neuropeptide-7TMR systems as drug targets and provides an overview of concepts in the evolution of vertebrate genomes and gene families. Subsequently, methods that use evolutionary concepts and comparative analysis techniques to aid in gene discovery, gene function identification, and novel drug design are provided along with case study examples.

Rational design of hypoallergens applied to the major cat allergen Fel d 1.

Science.gov (United States)

Saarne, T; Kaiser, L; Grönlund, H; Rasool, O; Gafvelin, G; van Hage-Hamsten, M

2005-05-01

Allergen-specific immunotherapy is the only treatment for allergic disease providing long-lasting symptom relief. Currently, it is mainly based on the use of crude allergen extracts. The treatment may be improved by the use of genetically engineered allergens, hypoallergens, aiming at a more effective and safer therapy. The aim of this study was to provide a rational design of hypoallergen candidates for immunotherapy by using structural information and knowledge of B and T cell epitopes of an allergen. The three-dimensional structure of the major cat allergen Fel d 1 was systematically altered by duplication of selected T cell epitopes and disruption of disulphide bonds. Seven Fel d 1 derivatives were generated and screened for allergenic reactivity in comparison with recombinant Fel d 1 in competition-ELISA. The allergenicity was further evaluated in basophil activation experiments and T cell reactivity was assessed in a lymphoproliferation assay. Three out of seven Fel d 1 derivatives, with two duplicated T cell epitopes and one or two disulphide bonds disrupted, were carefully evaluated. The three derivatives displayed a strong reduction in allergenicity with 400-900 times lower IgE-binding capacity than recombinant Fel d 1. In addition, they induced a lower degree of basophil activation and similar or stronger T cell proliferation than recombinant Fel d 1. By a rational approach, we have constructed three Fel d 1 hypoallergens with reduced IgE-binding capacities and retained T cell reactivities. This strategy may be applied to any well-characterized allergen to improve immunotherapy for allergic patients.

Personal Autonomy and Rational Suicide.

Science.gov (United States)

Webber, May A.; Shulman, Ernest

That certain suicides (which can be designated as rational) ought not to be interfered with is closely tied to the notion of the "right to autonomy." Specifically it is because the individual in question has this right that interference is prohibited. A proper understanding of the right to autonomy, while essential to understanding why…

Inaugurating Rationalization: Three Field Studies Find Increased Rationalization When Anticipated Realities Become Current.

Science.gov (United States)

Laurin, Kristin

2018-04-01

People will often rationalize the status quo, reconstruing it in an exaggeratedly positive light. They will even rationalize the status quo they anticipate, emphasizing the upsides and minimizing the downsides of sociopolitical realities they expect to take effect. Drawing on recent findings on the psychological triggers of rationalization, I present results from three field studies, one of which was preregistered, testing the hypothesis that an anticipated reality becoming current triggers an observable boost in people's rationalizations. San Franciscans rationalized a ban on plastic water bottles, Ontarians rationalized a targeted smoking ban, and Americans rationalized the presidency of Donald Trump, more in the days immediately after these realities became current compared with the days immediately before. Additional findings show evidence for a mechanism underlying these behaviors and rule out alternative accounts. These findings carry implications for scholarship on rationalization, for understanding protest behavior, and for policymakers.

A Rationally Designed TNF-α Epitope-Scaffold Immunogen Induces Sustained Antibody Response and Alleviates Collagen-Induced Arthritis in Mice.

Directory of Open Access Journals (Sweden)

Li Zhang

Full Text Available The TNF-α biological inhibitors have significantly improved the clinical outcomes of many autoimmune diseases, in particular rheumatoid arthritis. However, the practical uses are limited due to high costs and the risk of anti-drug antibody responses. Attempts to develop anti-TNF-α vaccines have generated encouraging data in animal models, however, data from clinical trials have not met expectations. In present study, we designed a TNF-α epitope-scaffold immunogen DTNF7 using the transmembrane domain of diphtheria toxin, named DTT as a scaffold. Molecular dynamics simulation shows that the grafted TNF-α epitope is entirely surface-exposed and presented in a native-like conformation while the rigid helical structure of DTT is minimally perturbed, thereby rendering the immunogen highly stable. Immunization of mice with alum formulated DTNF7 induced humoral responses against native TNF-α, and the antibody titer was sustained for more than 6 months, which supports a role of the universal CD4 T cell epitopes of DTT in breaking self-immune tolerance. In a mouse model of rheumatoid arthritis, DTNF7-alum vaccination markedly delayed the onset of collagen-induced arthritis, and reduced incidence as well as clinical score. DTT is presumed safe as an epitope carrier because a catalytic inactive mutant of diphtheria toxin, CRM197 has good clinical safety records as an active vaccine component. Taken all together, we show that DTT-based epitope vaccine is a promising strategy for prevention and treatment of autoimmune diseases.

Realization theory for rational systems: Minimal rational realizations

NARCIS (Netherlands)

J. Nemcová (Jana); J.H. van Schuppen (Jan)

2010-01-01

htmlabstractThe study of realizations of response maps is a topic of control and system theory. Realization theory is used in system identification and control synthesis. A minimal rational realization of a given response map p is a rational realization of p such that the dimension of its state

Impact of information on intentions to vaccinate in a potential epidemic: Swine-origin Influenza A (H1N1).

Science.gov (United States)

Chanel, Olivier; Luchini, Stéphane; Massoni, Sébastien; Vergnaud, Jean-Christophe

2011-01-01

Vaccination campaigns to prevent the spread of epidemics are successful only if the targeted populations subscribe to the recommendations of health authorities. However, because compulsory vaccination is hardly conceivable in modern democracies, governments need to convince their populations through efficient and persuasive information campaigns. In the context of the swine-origin A (H1N1) 2009 pandemic, we use an interactive study among the general public in the South of France, with 175 participants, to explore what type of information can induce change in vaccination intentions at both aggregate and individual levels. We find that individual attitudes to vaccination are based on rational appraisal of the situation, and that it is information of a purely scientific nature that has the only significant positive effect on intention to vaccinate. Copyright © 2010 Elsevier Ltd. All rights reserved.

The Boundedly Rational User Equilibrium : A parametric analysis with application to the Network Design Problem

NARCIS (Netherlands)

Eikenbroek, Oskar Adriaan Louis; Still, Georg J.; van Berkum, E.C.; Kern, Walter

In this paper, we study a static traffic assignment that accounts for the boundedly rational route choice behavior of travelers. This assignment induces uncertainties to the ex-ante evaluation of a policy measure: the boundedly rational assignment is non-unique and the indifference band is an

Induction of HIV neutralizing antibodies against the MPER of the HIV envelope protein by HA/gp41 chimeric protein-based DNA and VLP vaccines.

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Ling Ye

Full Text Available Several conserved neutralizing epitopes have been identified in the HIV Env protein and among these, the MPER of gp41 has received great attention and is widely recognized as a promising target. However, little success has been achieved in eliciting MPER-specific HIV neutralizing antibodies by a number of different vaccine strategies. We investigated the ability of HA/gp41 chimeric protein-based vaccines, which were designed to enhance the exposure of the MPER in its native conformation, to induce MPER-specific HIV neutralizing antibodies. In characterization of the HA/gp41 chimeric protein, we found that by mutating an unpaired Cys residue (Cys-14 in its HA1 subunit to a Ser residue, the modified chimeric protein HA-C14S/gp41 showed increased reactivity to a conformation-sensitive monoclonal antibody against HA and formed more stable trimers in VLPs. On the other hand, HA-C14S/gp41 and HA/gp41 chimeric proteins expressed on the cell surfaces exhibited similar reactivity to monoclonal antibodies 2F5 and 4E10. Immunization of guinea pigs using the HA-C14S/gp41 DNA or VLP vaccines induced antibodies against the HIV gp41 as well as to a peptide corresponding to a segment of MPER at higher levels than immunization by standard HIV VLPs. Further, sera from vaccinated guinea pigs were found to exhibit HIV neutralizing activities. Moreover, sera from guinea pigs vaccinated by HA-C14S/gp41 DNA and VLP vaccines but not the standard HIV VLPs, were found to neutralize HIV pseudovirions containing a SIV-4E10 chimeric Env protein. The virus neutralization could be blocked by a MPER-specific peptide, thus demonstrating induction of MPER-specific HIV neutralizing antibodies by this novel vaccine strategy. These results show that induction of MPER-specific HIV neutralizing antibodies can be achieved through a rationally designed vaccine strategy.

Meningococcal group B vaccines.

Science.gov (United States)

Findlow, Jamie

2013-06-01

Meningococcal disease remains a devastating and feared infection with a significant morbidity and mortality profile. The successful impact of meningococcal capsular group C glyconconjugate vaccines introduced into the UK infant immunization schedule in 1999, has resulted in >80% of disease now being attributable to meningococcal capsular group B (MenB). MenB glyconconjugate vaccines are not immunogenic and hence, vaccine design has focused on sub-capsular antigens. Recently, a four component vaccine to combat MenB disease (4CMenB) has progressed through clinical development and was approved by the European Medicines Agency at the end of 2012. This vaccine has proven safe and immunogenic and has been predicted to provide protection against ~73% of the MenB disease from England and Wales. Recommendation/implementation of the vaccine into the UK infant schedule is currently being evaluated. 4CMenB has the potential to provide protection against a significant proportion of MenB disease in the UK which is currently unpreventable.

Elaborating and Making Rational Decisions in Designing Process Operations of a Group of Holes

Directory of Open Access Journals (Sweden)

A. I. Solov'ev

2015-01-01

Full Text Available To manufacture engineering products are used expensive multi-purpose CNC machines with five operated coordinates, allowing a single setup of the work-piece to process a group of holes in the housing part from all sides.Because of the haphazard arrangement of a large number of holes available in the space it is difficult to ensure the effective use of these machines.Onsite operational research, conducted on six CNC GS-500 models, involved actual observations and time measurements during 15 working shifts, processing of observation results, and calculations of equipment performance parameters such as machine utilization rate, arrangement and changeover time loss, and real output. Time loss (downtime because of arrangement amounted 44.52%, while that of due to changeover was 20.1% of the total downtime value. These downtimes hide irrational design solutions concerning the engineering process and a large number of changeovers for a new operation to process a group of the specified work-pieces.It is found that to reduce the changeover downtimes it is necessary to increase, first of all, the average number of single tool travels per one setup in generalized characteristics of a group of the work-pieces. That means to increase a changeover concentration of processing within a single operation, as well as to choose rational values for machining a batch of the work-pieces. Under study conditions, it is, at least. 20-50 pieces.To implement a development of the principle of increasing concentration of the processing changeovers it is advised to apply the developed mathematical models, algorithms, and programs that can be used, as modules or their parts, in computer-aided design (CAD systems. This allows a 3-5 times reduction in time to find the rational option of the work-piece position on the machine work surface when developing a process technology, a review and an analysis of more than the usual number of such possible options. It also improves the

The Effect of Soy Sauce Waste in Ration on Performance of Mojosari Duck

Directory of Open Access Journals (Sweden)

G. A. A. Larasati

2017-06-01

Full Text Available The purpose of study was to determined the effect of soy sauce waste in ration in the ration on the performance of Mojosari duck. The materials used were 240 of Mojosari which are 20 weeks olds with average body weight 1,385.0 ± 130.85 grams (CV = 9.44%. Feed ingredients used were, rice bran, soybean meal, yellow corn, fish meal, pollard and premix. The design that used was Completely Randomized Design (CRD with 4 treatments and 6 replications.The treatment applied soy sauce waste at level 5, 7,5 and 10%. The parameters observed were consumption, egg production, feed conversion. The data were analyzed by analysis of variance with F test. The results showed that soy sauce waste did not effected on performance (consumption of ration, egg production, ration conversion of Mojosari duck. The conclusion of this research is soy sauce waste be used as feed stuff of Mojosari duck ration until level 10%.

Many faces of rationality: Implications of the great rationality debate for clinical decision‐making

Science.gov (United States)

Elqayam, Shira

2017-01-01

Abstract Given that more than 30% of healthcare costs are wasted on inappropriate care, suboptimal care is increasingly connected to the quality of medical decisions. It has been argued that personal decisions are the leading cause of death, and 80% of healthcare expenditures result from physicians' decisions. Therefore, improving healthcare necessitates improving medical decisions, ie, making decisions (more) rational. Drawing on writings from The Great Rationality Debate from the fields of philosophy, economics, and psychology, we identify core ingredients of rationality commonly encountered across various theoretical models. Rationality is typically classified under umbrella of normative (addressing the question how people “should” or “ought to” make their decisions) and descriptive theories of decision‐making (which portray how people actually make their decisions). Normative theories of rational thought of relevance to medicine include epistemic theories that direct practice of evidence‐based medicine and expected utility theory, which provides the basis for widely used clinical decision analyses. Descriptive theories of rationality of direct relevance to medical decision‐making include bounded rationality, argumentative theory of reasoning, adaptive rationality, dual processing model of rationality, regret‐based rationality, pragmatic/substantive rationality, and meta‐rationality. For the first time, we provide a review of wide range of theories and models of rationality. We showed that what is “rational” behaviour under one rationality theory may be irrational under the other theory. We also showed that context is of paramount importance to rationality and that no one model of rationality can possibly fit all contexts. We suggest that in context‐poor situations, such as policy decision‐making, normative theories based on expected utility informed by best research evidence may provide the optimal approach to medical decision�

Diagnosing avian influenza infection in vaccinated populations by systems for differentiating infected from vaccinated animals (DIVA).

Science.gov (United States)

Capua, I; Cattoli, G

2007-01-01

Vaccination against avian influenza is recommended as a tool to support control measures in countries affected by avian influenza. Vaccination is known to increase the resistance of susceptible birds to infection and also to reduce shedding; however, it does not always prevent infection. Vaccinated infected flocks can therefore be a source of infection and thus be responsible for the perpetuation of infection. To avoid the spread of infection in a vaccinated population, immunization strategies must allow differentiation of infected from vaccinated animals (DIVA), combined with an appropriate monitoring system. Vaccinated exposed flocks must be identified and managed by restriction policies that include controlled marketing and stamping-out. Several vaccines and diagnostic tests to detect infection in vaccinated populations are available, the tests having various properties and characteristics. In order to achieve eradication, the most appropriate DIVA vaccination strategy must be identified and an appropriate monitoring programme be designed, taking into account risk factors, the epidemiological situation and the socioeconomic implications of the policy.

Rational design, synthesis, and pharmacological evaluation of 2-azanorbornane-3-exo,5-endo-dicarboxylic acid

DEFF Research Database (Denmark)

Bunch, Lennart; Liljefors, Tommy; Greenwood, Jeremy R

2003-01-01

conformationally restricted (S)-glutamic acid (Glu) analogue intended as a mimic of the folded Glu conformation. The synthesis of 1 was completed in its racemic form in eight steps from commercially available starting materials. As a key step, the first facially selective hydroboration of a 5-methylidene[2......The design and synthesis of conformationally restricted analogues of alpha-amino acids is an often used strategy in medicinal chemistry research. Here we present the rational design, synthesis, and pharmacological evaluation of 2-azanorbornane-3-exo,5-endo-dicarboxylic acid (1), a novel...... studies on native 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) (IC(50) > 300 microM, [(3)H]AMPA) or kainic acid (IC(50) > 160 microM, [(3)H]kainic acid) receptors nor in binding studies on the cloned iGluR5,6 subtypes (IC(50) > 300 microM, [(3)H]kainic acid)....

Rational design of single-molecule magnets: a supramolecular approach.

Science.gov (United States)

Glaser, Thorsten

2011-01-07

Since the discovery that Mn(12)OAc acts as a single-molecule magnet (SMM), an increasing number of transition metal complexes have been demonstrated to behave as SMMs. The signature of a SMM is a slow relaxation of the magnetization at low temperatures accompanied by a magnetic hysteresis. The origin of SMM behaviour is the existence of an appreciable thermal barrier U for spin-reversal called magnetic anisotropy barrier which is related to the combination of a large total spin ground state (S(t)) and an easy-axis magnetic anisotropy. The extensive research on Mn(12)OAc and other SMMs has established more prerequisites for a rational development of new SMMs besides the high-spin ground state and the magnetic anisotropy: the symmetry should be at least C(3) to minimize the quantum tunneling of the magnetization through the anisotropy barrier but lower than cubic to avoid the cancellation of the local anisotropies upon projection onto the spin ground state. Based on these prerequisites, we have designed the ligand triplesalen which combines the phloroglucinol bridging unit for high spin ground states by the spin-polarization mechanism with a salen-like ligand environment for single-site magnetic anisotropies by a strong tetragonal ligand field. The C(3) symmetric, trinuclear complexes of the triplesalen ligand (talen(t-Bu(2)))(6-) exhibit a strong ligand folding resulting in an overall bowl-shaped molecular structure. This ligand folding preorganizes the axial coordination sites of the metal salen subunits for the complementary binding of three facial nitrogen atoms of a hexacyanometallate unit. This leads to a high driving force for the formation of heptanuclear complexes [M(t)(6)M(c)](n+) by the assembly of three molecular building blocks. Attractive van der Waals interactions of the tert-butyl phenyl units of two triplesalen trinuclear building blocks increase the driving force. In this respect, we have been able to synthesize the isostructural series [Mn(III)(6

Progress towards development of an HIV vaccine: report of the AIDS Vaccine 2009 Conference.

Science.gov (United States)

Ross, Anna Laura; Bråve, Andreas; Scarlatti, Gabriella; Manrique, Amapola; Buonaguro, Luigi

2010-05-01

The search for an HIV/AIDS vaccine is steadily moving ahead, generating and validating new concepts in terms of novel vectors for antigen delivery and presentation, new vaccine and adjuvant strategies, alternative approaches to design HIV-1 antigens for eliciting protective cross-neutralising antibodies, and identification of key mechanisms in HIV infection and modulation of the immune system. All these different perspectives are contributing to the unprecedented challenge of developing a protective HIV-1 vaccine. The high scientific value of this massive effort is its great impact on vaccinology as a whole, providing invaluable scientific information for the current and future development of new preventive vaccine as well as therapeutic knowledge-based infectious-disease and cancer vaccines. Copyright 2010 Elsevier Ltd. All rights reserved.

A simulation analysis to characterize the dynamics of vaccinating behaviour on contact networks.

Science.gov (United States)

Perisic, Ana; Bauch, Chris T

2009-05-28

and final number vaccinated. The qualitative outcome of rational, self interested behaviour under a voluntary vaccination policy can vary substantially depending on interactions between social contact structure, perceived vaccine and disease risks, and the way that individual vaccination decision-making is modelled.

A simulation analysis to characterize the dynamics of vaccinating behaviour on contact networks

Directory of Open Access Journals (Sweden)

Bauch Chris T

2009-05-01

differences in population-level outcomes such as final size and final number vaccinated. The qualitative outcome of rational, self interested behaviour under a voluntary vaccination policy can vary substantially depending on interactions between social contact structure, perceived vaccine and disease risks, and the way that individual vaccination decision-making is modelled.

Feline immunodeficiency virus model for designing HIV/AIDS vaccines.

Science.gov (United States)

Yamamoto, Janet K; Sanou, Missa P; Abbott, Jeffrey R; Coleman, James K

2010-01-01

Feline immunodeficiency virus (FIV) discovered in 1986 is a lentivirus that causes AIDS in domestic cats. FIV is classified into five subtypes (A-E), and all subtypes and circulating intersubtype recombinants have been identified throughout the world. A commercial FIV vaccine, consisting of inactivated subtype-A and -D viruses (Fel-O-Vax FIV, Fort Dodge Animal Health), was released in the United States in 2002. The United States Department of Agriculture approved the commercial release of Fel-O-Vax FIV based on two efficacy trials using 105 laboratory cats and a major safety trial performed on 689 pet cats. The prototype and commercial FIV vaccines had broad prophylactic efficacy against global FIV subtypes and circulating intersubtype recombinants. The mechanisms of cross-subtype efficacy are attributed to FIV-specific T-cell immunity. Findings from these studies are being used to define the prophylactic epitopes needed for an HIV-1 vaccine for humans.

Many faces of rationality: Implications of the great rationality debate for clinical decision-making.

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Djulbegovic, Benjamin; Elqayam, Shira

2017-10-01

Given that more than 30% of healthcare costs are wasted on inappropriate care, suboptimal care is increasingly connected to the quality of medical decisions. It has been argued that personal decisions are the leading cause of death, and 80% of healthcare expenditures result from physicians' decisions. Therefore, improving healthcare necessitates improving medical decisions, ie, making decisions (more) rational. Drawing on writings from The Great Rationality Debate from the fields of philosophy, economics, and psychology, we identify core ingredients of rationality commonly encountered across various theoretical models. Rationality is typically classified under umbrella of normative (addressing the question how people "should" or "ought to" make their decisions) and descriptive theories of decision-making (which portray how people actually make their decisions). Normative theories of rational thought of relevance to medicine include epistemic theories that direct practice of evidence-based medicine and expected utility theory, which provides the basis for widely used clinical decision analyses. Descriptive theories of rationality of direct relevance to medical decision-making include bounded rationality, argumentative theory of reasoning, adaptive rationality, dual processing model of rationality, regret-based rationality, pragmatic/substantive rationality, and meta-rationality. For the first time, we provide a review of wide range of theories and models of rationality. We showed that what is "rational" behaviour under one rationality theory may be irrational under the other theory. We also showed that context is of paramount importance to rationality and that no one model of rationality can possibly fit all contexts. We suggest that in context-poor situations, such as policy decision-making, normative theories based on expected utility informed by best research evidence may provide the optimal approach to medical decision-making, whereas in the context

Pathogen-mimicking vaccine delivery system designed with a bioactive polymer (inulin acetate) for robust humoral and cellular immune responses.

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Kumar, Sunny; Kesharwani, Siddharth S; Kuppast, Bhimanna; Bakkari, Mohammed Ali; Tummala, Hemachand

2017-09-10

New and improved vaccines are needed against challenging diseases such as malaria, tuberculosis, Ebola, influenza, AIDS, and cancer. The majority of existing vaccine adjuvants lack the ability to significantly stimulate the cellular immune response, which is required to prevent the aforementioned diseases. This study designed a novel particulate based pathogen-mimicking vaccine delivery system (PMVDS) to target antigen-presenting-cells (APCs) such as dendritic cells. The uniqueness of PMVDS is that the polymer used to prepare the delivery system, Inulin Acetate (InAc), activates the innate immune system. InAc was synthesized from the plant polysaccharide, inulin. PMVDS provided improved and persistent antigen delivery to APCs as an efficient vaccine delivery system, and simultaneously, activated Toll-Like Receptor-4 (TLR-4) on APCs to release chemokine's/cytokines as an immune-adjuvant. Through this dual mechanism, PMVDS robustly stimulated both the humoral (>32 times of IgG1 levels vs alum) and the cell-mediated immune responses against the encapsulated antigen (ovalbumin) in mice. More importantly, PMVDS stimulated both cytotoxic T cells and natural killer cells of cell-mediated immunity to provide tumor (B16-ova-Melanoma) protection in around 40% of vaccinated mice and significantly delayed tumor progression in rest of the mice. PMVDS is a unique bio-active vaccine delivery technology with broader applications for vaccines against cancer and several intracellular pathogens, where both humoral and cellular immune responses are desired. Copyright © 2017 Elsevier B.V. All rights reserved.

A Rapid and Improved Method to Generate Recombinant Dengue Virus Vaccine Candidates.

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Dhanasekaran Govindarajan

Full Text Available Dengue is one of the most important mosquito-borne infections accounting for severe morbidity and mortality worldwide. Recently, the tetravalent chimeric live attenuated Dengue vaccine Dengvaxia® was approved for use in several dengue endemic countries. In general, live attenuated vaccines (LAV are very efficacious and offer long-lasting immunity against virus-induced disease. Rationally designed LAVs can be generated through reverse genetics technology, a method of generating infectious recombinant viruses from full length cDNA contained in bacterial plasmids. In vitro transcribed (IVT viral RNA from these infectious clones is transfected into susceptible cells to generate recombinant virus. However, the generation of full-length dengue virus cDNA clones can be difficult due to the genetic instability of viral sequences in bacterial plasmids. To circumvent the need for a single plasmid containing a full length cDNA, in vitro ligation of two or three cDNA fragments contained in separate plasmids can be used to generate a full-length dengue viral cDNA template. However, in vitro ligation of multiple fragments often yields low quality template for IVT reactions, resulting in inconsistent low yield RNA. These technical difficulties make recombinant virus recovery less efficient. In this study, we describe a simple, rapid and efficient method of using LONG-PCR to recover recombinant chimeric Yellow fever dengue (CYD viruses as potential dengue vaccine candidates. Using this method, we were able to efficiently generate several viable recombinant viruses without introducing any artificial mutations into the viral genomes. We believe that the techniques reported here will enable rapid and efficient recovery of recombinant flaviviruses for evaluation as vaccine candidates and, be applicable to the recovery of other RNA viruses.

Vaccine Platforms to Control Arenaviral Hemorrhagic Fevers.

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Carrion, Ricardo; Bredenbeek, Peter; Jiang, Xiaohong; Tretyakova, Irina; Pushko, Peter; Lukashevich, Igor S

2012-11-20

Arenaviruses are rodent-borne emerging human pathogens. Diseases caused by these viruses, e.g., Lassa fever (LF) in West Africa and South American hemorrhagic fevers (HFs), are serious public health problems in endemic areas. We have employed replication-competent and replication-deficient strategies to design vaccine candidates potentially targeting different groups "at risk". Our leader LF vaccine candidate, the live reassortant vaccine ML29, is safe and efficacious in all tested animal models including non-human primates. In this study we showed that treatment of fatally infected animals with ML29 two days after Lassa virus (LASV) challenge protected 80% of the treated animals. In endemic areas, where most of the target population is poor and many live far from health care facilities, a single-dose vaccination with ML29 would be ideal solution. Once there is an outbreak, a fast-acting vaccine or post-exposure prophylaxis would be best. The 2(nd) vaccine technology is based on Yellow Fever (YF) 17D vaccine. We designed YF17D-based recombinant viruses expressing LASV glycoproteins (GP) and showed protective efficacy of these recombinants. In the current study we developed a novel technology to clone LASV nucleocapsid within YF17D C gene. Low immunogenicity and stability of foreign inserts must be addressed to design successful LASV/YFV bivalent vaccines to control LF and YF in overlapping endemic areas of West Africa. The 3(rd) platform is based on the new generation of alphavirus replicon virus-like-particle vectors (VLPV). Using this technology we designed VLPV expressing LASV GP with enhanced immunogenicity and bivalent VLPV expressing cross-reactive GP of Junin virus (JUNV) and Machupo virus (MACV), causative agents of Argentinian and Bolivian HF, respectively. A prime-boost regimen required for VLPV immunization might be practical for medical providers, military, lab personnel, and visitors in endemic areas.

Model for product development of vaccines against neglected tropical diseases: a vaccine against human hookworm.

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Bottazzi, Maria Elena; Brown, Ami Shah

2008-12-01

This article provides an overview of the advances in product development and technology transfer of the vaccine against human hookworm, with particular emphasis on the lessons learned and the challenges of developing a vaccine in the nonprofit sector. The comprehensive approach to vaccine development established by the Human Hookworm Vaccine Initiative (HHVI) identifies key operational and technical aspects that are essential for a successful partnership with a developing country vaccine manufacturer. This article also highlights the importance of a global access roadmap to guide the vaccine development program. The advancement of new products for the control of neglected tropical diseases portends great challenges for global access, including aspects related to vaccine design, product development and manufacture, vaccine introduction and distribution, financing, knowledge dissemination and intellectual property management. With only three vaccines for neglected tropical diseases in clinical trials - hookworm, leishmaniasis and schistosomiasis - we are at the nascent stages of developing vaccines for neglected populations. Product development public-private partnerships, such as the HHVI, continue to show great promise on this front and will eventually provide significant control tools for achieving millennium development goals related to poverty reduction, as well as child and maternal health.

Rationality and drug use: an experimental approach.

Science.gov (United States)

Blondel, Serge; Lohéac, Youenn; Rinaudo, Stéphane

2007-05-01

In rational addiction theory, higher discount rates encourage drug use. We test this hypothesis in the general framework of rationality and behaviour under risk. We do so using an experimental design with real monetary incentives. The decisions of 34 drug addicts are compared with those of a control group. The decisions of drug users (DU) are not any less consistent with standard theories of behaviour over time and under risk. Further, there is no difference in the estimated discount rate between drug users and the control group, but the former do appear to be more risk-seeking.

Molecular and Cellular Dynamics in the Skin, the Lymph Nodes, and the Blood of the Immune Response to Intradermal Injection of Modified Vaccinia Ankara Vaccine

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Pierre Rosenbaum

2018-04-01

Full Text Available New vaccine design approaches would be greatly facilitated by a better understanding of the early systemic changes, and those that occur at the site of injection, responsible for the installation of a durable and oriented protective response. We performed a detailed characterization of very early infection and host response events following the intradermal administration of the modified vaccinia virus Ankara as a live attenuated vaccine model in non-human primates. Integrated analysis of the data obtained from in vivo imaging, histology, flow cytometry, multiplex cytokine, and transcriptomic analysis using tools derived from systems biology, such as co-expression networks, showed a strong early local and systemic inflammatory response that peaked at 24 h, which was then progressively replaced by an adaptive response during the installation of the host response to the vaccine. Granulocytes, macrophages, and monocytoid cells were massively recruited during the local innate response in association with local productions of GM-CSF, IL-1β, MIP1α, MIP1β, and TNFα. We also observed a rapid and transient granulocyte recruitment and the release of IL-6 and IL-1RA, followed by a persistent phase involving inflammatory monocytes. This systemic inflammation was confirmed by molecular signatures, such as upregulations of IL-6 and TNF pathways and acute phase response signaling. Such comprehensive approaches improve our understanding of the spatiotemporal orchestration of vaccine-elicited immune response, in a live-attenuated vaccine model, and thus contribute to rational vaccine development.

Vaccine process technology.

Science.gov (United States)

Josefsberg, Jessica O; Buckland, Barry

2012-06-01

perspective, Quality by Design (QbD) and Process Analytical Technology (PAT) are important initiatives that can be applied effectively to many types of vaccine processes. Universal demand for vaccines requires that a manufacturer plan to supply tens and sometimes hundreds of millions of doses per year at low cost. To enable broader use, there is intense interest in improving temperature stability to allow for excursions from a rigid cold chain supply, especially at the point of vaccination. Finally, there is progress in novel routes of delivery to move away from the traditional intramuscular injection by syringe approach. Copyright © 2012 Wiley Periodicals, Inc.

Heterogeneity of Rabies Vaccination Recommendations across Asia

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Philippe Buchy

2017-07-01

Full Text Available Asian countries bear the greatest burden of the disease, with a majority (59% of rabies-related deaths occurring in Asia. In order to promote best practices, we summarized national human vaccination guidelines across this region, to highlight differences and similarities and to discuss the aspects that would benefit from updates. National management guidelines for rabies were retrieved from various sources to extract information on rabies pre- and post-exposure prophylaxis (PrEP, and PEP, booster vaccination, and route of administration. Rabies guidelines recommendations for wound management and PrEP across Asia are broadly aligned to the World Health Organization (WHO guidelines. For PEP, the 5-dose Essen, and the 4-dose Zagreb are the regimens of choice for intramuscular (IM, and the Thai Red Cross regimen for intradermal (ID, administration. Several national guidelines have yet to endorse ID vaccine administration. Most guidelines recommend rabies immunoglobulin in category III exposures. Booster recommendations are not included in all guidelines, with limited clarity on booster requirement across the spectrum of risk of rabies exposure. In conclusion, national recommendations across Asian countries differ and while some guidelines are closely aligned to the WHO recommendations, resource-saving ID administration and use of rational abbreviated schedules have yet to be endorsed.

Adolescent rationality.

Science.gov (United States)

Moshman, David

2013-01-01

Adolescents are commonly seen as irrational, a position supported to varying degrees by many developmentalists, who often appeal to recent research on adolescent brains. Careful review of relevant evidence, however, shows that (1) adults are less rational than is generally assumed, (2) adolescents (and adults) are categorically different from children with respect to the attainment of advanced levels of rationality and psychological functioning, and (3) adolescents and adults do not differ categorically from each other with respect to any rational competencies, irrational tendencies, brain structures, or neurological functioning. Development often continues in adolescence and beyond but categorical claims about adolescents as distinct from adults cannot be justified. A review of U.S. Supreme Court decisions concerning intellectual freedom, reproductive freedom, and criminal responsibility shows ongoing ambivalence and confusion about the rationality of adolescents. Developmental theory and research suggest that adolescents should be conceptualized as young adults, not immature brains, with important implications for their roles, rights, and responsibilities.

Challenges to the development of vaccines to hepatitis C virus that elicit neutralizing antibodies.

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Heidi Edelgard Drummer

2014-07-01

Full Text Available Despite 20 years of research, a vaccine to prevent hepatitis C virus (HCV infection has not been developed. A vaccine to prevent HCV will need to induce broadly reactive immunity able to prevent infection by the 7 genetically and antigenically distinct genotypes circulating world-wide. Hepatitis C virus encodes two surface exposed glycoproteins, E1 and E2 that function as a heterodimer to mediate viral entry. Neutralizing antibodies (NAbs to both E1 and E2 have been described with the major NAb target being E2. The function of E2 is to attach virions to host cells via cell surface receptors that include, but is not limited to, the tetraspanin CD81 and scavenger receptor B class I. However, E2 has developed a number of immune evasion strategies to limit the effectiveness of the NAb response and possibly limit the ability of the immune system to generate potent NAbs in natural infection. Hypervariable regions that shield the underlying core domain, subdominant neutralization epitopes and glycan shielding combine to make E2 a difficult target for the immune system. This review summarizes recent information on the role of neutralizing antibodies to prevent HCV infection, the targets of the neutralizing antibody response and structural information on glycoprotein E2 in complex with neutralizing antibodies. This new information should provide a framework for the rational design of new vaccine candidates that elicit highly potent broadly reactive NAbs to prevent HCV infection.

[The gentic principles for the design of live Salmonella vaccines].

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Petrovskaia, V G; Marakusha, B I; Bondarenko, V M

1996-01-01

The presently known methods of obtaining Salmonella vaccine strains are characterized, their advantages and drawbacks are noted. Great importance of the genetic safety of Salmonella attenuated strains to be controlled is emphasized, taking into account that they are also used as carrier strains for obtaining hybrid and gene-engineering (vector) vaccines carrying immunogenicity factors of other species of pathogenic microorganisms.

Influenza and Pneumonia Vaccination Rates and Factors Affecting Vaccination among Patients with Chronic Obstructive Pulmonary Disease

OpenAIRE

Aka Akt?rk, ?lk?; G?rek Dilekta?l?, Asl?; ?eng?l, Aysun; Musaffa Salep?i, Banu; Oktay, Nuray; D?ger, Mustafa; Ar?k Ta?y?kan, Hale; Durmu? Ko?ak, Nagihan

2017-01-01

Background: Influenza and pneumococcal vaccinations are recommended in chronic obstructive pulmonary disease patients to decrease associated risks at all stages. Although the prevalence of chronic obstructive pulmonary disease is high in our country, as previously reported, vaccination rates are low. Aims: To assess the vaccination rates of chronic obstructive pulmonary disease patients and factors that may affect these. Study Design: Multi-centre cross-sectional study. Methods: Patients admi...

Love and rationality: on some possible rational effects of love

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Gustavo Ortiz-Millán

Full Text Available In this paper I defend the idea that rather than disrupting rationality, as the common-sense conception has done it, love may actually help us to develop rational ways of thinking and acting. I make the case for romantic or erotic love, since this is the kind of love that is more frequently associated with irrationality in acting and thinking. I argue that this kind of love may make us develop epistemic and practical forms of rationality. Based on an analysis of its characteristic action tendencies, I argue that love may help us to develop an instrumental form of rationality in determining the best means to achieve the object of love. It may also narrow down the number of practical considerations that may help us to achieve our goals. Finally, love may generate rational ways of belief-formation by framing the parameters taken into account in perception and attention, and by bringing into light only a small portion of the epistemic information available. Love may make us perceive reality more acutely.

Rational design of highly potent HIV-1 fusion inhibitory proteins: Implication for developing antiviral therapeutics

International Nuclear Information System (INIS)

Ni Ling; Gao, George F.; Tien Po

2005-01-01

Recombinant protein containing one heptad-repeat 1 (HR1) segment and one HR2 segment of the HIV-1 gp41 (HR1-HR2) has been shown to fold into thermally stable six-helix bundle, representing the fusogenic core of gp41. In this study, we have used the fusogenic core as a scaffold to design HIV-1 fusion inhibitory proteins by linking another HR1 to the C terminus of HR1-HR2 (HR121) or additional HR2 to the N terminus of HR1-HR2 (HR212). Both recombinant proteins could be abundantly and solubly expressed and easily purified, exhibiting high stability and potent inhibitory activity on HIV-1 fusion with IC 50 values of 16.2 ± 2.8 and 2.8 ± 0.63 nM, respectively. These suggest that these rationally designed proteins can be further developed as novel anti-HIV-1 therapeutics

Dendrimers for Vaccine and Immunostimulatory Uses

DEFF Research Database (Denmark)

Heegaard, Peter M. H.; Boas, Ulrik; Sørensen, Nanna Skall

2010-01-01

for efficient immunostimulating compounds (adjuvants) that can increase the efficiency of vaccines, as dendrimers can provide molecularly defined multivalent scaffolds to produce highly defined conjugates with small molecule immunostimulators and/or antigens. The review gives an overview on the use...... of dendrimers as molecularly defined carriers/presenters of small antigens, including constructs that have built-in immunostimulatory (adjuvant) properties, and as stand-alone adjuvants that can be mixed with antigens to provide efficient vaccine formulations. These approaches allow the preparation...... of molecularly defined vaccines with highly predictable and specific properties and enable knowledge-based vaccine design substituting the traditional empirically based approaches for vaccine development and production....

Buccal and sublingual vaccine delivery.

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Kraan, Heleen; Vrieling, Hilde; Czerkinsky, Cecil; Jiskoot, Wim; Kersten, Gideon; Amorij, Jean-Pierre

2014-09-28

Because of their large surface area and immunological competence, mucosal tissues are attractive administration and target sites for vaccination. An important characteristic of mucosal vaccination is its ability to elicit local immune responses, which act against infection at the site of pathogen entry. However, mucosal surfaces are endowed with potent and sophisticated tolerance mechanisms to prevent the immune system from overreacting to the many environmental antigens. Hence, mucosal vaccination may suppress the immune system instead of induce a protective immune response. Therefore, mucosal adjuvants and/or special antigen delivery systems as well as appropriate dosage forms are required in order to develop potent mucosal vaccines. Whereas oral, nasal and pulmonary vaccine delivery strategies have been described extensively, the sublingual and buccal routes have received considerably less attention. In this review, the characteristics of and approaches for sublingual and buccal vaccine delivery are described and compared with other mucosal vaccine delivery sites. We discuss recent progress and highlight promising developments in the search for vaccine formulations, including adjuvants and suitable dosage forms, which are likely critical for designing a successful sublingual or buccal vaccine. Finally, we outline the challenges, hurdles to overcome and formulation issues relevant for sublingual or buccal vaccine delivery. Copyright © 2014. Published by Elsevier B.V.

Rational use of rubella vaccine for prevention of congenital rubella syndrome in the Americas

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Alan R. Hinman

1998-09-01

Full Text Available Rubella is a viral disease with minor morbidity and few complications unless it is contracted by a pregnant woman. Rubella infection during the first trimester of pregnancy often leads to fetal death or severe congenital defects (congenital rubella syndrome, CRS. Rubella remains endemic in many countries of Latin America and the Caribbean. It has been estimated that 20000 or more infants are perhaps born with CRS each year in Latin American and Caribbean countries. While the inclusion of rubella vaccination into routine childhood immunization will decrease rubella virus circulation among young children, it will not have immediate impact on the transmission of rubella among adults or the occurrence of CRS. A one-time mass campaign targeting both males and females 5 to 39 years of age with measles-mumps-rubella or measles-rubella vaccine followed by the use of measles-mumps-rubella vaccine in routine early childhood vaccination will prevent and control both rubella and CRS promptly. In April 1988, the Ministers of Health of the English-speaking Caribbean targeted rubella for elimination by the end of the year 2000 using the vaccination strategy outlined above. The rubella elimination experience of these countries will provide useful information for the eventual elimination of rubella virus from the Americas.La rubéola es una enfermedad vírica que produce poca morbilidad y pocas complicaciones, a no ser que la contraiga una mujer embarazada. La infección con rubéola durante el primer trimestre del embarazo a menudo termina en muerte fetal o en deformidades congénitas graves (síndrome de anomalías congénitas por rubéola, o SCR. La rubéola sigue siendo endémica en muchos países de América Latina y el Caribe. Se estima que quizá 20 000 niños o más nacen cada año con SCR en países latinoamericanos y caribeños. Si bien la adición de la vacuna contra la rubéola a los programas de inmunización infantil de rutina disminuirá la

CONTRIBUTIONS TO RATIONAL APPROXIMATION,

Science.gov (United States)

Some of the key results of linear Chebyshev approximation theory are extended to generalized rational functions. Prominent among these is Haar’s...linear theorem which yields necessary and sufficient conditions for uniqueness. Some new results in the classic field of rational function Chebyshev...Furthermore a Weierstrass type theorem is proven for rational Chebyshev approximation. A characterization theorem for rational trigonometric Chebyshev approximation in terms of sign alternation is developed. (Author)

Rational points, rational curves, and entire holomorphic curves on projective varieties

CERN Document Server

Gasbarri, Carlo; Roth, Mike; Tschinkel, Yuri

2015-01-01

This volume contains papers from the Short Thematic Program on Rational Points, Rational Curves, and Entire Holomorphic Curves and Algebraic Varieties, held from June 3-28, 2013, at the Centre de Recherches Mathématiques, Université de Montréal, Québec, Canada. The program was dedicated to the study of subtle interconnections between geometric and arithmetic properties of higher-dimensional algebraic varieties. The main areas of the program were, among others, proving density of rational points in Zariski or analytic topology on special varieties, understanding global geometric properties of rationally connected varieties, as well as connections between geometry and algebraic dynamics exploring new geometric techniques in Diophantine approximation.

Conventional influenza vaccines influence the performance of a universal influenza vaccine in mice.

Science.gov (United States)

Rowell, Janelle; Lo, Chia-Yun; Price, Graeme E; Misplon, Julia A; Epstein, Suzanne L; Garcia, Mayra

2018-02-08

Universal influenza vaccines are designed to protect against diverse strains of influenza virus. Preclinical testing of new vaccine candidates is usually done in naïve animals, despite intended use in the human population with its varied immune history including responses to previous vaccinations. As an approach more relevant to human use, we tested a candidate universal influenza vaccine in mice with a history of conventional vaccination. Female BALB/c mice were given two intramuscular doses of inactivated influenza vaccine (IIV) or diphtheria and tetanus toxoids vaccine (DT), one month apart. Another group was given two intranasal doses of live attenuated influenza virus (LAIV). One month after the second dose, mice were given the universal influenza vaccine: recombinant adenoviruses expressing influenza A nucleoprotein (A/NP) and matrix 2 (M2) (A/NP + M2-rAd). Immune responses to universal vaccine antigens A/NP and M2 were assessed by ELISA and interferon-γ ELISPOT. Protection was tested by challenge with mouse-adapted A/FM/1/47 (H1N1) and monitoring for weight loss and survival. Universal vaccine performance was enhanced, inhibited or unaffected by particular prior vaccinations. Mice given Afluria IIV and LAIV had greater antibody and T-cell response to A/NP than mice without prior vaccination, providing examples of enhanced A/NP + M2-rAd performance. Though Fluvirin IIV partially inhibited, the universal vaccine still provided considerable protection unlike conventional vaccination. Fluzone IIV and DT had no effect on A/NP + M2-rAd performance. Thus our results demonstrate that universal vaccine candidate A/NP + M2-rAd was at least partially effective in mice with diverse prior histories. However, the degree of protection and nature of the immune responses may be affected by a history of conventional vaccination and suggests that performance in humans would be influenced by immune history. Published by Elsevier Ltd.

Design and performance prediction of solar adsorption cooling for mobile vaccine refrigerator

Science.gov (United States)

Djubaedah, Euis; Taufan, Andi; Ratnasari, Nadhira; Fahrizal, Adjie; Hamidi, Qayyum; Nasruddin

2017-03-01

Adsorption cooling is a process that uses a drop-in pressure caused by the adsorption of adsorbate by adsorbent. Adsorption process creates a pressure drop which can bring down the temperature to the intended condition. This approach can be used in vaccine transportation as the vaccines need to be stored at low temperatures (2°C to 8°C for preserving vaccines). The pressure decrease can be obtained by adsorption water in zeolites and can also produce the temperature drop in the main chamber. The adsorption process of water will decrease until reaching saturation condition. Heat is needed to keep the system continuous as it starts a desorption process. From the simulation using MATLAB, it is found that the mobile vaccine refrigerator can reach the temperature of 2°C in 180 seconds with the amount of cooling power generated is up to 1530 W. The insulation can hold the allowable temperature range inside the vaccine cabin for 15.6795 hours.

Application of 3D-QSAR in the rational design of receptor ligands and enzyme inhibitors.

Science.gov (United States)

Mor, Marco; Rivara, Silvia; Lodola, Alessio; Lorenzi, Simone; Bordi, Fabrizio; Plazzi, Pier Vincenzo; Spadoni, Gilberto; Bedini, Annalida; Duranti, Andrea; Tontini, Andrea; Tarzia, Giorgio

2005-11-01

Quantitative structure-activity relationships (QSARs) are frequently employed in medicinal chemistry projects, both to rationalize structure-activity relationships (SAR) for known series of compounds and to help in the design of innovative structures endowed with desired pharmacological actions. As a difference from the so-called structure-based drug design tools, they do not require the knowledge of the biological target structure, but are based on the comparison of drug structural features, thus being defined ligand-based drug design tools. In the 3D-QSAR approach, structural descriptors are calculated from molecular models of the ligands, as interaction fields within a three-dimensional (3D) lattice of points surrounding the ligand structure. These descriptors are collected in a large X matrix, which is submitted to multivariate analysis to look for correlations with biological activity. Like for other QSARs, the reliability and usefulness of the correlation models depends on the validity of the assumptions and on the quality of the data. A careful selection of compounds and pharmacological data can improve the application of 3D-QSAR analysis in drug design. Some examples of the application of CoMFA and CoMSIA approaches to the SAR study and design of receptor or enzyme ligands is described, pointing the attention to the fields of melatonin receptor ligands and FAAH inhibitors.

Status of vaccine research and development of vaccines for leishmaniasis.

Science.gov (United States)

Gillespie, Portia M; Beaumier, Coreen M; Strych, Ulrich; Hayward, Tara; Hotez, Peter J; Bottazzi, Maria Elena

2016-06-03

A number of leishmaniasis vaccine candidates are at various stages of pre-clinical and clinical development. Leishmaniasis is a vector-borne neglected tropical disease (NTD) caused by a protozoan parasite of the genus Leishmania and transmitted to humans by the bite of a sand fly. Visceral leishmaniasis (VL, kala-azar) is a high mortality NTD found mostly in South Asia and East Africa, while cutaneous leishmaniasis (CL) is a disfiguring NTD highly endemic in the Middle East, Central Asia, North Africa, and the Americas. Estimates attribute 50,000 annual deaths and 3.3 million disability-adjusted life years to leishmaniasis. There are only a few approved drug treatments, no prophylactic drug and no vaccine. Ideally, an effective vaccine against leishmaniasis will elicit long-lasting immunity and protect broadly against VL and CL. Vaccines such as Leish-F1, F2 and F3, developed at IDRI and designed based on selected Leishmania antigen epitopes, have been in clinical trials. Other groups, including the Sabin Vaccine Institute in collaboration with the National Institutes of Health are investigating recombinant Leishmania antigens in combination with selected sand fly salivary gland antigens in order to augment host immunity. To date, both VL and CL vaccines have been shown to be cost-effective in economic modeling studies. Copyright © 2016 World Health Organization. Published by Elsevier Ltd.. All rights reserved.

Vaccines for the 21st century

Science.gov (United States)

Delany, Isabel; Rappuoli, Rino; De Gregorio, Ennio

2014-01-01

In the last century, vaccination has been the most effective medical intervention to reduce death and morbidity caused by infectious diseases. It is believed that vaccines save at least 2–3 million lives per year worldwide. Smallpox has been eradicated and polio has almost disappeared worldwide through global vaccine campaigns. Most of the viral and bacterial infections that traditionally affected children have been drastically reduced thanks to national immunization programs in developed countries. However, many diseases are not yet preventable by vaccination, and vaccines have not been fully exploited for target populations such as elderly and pregnant women. This review focuses on the state of the art of recent clinical trials of vaccines for major unmet medical needs such as HIV, malaria, TB, and cancer. In addition, we describe the innovative technologies currently used in vaccine research and development including adjuvants, vectors, nucleic acid vaccines, and structure-based antigen design. The hope is that thanks to these technologies, more diseases will be addressed in the 21st century by novel preventative and therapeutic vaccines. PMID:24803000

Irrational Rationality of Terrorism

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Robert Nalbandov

2013-12-01

Full Text Available The present article deals with the ontological problem of applying the rational choice frameworks to the study of terrorism. It testing the application of the rational choice to the “old” (before the end of the Cold War and the “new” (after the end of the Cold War terrorisms. It starts with analyzing the fundamentals of rationality and applies it at two levels: the individual (actors and group (collective via two outlooks: tactical (short-term and strategic (long-term. The main argument of the article is that while the “old” terrorism can be explained by the rational choice theory its “new” version represents a substantial departure from rationality.

Appendix to rationally designing of machine tools for example of universal lathe

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Pejović Branko B.

2015-01-01

Full Text Available In this paper, for the universal machine tool for turning and function of the thrust of the cutting speed for blasting area efficiency and stability of the tool and sectional filings. These dependencies were used to determine the main characteristics of the optimal and maximum operating power equipment. Based on this, an analysis of the increase in operating power equipment typical cases in order to adapt to the new needs of exploitation properties and improve productivity. Using the previous analysis, it was determined the best solution in terms of the rational design of machines, by ensuring the simultaneous use of the main features on the basis of increase in speed with the use of tools and higher stability. In order to better display problems, an analysis of the appropriate diagrams P-V and V-D. On a typical example of the manufacturing practice at the end of the work, we demonstrate improvement of exploitation characteristics of a universal machine through appropriate calculations in terms of new needs adjustment feature, where it is expected that the reconstruction of the smallest machines.

Lying for Strategic Advantage: Rational and Boundedly Rational Misrepresentation of Intentions

OpenAIRE

Crawford, Vincent P.

2001-01-01

Starting from Hendricks and McAfee's (2000) example of the Allies' decision to feint at Calais and attack at Normandy on D-Day, this paper models misrepresentation of intentions to competitors or enemies. Allowing for the possibility of bounded strategic rationality and rational players' responses to it yields a sensible account of lying via costless, noiseless messages. In many cases the model has generically unique pure-strategy sequential equilibria, in which rational players exploit bound...

Comparative Pathogenesis and Systems Biology for Biodefense Virus Vaccine Development

Directory of Open Access Journals (Sweden)

Gavin C. Bowick

2010-01-01

Full Text Available Developing vaccines to biothreat agents presents a number of challenges for discovery, preclinical development, and licensure. The need for high containment to work with live agents limits the amount and types of research that can be done using complete pathogens, and small markets reduce potential returns for industry. However, a number of tools, from comparative pathogenesis of viral strains at the molecular level to novel computational approaches, are being used to understand the basis of viral attenuation and characterize protective immune responses. As the amount of basic molecular knowledge grows, we will be able to take advantage of these tools not only to rationally attenuate virus strains for candidate vaccines, but also to assess immunogenicity and safety in silico. This review discusses how a basic understanding of pathogenesis, allied with systems biology and machine learning methods, can impact biodefense vaccinology.

The economics of HIV vaccines - Projecting the impact of HIV vaccination of infants in sub-Saharan Africa

NARCIS (Netherlands)

Bos, JM; Postma, MJ

2001-01-01

Objectives: (i) To project vaccine parameters, economic consequences and market size associated with HIV-1 vaccination of infants in sub-Saharan Africa through the Expanded Program on Immunisation (EPI); and (ii) to assess threshold values for price and effectiveness. Study design and methods:

Novel GMO-Based Vaccines against Tuberculosis: State of the Art and Biosafety Considerations.

Science.gov (United States)

Leunda, Amaya; Baldo, Aline; Goossens, Martine; Huygen, Kris; Herman, Philippe; Romano, Marta

2014-06-16

Novel efficient vaccines are needed to control tuberculosis (TB), a major cause of morbidity and mortality worldwide. Several TB vaccine candidates are currently in clinical and preclinical development. They fall into two categories, the one of candidates designed as a replacement of the Bacille Calmette Guérin (BCG) to be administered to infants and the one of sub-unit vaccines designed as booster vaccines. The latter are designed as vaccines that will be administered to individuals already vaccinated with BCG (or in the future with a BCG replacement vaccine). In this review we provide up to date information on novel tuberculosis (TB) vaccines in development focusing on the risk assessment of candidates composed of genetically modified organisms (GMO) which are currently evaluated in clinical trials. Indeed, these vaccines administered to volunteers raise biosafety concerns with respect to human health and the environment that need to be assessed and managed.

Green revolution vaccines, edible vaccines

African Journals Online (AJOL)

Admin

of development. Food vaccines may also help to suppress autoimmunity disorders such as Type-1. Diabetes. Key words: Edible vaccines, oral vaccines, antigen expression, food vaccines. INTRODUCTION. Vaccination involves the stimulation of the immune system to prepare it for the event of an invasion from a particular ...

Chikungunya virus fusion properties elucidated by single-particle and bulk approaches

NARCIS (Netherlands)

van Duijl-Richter, Mareike K. S.; Blijleven, Jelle S.; van Oijen, Antoine M.; Smit, Jolanda M.

Chikungunya virus (CHIKV) is a rapidly spreading, enveloped alphavirus causing fever, rash and debilitating polyarthritis. No specific treatment or vaccines are available to treat or prevent infection. For the rational design of vaccines and antiviral drugs, it is imperative to understand the

Current state and challenges in developing oral vaccines.

Science.gov (United States)

Vela Ramirez, Julia E; Sharpe, Lindsey A; Peppas, Nicholas A

2017-05-15

While vaccination remains the most cost effective strategy for disease prevention, communicable diseases persist as the second leading cause of death worldwide. There is a need to design safe, novel vaccine delivery methods to protect against unaddressed and emerging diseases. Development of vaccines administered orally is preferable to traditional injection-based formulations for numerous reasons including improved safety and compliance, and easier manufacturing and administration. Additionally, the oral route enables stimulation of humoral and cellular immune responses at both systemic and mucosal sites to establish broader and long-lasting protection. However, oral delivery is challenging, requiring formulations to overcome the harsh gastrointestinal (GI) environment and avoid tolerance induction to achieve effective protection. Here we address the rationale for oral vaccines, including key biological and physicochemical considerations for next-generation oral vaccine design. Copyright © 2017 Elsevier B.V. All rights reserved.

Ab-initio conformational epitope structure prediction using genetic algorithm and SVM for vaccine design.

Science.gov (United States)

Moghram, Basem Ameen; Nabil, Emad; Badr, Amr

2018-01-01

T-cell epitope structure identification is a significant challenging immunoinformatic problem within epitope-based vaccine design. Epitopes or antigenic peptides are a set of amino acids that bind with the Major Histocompatibility Complex (MHC) molecules. The aim of this process is presented by Antigen Presenting Cells to be inspected by T-cells. MHC-molecule-binding epitopes are responsible for triggering the immune response to antigens. The epitope's three-dimensional (3D) molecular structure (i.e., tertiary structure) reflects its proper function. Therefore, the identification of MHC class-II epitopes structure is a significant step towards epitope-based vaccine design and understanding of the immune system. In this paper, we propose a new technique using a Genetic Algorithm for Predicting the Epitope Structure (GAPES), to predict the structure of MHC class-II epitopes based on their sequence. The proposed Elitist-based genetic algorithm for predicting the epitope's tertiary structure is based on Ab-Initio Empirical Conformational Energy Program for Peptides (ECEPP) Force Field Model. The developed secondary structure prediction technique relies on Ramachandran Plot. We used two alignment algorithms: the ROSS alignment and TM-Score alignment. We applied four different alignment approaches to calculate the similarity scores of the dataset under test. We utilized the support vector machine (SVM) classifier as an evaluation of the prediction performance. The prediction accuracy and the Area Under Receiver Operating Characteristic (ROC) Curve (AUC) were calculated as measures of performance. The calculations are performed on twelve similarity-reduced datasets of the Immune Epitope Data Base (IEDB) and a large dataset of peptide-binding affinities to HLA-DRB1*0101. The results showed that GAPES was reliable and very accurate. We achieved an average prediction accuracy of 93.50% and an average AUC of 0.974 in the IEDB dataset. Also, we achieved an accuracy of 95

Antibiotic Resistance Determinant-Focused Acinetobacter baumannii Vaccine Designed Using Reverse Vaccinology.

Science.gov (United States)

Ni, Zhaohui; Chen, Yan; Ong, Edison; He, Yongqun

2017-02-21

As one of the most influential and troublesome human pathogens, Acinetobacter baumannii ( A. baumannii ) has emerged with many multidrug-resistant strains. After collecting 33 complete A. baumannii genomes and 84 representative antibiotic resistance determinants, we used the Vaxign reverse vaccinology approach to predict classical type vaccine candidates against A. baumannii infections and new type vaccine candidates against antibiotic resistance. Our genome analysis identified 35 outer membrane or extracellular adhesins that are conserved among all 33 genomes, have no human protein homology, and have less than 2 transmembrane helices. These 35 antigens include 11 TonB dependent receptors, 8 porins, 7 efflux pump proteins, and 2 fimbrial proteins (FilF and CAM87009.1). CAM86003.1 was predicted to be an adhesin outer membrane protein absent from 3 antibiotic-sensitive strains and conserved in 21 antibiotic-resistant strains. Feasible anti-resistance vaccine candidates also include one extracellular protein (QnrA), 3 RND type outer membrane efflux pump proteins, and 3 CTX-M type β-lactamases. Among 39 β-lactamases, A. baumannii CTX-M-2, -5, and -43 enzymes are predicted as adhesins and better vaccine candidates than other β-lactamases to induce preventive immunity and enhance antibiotic treatments. This report represents the first reverse vaccinology study to systematically predict vaccine antigen candidates against antibiotic resistance for a microbial pathogen.

ERM immersion vaccination and adjuvants

DEFF Research Database (Denmark)

Skov, J.; Chettri, J. K.; Jaafar, R. M.

2015-01-01

Two candidate adjuvants were tested with a commercial ERM dip vaccine (AquaVac™ Relera, MSD Animal Health) for rainbow trout in an experimental design compatible with common vaccination practices at farm level, i.e. immersion of fish in vaccine (±adjuvant) for 30 s. The adjuvants were...... the commercial product Montanide™ IMS 1312 VG PR (SEPPIC), and a soluble and ≥98% pure β-glucan from yeast (Saccharomyces cerevisiae) (Sigma-Aldrich). Hence, five experimental groups in duplicate were established and exposed to vaccine and adjuvants in the following combinations: AquaVac™ Relera (alone); Aqua......Vac™ Relera + Montanide™; AquaVac™ Relera + β-glucan; Montanide™ (alone); and β-glucan (alone). Approximately 450 degree days post-vaccination, the fish were bath-challenged with live Yersinia ruckeri to produce survival curves. Blood, skin and gills were sampled at selected time points during the course...

Determinants of Actor Rationality

DEFF Research Database (Denmark)

Ellegaard, Chris

Industrial companies must exercise influence on their suppliers (or supplier actors). Actor rationality is a central theme connected to this management task. In this article, relevant literature is studied with the purpose of shedding light on determinants of actor rationality. Two buyer-supplier...... relations are investigated in a multiple case study, leading to the proposal of various additional factors that determine and shape actor rationality. Moreover a conceptual model of rationality determinants in the buyer-supplier relation is proposed, a model that may help supply managers analyse...

Two Concepts of Rationality

Directory of Open Access Journals (Sweden)

Danny Frederick

2010-02-01

Full Text Available The dominant tradition in Western philosophy sees rationality as dictating. Thus rationality may require that we believe the best explanation and simple conceptual truths and that we infer in accordance with evident rules of inference. I argue that, given what we know about the growth of knowledge, this authoritarian concept of rationality leads to absurdities and should be abandoned. I then outline a libertarian concept of rationality, derived from Popper, which eschews the dictates and which sees a rational agent as one who questions, criticises, conjectures and experiments. I argue that, while the libertarian approach escapes the absurdities of the authoritarian, it requires two significant developments and an important clarification to be made fully consistent with itself.

Rationality and institutions : an inquiry into the normative implications of rational choice theory

OpenAIRE

Engelen, Bart

2007-01-01

I aim to analyze in this dissertation what a desirable basic institutional structure looks like from the perspective of rationality. While the main topic is thus normative in nature, I start by clarifying in the first part what the notion of rationality exactly entails. I do so by focusing explicitly on the economic conception of rationality, according to which a rational individual is motivated to serve his self-interest on the basis of cost-benefit calculations. Such a Homo Economicus is ch...

Rational discovery of dengue type 2 non-competitive inhibitors.

Science.gov (United States)

Heh, Choon H; Othman, Rozana; Buckle, Michael J C; Sharifuddin, Yusrizam; Yusof, Rohana; Rahman, Noorsaadah A

2013-07-01

Various works have been carried out in developing therapeutics against dengue. However, to date, no effective vaccine or anti-dengue agent has yet been discovered. The development of protease inhibitors is considered as a promising option, but most previous works have involved competitive inhibition. In this study, we focused on rational discovery of potential anti-dengue agents based on non-competitive inhibition of DEN-2 NS2B/NS3 protease. A homology model of the DEN-2 NS2B/NS3 protease (using West Nile Virus NS2B/NS3 protease complex, 2FP7, as the template) was used as the target, and pinostrobin, a flavanone, was used as the standard ligand. Virtual screening was performed involving a total of 13 341 small compounds, with the backbone structures of chalcone, flavanone, and flavone, available in the ZINC database. Ranking of the resulting compounds yielded compounds with higher binding affinities compared with the standard ligand. Inhibition assay of the selected top-ranking compounds against DEN-2 NS2B/NS3 proteolytic activity resulted in significantly better inhibition compared with the standard and correlated well with in silico results. In conclusion, via this rational discovery technique, better inhibitors were identified. This method can be used in further work to discover lead compounds for anti-dengue agents. © 2013 John Wiley & Sons A/S.

Catalase epitopes vaccine design for Helicobacter pylori: A ...

African Journals Online (AJOL)

Jane

2011-08-15

Aug 15, 2011 ... colored region and P1 anchor or the starting residue of each ..... score of MVNKDVKQTT; * 1, MVNKDVKQTT is a composition of two epitopes: MVNKDVKQT and .... Therapeutic efficacy of a multi-epitope vaccine against.

Quality by design approach in the development of an ultra-high-performance liquid chromatography method for Bexsero meningococcal group B vaccine.

Science.gov (United States)

Nompari, Luca; Orlandini, Serena; Pasquini, Benedetta; Campa, Cristiana; Rovini, Michele; Del Bubba, Massimo; Furlanetto, Sandra

2018-02-01

Bexsero is the first approved vaccine for active immunization of individuals from 2 months of age and older to prevent invasive disease caused by Neisseria meningitidis serogroup B. The active components of the vaccine are Neisseria Heparin Binding Antigen, factor H binding protein, Neisseria adhesin A, produced in Escherichia coli cells by recombinant DNA technology, and Outer Membrane Vesicles (expressing Porin A and Porin B), produced by fermentation of Neisseria meningitidis strain NZ98/254. All the Bexsero active components are adsorbed on aluminum hydroxide and the unadsorbed antigens content is a product critical quality attribute. In this paper the development of a fast, selective and sensitive ultra-high-performance liquid chromatography (UHPLC) method for the determination of the Bexsero antigens in the vaccine supernatant is presented. For the first time in the literature, the Quality by Design (QbD) principles were applied to the development of an analytical method aimed to the quality control of a vaccine product. The UHPLC method was fully developed within the QbD framework, the new paradigm of quality outlined in International Conference on Harmonisation guidelines. Critical method attributes (CMAs) were identified with the capacity factor of Neisseria Heparin Binding Antigen, antigens resolution and peak areas. After a scouting phase, aimed at selecting a suitable and fast UHPLC operative mode for the vaccine antigens separation, risk assessment tools were employed to define the critical method parameters to be considered in the screening phase. Screening designs were applied for investigating at first the effects of vial type and sample concentration, and then the effects of injection volume, column type, organic phase starting concentration, ramp time and temperature. Response Surface Methodology pointed out the presence of several significant interaction effects, and with the support of Monte-Carlo simulations led to map out the design space, at

A practical approach for exploration and modeling of the design space of a bacterial vaccine cultivation process.

Science.gov (United States)

Streefland, M; Van Herpen, P F G; Van de Waterbeemd, B; Van der Pol, L A; Beuvery, E C; Tramper, J; Martens, D E; Toft, M

2009-10-15

A licensed pharmaceutical process is required to be executed within the validated ranges throughout the lifetime of product manufacturing. Changes to the process, especially for processes involving biological products, usually require the manufacturer to demonstrate that the safety and efficacy of the product remains unchanged by new or additional clinical testing. Recent changes in the regulations for pharmaceutical processing allow broader ranges of process settings to be submitted for regulatory approval, the so-called process design space, which means that a manufacturer can optimize his process within the submitted ranges after the product has entered the market, which allows flexible processes. In this article, the applicability of this concept of the process design space is investigated for the cultivation process step for a vaccine against whooping cough disease. An experimental design (DoE) is applied to investigate the ranges of critical process parameters that still result in a product that meets specifications. The on-line process data, including near infrared spectroscopy, are used to build a descriptive model of the processes used in the experimental design. Finally, the data of all processes are integrated in a multivariate batch monitoring model that represents the investigated process design space. This article demonstrates how the general principles of PAT and process design space can be applied for an undefined biological product such as a whole cell vaccine. The approach chosen for model development described here, allows on line monitoring and control of cultivation batches in order to assure in real time that a process is running within the process design space.

Frequency of adverse events after vaccination with different vaccinia strains.

Directory of Open Access Journals (Sweden)

Mirjam Kretzschmar

2006-08-01

Full Text Available BACKGROUND: Large quantities of smallpox vaccine have been stockpiled to protect entire nations against a possible reintroduction of smallpox. Planning for an appropriate use of these stockpiled vaccines in response to a smallpox outbreak requires a rational assessment of the risks of vaccination-related adverse events, compared to the risk of contracting an infection. Although considerable effort has been made to understand the dynamics of smallpox transmission in modern societies, little attention has been paid to estimating the frequency of adverse events due to smallpox vaccination. Studies exploring the consequences of smallpox vaccination strategies have commonly used a frequency of approximately one death per million vaccinations, which is based on a study of vaccination with the New York City Board of Health (NYCBH strain of vaccinia virus. However, a multitude of historical studies of smallpox vaccination with other vaccinia strains suggest that there are strain-related differences in the frequency of adverse events after vaccination. Because many countries have stockpiled vaccine based on the Lister strain of vaccinia virus, a quantitative evaluation of the adverse effects of such vaccines is essential for emergency response planning. We conducted a systematic review and statistical analysis of historical data concerning vaccination against smallpox with different strains of vaccinia virus. METHODS AND FINDINGS: We analyzed historical vaccination data extracted from the literature. We extracted data on the frequency of postvaccinal encephalitis and death with respect to vaccinia strain and age of vaccinees. Using a hierarchical Bayesian approach for meta-analysis, we estimated the expected frequencies of postvaccinal encephalitis and death with respect to age at vaccination for smallpox vaccines based on the NYCBH and Lister vaccinia strains. We found large heterogeneity between findings from different studies and a time-period effect

Rational Behavior Training: A Seven Lesson Sequence for Teaching Rational Behavior Skills to Students with Social and Emotional Disabilities.

Science.gov (United States)

Patton, Patricia Lucey

This seven lesson curriculum sequence is designed to help teachers teach principles of Rational Behavior Training (RBT) which targets thinking behaviors, feeling behaviors, and behavioral responses to the environment. The program is appropriate for students with social and emotional disabilities and also develops reading, writing, spelling,…

Bacterium-like Particles for efficient immune stimulation of existing vaccines and new subunit vaccines in mucosal applications

Directory of Open Access Journals (Sweden)

Natalija eVan Braeckel-Budimir

2013-09-01

Full Text Available The successful development of a mucosal vaccine critically depends on the use of a safe and effective immunostimulant and/or carrier system. This review describes the effectiveness and mode of action of an immunostimulating particle derived from bacteria in mucosal subunit vaccines. The non-living particles, designated Bacterium-like Particles (BLPs are based on the food-grade bacterium Lactococcus lactis. The focus of the overview is on the development of intranasal BLP-based vaccines to prevent diseases caused by influenza and respiratory syncytial virus, and includes a selection of Phase I clinical data for the intranasal FluGEM vaccine.

Novel GMO-Based Vaccines against Tuberculosis: State of the Art and Biosafety Considerations

Science.gov (United States)

Leunda, Amaya; Baldo, Aline; Goossens, Martine; Huygen, Kris; Herman, Philippe; Romano, Marta

2014-01-01

Novel efficient vaccines are needed to control tuberculosis (TB), a major cause of morbidity and mortality worldwide. Several TB vaccine candidates are currently in clinical and preclinical development. They fall into two categories, the one of candidates designed as a replacement of the Bacille Calmette Guérin (BCG) to be administered to infants and the one of sub-unit vaccines designed as booster vaccines. The latter are designed as vaccines that will be administered to individuals already vaccinated with BCG (or in the future with a BCG replacement vaccine). In this review we provide up to date information on novel tuberculosis (TB) vaccines in development focusing on the risk assessment of candidates composed of genetically modified organisms (GMO) which are currently evaluated in clinical trials. Indeed, these vaccines administered to volunteers raise biosafety concerns with respect to human health and the environment that need to be assessed and managed. PMID:26344627

Novel GMO-Based Vaccines against Tuberculosis: State of the Art and Biosafety Considerations

Directory of Open Access Journals (Sweden)

Amaya Leunda

2014-06-01

Full Text Available Novel efficient vaccines are needed to control tuberculosis (TB, a major cause of morbidity and mortality worldwide. Several TB vaccine candidates are currently in clinical and preclinical development. They fall into two categories, the one of candidates designed as a replacement of the Bacille Calmette Guérin (BCG to be administered to infants and the one of sub-unit vaccines designed as booster vaccines. The latter are designed as vaccines that will be administered to individuals already vaccinated with BCG (or in the future with a BCG replacement vaccine. In this review we provide up to date information on novel tuberculosis (TB vaccines in development focusing on the risk assessment of candidates composed of genetically modified organisms (GMO which are currently evaluated in clinical trials. Indeed, these vaccines administered to volunteers raise biosafety concerns with respect to human health and the environment that need to be assessed and managed.

Rationing medical education.

African Journals Online (AJOL)

This paper discussed the pros and cons of the application of rationing to medical education and the different ... Different types of rationing exist in healthcare professional education. ... state-of-the-art resources, technology and tutors con-.

Rationality problem for algebraic tori

CERN Document Server

Hoshi, Akinari

2017-01-01

The authors give the complete stably rational classification of algebraic tori of dimensions 4 and 5 over a field k. In particular, the stably rational classification of norm one tori whose Chevalley modules are of rank 4 and 5 is given. The authors show that there exist exactly 487 (resp. 7, resp. 216) stably rational (resp. not stably but retract rational, resp. not retract rational) algebraic tori of dimension 4, and there exist exactly 3051 (resp. 25, resp. 3003) stably rational (resp. not stably but retract rational, resp. not retract rational) algebraic tori of dimension 5. The authors make a procedure to compute a flabby resolution of a G-lattice effectively by using the computer algebra system GAP. Some algorithms may determine whether the flabby class of a G-lattice is invertible (resp. zero) or not. Using the algorithms, the suthors determine all the flabby and coflabby G-lattices of rank up to 6 and verify that they are stably permutation. The authors also show that the Krull-Schmidt theorem for G-...

Rational Approximations to Rational Models: Alternative Algorithms for Category Learning

Science.gov (United States)

Sanborn, Adam N.; Griffiths, Thomas L.; Navarro, Daniel J.

2010-01-01

Rational models of cognition typically consider the abstract computational problems posed by the environment, assuming that people are capable of optimally solving those problems. This differs from more traditional formal models of cognition, which focus on the psychological processes responsible for behavior. A basic challenge for rational models…

Adsorption of rationally designed "surf-tides" to a liquid-crystal interface.

Science.gov (United States)

Badami, Joseph V; Bernstein, Chaim; Maldarelli, Charles; Tu, Raymond S

2015-09-07

The interfacial adsorption of proteins in surfactant laden systems occurs both in nature and industrial processing, yet much of the fundamental behavior behind these systems is still not well understood. We report the development of a system that monitors optical transitions of a liquid-crystalline/aqueous interface to examine the dynamics of adsorption of two rationally designed model peptide molecules. The two molecules synthesized in this study were both designed to become surface-active upon folding and contain the same net charge of +3, but one of the peptides, K-2.5, has its three charges separated by 2.5 amino acids as compared to K-6.0, which has its three charges separated by 6 amino acids. Our study examines the roles that surfactant adsorption, peptide charge distribution and secondary structure have on the relative adsorption dynamics of these two models peptides onto a fluid/fluid interface. Using the optical detection of molecular adsorption and image analysis of these events, we obtain quantitative information about the dynamics as a function of the charge spacing and initial peptide concentration. We show that both peptides initially follow a diffusion-limited adsorption model onto the interface. Additionally, our results suggest that the K-6.0 peptides demonstrate enhanced adsorption kinetics, where the enhanced rates are a consequence of the well-folded adsorbed state and spatial distribution on the surface. These findings provide further insights into the role that charge spacing has on secondary structure and subsequently the dynamics of adsorption, while developing a versatile system capable of extracting quantitative information from a simple inexpensive optical system.

Development of improved pertussis vaccine.

Science.gov (United States)

Rumbo, Martin; Hozbor, Daniela

2014-01-01

Rates of infection with Bordetella pertussis, the gram-negative bacterium that causes the respiratory disease called whooping cough or pertussis, have not abated and 16 million cases with almost 200,000 deaths are estimated by the WHO to have occurred worldwide in 2008. Despite relatively high vaccination rates, the disease has come back in recent years to afflict people in numbers not seen since the pre-vaccine days. Indeed, pertussis is now recognized as a frequent infection not only in newborn and infants but also in adults. The disease symptoms also can be induced by the non-vaccine-preventable infection with the close species B. parapertussis for which an increasing number of cases have been reported. The epidemiologic situation and current knowledge of the limitations of pertussis vaccine point out the need to design improved vaccines. Several alternative approaches and their challenges are summarized.

METHODOLOGICAL ASPECTS OF RATIONAL DESIGN FORMATION OF INFRASTRUCTURE OF AGRARIAN SECTOR OF UKRAINE

Directory of Open Access Journals (Sweden)

Ivan Korchynskyy

2016-11-01

Full Text Available Methodological aspects of formation of rational design of infrastructure of agrarian sector of Ukraine on the basis of the institutional approach and laws of architectonics are examined. It is shown that the agrarian sector of Ukraine is a complex socio-economic system, the formation and development of which is in the process of market transformation what is caused by institutional influences. In general the process of relations institutionalization imply their formalization and standardization, in other case the subject of public life could not predict the actions of other entities associated with him and ensure their cooperation. One of the specific characteristic of human society is formed institutional system that regulates behaviour. In the article the factors of influence on the conduct of being in charge subjects are considered in the conditions of development of market economy. The special attention is spared the institutional factors of the economy growing. Methodology. The meaning of “agricultural field” and “infrastructure” and their mutual consistency is classified. As the scientific method, the institutional approach of principles of architectonics has been used, which allowed to justify the creation of a rational approach to the design of infrastructure in agrarian sector as a whole on the basis, relation and interdependence of its elements, based on the fundamental laws of architectonics (law of equilibrium, law of the golden mean structuring. The article demonstrates a necessary of the choice of a theory of institutionalism as the main methodological basis for the study of the process of innovation development of economic system of Ukraine. It is determined that the inefficient activities of institutions in Ukraine are the main cause of the low level of innovation, which has a negative impact on the development of the economy as a whole. Results. Research points on new aspects of infrastructure as a part of the entire

Vaccines Meet Big Data: State-of-the-Art and Future Prospects. From the Classical 3Is (“Isolate–Inactivate–Inject” Vaccinology 1.0 to Vaccinology 3.0, Vaccinomics, and Beyond: A Historical Overview

Directory of Open Access Journals (Sweden)

Nicola Luigi Bragazzi

2018-03-01

Full Text Available Vaccines are public health interventions aimed at preventing infections-related mortality, morbidity, and disability. While vaccines have been successfully designed for those infectious diseases preventable by preexisting neutralizing specific antibodies, for other communicable diseases, additional immunological mechanisms should be elicited to achieve a full protection. “New vaccines” are particularly urgent in the nowadays society, in which economic growth, globalization, and immigration are leading to the emergence/reemergence of old and new infectious agents at the animal–human interface. Conventional vaccinology (the so-called “vaccinology 1.0” was officially born in 1796 thanks to the contribution of Edward Jenner. Entering the twenty-first century, vaccinology has shifted from a classical discipline in which serendipity and the Pasteurian principle of the three Is (isolate, inactivate, and inject played a major role to a science, characterized by a rational design and plan (“vaccinology 3.0”. This shift has been possible thanks to Big Data, characterized by different dimensions, such as high volume, velocity, and variety of data. Big Data sources include new cutting-edge, high-throughput technologies, electronic registries, social media, and social networks, among others. The current mini-review aims at exploring the potential roles as well as pitfalls and challenges of Big Data in shaping the future vaccinology, moving toward a tailored and personalized vaccine design and administration.

Use of geographic information systems in rabies vaccination campaigns.

Science.gov (United States)

Grisi-Filho, José Henrique de Hildebrand e; Amaku, Marcos; Dias, Ricardo Augusto; Montenegro Netto, Hildebrando; Paranhos, Noemia Tucunduva; Mendes, Maria Cristina Novo Campos; Ferreira Neto, José Soares; Ferreira, Fernando

2008-12-01

To develop a method to assist in the design and assessment of animal rabies control campaigns. A methodology was developed based on geographic information systems to estimate the animal (canine and feline) population and density per census tract and per subregion (known as "Subprefeituras") in the city of São Paulo (Southeastern Brazil) in 2002. The number of vaccination units in a given region was estimated to achieve a certain proportion of vaccination coverage. Census database was used for the human population, as well as estimates ratios of dog:inhabitant and cat:inhabitant. Estimated figures were 1,490,500 dogs and 226,954 cats in the city, i.e. an animal population density of 1138.14 owned animals per km(2). In the 2002 campaign, 926,462 were vaccinated, resulting in a vaccination coverage of 54%. The estimated number of vaccination units to be able to reach a 70%-vaccination coverage, by vaccinating 700 animals per unit on average, was 1,729. These estimates are presented as maps of animal density according to census tracts and "Subprefeituras". The methodology used in the study may be applied in a systematic way to the design and evaluation of rabies vaccination campaigns, enabling the identification of areas of critical vaccination coverage.

Schistosomiasis vaccine development: approaches and prospects

Directory of Open Access Journals (Sweden)

N. R. Bergquist

1995-04-01

Full Text Available Mounting evidence for acquired immunity to schistosomiasis in humans supports the case for immunological intervention. On the other hand, rapid reinfection poses a threat to younger age groups due to the slow maturation of natural resistance. However, rational approaches, based on advances in immunology and molecular biology, have substantially increased the odds of producing an effective vaccine. Since the parasite cannot replicate in the human host and serious morbidity generally occurs only after a relatively long period of heavy worm burden, complete protection against infection is not essential. The chances of success would increase if more than one of the various host/parasite interphases were targeted, for example reducing morbidity through decreased worm loads as well as through suppression of egg production. Several promising schistosome antigens have now reached an advanced phase of development and are currently undergoing independent confirmatory testing according to a standardized protocol. A few molecules are being contemplated for scaled-up production but, so far, only one has reached the stage of industrial manufacture and safety testing. Since schistosomiasis cannot realistically be controlled by a single approach, vaccination is envisaged to be implemented in conjunction with other means of control, notably chemotherapy.

What criteria do decision makers in Thailand use to set priorities for vaccine introduction?

Science.gov (United States)

Pooripussarakul, Siriporn; Riewpaiboon, Arthorn; Bishai, David; Muangchana, Charung; Tantivess, Sripen

2016-08-02

There is a need to identify rational criteria and set priorities for vaccines. In Thailand, many licensed vaccines are being considering for introduction into the Expanded Program on Immunization; thus, the government has to make decisions about which vaccines should be adopted. This study aimed to set priorities for new vaccines and to facilitate decision analysis. We used a best-worst scaling study for rank-ordering of vaccines. The candidate vaccines were determined by a set of criteria, including burden of disease, target age group, budget impact, side effect, effectiveness, severity of disease, and cost of vaccine. The criteria were identified from a literature review and by in-depth, open-ended interviews with experts. The priority-setting model was conducted among three groups of stakeholders, including policy makers, healthcare professionals and healthcare administrators. The vaccine data were mapped and then calculated for the probability of selection. From the candidate vaccines, the probability of hepatitis B vaccine being selected by all respondents (96.67 %) was ranked first. This was followed, respectively, by pneumococcal conjugate vaccine-13 (95.09 %) and Haemophilus influenzae type b vaccine (90.87 %). The three groups of stakeholders (policy makers, healthcare professionals and healthcare administrators) showed the same ranking trends. Most severe disease, high fever rate and high disease burden showed the highest coefficients for criterion levels being selected by all respondents. This result can be implied that a vaccine which can prevent most severe disease with high disease burden and has low safety has a greater chance of being selected by respondents in this study. The priority setting of vaccines through a multiple-criteria approach could contribute to transparency and accountability in the decision-making process. This is a step forward in the development of an evidence-based approach that meets the need of developing country. The

What criteria do decision makers in Thailand use to set priorities for vaccine introduction?

Directory of Open Access Journals (Sweden)

Siriporn Pooripussarakul

2016-08-01

Full Text Available Abstract Background There is a need to identify rational criteria and set priorities for vaccines. In Thailand, many licensed vaccines are being considering for introduction into the Expanded Program on Immunization; thus, the government has to make decisions about which vaccines should be adopted. This study aimed to set priorities for new vaccines and to facilitate decision analysis. Methods We used a best-worst scaling study for rank-ordering of vaccines. The candidate vaccines were determined by a set of criteria, including burden of disease, target age group, budget impact, side effect, effectiveness, severity of disease, and cost of vaccine. The criteria were identified from a literature review and by in-depth, open-ended interviews with experts. The priority-setting model was conducted among three groups of stakeholders, including policy makers, healthcare professionals and healthcare administrators. The vaccine data were mapped and then calculated for the probability of selection. Results From the candidate vaccines, the probability of hepatitis B vaccine being selected by all respondents (96.67 % was ranked first. This was followed, respectively, by pneumococcal conjugate vaccine-13 (95.09 % and Haemophilus influenzae type b vaccine (90.87 %. The three groups of stakeholders (policy makers, healthcare professionals and healthcare administrators showed the same ranking trends. Most severe disease, high fever rate and high disease burden showed the highest coefficients for criterion levels being selected by all respondents. This result can be implied that a vaccine which can prevent most severe disease with high disease burden and has low safety has a greater chance of being selected by respondents in this study. Conclusions The priority setting of vaccines through a multiple-criteria approach could contribute to transparency and accountability in the decision-making process. This is a step forward in the development of an evidence

Impact of committed individuals on vaccination behavior

Science.gov (United States)

Liu, Xiao-Tao; Wu, Zhi-Xi; Zhang, Lianzhong

2012-11-01

We study how the presence of committed vaccinators, a small fraction of individuals who consistently hold the vaccinating strategy and are immune to influence, impact the vaccination dynamics in well-mixed and spatially structured populations. For this purpose, we develop an epidemiological game-theoretic model of a flu-like vaccination by integrating an epidemiological process into a simple agent-based model of adaptive learning, where individuals (except for those committed ones) use anecdotal evidence to estimate costs and benefits of vaccination. We show that the committed vaccinators, acting as “steadfast role models” in the populations, can efficiently avoid the clustering of susceptible individuals and stimulate other imitators to take vaccination, hence contributing to the promotion of vaccine uptake. We substantiate our findings by making comparative studies of our model on a full lattice and on a randomly diluted one. Our work is expected to provide valuable information for decision-making and design more effective disease-control strategy.

Emerging and continuing trends in vaccine opposition website content.

Science.gov (United States)

Bean, Sandra J

2011-02-24

Anti-vaccination websites appeal to persons searching the Internet for vaccine information that reinforces their predilection to avoid vaccination for themselves or their children. Few published studies have systematically examined these sites. The aim of this study was to employ content analysis as a useful tool for examining and comparing anti-vaccination websites for recurring and changing emphases in content, design, and credibility themes since earlier anti-vaccination website content analyses were conducted. Between February and May 2010, using a commonly available search engine followed by a deep web search, 25 websites that contained anti-vaccination content were reviewed and analyzed for 24 content, 14 design, and 13 credibility attributes. Although several content claims remained similar to earlier analyses, two new themes emerged: (1) the 2009 H1N1 epidemic threat was "manufactured," and (2) the increasing presence of so-called "expert" testimony in opposing vaccination. Anti-vaccination websites are constantly changing in response to the trends in public health and the success of vaccination. Monitoring the changes can permit public health workers to mount programs more quickly to counter the opposition arguments. Additionally, opposition claims commonly appeal to emotions whereas the supporting claims appeal to reason. Effective vaccine support may be better served by including more emotionally compelling content. Copyright © 2011 Elsevier Ltd. All rights reserved.

Optimal public rationing and price response.

Science.gov (United States)

Grassi, Simona; Ma, Ching-To Albert

2011-12-01

We study optimal public health care rationing and private sector price responses. Consumers differ in their wealth and illness severity (defined as treatment cost). Due to a limited budget, some consumers must be rationed. Rationed consumers may purchase from a monopolistic private market. We consider two information regimes. In the first, the public supplier rations consumers according to their wealth information (means testing). In equilibrium, the public supplier must ration both rich and poor consumers. Rationing some poor consumers implements price reduction in the private market. In the second information regime, the public supplier rations consumers according to consumers' wealth and cost information. In equilibrium, consumers are allocated the good if and only if their costs are below a threshold (cost effectiveness). Rationing based on cost results in higher equilibrium consumer surplus than rationing based on wealth. Copyright © 2011 Elsevier B.V. All rights reserved.

Engineering synthetic vaccines using cues from natural immunity

Science.gov (United States)

Irvine, Darrell J.; Swartz, Melody A.; Szeto, Gregory L.

2013-11-01

Vaccines aim to protect against or treat diseases through manipulation of the immune response, promoting either immunity or tolerance. In the former case, vaccines generate antibodies and T cells poised to protect against future pathogen encounter or attack diseased cells such as tumours; in the latter case, which is far less developed, vaccines block pathogenic autoreactive T cells and autoantibodies that target self tissue. Enormous challenges remain, however, as a consequence of our incomplete understanding of human immunity. A rapidly growing field of research is the design of vaccines based on synthetic materials to target organs, tissues, cells or intracellular compartments; to co-deliver immunomodulatory signals that control the quality of the immune response; or to act directly as immune regulators. There exists great potential for well-defined materials to further our understanding of immunity. Here we describe recent advances in the design of synthetic materials to direct immune responses, highlighting successes and challenges in prophylactic, therapeutic and tolerance-inducing vaccines.

An Overview of Vaccination Strategies and Antigen Delivery Systems for Streptococcus agalactiae Vaccines in Nile Tilapia (Oreochromis niloticus).

Science.gov (United States)

Munang'andu, Hetron Mweemba; Paul, Joydeb; Evensen, Øystein

2016-12-13

Streptococcus agalactiae is an emerging infectious disease adversely affecting Nile tilapia ( Niloticus oreochromis ) production in aquaculture. Research carried out in the last decade has focused on developing protective vaccines using different strategies, although no review has been carried out to evaluate the efficacy of these strategies. The purpose of this review is to provide a synopsis of vaccination strategies and antigen delivery systems currently used for S. agalactiae vaccines in tilapia. Furthermore, as shown herein, current vaccine designs include the use of replicative antigen delivery systems, such as attenuated virulent strains, heterologous vectors and DNA vaccines, while non-replicative vaccines include the inactivated whole cell (IWC) and subunit vaccines encoding different S. agalactiae immunogenic proteins. Intraperitoneal vaccination is the most widely used immunization strategy, although immersion, spray and oral vaccines have also been tried with variable success. Vaccine efficacy is mostly evaluated by use of the intraperitoneal challenge model aimed at evaluating the relative percent survival (RPS) of vaccinated fish. The major limitation with this approach is that it lacks the ability to elucidate the mechanism of vaccine protection at portals of bacterial entry in mucosal organs and prevention of pathology in target organs. Despite this, indications are that the correlates of vaccine protection can be established based on antibody responses and antigen dose, although these parameters require optimization before they can become an integral part of routine vaccine production. Nevertheless, this review shows that different approaches can be used to produce protective vaccines against S. agalactiae in tilapia although there is a need to optimize the measures of vaccine efficacy.

An Overview of Vaccination Strategies and Antigen Delivery Systems for Streptococcus agalactiae Vaccines in Nile Tilapia (Oreochromis niloticus)

Science.gov (United States)

Munang’andu, Hetron Mweemba; Paul, Joydeb; Evensen, Øystein

2016-01-01

Streptococcus agalactiae is an emerging infectious disease adversely affecting Nile tilapia (Niloticus oreochromis) production in aquaculture. Research carried out in the last decade has focused on developing protective vaccines using different strategies, although no review has been carried out to evaluate the efficacy of these strategies. The purpose of this review is to provide a synopsis of vaccination strategies and antigen delivery systems currently used for S. agalactiae vaccines in tilapia. Furthermore, as shown herein, current vaccine designs include the use of replicative antigen delivery systems, such as attenuated virulent strains, heterologous vectors and DNA vaccines, while non-replicative vaccines include the inactivated whole cell (IWC) and subunit vaccines encoding different S. agalactiae immunogenic proteins. Intraperitoneal vaccination is the most widely used immunization strategy, although immersion, spray and oral vaccines have also been tried with variable success. Vaccine efficacy is mostly evaluated by use of the intraperitoneal challenge model aimed at evaluating the relative percent survival (RPS) of vaccinated fish. The major limitation with this approach is that it lacks the ability to elucidate the mechanism of vaccine protection at portals of bacterial entry in mucosal organs and prevention of pathology in target organs. Despite this, indications are that the correlates of vaccine protection can be established based on antibody responses and antigen dose, although these parameters require optimization before they can become an integral part of routine vaccine production. Nevertheless, this review shows that different approaches can be used to produce protective vaccines against S. agalactiae in tilapia although there is a need to optimize the measures of vaccine efficacy. PMID:27983591

Serum reactome induced by Bordetella pertussis infection and Pertussis vaccines: qualitative differences in serum antibody recognition patterns revealed by peptide microarray analysis.

Science.gov (United States)

Valentini, Davide; Ferrara, Giovanni; Advani, Reza; Hallander, Hans O; Maeurer, Markus J

2015-07-01

Pertussis (whooping cough) remains a public health problem despite extensive vaccination strategies. Better understanding of the host-pathogen interaction and the detailed B. pertussis (Bp) target recognition pattern will help in guided vaccine design. We characterized the specific epitope antigen recognition profiles of serum antibodies ('the reactome') induced by whooping cough and B. pertussis (Bp) vaccines from a case-control study conducted in 1996 in infants enrolled in a Bp vaccine trial in Sweden (Gustafsson, NEJM, 1996, 334, 349-355). Sera from children with whooping cough, vaccinated with Diphtheria Tetanus Pertussis (DTP) whole-cell (wc), acellular 5 (DPTa5), or with the 2 component (a2) vaccines and from infants receiving only DT (n=10 for each group) were tested with high-content peptide microarrays containing 17 Bp proteins displayed as linear (n=3175) peptide stretches. Slides were incubated with serum and peptide-IgG complexes detected with Cy5-labeled goat anti-human IgG and analyzed using a GenePix 4000B microarray scanner, followed by statistical analysis, using PAM (Prediction Analysis for Microarrays) and the identification of uniquely recognized peptide epitopes. 367/3,085 (11.9%) peptides were recognized in 10/10 sera from children with whooping cough, 239 (7.7%) in DTPwc, 259 (8.4%) in DTPa5, 105 (3.4%) DTPa2, 179 (5.8%) in the DT groups. Recognition of strongly recognized peptides was similar between whooping cough and DPTwc, but statistically different between whooping cough vs. DTPa5 (p<0.05), DTPa2 and DT (p<0.001 vs. both) vaccines. 6/3,085 and 2/3,085 peptides were exclusively recognized in (10/10) sera from children with whooping cough and DTPa2 vaccination, respectively. DTPwc resembles more closely the whooping cough reactome as compared to acellular vaccines. We could identify a unique recognition signature common for each vaccination group (10/10 children). Peptide microarray technology allows detection of subtle differences in

Exploring rationality in schizophrenia

DEFF Research Database (Denmark)

Revsbech, Rasmus; Mortensen, Erik Lykke; Owen, Gareth

2015-01-01

Background Empirical studies of rationality (syllogisms) in patients with schizophrenia have obtained different results. One study found that patients reason more logically if the syllogism is presented through an unusual content. Aims To explore syllogism-based rationality in schizophrenia. Meth...... differences became non-significant. Conclusions When taking intelligence and neuropsychological performance into account, patients with schizophrenia and controls perform similarly on syllogism tests of rationality.......Background Empirical studies of rationality (syllogisms) in patients with schizophrenia have obtained different results. One study found that patients reason more logically if the syllogism is presented through an unusual content. Aims To explore syllogism-based rationality in schizophrenia. Method...... Thirty-eight first-admitted patients with schizophrenia and 38 healthy controls solved 29 syllogisms that varied in presentation content (ordinary v. unusual) and validity (valid v. invalid). Statistical tests were made of unadjusted and adjusted group differences in models adjusting for intelligence...

Respect for rational autonomy.

Science.gov (United States)

Walker, Rebecca L

2009-12-01

The standard notion of autonomy in medical ethics does not require that autonomous choices not be irrational. The paper gives three examples of seemingly irrational patient choices and discusses how a rational autonomy analysis differs from the standard view. It then considers whether a switch to the rational autonomy view would lead to overriding more patient decisions but concludes that this should not be the case. Rather, a determination of whether individual patient decisions are autonomous is much less relevant than usually considered in determining whether health care providers must abide by these decisions. Furthermore, respect for rational autonomy entails strong positive requirements of respect for the autonomy of the person as a rational decision maker. The rationality view of autonomy is conceptually stronger than the standard view, allows for a more nuanced understanding of the practical moral calculus involved in respecting patient autonomy, and promotes positive respect for patient autonomy.

Embodying rationality

OpenAIRE

Mastrogiorgio, Antonio; Petracca, Enrico

2016-01-01

The current notions of bounded rationality in economics share distinctive features with Simon’s original notion, which still influences the theoretical and experimental research in the fields of choice, judgment, decision making, problem solving, and social cognition. All these notions of bounded rationality are in fact equally rooted in the information-processing approach to human cognition, expressing the view that reasoning is disembodied and that it can be reduced to the processing of abs...

Suicide: rationality and responsibility for life.

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Ho, Angela Onkay

2014-03-01

Death by suicide is widely held as an undesirable outcome. Most Western countries place emphasis on patient autonomy, a concept of controversy in relation to suicide. This paper explores the tensions between patients' rights and many societies' overarching desire to prevent suicide, while clarifying the relations between mental disorders, mental capacity, and rational suicide. A literature search was conducted using search terms of suicide and ethics in the PubMed and LexisNexis Academic databases. Article titles and abstracts were reviewed and deemed relevant if the paper addressed topics of rational suicide, patient autonomy or rights, or responsibility for life. Further articles were found from reference lists and by suggestion from preliminary reviewers of this paper. Suicidal behaviour in a person cannot be reliably predicted, yet various associations and organizations have developed standards of care for managing patients exhibiting suicidal behaviour. The responsibility for preventing suicide tends to be placed on the treating clinician. In cases where a person is capable of making treatment decisions--uninfluenced by any mental disorder--there is growing interest in the concept of rational suicide. There is much debate about whether suicide can ever be rational. Designating suicide as an undesirable event that should never occur raises the debate of who is responsible for one's life and runs the risk of erroneously attributing blame for suicide. While upholding patient rights of autonomy in psychiatric care is laudable, cases of suicidality warrant a delicate consideration of clinical judgment, duty of care, and legal obligations.

High-throughput sequencing of natively paired antibody chains provides evidence for original antigenic sin shaping the antibody response to influenza vaccination.

Science.gov (United States)

Tan, Yann-Chong; Blum, Lisa K; Kongpachith, Sarah; Ju, Chia-Hsin; Cai, Xiaoyong; Lindstrom, Tamsin M; Sokolove, Jeremy; Robinson, William H

2014-03-01

We developed a DNA barcoding method to enable high-throughput sequencing of the cognate heavy- and light-chain pairs of the antibodies expressed by individual B cells. We used this approach to elucidate the plasmablast antibody response to influenza vaccination. We show that >75% of the rationally selected plasmablast antibodies bind and neutralize influenza, and that antibodies from clonal families, defined by sharing both heavy-chain VJ and light-chain VJ sequence usage, do so most effectively. Vaccine-induced heavy-chain VJ regions contained on average >20 nucleotide mutations as compared to their predicted germline gene sequences, and some vaccine-induced antibodies exhibited higher binding affinities for hemagglutinins derived from prior years' seasonal influenza as compared to their affinities for the immunization strains. Our results show that influenza vaccination induces the recall of memory B cells that express antibodies that previously underwent affinity maturation against prior years' seasonal influenza, suggesting that 'original antigenic sin' shapes the antibody response to influenza vaccination. Published by Elsevier Inc.

Capital Requirements and Credit Rationing

OpenAIRE

Itai Agur

2010-01-01

This paper analyzes the trade-off between financial stability and credit rationing that arises when increasing capital requirements. It extends the Stiglitz-Weiss model of credit rationing to allow for bank default. Bank capital structure then matters for lending incentives. With default and rationing endogenous, optimal capital requirements can be analyzed. Introducing bank financiers, the paper also shows that uninsured funding raises the sensitivity of rationing to capital requirements. In...

Rationally designed, heterologous S. cerevisiae transcripts expose novel expression determinants

Science.gov (United States)

Ben-Yehezkel, Tuval; Atar, Shimshi; Zur, Hadas; Diament, Alon; Goz, Eli; Marx, Tzipy; Cohen, Rafael; Dana, Alexandra; Feldman, Anna; Shapiro, Ehud; Tuller, Tamir

2015-01-01

Deducing generic causal relations between RNA transcript features and protein expression profiles from endogenous gene expression data remains a major unsolved problem in biology. The analysis of gene expression from heterologous genes contributes significantly to solving this problem, but has been heavily biased toward the study of the effect of 5′ transcript regions and to prokaryotes. Here, we employ a synthetic biology driven approach that systematically differentiates the effect of different regions of the transcript on gene expression up to 240 nucleotides into the ORF. This enabled us to discover new causal effects between features in previously unexplored regions of transcripts, and gene expression in natural regimes. We rationally designed, constructed, and analyzed 383 gene variants of the viral HRSVgp04 gene ORF, with multiple synonymous mutations at key positions along the transcript in the eukaryote S. cerevisiae. Our results show that a few silent mutations at the 5′UTR can have a dramatic effect of up to 15 fold change on protein levels, and that even synonymous mutations in positions more than 120 nucleotides downstream from the ORF 5′end can modulate protein levels up to 160%–300%. We demonstrate that the correlation between protein levels and folding energy increases with the significance of the level of selection of the latter in endogenous genes, reinforcing the notion that selection for folding strength in different parts of the ORF is related to translation regulation. Our measured protein abundance correlates notably(correlation up to r = 0.62 (p=0.0013)) with mean relative codon decoding times, based on ribosomal densities (Ribo-Seq) in endogenous genes, supporting the conjecture that translation elongation and adaptation to the tRNA pool can modify protein levels in a causal/direct manner. This report provides an improved understanding of transcript evolution, design principles of gene expression regulation, and suggests simple

Understanding vaccines: a public imperative.

Science.gov (United States)

Federman, Ross S

2014-12-01

Though once a discovery greatly celebrated by the nation, the vaccine has come under fire in recent decades from skeptics, critics, and a movement set into motion by fraudulent scientists and fueled by frustrated parents looking for answers to the autism conundrum. There is enough denialist resistance to vaccination to bring upon renewed fear of young children and infants becoming infected with diseases, the threats of which had been functionally eradicated from the United States. In more recent years, the surge in independent online journalism and blogging has invited many to rapidly share their opinions with millions of readers and, importantly, has appeared to open the door for opinion to be portrayed as fact. As a result, many parents are inundated with horror stories of vaccine dangers, all designed to eat away at them emotionally while the medical and scientific communities have mounted their characteristic response by sharing the facts, the data, and all of the reliable peer-reviewed and well-cited research to show that vaccines are safe and effective. It has become clear to me that facts are no match for emotion, but perhaps an understanding behind vaccine methodology will help parents overcome these fears of vaccinating. By helping those who doubt vaccines better understand what vaccines really are and how they work in such an incredibly engineered fashion, we may have a stronger weapon than we realize in battling the emotional arsenal that comes from the fear and skepticism of vaccinating.

Use of adenoviral vectors as veterinary vaccines.

Science.gov (United States)

Ferreira, T B; Alves, P M; Aunins, J G; Carrondo, M J T

2005-10-01

Vaccines are the most effective and inexpensive prophylactic tool in veterinary medicine. Ideally, vaccines should induce a lifelong protective immunity against the target pathogen while not causing clinical or pathological signs of diseases in the vaccinated animals. However, such ideal vaccines are rare in the veterinary field. Many vaccines are either of limited effectiveness or have harmful side effects. In addition, there are still severe diseases with no effective vaccines. A very important criterion for an ideal vaccine in veterinary medicine is low cost; this is especially important in developing countries and even more so for poultry vaccination, where vaccines must sell for a few cents a dose. Traditional approaches include inactivated vaccines, attenuated live vaccines and subunit vaccines. Recently, genetic engineering has been applied to design new, improved vaccines. Adenovirus vectors are highly efficient for gene transfer in a broad spectrum of cell types and species. Moreover, adenoviruses often induce humoral, mucosal and cellular immune responses to antigens encoded by the inserted foreign genes. Thus, adenoviruses have become a vector of choice for delivery and expression of foreign proteins for vaccination. Consequently, the market requirements for adenovirus vaccines are increasing, creating a need for production methodologies of concentrated vectors with warranted purity and efficacy. This review summarizes recent developments and approaches of adenovirus production and purification as the application of these vectors, including successes and failures in clinical applications to date.

Carrier protein influences immunodominance of a known epitope: implication in peptide vaccine design.

Science.gov (United States)

Ghosh, Moumita; Solanki, Ashish K; Roy, Koushik; Dhoke, Reema R; Ashish; Roy, Syamal

2013-09-23

We investigated how the processing of a given antigen by antigen presenting cells (APC) is dictated by the conformation of the antigen and how this governs the immunodominance hierarchy. To address the question, a known immunodominant sequence of bacteriophage lambda repressor N-terminal sequence 12-26 [λR(12-26)] was engineered at the N and C termini of a heterologous leishmanial protein, Kinetoplastid membrane protein-11 (KMP-11); the resulting proteins were defined as N-KMP-11 and C-KMP-11 respectively. The presence of λR(12-26) in N-KMP-11 and C-KMP-11 was established by western blot analysis with antibody to λR(12-26) peptide. N-KMP-11 but not C-KMP-11 could stimulate the anti λR(12-26) T-cell clonal population very efficiently in the presence of APCs. Priming of BALB/c mice with N-KMP-11 or C-KMP-11 generated similar levels of anti-KMP-11 IgG, but anti-λR(12-26) specific IgG was observed only upon priming with N-KMP-11. Interestingly, uptake of both N-KMP-11 and C-KMP-11 by APCs was similar but catabolism of N-KMP-11 but not C-KMP-11 was biphasic and fast at the initial time point. Kratky plots of small angle X-ray scattering showed that while N-KMP-11 adopts flexible Gaussian type of topology, C-KMP-11 prefers Globular nature. To show that KMP-11 is not unique as a carrier protein, an epitope (SPITBTNLBTMBK) of Plasmodium yoelii (PY) apical membrane protein 1[AMA-1 (136-148)], is placed at the C and N terminals of a dominant T-cell epitope of ovalbumin protein OVA(323-339) and the resulting peptides are defined as PY-OVA and OVA-PY respectively. Interestingly, only OVA-PY could stimulate anti-OVA T-cells and produce IgG response upon priming of BALB/c mice with it. Thus for rational design of peptide vaccine it is important to place the dominant epitope appropriately in the context of the carrier protein. Copyright © 2013 Elsevier Ltd. All rights reserved.

Reproductive toxicity testing of vaccines

International Nuclear Information System (INIS)

Verdier, Francois; Barrow, Paul C.; Burge, Joeelle

2003-01-01

Vaccines play a major role in the prevention of human birth defects by protecting the pregnant woman from teratogenic or otherwise harmful infections. Until now, it has not been common practice to perform preclinical developmental toxicity tests for new vaccines. Despite the excellent safety record of vaccines, increased attention is now being given to the feasibility of screening new vaccines for developmental hazards in animals before their use in humans. Contrary to previous assumptions, many vaccines are now given to potentially pregnant women. Any new components of the vaccine formulation (adjuvants, excipients, stabilisers, preservatives, etc...) could also be tested for influences on development, although based on past experience the risks are limited by the very low dosages used. The conferred immunity following vaccination lasts for several years. Therefore, the developing conceptus may theoretically be exposed to the induced antibodies and/or sensitised T-cells, even if the pregnant woman was last vaccinated during childhood (particularly if she encounters the antigen during pregnancy through exposure to infection). However, it should be kept in mind that viral or bacterial infections represent a higher risk for a pregnant woman than the potential adverse effects related to vaccination or the associated immune response. Non-clinical safety studies may be employed as an aid for hazard identification. In these studies interactions of the vaccine with the maternal immune system or with the developmental systems of the offspring are considered. Post-natal examinations are necessary to detect all possible manifestations of developmental toxicity, such as effects on the immune system. Species selection for the preclinical studies is based on immunogenicity to the vaccine and the relative timing and rate of transfer of maternal antibodies to the offspring. A single study design is proposed for the pre- and post-natal developmental assessments of vaccines in

[Rationalization and rationing at the bedside. A normative and empirical status quo analysis].

Science.gov (United States)

Strech, D

2014-02-01

The topic of bedside rationing is increasingly discussed in Germany. Further need for clarification exists for the question how bedside rationing (e.g., in the area of overcare) can be justified despite coexistent inefficiencies. This paper outlines and analyses the relationship of waste avoidance and rationing from an ethical perspective. Empirical findings regarding the status quo of bedside rationing and rationalization are presented. These normative and empirical explorations will then be further specified regarding opportunities for future physician-driven activities to tackle overuse. The self-government partners in Germany should communicate more explicitly within their communities and to the public how and with which benchmarks they aim to reduce inefficient health care (overuse) in an appropriate manner. Physician-driven activities such as the "Choosing Wisely®" initiative in the USA could provide a first step to raise the awareness for overuse among physicians as well as in the public.

Influenza and Pneumonia Vaccination Rates and Factors Affecting Vaccination among Patients with Chronic Obstructive Pulmonary Disease

Directory of Open Access Journals (Sweden)

Ülkü Aka Aktürk

2017-06-01

Full Text Available Background: Influenza and pneumococcal vaccinations are recommended in chronic obstructive pulmonary disease patients to decrease associated risks at all stages. Although the prevalence of chronic obstructive pulmonary disease is high in our country, as previously reported, vaccination rates are low. Aims: To assess the vaccination rates of chronic obstructive pulmonary disease patients and factors that may affect these. Study Design: Multi-centre cross-sectional study. Methods: Patients admitted to the chest diseases clinics of six different centres between 1 February 2013 and 1 January 2014 with a pre-diagnosis of Chronic obstructive pulmonary disease according to the Global initiative for chronic obstructive lung disease criteria, who were in a stable condition were included in the study. The survey, which included demographic characteristics, socio-economic status, severity of disease and vaccination information, was first tested on a small patient population before the study. The survey was completed by the investigators after obtaining written informed consent. Results: The average age of the 296 included patients was 66.3±9.3 years and 91.9% were male. Of these, 36.5% had the influenza vaccination and 14.1% had the pneumococcal vaccination. The most common reason for not being vaccinated was ‘no recommendation by doctors’: 57.2% in the case of influenza vaccinations, and 46.8% in the case of pneumococcal vaccinations. Both vaccination rates were significantly higher in those patients with comorbidities (influenza vaccination p0.05. Vaccination rates were significantly higher in those with a white-collar occupation and higher education level, and who presented to a university hospital (p<0.001. Conclusion: Medical professionals do not request vaccinations as often as the International Guidelines suggest for chronic obstructive pulmonary disease patients. Awareness of the importance of these vaccinations among both doctors and patients

Core/shell PLGA microspheres with controllable in vivo release profile via rational core phase design.

Science.gov (United States)

Yu, Meiling; Yao, Qing; Zhang, Yan; Chen, Huilin; He, Haibing; Zhang, Yu; Yin, Tian; Tang, Xing; Xu, Hui

2018-02-27

the microspheres prepared by various methods were mainly controlled by either the porosity inside the microspheres or the degradation of materials, which could, therefore, lead to different release behaviours. This results indicated great potential of the PLGA microsphere formulation as an injectable depot for controllable in vivo release profile via rational core phase design. Core/shell microspheres fabricated by modified double emulsification-solvent evaporation methods, with various inner phases, to obtain high loading drugs system, as well as appropriate release behaviours. Accordingly, control in vivo release profile via rational core phase design.

Vaccine decision-making begins in pregnancy: Correlation between vaccine concerns, intentions and maternal vaccination with subsequent childhood vaccine uptake.

Science.gov (United States)

Danchin, M H; Costa-Pinto, J; Attwell, K; Willaby, H; Wiley, K; Hoq, M; Leask, J; Perrett, K P; O'Keefe, Jacinta; Giles, M L; Marshall, H

2017-08-12

Maternal and childhood vaccine decision-making begins prenatally. Amongst pregnant Australian women we aimed to ascertain vaccine information received, maternal immunisation uptake and attitudes and concerns regarding childhood vaccination. We also aimed to determine any correlation between a) intentions and concerns regarding childhood vaccination, (b) concerns about pregnancy vaccination, (c) socioeconomic status (SES) and (d) uptake of influenza and pertussis vaccines during pregnancy and routine vaccines during childhood. Women attending public antenatal clinics were recruited in three Australian states. Surveys were completed on iPads. Follow-up phone surveys were done three to six months post delivery, and infant vaccination status obtained via the Australian Childhood Immunisation Register (ACIR). Between October 2015 and March 2016, 975 (82%) of 1184 mothers consented and 406 (42%) agreed to a follow up survey, post delivery. First-time mothers (445; 49%) had significantly more vaccine concerns in pregnancy and only 73% had made a decision about childhood vaccination compared to 89% of mothers with existing children (p-valuepost delivery survey, 46% and 82% of mothers reported receiving pregnancy influenza and pertussis vaccines respectively. The mother's degree of vaccine hesitancy and two attitudinal factors were correlated with vaccine uptake post delivery. There was no association between reported maternal vaccine uptake or SES and childhood vaccine uptake. First time mothers are more vaccine hesitant and undecided about childhood vaccination, and only two thirds of all mothers believed they received enough information during pregnancy. New interventions to improve both education and communication on childhood and maternal vaccines, delivered by midwives and obstetricians in the Australian public hospital system, may reduce vaccine hesitancy for all mothers in pregnancy and post delivery, particularly first-time mothers. Copyright © 2017 Elsevier Ltd

Rational BRDF.

Science.gov (United States)

Pacanowski, Romain; Salazar Celis, Oliver; Schlick, Christophe; Granier, Xavier; Poulin, Pierre; Cuyt, Annie

2012-11-01

Over the last two decades, much effort has been devoted to accurately measuring Bidirectional Reflectance Distribution Functions (BRDFs) of real-world materials and to use efficiently the resulting data for rendering. Because of their large size, it is difficult to use directly measured BRDFs for real-time applications, and fitting the most sophisticated analytical BRDF models is still a complex task. In this paper, we introduce Rational BRDF, a general-purpose and efficient representation for arbitrary BRDFs, based on Rational Functions (RFs). Using an adapted parametrization, we demonstrate how Rational BRDFs offer 1) a more compact and efficient representation using low-degree RFs, 2) an accurate fitting of measured materials with guaranteed control of the residual error, and 3) efficient importance sampling by applying the same fitting process to determine the inverse of the Cumulative Distribution Function (CDF) generated from the BRDF for use in Monte-Carlo rendering.

Improvement of different vaccine delivery systems for cancer therapy

Directory of Open Access Journals (Sweden)

Safaiyan Shima

2011-01-01

Full Text Available Abstract Cancer vaccines are the promising tools in the hands of the clinical oncologist. Many tumor-associated antigens are excellent targets for immune therapy and vaccine design. Optimally designed cancer vaccines should combine the best tumor antigens with the most effective immunotherapy agents and/or delivery strategies to achieve positive clinical results. Various vaccine delivery systems such as different routes of immunization and physical/chemical delivery methods have been used in cancer therapy with the goal to induce immunity against tumor-associated antigens. Two basic delivery approaches including physical delivery to achieve higher levels of antigen production and formulation with microparticles to target antigen-presenting cells (APCs have demonstrated to be effective in animal models. New developments in vaccine delivery systems will improve the efficiency of clinical trials in the near future. Among them, nanoparticles (NPs such as dendrimers, polymeric NPs, metallic NPs, magnetic NPs and quantum dots have emerged as effective vaccine adjuvants for infectious diseases and cancer therapy. Furthermore, cell-penetrating peptides (CPP have been known as attractive carrier having applications in drug delivery, gene transfer and DNA vaccination. This review will focus on the utilization of different vaccine delivery systems for prevention or treatment of cancer. We will discuss their clinical applications and the future prospects for cancer vaccine development.

Surface Termination of M1 Phase and Rational Design of Propane Ammoxidation Catalysts

Energy Technology Data Exchange (ETDEWEB)

Guliants, Vadim [Univ. of Cincinnati, OH (United States)

2015-02-16

This final report describes major accomplishments in this research project which has demonstrated that the M1 phase is the only crystalline phase required for propane ammoxidation to acrylonitrile and that a surface monolayer terminating the ab planes of the M1 phase is responsible for their activity and selectivity in this reaction. Fundamental studies of the topmost surface chemistry and mechanism of propane ammoxidation over the Mo-V-(Te,Sb)-(Nb,Ta)-O M1 and M2 phases resulted in the development of quantitative understanding of the surface molecular structure – reactivity relationships for this unique catalytic system. These oxides possess unique catalytic properties among mixed metal oxides, because they selectively catalyze three alkane transformation reactions, namely propane ammoxidation to acrylonitrile, propane oxidation to acrylic acid and ethane oxidative dehydrogenation, all of considerable economic significance. Therefore, the larger goal of this research was to expand this catalysis to other alkanes of commercial interest, and more broadly, demonstrate successful approaches to rational design of improved catalysts that can be applied to other selective (amm)oxidation processes.

Polymorphism in liver-stage malaria vaccine candidate proteins: immune evasion and implications for vaccine design.

Science.gov (United States)

Flanagan, Katie L; Wilson, Kirsty L; Plebanski, Magdalena

2016-01-01

The pre-erythrocytic stage of infection by malaria parasites represents a key target for vaccines that aim to eradicate malaria. Two important broad immune evasion strategies that can interfere with vaccine efficacy include the induction of dendritic cell (DC) dysfunction and regulatory T cells (Tregs) by blood-stage malaria parasites, leading to inefficient priming of T cells targeting liver-stage infections. The parasite also uses 'surgical strike' strategies, whereby polymorphism in pre-erythrocytic antigens can interfere with host immunity. Specifically, we review how even single amino acid changes in T cell epitopes can lead to loss of binding to major histocompatibility complex (MHC), lack of cross-reactivity, or antagonism and immune interference, where simultaneous or sequential stimulation with related variants of the same T cell epitope can cause T cell anergy or the conversion of effector to immunosuppressive T cell phenotypes.

Is It Rational to Assume that Infants Imitate Rationally? A Theoretical Analysis and Critique

Science.gov (United States)

Paulus, Markus

2012-01-01

It has been suggested that preverbal infants evaluate the efficiency of others' actions (by applying a "principle of rational action") and that they imitate others' actions rationally. The present contribution presents a conceptual analysis of the claim that preverbal infants imitate rationally. It shows that this ability rests on at least three…

Adapting Rational Unified Process (RUP) approach in designing a secure e-Tendering model

Science.gov (United States)

Mohd, Haslina; Robie, Muhammad Afdhal Muhammad; Baharom, Fauziah; Darus, Norida Muhd; Saip, Mohamed Ali; Yasin, Azman

2016-08-01

e-Tendering is an electronic processing of the tender document via internet and allow tenderer to publish, communicate, access, receive and submit all tender related information and documentation via internet. This study aims to design the e-Tendering system using Rational Unified Process approach. RUP provides a disciplined approach on how to assign tasks and responsibilities within the software development process. RUP has four phases that can assist researchers to adjust the requirements of various projects with different scope, problem and the size of projects. RUP is characterized as a use case driven, architecture centered, iterative and incremental process model. However the scope of this study only focusing on Inception and Elaboration phases as step to develop the model and perform only three of nine workflows (business modeling, requirements, analysis and design). RUP has a strong focus on documents and the activities in the inception and elaboration phases mainly concern the creation of diagrams and writing of textual descriptions. The UML notation and the software program, Star UML are used to support the design of e-Tendering. The e-Tendering design based on the RUP approach can contribute to e-Tendering developers and researchers in e-Tendering domain. In addition, this study also shows that the RUP is one of the best system development methodology that can be used as one of the research methodology in Software Engineering domain related to secured design of any observed application. This methodology has been tested in various studies in certain domains, such as in Simulation-based Decision Support, Security Requirement Engineering, Business Modeling and Secure System Requirement, and so forth. As a conclusion, these studies showed that the RUP one of a good research methodology that can be adapted in any Software Engineering (SE) research domain that required a few artifacts to be generated such as use case modeling, misuse case modeling, activity

Conjugate Meningococcal Vaccines Development: GSK Biologicals Experience

Directory of Open Access Journals (Sweden)

Jacqueline M. Miller

2011-01-01

Full Text Available Meningococcal diseases are serious threats to global health, and new vaccines specifically tailored to meet the age-related needs of various geographical areas are required. This paper focuses on the meningococcal conjugate vaccines developed by GSK Biologicals. Two combined conjugate vaccines were developed to help protect infants and young children in countries where the incidence of meningococcal serogroup C or serogroup C and Y disease is important: Hib-MenC-TT vaccine, which offers protection against Haemophilus influenzae type b and Neisseria meningitidis serogroup C diseases, is approved in several countries; and Hib-MenCY-TT vaccine, which adds N. meningitidis serogroup Y antigen, is currently in the final stages of development. Additionally, a tetravalent conjugate vaccine (MenACWY-TT designed to help protect against four meningococcal serogroups is presently being evaluated for global use in all age groups. All of these vaccines were shown to be highly immunogenic and to have clinically acceptable safety profiles.

Conjugate Meningococcal Vaccines Development: GSK Biologicals Experience

Science.gov (United States)

Miller, Jacqueline M.; Mesaros, Narcisa; Van Der Wielen, Marie; Baine, Yaela

2011-01-01

Meningococcal diseases are serious threats to global health, and new vaccines specifically tailored to meet the age-related needs of various geographical areas are required. This paper focuses on the meningococcal conjugate vaccines developed by GSK Biologicals. Two combined conjugate vaccines were developed to help protect infants and young children in countries where the incidence of meningococcal serogroup C or serogroup C and Y disease is important: Hib-MenC-TT vaccine, which offers protection against Haemophilus influenzae type b and Neisseria meningitidis serogroup C diseases, is approved in several countries; and Hib-MenCY-TT vaccine, which adds N. meningitidis serogroup Y antigen, is currently in the final stages of development. Additionally, a tetravalent conjugate vaccine (MenACWY-TT) designed to help protect against four meningococcal serogroups is presently being evaluated for global use in all age groups. All of these vaccines were shown to be highly immunogenic and to have clinically acceptable safety profiles. PMID:21991444

Bounded Rationality and Budgeting

OpenAIRE

Ibrahim, Mukdad

2016-01-01

This article discusses the theory of bounded rationality which had been introduced by Herbert Simon in the 1950s. Simon introduced the notion of bounded rationality stating that while decision-makers strive for rationality, they are limited by the effect of the environment, their information process capacity and by the constraints on their information storage and retrieval capabilities. Moreover, this article tries to specifically blend this notion into budgeting, using the foundations of inc...

Biomimetics: From Bioinformatics to Rational Design of Dendrimers as Gene Carriers

Science.gov (United States)

Araya-Durán, Ingrid; Varas-Concha, Ignacio; Almonacid, Daniel Eduardo; González-Nilo, Fernando Danilo

2015-01-01

Biomimetics, or the use of principles of Nature for developing new materials, is a paradigm that could help Nanomedicine tremendously. One of the current challenges in Nanomedicine is the rational design of new efficient and safer gene carriers. Poly(amidoamine) (PAMAM) dendrimers are a well-known class of nanoparticles, extensively used as non-viral nucleic acid carriers, due to their positively charged end-groups. Yet, there are still several aspects that can be improved for their successful application in in vitro and in vivo systems, including their affinity for nucleic acids as well as lowering their cytotoxicity. In the search of new functional groups that could be used as new dendrimer-reactive groups, we followed a biomimetic approach to determine the amino acids with highest prevalence in protein-DNA interactions. Then we introduced them individually as terminal groups of dendrimers, generating a new class of nanoparticles. Molecular dynamics studies of two systems: PAMAM-Arg and PAMAM-Lys were also performed in order to describe the formation of complexes with DNA. Results confirmed that the introduction of amino acids as terminal groups in a dendrimer increases their affinity for DNA and the interactions in the complexes were characterized at atomic level. We end up by briefly discussing additional modifications that can be made to PAMAM dendrimers to turned them into promising new gene carriers. PMID:26382062

Effects of behavioral response and vaccination policy on epidemic spreading--an approach based on evolutionary-game dynamics.

Science.gov (United States)

Zhang, Hai-Feng; Wu, Zhi-Xi; Tang, Ming; Lai, Ying-Cheng

2014-07-11

How effective are governmental incentives to achieve widespread vaccination coverage so as to prevent epidemic outbreak? The answer largely depends on the complex interplay among the type of incentive, individual behavioral responses, and the intrinsic epidemic dynamics. By incorporating evolutionary games into epidemic dynamics, we investigate the effects of two types of incentives strategies: partial-subsidy policy in which certain fraction of the cost of vaccination is offset, and free-subsidy policy in which donees are randomly selected and vaccinated at no cost. Through mean-field analysis and computations, we find that, under the partial-subsidy policy, the vaccination coverage depends monotonically on the sensitivity of individuals to payoff difference, but the dependence is non-monotonous for the free-subsidy policy. Due to the role models of the donees for relatively irrational individuals and the unchanged strategies of the donees for rational individuals, the free-subsidy policy can in general lead to higher vaccination coverage. Our findings indicate that any disease-control policy should be exercised with extreme care: its success depends on the complex interplay among the intrinsic mathematical rules of epidemic spreading, governmental policies, and behavioral responses of individuals.

A Rapporteur's Summary : Research on Dengue Vaccine

OpenAIRE

Kitamura, Takashi

1994-01-01

Dengue virus is a member of flavivirus group. Diseases caused by flaviviruses have been a scourge of mankind for long history of human kind; with yellow fever at the top, followed by dengue fever, Japanese encephalitis (JE) and Russian spring-summer encephalitis (RSSE). Due to the dvevelopment of a safe and efficacious live-attenuated vaccine against yellow fever as a first laboratory-designed virus vaccine, this disease is no longer a threat in countries where adequate vaccination is practic...

Vaccines today, vaccines tomorrow: a perspective.

Science.gov (United States)

Loucq, Christian

2013-01-01

Vaccines are considered as one of the major contributions of the 20th century and one of the most cost effective public health interventions. The International Vaccine Institute has as a mission to discover, develop and deliver new and improved vaccines against infectious diseases that affects developing nations. If Louis Pasteur is known across the globe, vaccinologists like Maurice Hilleman, Jonas Salk and Charles Mérieux are known among experts only despite their contribution to global health. Thanks to a vaccine, smallpox has been eradicated, polio has nearly disappeared, Haemophilus influenzae B, measles and more recently meningitis A are controlled in many countries. While a malaria vaccine is undergoing phase 3, International Vaccine Institute, in collaboration with an Indian manufacturer has brought an oral inactivated cholera vaccine to pre-qualification. The field of vaccinology has undergone major changes thanks to philanthropists such as Bill and Melinda Gates, initiatives like the Decade of Vaccines and public private partnerships. Current researches on vaccines have more challenging targets like the dengue viruses, malaria, human immunodeficiency virus, the respiratory syncytial virus and nosocomial diseases. Exciting research is taking place on new adjuvants, nanoparticles, virus like particles and new route of administration. An overcrowded infant immunization program, anti-vaccine groups, immunizing a growing number of elderlies and delivering vaccines to difficult places are among challenges faced by vaccinologists and global health experts.

Rational valuations

Directory of Open Access Journals (Sweden)

Georg Spielthenner

2007-01-01

Full Text Available Valuations are ubiquitous. We may be for or against genetically modified food; we find some politicians irresponsible; we prefer Beethoven to rock ‘n’ roll or vice versa; some enjoy bird-watching while others find it boring; and we may think that we have to tighten up on green-house gas emissions. Valuing is pervasive and often we are not even aware that we are valuing. However, many of ourvaluations are ill grounded and rationally defective. They are frequently based on misinformation, sloppy thinking, prejudice, and are biased in many ways as psychological research shows. For this reason there is widespread agreement among phi-losophers that we need an account of substantive valuational rationality, both for the theory of practical reasoning and for ethics as well. My main objectin this paper is to outline such an account and to present a principle that allows a non-technical rational criticism of valuations

Rational emotions.

Science.gov (United States)

Meshulam, Meir; Winter, Eyal; Ben-Shakhar, Gershon; Aharon, Itzhak

2012-01-01

We present here the concept of rational emotions: Emotions may be directly controlled and utilized in a conscious, analytic fashion, enabling an individual to size up a situation, to determine that a certain "mental state" is strategically advantageous and adjust accordingly. Building on the growing body of literature recognizing the vital role of emotions in determining decisions, we explore the complementary role of rational choice in choosing emotional states. Participants played the role of "recipient" in the dictator game, in which an anonymous "dictator" decides how to split an amount of money between himself and the recipient. A subset of recipients was given a monetary incentive to be angry at low-split offers. That subset demonstrated increased physiological arousal at low offers relative to high offers as well as more anger than other participants. These results provide a fresh outlook on human decision-making and contribute to the continuing effort to build more complete models of rational behavior.

Models for Rational Number Bases

Science.gov (United States)

Pedersen, Jean J.; Armbruster, Frank O.

1975-01-01

This article extends number bases to negative integers, then to positive rationals and finally to negative rationals. Methods and rules for operations in positive and negative rational bases greater than one or less than negative one are summarized in tables. Sample problems are explained and illustrated. (KM)

Rational Design of Disulfide Bonds Increases Thermostability of a Mesophilic 1,3-1,4-β-Glucanase from Bacillus terquilensis.

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Chengtuo Niu

Full Text Available 1,3-1,4-β-glucanase is an important biocatalyst in brewing industry and animal feed industry, while its low thermostability often reduces its application performance. In this study, the thermostability of a mesophilic β-glucanase from Bacillus terquilensis was enhanced by rational design and engineering of disulfide bonds in the protein structure. Protein spatial configuration was analyzed to pre-exclude the residues pairs which negatively conflicted with the protein structure and ensure the contact of catalytic center. The changes in protein overall and local flexibility among the wild-type enzyme and the designated mutants were predicted to select the potential disulfide bonds for enhancement of thermostability. Two residue pairs (N31C-T187C and P102C-N125C were chosen as engineering targets and both of them were proved to significantly enhance the protein thermostability. After combinational mutagenesis, the double mutant N31C-T187C/P102C-N125C showed a 48.3% increase in half-life value at 60°C and a 4.1°C rise in melting temperature (Tm compared to wild-type enzyme. The catalytic property of N31C-T187C/P102C-N125C mutant was similar to that of wild-type enzyme. Interestingly, the optimal pH of double mutant was shifted from pH6.5 to pH6.0, which could also increase its industrial application. By comparison with mutants with single-Cys substitutions, the introduction of disulfide bonds and the induced new hydrogen bonds were proved to result in both local and overall rigidification and should be responsible for the improved thermostability. Therefore, the introduction of disulfide bonds for thermostability improvement could be rationally and highly-effectively designed by combination with spatial configuration analysis and molecular dynamics simulation.

Vaccine development for emerging virulent infectious diseases.

Science.gov (United States)

Maslow, Joel N

2017-10-04

The recent outbreak of Zaire Ebola virus in West Africa altered the classical paradigm of vaccine development and that for emerging infectious diseases (EIDs) in general. In this paper, the precepts of vaccine discovery and advancement through pre-clinical and clinical assessment are discussed in the context of the recent Ebola virus, Middle East Respiratory Syndrome coronavirus (MERS-CoV), and Zika virus outbreaks. Clinical trial design for diseases with high mortality rates and/or high morbidity in the face of a global perception of immediate need and the factors that drive design in the face of a changing epidemiology are presented. Vaccines for EIDs thus present a unique paradigm to standard development precepts. Copyright © 2017 Elsevier Ltd. All rights reserved.

Recombinant Newcastle disease virus-vectored vaccines against human and animal infectious diseases.

Science.gov (United States)

Duan, Zhiqiang; Xu, Houqiang; Ji, Xinqin; Zhao, Jiafu

2015-01-01

Recent advances in recombinant genetic engineering techniques have brought forward a leap in designing new vaccines in modern medicine. One attractive strategy is the application of reverse genetics technology to make recombinant Newcastle disease virus (rNDV) deliver protective antigens of pathogens. In recent years, numerous studies have demonstrated that rNDV-vectored vaccines can induce quicker and better humoral and mucosal immune responses than conventional vaccines and are protective against pathogen challenges. With deeper understanding of NDV molecular biology, it is feasible to develop gene-modified rNDV vaccines accompanied by good safety, high efficacy, low toxicity and better immunogenicity. This review summarizes the development of reverse genetics technology in using NDV as a promising vaccine vector to design new vaccines for human and animal use.

Rational design of modular circuits for gene transcription: A test of the bottom-up approach

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Giordano Emanuele

2010-11-01

Full Text Available Abstract Background Most of synthetic circuits developed so far have been designed by an ad hoc approach, using a small number of components (i.e. LacI, TetR and a trial and error strategy. We are at the point where an increasing number of modular, inter-changeable and well-characterized components is needed to expand the construction of synthetic devices and to allow a rational approach to the design. Results We used interchangeable modular biological parts to create a set of novel synthetic devices for controlling gene transcription, and we developed a mathematical model of the modular circuits. Model parameters were identified by experimental measurements from a subset of modular combinations. The model revealed an unexpected feature of the lactose repressor system, i.e. a residual binding affinity for the operator site by induced lactose repressor molecules. Once this residual affinity was taken into account, the model properly reproduced the experimental data from the training set. The parameters identified in the training set allowed the prediction of the behavior of networks not included in the identification procedure. Conclusions This study provides new quantitative evidences that the use of independent and well-characterized biological parts and mathematical modeling, what is called a bottom-up approach to the construction of gene networks, can allow the design of new and different devices re-using the same modular parts.

Are security analysts rational? a literature review

OpenAIRE

Peixinho, Rúben; Coelho, Luís; Taffler, Richard J.

2005-01-01

Rational choice theory and bounded rationality constitute the basis for the discussion in several areas regarding human rationality. In finance, this discussion has been made between traditional finance and behavioural finance approach, which have different perspectives concerning market agents’ rationality. This paper reviews several studies addressing rationality among security analysts. The analysis shows that analysts’systematic optimism seems to be inconsistent with rationality....

Superior control of HIV-1 replication by CD8+ T cells targeting conserved epitopes: implications for HIV vaccine design.

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Pratima Kunwar

Full Text Available A successful HIV vaccine will likely induce both humoral and cell-mediated immunity, however, the enormous diversity of HIV has hampered the development of a vaccine that effectively elicits both arms of the adaptive immune response. To tackle the problem of viral diversity, T cell-based vaccine approaches have focused on two main strategies (i increasing the breadth of vaccine-induced responses or (ii increasing vaccine-induced responses targeting only conserved regions of the virus. The relative extent to which set-point viremia is impacted by epitope-conservation of CD8(+ T cell responses elicited during early HIV-infection is unknown but has important implications for vaccine design. To address this question, we comprehensively mapped HIV-1 CD8(+ T cell epitope-specificities in 23 ART-naïve individuals during early infection and computed their conservation score (CS by three different methods (prevalence, entropy and conseq on clade-B and group-M sequence alignments. The majority of CD8(+ T cell responses were directed against variable epitopes (p<0.01. Interestingly, increasing breadth of CD8(+ T cell responses specifically recognizing conserved epitopes was associated with lower set-point viremia (r = - 0.65, p = 0.009. Moreover, subjects possessing CD8(+ T cells recognizing at least one conserved epitope had 1.4 log10 lower set-point viremia compared to those recognizing only variable epitopes (p = 0.021. The association between viral control and the breadth of conserved CD8(+ T cell responses may be influenced by the method of CS definition and sequences used to determine conservation levels. Strikingly, targeting variable versus conserved epitopes was independent of HLA type (p = 0.215. The associations with viral control were independent of functional avidity of CD8(+ T cell responses elicited during early infection. Taken together, these data suggest that the next-generation of T-cell based HIV-1 vaccines should focus

Design and statistical considerations for studies evaluating the efficacy of a single dose of the human papillomavirus (HPV) vaccine.

Science.gov (United States)

Sampson, Joshua N; Hildesheim, Allan; Herrero, Rolando; Gonzalez, Paula; Kreimer, Aimee R; Gail, Mitchell H

2018-05-01

Cervical cancer is a leading cause of cancer mortality in women worldwide. Human papillomavirus (HPV) types 16 and 18 cause about 70% of all cervical cancers. Clinical trials have demonstrated that three doses of either commercially available HPV vaccine, Cervarix ® or Gardasil ®, prevent most new HPV 16/18 infections and associated precancerous lesions. Based on evidence of immunological non-inferiority, 2-dose regimens have been licensed for adolescents in the United States, European Union, and elsewhere. However, if a single dose were effective, vaccine costs would be reduced substantially and the logistics of vaccination would be greatly simplified, enabling vaccination programs in developing countries. The National Cancer Institute (NCI) and the Agencia Costarricense de Investigaciones Biomédicas (ACIB) are conducting, with support from the Bill & Melinda Gates Foundation and the International Agency for Research on Cancer (IARC), a large 24,000 girl study to evaluate the efficacy of a 1-dose regimen. The first component of the study is a four-year non-inferiority trial comparing 1- to 2-dose regimens of the two licensed vaccines. The second component is an observational study that estimates the vaccine efficacy (VE) of each regimen by comparing the HPV infection rates in the trial arms to those in a contemporaneous survey group of unvaccinated girls. In this paper, we describe the design and statistical analysis for this study. We explain the advantage of defining non-inferiority on the absolute risk scale when the expected event rate is near 0 and, given this definition, suggest an approach to account for missing clinic visits. We then describe the problem of estimating VE in the absence of a randomized placebo arm and offer our solution. Copyright © 2018. Published by Elsevier Inc.

Ontology-based literature mining of E. coli vaccine-associated gene interaction networks.

Science.gov (United States)

Hur, Junguk; Özgür, Arzucan; He, Yongqun

2017-03-14

Pathogenic Escherichia coli infections cause various diseases in humans and many animal species. However, with extensive E. coli vaccine research, we are still unable to fully protect ourselves against E. coli infections. To more rational development of effective and safe E. coli vaccine, it is important to better understand E. coli vaccine-associated gene interaction networks. In this study, we first extended the Vaccine Ontology (VO) to semantically represent various E. coli vaccines and genes used in the vaccine development. We also normalized E. coli gene names compiled from the annotations of various E. coli strains using a pan-genome-based annotation strategy. The Interaction Network Ontology (INO) includes a hierarchy of various interaction-related keywords useful for literature mining. Using VO, INO, and normalized E. coli gene names, we applied an ontology-based SciMiner literature mining strategy to mine all PubMed abstracts and retrieve E. coli vaccine-associated E. coli gene interactions. Four centrality metrics (i.e., degree, eigenvector, closeness, and betweenness) were calculated for identifying highly ranked genes and interaction types. Using vaccine-related PubMed abstracts, our study identified 11,350 sentences that contain 88 unique INO interactions types and 1,781 unique E. coli genes. Each sentence contained at least one interaction type and two unique E. coli genes. An E. coli gene interaction network of genes and INO interaction types was created. From this big network, a sub-network consisting of 5 E. coli vaccine genes, including carA, carB, fimH, fepA, and vat, and 62 other E. coli genes, and 25 INO interaction types was identified. While many interaction types represent direct interactions between two indicated genes, our study has also shown that many of these retrieved interaction types are indirect in that the two genes participated in the specified interaction process in a required but indirect process. Our centrality analysis of

Future product design

DEFF Research Database (Denmark)

Andreasen, Mogens Myrup

1997-01-01

This paper (in form of overheads) formulate new challenges and possibilities for engineering design, utilizing rationalization effect from modularisation, re-use and transparaency.......This paper (in form of overheads) formulate new challenges and possibilities for engineering design, utilizing rationalization effect from modularisation, re-use and transparaency....

Rationally reduced libraries for combinatorial pathway optimization minimizing experimental effort.

Science.gov (United States)

Jeschek, Markus; Gerngross, Daniel; Panke, Sven

2016-03-31

Rational flux design in metabolic engineering approaches remains difficult since important pathway information is frequently not available. Therefore empirical methods are applied that randomly change absolute and relative pathway enzyme levels and subsequently screen for variants with improved performance. However, screening is often limited on the analytical side, generating a strong incentive to construct small but smart libraries. Here we introduce RedLibs (Reduced Libraries), an algorithm that allows for the rational design of smart combinatorial libraries for pathway optimization thereby minimizing the use of experimental resources. We demonstrate the utility of RedLibs for the design of ribosome-binding site libraries by in silico and in vivo screening with fluorescent proteins and perform a simple two-step optimization of the product selectivity in the branched multistep pathway for violacein biosynthesis, indicating a general applicability for the algorithm and the proposed heuristics. We expect that RedLibs will substantially simplify the refactoring of synthetic metabolic pathways.

Empirical evidence for resource-rational anchoring and adjustment.

Science.gov (United States)

Lieder, Falk; Griffiths, Thomas L; M Huys, Quentin J; Goodman, Noah D

2018-04-01

People's estimates of numerical quantities are systematically biased towards their initial guess. This anchoring bias is usually interpreted as sign of human irrationality, but it has recently been suggested that the anchoring bias instead results from people's rational use of their finite time and limited cognitive resources. If this were true, then adjustment should decrease with the relative cost of time. To test this hypothesis, we designed a new numerical estimation paradigm that controls people's knowledge and varies the cost of time and error independently while allowing people to invest as much or as little time and effort into refining their estimate as they wish. Two experiments confirmed the prediction that adjustment decreases with time cost but increases with error cost regardless of whether the anchor was self-generated or provided. These results support the hypothesis that people rationally adapt their number of adjustments to achieve a near-optimal speed-accuracy tradeoff. This suggests that the anchoring bias might be a signature of the rational use of finite time and limited cognitive resources rather than a sign of human irrationality.

Bioengineering towards self-assembly of particulate vaccines.

Science.gov (United States)

Rehm, Bernd H A

2017-12-01

There is an unmet demand for safe and efficient vaccines for prevention of various infectious diseases. Subunit vaccines comprise selected pathogen specific antigens are a safe alternative to whole organism vaccines. However they often lack immunogenicity. Natural and synthetic self-assembling polymers and proteins will be reviewed in view their use to encapsulate and/or display antigens to serve as immunogenic antigen carriers for induction of protective immunity. Recent advances made in in vivo assembly of antigen-displaying polyester inclusions will be a focus. Particulate vaccines are inherently immunogenic due to enhanced uptake by antigen presenting cells which process antigens mediating adaptive immune responses. Bioengineering approaches enable the design of tailor-made particulate vaccines to fine tune immune responses towards protective immunity. Copyright © 2017 Elsevier Ltd. All rights reserved.

Estimating population effects of vaccination using large, routinely collected data.

Science.gov (United States)

Halloran, M Elizabeth; Hudgens, Michael G

2018-01-30

Vaccination in populations can have several kinds of effects. Establishing that vaccination produces population-level effects beyond the direct effects in the vaccinated individuals can have important consequences for public health policy. Formal methods have been developed for study designs and analysis that can estimate the different effects of vaccination. However, implementing field studies to evaluate the different effects of vaccination can be expensive, of limited generalizability, or unethical. It would be advantageous to use routinely collected data to estimate the different effects of vaccination. We consider how different types of data are needed to estimate different effects of vaccination. The examples include rotavirus vaccination of young children, influenza vaccination of elderly adults, and a targeted influenza vaccination campaign in schools. Directions for future research are discussed. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Limited rationality and strategic interaction

DEFF Research Database (Denmark)

Fehr, Ernst; Tyran, Jean-Robert