WorldWideScience

Sample records for cell responses needed

  1. Biosolar cells: global artificial photosynthesis needs responsive matrices with quantum coherent kinetic control for high yield.

    Science.gov (United States)

    Purchase, R L; de Groot, H J M

    2015-06-06

    This contribution discusses why we should consider developing artificial photosynthesis with the tandem approach followed by the Dutch BioSolar Cells consortium, a current operational paradigm for a global artificial photosynthesis project. We weigh the advantages and disadvantages of a tandem converter against other approaches, including biomass. Owing to the low density of solar energy per unit area, artificial photosynthetic systems must operate at high efficiency to minimize the land (or sea) area required. In particular, tandem converters are a much better option than biomass for densely populated countries and use two photons per electron extracted from water as the raw material into chemical conversion to hydrogen, or carbon-based fuel when CO2 is also used. For the average total light sum of 40 mol m(-2) d(-1) for The Netherlands, the upper limits are many tons of hydrogen or carbon-based fuel per hectare per year. A principal challenge is to forge materials for quantitative conversion of photons to chemical products within the physical limitation of an internal potential of ca 2.9 V. When going from electric charge in the tandem to hydrogen and back to electricity, only the energy equivalent to 1.23 V can be stored in the fuel and regained. A critical step is then to learn from nature how to use the remaining difference of ca 1.7 V effectively by triple use of one overpotential for preventing recombination, kinetic stabilization of catalytic intermediates and finally generating targeted heat for the release of oxygen. Probably the only way to achieve this is by using bioinspired responsive matrices that have quantum-classical pathways for a coherent conversion of photons to fuels, similar to what has been achieved by natural selection in evolution. In appendix A for the expert, we derive a propagator that describes how catalytic reactions can proceed coherently by a convergence of time scales of quantum electron dynamics and classical nuclear dynamics. We

  2. CD8+ T Cells Need a Little Help(er) for Sustained Antitumor Response | Center for Cancer Research

    Science.gov (United States)

    The immune system comprises a powerful army of specialized cells and molecules that protect the body against invading foreign agents. For years, researchers have been trying to find a way to turn the wrath of the immune system against cancer. A significant amount of work related to cancer immunotherapy has focused on the potential of CD8+ cytotoxic T cells to attack and eliminate cancer cells. However, this approach has proved challenging for two reasons. First, there are several mechanisms in place to make sure that T cells and other components of the immune system ignore “self” molecules and cells, even if these cells become cancerous. Second, tumor microenvironments are often characterized by the presence of immunosuppressive factors capable of stifling T cell activation (a process called tolerization).  

  3. NKT Cell Responses to B Cell Lymphoma.

    Science.gov (United States)

    Li, Junxin; Sun, Wenji; Subrahmanyam, Priyanka B; Page, Carly; Younger, Kenisha M; Tiper, Irina V; Frieman, Matthew; Kimball, Amy S; Webb, Tonya J

    2014-06-01

    Natural killer T (NKT) cells are a unique subset of CD1d-restricted T lymphocytes that express characteristics of both T cells and natural killer cells. NKT cells mediate tumor immune-surveillance; however, NKT cells are numerically reduced and functionally impaired in lymphoma patients. Many hematologic malignancies express CD1d molecules and co-stimulatory proteins needed to induce anti-tumor immunity by NKT cells, yet most tumors are poorly immunogenic. In this study, we sought to investigate NKT cell responses to B cell lymphoma. In the presence of exogenous antigen, both mouse and human NKT cell lines produce cytokines following stimulation by B cell lymphoma lines. NKT cell populations were examined ex vivo in mouse models of spontaneous B cell lymphoma, and it was found that during early stages, NKT cell responses were enhanced in lymphoma-bearing animals compared to disease-free animals. In contrast, in lymphoma-bearing animals with splenomegaly and lymphadenopathy, NKT cells were functionally impaired. In a mouse model of blastoid variant mantle cell lymphoma, treatment of tumor-bearing mice with a potent NKT cell agonist, α-galactosylceramide (α-GalCer), resulted in a significant decrease in disease pathology. Ex vivo studies demonstrated that NKT cells from α-GalCer treated mice produced IFN-γ following α-GalCer restimulation, unlike NKT cells from vehicle-control treated mice. These data demonstrate an important role for NKT cells in the immune response to an aggressive hematologic malignancy like mantle cell lymphoma.

  4. Do migrating cells need a nucleus?

    Science.gov (United States)

    Hawkins, Rhoda J

    2018-03-05

    How the nucleus affects cell polarity and migration is unclear. In this issue, Graham et al. (2018. J. Cell Biol. https://doi.org/10.1083/jcb.201706097) show that enucleated cells polarize and migrate in two but not three dimensions and propose that the nucleus is a necessary component of the molecular clutch regulating normal mechanical responses. © 2018 Hawkins.

  5. Transportation needs assessment: Emergency response section

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1989-05-01

    The transportation impacts of moving high level nuclear waste (HLNW) to a repository at Yucca Mountain in Nevada are of concern to the residents of the State as well as to the residents of other states through which the nuclear wastes might be transported. The projected volume of the waste suggests that shipments will occur on a daily basis for some period of time. This will increase the risk of accidents, including a catastrophic incident. Furthermore, as the likelihood of repository construction and operation and waste shipments increase, so will the attention given by the national media. This document is not to be construed as a willingness to accept the HLNW repository on the part of the State. Rather it is an initial step in ensuring that the safety and well-being of Nevada residents and visitors and the State`s economy will be adequately addressed in federal decision-making pertaining to the transportation of HLNW into and across Nevada for disposal in the proposed repository. The Preferred Transportation System Needs Assessment identifies critical system design elements and technical and social issues that must be considered in conducting a comprehensive transportation impact analysis. Development of the needs assessment and the impact analysis is especially complex because of the absence of information and experience with shipping HLNW and because of the ``low probability, high consequence`` aspect of the transportation risk.

  6. Transportation needs assessment: Emergency response section

    International Nuclear Information System (INIS)

    1989-05-01

    The transportation impacts of moving high level nuclear waste (HLNW) to a repository at Yucca Mountain in Nevada are of concern to the residents of the State as well as to the residents of other states through which the nuclear wastes might be transported. The projected volume of the waste suggests that shipments will occur on a daily basis for some period of time. This will increase the risk of accidents, including a catastrophic incident. Furthermore, as the likelihood of repository construction and operation and waste shipments increase, so will the attention given by the national media. This document is not to be construed as a willingness to accept the HLNW repository on the part of the State. Rather it is an initial step in ensuring that the safety and well-being of Nevada residents and visitors and the State's economy will be adequately addressed in federal decision-making pertaining to the transportation of HLNW into and across Nevada for disposal in the proposed repository. The Preferred Transportation System Needs Assessment identifies critical system design elements and technical and social issues that must be considered in conducting a comprehensive transportation impact analysis. Development of the needs assessment and the impact analysis is especially complex because of the absence of information and experience with shipping HLNW and because of the ''low probability, high consequence'' aspect of the transportation risk

  7. Cell response to surgery.

    LENUS (Irish Health Repository)

    Ni Choileain, Niamh

    2012-02-03

    OBJECTIVES: To describe the profound alterations in host immunity that are produced by major surgery as demonstrated by experimental and clinical studies, and to evaluate the benefits of therapeutic strategies aimed at attenuating perioperative immune dysfunction. DATA SOURCES: A review of the English-language literature was conducted, incorporating searches of the MEDLINE, EMBASE, and Cochrane collaboration databases to identify laboratory and clinical studies investigating the cellular response to surgery. STUDY SELECTION: Original articles and case reports describing immune dysfunction secondary to surgical trauma were included. DATA EXTRACTION: The results were compiled to show outcomes of different studies and were compared. DATA SYNTHESIS: Current evidence indicates that the early systemic inflammatory response syndrome observed after major surgery that is characterized by proinflammatory cytokine release, microcirculatory disturbance, and cell-mediated immune dysfunction is followed by a compensatory anti-inflammatory response syndrome, which predisposes the patient to opportunistic infection, multiple organ dysfunction syndrome, and death. Because there are currently no effective treatment options for multiple organ dysfunction syndrome, measures to prevent its onset should be initiated at an early stage. Accumulating experimental evidence suggests that targeted therapeutic strategies involving immunomodulatory agents such as interferon gamma, granulocyte colony-stimulating factor, the prostaglandin E(2) antagonist, indomethacin, and pentoxifylline may be used for the treatment of systemic inflammatory response syndrome to prevent the onset of multiple organ dysfunction syndrome. CONCLUSIONS: Surgical trauma produces profound immunological dysfunction. Therapeutic strategies directed at restoring immune homeostasis should aim to redress the physiological proinflammatory-anti-inflammatory cell imbalance associated with major surgery.

  8. Assessment of Research Needs for Advanced Fuel Cells

    Energy Technology Data Exchange (ETDEWEB)

    Penner, S.S.

    1985-11-01

    The DOE Advanced Fuel Cell Working Group (AFCWG) was formed and asked to perform a scientific evaluation of the current status of fuel cells, with emphasis on identification of long-range research that may have a significant impact on the practical utilization of fuel cells in a variety of applications. The AFCWG held six meetings at locations throughout the country where fuel cell research and development are in progress, for presentations by experts on the status of fuel cell research and development efforts, as well as for inputs on research needs. Subsequent discussions by the AFCWG have resulted in the identification of priority research areas that should be explored over the long term in order to advance the design and performance of fuel cells of all types. Surveys describing the salient features of individual fuel cell types are presented in Chapters 2 to 6 and include elaborations of long-term research needs relating to the expeditious introduction of improved fuel cells. The Introduction and the Summary (Chapter 1) were prepared by AFCWG. They were repeatedly revised in response to comments and criticism. The present version represents the closest approach to a consensus that we were able to reach, which should not be interpreted to mean that each member of AFCWG endorses every statement and every unexpressed deletion. The Introduction and Summary always represent a majority view and, occasionally, a unanimous judgment. Chapters 2 to 6 provide background information and carry the names of identified authors. The identified authors of Chapters 2 to 6, rather than AFCWG as a whole, bear full responsibility for the scientific and technical contents of these chapters.

  9. Computer Security Incident Response Team Effectiveness: A Needs Assessment

    Directory of Open Access Journals (Sweden)

    Rick Van der Kleij

    2017-12-01

    Full Text Available Computer security incident response teams (CSIRTs respond to a computer security incident when the need arises. Failure of these teams can have far-reaching effects for the economy and national security. CSIRTs often have to work on an ad hoc basis, in close cooperation with other teams, and in time constrained environments. It could be argued that under these working conditions CSIRTs would be likely to encounter problems. A needs assessment was done to see to which extent this argument holds true. We constructed an incident response needs model to assist in identifying areas that require improvement. We envisioned a model consisting of four assessment categories: Organization, Team, Individual and Instrumental. Central to this is the idea that both problems and needs can have an organizational, team, individual, or technical origin or a combination of these levels. To gather data we conducted a literature review. This resulted in a comprehensive list of challenges and needs that could hinder or improve, respectively, the performance of CSIRTs. Then, semi-structured in depth interviews were held with team coordinators and team members of five public and private sector Dutch CSIRTs to ground these findings in practice and to identify gaps between current and desired incident handling practices. This paper presents the findings of our needs assessment and ends with a discussion of potential solutions to problems with performance in incident response.

  10. Computer security incident response team effectiveness : A needs assessment

    NARCIS (Netherlands)

    Kleij, R. van der; Kleinhuis, G.; Young, H.J.

    2017-01-01

    Computer security incident response teams (CSIRTs) respond to a computer security incident when the need arises. Failure of these teams can have far-reaching effects for the economy and national security. CSIRTs often have to work on an ad-hoc basis, in close cooperation with other teams, and in

  11. Challenges and Counselling Needs of Sickle Cell Patients Attending ...

    African Journals Online (AJOL)

    Challenges and Counselling Needs of Sickle Cell Patients Attending University of Ilorin Teaching Hospital. ... pains are the major challenges confronting the respondents while occasional embarrassment due to unexpected sickness accompanying sickle cell disorder and stigma are the most serious counselling needs.

  12. Cell cycle checkpoints: reversible when possible, irreversible when needed

    NARCIS (Netherlands)

    Krenning, L.

    2015-01-01

    Cell cycle checkpoints are reversible in nature, and can prevent progression into the next cell cycle phase if needed. In the case of DNA damage, cells can prevent progression from G1 into S phase, and from G2 into mitosis in the presence of DNA double strand breaks. Following DNA repair, these

  13. Hazardous Materials Management and Emergency Response training Center needs assessment

    International Nuclear Information System (INIS)

    McGinnis, K.A.; Bolton, P.A.; Robinson, R.K.

    1993-09-01

    For the Hanford Site to provide high-quality training using simulated job-site situations to prepare the 4,000 Site workers and 500 emergency responders for known and unknown hazards a Hazardous Materials Management and Emergency Response Training Center is needed. The center will focus on providing classroom lecture as well as hands-on, realistic training. The establishment of the center will create a partnership among the US Department of Energy; its contractors; labor; local, state, and tribal governments; and Xavier and Tulane Universities of Louisiana. This report presents the background, history, need, benefits, and associated costs of the proposed center

  14. Cell phone-induced ostracism threatens fundamental needs.

    Science.gov (United States)

    Hales, Andrew H; Dvir, Maayan; Wesselmann, Eric D; Kruger, Daniel J; Finkenauer, Catrin

    2018-02-13

    Cell phones are useful tools with both practical and social benefits. However, using them in the context of face-to-face conversations may be problematic. We consider this behavior a form of ostracism and test its effects on the satisfaction of basic psychological needs for belonging, self-esteem, control, and meaningful existence. In Study 1 participants who recalled a time in which a friend was checking a cell phone during a serious conversation reported feeling more ostracized (ignored and excluded), greater pain, and threat to basic needs than participants recalling a conversation without a cell phone interruption or a control event. Study 2 replicated and extended this effect: Cell phone-induced ostracism's effects were partially mediated by decreased feelings of relational evaluation, and threatened basic needs both in serious and casual conversation contexts. Findings from both studies also indicated that cell phone-induced ostracism hurts women more so than men.

  15. Emergency Response Capability Baseline Needs Assessment Compliance Assessment

    Energy Technology Data Exchange (ETDEWEB)

    Sharry, John A. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

    2013-09-16

    This document is the second of a two-part analysis of Emergency Response Capabilities of Lawrence Livermore National Laboratory. The first part, 2013 Baseline Needs Assessment Requirements Document established the minimum performance criteria necessary to meet mandatory requirements. This second part analyses the performance of Lawrence Livermore Laboratory Emergency Management Department to the contents of the Requirements Document. The document was prepared based on an extensive review of information contained in the 2009 BNA, the 2012 BNA document, a review of Emergency Planning Hazards Assessments, a review of building construction, occupancy, fire protection features, dispatch records, LLNL alarm system records, fire department training records, and fire department policies and procedures.

  16. Hydrogen Storage Needs for Early Motive Fuel Cell Markets

    Energy Technology Data Exchange (ETDEWEB)

    Kurtz, J.; Ainscough, C.; Simpson, L.; Caton, M.

    2012-11-01

    The National Renewable Energy Laboratory's (NREL) objective for this project is to identify performance needs for onboard energy storage of early motive fuel cell markets by working with end users, manufacturers, and experts. The performance needs analysis is combined with a hydrogen storage technology gap analysis to provide the U.S. Department of Energy (DOE) Fuel Cell Technologies Program with information about the needs and gaps that can be used to focus research and development activities that are capable of supporting market growth.

  17. Information needs for the rapid response team electronic clinical tool.

    Science.gov (United States)

    Barwise, Amelia; Caples, Sean; Jensen, Jeffrey; Pickering, Brian; Herasevich, Vitaly

    2017-10-02

    Information overload in healthcare is dangerous. It can lead to critical errors and delays. During Rapid Response Team (RRT) activations providers must make decisions quickly to rescue patients from physiological deterioration. In order to understand the clinical data required and how best to present that information in electronic systems we aimed to better assess the data needs of providers on the RRT when they respond to an event. A web based survey to evaluate clinical data requirements was created and distributed to all RRT providers at our institution. Participants were asked to rate the importance of each data item in guiding clinical decisions during a RRT event response. There were 96 surveys completed (24.5% response rate) with fairly even distribution throughout all clinical roles on the RRT. Physiological data including heart rate, respiratory rate, and blood pressure were ranked by more than 80% of responders as being critical information. Resuscitation status was also considered critically useful by more than 85% of providers. There is a limited dataset that is considered important during an RRT. The data is widely available in EMR. The findings from this study could be used to improve user-centered EMR interfaces.

  18. Emergency Response Capability Baseline Needs Assessment - Compliance Assessment

    Energy Technology Data Exchange (ETDEWEB)

    Sharry, John A. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

    2016-09-01

    This document was prepared by John A. Sharry, LLNL Fire Marshal and Division Leader for Fire Protection and was reviewed by LLNL Emergency Management Department Head, James Colson. This document is the second of a two-part analysis on Emergency Response Capabilities of Lawrence Livermore National Laboratory. The first part, 2016 Baseline Needs Assessment Requirements Document established the minimum performance criteria necessary to meet mandatory requirements. This second part analyses the performance of Lawrence Livermore Laboratory Emergency Management Department to the contents of the Requirements Document. The document was prepared based on an extensive review of information contained in the 2016 BNA, a review of Emergency Planning Hazards Assessments, a review of building construction, occupancy, fire protection features, dispatch records, LLNL alarm system records, fire department training records, and fire department policies and procedures. The 2013 BNA was approved by NNSA’s Livermore Field Office on January 22, 2014.

  19. Hanford Site emergency response needs, Volumes 1 and 2

    International Nuclear Information System (INIS)

    Good, D.E.

    1996-01-01

    This report presents the results of a comprehensive third party needs assessment of the Hanford Fire Department (HFD), conducted by Hughes Associates Inc. The assessment was commissioned with the intent of obtaining an unbiased report which could be used as a basis for identifying needed changes/modifications to the fire department and its services. This report serves several functions: (1) it documents current and future site operations and associated hazards and risks identified as a result of document review, site and facility surveys, and interviews with knowledgeable personnel; (2) describes the HFD in terms of organization, existing resources and response capabilities; (3) identifies regulatory and other requirements that are applicable to the HFD and includes a discussion of associated legal liabilities; and (4) provides recommendations based on applicable requirements and existing conditions. Each recommendation is followed by a supporting statement to clarify the intent or justification of the recommendation. This report will be followed by a Master Plan document which will present an implementation method for the recommendations (with associated costs) considered to be essential to maintaining adequate, cost effective emergency services at the Hanford site in the next five to seven years

  20. Hanford Site emergency response needs, Volumes 1 and 2

    Energy Technology Data Exchange (ETDEWEB)

    Good, D.E.

    1996-04-16

    This report presents the results of a comprehensive third party needs assessment of the Hanford Fire Department (HFD), conducted by Hughes Associates Inc. The assessment was commissioned with the intent of obtaining an unbiased report which could be used as a basis for identifying needed changes/modifications to the fire department and its services. This report serves several functions: (1) it documents current and future site operations and associated hazards and risks identified as a result of document review, site and facility surveys, and interviews with knowledgeable personnel; (2) describes the HFD in terms of organization, existing resources and response capabilities; (3) identifies regulatory and other requirements that are applicable to the HFD and includes a discussion of associated legal liabilities; and (4) provides recommendations based on applicable requirements and existing conditions. Each recommendation is followed by a supporting statement to clarify the intent or justification of the recommendation. This report will be followed by a Master Plan document which will present an implementation method for the recommendations (with associated costs) considered to be essential to maintaining adequate, cost effective emergency services at the Hanford site in the next five to seven years.

  1. Fuel Cells: Status and Technical/Economic Needs

    Science.gov (United States)

    Rambach, Glenn

    1996-01-01

    The need for fuel cell and alternative fuels has become increasingly important in that the U.S. spends 1 billion dollars per week to import oil, and is expected to import 80-100 billion per year in oil by the year 2010. These imports account for half of our oil supply. If 20% of the U.S. vehicle fleet were powered by fuel cells there would be: an offset 1.1 million barrels of oil per day; and a reduction of 2 million tons per year of regulated air pollutants. Fueling fuel cells with hydrogen from reformed natural gas results in more than 90% reduction in regulated emissions, and a 70% reduction in CO2, a greenhouse gas. And fueling fuel cells with hydrogen from renewables (wind, solar geothermal, hydro) results in total elimination of all emissions. When fuel cells become commercialized: they will improve America's economic competitiveness; and the regions where they are produced will benefit economically.

  2. SUSTAINABILITY AND COMPANY’S CORPORATE SOCIAL RESPONSIBILITY NEED

    Directory of Open Access Journals (Sweden)

    MONICA VIOLETA ACHIM

    2012-05-01

    Full Text Available The company is a living organism, is an entity and its analysis should be made taking into account the whole system. The company is a dynamic environment, which has as a mainly aims to add value for all participants in the economic life. In the organizations, the achievement of the concept of sustainable development is achieved through the concept of societal responsibility of the organizations. For this scope we need to use the term introduced by Elkington namely “The Triple Bottom Line” which involve economic prosperity, environmental compliance and improve social cohesion. [11]. So, “The Triple Bottom Line” can be defined as an approach for measuring the overall performance of an organization according to its triple contribution to the three aspects mentioned above. The new conceptual framework change radically the final aim of a company because it is not anymore maximizing the value of shares held by shareholders, but it is maximizing value for all stakeholders, where shareholders are just another category of stakeholders. Sustainable development and globalization require new performance standards that exceed the economic field, for both national company and international ones. As a consequence, these standards must be integrated into the company's development strategy, to ensure sustainability of activities carried, by the harmonization of economic, social and environmental objectives.

  3. A Global Stem Cell Niche – Need of the Hour

    Directory of Open Access Journals (Sweden)

    Editorial

    2014-11-01

    Full Text Available A Global Stem Cell Niche – Need of the Hour The time, this issue is online, most of us would be aware of the world’s first induced pluripotent stem (iPS cell based clinical trial for age-related macular degeneration which is underway in Japan. The first patient in the trial has been transplanted with the cell sheets of retinal pigment epithelium derived from the patient's own iPS cells in September 2014 [1] and is under follow-up. As we are overwhelmed with this scientific feat, an analysis of the trends of stem cell based clinical trials globally [2] makes us realize that there is a wide variation in the clinical trials between the nations, with differences being observed in diseases that are given priority, cell sources that are being chosen, principles of ethics, regulatory frameworks etc,. A realization dawns that the scientific communities in each group or country have their own niche of cell based research leading to the above mentioned variations. While in Japan, a hi-tech iPS trial has started, Mazini et al from Morocco, describe the hurdles in creating a public cord blood bank in their country with a background of the regulatory guidelines existing there while Lee et al's work from the United States of America (USA focuses on microencapsulation of adipose derived stem cells. While each of the above subject are equally important, a global consortium is the need of the hour, where interactions among all the stake holders of cell based therapies can be established for enabling exchange of information, technology, solutions and products, thereby avoiding repetition of the same work, while gaining the insight of different viewpoints into solving an issue which could be of significance either to a local community or the entire global society. References: Reardon S, Cyranoski D. Japan stem-cell trial stirs envy. Nature. 2014 ;513(7518:287-8. Li MD, Atkins H, Bubela T. The global landscape of stem cell clinical trials. Regen Med. 2014;9(1:27-39.

  4. Human regulatory B cells control the TFH cell response.

    Science.gov (United States)

    Achour, Achouak; Simon, Quentin; Mohr, Audrey; Séité, Jean-François; Youinou, Pierre; Bendaoud, Boutahar; Ghedira, Ibtissem; Pers, Jacques-Olivier; Jamin, Christophe

    2017-07-01

    Follicular helper T (T FH ) cells support terminal B-cell differentiation. Human regulatory B (Breg) cells modulate cellular responses, but their control of T FH cell-dependent humoral immune responses is unknown. We sought to assess the role of Breg cells on T FH cell development and function. Human T cells were polyclonally stimulated in the presence of IL-12 and IL-21 to generate T FH cells. They were cocultured with B cells to induce their terminal differentiation. Breg cells were included in these cultures, and their effects were evaluated by using flow cytometry and ELISA. B-cell lymphoma 6, IL-21, inducible costimulator, CXCR5, and programmed cell death protein 1 (PD-1) expressions increased on stimulated human T cells, characterizing T FH cell maturation. In cocultures they differentiated B cells into CD138 + plasma and IgD - CD27 + memory cells and triggered immunoglobulin secretions. Breg cells obtained by Toll-like receptor 9 and CD40 activation of B cells prevented T FH cell development. Added to T FH cell and B-cell cocultures, they inhibited B-cell differentiation, impeded immunoglobulin secretions, and expanded Foxp3 + CXCR5 + PD-1 + follicular regulatory T cells. Breg cells modulated IL-21 receptor expressions on T FH cells and B cells, and their suppressive activities involved CD40, CD80, CD86, and intercellular adhesion molecule interactions and required production of IL-10 and TGF-β. Human Breg cells control T FH cell maturation, expand follicular regulatory T cells, and inhibit the T FH cell-mediated antibody secretion. These novel observations demonstrate a role for the Breg cell in germinal center reactions and suggest that deficient activities might impair the T FH cell-dependent control of humoral immunity and might lead to the development of aberrant autoimmune responses. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  5. Needs Analysis of Responsibility Curriculum for Primary School Students

    Science.gov (United States)

    Güven, Semra; Öztürk, Aysun; Duman, Serap Nur

    2016-01-01

    Responsibility is among the most basic concepts that are expected to be taught at early ages and directly affect our personal and social life. Although, it is regarded as a value with its affective dimension; responsibility, a fundamental skill that we should learn formally or informally, starts with the children's introduction to their immediate…

  6. Regulation of T cell responses in atherosclerosis

    NARCIS (Netherlands)

    Puijvelde, Gijsbrecht Henricus Maria van

    2007-01-01

    One of the most important characteristics of atherosclerosis is the chronic inflammatory response in which T cells and NKT cells are very important. In this thesis several methods to modulate the activity of these T and NKT cells in atherosclerosis are described. The induction of regulatory T cells

  7. Emergency Response Capability Baseline Needs Assessment - Requirements Document

    Energy Technology Data Exchange (ETDEWEB)

    Sharry, J A

    2016-10-04

    This document was prepared by John A. Sharry, LLNL Fire Marshal and LLNL Division Leader for Fire Protection and reviewed by LLNL Emergency Management Department Head James Colson. The document follows and expands upon the format and contents of the DOE Model Fire Protection Baseline Capabilities Assessment document contained on the DOE Fire Protection Web Site, but only addresses emergency response.

  8. Controlled Delivery of Human Cells by Temperature Responsive Microcapsules

    Science.gov (United States)

    Mak, W.C.; Olesen, K.; Sivlér, P.; Lee, C.J.; Moreno-Jimenez, I.; Edin, J.; Courtman, D.; Skog, M.; Griffith, M.

    2015-01-01

    Cell therapy is one of the most promising areas within regenerative medicine. However, its full potential is limited by the rapid loss of introduced therapeutic cells before their full effects can be exploited, due in part to anoikis, and in part to the adverse environments often found within the pathologic tissues that the cells have been grafted into. Encapsulation of individual cells has been proposed as a means of increasing cell viability. In this study, we developed a facile, high throughput method for creating temperature responsive microcapsules comprising agarose, gelatin and fibrinogen for delivery and subsequent controlled release of cells. We verified the hypothesis that composite capsules combining agarose and gelatin, which possess different phase transition temperatures from solid to liquid, facilitated the destabilization of the capsules for cell release. Cell encapsulation and controlled release was demonstrated using human fibroblasts as model cells, as well as a therapeutically relevant cell line—human umbilical vein endothelial cells (HUVECs). While such temperature responsive cell microcapsules promise effective, controlled release of potential therapeutic cells at physiological temperatures, further work will be needed to augment the composition of the microcapsules and optimize the numbers of cells per capsule prior to clinical evaluation. PMID:26096147

  9. Controlled Delivery of Human Cells by Temperature Responsive Microcapsules

    Directory of Open Access Journals (Sweden)

    W.C. Mak

    2015-06-01

    Full Text Available Cell therapy is one of the most promising areas within regenerative medicine. However, its full potential is limited by the rapid loss of introduced therapeutic cells before their full effects can be exploited, due in part to anoikis, and in part to the adverse environments often found within the pathologic tissues that the cells have been grafted into. Encapsulation of individual cells has been proposed as a means of increasing cell viability. In this study, we developed a facile, high throughput method for creating temperature responsive microcapsules comprising agarose, gelatin and fibrinogen for delivery and subsequent controlled release of cells. We verified the hypothesis that composite capsules combining agarose and gelatin, which possess different phase transition temperatures from solid to liquid, facilitated the destabilization of the capsules for cell release. Cell encapsulation and controlled release was demonstrated using human fibroblasts as model cells, as well as a therapeutically relevant cell line—human umbilical vein endothelial cells (HUVECs. While such temperature responsive cell microcapsules promise effective, controlled release of potential therapeutic cells at physiological temperatures, further work will be needed to augment the composition of the microcapsules and optimize the numbers of cells per capsule prior to clinical evaluation.

  10. Clinical trials for stem cell transplantation: when are they needed?

    OpenAIRE

    Van Pham, Phuc

    2016-01-01

    In recent years, both stem cell research and the clinical application of these promising cells have increased rapidly. About 1000 clinical trials using stem cells have to date been performed globally. More importantly, more than 10 stem cell-based products have been approved in some countries. With the rapid growth of stem cell applications, some countries have used clinical trials as a tool to diminish the rate of clinical stem cell applications. However, the point at which stem cell clinica...

  11. Responses of Cells to Flow in Vitro

    Directory of Open Access Journals (Sweden)

    Shigehiro Hashimoto

    2013-06-01

    Full Text Available The response of cells to a flow has been studied in vitro. The response of cells was examined in two types of flow channels: a circumnutating flow in a donut-shaped open channel in a culture dish, and a one-way flow in a parallelepiped rhombus flow channel. Variation was made on the material of the parallelepiped channel to study on adhesion of cells to the plates: glass and polydimethylsiloxane. Behavior of cells on the plate was observed under a flow of a medium with an inverted phase-contrast-microscope. The shear stress on the plate is calculated with an estimated parabolic distribution of the velocity between the parallel plates. The adhesion of cells was evaluated with the cumulated shear, which is a product of the shear stress and the exposure time. The experimental results show that cells are responsive to the flow, which governs orientation, exfoliation, and differentiation. The response depends on the kinds of cells: endothelial cells orient along the stream line, although myocytes orient perpendicular to the stream line. The adhesion depends on the combination between scaffold and cell: myocytes are more adhesive to glass than cartilage cells, and fibroblasts are more adhesive to oxygenated polydimethylsiloxane than glass.

  12. Clinical trials for stem cell transplantation: when are they needed?

    Science.gov (United States)

    Van Pham, Phuc

    2016-04-27

    In recent years, both stem cell research and the clinical application of these promising cells have increased rapidly. About 1000 clinical trials using stem cells have to date been performed globally. More importantly, more than 10 stem cell-based products have been approved in some countries. With the rapid growth of stem cell applications, some countries have used clinical trials as a tool to diminish the rate of clinical stem cell applications. However, the point at which stem cell clinical trials are essential remains unclear. This commentary discusses when stem cell clinical trials are essential for stem cell transplantation therapies.

  13. Frequency Responses of Rat Retinal Ganglion Cells.

    Directory of Open Access Journals (Sweden)

    Alex E Hadjinicolaou

    Full Text Available There are 15-20 different types of retinal ganglion cells (RGC in the mammalian retina, each encoding different aspects of the visual scene. The mechanism by which post-synaptic signals from the retinal network generate spikes is determined by each cell's intrinsic electrical properties. Here we investigate the frequency responses of morphologically identified rat RGCs using intracellular injection of sinusoidal current waveforms, to assess their intrinsic capabilities with minimal contributions from the retinal network. Recorded cells were classified according to their morphological characteristics (A, B, C or D-type and their stratification (inner (i, outer (o or bistratified in the inner plexiform layer (IPL. Most cell types had low- or band-pass frequency responses. A2, C1 and C4o cells were band-pass with peaks of 15-30 Hz and low-pass cutoffs above 56 Hz (A2 cells and ~42 Hz (C1 and C4o cells. A1 and C2i/o cells were low-pass with peaks of 10-15 Hz (cutoffs 19-25 Hz. Bistratified D1 and D2 cells were also low-pass with peaks of 5-10 Hz (cutoffs ~16 Hz. The least responsive cells were the B2 and C3 types (peaks: 2-5 Hz, cutoffs: 8-11 Hz. We found no difference between cells stratifying in the inner and outer IPL (i.e., ON and OFF cells or between cells with large and small somas or dendritic fields. Intrinsic physiological properties (input resistance, spike width and sag had little impact on frequency response at low frequencies, but account for 30-40% of response variability at frequencies >30 Hz.

  14. T-cell response in human leishmaniasis

    DEFF Research Database (Denmark)

    Kharazmi, A; Kemp, K; Ismail, A

    1999-01-01

    from cutaneous leishmaniasis (CL) responded by IFN-gamma production following stimulation with Leishmania antigens whereas cells from patients recovered from visceral leishmaniasis (VL) showed a mixed pattern of IFN-gamma and IL-4 responses. The cells producing these cytokines were predominantly CD4......In the present communication we provide evidence for the existence of a Th1/Th2 dichotomy in the T-cell response to Leishmania antigens in human leishmaniasis. Our data suggest that the pattern of IL-4 and IFN-gamma response is polarised in these patients. Lymphocytes from individuals recovered......+. Furthermore, IL-10 plays an important role in the development of post kala azar dermal leishmaniasis (PKDL) from VL. The balance between the parasitic-specific T-cell response plays an important regulatory role in determining the outcome of Leishmania infections in humans....

  15. T-cell response in human leishmaniasis

    DEFF Research Database (Denmark)

    Kharazmi, A; Kemp, K; Ismail, A

    1999-01-01

    In the present communication we provide evidence for the existence of a Th1/Th2 dichotomy in the T-cell response to Leishmania antigens in human leishmaniasis. Our data suggest that the pattern of IL-4 and IFN-gamma response is polarised in these patients. Lymphocytes from individuals recovered...... from cutaneous leishmaniasis (CL) responded by IFN-gamma production following stimulation with Leishmania antigens whereas cells from patients recovered from visceral leishmaniasis (VL) showed a mixed pattern of IFN-gamma and IL-4 responses. The cells producing these cytokines were predominantly CD4......+. Furthermore, IL-10 plays an important role in the development of post kala azar dermal leishmaniasis (PKDL) from VL. The balance between the parasitic-specific T-cell response plays an important regulatory role in determining the outcome of Leishmania infections in humans....

  16. Cytomegalovirus evasion of natural killer cell responses.

    Science.gov (United States)

    Farrell, H E; Degli-Esposti, M A; Davis-Poynter, N J

    1999-04-01

    Natural killer (NK) cells are an important component of the innate cellular immune system. They are particularly important during the early immune responses following virus infection, prior to the induction of cytotoxic T cells (CTL). Unlike CTL, which recognize specific peptides displayed on the surface of cells by class I MHC, NK cells respond to aberrant expression of cell surface molecules, in particular class I MHC, in a non-specific manner. Thus, cells expressing low levels of surface class I MHC are susceptible to recognition by NK cells, with concomitant triggering of cytolytic and cytokine-mediated responses. Many viruses, including the cytomegaloviruses, downregulate cell surface MHC class I: this is likely to provide protection against CTL-mediated clearance of infected cells, but may also render infected cells sensitive to NK-cell attack. This review focuses upon cytomegalovirus-encoded proteins that are believed to promote evasion of NK-cell-mediated immunity. The class I MHC homologues, encoded by all cytomegaloviruses characterised to date, have been implicated as molecular 'decoys', which may mimic the ability of cellular MHC class I to inhibit NK-cell functions. Results from studies in vitro are not uniform, but in general they support the proposal that the class I homologues engage inhibitory receptors from NK cells and other cell types that normally interact with cellular class I. Consistent with this, in vivo studies of murine cytomegalovirus indicate that the class I homologue is required for efficient evasion of NK-cell-mediated clearance. Recently a second murine cytomegalovirus protein, a C-C chemokine homologue, has been implicated as promoting evasion of NK and T-cell-mediated clearance in vivo.

  17. Immunolabeling artifacts and the need for live-cell imaging

    NARCIS (Netherlands)

    Schnell, Ulrike; Dijk, Freark; Sjollema, Klaas A.; Giepmans, Ben N. G.

    Fluorescent fusion proteins have revolutionized examination of proteins in living cells. Still, studies using these proteins are met with criticism because proteins are modified and ectopically expressed, in contrast to immunofluorescence studies. However, introducing immunoreagents inside cells can

  18. Endothelial Cell Response to Fusobacterium nucleatum.

    Science.gov (United States)

    Mendes, Reila Tainá; Nguyen, Daniel; Stephens, Danielle; Pamuk, Ferda; Fernandes, Daniel; Van Dyke, Thomas E; Kantarci, Alpdogan

    2016-07-01

    Vascular response is an essential aspect of an effective immune response to periodontal disease pathogens, as new blood vessel formation contributes to wound healing and inflammation. Gaining a greater understanding of the factors that affect vascular response may then contribute to future breakthroughs in dental medicine. In this study, we have characterized the endothelial cell response to the common bacterium Fusobacterium nucleatum, an important bridging species that facilitates the activity of late colonizers of the dental biofilm. Endothelial cells were infected with Fusobacterium nucleatum (strain 25586) for periods of 4, 12, 24, or 48 h. Cell proliferation and tube formation were analyzed, and expression of adhesion molecules (CD31 and CD34) and vascular endothelial growth factor (VEGF) receptors 1 and 2 was measured by fluorescence-activated cell sorter (FACS) analysis. Data indicate that F. nucleatum impaired endothelial cell proliferation and tube formation. The findings suggest that the modified endothelial cell response acts as a mechanism promoting the pathogenic progression of periodontal diseases and may potentially suggest the involvement of periodontopathogens in systemic diseases associated with periodontal inflammation. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  19. Distinct metabolic responses of an ovarian cancer stem cell line.

    Science.gov (United States)

    Vermeersch, Kathleen A; Wang, Lijuan; McDonald, John F; Styczynski, Mark P

    2014-12-18

    Cancer metabolism is emerging as an important focus area in cancer research. However, the in vitro cell culture conditions under which much cellular metabolism research is performed differ drastically from in vivo tumor conditions, which are characterized by variations in the levels of oxygen, nutrients like glucose, and other molecules like chemotherapeutics. Moreover, it is important to know how the diverse cell types in a tumor, including cancer stem cells that are believed to be a major cause of cancer recurrence, respond to these variations. Here, in vitro environmental perturbations designed to mimic different aspects of the in vivo environment were used to characterize how an ovarian cancer cell line and its derived, isogenic cancer stem cells metabolically respond to environmental cues. Mass spectrometry was used to profile metabolite levels in response to in vitro environmental perturbations. Docetaxel, the chemotherapeutic used for this experiment, caused significant metabolic changes in amino acid and carbohydrate metabolism in ovarian cancer cells, but had virtually no metabolic effect on isogenic ovarian cancer stem cells. Glucose deprivation, hypoxia, and the combination thereof altered ovarian cancer cell and cancer stem cell metabolism to varying extents for the two cell types. Hypoxia had a much larger effect on ovarian cancer cell metabolism, while glucose deprivation had a greater effect on ovarian cancer stem cell metabolism. Core metabolites and pathways affected by these perturbations were identified, along with pathways that were unique to cell types or perturbations. The metabolic responses of an ovarian cancer cell line and its derived isogenic cancer stem cells differ greatly under most conditions, suggesting that these two cell types may behave quite differently in an in vivo tumor microenvironment. While cancer metabolism and cancer stem cells are each promising potential therapeutic targets, such varied behaviors in vivo would need to

  20. Metabolomic Responses of Guard Cells and Mesophyll Cells to Bicarbonate

    Science.gov (United States)

    Misra, Biswapriya B.; de Armas, Evaldo; Tong, Zhaohui; Chen, Sixue

    2015-01-01

    Anthropogenic CO2 presently at 400 ppm is expected to reach 550 ppm in 2050, an increment expected to affect plant growth and productivity. Paired stomatal guard cells (GCs) are the gate-way for water, CO2, and pathogen, while mesophyll cells (MCs) represent the bulk cell-type of green leaves mainly for photosynthesis. We used the two different cell types, i.e., GCs and MCs from canola (Brassica napus) to profile metabolomic changes upon increased CO2 through supplementation with bicarbonate (HCO3 -). Two metabolomics platforms enabled quantification of 268 metabolites in a time-course study to reveal short-term responses. The HCO3 - responsive metabolomes of the cell types differed in their responsiveness. The MCs demonstrated increased amino acids, phenylpropanoids, redox metabolites, auxins and cytokinins, all of which were decreased in GCs in response to HCO3 -. In addition, the GCs showed differential increases of primary C-metabolites, N-metabolites (e.g., purines and amino acids), and defense-responsive pathways (e.g., alkaloids, phenolics, and flavonoids) as compared to the MCs, indicating differential C/N homeostasis in the cell-types. The metabolomics results provide insights into plant responses and crop productivity under future climatic changes where elevated CO2 conditions are to take center-stage. PMID:26641455

  1. T-cell responses in malaria

    DEFF Research Database (Denmark)

    Hviid, L; Jakobsen, P H; Abu-Zeid, Y A

    1992-01-01

    vaccine. Despite this, no efficient operative vaccine is currently available. A large amount of information on T-cell responses to malaria antigens has been accumulated, concerning antigens derived from all stages of the parasite life cycle. The present review summarizes some of that information......Malaria is caused by infection with protozoan parasites of the genus Plasmodium. It remains one of the most severe health problems in tropical regions of the world, and the rapid spread of resistance to drugs and insecticides has stimulated intensive research aimed at the development of a malaria......, and discusses factors affecting the responses of T cells to malaria antigens....

  2. T-cell responses in malaria

    DEFF Research Database (Denmark)

    Hviid, L; Jakobsen, P H; Abu-Zeid, Y A

    1992-01-01

    Malaria is caused by infection with protozoan parasites of the genus Plasmodium. It remains one of the most severe health problems in tropical regions of the world, and the rapid spread of resistance to drugs and insecticides has stimulated intensive research aimed at the development of a malaria...... vaccine. Despite this, no efficient operative vaccine is currently available. A large amount of information on T-cell responses to malaria antigens has been accumulated, concerning antigens derived from all stages of the parasite life cycle. The present review summarizes some of that information......, and discusses factors affecting the responses of T cells to malaria antigens....

  3. Nanomaterials for Engineering Stem Cell Responses.

    Science.gov (United States)

    Kerativitayanan, Punyavee; Carrow, James K; Gaharwar, Akhilesh K

    2015-08-05

    Recent progress in nanotechnology has stimulated the development of multifunctional biomaterials for tissue engineering applications. Synergistic interactions between nanomaterials and stem cell engineering offer numerous possibilities to address some of the daunting challenges in regenerative medicine, such as controlling trigger differentiation, immune reactions, limited supply of stem cells, and engineering complex tissue structures. Specifically, the interactions between stem cells and their microenvironment play key roles in controlling stem cell fate, which underlines therapeutic success. However, the interactions between nanomaterials and stem cells are not well understood, and the effects of the nanomaterials shape, surface morphology, and chemical functionality on cellular processes need critical evaluation. In this Review, focus is put on recent development in nanomaterial-stem cell interactions, with specific emphasis on their application in regenerative medicine. Further, the emerging technologies based on nanomaterials developed over the past decade for stem cell engineering are reviewed, as well as the potential applications of these nanomaterials in tissue regeneration, stem cell isolation, and drug/gene delivery. It is anticipated that the enhanced understanding of nanomaterial-stem cell interactions will facilitate improved biomaterial design for a range of biomedical and biotechnological applications. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  4. Operational Research: Flexible Response to the Needs of Canadian Defence through the Postwar Years.

    Science.gov (United States)

    1980-11-01

    D- 4 OPERAT IONAL RESEARCH :FLE XIBLE RESPONSE TO THE NEEDS OF CANADIA-ETCIU) No V 80 G R LINDSEY UNCLASSIFIED ORAE-MI3OT 7 AAA981OERAIOA...RESPONSE TO THE NEEDS 00 OF CANADIAN DEFENCE THROUGH THE POSTWAR YEARS o BY G.R. LINDSEY DTIC -vaELECTEV APR 2 4 i98i A ORAE MEMORANDUM NO. M103 __ORAE_...OPERATIONAL RESEARCH: FLEXIBLE RESPONSE TO THE NEEDS OF CANADIAN DEFENCE THROUGH THE POSTWAR YEARS Contents Page Abstract/Sommaire

  5. Directional Cell Migration in Response to Repeated Substratum Stretching

    Science.gov (United States)

    Okimura, Chika; Iwadate, Yoshiaki

    2017-10-01

    Crawling migration plays an essential role in a variety of biological phenomena, including development, wound healing, and immune system function. Migration properties such as anterior-posterior polarity, directionality, and velocity are regulated not only by the reception of a chemoattractant but also by sensing mechanical inputs from the external environment. In this review, we describe the mechanical response of migrating cells, particularly under repeated stretching of the elastic substratum, highlighting the fact that there appear to be two independent mechanosensing systems that generate the polarity needed for migration. Cells that have no stress fibers, such as Dictyostelium cells and neutrophil-like differentiated HL-60 cells, migrate perpendicular to the stretching direction via myosin II localization. Cells that do possess stress fibers, however, such as fish keratocytes, migrate parallel to the stretching via a stress-fiber-dependent process.

  6. Patenting human stem cells: an urgent need for a clarification.

    Science.gov (United States)

    Byk, Christian

    2008-09-01

    Patenting human stem cells has become one of the most controversial issues of the bioethics field at the beginning of the XXIst century, at least in industrial countries. This article relates the story of the long legal adventure that preceded the ruling of the Warf case by the Enlarged board of appeal of the European Patent Office on 25th November 2008.

  7. Radiation response of rodent neural precursor cells

    International Nuclear Information System (INIS)

    Limoli, C.L.; Fike, J.R.

    2003-01-01

    Full text: Therapeutic irradiation of the brain can cause cognitive dysfunction that is not treatable or well understood. Several lines of evidence from our laboratory suggest that radiation induced inhibition of neurogenesis in the hippocampus may be involved. To understand the mechanisms underlying these observations, we initiated studies using neural precursor cells isolated from the adult rat hippocampus. Cells were cultured exponentially and analyzed for acute (0-24h) and chronic (3-33 day) changes in apoptosis and oxidative stress following exposure to X-rays. Oxidative stress was measured using a dye sensitive to reactive oxygen species (ROS) and apoptosis was measured using annexin V binding; each endpoint was quantified by fluorescent automated cell sorting (FACS). Following exposure to X-rays, neural precursor cells exhibit a dose-responsive increase in the level of ROS and apoptosis over acute and chronic time frames. ROS and apoptosis were maximal at 12h, increasing 35 and 37% respectively over that of unirradiated controls. ROS and apoptosis peaked again at 24h, increasing 31 and 21% respectively over controls. Chronic levels of ROS and apoptosis were persistently elevated in a dose-dependent manner. ROS showed significant increases (34-180%) over a 3-4 week interval, while increases in apoptosis were less dramatic, rising 45% by week one before dropping to background. Irradiation of rat neural precursor cells was associated with an increase in p53 protein levels, and the activation of G1/S and G2/M checkpoints. These data suggest that the apoptotic and ROS responses may be tied to p53 dependent regulation of cell cycle control and stress activated pathways. We propose that oxidative stress plays a critical role in the radiation response of neural precursor cells, and discuss how this might contribute to the inhibition of neurogenesis and the cognitive impairment observed in the irradiated CNS

  8. Cell Wall Metabolism in Response to Abiotic Stress

    Directory of Open Access Journals (Sweden)

    Hyacinthe Le Gall

    2015-02-01

    Full Text Available This review focuses on the responses of the plant cell wall to several abiotic stresses including drought, flooding, heat, cold, salt, heavy metals, light, and air pollutants. The effects of stress on cell wall metabolism are discussed at the physiological (morphogenic, transcriptomic, proteomic and biochemical levels. The analysis of a large set of data shows that the plant response is highly complex. The overall effects of most abiotic stress are often dependent on the plant species, the genotype, the age of the plant, the timing of the stress application, and the intensity of this stress. This shows the difficulty of identifying a common pattern of stress response in cell wall architecture that could enable adaptation and/or resistance to abiotic stress. However, in most cases, two main mechanisms can be highlighted: (i an increased level in xyloglucan endotransglucosylase/hydrolase (XTH and expansin proteins, associated with an increase in the degree of rhamnogalacturonan I branching that maintains cell wall plasticity and (ii an increased cell wall thickening by reinforcement of the secondary wall with hemicellulose and lignin deposition. Taken together, these results show the need to undertake large-scale analyses, using multidisciplinary approaches, to unravel the consequences of stress on the cell wall. This will help identify the key components that could be targeted to improve biomass production under stress conditions.

  9. The interplay between partners' responsiveness and patients' need for emotional expression in couples coping with cancer

    NARCIS (Netherlands)

    Dagan, Meirav; Sanderman, Robbert; Hoff, Christiaan; Meijerink, W. J. H. Jeroen; Baas, Peter C.; van Haastert, Michiel; Hagedoorn, Mariët

    2014-01-01

    The central aim of this longitudinal observational study was to test whether patients with a high need for emotional expression are especially sensitive to their partners' responsive behavior, and therefore at risk for depressive symptoms when responsiveness is withheld. Patients with colorectal

  10. Multifunctional T-cell Analyses to Study Response and Progression in Adoptive Cell Transfer Immunotherapy

    Science.gov (United States)

    Ma, Chao; Cheung, Ann F.; Chodon, Thinle; Koya, Richard C.; Wu, Zhongqi; Ng, Charles; Avramis, Earl; Cochran, Alistair J.; Witte, Owen N.; Baltimore, David; Chmielowski, Bartosz; Economou, James S.; Comin-Anduix, Begonya; Ribas, Antoni; Heath, James R.

    2013-01-01

    Adoptive cell transfer (ACT) of genetically engineered T cells expressing cancer-specific T-cell receptors (TCR) is a promising cancer treatment. Here, we investigate the in vivo functional activity and dynamics of the transferred cells by analyzing samples from 3 representative patients with melanoma enrolled in a clinical trial of ACT with TCR transgenic T cells targeted against the melanosomal antigen MART-1. The analyses included evaluating 19 secreted proteins from individual cells from phenotypically defined T-cell subpopulations, as well as the enumeration of T cells with TCR antigen specificity for 36 melanoma antigens. These analyses revealed the coordinated functional dynamics of the adoptively transferred, as well as endogenous, T cells, and the importance of highly functional T cells in dominating the antitumor immune response. This study highlights the need to develop approaches to maintaining antitumor T-cell functionality with the aim of increasing the long-term efficacy of TCR-engineered ACT immunotherapy. SIGNIFICANCE A longitudinal functional study of adoptively transferred TCR–engineered lymphocytes yielded revealing snapshots for understanding the changes of antitumor responses over time in ACT immunotherapy of patients with advanced melanoma. PMID:23519018

  11. How Many Responses Do We Need? Using Generalizability Analysis to Estimate Minimum Necessary Response Rates for Online Student Evaluations.

    Science.gov (United States)

    Gerbase, Margaret W; Germond, Michèle; Cerutti, Bernard; Vu, Nu V; Baroffio, Anne

    2015-01-01

    CONSTRUCT: The study compares paper and online ratings of instructional units and analyses, with the G-study using the symmetry principle, the response rates needed to ensure acceptable precision of the measure when compliance is low. Students' ratings of teaching contribute to the quality of medical training programs. To date, many schools have replaced pen-and-paper questionnaires with electronic forms, despite the lower response rates consistently reported with the latter. Few available studies have examined the effects of low response rates on the reliability and precision of the evaluation measure. Moreover, the minimum number of raters to target when response rates are low remains unclear. Descriptive data were derived from 799 students' paper and online ratings of 11 preclinical instructional units (PIUs). Reliability was assessed by Cronbach's alpha coefficients. The generalizability method applying the symmetry principle approach was used to analyze the precision of the measure with a reference standard error of mean (SEM) set at 0.10; optimization models were built to estimate minimum response rates. Overall, response rates were 74% and 30% (p online questionnaires. Higher SEM levels and significantly larger 95% confidence intervals of PIUs rating scores were observed with online evaluations. To keep the SEM within preset limits of precision, a minimum of 48% response rate was estimated for online formats. The proposed generalizability analysis allowed estimating the minimum response needed to maintain acceptable precision in online evaluations. The effects of response rates on accuracy are discussed.

  12. The T Cell Response to Staphylococcus aureus

    Science.gov (United States)

    Bröker, Barbara M.; Mrochen, Daniel; Péton, Vincent

    2016-01-01

    Staphylococcus aureus (S. aureus) is a dangerous pathogen and a leading cause of both nosocomial and community acquired bacterial infection worldwide. However, on the other hand, we are all exposed to this bacterium, often within the first hours of life, and usually manage to establish equilibrium and coexist with it. What does the adaptive immune system contribute toward lifelong control of S. aureus? Will it become possible to raise or enhance protective immune memory by vaccination? While in the past the S. aureus-specific antibody response has dominated this discussion, the research community is now coming to appreciate the role that the cellular arm of adaptive immunity, the T cells, plays. There are numerous T cell subsets, each with differing functions, which together have the ability to orchestrate the immune response to S. aureus and hence to tip the balance between protection and pathology. This review summarizes the state of the art in this dynamic field of research. PMID:26999219

  13. Apoptotic response of malignant rhabdoid tumor cells

    Directory of Open Access Journals (Sweden)

    Nocentini Silvano

    2003-07-01

    Full Text Available Abstract Background Malignant rhabdoid tumors (MRTs are extremely aggressive and resist current radio- and chemotherapic treatments. To gain insight into the dysfunctions of MRT cells, the apoptotic response of a model cell line, MON, was analyzed after exposure to several genotoxic and non-genotoxic agents employed separately or in association. Results Fluorescence microscopy of chromatin morphology and electrophoretic analysis of internucleosomal DNA fragmentation revealed that MON cells were, comparatively to HeLa cells, resistant to apoptosis after treatment with etoposide, cisplatin (CisPt or X-rays, but underwent some degree of apoptosis after ultraviolet (UV C irradiation. Concomitant treatment of MON cells with X-rays or vinblastine and the phosphatidylinositol 3-kinase (PI3-K inhibitor wortmannin resulted in synergistic induction of apoptosis. Western blot analysis showed that the p53 protein was upregulated in MON cells after exposure to all the different agents tested, singly or in combination. In treated cells, the p53 downstream effectors p21WAF1/CIP1, Mdm2 and Bax were induced with some inconsistency with regard to the accumulation of p53. Poly ADP-ribose polymerase (PARP cleavage, indicative of ongoing apoptosis, occurred in UVC-irradiated cells and, especially, in cells treated with combinations of X-rays or vinblastine with wortmannin. However, there was moderate or no PARP cleavage in cells treated with CisPt, X-rays, vinblastine or wortmannin singly or with the combinations X-rays plus CisPt or vinblastine and CisPt plus vinblastine or wortmannin. The synergistic effect on the induction of apoptosis exerted by some agent combinations corresponded with synergy in respect of MON cell growth inhibition. Conclusion These results suggest abnormalities in the p53 pathway and apoptosis control in MRT cells. The Ras/PI3-K/AKT signaling pathway might also be deregulated in these cells by generating an excess of survival factors. These

  14. Need-based up-regulation of protein levels in response to deletion of their duplicate genes.

    Directory of Open Access Journals (Sweden)

    Alexander DeLuna

    2010-03-01

    Full Text Available Many duplicate genes maintain functional overlap despite divergence over long evolutionary time scales. Deleting one member of a paralogous pair often has no phenotypic effect, unless its paralog is also deleted. It has been suggested that this functional compensation might be mediated by active up-regulation of expression of a gene in response to deletion of its paralog. However, it is not clear how prevalent such paralog responsiveness is, nor whether it is hardwired or dependent on feedback from environmental conditions. Here, we address these questions at the genomic scale using high-throughput flow cytometry of single-cell protein levels in differentially labeled cocultures of wild-type and paralog-knockout Saccharomyces cerevisiae strains. We find that only a modest fraction of proteins (22 out of 202 show significant up-regulation to deletion of their duplicate genes. However, these paralog-responsive proteins match almost exclusively duplicate pairs whose overlapping function is required for growth. Moreover, media conditions that add or remove requirements for the function of a duplicate gene pair specifically eliminate or create paralog responsiveness. Together, our results suggest that paralog responsiveness in yeast is need-based: it appears only in conditions in which the gene function is required. Physiologically, such need-based responsiveness could provide an adaptive mechanism for compensation of genetic, environmental, or stochastic perturbations in protein abundance.

  15. Psychological need satisfaction, intrinsic motivation and affective response to exercise in adolescents

    Science.gov (United States)

    Schneider, Margaret L.; Kwan, Bethany M.

    2013-01-01

    Objectives To further understanding of the factors influencing adolescents’ motivations for physical activity, the relationship of variables derived from Self-Determination Theory to adolescents’ affective response to exercise was examined. Design Correlational. Method Adolescents (N = 182) self-reported psychological needs satisfaction (perceived competence, relatedness, and autonomy) and intrinsic motivation related to exercise. In two clinic visits, adolescents reported their affect before, during, and after a moderate-intensity and a hard-intensity exercise task. Results Affective response to exercise and psychological needs satisfaction independently contributed to the prediction of intrinsic motivation in hierarchical linear regression models. The association between affective response to exercise and intrinsic motivation was partially mediated by psychological needs satisfaction. Conclusions Intrinsic motivation for exercise among adolescents may be enhanced when the environment supports perceived competence, relatedness, and autonomy, and when adolescents participate in activities that they find enjoyable. PMID:24015110

  16. Psychological need satisfaction, intrinsic motivation and affective response to exercise in adolescents.

    Science.gov (United States)

    Schneider, Margaret L; Kwan, Bethany M

    2013-09-01

    To further understanding of the factors influencing adolescents' motivations for physical activity, the relationship of variables derived from Self-Determination Theory to adolescents' affective response to exercise was examined. Correlational. Adolescents ( N = 182) self-reported psychological needs satisfaction (perceived competence, relatedness, and autonomy) and intrinsic motivation related to exercise. In two clinic visits, adolescents reported their affect before, during, and after a moderate-intensity and a hard-intensity exercise task. Affective response to exercise and psychological needs satisfaction independently contributed to the prediction of intrinsic motivation in hierarchical linear regression models. The association between affective response to exercise and intrinsic motivation was partially mediated by psychological needs satisfaction. Intrinsic motivation for exercise among adolescents may be enhanced when the environment supports perceived competence, relatedness, and autonomy, and when adolescents participate in activities that they find enjoyable.

  17. The Unfolded Protein Response and Cell Fate Control.

    Science.gov (United States)

    Hetz, Claudio; Papa, Feroz R

    2018-01-18

    The secretory capacity of a cell is constantly challenged by physiological demands and pathological perturbations. To adjust and match the protein-folding capacity of the endoplasmic reticulum (ER) to changing secretory needs, cells employ a dynamic intracellular signaling pathway known as the unfolded protein response (UPR). Homeostatic activation of the UPR enforces adaptive programs that modulate and augment key aspects of the entire secretory pathway, whereas maladaptive UPR outputs trigger apoptosis. Here, we discuss recent advances into how the UPR integrates information about the intensity and duration of ER stress stimuli in order to control cell fate. These findings are timely and significant because they inform an evolving mechanistic understanding of a wide variety of human diseases, including diabetes mellitus, neurodegeneration, and cancer, thus opening up the potential for new therapeutic modalities to treat these diverse diseases. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Regulatory T Cells in Radiotherapeutic Responses

    International Nuclear Information System (INIS)

    Schaue, Dörthe; Xie, Michael W.; Ratikan, Josephine A.; McBride, William H.

    2012-01-01

    Radiation therapy (RT) can extend its influence in cancer therapy beyond what can be attributed to in-field cytotoxicity by modulating the immune system. While complex, these systemic effects can help tip the therapeutic balance in favor of treatment success or failure. Engagement of the immune system is generally through recognition of damage-associated molecules expressed or released as a result of tumor and normal tissue radiation damage. This system has evolved to discriminate pathological from physiological forms of cell death by signaling “danger.” The multiple mechanisms that can be evoked include a shift toward a pro-inflammatory, pro-oxidant microenvironment that can promote maturation of dendritic cells and, in cancer treatment, the development of effector T cell responses to tumor-associated antigens. Control over these processes is exerted by regulatory T cells (Tregs), suppressor macrophages, and immunosuppressive cytokines that act in consort to maintain tolerance to self, limit tissue damage, and re-establish tissue homeostasis. Unfortunately, by the time RT for cancer is initiated the tumor-host relationship has already been sculpted in favor of tumor growth and against immune-mediated mechanisms for tumor regression. Reversing this situation is a major challenge. However, recent data show that removal of Tregs can tip the balance in favor of the generation of radiation-induced anti-tumor immunity. The clinical challenge is to do so without excessive depletion that might precipitate serious autoimmune reactions and increase the likelihood of normal tissue complications. The selective modulation of Treg biology to maintain immune tolerance and control of normal tissue damage, while releasing the “brakes” on anti-tumor immune responses, is a worthy aim with promise for enhancing the therapeutic benefit of RT for cancer.

  19. Regulatory T cells in radiotherapeutic responses

    Directory of Open Access Journals (Sweden)

    Dörthe eSchaue

    2012-08-01

    Full Text Available Radiation therapy (RT can extend its influence in cancer therapy beyond what can be attributed to in-field cytotoxicity by modulating the immune system. While complex, these systemic effects can help tip the therapeutic balance in favor of treatment success or failure. Engagement of the immune system is generally through recognition of damage-associated molecules expressed or released as a result of tumor and normal tissue radiation damage. This system has evolved to discriminate pathological from physiological forms of cell death by signaling danger. The multiple mechanisms that can be evoked include a shift towards a pro-inflammatory, pro-oxidant microenvironment that can promote maturation of dendritic cells and, in cancer treatment, the development of effector T cell responses to tumor-associated antigens. Control over these processes is exerted by regulatory T cells (Tregs, suppressor macrophages and immunosuppressive cytokines that act in consort to maintain tolerance to self, limit tissue damage, and re-establish tissue homeostasis. Unfortunately, by the time RT for cancer is initiated the tumor-host relationship has already been sculpted in favor of tumor growth and against immune-mediated mechanisms for tumor regression. Reversing this situation is a major challenge. However, recent data show that removal of Tregs can tip the balance in favor of the generation of radiation-induced anti-tumor immunity. The clinical challenge is to do so without excessive depletion that might precipitate serious autoimmune reactions and increase the likelihood of normal tissue complications. The selective modulation of Treg biology to maintain immune tolerance and control of normal tissue damage, while releasing the brakes on anti-tumor immune responses, is a worthy aim with promise for enhancing the therapeutic benefit of RT for cancer.

  20. Cell Culture Assay for Human Noroviruses [response

    Energy Technology Data Exchange (ETDEWEB)

    Straub, Tim M.; Honer Zu Bentrup, Kerstin; Orosz Coghlan, Patricia; Dohnalkova, Alice; Mayer, Brooke K.; Bartholomew, Rachel A.; Valdez, Catherine O.; Bruckner-Lea, Cindy J.; Gerba, Charles P.; Abbaszadegan, Morteza A.; Nickerson, Cheryl A.

    2007-07-01

    We appreciate the comments provided by Leung et al., in response to our recently published article “In Vitro Cell Culture Infectivity Assay for Human Noroviruses” by Straub et al. (1). The specific aim of our project was to develop an in vitro cell culture infectivity assay for human noroviruses (hNoV) to enhance risk assessments when they are detected in water supplies. Reverse transcription (RT) qualitative or quantitative PCR are the primary assays for waterborne NoV monitoring. However, these assays cannot distinguish between infectious vs. non-infectious virions. When hNoV is detected in water supplies, information provided by our infectivity assay will significantly improve risk assessment models and protect human health, regardless of whether we are propagating NoV. Indeed, in vitro cell culture infectivity assays for the waterborne pathogen Cryptosporidium parvum that supplement approved fluorescent microscopy assays, do not result in amplification of the environmentally resistant hard-walled oocysts (2). However, identification of life cycle stages in cell culture provides evidence of infectious oocysts in a water supply. Nonetheless, Leung et al.’s assertion regarding the suitability of our method for the in vitro propagation of high titers of NoV is valid for the medical research community. In this case, well-characterized challenge pools of virus would be useful for developing and testing diagnostics, therapeutics, and vaccines. As further validation of our published findings, we have now optimized RT quantitative PCR to assess the level of viral production in cell culture, where we are indeed finding significant increases in viral titer. The magnitude and time course of these increases is dependent on both virus strain and multiplicity of infection. We are currently preparing a manuscript that will discuss these findings in greater detail, and the implications this may have for creating viral challenge pools

  1. Adipose tissue-derived mesenchymal stem cells acquire bone cell-like responsiveness to fluid shear stress on osteogenic stimulation

    NARCIS (Netherlands)

    Knippenberg, M.; Helder, M.N.; Doulabi, B.Z.; Semeins, C.M.; Wuisman, P.I.J.M.; Klein-Nulend, J.

    2005-01-01

    To engineer bone tissue, mechanosensitive cells are needed that are able to perform bone cell-specific functions, such as (re)modeling of bone tissue. In vivo, local bone mass and architecture are affected by mechanical loading, which is thought to provoke a cellular response via loading-induced

  2. Plant Cell Adaptive Responses to Microgravity

    Science.gov (United States)

    Kordyum, Elizabeth; Kozeko, Liudmyla; Talalaev, Alexandr

    simulated microgravity and temperature elevation have different effects on the small HSP genes belonging to subfamilies with different subcellular localization: cytosol/nucleus - PsHSP17.1-CII and PsHSP18.1-CI, cloroplasts - PsHSP26.2-Cl, endoplasmatic reticulum - PsHSP22.7-ER and mitochondria - PsHSP22.9-M: unlike high temperature, clinorotation does not cause denaturation of cell proteins, that confirms the sHSP chaperone function. Dynamics of investigated gene expression in pea seedlings growing 5 days after seed germination under clinorotation was similar to that in the stationary control. Similar patterns in dynamics of sHSP gene expression in the stationary control and under clinorotation may be one of mechanisms providing plant adaptation to simulated microgravity. It is pointed that plant cell responses in microgravity and under clinorotation vary according to growth phase, physiological state, and taxonomic position of the object. At the same time, the responses have, to some degree, a similar character reflecting the changes in cell organelle functional load. Thus, next certain changes in the structure and function of plant cells may be considered as adaptive: 1) an increase in the unsaturated fatty acid content in the plasmalemma, 2) rearrangements of organelle ultrastructure and an increase in their functional load, 3) an increase in cortical F-actin under destabilization of tubulin microtubules, 4) the level of gene expression and synthesis of heat shock proteins, 5) alterations of the enzyme and antioxidant system activity. The dynamics of these patterns demonstrated that the adaptation occurs on the principle of self-regulating systems in the limits of physiological norm reaction. The very importance of changed expression of genes involved in different cellular processes, especially HSP genes, in cell adaptation to altered gravity is discussed.

  3. A Needs-Driven and Responsive Approach to Supporting the Research Endeavours of Academic Librarians

    Directory of Open Access Journals (Sweden)

    Ken N. Meadows

    2013-12-01

    Full Text Available In this article, the authors describe a grassroots model for research support and explore the success and evolving directions of this model based on three iterative needs assessments administered by the Librarian and Archivist Research Support Network (LARSN Steering Committee at The University of Western Ontario. Needs assessments were identified as a critical tool to ensure that LARSN programming is relevant to librarians’ and archivists’ changing research needs. In the first four years of LARSN, three needs assessments were administered: in fall 2007, fall 2009, and spring 2011. The iterative needs assessments aimed to capture how the environment and research needs were evolving over time and the ways in which LARSN might continue to support a healthy and productive research environment. LARSN is faced with challenges that include a diversity of needs within its community, inconsistent participation levels in LARSN initiatives, and the inability to be all things to all people at all times. Still, LARSN is well received overall and rated positively by its community members. This is, in large part, because it has stayed true to its original mission to be needs-driven and responsive.

  4. Medical education, social responsibility and praxis: Responding to the needs of all children.

    Science.gov (United States)

    Martimianakis, Maria Athina

    2016-01-01

    While poverty is a recognized risk factor for ill health, directly intervening on the effects of poverty has traditionally been considered to fall outside the realm of a physician's daily practice. Yet, to appropriately respond to the health needs of all children, we have the social responsibility to help our trainees become competent health advocates. Experiential learning approaches can be used to aid students in developing identities and competencies as health advocates. Experiencing illness outside the sterility of the clinic, from the patient's point of view, encourages students to seek the knowledge they need to care for patients who are disenfranchised, socially vulnerable and/or marginalized.

  5. Interaction with Epithelial Cells Modifies Airway Macrophage Response to Ozone

    Science.gov (United States)

    The initial innate immune response to ozone (03) in the lung is orchestrated by structural cells, such as epithelial cells, and resident immune cells, such as airway macrophages (Macs). We developed an epithelial cell-Mac coculture model to investigate how epithelial cell-derived...

  6. Improving Systematic Response in the Face of Homicide: Family and Friends of Homicide Victims Service Needs.

    Science.gov (United States)

    Metzger, Jed; Mastrocinque, Jeanna M; Navratil, Peter; Cerulli, Catherine

    2015-01-01

    Homicide is a pressing issue in America. This study used qualitative data obtained from focus groups of family and friends of homicide victims (FFHV) to assess and better meet the needs of victims post homicide. The study results posit myriad changes to the systematic response to homicide. The article concludes with recommendations for training and resources, with specific attention to legal, law enforcement, medical, and behavioral health providers.

  7. Response to DNA damage: why do we need to focus on protein phosphatases?

    Directory of Open Access Journals (Sweden)

    Midori eShimada

    2013-01-01

    Full Text Available Eukaryotic cells are continuously threatened by unavoidable errors during normal DNA replication or various sources of genotoxic stresses that cause DNA damage or stalled replication. To maintain genomic integrity, cells have developed a coordinated signaling network, known as the DNA damage response (DDR. Following DNA damage, sensor molecules detect the presence of DNA damage and transmit signals to downstream transducer molecules. This in turn conveys the signals to numerous effectors, which initiate a large number of specific biological responses, including transient cell cycle arrest mediated by checkpoints, DNA repair, and apoptosis. It is recently becoming clear that dephosphorylation events are involved in keeping DDR factors inactive during normal cell growth. Moreover, dephosphorylation is required to shut off checkpoint arrest following DNA damage and has been implicated in the activation of the DDR. Spatial and temporal regulation of phosphorylation events is essential for the DDR, and fine-tuning of phosphorylation is partly mediated by protein phosphatases. While the role of kinases in the DDR has been well documented, the complex roles of protein dephosphorylation have only recently begun to be investigated. Therefore, it is important to focus on the role of phosphatases and to determine how their activity is regulated upon DNA damage. In this work, we summarize current knowledge on the involvement of serine/threonine phosphatases, especially the protein phosphatase 1, protein phosphatase 2A, and protein phosphatase Mg2+/Mn2+-dependent families, in the DDR.

  8. Human dental pulp cells exhibit bone cell-like responsiveness to fluid shear stress.

    Science.gov (United States)

    Kraft, David Christian Evar; Bindslev, Dorth Arenholt; Melsen, Birte; Klein-Nulend, Jenneke

    2011-02-01

    For engineering bone tissue to restore, for example, maxillofacial defects, mechanosensitive cells are needed that are able to conduct bone cell-specific functions, such as bone remodelling. Mechanical loading affects local bone mass and architecture in vivo by initiating a cellular response via loading-induced flow of interstitial fluid. After surgical removal of ectopically impacted third molars, human dental pulp tissue is an easily accessible and interesting source of cells for mineralized tissue engineering. The aim of this study was to determine whether human dental pulp-derived cells (DPC) are responsive to mechanical loading by pulsating fluid flow (PFF) upon stimulation of mineralization in vitro. Human DPC were incubated with or without mineralization medium containing differentiation factors for 3 weeks. Cells were subjected to 1-h PFF (0.7 ± 0.3 Pa, 5 Hz) and the response was quantified by measuring nitric oxide (NO) and prostaglandin E₂ (PGE₂) production, and gene expression of cyclooxygenase (COX)-1 and COX-2. We found that DPC are intrinsically mechanosensitive and, like osteogenic cells, respond to PFF-induced fluid shear stress. PFF stimulated NO and PGE₂ production, and up-regulated COX-2 but not COX-1 gene expression. In DPC cultured under mineralizing conditions, the PFF-induced NO, but not PGE₂, production was significantly enhanced. These data suggest that human DPC, like osteogenic cells, acquire responsiveness to pulsating fluid shear stress in mineralizing conditions. Thus DPC might be able to perform bone-like functions during mineralized tissue remodeling in vivo, and therefore provide a promising new tool for mineralized tissue engineering to restore, for example, maxillofacial defects.

  9. Lawrence Livermore National Laboratory Emergency Response Capability Baseline Needs Assessment Requirement Document

    Energy Technology Data Exchange (ETDEWEB)

    Sharry, J A

    2009-12-30

    This revision of the LLNL Fire Protection Baseline Needs Assessment (BNA) was prepared by John A. Sharry, LLNL Fire Marshal and LLNL Division Leader for Fire Protection and reviewed by Martin Gresho, Sandia/CA Fire Marshal. The document follows and expands upon the format and contents of the DOE Model Fire Protection Baseline Capabilities Assessment document contained on the DOE Fire Protection Web Site, but only address emergency response. The original LLNL BNA was created on April 23, 1997 as a means of collecting all requirements concerning emergency response capabilities at LLNL (including response to emergencies at Sandia/CA) into one BNA document. The original BNA documented the basis for emergency response, emergency personnel staffing, and emergency response equipment over the years. The BNA has been updated and reissued five times since in 1998, 1999, 2000, 2002, and 2004. A significant format change was performed in the 2004 update of the BNA in that it was 'zero based.' Starting with the requirement documents, the 2004 BNA evaluated the requirements, and determined minimum needs without regard to previous evaluations. This 2010 update maintains the same basic format and requirements as the 2004 BNA. In this 2010 BNA, as in the previous BNA, the document has been intentionally divided into two separate documents - the needs assessment (1) and the compliance assessment (2). The needs assessment will be referred to as the BNA and the compliance assessment will be referred to as the BNA Compliance Assessment. The primary driver for separation is that the needs assessment identifies the detailed applicable regulations (primarily NFPA Standards) for emergency response capabilities based on the hazards present at LLNL and Sandia/CA and the geographical location of the facilities. The needs assessment also identifies areas where the modification of the requirements in the applicable NFPA standards is appropriate, due to the improved fire protection

  10. In response to need: an analysis of social work roles over time.

    Science.gov (United States)

    Kerson, Toba Schwaber; McCoyd, Judith L M

    2013-10-01

    In this qualitative research synthesis, interviews with 22 early health-related social workers were reexamined to identify themes that emerged when these social workers discussed the roles and goals of their work. Those interviews, with colleagues of Ida M. Cannon and those leaders in the next generation of social workers who had practiced during the first half of the 20th century, were conducted in 1976. For this study, the themes that emerged from the original interview data as social workers' responses to perceived needs were then compared with data consisting of 80 cases, drawn from four more recent casebooks (1982, 1989, 1996, 2010), that followed a framework of practice in context. The comparison demonstrated that themes remain consistent over time and include responses to needs created by wars, due to new and underserved populations, created by public health crises, created by technological advances, experienced by organizations, and resulting from economic and policy issues, as well as needs of clients. Analysis also suggests that caution is in order to avoid being co-opted by organizations and others in power at the cost of the profession's social justice mission and ethical imperatives.

  11. Cell cycle progression in response to oxygen levels.

    Science.gov (United States)

    Ortmann, Brian; Druker, Jimena; Rocha, Sonia

    2014-09-01

    Hypoxia' or decreases in oxygen availability' results in the activation of a number of different responses at both the whole organism and the cellular level. These responses include drastic changes in gene expression, which allow the organism (or cell) to cope efficiently with the stresses associated with the hypoxic insult. A major breakthrough in the understanding of the cellular response to hypoxia was the discovery of a hypoxia sensitive family of transcription factors known as the hypoxia inducible factors (HIFs). The hypoxia response mounted by the HIFs promotes cell survival and energy conservation. As such, this response has to deal with important cellular process such as cell division. In this review, the integration of oxygen sensing with the cell cycle will be discussed. HIFs, as well as other components of the hypoxia pathway, can influence cell cycle progression. The role of HIF and the cell molecular oxygen sensors in the control of the cell cycle will be reviewed.

  12. Emergency management in the Swedish electricity market: The need to challenge the responsibility gap

    International Nuclear Information System (INIS)

    Palm, Jenny

    2008-01-01

    A secure energy supply is a basic need of society. Along with electricity market deregulation, a responsibility gap has arisen, where private energy companies lack economic incentives to invest in an electricity distribution grid that is secured to the level desired by society. This article discusses the emergency management strategies of municipal authorities for securing the electricity supply, according to a networked, or 'governance', control and direction structure, and how this influences the relationship between electricity companies and Swedish municipalities. The Swedish electricity system has traditionally developed in a monopoly context. Since electricity market deregulation, the responsibility for electricity supply security has become unclear; field studies of Swedish municipalities indicate that all actors still seem to be seeking to find their proper roles in the deregulated market. Municipalities still expect to exercise influence over private energy company decisions regarding prioritization of emergency power deliveries. Energy companies vacillate between emphasizing their need to regard economic factors and their sense of responsibility for providing a secure electricity supply to vital municipal functions (even though municipalities may lack contracts specifying this)

  13. United States Army Annual Financial Statement FY00. The Army in Transformation Responsive to the Needs of the Nation

    Science.gov (United States)

    2000-01-01

    United States Army Annual Financial Statement “The Army in Transformation—Responsive to the Needs of the Nation” The picture of the digitized soldier...mailing the postage paid comment card enclosed at the back of this report. “The Army in Transformation —Responsive to the Needs of the Nation” “The...Army in Transformation —Responsive to the Needs of the Nation” “The Army in Transformation—Responsive to the Needs of the Nation” Table of Contents FY00

  14. Optimizing health system response to patient's needs: an argument for the importance of functioning information.

    Science.gov (United States)

    Hopfe, Maren; Prodinger, Birgit; Bickenbach, Jerome E; Stucki, Gerold

    2017-06-06

    Current health systems are increasingly challenged to meet the needs of a growing number of patients living with chronic and often multiple health conditions. The primary outcome of care, it is argued, is not merely curing disease but also optimizing functioning over a person's life span. According to the World Health Organization, functioning can serve as foundation for a comprehensive picture of health and augment the biomedical perspective with a broader and more comprehensive picture of health as it plays out in people's lives. The crucial importance of information about patient's functioning for a well-performing health system, however, has yet to be sufficiently appreciated. This paper argues that functioning information is fundamental in all components of health systems and enhances the capacity of health systems to optimize patients' health and health-related needs. Beyond making sense of biomedical disease patterns, health systems can profit from using functioning information to improve interprofessional collaboration and achieve cross-cutting disease treatment outcomes. Implications for rehabilitation Functioning is a key health outcome for rehabilitation within health systems. Information on restoring, maintaining, and optimizing human functioning can strengthen health system response to patients' health and rehabilitative needs. Functioning information guides health systems to achieve cross-cutting health outcomes that respond to the needs of the growing number of individuals living with chronic and multiple health conditions. Accounting for individuals functioning helps to overcome fragmentation of care and to improve interprofessional collaboration across settings.

  15. Basic psychological need satisfaction, stress-related appraisals, and dancers' cortisol and anxiety responses.

    Science.gov (United States)

    Quested, Eleanor; Bosch, Jos A; Burns, Victoria E; Cumming, Jennifer; Ntoumanis, Nikos; Duda, Joan L

    2011-12-01

    Self-determination theory (Deci & Ryan, 2000) posits basic psychological need satisfaction (BPNS) as essential for optimal functioning and health. Grounded in this framework, the current study examined the role of BPNS in dancers' cognitive appraisals and hormonal and emotional responses to performance stress. Dancers reported their degree of BPNS 1 month before a solo performance. Threat and challenge appraisals of the solo were recorded 2 hr before the performance. Salivary cortisol and anxiety were measured 15 min before, and 15, 30, 45, and 60 min postperformance. Higher BPNS was associated with lower cortisol responses and anxiety intensity. Challenge appraisals mediated the association between BPNS and cortisol. Threat appraisals mediated the BPNS-anxiety intensity relationship. These findings point to the potential importance of performers' BPNS for optimal emotional and hormonal homeostasis in performance conditions.

  16. Identifying and Prioritizing Information Needs and Research Priorities of Public Health Emergency Preparedness and Response Practitioners.

    Science.gov (United States)

    Siegfried, Alexa L; Carbone, Eric G; Meit, Michael B; Kennedy, Mallory J; Yusuf, Hussain; Kahn, Emily B

    2017-10-01

    This study describes findings from an assessment conducted to identify perceived knowledge gaps, information needs, and research priorities among state, territorial, and local public health preparedness directors and coordinators related to public health emergency preparedness and response (PHPR). The goal of the study was to gather information that would be useful for ensuring that future funding for research and evaluation targets areas most critical for advancing public health practice. We implemented a mixed-methods approach to identify and prioritize PHPR research questions. A web survey was sent to all state, city, and territorial health agencies funded through the Public Health Emergency Preparedness (PHEP) Cooperative Agreement program and a sample of local health departments (LHDs). Three focus groups of state and local practitioners and subject matter experts from the Centers for Disease Control and Prevention (CDC) were subsequently conducted, followed by 3 meetings of an expert panel of PHPR practitioners and CDC experts to prioritize and refine the research questions. We identified a final list of 44 research questions that were deemed by study participants as priority topics where future research can inform PHPR programs and practice. We identified differences in perceived research priorities between PHEP awardees and LHD survey respondents; the number of research questions rated as important was greater among LHDs than among PHEP awardees (75%, n=33, compared to 24%, n=15). The research questions identified provide insight into public health practitioners' perceived knowledge gaps and the types of information that would be most useful for informing and advancing PHPR practice. The study also points to a higher level of information need among LHDs than among PHEP awardees. These findings are important for CDC and the PHPR research community to ensure that future research studies are responsive to practitioners' needs and provide the information

  17. B cells and functional antibody responses to combat influenza

    Directory of Open Access Journals (Sweden)

    Giuseppe eLofano

    2015-06-01

    Full Text Available Vaccination against influenza (Flu is the most effective way to protect the population. Current vaccines provide protection by stimulating functional B- and T-cell responses, however, they are poorly immunogenic in particular segments of the population and need to be reformulated almost every year due to the genetic instability of the virus. Next generation Flu vaccines should be designed to induce cross-reactivity, confer protection against pandemic outbreaks, and promote long-lasting immune responses among individuals at higher risk of infection. Multiple strategies are being developed for the induction of broad functional humoral immunity, including the use of adjuvants, heterologous prime-boost strategies, and epitope-based antigen design. The basic approach is to mimic natural responses to influenza virus infection by promoting cross-reactive neutralizing antibodies that directly prevent the infection. This review provides an overview of the mechanisms underlying humoral responses to influenza vaccination or natural infection, and discusses promising strategies to control influenza virus.

  18. β-Cell Replacement Strategies: The Increasing Need for a “β-Cell Dogma”

    Directory of Open Access Journals (Sweden)

    Andhira Vieira

    2017-06-01

    Full Text Available Type 1 diabetes is an auto-immune disease resulting in the loss of pancreatic β-cells and, consequently, in chronic hyperglycemia. Insulin supplementation allows diabetic patients to control their glycaemia quite efficiently, but treated patients still display an overall shortened life expectancy and an altered quality of life as compared to their healthy counterparts. In this context and due to the ever increasing number of diabetics, establishing alternative therapies has become a crucial research goal. Most current efforts therefore aim at generating fully functional insulin-secreting β-like cells using multiple approaches. In this review, we screened the literature published since 2011 and inventoried the selected markers used to characterize insulin-secreting cells generated by in vitro differentiation of stem/precursor cells or by means of in vivo transdifferentiation. By listing these features, we noted important discrepancies when comparing the different approaches for the initial characterization of insulin-producing cells as true β-cells. Considering the recent advances achieved in this field of research, the necessity to establish strict guidelines has become a subject of crucial importance, especially should one contemplate the next step, which is the transplantation of in vitro or ex vivo generated insulin-secreting cells in type 1 diabetic patients.

  19. B Cells Promote Th1- Skewed NKT Cell Response by CD1d-TCR Interaction

    OpenAIRE

    Shin, Jung Hoon; Park, Se-Ho

    2013-01-01

    CD1d expressing dendritic cells (DCs) are good glyco-lipid antigen presenting cells for NKT cells. However, resting B cells are very weak stimulators for NKT cells. Although ?-galactosylceramide (?-GalCer) loaded B cells can activate NKT cells, it is not well defined whether B cells interfere NKT cell stimulating activity of DCs. Unexpectedly, we found in this study that B cells can promote Th1-skewed NKT cell response, which means a increased level of IFN-? by NKT cells, concomitant with a d...

  20. Aging impairs recipient T cell intrinsic and extrinsic factors in response to transplantation.

    Directory of Open Access Journals (Sweden)

    Hua Shen

    Full Text Available As increasing numbers of older people are listed for solid organ transplantation, there is an urgent need to better understand how aging modifies alloimmune responses. Here, we investigated whether aging impairs the ability of donor dendritic cells or recipient immunity to prime alloimmune responses to organ transplantation.Using murine experimental models, we found that aging impaired the host environment to expand and activate antigen specific CD8(+ T cells. Additionally, aging impaired the ability of polyclonal T cells to induce acute allograft rejection. However, the alloimmune priming capability of donor dendritic cells was preserved with aging.Aging impairs recipient responses, both T cell intrinsic and extrinsic, in response to organ transplantation.

  1. B Cells Promote Th1- Skewed NKT Cell Response by CD1d-TCR Interaction.

    Science.gov (United States)

    Shin, Jung Hoon; Park, Se-Ho

    2013-10-01

    CD1d expressing dendritic cells (DCs) are good glyco-lipid antigen presenting cells for NKT cells. However, resting B cells are very weak stimulators for NKT cells. Although α-galactosylceramide (α-GalCer) loaded B cells can activate NKT cells, it is not well defined whether B cells interfere NKT cell stimulating activity of DCs. Unexpectedly, we found in this study that B cells can promote Th1-skewed NKT cell response, which means a increased level of IFN-γ by NKT cells, concomitant with a decreased level of IL-4, in the circumstance of co-culture of DCs and B Cells. Remarkably, the response promoted by B cells was dependent on CD1d expression of B cells.

  2. The care of Filipino juvenile offenders in residential facilities evaluated using the risk-need-responsivity model

    NARCIS (Netherlands)

    Spruit, A.; Wissink, I.B.; Stams, G.J.J.M.

    According to the risk-need-responsivity model of offender, assessment and rehabilitation treatment should target specific factors that are related to re-offending. This study evaluates the residential care of Filipino juvenile offenders using the risk-need-responsivity model. Risk analyses and

  3. Cardio–Pulmonary Response Of Patients With Sickle Cell Anaemia ...

    African Journals Online (AJOL)

    The purpose of this study was to compare the response of sickle cell anaemia patients with their age-matched counterparts to exercise test. This was to see whether patients with sickle cell disease could be given exercise therapy without any risk of adverse cardio-respiratory response during the course of physical ...

  4. Fluoride inhibits the response of bone cells to mechanical loading

    NARCIS (Netherlands)

    Willems, H.M.E.; van den Heuvel, E.G.H.M.; Castelein, S.; Buisman, J.K.; Bronckers, A.L.J.J.; Bakker, A.D.; Klein-Nulend, J.

    2011-01-01

    The response of bone cells to mechanical loading is mediated by the cytoskeleton. Since the bone anabolic agent fluoride disrupts the cytoskeleton, we investigated whether fluoride affects the response of bone cells to mechanical loading, and whether this is cytoskeleton mediated. The

  5. Regulatory CD4+CD25+ T cells restrict memory CD8+ T cell responses.

    Science.gov (United States)

    Kursar, Mischo; Bonhagen, Kerstin; Fensterle, Joachim; Köhler, Anne; Hurwitz, Robert; Kamradt, Thomas; Kaufmann, Stefan H E; Mittrücker, Hans-Willi

    2002-12-16

    CD4+ T cell help is important for the generation of CD8+ T cell responses. We used depleting anti-CD4 mAb to analyze the role of CD4+ T cells for memory CD8+ T cell responses after secondary infection of mice with the intracellular bacterium Listeria monocytogenes, or after boost immunization by specific peptide or DNA vaccination. Surprisingly, anti-CD4 mAb treatment during secondary CD8+ T cell responses markedly enlarged the population size of antigen-specific CD8+ T cells. After boost immunization with peptide or DNA, this effect was particularly profound, and antigen-specific CD8+ T cell populations were enlarged at least 10-fold. In terms of cytokine production and cytotoxicity, the enlarged CD8+ T cell population consisted of functional effector T cells. In depletion and transfer experiments, the suppressive function could be ascribed to CD4+CD25+ T cells. Our results demonstrate that CD4+ T cells control the CD8+ T cell response in two directions. Initially, they promote the generation of a CD8+ T cell responses and later they restrain the strength of the CD8+ T cell memory response. Down-modulation of CD8+ T cell responses during infection could prevent harmful consequences after eradication of the pathogen.

  6. Investigation of the response of low-dose irradiated cells. Pt. 2. Radio-adaptive response of human embryonic cells is related to cell-to-cell communication

    International Nuclear Information System (INIS)

    Ishii, Keiichiro; Watanabe, Masami.

    1994-01-01

    To clarify the radio-adaptive response of normal cells to low-dose radiation, we irradiated human embryonic cells and HeLa cells with low-dose X-ray and examined the changes in sensitivity to subsequent high-dose X-irradiation. The results obtained were as follows; (1) When HE cells were irradiated by a high-dose of 200 cGy, the growth ratio of the living cells five days after the irradiation decreased to 37% of that of the cells which received no X-irradiation. When the cells received a preliminary irradiation of 10 to 20 cGy four hours before the irradiation of 200 cGy, the relative growth ratios increased significantly to 45-53%. (2) This preliminary irradiation effect was not observed in HeLa cells, being cancer cells. (3) When the HE cells suspended in a Ca 2+ iron-free medium or TPA added medium while receiving the preliminary irradiation of 13 cGy, the effect of the preliminary irradiation in increasing the relative growth ratio of living cells was not observed. (4) This indicates that normal cells shows an adaptive response to low-dose radiation and become more radioresistant. This phenomenon is considered to involve cell-to-cell communication maintained in normal cells and intracellular signal transduction in which Ca 2+ ion plays a role. (author)

  7. Cell-autonomous stress responses in innate immunity.

    Science.gov (United States)

    Moretti, Julien; Blander, J Magarian

    2017-01-01

    The innate immune response of phagocytes to microbes has long been known to depend on the core signaling cascades downstream of pattern recognition receptors (PRRs), which lead to expression and production of inflammatory cytokines that counteract infection and induce adaptive immunity. Cell-autonomous responses have recently emerged as important mechanisms of innate immunity. Either IFN-inducible or constitutive, these processes aim to guarantee cell homeostasis but have also been shown to modulate innate immune response to microbes and production of inflammatory cytokines. Among these constitutive cell-autonomous responses, autophagy is prominent and its role in innate immunity has been well characterized. Other stress responses, such as metabolic stress, the ER stress/unfolded protein response, mitochondrial stress, or the DNA damage response, seem to also be involved in innate immunity, although the precise mechanisms by which they regulate the innate immune response are not yet defined. Of importance, these distinct constitutive cell-autonomous responses appear to be interconnected and can also be modulated by microbes and PRRs, which add further complexity to the interplay between innate immune signaling and cell-autonomous responses in the mediation of an efficient innate immune response. © Society for Leukocyte Biology.

  8. Need for cognitive rehabilitation for children with sickle cell disease and strokes.

    Science.gov (United States)

    King, Allison A; DeBaun, Michael R; White, Desiree A

    2008-02-01

    Stroke is a significant cause of morbidity among children with sickle cell disease (SCD). Approximately 30% of children with sickle cell anemia will have either an overt stroke or silent infarct (an injury to the brain that does not have any focal neurological findings or a history of focal neurological deficits). Despite the strong association between stroke and cognitive deficits and poor educational attainment, few interventions have been developed to address this vulnerable population of children. A cognitive rehabilitation program was piloted to improve the memory and educational achievement of children with sickle cell disease and stroke. While the intervention was feasible, additional research is needed to establish efficacy. Ongoing studies are designed to improve the cognitive impairment for children with SCD and stroke. The health and educational systems will need to work as partners to improve the cognitive and educational outcomes of these children after they suffer from stroke.

  9. Stem Cells Matter in Response to Fasting

    Directory of Open Access Journals (Sweden)

    Badi Sri Sailaja

    2015-12-01

    Full Text Available The molecular processes underlying intestinal adaptation to fasting and re-feeding remain largely uncharacterized. In this issue of Cell Reports, Richmond et al. report that dormant intestinal stem cells are regulated by PTEN and nutritional status.

  10. Design principles for CANDU control centres in response to evolving utility business needs

    International Nuclear Information System (INIS)

    Davey, E.

    2002-01-01

    Nuclear generation operators are facing a challenging business environment at the beginning of the new millennium. Evolving changes in business context, competitive commercial pressures, and changes in technology have dictated recurring evaluation of operational practices and the adequacy of supporting tools, and the pursuit of opportunities for operational improvement. A key area of utility operations that has been impacted by these changes is the nuclear plant control centre. Changes to workspace layout, equipment provisions, staffing, and work organization are examples of some of the adjustments being introduced to improve operational and safety effectiveness. This paper discusses some of the key factors influencing these changes and identifies additional design principles for CANDU control centres that will enable new control centre designs and retrofits of existing control centres to remain relevant and responsive to utility needs. (author)

  11. Examining the response programming function of the Quiet Eye: Do tougher shots need a quieter eye?

    Science.gov (United States)

    Walters-Symons, Rosanna; Wilson, Mark; Klostermann, Andre; Vine, Samuel

    2018-02-01

    Support for the proposition that the Quiet Eye (QE) duration reflects a period of response programming (including task parameterisation) has come from research showing that an increase in task difficulty is associated with increases in QE duration. Here, we build on previous research by manipulating three elements of task difficulty that correspond with different parameters of golf-putting performance; force production, impact quality and target line. Longer QE durations were found for more complex iterations of the task and furthermore, more sensitive analyses of the QE duration suggest that the early QE proportion (prior to movement initiation) is closely related to force production and impact quality. However, these increases in QE do not seem functional in terms of supporting improved performance. Further research is needed to explore QE's relationship with performance under conditions of increased difficulty.

  12. Culturally responsive middle school science: A case study of needs, demands, and challenges

    Science.gov (United States)

    Woodrow, Kelli Ellen

    2007-12-01

    Culturally responsive programming has been proposed as a remedy for the well-documented disconnect between schools and the ethnically and culturally diverse students who attend them. These programs often focus on creating instructional materials and pedagogical practices that are aligned with the knowledges, perspectives and practices of these students. This study builds on that literature and examines the needs, demands, and challenges of developing a culturally responsive health science program for ethnically and culturally diverse urban middle school students. I approached this problem through a content analysis of the intended curriculum and a microethnography of the enacted curriculum. In my analysis of the intended curriculum, I adapted a science textbook analysis instrument created by the American Association for the Advancement of Science (AAAS) to include criteria related to identified features of culturally responsive education. Using these modified analytic criteria, I found that the pilot drafts of the curricular materials excelled in the areas of engaging students in relevant phenomenon but lacked many of these specifically culturally responsive elements. Recommendations were made to redress these deficiencies. In my analysis of the enacted curriculum, I observed in five eighth grade classrooms where the program was being implemented. I used participant observation, audio and video tape recordings, artifacts, and interviews over a six-month period to investigate teacher/student interactions, the social organization of the classrooms, and students' culturally distinctive knowledge resources---or what is sometimes referred to as their "funds of knowledge." I found that the affective interactions between teachers and students were precursors to any reform, and that students and teachers similarly defined these interactions as "teacher care." In addition, I found that the social organization of the classroom often privileged official content and ways of

  13. Changing the paradigm of emergency response: The need for first-care providers.

    Science.gov (United States)

    Bobko, Joshua P; Kamin, Richard

    2015-01-01

    There is a major gap in the security of the critical infrastructure - civilian medical response to atypical emergencies. Clear evidence demonstrates that, despite ongoing improvements to the first-responder system, there exists an inherent delay in the immediate medical care at the scene of an emergency. This delay can only be reduced through a societal shift in reliance on police and fire response and by extending the medical system into all communities. Additionally, through analysis of military data, it is known that immediately addressing the common injury patterns following a traumatic event will save lives. The predictable nature of these injuries, coupled with an unavoidable delay in the arrival of first responders, necessitates the need for immediate care on scene. Initial care is often rendered by bystanders, typically armed only with basic first-aid training based on medical emergencies and does not adequately address the traumatic injury patterns seen in disasters. Implementing an approach similar to the American Cardiac Arrest Act can improve outcomes to traumatic events. This paper analyses the latest data on active shooter incidents and proposes that the creation of a network of trauma-trained medic extenders would improve all communities' resilience to catastrophic disaster.

  14. Cellular automaton model of cell response to targeted radiation

    International Nuclear Information System (INIS)

    Richard, M.; Kirkby, K.J.; Webb, R.P.; Kirkby, N.F.

    2009-01-01

    It has been shown that the response of cells to low doses of radiation is not linear and cannot be accurately extrapolated from the high dose response. To investigate possible mechanisms involved in the behaviour of cells under very low doses of radiation, a cellular automaton (CA) model was created. The diffusion and consumption of glucose in the culture dish were computed in parallel to the growth of cells. A new model for calculating survival probability was introduced; the communication between targeted and non-targeted cells was also included. Early results on the response of non-confluent cells to targeted irradiation showed the capability of the model to take account for the non-linear response in the low-dose domain

  15. System-wide Analysis of the T Cell Response

    Directory of Open Access Journals (Sweden)

    Ruxandra Covacu

    2016-03-01

    Full Text Available The T cell receptor (TCR controls the cellular adaptive immune response to antigens, but our understanding of TCR repertoire diversity and response to challenge is still incomplete. For example, TCR clones shared by different individuals with minimal alteration to germline gene sequences (public clones are detectable in all vertebrates, but their significance is unknown. Although small in size, the zebrafish TCR repertoire is controlled by processes similar to those operating in mammals. Thus, we studied the zebrafish TCR repertoire and its response to stimulation with self and foreign antigens. We found that cross-reactive public TCRs dominate the T cell response, endowing a limited TCR repertoire with the ability to cope with diverse antigenic challenges. These features of vertebrate public TCRs might provide a mechanism for the rapid generation of protective T cell immunity, allowing a short temporal window for the development of more specific private T cell responses.

  16. Mesenchymal stem cells induce dermal fibroblast responses to injury

    International Nuclear Information System (INIS)

    Smith, Andria N.; Willis, Elise; Chan, Vincent T.; Muffley, Lara A.; Isik, F. Frank; Gibran, Nicole S.; Hocking, Anne M.

    2010-01-01

    Although bone marrow-derived mesenchymal stem cells have been shown to promote repair when applied to cutaneous wounds, the mechanism for this response remains to be determined. The aim of this study was to determine the effects of paracrine signaling from mesenchymal stem cells on dermal fibroblast responses to injury including proliferation, migration and expression of genes important in wound repair. Dermal fibroblasts were co-cultured with bone marrow-derived mesenchymal stem cells grown in inserts, which allowed for paracrine interactions without direct cell contact. In this co-culture model, bone marrow-derived mesenchymal stem cells regulate dermal fibroblast proliferation, migration and gene expression. When co-cultured with mesenchymal stem cells, dermal fibroblasts show increased proliferation and accelerated migration in a scratch assay. A chemotaxis assay also demonstrated that dermal fibroblasts migrate towards bone marrow-derived mesenchymal stem cells. A PCR array was used to analyze the effect of mesenchymal stem cells on dermal fibroblast gene expression. In response to mesenchymal stem cells, dermal fibroblasts up-regulate integrin alpha 7 expression and down-regulate expression of ICAM1, VCAM1 and MMP11. These observations suggest that mesenchymal stem cells may provide an important early signal for dermal fibroblast responses to cutaneous injury.

  17. The radiation response of cells recovering after chronic hypoxia

    International Nuclear Information System (INIS)

    Kwok, T.T.; Sutherland, R.M.

    1989-01-01

    Experiments were performed to study the influence of hypoxic pretreatment on the radiation response of A431 human squamous carcinoma cells. Reaeration for 10 min after chronic hypoxia (greater than 2 h) was found to enhance the radiosensitivity of A431 cells, and the maximal effect was seen for those cells reaerated after 12 h of hypoxia. The radiosensitivity enhancement for reaerated cells after 12 h of hypoxia was maximized by 5 min after the return to aerobic conditions and reached the control level by 12 h of reaeration. This enhanced radiosensitive state was characterized by a reduced shoulder region and increased slope of the radiation dose-response curve for cells in both the exponential and plateau phases of growth. There was a slight increase in the number of G1 and decrease in the number of S and G2 + M cells for both exponential- and plateau-phase cultures following 12 h hypoxic treatment. Although growth inhibition induced by 12 h of hypoxia was seen for cells in the exponential phase, there was no cell number change in the plateau-phase culture after hypoxia. Plating efficiency (PE) of cells in both growth phases was reduced by 30% after hypoxia. Furthermore, in the exponential-phase culture, the extent of reduction in PE after hypoxia was similar among cells in different phases of the cell cycle. Although S-phase cells in exponentially growing cultures were relatively more resistant to radiation than G1 and G2 + M cells, the cell age-response pattern was the same whether the cells had been aerobic or hypoxic before reaeration and irradiation. Furthermore, the enhancement ratio associated with reaeration after 12 h of hypoxia for these three subpopulations of cells was 1.3. Our results indicate that the increase in radiosensitivity due to reaeration after chronic hypoxia is unlikely to be related to the changes of cell cycle stage and growth phase during hypoxic treatment

  18. Epidermal stem cells response to radiative genotoxic stress

    International Nuclear Information System (INIS)

    Marie, Melanie

    2013-01-01

    Human skin is the first organ exposed to various environmental stresses, which requires the development by skin stem cells of specific mechanisms to protect themselves and to ensure tissue homeostasis. As stem cells are responsible for the maintenance of epidermis during individual lifetime, the preservation of genomic integrity in these cells is essential. My PhD aimed at exploring the mechanisms set up by epidermal stem cells in order to protect themselves from two genotoxic stresses, ionizing radiation (Gamma Rays) and ultraviolet radiation (UVB). To begin my PhD, I have taken part of the demonstration of protective mechanisms used by keratinocyte stem cells after ionizing radiation. It has been shown that these cells are able to rapidly repair most types of radiation-induced DNA damage. Furthermore, we demonstrated that this repair is activated by the fibroblast growth factor 2 (FGF2). In order to know if this protective mechanism is also operating in cutaneous carcinoma stem cells, we investigated the response to gamma Rays of carcinoma stem cells isolated from a human carcinoma cell line. As in normal keratinocyte stem cells, we demonstrated that cancer stem cells could rapidly repair radio-induced DNA damage. Furthermore, fibroblast growth factor 2 also mediates this repair, notably thanks to its nuclear isoforms. The second project of my PhD was to study human epidermal stem cells and progenitors responses to UVB radiation. Once cytometry and irradiation conditions were set up, the toxicity of UVB radiation has been evaluate in the primary cell model. We then characterized UVB photons effects on cell viability, proliferation and repair of DNA damage. This study allowed us to bring out that responses of stem cells and their progeny to UVB are different, notably at the level of part of their repair activity of DNA damage. Moreover, progenitors and stem cells transcriptomic responses after UVB irradiation have been study in order to analyze the global

  19. Neuroinflammation: a need to understand microglia as resident cells of the developing brain.

    Science.gov (United States)

    Harry, G Jean

    2012-06-01

    Neuroinflammation and microglia as the resident immune cells of the brain has garnered a significant amount of interest with regards to brain injury and neurotoxicology. Much of this interest and research has been focused on responses in the adult brain with little attention paid to the role of these cells during development. The available data suggests that one must view microglia and their processes during development somewhat differently. In addition, modification to microglia during development may lay a framework for subtle to significant changes in the susceptibility of the mature brain to secondary insults. A number of these point are now being raised for consideration. Published by Elsevier B.V.

  20. The In Vitro Response of Tissue Stem Cells to Irradiation With Different Linear Energy Transfers

    Energy Technology Data Exchange (ETDEWEB)

    Nagle, Peter W.; Hosper, Nynke A. [Department of Cell Biology, University of Groningen, University Medical Center Groningen, Groningen (Netherlands); Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen (Netherlands); Ploeg, Emily M. [Department of Cell Biology, University of Groningen, University Medical Center Groningen, Groningen (Netherlands); Goethem, Marc-Jan van [Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen (Netherlands); KVI-Center for Advanced Radiation Research, University of Groningen, Groningen (Netherlands); Brandenburg, Sytze [KVI-Center for Advanced Radiation Research, University of Groningen, Groningen (Netherlands); Langendijk, Johannes A. [Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen (Netherlands); Chiu, Roland K. [Department of Cell Biology, University of Groningen, University Medical Center Groningen, Groningen (Netherlands); Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen (Netherlands); Coppes, Robert P., E-mail: r.p.coppes@umcg.nl [Department of Cell Biology, University of Groningen, University Medical Center Groningen, Groningen (Netherlands); Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen (Netherlands)

    2016-05-01

    Purpose: A reduction in the dose, irradiated volume, and sensitivity of, in particular, normal tissue stem cells is needed to advance radiation therapy. This could be obtained with the use of particles for radiation therapy. However, the radiation response of normal tissue stem cells is still an enigma. Therefore, in the present study, we developed a model to investigate the in vitro response of stem cells to particle irradiation. Methods and Materials: We used the immortalized human salivary gland (HSG) cell line resembling salivary gland (SG) cells to translate the radiation response in 2-dimensional (2D) to 3-dimensional (3D) conditions. This response was subsequently translated to the response of SG stem cells (SGSCs). Dispersed single cells were irradiated with photons or carbon ions at different linear energy transfers (LETs; 48.76 ± 2.16, 149.9 ± 10.8, and 189 ± 15 keV/μm). Subsequently, 2D or 3D clonogenicity was determined by counting the colonies or secondary stem cell-derived spheres in Matrigel. γH2AX immunostaining was used to assess DNA double strand break repair. Results: The 2D response of HSG cells showed a similar increase in dose response to increasing higher LET irradiation as other cell lines. The 3D response of HSG cells to increasing LET irradiation was reduced compared with the 2D response. Finally, the response of mouse SGSCs to photons was similar to the 3D response of HSG cells. The response to higher LET irradiation was reduced in the stem cells. Conclusions: Mouse SGSC radiosensitivity seems reduced at higher LET radiation compared with transformed HSG cells. The developed model to assess the radiation response of SGSCs offers novel possibilities to study the radiation response of normal tissue in vitro.

  1. Bacterial CpG-DNA activates dendritic cells in vivo: T helper cell-independent cytotoxic T cell responses to soluble proteins.

    Science.gov (United States)

    Sparwasser, T; Vabulas, R M; Villmow, B; Lipford, G B; Wagner, H

    2000-12-01

    Receptors for conserved molecular patterns associated with microbial pathogens induce synthesis of co-stimulatory molecules and cytokines in immature dendritic cells (DC), as do antigen-reactive CD4 T helper cells via CD40 signaling. Once activated, antigen-presenting DC may activate CD8 T cell responses in a T helper cell-independent fashion. Using immunostimulatory CpG-oligonucleotides (ODN) mimicking bacterial CpG-DNA, we tested whether CpG-DNA bypasses the need for T helper cells in CTL responses towards proteins by directly activating antigen-presenting DC to transit into professional APC. We describe that immature DC in situ constitutively process soluble proteins and generate CD8 T cell determinants yet CD8 T cell responses remain abortive. Induction of primary antigen-specific CD8 cytotoxic T lymphocyte (CTL)-mediated responses becomes initiated in wild-type as well as T helper cell-deficient mice, provided soluble protein and CpG-ODN are draining into the same lymph node. Specifically we show that CpG-ODN trigger antigen-presenting immature DC within the draining lymph node to acutely up-regulate co-stimulatory molecules and produce IL-12. These results provide new insights for generating in vivo efficient CTL responses to soluble proteins which may influence vaccination strategies.

  2. The T Cell Response to Actinobacillus actinomycetemcomitans

    Science.gov (United States)

    2006-05-01

    50-54). Other factors enable Aa to attach to extracellular matrix proteins and invade epithelial cells; thereby making them resistant to non...aggressive therapy involving surgical intervention in conjunction with systemic antibiotics, including metronidazole, amoxicillin , or tetracycline...family derivatives (38-40). The increasing resistance of A. actinomycetemcomitans to antibiotics is prompting concern among the dental community, as

  3. Inhibition of host cell translation elongation by Legionella pneumophila blocks the host cell unfolded protein response.

    Science.gov (United States)

    Hempstead, Andrew D; Isberg, Ralph R

    2015-12-08

    Cells of the innate immune system recognize bacterial pathogens by detecting common microbial patterns as well as pathogen-specific activities. One system that responds to these stimuli is the IRE1 branch of the unfolded protein response (UPR), a sensor of endoplasmic reticulum (ER) stress. Activation of IRE1, in the context of Toll-like receptor (TLR) signaling, induces strong proinflammatory cytokine induction. We show here that Legionella pneumophila, an intravacuolar pathogen that replicates in an ER-associated compartment, blocks activation of the IRE1 pathway despite presenting pathogen products that stimulate this response. L. pneumophila TLR ligands induced the splicing of mRNA encoding XBP1s, the main target of IRE1 activity. L. pneumophila was able to inhibit both chemical and bacterial induction of XBP1 splicing via bacterial translocated proteins that interfere with host protein translation. A strain lacking five translocated translation elongation inhibitors was unable to block XBP1 splicing, but this could be rescued by expression of a single such inhibitor, consistent with limitation of the response by translation elongation inhibitors. Chemical inhibition of translation elongation blocked pattern recognition receptor-mediated XBP1 splicing, mimicking the effects of the bacterial translation inhibitors. In contrast, host cell-promoted inhibition of translation initiation in response to the pathogen was ineffective in blocking XBP1 splicing, demonstrating the need for the elongation inhibitors for protection from the UPR. The inhibition of host translation elongation may be a common strategy used by pathogens to limit the innate immune response by interfering with signaling via the UPR.

  4. Individual cell-based models of cell scatter of ARO and MLP-29 cells in response to hepatocyte growth factor.

    Science.gov (United States)

    Scianna, Marco; Merks, Roeland M H; Preziosi, Luigi; Medico, Enzo

    2009-09-07

    The different behaviors of colonies of two cell lines, ARO (thyroid carcinoma-derived cells) and MLP-29 (mouse liver progenitor cells), in response to hepatocyte growth factor (HGF) are described deducing suitable cellular Potts models (CPM). It is shown how increased motility and decreased adhesiveness are responsible for cell-cell dissociation and tissue invasion in the ARO cells. On the other hand, it is shown that, in addition to the biological mechanisms above, it is necessary to include directional persistence in cell motility and HGF diffusion to describe the scattering and the branching processes characteristic of MLP-29 cells.

  5. iNKT cells suppress the CD8+ T cell response to a murine Burkitt's-like B cell lymphoma.

    Directory of Open Access Journals (Sweden)

    Ryan L Bjordahl

    Full Text Available The T cell response to B cell lymphomas differs from the majority of solid tumors in that the malignant cells themselves are derived from B lymphocytes, key players in immune response. B cell lymphomas are therefore well situated to manipulate their surrounding microenvironment to enhance tumor growth and minimize anti-tumor T cell responses. We analyzed the effect of T cells on the growth of a transplantable B cell lymphoma and found that iNKT cells suppressed the anti-tumor CD8(+ T cell response. Lymphoma cells transplanted into syngeneic wild type (WT mice or Jalpha18(-/- mice that specifically lack iNKT cells grew initially at the same rate, but only the mice lacking iNKT cells were able to reject the lymphoma. This effect was due to the enhanced activity of tumor-specific CD8(+ T cells in the absence of iNKT cells, and could be partially reversed by reconstitution of iNKT cells in Jalpha 18(-/- mice. Treatment of tumor-bearing WT mice with alpha -galactosyl ceramide, an activating ligand for iNKT cells, reduced the number of tumor-specific CD8(+ T cells. In contrast, lymphoma growth in CD1d1(-/- mice that lack both iNKT and type II NKT cells was similar to that in WT mice, suggesting that type II NKT cells are required for full activation of the anti-tumor immune response. This study reveals a tumor-promoting role for iNKT cells and suggests their capacity to inhibit the CD8(+ T cell response to B cell lymphoma by opposing the effects of type II NKT cells.

  6. Heterogeneity in cancer cells: variation in drug response in different primary and secondary colorectal cancer cell lines in vitro.

    Science.gov (United States)

    Arul, Melanie; Roslani, April Camilla; Cheah, Swee Hung

    2017-05-01

    Tumor heterogeneity may give rise to differential responses to chemotherapy drugs. Therefore, unraveling tumor heterogeneity has an implication for biomarker discovery and cancer therapeutics. To test this phenomenon, we investigated the differential responses of three secondary colorectal cancer cell lines of different origins (HCT116, HT29, and SW620 cells) and four novel primary cell lines obtained from different colorectal cancer patients to 5-fluorouracil (5-FU) and oxaliplatin (L-OHP) and explored the differences in gene expression among the primary cell lines in response to exposure to cytotoxic drugs. Cells were exposed to different doses of 5-FU and L-OHP separately or in combinations of equitoxic drug or equimolar drug ratios (median effect of Chou-Talalay principle). Cell viability was assessed using MTT assay and the respective IC 50 values were determined. Changes in gene expression in primary cell lines after exposure to the same drug doses were compared using real-time PCR array. The sensitivities (IC 50 ) of different cell lines, both secondary and primary, to 5-FU and L-OHP were significantly different, whether in monotherapy or combined treatment. Primary cell lines needed higher doses to reach IC 50 . There were variations in gene expression among the primary cell lines of different chemosensitivities to the challenge of the same combined dose of 5-FU and L-OHP. The results confirm the heterogeneous nature of colorectal cancer cells from different patient tumors. Studies using primary cancer cells established from patient's tumors rather than secondary cell lines will more closely reflect the actual character of the disease.

  7. Phenomenon of adaptive response of cells in radiobiology

    International Nuclear Information System (INIS)

    Fillipovich, I.V.

    1991-01-01

    Consideration is given to various adaptive reactions to low-level radiation, their association with an absorbed dose, dose rate, radiation quality and time-interval between exposures, as well as with a cell cycle phase. Possible mechanisms of the adaptive response and the character and role of DNA damages, that can induce gene expression of the adaptive response, are discussed. The data on the influence of a preliminary long-term exposure to low-level radiation on the radiosensitivity of biological objects are analyzed with due regard for the adaptive cell response. It is concluded that the adaptive response of cells to ionizing radiation is a particular case of the phenomenon of cell adaptation of the effect of genotoxic factors of the environment

  8. Sexual Assault: Better Resource Management Needed to Improve Prevention and Response in the Army National Guard and Army Reserve

    Science.gov (United States)

    2017-02-01

    the commanding officer of an accused servicemember. 21Army Regulation 600-20 defines sexual harassment as a form of gender discrimination that...SEXUAL ASSAULT Better Resource Management Needed to Improve Prevention and Response in the Army National Guard and Army...Resource Management Needed to Improve Prevention and Response in the Army National Guard and Army Reserve What GAO Found The Army National Guard

  9. In vitro mesenchymal stem cell response to a CO{sub 2} laser modified polymeric material

    Energy Technology Data Exchange (ETDEWEB)

    Waugh, D.G., E-mail: d.waugh@chester.ac.uk [Laser Engineering and Manufacturing Research Centre, Faculty of Science and Engineering, University of Chester, Chester CH1 4BJ (United Kingdom); Hussain, I. [School of Life Sciences, Brayford Pool, University of Lincoln, Lincoln LN6 7TS (United Kingdom); Lawrence, J.; Smith, G.C. [Laser Engineering and Manufacturing Research Centre, Faculty of Science and Engineering, University of Chester, Chester CH1 4BJ (United Kingdom); Cosgrove, D. [School of Life Sciences, Brayford Pool, University of Lincoln, Lincoln LN6 7TS (United Kingdom); Toccaceli, C. [Laser Engineering and Manufacturing Research Centre, Faculty of Science and Engineering, University of Chester, Chester CH1 4BJ (United Kingdom)

    2016-10-01

    With an ageing world population it is becoming significantly apparent that there is a need to produce implants and platforms to manipulate stem cell growth on a pharmaceutical scale. This is needed to meet the socio-economic demands of many countries worldwide. This paper details one of the first ever studies in to the manipulation of stem cell growth on CO{sub 2} laser surface treated nylon 6,6 highlighting its potential as an inexpensive platform to manipulate stem cell growth on a pharmaceutical scale. Through CO{sub 2} laser surface treatment discrete changes to the surfaces were made. That is, the surface roughness of the nylon 6,6 was increased by up to 4.3 μm, the contact angle was modulated by up to 5° and the surface oxygen content increased by up to 1 atom %. Following mesenchymal stem cell growth on the laser treated samples, it was identified that CO{sub 2} laser surface treatment gave rise to an enhanced response with an increase in viable cell count of up to 60,000 cells/ml when compared to the as-received sample. The effect of surface parameters modified by the CO{sub 2} laser surface treatment on the mesenchymal stem cell response is also discussed along with potential trends that could be identified to govern the mesenchymal stem cell response.

  10. Epilepsy in India II: Impact, burden, and need for a multisectoral public health response

    Directory of Open Access Journals (Sweden)

    Senthil Amudhan

    2015-01-01

    Full Text Available Epilepsy is a common neurological disorder whose consequences are influenced socially and culturally, especially in India. This review (second of the two part series was carried out to understand the social impact and economic burden to develop comprehensive program for control and prevention of epilepsy. Epilepsy is known to have adverse effect on education, employment, marriage, and other essential social opportunities. Economic burden associated with epilepsy is very high with treatment and travel costs emerging as an important contributing factor. A vicious cycle between economic burden and poor disease outcome is clear. There is no significant change in the perception, stigma, and discrimination of epilepsy across the country despite improvement in educational and social parameters over the time. The huge treatment gap and poor quality of life is further worsened by the associated comorbidities and conditions. Thus, a multidisciplinary response is needed to address the burden and impact of epilepsy which calls for an integrated and multipronged approach for epilepsy care, prevention, and rehabilitation. Service delivery, capacity building, integration into the existing program, mobilizing public support, and increasing public awareness will be the hallmarks of such an integrated approach in a public health model.

  11. Unraveling the Mystery of Auditory Brainstem Response Corrections: The Need for Universal Standards.

    Science.gov (United States)

    Norrix, Linda W; Velenovsky, David

    The auditory brainstem response (ABR) is used to estimate behavioral hearing thresholds in infants and difficult-to-test populations. Differences between the toneburst ABR and behavioral thresholds exist making the correspondence between the two measures less than perfect. Some authors have suggested that corrections be applied to ABR thresholds to account for these differences. However, because there is no agreed upon universal standard, confusion regarding the use of corrections exists. The primary purpose of this article is to review the reasoning behind and use of corrections when the toneburst ABR is employed to estimate behavioral hearing thresholds. We also discuss other considerations that all audiologists should be aware of when obtaining and reporting ABR test results. A review of the purpose and use of corrections reveals no consensus as to whether they should be applied or which should be used. Additionally, when ABR results are adjusted, there is no agreement as to whether additional corrections for hearing loss or the age of the client are necessary. This lack of consensus can be confusing for all individuals working with hearing-impaired children and their families. Toneburst ABR thresholds do not perfectly align with behavioral hearing thresholds. Universal protocols for the use of corrections are needed. Additionally, evidence-based procedures must be employed to obtain valid ABRs that will accurately estimate hearing thresholds. American Academy of Audiology

  12. Thomas Alva Edison—battery and device innovation in response to application's needs

    Science.gov (United States)

    Salkind, Alvin J.; Israel, Paul

    Thomas Alva Edison, the most prolific inventor in North America, with over 1000 patents, was the descendant of early settlers from the Netherlands to the Hudson Valley region of New York/New Jersey. However, his genealogical trail encompasses many cities, provinces, states, and countries, including Holland, France, Scotland, New Amsterdam, New York, New Jersey, Nova Scotia, Ontario, Ohio, and Michigan. He was motivated to develop and invent in response to perceived needs of commercial devices and was the creator of the concept of an industrial research laboratory. His activities covered a wide-range of chemical, electrical, medical, metallurgical, entertainment, and communication devices and led to the creation of major worldwide industries. However, his expressed underlying concern was the "service it might give others". This presentation reviews commercial developments in comparison with the technologies and motivations of the time and is illustrated by material from the Rutgers University 'Edison Papers Project', Edison's personal notes found in the Edison Battery Factory and preserved by Professor Salkind, and records of The Electrochemical Society.

  13. Occupational safety and health's role in sustainable, responsible nanotechnology: gaps and needs.

    Science.gov (United States)

    Iavicoli, S; Rondinone, B M; Boccuni, F

    2009-06-01

    The newly fledged nanotechnologies offer opportunities for social development, but uncertainties prevail about their impact on human and environmental health. There is still a huge gap between technological progress and research into the health and safety aspects of nanomaterials. This is clear from the quantity of nanoproducts already on the market--more than 600--and the public and private funds dedicated to the development of nanotechnologies, which are almost a hundred times those available for research into their effects on health and safety. Estimates have it that by 2014, nanotechnologies will be widely used in our society and ten million new jobs will be created. Therefore, it becomes essential to plan an integrated approach to specific risk analysis at work. The following gaps and needs come to light: limited information, difficulties in relating nanotechnologies and production of nanomaterials to specific areas of application, efforts required to assess the hazards posed by nanomaterials in realistic exposure conditions, ethical issues about nanotechnology in the workplace likely to arise from today's knowledge about the hazards of nanomaterials and the risks they may pose to workers. An integrated approach to research, cooperation, and communication strategies is essential if we are to direct our efforts toward responsible and sustainable growth of nanotechnologies.

  14. Dynamics of NKT-Cell Responses to Chlamydial Infection.

    Science.gov (United States)

    Shekhar, Sudhanshu; Joyee, Antony George; Yang, Xi

    2015-01-01

    Natural killer T (NKT) cells have gained great attention owing to their critical functional roles in immunity to various pathogens. In this review, we provide an overview of the current knowledge on the role of NKT cells in host defense against and pathogenesis due to Chlamydia, which is an intracellular bacterial pathogen that poses a threat to the public health worldwide. Accumulating evidence has demonstrated that NKT cells, particularly invariant NKT (iNKT) cells, play a crucial role in host defense against chlamydial infections, especially in C. pneumoniae infection. iNKT cells can promote type-1 protective responses to C. pneumoniae by inducing enhanced production of IL-12 by dendritic cells (DCs), in particular CD8α+ DCs, which promote the differentiation of naive T cells into protective IFN-γ-producing Th1/Tc1 type CD4+/CD8+ T cells. This iNKT-cell-mediated modulation of DC function is largely dependent upon CD40-CD40L interaction, IFN-γ production, and cell-to-cell contact. In addition, iNKT cells modulate the function of natural killer cells. NKT cells may be also involved in the pathogenesis of some chlamydial diseases by inducing different patterns of cytokine production. A better understanding of NKT-cell biology will enable us to rationally design prophylactic and therapeutic tools to combat infectious diseases.

  15. Transient response of a proton exchange membrane fuel cell

    Science.gov (United States)

    Weydahl, Helge; Møller-Holst, Steffen; Hagen, Georg; Børresen, Børre

    The transient response of a proton exchange membrane fuel cell (PEMFC) supplied with pure hydrogen and oxygen was investigated by load step measurements assisted by electrochemical impedance spectroscopy and chronoamperometry. Using an in-house designed resistance board, the uncontrolled response in both cell voltage and current upon step changes in a resistive load was observed. The PEMFC was found to respond quickly and reproducibly to load changes. The transient PEMFC response was limited by a cathodic charge transfer process with a potential-dependent response time. For load steps to high-current densitities, a second transient process with a constant response time was observed. This transient was offset from the charge transfer transient by a temporarily stable plateau. Results from chronoamperometry indicated that the second transient could be related to a diffusion process. Transient paths were plotted in the V- i diagram, matching a predicted pattern with overshooting cell voltage and current during a load step.

  16. Survivin-specific T-cell reactivity correlates with tumor response and patient survival

    DEFF Research Database (Denmark)

    Becker, Jürgen C; Andersen, Mads H; Hofmeister-Müller, Valeska

    2012-01-01

    Therapeutic vaccination directed to induce an anti-tumoral T-cell response is a field of extensive investigation in the treatment of melanoma. However, many vaccination trials in melanoma failed to demonstrate a correlation between the vaccine-specific immune response and therapy outcome. This has...... been mainly attributed to immune escape by antigen loss, rendering us in the need of new vaccination targets....

  17. Responses of fibroblasts and glial cells to nanostructured platinum surfaces

    Energy Technology Data Exchange (ETDEWEB)

    Pennisi, C P; Sevcencu, C; Yoshida, K [Center for Sensory-Motor Interaction (SMI), Aalborg University, Aalborg (Denmark); Dolatshahi-Pirouz, A; Foss, M; Larsen, A Nylandsted; Besenbacher, F [Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Aarhus (Denmark); Hansen, J Lundsgaard [Department of Physics and Astronomy, Aarhus University, Aarhus (Denmark); Zachar, V, E-mail: cpennisi@hst.aau.d [Laboratory for Stem Cell Research, Aalborg University (Denmark)

    2009-09-23

    The chronic performance of implantable neural prostheses is affected by the growth of encapsulation tissue onto the stimulation electrodes. Encapsulation is associated with activation of connective tissue cells at the electrode's metallic contacts, usually made of platinum. Since surface nanotopography can modulate the cellular responses to materials, the aim of the present work was to evaluate the 'in vitro' responses of connective tissue cells to platinum strictly by modulating its surface nanoroughness. Using molecular beam epitaxy combined with sputtering, we produced platinum nanostructured substrates consisting of irregularly distributed nanopyramids and investigated their effect on the proliferation, cytoskeletal organization and cellular morphology of primary fibroblasts and transformed glial cells. Cells were cultured on these substrates and their responses to surface roughness were studied. After one day in culture, the fibroblasts were more elongated and their cytoskeleton less mature when cultured on rough substrates. This effect increased as the roughness of the surface increased and was associated with reduced cell proliferation throughout the observation period (4 days). Morphological changes also occurred in glial cells, but they were triggered by a different roughness scale and did not affect cellular proliferation. In conclusion, surface nanotopography modulates the responses of fibroblasts and glial cells to platinum, which may be an important factor in optimizing the tissue response to implanted neural electrodes.

  18. Responses of fibroblasts and glial cells to nanostructured platinum surfaces

    Science.gov (United States)

    Pennisi, C. P.; Sevcencu, C.; Dolatshahi-Pirouz, A.; Foss, M.; Lundsgaard Hansen, J.; Nylandsted Larsen, A.; Zachar, V.; Besenbacher, F.; Yoshida, K.

    2009-09-01

    The chronic performance of implantable neural prostheses is affected by the growth of encapsulation tissue onto the stimulation electrodes. Encapsulation is associated with activation of connective tissue cells at the electrode's metallic contacts, usually made of platinum. Since surface nanotopography can modulate the cellular responses to materials, the aim of the present work was to evaluate the 'in vitro' responses of connective tissue cells to platinum strictly by modulating its surface nanoroughness. Using molecular beam epitaxy combined with sputtering, we produced platinum nanostructured substrates consisting of irregularly distributed nanopyramids and investigated their effect on the proliferation, cytoskeletal organization and cellular morphology of primary fibroblasts and transformed glial cells. Cells were cultured on these substrates and their responses to surface roughness were studied. After one day in culture, the fibroblasts were more elongated and their cytoskeleton less mature when cultured on rough substrates. This effect increased as the roughness of the surface increased and was associated with reduced cell proliferation throughout the observation period (4 days). Morphological changes also occurred in glial cells, but they were triggered by a different roughness scale and did not affect cellular proliferation. In conclusion, surface nanotopography modulates the responses of fibroblasts and glial cells to platinum, which may be an important factor in optimizing the tissue response to implanted neural electrodes.

  19. The Interplay between Adolescent Needs and Secondary School Structures: Fostering Developmentally Responsive Middle and High School Environments across the Transition

    Science.gov (United States)

    Ellerbrock, Cheryl R.; Kiefer, Sarah M.

    2013-01-01

    Understanding the developmental responsiveness of secondary school environments may be an important factor in supporting students as they make the transition from one school to the next. Students' needs may or may not be met depending on the nature of the fit between their basic and developmental needs and secondary school structures at the middle…

  20. 20 CFR 670.550 - What responsibilities do Job Corps centers have in assisting students with child care needs?

    Science.gov (United States)

    2010-04-01

    ... have in assisting students with child care needs? (a) Job Corps centers are responsible for coordinating with outreach and admissions agencies to assist students with making arrangements for child care... have in assisting students with child care needs? 670.550 Section 670.550 Employees' Benefits...

  1. Tissue specific heterogeneity in effector immune cell response

    Directory of Open Access Journals (Sweden)

    Saba eTufail

    2013-08-01

    Full Text Available Post pathogen invasion, migration of effector T-cell subsets to specific tissue locations is of prime importance for generation of robust immune response. Effector T cells are imprinted with distinct ‘homing codes’ (adhesion molecules and chemokine receptors during activation which regulate their targeted trafficking to specific tissues. Internal cues in the lymph node microenvironment along with external stimuli from food (vitamin A and sunlight (vitamin D3 prime dendritic cells, imprinting them to play centrestage in the induction of tissue tropism in effector T cells. B cells as well, in a manner similar to effector T cells, exhibit tissue tropic migration. In this review, we have focused on the factors regulating the generation and migration of effector T cells to various tissues alongwith giving an overview of tissue tropism in B cells.

  2. Civil Support: DOD Needs to Clarify Its Roles and Responsibilities for Defense Support of Civil Authorities during Cyber Incidents

    Science.gov (United States)

    2016-04-01

    CIVIL SUPPORT DOD Needs to Clarify Its Roles and Responsibilities for Defense Support of Civil Authorities during...Clarify Its Roles and Responsibilities for Defense Support of Civil Authorities during Cyber Incidents Why GAO Did This Study Cyber threats to U.S...recognizes that the department plays a crucial role in supporting a national effort to confront cyber threats to critical infrastructure. House

  3. T Cell Responses: Naive to Memory and Everything in Between

    Science.gov (United States)

    Pennock, Nathan D.; White, Jason T.; Cross, Eric W.; Cheney, Elizabeth E.; Tamburini, Beth A.; Kedl, Ross M.

    2013-01-01

    The authors describe the actions that take place in T cells because of their amazing capacity to proliferate and adopt functional roles aimed at clearing a host of an infectious agent. There is a drastic decline in the T cell population once the primary response is over and the infection is terminated. What remains afterward is a population of T…

  4. Cyperus scariosus Chloroform Fraction Inhibits T cell Responses in ...

    African Journals Online (AJOL)

    Erah

    CSC did not significantly (p < 0.01) suppress Th2 (IL-4) system. Conclusion: The findings from this investigation reveal that C. scariosus causes immunosuppression by inhibiting Th1 cytokines. Keywords: Cyperus scariosus; Immunosuppression; Humoral antibody titre; Cell-mediated immune response; CD 4+ T- helper cells ...

  5. Investigating Human Dendritic Cell Immune Responses to Borrelia burgdorferi

    NARCIS (Netherlands)

    Mason, Lauren M. K.; Hovius, Joppe W. R.

    2018-01-01

    Dendritic cells (DCs) are professional antigen-presenting cells that recognize and phagocytose pathogens, and help to orchestrate adaptive immune responses to combat them. DCs are abundant in the skin where Borrelia burgdorferi first enters the body during a tick bite, and are thus critical in

  6. Regulatory T Cells and Host Anti-CML Responses

    National Research Council Canada - National Science Library

    Wong, Jr, K. K

    2008-01-01

    CD4+CD25+FoxP-3+ regulatory T-cells (Tregs) suppress immune responses to "self" antigens, but also have been shown to suppress host anti-tumor responses in several human malignancies, including breast, gastrointestinal, and ovarian cancer...

  7. Radiation adaptive response for the growth of cultured glial cells

    International Nuclear Information System (INIS)

    Suzuki, S.; Miura, Y.; Kano, M.; Toda, T.; Urano, S.

    2003-01-01

    Full text: To examine the molecular mechanism of radiation adaptive response (RAR) for the growth of cultured glial cells and to investigate the influence of aging on the response, glial cells were cultured from young and aged rats (1 month and 24 months old). RAR for the growth of glial cells conditioned with a low dose of X-rays and subsequently exposed to a high dose of X-rays was examined for cell number and BrdU incorporation. Involvement of the subcellular signaling pathway factors in RAR was investigated using their inhibitors, activators and mutated glial cells. RAR was observed in cells cultured from young rats, but was not in cells from aged rats. The inhibitors of protein kinase C (PKC) and DNA-dependent protein kinase (DNA-PK) or phosphatidylinositol 3-kinase (PI3K) suppressed RAR. The activators of PKC instead of low dose irradiation also caused RAR. Moreover, glial cells cultured from severe combined immunodeficiency (scid) mice (CB-17 scid) and ataxia-telangiectasia (AT) cells from AT patients showed no RAR. These results indicated that PKC, ATM, DNAPK and/or PI3K were involved in RAR for growth and BrdU incorporation of cultured glial cells and RAR decreased with aging. Proteomics data of glial cells exposed to severe stress of H 2 O 2 or X-rays also will be presented in the conference since little or no difference has not been observed with slight stress yet

  8. Temporal Analyses of the Response of Intervertebral Disc Cells and Mesenchymal Stem Cells to Nutrient Deprivation

    Directory of Open Access Journals (Sweden)

    Sarah A. Turner

    2016-01-01

    Full Text Available Much emphasis has been placed recently on the repair of degenerate discs using implanted cells, such as disc cells or bone marrow derived mesenchymal stem cells (MSCs. This study examines the temporal response of bovine and human nucleus pulposus (NP cells and MSCs cultured in monolayer following exposure to altered levels of glucose (0, 3.15, and 4.5 g/L and foetal bovine serum (0, 10, and 20% using an automated time-lapse imaging system. NP cells were also exposed to the cell death inducers, hydrogen peroxide and staurosporine, in comparison to serum starvation. We have demonstrated that human NP cells show an initial “shock” response to reduced nutrition (glucose. However, as time progresses, NP cells supplemented with serum recover with minimal evidence of cell death. Human NP cells show no evidence of proliferation in response to nutrient supplementation, whereas MSCs showed greater response to increased nutrition. When specifically inducing NP cell death with hydrogen peroxide and staurosporine, as expected, the cell number declined. These results support the concept that implanted NP cells or MSCs may be capable of survival in the nutrient-poor environment of the degenerate human disc, which has important clinical implications for the development of IVD cell therapies.

  9. Gold nanoparticle-mediated laser stimulation induces a complex stress response in neuronal cells.

    Science.gov (United States)

    Johannsmeier, Sonja; Heeger, Patrick; Terakawa, Mitsuhiro; Kalies, Stefan; Heisterkamp, Alexander; Ripken, Tammo; Heinemann, Dag

    2018-04-25

    Stimulation of neuronal cells generally resorts to electric signals. Recent advances in laser-based stimulation methods could present an alternative with superior spatiotemporal resolution. The avoidance of electronic crosstalk makes these methods attractive for in vivo therapeutic application. In particular, nano-mediators, such as gold nanoparticles, can be used to transfer the energy from a laser pulse to the cell membrane and subsequently activate excitable cells. Although the underlying mechanisms of neuronal activation have been widely unraveled, the overall effect on the targeted cell is not understood. Little is known about the physiological and pathophysiological impact of a laser pulse targeted onto nanoabsorbers on the cell membrane. Here, we analyzed the reaction of the neuronal murine cell line Neuro-2A and murine primary cortical neurons to gold nanoparticle mediated laser stimulation. Our study reveals a severe, complex and cell-type independent stress response after laser irradiation, emphasizing the need for a thorough assessment of this approach's efficacy and safety.

  10. Ultraviolet responses of Gorlin syndrome primary skin cells.

    Science.gov (United States)

    Brellier, F; Valin, A; Chevallier-Lagente, O; Gorry, P; Avril, M-F; Magnaldo, T

    2008-08-01

    Gorlin syndrome, or naevoid basal cell carcinoma syndrome (NBCCS), is an autosomal dominant disorder associated with mutations in the PTCH1 gene, which encodes the receptor of SONIC HEDGEHOG. In addition to developmental abnormalities, patients with NBCCS are prone to basal cell carcinoma (BCC), the most frequent type of nonmelanoma skin cancer in humans. As ultraviolet (UV) exposure plays a prominent role in the development of sporadic BCC, we aimed to determine whether primary NBCCS skin cells exhibit differential responses to UV exposure compared with wild-type (WT) skin cells. Primary fibroblast and keratinocyte strains were isolated from nonlesional skin biopsies of 10 patients with characteristic NBCCS traits. After identification of PTCH1 mutations, capacities of NBCCS cells to repair UV-induced DNA lesions and to survive after UV irradiation, as well as p53 responses, were compared with those of WT skin cells. The c1763insG PTCH1 mutation is described for the first time. DNA repair and cell survival analyses following UV irradiation revealed no obvious differences between responses of NBCCS and WT fibroblasts and keratinocytes. However, p53 accumulation after UV irradiation was abnormally persistent in all NBCCS primary keratinocyte strains compared with WT keratinocytes. Our observations that NBCCS cells harbour normal DNA repair and survival capacities following UV irradiation better explain that BCC proneness of patients with NBCCS does not solely concern body areas exposed to sunlight and suggest rather that it might be due to cell cycle alterations.

  11. Developing robust, hydrogel-based, nanofiber-enabled encapsulation devices (NEEDs) for cell therapies.

    Science.gov (United States)

    An, Duo; Ji, Yewei; Chiu, Alan; Lu, Yen-Chun; Song, Wei; Zhai, Lei; Qi, Ling; Luo, Dan; Ma, Minglin

    2015-01-01

    Cell encapsulation holds enormous potential to treat a number of hormone deficient diseases and endocrine disorders. We report a simple and universal approach to fabricate robust, hydrogel-based, nanofiber-enabled encapsulation devices (NEEDs) with macroscopic dimensions. In this design, we take advantage of the well-known capillary action that holds wetting liquid in porous media. By impregnating the highly porous electrospun nanofiber membranes of pre-made tubular or planar devices with hydrogel precursor solutions and subsequent crosslinking, we obtained various nanofiber-enabled hydrogel devices. This approach is broadly applicable and does not alter the water content or the intrinsic chemistry of the hydrogels. The devices retained the properties of both the hydrogel (e.g. the biocompatibility) and the nanofibers (e.g. the mechanical robustness). The facile mass transfer was confirmed by encapsulation and culture of different types of cells. Additional compartmentalization of the devices enabled paracrine cell co-cultures in single implantable devices. Lastly, we provided a proof-of-concept study on potential therapeutic applications of the devices by encapsulating and delivering rat pancreatic islets into chemically-induced diabetic mice. The diabetes was corrected for the duration of the experiment (8 weeks) before the implants were retrieved. The retrieved devices showed minimal fibrosis and as expected, live and functional islets were observed within the devices. This study suggests that the design concept of NEEDs may potentially help to overcome some of the challenges in the cell encapsulation field and therefore contribute to the development of cell therapies in future. Copyright © 2014 Elsevier Ltd. All rights reserved.

  12. Studies on adaptive responses in Chinese hamster cells

    International Nuclear Information System (INIS)

    Michelin, S.C.; Perez, M.R. Del; Dubner, D.; Gisone, P.A.

    1997-01-01

    For many years the possibility has been considered of low doses of radiation inducing adaptive responses in cells and organisms against the mutagenic effects of radiation. Currently, a number of experimental data appraise the existence of an adaptive response that is characterized by a decrease of radiation induced genetic damages. The understanding of the molecular mechanism involved in this phenomenon permits to estimate the effects and risks of low dose exposure. In this work, preliminary results of studies on the induction of adaptive response in cells subjected to different doses of ionizing radiation are presented

  13. The STATs in cell stress-type responses

    Directory of Open Access Journals (Sweden)

    Best James

    2004-08-01

    Full Text Available Abstract In the early 1990's, a new cell signaling pathway was described. This new paradigm, now known as the JAK/STAT pathway, has been extensively investigated in immune-type cells in response to interferons and interleukins. However, recent evidence suggests that the JAK/STAT pathway also mediates diverse cellular responses to various forms of biological stress including hypoxia/reperfusion, endotoxin, ultraviolet light, and hyperosmolarity. The current literature describing the JAK/STAT pathway's role in cellular stress responses has been reviewed herein, but it is clear that our knowledge in this area is far from complete.

  14. PET/CT imaging in response evaluation of patients with small cell lung cancer

    DEFF Research Database (Denmark)

    Fischer, Barbara M; Mortensen, Jann; Langer, Seppo W

    2006-01-01

    UNLABELLED: There is an increasing amount of evidence on the usability of PET in response evaluation of non-small cell lung cancer. However, data on SCLC is scarce and mainly retrospective. This prospective study assesses the use of PET (positron emission tomography) and PET/CT in response...... evaluation of patients with small cell lung cancer (SCLC). METHODS: Assignment of early and final response was compared between PET, PET/CT, and CT in 20 patients with SCLC. Final response as assigned by CT (RECIST) served as reference. RESULTS: At response evaluation after one cycle of chemotherapy major...... by PET/CT is feasible, but it is uncertain whether it adds further information to evaluation by RECIST, thus further studies and standardization of methods are needed....

  15. Antitumor Responses of Invariant Natural Killer T Cells

    Directory of Open Access Journals (Sweden)

    Jennie B. Altman

    2015-01-01

    Full Text Available Natural killer T (NKT cells are innate-like lymphocytes that were first described in the late 1980s. Since their initial description, numerous studies have collectively shed light on their development and effector function. These studies have highlighted the unique requirements for the activation of these lymphocytes and the functional responses that distinguish these cells from other effector lymphocyte populations such as conventional T cells and NK cells. This body of literature suggests that NKT cells play diverse nonredundant roles in a number of disease processes, including the initiation and propagation of airway hyperreactivity, protection against a variety of pathogens, development of autoimmunity, and mediation of allograft responses. In this review, however, we focus on the role of a specific lineage of NKT cells in antitumor immunity. Specifically, we describe the development of invariant NKT (iNKT cells and the factors that are critical for their acquisition of effector function. Next, we delineate the mechanisms by which iNKT cells influence and modulate the activity of other immune cells to directly or indirectly affect tumor growth. Finally, we review the successes and failures of clinical trials employing iNKT cell-based immunotherapies and explore the future prospects for the use of such strategies.

  16. Healthy human T-Cell Responses to Aspergillus fumigatus antigens.

    Directory of Open Access Journals (Sweden)

    Neelkamal Chaudhary

    2010-02-01

    Full Text Available Aspergillus fumigatus is associated with both invasive and allergic pulmonary diseases, in different hosts. The organism is inhaled as a spore, which, if not cleared from the airway, germinates into hyphal morphotypes that are responsible for tissue invasion and resultant inflammation. Hyphae secrete multiple products that function as antigens, evoking both a protective (T(H1-T(H17 and destructive allergic (T(H2 immunity. How Aspergillus allergens (Asp f proteins participate in the development of allergic sensitization is unknown.To determine whether Asp f proteins are strictly associated with T(H2 responses, or represent soluble hyphal products recognized by healthy hosts, human T cell responses to crude and recombinant products were characterized by ELISPOT. While responses (number of spots producing IFN-gamma, IL-4 or IL-17 to crude hyphal antigen preparations were weak, responses to recombinant Asp f proteins were higher. Recombinant allergens stimulated cells to produce IFN-gamma more so than IL-4 or IL-17. Volunteers exhibited a diverse CD4+ and CD8+ T cell antigen recognition profile, with prominent CD4 T(H1-responses to Asp f3 (a putative peroxismal membrane protein, Asp f9/16 (cell wall glucanase, Asp f11 (cyclophilin type peptidyl-prolyl isomerase and Asp f22 (enolase. Strong IFN-gamma responses were reproduced in most subjects tested over 6 month intervals.Products secreted after conidial germination into hyphae are differentially recognized by protective T cells in healthy, non-atopic individuals. Defining the specificity of the human T cell repertoire, and identifying factors that govern early responses may allow for development of novel diagnostics and therapeutics for both invasive and allergic Aspergillus diseases.

  17. Healthy human T-Cell Responses to Aspergillus fumigatus antigens.

    Science.gov (United States)

    Chaudhary, Neelkamal; Staab, Janet F; Marr, Kieren A

    2010-02-17

    Aspergillus fumigatus is associated with both invasive and allergic pulmonary diseases, in different hosts. The organism is inhaled as a spore, which, if not cleared from the airway, germinates into hyphal morphotypes that are responsible for tissue invasion and resultant inflammation. Hyphae secrete multiple products that function as antigens, evoking both a protective (T(H)1-T(H)17) and destructive allergic (T(H)2) immunity. How Aspergillus allergens (Asp f proteins) participate in the development of allergic sensitization is unknown. To determine whether Asp f proteins are strictly associated with T(H)2 responses, or represent soluble hyphal products recognized by healthy hosts, human T cell responses to crude and recombinant products were characterized by ELISPOT. While responses (number of spots producing IFN-gamma, IL-4 or IL-17) to crude hyphal antigen preparations were weak, responses to recombinant Asp f proteins were higher. Recombinant allergens stimulated cells to produce IFN-gamma more so than IL-4 or IL-17. Volunteers exhibited a diverse CD4+ and CD8+ T cell antigen recognition profile, with prominent CD4 T(H)1-responses to Asp f3 (a putative peroxismal membrane protein), Asp f9/16 (cell wall glucanase), Asp f11 (cyclophilin type peptidyl-prolyl isomerase) and Asp f22 (enolase). Strong IFN-gamma responses were reproduced in most subjects tested over 6 month intervals. Products secreted after conidial germination into hyphae are differentially recognized by protective T cells in healthy, non-atopic individuals. Defining the specificity of the human T cell repertoire, and identifying factors that govern early responses may allow for development of novel diagnostics and therapeutics for both invasive and allergic Aspergillus diseases.

  18. Nanosecond electric pulses trigger actin responses in plant cells

    International Nuclear Information System (INIS)

    Berghoefer, Thomas; Eing, Christian; Flickinger, Bianca; Hohenberger, Petra; Wegner, Lars H.; Frey, Wolfgang; Nick, Peter

    2009-01-01

    We have analyzed the cellular effects of nanosecond pulsed electrical fields on plant cells using fluorescently tagged marker lines in the tobacco cell line BY-2 and confocal laser scanning microscopy. We observe a disintegration of the cytoskeleton in the cell cortex, followed by contraction of actin filaments towards the nucleus, and disintegration of the nuclear envelope. These responses are accompanied by irreversible permeabilization of the plasma membrane manifest as uptake of Trypan Blue. By pretreatment with the actin-stabilizing drug phalloidin, the detachment of transvacuolar actin from the cell periphery can be suppressed, and this treatment can also suppress the irreversible perforation of the plasma membrane. We discuss these findings in terms of a model, where nanosecond pulsed electric fields trigger actin responses that are key events in the plant-specific form of programmed cell death.

  19. Immunotherapeutic strategies targeting Natural killer T cell responses in cancer

    Science.gov (United States)

    Shissler, Susannah C.; Bollino, Dominique R.; Tiper, Irina V.; Bates, Joshua; Derakhshandeh, Roshanak; Webb, Tonya J.

    2017-01-01

    Natural killer T (NKT) cells are a unique subset of lymphocytes that bridge the innate and adaptive immune system. NKT cells possess a classic αβ T-cell receptor (TCR) that is able to recognize self and foreign glycolipid antigens presented by the nonclassical class I major histocompatibility complex (MHC) molecule, CD1d. Type I NKT cells (referred to as invariant NKT cells) express a semi-invariant Vα14Jα18 TCR in mice and Vα24Jα18 TCR in humans. Type II NKT cells are CD1d-restricted T cells that express a more diverse set of TCR α chains. The two types of NKT cells often exert opposing effects especially in tumor immunity, where Type II cells generally suppress tumor immunity while Type I NKT cells can enhance antitumor immune responses. In this review, we focus on the role of NKT cells in cancer. We discuss their effector and suppressive functions, as well as describe preclinical and clinical studies utilizing therapeutic strategies focused on harnessing their potent anti-tumor effector functions, and conclude with a discussion on potential next steps for the utilization of NKT cell targeted therapies for the treatment of cancer. PMID:27393665

  20. Hepatoblastoma: A Need for Cell Lines and Tissue Banks to Develop Targeted Drug Therapies

    Directory of Open Access Journals (Sweden)

    Rishi Raj Rikhi

    2016-03-01

    Full Text Available Limited research exists regarding the most aggressive forms of hepatoblastoma. Cell lines of the rare subtypes of hepatoblastoma with poor prognosis are not only difficult to attain, but are challenging to characterize histologically. A community approach to educating parents and families of the need for donated tissue is necessary for scientists to have access to resources for murine models and drug discovery. Herein we describe the currently available resources, the today’s existing gaps in research, and the path to move forward for uniform cure of hepatoblastoma.

  1. T-cell activation and early gene response in dogs.

    Science.gov (United States)

    Mortlock, Sally-Anne; Wei, Jerry; Williamson, Peter

    2015-01-01

    T-cells play a crucial role in canine immunoregulation and defence against invading pathogens. Proliferation is fundamental to T-cell differentiation, homeostasis and immune response. Initiation of proliferation following receptor mediated stimuli requires a temporally programmed gene response that can be identified as immediate-early, mid- and late phases. The immediate-early response genes in T-cell activation engage the cell cycle machinery and promote subsequent gene activation events. Genes involved in this immediate-early response in dogs are yet to be identified. The present study was undertaken to characterise the early T-cell gene response in dogs to improve understanding of the genetic mechanisms regulating immune function. Gene expression profiles were characterised using canine gene expression microarrays and quantitative reverse transcription PCR (qRT-PCR), and paired samples from eleven dogs. Significant functional annotation clusters were identified following stimulation with phytohemagluttinin (PHA) (5μg/ml), including the Toll-like receptor signaling pathway and phosphorylation pathways. Using strict statistical criteria, 13 individual genes were found to be differentially expressed, nine of which have ontologies that relate to proliferation and cell cycle control. These included, prostaglandin-endoperoxide synthase 2 (PTGS2/COX2), early growth response 1 (EGR1), growth arrest and DNA damage-inducible gene (GADD45B), phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1), V-FOS FBJ murine osteosarcoma viral oncogene homolog (FOS), early growth response 2 (EGR2), hemogen (HEMGN), polo-like kinase 2 (PLK2) and polo-like kinase 3 (PLK3). Differential gene expression was re-examined using qRT-PCR, which confirmed that EGR1, EGR2, PMAIP1, PTGS2, FOS and GADD45B were significantly upregulated in stimulated cells and ALAS2 downregulated. PTGS2 and EGR1 showed the highest levels of response in these dogs. Both of these genes are involved in cell cycle

  2. T-cell activation and early gene response in dogs.

    Directory of Open Access Journals (Sweden)

    Sally-Anne Mortlock

    Full Text Available T-cells play a crucial role in canine immunoregulation and defence against invading pathogens. Proliferation is fundamental to T-cell differentiation, homeostasis and immune response. Initiation of proliferation following receptor mediated stimuli requires a temporally programmed gene response that can be identified as immediate-early, mid- and late phases. The immediate-early response genes in T-cell activation engage the cell cycle machinery and promote subsequent gene activation events. Genes involved in this immediate-early response in dogs are yet to be identified. The present study was undertaken to characterise the early T-cell gene response in dogs to improve understanding of the genetic mechanisms regulating immune function. Gene expression profiles were characterised using canine gene expression microarrays and quantitative reverse transcription PCR (qRT-PCR, and paired samples from eleven dogs. Significant functional annotation clusters were identified following stimulation with phytohemagluttinin (PHA (5μg/ml, including the Toll-like receptor signaling pathway and phosphorylation pathways. Using strict statistical criteria, 13 individual genes were found to be differentially expressed, nine of which have ontologies that relate to proliferation and cell cycle control. These included, prostaglandin-endoperoxide synthase 2 (PTGS2/COX2, early growth response 1 (EGR1, growth arrest and DNA damage-inducible gene (GADD45B, phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1, V-FOS FBJ murine osteosarcoma viral oncogene homolog (FOS, early growth response 2 (EGR2, hemogen (HEMGN, polo-like kinase 2 (PLK2 and polo-like kinase 3 (PLK3. Differential gene expression was re-examined using qRT-PCR, which confirmed that EGR1, EGR2, PMAIP1, PTGS2, FOS and GADD45B were significantly upregulated in stimulated cells and ALAS2 downregulated. PTGS2 and EGR1 showed the highest levels of response in these dogs. Both of these genes are involved in

  3. Rapid flow-induced responses in endothelial cells

    Science.gov (United States)

    Stamatas, G. N.; McIntire, L. V.

    2001-01-01

    Endothelial cells alter their morphology, growth rate, and metabolism in response to fluid shear stress. To study rapid flow-induced responses in the 3D endothelial cell morphology and calcium distribution, coupled fluorescence microscopy with optical sectioning, digital imaging, and numerical deconvolution techniques have been utilized. Results demonstrate that within the first minutes of flow application nuclear calcium is increasing. In the same time frame whole cell height and nuclear height are reduced by about 1 microm. Whole cell height changes may facilitate reduction of shear stress gradients on the luminal surface, whereas nuclear structural changes may be important for modulating endothelial growth rate and metabolism. To study the role of the cytoskeleton in these responses, endothelial cells have been treated with specific disrupters (acrylamide, cytochalasin D, and colchicine) of each of the cytoskeleton elements (intermediate filaments, microfilaments, and microtubules, respectively). None of these compounds had any effect on the shear-induced calcium response. Cytochalasin D and acrylamide did not affect the shear-induced nuclear morphology changes. Colchicine, however, completely abrogated the response, indicating that microtubules may be implicated in force transmission from the plasma membrane to the nucleus. A pedagogical model based on tensegrity theory principles is presented that is consistent with the results on the 3D endothelial morphology.

  4. Mineralization and Osteoblast Cells Response of Nanograde Pearl Powders

    Directory of Open Access Journals (Sweden)

    Jian-Chih Chen

    2013-01-01

    Full Text Available The main objective of this study is to characterize the thermal, mineralization, and osteoblast cells response of pearl nanocrystallites. The results obtained from X-ray diffraction, FTIR spectra demonstrate that the pearl nano-crystallites can induce the formation of an HA layer on their surface in SBF, even after only short soaking periods. The in vitro cell response to nano-grade pearl powders is assessed by evaluating the cytotoxicity against a mouse embryonic fibroblast cell line and by characterizing the attachment ability and alkaline phosphatase activity of mouse bone cells (MC3T3-E1, abbreviated to E1 and bone marrow stromal precursor (D1 cells. The cytotoxicities of pearls were tested by the filtration and culture of NIH-3T3 mouse embryonic fibroblast cells. The viability of the cultured cells in media containing pearl crystallites for 24 and 72 h is greater than 90%. The bone cells seen in these micrographs are elongated and align predominately along the pearl specimen. The cells observed in these images also appeared well attached and cover the surface almost completely after 1 h. The pearl nanocrystallites had a positive effect on the osteogenic ability of ALP activity, and this promoted the osteogenic differentiation of MSCs significantly at explanations.

  5. The National Response System: The Need to Leverage Networks and Knowledge

    National Research Council Canada - National Science Library

    Compagnoni, Barry A

    2006-01-01

    .... When viewing our national response from the perspective of network theory and knowledge management, specific gaps are identified in doctrine, organizational composition and technological capability...

  6. Relation between radio-adaptive response and cell to cell communication

    International Nuclear Information System (INIS)

    Keiichiro Ishii

    1996-01-01

    Ionizing radiation has been considered to cause severe damages to DNA and do harm to cells in proportion to the dose, however low it might be. In 1984, Wolff et al. showed that human peripheral lymphocytes adapted to the low-dose radiation from 3 H-TdR added in culture medium and became resistant to the subsequent irradiation with high-doses of X-rays. This response, which is called radio-adaptive response, is also induced by X-rays and gamma-rays in human lymphocytes and Chinese hamster V79 cells. However, the mechanisms of and conditions for adaptive responses to radiation have not been clarified. With an objective of clarifying the conditions for adaptive responses of cells to radiation, we examined how the cell to cell communication is involved in the adaptive responses. We irradiated normal human embryo-derived (HE) cells and cancer cells (HeLa) in culture at high density with low-dose X-ray and examined their radio-adaptive responses by measuring the changes in sensitivity to subsequent high-dose X-ray irradiation using the Trypan Blue dye-exclusion test method. We also conducted experiments to examine the effects of Ca 2+ ions and Phorbol 12-Myristate 13-Acetate (TPA) which are supposed to be involved in cell to cell communication. (author)

  7. Evaluating Stem Cell Response to a Spider Silk Scaffold

    Science.gov (United States)

    Hafner, Katherine Lee

    Micropatterning on a surface using fibers, channels, and troughs, can act as an effective means of inducing cell attachment and alignment. These morphological and pattern changes as a response to physical cues can impact the potential that a cell has to differentiate into a different cell line. This thesis evaluated the response of human dental pulp stem cells (DPSCs), and other cell types, to spider dragline silk fibers, a potential scaffold material for tissue regeneration, and further observed the effects of morphology, orientation, and composition of silk on the adherence of cells. Several cell lines were studied in this thesis, including adipose derived stem cells (ADSCs), osteoblasts (7F2s), and fibroblasts (3T3s), but DPSCs were the main cell type of interest. This is due to the fact that DPSCs are a proposed source of stem cells for nerve regeneration based on their close embryonic origin to neurons and the ease with which DPSCs can be obtained from a donor. The cells' morphologies and spread patterns were characterized after they were plated onto Nephila clavipes dragline fibers in media. The inclusion of 3T3s and 7F2s in this study allowed for both direct comparisons to prior published work and a qualitative comparison to the morphology of the DPSCs. After twelve days, the DPSCs exhibited greater relative alignment and adherence to the spider dragline fibers than the 3T3s and 7F2s when silk was wrapped in an aligned orientation rather than a random orientation. The impact of a common sterilization method (ultraviolet light) on the spider dragline fiber surface and subsequent cell response to this modified surface was also characterized. Exposure of the silk to ultraviolet light did not have a measureable effect on cell alignment, but it did eliminate bacterial growth and changed fiber surface roughness. Spiders' exposure to stressful environments did not have an effect on silk to impair cell alignment or adhesion, and synthetic recombinant protein silk

  8. Advancing induced pluripotent stem cell (iPSC) technology by assessing genetic instability and immune response

    OpenAIRE

    Requena Osete, Jordi

    2017-01-01

    [eng] Induced pluripotent stem cells (iPSC) can be made from adult somatic cells by reprogramming them with Oct4, Sox2, Klf4 and c-Myc. IPSC have given rise to a new technology to study and treat human disease (Takahashi et al., 2007). However, before iPSC clinical application, we need to step back and address two main challenges: (i) Genetic stability of iPSC. (ii) Immune response of iPSC-derived cells. To address these key issues, the overall mission of this PhD thesis is to adva...

  9. Perception of needs and responses in food security: divergence between households and stakeholders.

    Science.gov (United States)

    Hamelin, Anne-Marie; Mercier, Céline; Bédard, Annie

    2008-12-01

    The aim of the study was (i) to describe the needs of food-insecure households and their assessment of community programmes, as expressed by households and perceived by stakeholders; and (ii) to examine the similarities and differences between households' and stakeholders' perceptions in Quebec City area. A semi-structured interview and sociodemographic questionnaire with fifty-five households and fifty-nine stakeholders (community workers, managers, donor agencies). The transcriptions were subjected to content analysis and inter-coder reliability measurement. The respondents' perceptions converge towards three main categories of needs: needs specific to food security, conditions necessary for achieving food security and related needs. There was agreement on the necessity of better financial resources, although the impact of financial resources alone may be uncertain in the opinion of some stakeholders. Different perceptions of needs and of their fulfilment by community programmes emerge between both groups. Despite households found positive aspects, they complained that quality of food and access were major needs neglected. Their account suggests overall a partial fit between the programmes and food security needs; even a combination of programmes (e.g. collective kitchens, purchasing groups, community gardens) was insufficient to adequately meet these needs. In contrast, most stakeholders perceived that the household's primary need was a basic amount of food and that the households were satisfied with programmes. It is urgent to evaluate the overall effect of community programmes on specific aspects of household food insecurity. The results emphasise that community programmes alone cannot bring about social change needed to prevent food insecurity.

  10. Transcriptional regulation during CD8 T-cell immune responses.

    Science.gov (United States)

    Munitic, Ivana; Evaristo, César; Sung, Hsueh Cheng; Rocha, Benedita

    2010-01-01

    Naïve CD8 T cells differentiate in response to antigen stimulation. They acquire the capacity to express multiple effector molecules and mediate effector functions that contribute to infection control. Once antigen loads are reduced they revert progressively to a less activated status and eventually reach a steady-state referred to as "memory" that is very different from that of naive cells. Indeed, these "memory" cells are "ready-to-go" populations that acquired the capacity to respond more efficiently to antigen stimulation. They modify their cell cycle machinery in order to divide faster; they likely improve DNA repair and other cell survival mechanisms in order to survive during division and thus to generate much larger clones of effector cells; finally, they also mediate effector functions much faster. These modifications are the consequence of changes in the expression of multiple genes, i.e., on the utilization of a new transcription program.

  11. Starburst cells nondirectionally facilitate the responses of direction-selective retinal ganglion cells.

    Science.gov (United States)

    Chiao, Chuan-Chin; Masland, Richard H

    2002-12-15

    The mechanism of direction selectivity in retinal ganglion cells remains controversial. An important issue is how the starburst amacrine cells, which are known to provide a major synaptic input to the direction-selective ganglion cells, participate in the directional discrimination. Here, we present evidence that the cholinergic outputs of the starburst cells affect the responses of the ganglion cells symmetrically; they provide a feedforward excitation that facilitates the response of the ganglion cells to movement in both the preferred and null directions. This seems to place a constraint on models of the directional discrimination in which the starburst cells participate, namely, that their cholinergic synapses be nondirectional in their effects on the ganglion cells.

  12. Single-cell bioelectrical impedance platform for monitoring cellular response to drug treatment

    Science.gov (United States)

    Asphahani, Fareid; Wang, Kui; Thein, Myo; Veiseh, Omid; Yung, Sandy; Xu, Jian; Zhang, Miqin

    2011-02-01

    The response of cells to a chemical or biological agent in terms of their impedance changes in real-time is a useful mechanism that can be utilized for a wide variety of biomedical and environmental applications. The use of a single-cell-based analytical platform could be an effective approach to acquiring more sensitive cell impedance measurements, particularly in applications where only diminutive changes in impedance are expected. Here, we report the development of an on-chip cell impedance biosensor with two types of electrodes that host individual cells and cell populations, respectively, to study its efficacy in detecting cellular response. Human glioblastoma (U87MG) cells were patterned on single- and multi-cell electrodes through ligand-mediated natural cell adhesion. We comparatively investigated how these cancer cells on both types of electrodes respond to an ion channel inhibitor, chlorotoxin (CTX), in terms of their shape alternations and impedance changes to exploit the fine detectability of the single-cell-based system. The detecting electrodes hosting single cells exhibited a significant reduction in the real impedance signal, while electrodes hosting confluent monolayer of cells showed little to no impedance change. When single-cell electrodes were treated with CTX of different doses, a dose-dependent impedance change was observed. This enables us to identify the effective dose needed for this particular treatment. Our study demonstrated that this single-cell impedance system may potentially serve as a useful analytical tool for biomedical applications such as environmental toxin detection and drug evaluation.

  13. Bisphosphonates target B cells to enhance humoral immune responses

    Science.gov (United States)

    Tonti, Elena; Jiménez de Oya, Nereida; Galliverti, Gabriele; Moseman, E. Ashley; Di Lucia, Pietro; Amabile, Angelo; Sammicheli, Stefano; De Giovanni, Marco; Sironi, Laura; Chevrier, Nicolas; Sitia, Giovanni; Gennari, Luigi; Guidotti, Luca G.; von Andrian, Ulrich H.; Iannacone, Matteo

    2013-01-01

    Summary Bisphosphonates are a class of drugs that are widely used to inhibit loss of bone mass in patients. We show here that the administration of clinically relevant doses of bisphosphonates in mice increases antibody responses to live and inactive viruses, proteins, haptens and existing commercial vaccine formulations. Bisphosphonates exert this adjuvant-like activity in the absence of CD4+ and γδ T cells, neutrophils or dendritic cells and their effect does not rely on local macrophage depletion nor does it depend upon Toll-like receptor signaling or the inflammasome. Rather, bisphosphonates target directly B cells and enhance B cell expansion and antibody production upon antigen encounter. These data establish bisphosphonates as a novel class of adjuvants that boost humoral immune responses. PMID:24120862

  14. Bisphosphonates Target B Cells to Enhance Humoral Immune Responses

    Directory of Open Access Journals (Sweden)

    Elena Tonti

    2013-10-01

    Full Text Available Bisphosphonates are a class of drugs that are widely used to inhibit loss of bone mass in patients. We show here that the administration of clinically relevant doses of bisphosphonates in mice increases antibody responses to live and inactive viruses, proteins, haptens, and existing commercial vaccine formulations. Bisphosphonates exert this adjuvant-like activity in the absence of CD4+ and γδ T cells, neutrophils, or dendritic cells, and their effect does not rely on local macrophage depletion, Toll-like receptor signaling, or the inflammasome. Rather, bisphosphonates target directly B cells and enhance B cell expansion and antibody production upon antigen encounter. These data establish bisphosphonates as an additional class of adjuvants that boost humoral immune responses.

  15. Macrophages in cardiac homeostasis, injury responses and progenitor cell mobilisation

    Directory of Open Access Journals (Sweden)

    Alexander R. Pinto

    2014-11-01

    Full Text Available Macrophages are an immune cell type found in every organ of the body. Classically, macrophages are recognised as housekeeping cells involved in the detection of foreign antigens and danger signatures, and the clearance of tissue debris. However, macrophages are increasingly recognised as a highly versatile cell type with a diverse range of functions that are important for tissue homeostasis and injury responses. Recent research findings suggest that macrophages contribute to tissue regeneration and may play a role in the activation and mobilisation of stem cells. This review describes recent advances in our understanding of the role played by macrophages in cardiac tissue maintenance and repair following injury. We examine the involvement of exogenous and resident tissue macrophages in cardiac inflammatory responses and their potential activity in regulating cardiac regeneration.

  16. The Inflammation Response to DEHP through PPARγ in Endometrial Cells

    Directory of Open Access Journals (Sweden)

    Qiansheng Huang

    2016-03-01

    Full Text Available Epidemiological studies have shown the possible link between phthalates and endometrium-related gynecological diseases, however the molecular mechanism(s behind this is/are still unclear. In the study, both primary cultured endometrial cells and an endometrial adenocarcinoma cell line (Ishikawa were recruited to investigate the effects of di-(2-ethylhexyl phthalate (DEHP at human-relevant concentrations. The results showed that DEHP did not affect the viability of either type of cell, which showed different responses to inflammation. Primary cultured cells showed stronger inflammatory reactions than the Ishikawa cell line. The expression of inflammatory factors was induced both at the mRNA and protein levels, however the inflammation did not induce the progress of epithelial-mesenchymal transition (EMT as the protein levels of EMT markers were not affected after exposure to either cell type. Further study showed that the mRNA levels of peroxisome proliferator-activated receptor gamma (PPARγ wereup-regulated after exposure. In all, our study showed that human-relevant concentrations of DEHP could elicit the inflammatory response in primary cultured endometrial cells rather than in Ishikawa cell line. PPARγ may act as the mediating receptor in the inflammation reaction.

  17. Corporate philanthropic responses to emergent human needs: the role of organizational attention focus

    NARCIS (Netherlands)

    Muller, A.; Whiteman, G.

    2015-01-01

    Research on corporate philanthropy typically focuses on organization-external pressures and aggregated donation behavior. Hence, our understanding of the organization-internal structures that determine whether a given organization will respond philanthropically to a specific human need remains

  18. Reticence vs. Responsibility: Why Climate Scientists Sometimes Need to Think Like Emergency Room Doctors

    Science.gov (United States)

    Peacock, K.

    2013-12-01

    Hansen (2007), Brysse et al (2012), and Oreskes (2013) have drawn attention to the too-frequent reticence of climate scientists---the unwillingness to err on the side of predicting extreme outcomes or recommend strong action to prevent those outcomes. In Hansen's words, this may hinder 'communication with the public about dangers of global warming' and thereby lessen the chance of effective responses to this urgent threat. Scientists may be reticent about the kinds of extreme outcomes that could occur (ice sheet collapse, oceanic anoxia, killer heat waves, etc.), the probabilities of such outcomes, or the options for preventing or mitigating such outcomes. I will review the reasons, some understandable and some regrettable, for such reticence. (The latter could include the 'seepage' into professional discourse of the often-poisonous atmosphere of climate science denialism; Lewandowsky 2013.) My major aim will be to argue that scientists need a clearly defined ethical framework that coheres with the scientific ethos, and I will suggest that the place to look for such an ethical framework is in the realm of professional ethics. I will review key features of the learned professions such as medicine and engineering, where practitioners (such as emergency room physicians) are necessarily attuned to the imperative of making life-or-death decisions and recommendations in real time, under conditions of uncertainty. I hardly mean to suggest that pure science does not have a professional ethos of its own, but research science as such is not a legally constituted profession (like medicine) and it is focussed on the disinterested search for reliable knowledge above all other goals. Medicine and engineering depend upon and contribute to scientific knowledge but they are aimed at practical ends as well---the welfare of patients or protection of the public as a whole. Also, it is in the nature of engineering and other learned professions that (like pure science) they often

  19. Cell microcarriers and microcapsules of stimuli-responsive polymers.

    Science.gov (United States)

    Brun-Graeppi, Amanda K Andriola Silva; Richard, Cyrille; Bessodes, Michel; Scherman, Daniel; Merten, Otto-Wilhelm

    2011-02-10

    Cell microcarriers and microcapsules have presented a wide range of potential applications. This article overviews their role in biotechnology with focus on the progress accomplished using stimuli-responsive polymers. Key properties of cell microcarriers and microcapsules are identified, followed by a description of the chemistry and gel formation mechanism of some of the stimuli-responsive polymers used to design them. Production methods are introduced and characterization techniques for evaluating such microsystems are equally presented. Copyright © 2010 Elsevier B.V. All rights reserved.

  20. Spectral response of a polycrystalline silicon solar cell

    International Nuclear Information System (INIS)

    Ba, B.; Kane, M.

    1994-10-01

    A theoretical study of the spectral response of a polycrystalline silicon n-p junction solar cell is presented. The case of a fibrously oriented grain structure, involving grain boundary recombination velocity and grain size effects is discussed. The contribution of the base region on the internal quantum efficiency Q int is computed for different grain sizes and grain boundary recombination velocities in order to examine their influence. Suggestions are also made for the determination of base diffusion length in polycrystalline silicon solar cells using the spectral response method. (author). 15 refs, 4 figs

  1. Ionizing radiation response of primary normal human lens epithelial cells.

    Directory of Open Access Journals (Sweden)

    Nobuyuki Hamada

    Full Text Available Whilst the cataractogenic potential of ionizing radiation has been known for over the past 120 years, little is known about radiation responses of lens cells. Our previous work was the first to evaluate the radiosensitivity of lens cells with the clonogenic assay, documenting that the survival of HLEC1 human lens epithelial cells is comparable to that of WI-38 human lung fibroblasts. Moreover, HLEC1 cells were found to contain subsets where irradiation stimulates proliferation or facilitates formation of abortive colonies with fewer cells than human fibroblasts. This study aims to gain insights into these mechanisms. Irradiation of HLEC1 cells with 10% survival dose caused a growth delay but did not reduce viability. HLEC1 cells at high cumulative population doubling level were more susceptible to radiogenic premature senescence than WI-38 cells. Concerning p53 binding protein 1 (53BP1 foci, HLEC1 cells harbored less spontaneous foci but more radiogenic foci than in WI-38 cells, and the focus number returned to spontaneous levels within 48 h postirradiation both in HLEC1 and WI-38. The chemical inhibition of DNA repair kinases ataxia telangiectasia mutated, DNA-dependent protein kinase or both delayed and attenuated the appearance and disappearance of radiogenic 53BP1 foci, increased radiogenic premature senescence and enhanced clonogenic inactivation. The DNA microarray analysis suggested both radiogenic stimulation and inhibition of cell proliferation. Treatment with conditioned medium from irradiated cells did not change growth and the plating efficiency of nonirradiated cells. These results partially explain mechanisms of our previous observations, such that unrepaired or incompletely repaired DNA damage causes a growth delay in a subset of HLEC1 cells without changing viability through induction of premature senescence, thereby leading to clonogenic inactivation, but that growth is stimulated in another subset via as yet unidentified

  2. Sensory Transduction of the CO2 Response of Guard Cells

    Energy Technology Data Exchange (ETDEWEB)

    Dr. Eduardo Zeiger

    2003-06-30

    Stomata have a key role in the regulation of gas exchange and intercellular CO2 concentrations of leaves. Guard cells sense internal and external signals in the leaf environment and transduce these signals into osmoregulatory processes that control stomatal apertures. This research proposal addresses the characterization of the sensory transduction of the CO2 signal in guard cells. Recent studies have shown that in Vicia leaves kept at constant light and temperature in a growth chamber, changes in ambient CO2 concentrations cause large changes in guard cell zeaxanthin that are linear with CO2-dependent changes in stomatal apertures. Research proposed here will test the hypothesis that zeaxanthin function as a transducer of CO2 signals in guard cells. Three central aspects of this hypothesis will be investigated: CO2 sensing by the carboxylation reaction of Rubisco in the guard cell chloroplast, which would modulate zeaxanthin concentrations via changes in lumen pH; transduction of the CO2 signal by zeaxanthin via a transducing cascade that controls guard cell osmoregulation; and blue light dependence of the CO2 signal transduction by zeaxanthin, required for the formation of an isomeric form of zeaxanthin that is physiologically active as a transducer. The role of Rubisco in CO2 sensing will be investigated in experiments characterizing the stomatal response to CO2 in the Arabidopsis mutants R100 and rca-, which have reduced rates of Rubisco-dependent carboxylation. The role of zeaxanthin as a CO2 transducer will be studied in npq1, a zeaxanthin-less mutant. The blue light-dependence of CO2 sensing will be studied in experiments characterizing the stomatal response to CO2 under red light. Arabidopsis mutants will also be used in further studies of an acclimation of the stomatal response to CO2, and a possible role of the xanthophyll cycle of the guard cell chloroplast in acclimations of the stomatal response to CO2. Studies on the osmoregulatory role of sucrose in

  3. ERK2 Mediates Metabolic Stress Response to Regulate Cell Fate.

    Science.gov (United States)

    Shin, Sejeong; Buel, Gwen R; Wolgamott, Laura; Plas, David R; Asara, John M; Blenis, John; Yoon, Sang-Oh

    2015-08-06

    Insufficient nutrients disrupt physiological homeostasis, resulting in diseases and even death. Considering the physiological and pathological consequences of this metabolic stress, the adaptive responses that cells utilize under this condition are of great interest. We show that under low-glucose conditions, cells initiate adaptation followed by apoptosis responses using PERK/Akt and MEK1/ERK2 signaling, respectively. For adaptation, cells engage the ER stress-induced unfolded protein response, which results in PERK/Akt activation and cell survival. Sustained and extreme energetic stress promotes a switch to isoform-specific MEK1/ERK2 signaling, induction of GCN2/eIF2α phosphorylation, and ATF4 expression, which overrides PERK/Akt-mediated adaptation and induces apoptosis through ATF4-dependent expression of pro-apoptotic factors including Bid and Trb3. ERK2 activation during metabolic stress contributes to changes in TCA cycle and amino acid metabolism, and cell death, which is suppressed by glutamate and α-ketoglutarate supplementation. Taken together, our results reveal promising targets to protect cells or tissues from metabolic stress. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. Inter-donor variation in cell subset specific immune signaling responses in healthy individuals.

    Science.gov (United States)

    Longo, Diane M; Louie, Brent; Wang, Ena; Pos, Zoltan; Marincola, Francesco M; Hawtin, Rachael E; Cesano, Alessandra

    2012-01-01

    Single cell network profiling (SCNP) is a multi-parameter flow cytometry based approach that allows for the simultaneous interrogation of intracellular signaling pathways in multiple cell subpopulations within heterogeneous tissues, without the need for individual cell subset isolation. Thus, the technology is extremely well-suited for characterizing the multitude of interconnected signaling pathways and immune cell subpopulations that regulate the function of the immune system. Recently, SCNP was applied to generate a functional map of the healthy human immune cell signaling network by profiling immune signaling pathways downstream of 12 immunomodulators in 7 distinct immune cell subsets within peripheral blood mononuclear cells (PBMCs) from 60 healthy donors. In the study reported here, the degree of inter-donor variation in the magnitude of the immune signaling responses was analyzed. The highest inter-donor differences in immune signaling pathway activity occurred following perturbation of the immune signaling network, rather than in basal signaling. When examining the full panel of immune signaling responses, as one may expect, the overall degree of inter-donor variation was positively correlated (r = 0.727) with the magnitude of node response (i.e. a larger median signaling response was associated with greater inter-donor variation). However, when examining the degree of heterogeneity across cell subpopulations for individual signaling nodes, cell subset specificity in the degree of inter-donor variation was observed for several nodes. For such nodes, relatively weak correlations between inter-donor variation and the magnitude of the response were observed. Further, within the phenotypically distinct subpopulations, a fraction of the immune signaling responses had bimodal response profiles in which (a) only a portion of the cells had elevated phospho-protein levels following modulation and (b) the proportion of responsive cells varied by donor. These data

  5. The response of human and rodent cells to hyperthermia

    International Nuclear Information System (INIS)

    Roizin-Towle, L.; Pirro, J.P.

    1991-01-01

    Inherent cellular radiosensitivity in vitro has been shown to be a good predictor of human tumor response in vivo. In contrast, the importance of the intrinsic thermosensitivity of normal and neoplastic human cells as a factor in the responsiveness of human tumors to adjuvant hyperthermia has never been analyzed systematically. A comparison of thermal sensitivity and thermo-radiosensitization in four rodent and eight human-derived cell lines was made in vitro. Arrhenius plots indicated that the rodent cells were more sensitive to heat killing than the human, and the break-point was 0.5 degrees C higher for the human than rodent cells. The relationship between thermal sensitivity and the interaction of heat with X rays at low doses was documented by thermal enhancement ratios (TER's). Cells received either a 1 hr exposure to 43 degrees C or a 20 minute treatment at 45 degrees C before exposure to 300 kVp X rays. Thermal enhancement ratios ranged from 1.0 to 2.7 for human cells heated at 43 degrees C and from 2.1 to 5.3 for heat exposures at 45 degrees C. Thermal enhancement ratios for rodent cells were generally 2 to 3 times higher than for human cells, because of the fact that the greater thermosensitivity of rodent cells results in a greater enhancement of radiation damage. Intrinsic thermosensitivity of human cells has relevance to the concept of thermal dose; intrinsic thermo-radiosensitization of a range of different tumor cells is useful in documenting the interactive effects of radiation combined with heat

  6. Educational needs concerning disaster preparedness and response: a comparison of undergraduate nursing students from Istanbul, Turkey, and Miyazaki, Japan.

    Science.gov (United States)

    Oztekın, Seher Deniz; Larson, Eric Edwin; Altun Uğraş, Gülay; Yüksel, Serpil

    2014-04-01

    To compare 4 year undergraduate nursing students' educational needs concerning disaster preparedness and response in Istanbul and Miyazaki. This was a 13 question descriptive/comparative survey. Females, aged 18-22 years, and in their second year of their nursing programs, rarely participate in disaster preparedness and response courses at their universities (75.2%) or outside (89.8%). Educational needs of Miyazaki's students who had already participated in these courses (85%) were higher than in Istanbul's (67.2%). Of those whose educational needs had not been met, 55.9% were considering taking another lecture/course in one of the following years (Istanbul, 47.4%; Miyazaki, 71.4%). The majority of students from Istanbul reported some knowledge about disaster preparedness and response from courses at their universities while Miyazaki's students showed less. Effective teaching methods/resources were mock drills. Nursing interventions in disaster situations in "response competencies" were preferred issues to be included in course content (Istanbul, 90.4%; Miyazaki, 93.1%). Most student nurses had no expectations on skills that could be gained from a disaster preparedness and response course/culture of disaster lecture (Istanbul, 48.7%; Miyazaki, 34.5%). Nursing students in both cities seem more likely to participate in disaster preparedness and response courses/lectures. The present study also addresses the need to incorporate mass casualty care and disaster management skills into undergraduate curricula. Core contents for nursing curricula in both cities need to be continued. Outcome competencies must be identified and validated through further research. © 2013 The Authors. Japan Journal of Nursing Science © 2013 Japan Academy of Nursing Science.

  7. T cell regulation of the thymus-independent antibody response to trinitrophenylated-Brucella abortus (TNP-BA)

    Energy Technology Data Exchange (ETDEWEB)

    Tanay, A.; Strober, S.

    1985-06-01

    The authors have previously observed a reduction of the T cell-dependent primary antibody response to dinitrophenylated keyhole limpet hemocyanin, and an enhancement of the T cell-independent response to trinitrophenylated Brucella abortus (TNP-BA) in BALB/c mice after treatment with total lymphoid irradiation (TLI). To elucidate the relative contribution of T and B cells to the enhanced T cell-independent antibody responses after TLI, a syngeneic primary adoptive transfer system was utilized whereby irradiated hosts were reconstituted with unfractionated spleen cells or a combination of purified T and B cells from TLI-treated and untreated control mice. Antibody responses of purified splenic B cells from TLI-treated BALB/c mice (TLI/B) to TNP-BA were enhanced 10-fold as compared with those of unfractionated (UF) spleen cells or B cells from normal (NL) BALB/c mice (NL/UF and NL/B, respectively). Splenic T cells from normal animals (NL/T) suppressed the anti-TNP-BA response of TLI/B by more than 100-fold. NL/T neither suppressed nor enhanced the response of NL/B. On the other hand, T cells from TLI-treated mice (TLI/T) enhanced by 100-fold the anti-TNP-BA response of NL/B, but neither suppressed nor enhanced the response of TLI/B. Thus, T cells can regulate the T cell-independent antibody response to TNP-BA. However, experimental manipulation of the T and B cell populations is needed to demonstrate the regulatory functions.

  8. B cell activating factor (BAFF) selects IL-10-B cells over IL-10+B cells during inflammatory responses.

    Science.gov (United States)

    Ma, Ning; Zhang, Yu; Liu, Qilin; Wang, Zhiding; Liu, Xiaoling; Zhu, Gaizhi; Yu, Dandan; Han, Gencheng; Chen, Guojiang; Hou, Chunmei; Wang, Tianxiao; Ma, Yuanfang; Shen, Beifen; Li, Yan; Xiao, He; Wang, Renxi

    2017-05-01

    B cell activating factor (BAFF) regulates B cell maturation, survival, function, and plays a critical pathogenic role in autoimmune diseases. It remains unclear how BAFF affects IL-10 - B cells versus regulatory B cells (Bregs) in inflammatory responses. In this study, we found that IL-10-expressing Bregs decreased in lupus-prone MRL/lpr mice and experimental allergic encephalomyelitis (EAE) mice. On blockade of the effects of BAFF with TACI-IgG, IL-10 + Bregs were upregulated in MRL/lpr and EAE mice. In addition, BAFF expanded IL-10 + B cells over IL-10 - B cells under noninflammatory conditions in vitro, whereas it expanded IL-10 - B cells over IL-10 + B cells during inflammatory responses, such as stimulation with autoantigen and LPS. Finally, the selection of IL-10 - B cells over IL-10 + B cells by BAFF was dependent on BAFF receptors (BAFFR, TACI, and BCMA) that were upregulated by inflammatory responses. This study suggests that BAFF selects IL-10 - B cells over IL-10 + regulatory B cells via BAFF receptors in inflammatory responses. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. An Arabidopsis kinase cascade influences auxin-responsive cell expansion.

    Science.gov (United States)

    Enders, Tara A; Frick, Elizabeth M; Strader, Lucia C

    2017-10-01

    Mitogen-activated protein kinase (MPK) cascades are conserved mechanisms of signal transduction across eukaryotes. Despite the importance of MPK proteins in signaling events, specific roles for many Arabidopsis MPK proteins remain unknown. Multiple studies have suggested roles for MPK signaling in a variety of auxin-related processes. To identify MPK proteins with roles in auxin response, we screened mpk insertional alleles and identified mpk1-1 as a mutant that displays hypersensitivity in auxin-responsive cell expansion assays. Further, mutants defective in the upstream MAP kinase kinase MKK3 also display hypersensitivity in auxin-responsive cell expansion assays, suggesting that this MPK cascade affects auxin-influenced cell expansion. We found that MPK1 interacts with and phosphorylates ROP BINDING PROTEIN KINASE 1 (RBK1), a protein kinase that interacts with members of the Rho-like GTPases from Plants (ROP) small GTPase family. Similar to mpk1-1 and mkk3-1 mutants, rbk1 insertional mutants display auxin hypersensitivity, consistent with a possible role for RBK1 downstream of MPK1 in influencing auxin-responsive cell expansion. We found that RBK1 directly phosphorylates ROP4 and ROP6, supporting the possibility that RBK1 effects on auxin-responsive cell expansion are mediated through phosphorylation-dependent modulation of ROP activity. Our data suggest a MKK3 • MPK1 • RBK1 phosphorylation cascade that may provide a dynamic module for altering cell expansion. © 2017 The Authors The Plant Journal © 2017 John Wiley & Sons Ltd.

  10. Semiallogenic fusions of MSI+ tumor cells and activated B cells induce MSI-specific T cell responses

    Directory of Open Access Journals (Sweden)

    Klier Ulrike

    2011-09-01

    Full Text Available Abstract Background Various strategies have been developed to transfer tumor-specific antigens into antigen presenting cells in order to induce cytotoxic T cell responses against tumor cells. One approach uses cellular vaccines based on fusions of autologous antigen presenting cells and allogeneic tumor cells. The fusion cells combine antigenicity of the tumor cell with optimal immunostimulatory capacity of the antigen presenting cells. Microsatellite instability caused by mutational inactivation of DNA mismatch repair genes results in translational frameshifts when affecting coding regions. It has been shown by us and others that these mutant proteins lead to the presentation of immunogenic frameshift peptides that are - in principle - recognized by a multiplicity of effector T cells. Methods We chose microsatellite instability-induced frameshift antigens as ideal to test for induction of tumor specific T cell responses by semiallogenic fusions of microsatellite instable carcinoma cells with CD40-activated B cells. Two fusion clones of HCT116 with activated B cells were selected for stimulation of T cells autologous to the B cell fusion partner. Outgrowing T cells were phenotyped and tested in functional assays. Results The fusion clones expressed frameshift antigens as well as high amounts of MHC and costimulatory molecules. Autologous T cells stimulated with these fusions were predominantly CD4+, activated, and reacted specifically against the fusion clones and also against the tumor cell fusion partner. Interestingly, a response toward 6 frameshift-derived peptides (of 14 tested could be observed. Conclusion Cellular fusions of MSI+ carcinoma cells and activated B cells combine the antigen-presenting capacity of the B cell with the antigenic repertoire of the carcinoma cell. They present frameshift-derived peptides and can induce specific and fully functional T cells recognizing not only fusion cells but also the carcinoma cells. These

  11. Semiallogenic fusions of MSI+ tumor cells and activated B cells induce MSI-specific T cell responses

    International Nuclear Information System (INIS)

    Garbe, Yvette; Klier, Ulrike; Linnebacher, Michael

    2011-01-01

    Various strategies have been developed to transfer tumor-specific antigens into antigen presenting cells in order to induce cytotoxic T cell responses against tumor cells. One approach uses cellular vaccines based on fusions of autologous antigen presenting cells and allogeneic tumor cells. The fusion cells combine antigenicity of the tumor cell with optimal immunostimulatory capacity of the antigen presenting cells. Microsatellite instability caused by mutational inactivation of DNA mismatch repair genes results in translational frameshifts when affecting coding regions. It has been shown by us and others that these mutant proteins lead to the presentation of immunogenic frameshift peptides that are - in principle - recognized by a multiplicity of effector T cells. We chose microsatellite instability-induced frameshift antigens as ideal to test for induction of tumor specific T cell responses by semiallogenic fusions of microsatellite instable carcinoma cells with CD40-activated B cells. Two fusion clones of HCT116 with activated B cells were selected for stimulation of T cells autologous to the B cell fusion partner. Outgrowing T cells were phenotyped and tested in functional assays. The fusion clones expressed frameshift antigens as well as high amounts of MHC and costimulatory molecules. Autologous T cells stimulated with these fusions were predominantly CD4 + , activated, and reacted specifically against the fusion clones and also against the tumor cell fusion partner. Interestingly, a response toward 6 frameshift-derived peptides (of 14 tested) could be observed. Cellular fusions of MSI + carcinoma cells and activated B cells combine the antigen-presenting capacity of the B cell with the antigenic repertoire of the carcinoma cell. They present frameshift-derived peptides and can induce specific and fully functional T cells recognizing not only fusion cells but also the carcinoma cells. These hybrid cells may have great potential for cellular immunotherapy and

  12. Inferring Toxicological Responses of HepG2 Cells from ...

    Science.gov (United States)

    Understanding the dynamic perturbation of cell states by chemicals can aid in for predicting their adverse effects. High-content imaging (HCI) was used to measure the state of HepG2 cells over three time points (1, 24, and 72 h) in response to 976 ToxCast chemicals for 10 different concentrations (0.39-200µM). Cell state was characterized by p53 activation (p53), c-Jun activation (SK), phospho-Histone H2A.x (OS), phospho-Histone H3 (MA), alpha tubulin (Mt), mitochondrial membrane potential (MMP), mitochondrial mass (MM), cell cycle arrest (CCA), nuclear size (NS) and cell number (CN). Dynamic cell state perturbations due to each chemical concentration were utilized to infer coarse-grained dependencies between cellular functions as Boolean networks (BNs). BNs were inferred from data in two steps. First, the data for each state variable were discretized into changed/active (> 1 standard deviation), and unchanged/inactive values. Second, the discretized data were used to learn Boolean relationships between variables. In our case, a BN is a wiring diagram between nodes that represent 10 previously described observable phenotypes. Functional relationships between nodes were represented as Boolean functions. We found that inferred BN show that HepG2 cell response is chemical and concentration specific. We observed presence of both point and cycle BN attractors. In addition, there are instances where Boolean functions were not found. We believe that this may be either

  13. Lysophosphatidic acid mediates pleiotropic responses in skeletal muscle cells

    International Nuclear Information System (INIS)

    Jean-Baptiste, Gael; Yang Zhao; Khoury, Chamel; Greenwood, Michael T.

    2005-01-01

    Lysophosphatidic acid (LPA) is a potent modulator of growth, cell survival, and apoptosis. Although all four LPA receptors are expressed in skeletal muscle, very little is known regarding the role they play in this tissue. We used RT-PCR to demonstrate that cultured skeletal muscle C2C12 cells endogenously express multiple LPA receptor subtypes. The demonstration that LPA mediates the activation of ERK1/2 MAP kinase and Akt/PKB in C2C12 cells is consistent with the widely observed mitogenic properties of LPA. In spite of these observations, LPA did not induce proliferation in C2C12 cells. Paradoxically, we found that prolonged treatment of C2C12 cells with LPA led to caspase 3 and PARP cleavage as well as the activation of stress-associated MAP kinases JNK and p38. In spite of these typically pro-apoptotic responses, LPA did not induce cell death. Blocking ERK1/2 and Akt/PKB activation with specific pharmacological inhibitors, nevertheless, stimulated LPA-mediated apoptosis. Taken together, these results suggest that both mitogenic and apoptotic responses serve to counterbalance the effects of LPA in cultured C2C12 cells

  14. T cell Bim levels reflect responses to anti–PD-1 cancer therapy

    Science.gov (United States)

    Dronca, Roxana S.; Liu, Xin; Harrington, Susan M.; Chen, Lingling; Cao, Siyu; Kottschade, Lisa A.; McWilliams, Robert R.; Block, Matthew S.; Nevala, Wendy K.; Thompson, Michael A.; Mansfield, Aaron S.; Park, Sean S.; Markovic, Svetomir N.

    2016-01-01

    Immune checkpoint therapy with PD-1 blockade has emerged as an effective therapy for many advanced cancers; however, only a small fraction of patients achieve durable responses. To date, there is no validated blood-based means of predicting the response to PD-1 blockade. We report that Bim is a downstream signaling molecule of the PD-1 pathway, and its detection in T cells is significantly associated with expression of PD-1 and effector T cell markers. High levels of Bim in circulating tumor-reactive (PD-1+CD11ahiCD8+) T cells were prognostic of poor survival in patients with metastatic melanoma who did not receive anti–PD-1 therapy and were also predictive of clinical benefit in patients with metastatic melanoma who were treated with anti–PD-1 therapy. Moreover, this circulating tumor-reactive T cell population significantly decreased after successful anti–PD-1 therapy. Our study supports a crucial role of Bim in both T cell activation and apoptosis as regulated by PD-1 and PD-L1 interactions in effector CD8+ T cells. Measurement of Bim levels in circulating T cells of patients with cancer may provide a less invasive strategy to predict and monitor responses to anti–PD-1 therapy, although future prospective analyses are needed to validate its utility. PMID:27182556

  15. Limits of ?Skills And Drills? Interventions to Improving Obstetric and Newborn Emergency Response: What More Do We Need to Learn?

    OpenAIRE

    Ricca, Jim

    2016-01-01

    A ?skills and drills? intervention in 4 hospitals in Karnataka, India, produced modest improvement in provider knowledge and skills but not in actual response to obstetric and newborn emergencies. We explore possible explanations, which include (1) the need for a more intensive intervention; (2) other weaknesses in the health system; and (3) behavioral or organizational barriers related to hierarchical structures, roles, and team formation.

  16. Interstitial cells of Cajal mediate mechanosensitive responses in the stomach

    Science.gov (United States)

    Won, Kyung-Jong; Sanders, Kenton M.; Ward, Sean M.

    2005-10-01

    Changes in motor activity are a basic response to filling of smooth muscle organs. Responses to gastric filling, for example, are thought to be regulated by neural reflexes. Here, we demonstrate a previously uncharacterized aspect of stretch-dependent responses in visceral smooth muscles that is mediated by mechanosensitive interstitial cells of Cajal. Length ramps were applied to the murine antral muscles while recording intracellular electrical activity and isometric force. Stretching muscles by an average of 27 ± 1% of resting length resulted in 5 mN of force. Increasing length caused membrane depolarization and increased slow-wave frequency. The responses were dependent on the rate of stretch. Stretch-dependent responses were not inhibited by neuronal antagonists or nifedipine. Increases in slow-wave frequency, but not membrane depolarization, were inhibited by reducing external Ca2+ (100 μM) and by Ni2+ (250 μM). Responses to stretch were inhibited by indomethacin (1 μM) and were absent in cyclooxygenase II-deficient mice, suggesting that cyclooxygenase II-derived eicosanoids may mediate these responses. Dual microelectrode impalements of muscle cells within the corpus and antrum showed that stretch-induced changes in slow-wave frequency uncoupled proximal-to-distal propagation of slow waves. This uncoupling could interfere with gastric peristalsis and impede gastric emptying. Stretch of antral muscles of W/WV mice, which lack intramuscular interstitial cells of Cajal, did not affect membrane depolarization or slow-wave frequency. These data demonstrate a previously uncharacterized nonneural stretch reflex in gastric muscles and provide physiological evidence demonstrating a mechanosensitive role for interstitial cells of Cajal in smooth muscle tissues. gastric compliance | pacemaker | stretch | slow waves | propagation

  17. The Response of Higher Education Institutions in Namibia to the Needs of Students with Disabilities

    Science.gov (United States)

    Hugo, A. J.

    2012-01-01

    This article reports on research that was done about the way in which institutions of higher education in Namibia respond to the needs of students with disabilities. Five categories emanated from the data, namely prevalence of disability; management of disability-related data by institutions of higher education; modes of identification and…

  18. Homeless and Disabled: Rights, Responsibilities, and Recommendations for Serving Young Children with Special Needs

    Science.gov (United States)

    Gargiulo, Richard M.

    2006-01-01

    Homelessness is a growing social problem in the United States. Especially vulnerable to this phenomenon are young children because homelessness is viewed as a breeding ground for disabilities. Despite federal legislation ensuring educational opportunities, the educational needs of children who are homeless are frequently unfulfilled. This article…

  19. Is Singapore's School Geography Becoming Too Responsive to the Changing Needs of Society?

    Science.gov (United States)

    Chang, Chew-Hung

    2014-01-01

    In understanding the divergences and commonalities in the representations of geography across different national settings, the case of Singapore is examined through the notion of politicisation of school curricula to meet the needs of "significant power groups". In particular, the development of school geography in Singapore and its…

  20. Responses to Information Systems Graduate Preparation and Job Needs: Implications for Higher Education

    Science.gov (United States)

    Simon, DeShea; Jackson, Kanata

    2015-01-01

    This study examined the perspectives on academic preparation and job skill needs of Information Systems program graduates from an Eastern state in the US. A historical review of the literature surrounding information systems skill requirements was conducted for this study, to provide an understanding of the changes in information systems over the…

  1. CD4 + CELL RESPONSE TO ANTI-RETROVIRAL THERAPY (ARTs ...

    African Journals Online (AJOL)

    East African Medical Journal Vol. 90 No. 12 (Supplement) December 2013. CD4 + CELL RESPONSE TO ANTI-RETROVIRAL THERAPY (ARTs) IN ROUTINE CLINICAL CARE OVER ONE YEAR. PERIOD IN A COHORT OF HAART NAIVE, HIV POSITIVE KENYAN PATIENTS. C. F. Otieno, MBChB, MMed (Int. Med), ...

  2. The Role of the Immune Response in Merkel Cell Carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Triozzi, Pierre L., E-mail: triozzp@ccf.org [Taussig Cancer Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195 (United States); Fernandez, Anthony P. [Departments of Dermatology and Anatomic Pathology, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195 (United States)

    2013-02-28

    Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer. The Merkel cell polyomavirus (MCPyV) is implicated in its pathogenesis. Immune mechanisms are also implicated. Patients who are immunosuppressed have an increased risk. There is evidence that high intratumoral T-cell counts and immune transcripts are associated with favorable survival. Spontaneous regressions implicate immune effector mechanisms. Immunogenicity is also supported by observation of autoimmune paraneoplastic syndromes. Case reports suggest that immune modulation, including reduction of immune suppression, can result in tumor regression. The relationships between MCPyV infection, the immune response, and clinical outcome, however, remain poorly understood. Circulating antibodies against MCPyV antigens are present in most individuals. MCPyV-reactive T cells have been detected in both MCC patients and control subjects. High intratumoral T-cell counts are also associated with favorable survival in MCPyV-negative MCC. That the immune system plays a central role in preventing and controlling MCC is supported by several observations. MCCs often develop, however, despite the presence of humoral and cellular immune responses. A better understanding on how MCPyV and MCC evade the immune response will be necessary to develop effective immunotherapies.

  3. The Role of the Immune Response in Merkel Cell Carcinoma

    International Nuclear Information System (INIS)

    Triozzi, Pierre L.; Fernandez, Anthony P.

    2013-01-01

    Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer. The Merkel cell polyomavirus (MCPyV) is implicated in its pathogenesis. Immune mechanisms are also implicated. Patients who are immunosuppressed have an increased risk. There is evidence that high intratumoral T-cell counts and immune transcripts are associated with favorable survival. Spontaneous regressions implicate immune effector mechanisms. Immunogenicity is also supported by observation of autoimmune paraneoplastic syndromes. Case reports suggest that immune modulation, including reduction of immune suppression, can result in tumor regression. The relationships between MCPyV infection, the immune response, and clinical outcome, however, remain poorly understood. Circulating antibodies against MCPyV antigens are present in most individuals. MCPyV-reactive T cells have been detected in both MCC patients and control subjects. High intratumoral T-cell counts are also associated with favorable survival in MCPyV-negative MCC. That the immune system plays a central role in preventing and controlling MCC is supported by several observations. MCCs often develop, however, despite the presence of humoral and cellular immune responses. A better understanding on how MCPyV and MCC evade the immune response will be necessary to develop effective immunotherapies

  4. Sovereign wealth fund investments and the need to undertake socially responsible investment

    OpenAIRE

    Yin, Wei

    2017-01-01

    There is an increasing consensus that, beyond financial returns, investors should also consider the environmental and social impacts of their business activities. Major institutional investors currently are entering the realm of socially responsible investment (SRI), which incorporates environmental, social, and governance (ESG) factors into decision-making based on internationally recognized standards and principles. As influential institutional investors, sovereign wealth funds ...

  5. Special Education Administrators' Response to the Educational Needs of Foster Care Youth: Collaborative or Disjointed?

    Science.gov (United States)

    Palladino, John; Haar, Jean

    2011-01-01

    Although the literature discusses the deleterious educational outcomes that foster care students endure, little attention has focused on school personnel's responses to the phenomenon. Despite the documented relationship between foster care and special education, a missing contribution is the voice of special education administrators. In turn, the…

  6. Management Improvements Needed in Commander’s Emergency Response Program in Afghanistan

    Science.gov (United States)

    2011-11-21

    SIGIR Report No. SIGIR-09-026, “Commander’s Emergency Response Program: Hotel Construction Completed, But Project Management Issues Remain,” July 26...stations, bus stations, and seaports ). The operations deal with the control of the system, such as traffic signals and ramp meters, railroad switches, air

  7. Response to the health and nutrition needs of people affected by ...

    African Journals Online (AJOL)

    ... leaders were done to assess the health and nutrition related responses of the different stakeholders. Results: Disaster Preparedness and Prevention Commissions (DPPC) at district level did not have documented contingency planning, vulnerability assessment and risk mapping and zoning related to drought emergency.

  8. Molecular mechanisms of radioadaptive responses in human lymphoblastoid cells

    International Nuclear Information System (INIS)

    Kakimoto, Ayana; Taki, Keiko; Nakajima, Tetsuo

    2008-01-01

    Radioadaptive response is a biodefensive response observed in a variety of mammalian cells and animals where exposure to low dose radiation induces resistance against the subsequent high dose radiation. Elucidation of its mechanisms is important for risk estimation of low dose radiation because the radioadaptive response implies that low dose radiation affects cells/individuals in a different manner from high dose radiation. In the present study, we explored the molecular mechanisms of the radioadaptive response in human lymphoblastoid cells AHH-1 in terms of mutation at the hypoxanthine phosphoribosyltransferase (HPRT) gene locus. First we observed that preexposure to the priming dose in the range from 0.02 Gy to 0.2 Gy significantly reduced mutation frequency at HPRT gene locus after irradiation with 3 Gy of X rays. As no significant adaptive response was observed with the priming dose of 0.005 Gy, it was indicated that the lower limit of the priming dose to induce radioadaptive response may be between 0.005 Gy and 0.02 Gy. Second, we examined the effect of 3-amino-benzamide (3AB), an inhibitor of poly(ADP-ribose)polymerase1, which has been reported to inhibit the radioadaptive response in terms of chromosome aberration. However we could observe significant radioadaptive responses in terms of mutation even in the presence of 3AB. These findings suggested that molecular mechanisms of the radioadaptive response in terms of mutation may be different from that for radioadaptive responses in terms of chromosomal aberration, although we could not exclude a possibility that the differential effects of 3AB was due to cell type difference. Finally, by performing a comprehensive analysis of alterations in gene expression using high coverage expression profiling (HiCEP), we could identify 17 genes whose expressions were significantly altered 6 h after irradiation with 0.02 Gy. We also found 17 and 20 genes, the expressions of which were different with or without priming

  9. Antibody B cell responses in HIV-1 infection.

    Science.gov (United States)

    Mouquet, Hugo

    2014-11-01

    In rare cases, B cells can supply HIV-1-infected individuals with unconventional antibodies equipped to neutralize the wide diversity of viral variants. Innovations in single-cell cloning, high-throughput sequencing, and structural biology methods have enabled the capture and thorough characterization of these exceptionally potent broadly neutralizing antibodies (bNAbs). Here, I review the recent findings in humoral responses to HIV-1, focusing on the interplay between naturally occurring bNAbs and the virus both at systemic and mucosal levels. In this context, I discuss how an improved understanding of bNAb generation may provide invaluable insight into the fundamental mechanisms governing adaptive B cell responses to viruses, and how this knowledge is currently contributing to the development of vaccine and therapeutic strategies against HIV-1. Copyright © 2014 Elsevier Ltd. All rights reserved.

  10. Narrative Based Medicine as a tool for needs assessment of patients undergoing hematopoietic stem cell transplantation.

    Science.gov (United States)

    Gargiulo, Gianpaolo; Sansone, Vincenza; Rea, Teresa; Artioli, Giovanna; Botti, Stefano; Continisio, Grazia Isabella; Ferri, Paola; Masi, Daniela; Risitano, Antonio Maria; Simeone, Silvio; La Sala, Rachele

    2017-03-14

    In the last years we have seen an ever increasing number of patients with haematologic disorders who need hematopoietic stem cell transplantation (HSCT). The whole sector of HSCT results, infact to be in a continous scientific and technological clinical progress, offering a very advanced care. Despite this, some aspects are underconsidered, some of which could be fundamental to determine the success of the care pathway, such as the experience of the illness by the patient. Using a Narrative Based Medicine approach we wanted to investigate clinical, psychosocial and organizational aspects of the patient's journey whilst undergoing HSCT. Various narrative interviews were conducted using non-structured approach. Results were analysed by thematic contents. Psycological dimension is the most compromised: above all emerged sentiments of oppression linked to the isolation period in the Low Bacterial Load (LBL) room. To note are also the different dynamics with which the patients perceive the organisation and hospital structures, and how much these factors can influence their care experience. Results suggest the need in clinical practice of an integration between qualitative and clinical approach, so as to permit the psychosocial and relational necessities to emerge, often unexpressed by patients undergoing HSCT.

  11. Deletion of BCG Hip1 protease enhances dendritic cell and CD4 T cell responses.

    Science.gov (United States)

    Bizzell, Erica; Sia, Jonathan Kevin; Quezada, Melanie; Enriquez, Ana; Georgieva, Maria; Rengarajan, Jyothi

    2017-12-28

    Dendritic cells (DCs) play a key role in the generation of CD4 T cell responses to pathogens. Mycobacterium tuberculosis (Mtb) harbors immune evasion mechanisms that impair DC responses and prevent optimal CD4 T cell immunity. The vaccine strain Mycobacterium bovis Bacille Calmette-Guérin (BCG) shares many of the immune evasion proteins utilized by Mtb, but the role of these proteins in DC and T cell responses elicited by BCG is poorly understood. We previously reported that the Mtb serine protease, Hip1, promotes sub-optimal DC responses during infection. Here, we tested the hypothesis that BCG Hip1 modulates DC functions and prevents optimal antigen-specific CD4 T cell responses that limit the immunogenicity of BCG. We generated a strain of BCG lacking hip1 (BCGΔhip1) and show that it has superior capacity to induce DC maturation and cytokine production compared with the parental BCG. Furthermore, BCGΔhip1-infected DCs were more effective at driving the production of IFN-γ and IL-17 from antigen-specific CD4 T cells in vitro. Mucosal transfer of BCGΔhip1-infected DCs into mouse lungs induced robust CD4 T cell activation in vivo and generated antigen-specific polyfunctional CD4 T cell responses in the lungs. Importantly, BCGΔhip1-infected DCs enhanced control of pulmonary bacterial burden following Mtb aerosol challenge compared with the transfer of BCG-infected DCs. These results reveal that BCG employs Hip1 to impair DC activation, leading to attenuated lung CD4 T cell responses with limited capacity to control Mtb burden after challenge. ©2017 Society for Leukocyte Biology.

  12. Responses to recipient and donor B cells by genetically donor T cells from human haploidentical chimeras

    International Nuclear Information System (INIS)

    Schiff, S.; Sampson, H.; Buckley, R.

    1986-01-01

    Following administration of haploidentical stem cells to infants with severe combined immunodeficiency (SCID), mature T cells of donor karyotype appear later in the recipient without causing graft-versus-host disease. To investigate the effect of the host environment on the responsiveness of these genetically donor T cells, blood B and T lymphocytes from 6 SCID recipients, their parental donors and unrelated controls were purified by double SRBC rosetting. T cells were stimulated by irradiated B cells at a 1:1 ratio in 6 day cultures. Engrafted T cells of donor karyotype gave much smaller responses to irradiated genetically recipient B cells than did fresh donor T cells. Moreover, engrafted T cells of donor karyotype from two of the three SCIDs who are longest post-transplantation responded more vigorously (14,685 and 31,623 cpm) than fresh donor T cells (5141 and 22,709 cpm) to donor B cells. These data indicate that T lymphocytes which have matured from donor stem cells in the recipient microenvironment behave differently from those that have matured in the donor

  13. Human dental pulp cells exhibit bone cell-like responsiveness to fluid shear stress

    NARCIS (Netherlands)

    Kraft, D.C.E.; Bindslev, D.A.; Melsen, B.; Klein-Nulend, J.

    2011-01-01

    Background aims. For engineering bone tissue to restore, for example, maxillofacial defects, mechanosensitive cells are needed that are able to conduct bone cell-specific functions, such as bone remodelling. Mechanical loading affects local bone mass and architecture in vivo by initiating a cellular

  14. Estradiol partially recapitulates murine pituitary cell cycle response to pregnancy.

    Science.gov (United States)

    Toledano, Yoel; Zonis, Svetlana; Ren, Song-Guang; Wawrowsky, Kolja; Chesnokova, Vera; Melmed, Shlomo

    2012-10-01

    Because pregnancy and estrogens both induce pituitary lactotroph hyperplasia, we assessed the expression of pituitary cell cycle regulators in two models of murine pituitary hyperplasia. Female mice were assessed during nonpregnancy, pregnancy, day of delivery, and postpartum. We also implanted estradiol (E(2)) pellets in female mice and studied them for 2.5 months. Pituitary weight in female mice increased 2-fold after E(2) administration and 1.4-fold at day of delivery, compared with placebo-treated or nonpregnant females. Pituitary proliferation, as assessed by proliferating cell nuclear antigen and/or Ki-67 staining, increased dramatically during both mid-late pregnancy and E(2) administration, and lactotroph hyperplasia was also observed. Pregnancy induced pituitary cell cycle proliferative and inhibitory responses at the G(1)/S checkpoint. Differential cell cycle regulator expression included cyclin-dependent kinase inhibitors, p21(Cip1), p27(Kip1), and cyclin D1. Pituitary cell cycle responses to E(2) administration partially recapitulated those effects observed at mid-late pregnancy, coincident with elevated circulating mouse E(2), including increased expression of proliferating cell nuclear antigen, Ki-67, p15(INK4b), and p21(Cip1). Nuclear localization of pituitary p21(Cip1) was demonstrated at mid-late pregnancy but not during E(2) administration, suggesting a cell cycle inhibitory role for p21(Cip1) in pregnancy, yet a possible proproliferative role during E(2) administration. Most observed cell cycle protein alterations were reversed postpartum. Murine pituitary meets the demand for prolactin during lactation associated with induction of both cell proliferative and inhibitory pathways, mediated, at least partially, by estradiol.

  15. Government/industry response to questionnaire on space mechanisms/tribology technology needs

    Science.gov (United States)

    Fusaro, Robert L.

    1991-01-01

    President Bush has proposed that the U.S. undertake an ambitious mission of manned and robotic exploration of the solar system. This mission will require advanced mechanical moving components, such as bearings, gears, seals, lubricants, etc. There has been concern in the NASA community that the current technology level in these mechanical component/tribology areas may not be adequate to meet the goals of such a mission. To attempt to answer this, NASA-Lewis has sent out a questionnaire to government and industry workers (who have been involved in space mechanism research, design, and implementation) to ask their opinion if the current space mechanisms technology (mechanical components/tribology) is adequate to meet future NASA Missions needs and goals. If they deemed that the technology base inadequate, they were asked to specify the areas of greatest need. The unedited remarks of those who responded to the survey are presented.

  16. Cell response to quasi-monochromatic light with different coherence

    Energy Technology Data Exchange (ETDEWEB)

    Budagovsky, A V; Solovykh, N V [I.V.Michurin All-Russian Recearch Institute of Fruit Crops Genetics and Breeding (Russian Federation); Budagovskaya, O N [I.V.Michurin All-Russia Research and Development Institute of Gardening, Michurinsk, Tambov region (Russian Federation); Budagovsky, I A [P N Lebedev Physics Institute, Russian Academy of Sciences, Moscow (Russian Federation)

    2015-04-30

    The problem of the light coherence effect on the magnitude of the photoinduced cell response is discussed. The origins of ambiguous interpretation of the known experimental results are considered. Using the biological models, essentially differing in anatomy, morphology and biological functions (acrospires of radish, blackberry microsprouts cultivated in vitro, plum pollen), the effect of statistical properties of quasi-monochromatic light (λ{sub max} = 633 nm) on the magnitude of the photoinduced cell response is shown. It is found that for relatively low spatial coherence, the cell functional activity changes insignificantly. The maximal enhancement of growing processes (stimulating effect) is observed when the coherence length L{sub coh} and the correlation radius r{sub cor} are greater than the cell size, i.e., the entire cell fits into the field coherence volume. In this case, the representative indicators (germination of seeds and pollen, the spears length) exceeds those of non-irradiated objects by 1.7 – 3.9 times. For more correct assessment of the effect of light statistical properties on photocontrol processes, it is proposed to replace the qualitative description (coherent – incoherent) with the quantitative one, using the determination of spatial and temporal correlation functions and comparing them with the characteristic dimensions of the biological structures, e.g., the cell size. (biophotonics)

  17. Molecular clutch drives cell response to surface viscosity.

    Science.gov (United States)

    Bennett, Mark; Cantini, Marco; Reboud, Julien; Cooper, Jonathan M; Roca-Cusachs, Pere; Salmeron-Sanchez, Manuel

    2018-02-06

    Cell response to matrix rigidity has been explained by the mechanical properties of the actin-talin-integrin-fibronectin clutch. Here the molecular clutch model is extended to account for cell interactions with purely viscous surfaces (i.e., without an elastic component). Supported lipid bilayers present an idealized and controllable system through which to study this concept. Using lipids of different diffusion coefficients, the mobility (i.e., surface viscosity) of the presented ligands (in this case RGD) was altered by an order of magnitude. Cell size and cytoskeletal organization were proportional to viscosity. Furthermore, there was a higher number of focal adhesions and a higher phosphorylation of FAK on less-mobile (more-viscous) surfaces. Actin retrograde flow, an indicator of the force exerted on surfaces, was also seen to be faster on more mobile surfaces. This has consequential effects on downstream molecules; the mechanosensitive YAP protein localized to the nucleus more on less-mobile (more-viscous) surfaces and differentiation of myoblast cells was enhanced on higher viscosity. This behavior was explained within the framework of the molecular clutch model, with lower viscosity leading to a low force loading rate, preventing the exposure of mechanosensitive proteins, and with a higher viscosity causing a higher force loading rate exposing these sites, activating downstream pathways. Consequently, the understanding of how viscosity (regardless of matrix stiffness) influences cell response adds a further tool to engineer materials that control cell behavior. Copyright © 2018 the Author(s). Published by PNAS.

  18. Department of the Navy Family Advocacy Program: Service Need and Service Response. Phase II Report: Assessment

    Science.gov (United States)

    1983-08-01

    cases where physical injuries are minimal, or in sexual assualt and rape cases when victims reports the incident days after the attack. In the latter case...Military Family Advocacy; Child Abuse; Spouse Abuse; Sexual Assault; Rape 20. ABSTRACT (Contnue on reverse If neeoery and Identify by block number...child abuse, spouse abuse, and sexual assault or rape. The report also identifies program needs and recommendations for program inmrovement. Findings

  19. Heterogeneous response of isolated adult rat heart cells to insulin

    International Nuclear Information System (INIS)

    Haworth, R.A.; Hunter, D.R.; Berkoff, H.A.

    1984-01-01

    3-O-Methylglucose uptake by Ca2+-resistant adult rat heart cells in suspension was measured, free of artifactual inhibitor-insensitive uptake, and with an accuracy of +/- 1.9% pellet water. (Ca2+-resistant cells are cells which retain their original rod-shaped morphology in the presence of physiological levels of Ca2+.) High levels of insulin (10(-6) M) stimulated the rate of 3-O-methylglucose uptake approximately 10-fold. In the presence of low levels of insulin (3 X 10(-11) M, 10(-10) M) uptake was biphasic; it could not be described by a single exponential function within experimental error, but required the sum of two exponentials. Deviation from a single exponential function was not so great with high levels of insulin (10(-6) M) or no insulin. Cell sugar uptake was also investigated using autoradiography of cells which had accumulated [2-14C]deoxyglucose under similar conditions. This showed considerable heterogeneity of 2-deoxyglucose uptake by cells treated with low levels of insulin, but significantly less heterogeneity of 2-deoxyglucose uptake by cells treated with high levels of insulin. It is concluded that the deviation of 3-O-methylglucose uptake from a single exponential observed at low insulin levels can be accounted for in terms of a heterogeneous response of cells to insulin

  20. Innate immune response to pulmonary contusion: identification of cell type-specific inflammatory responses.

    Science.gov (United States)

    Hoth, J Jason; Wells, Jonathan D; Yoza, Barbara K; McCall, Charles E

    2012-04-01

    Lung injury from pulmonary contusion is a common traumatic injury, predominantly seen after blunt chest trauma, such as in vehicular accidents. The local and systemic inflammatory response to injury includes activation of innate immune receptors, elaboration of a variety of inflammatory mediators, and recruitment of inflammatory cells to the injured lung. Using a mouse model of pulmonary contusion, we had previously shown that innate immune Toll-like receptors 2 and 4 (TLR2 and TLR4) mediate the inflammatory response to lung injury. In this study, we used chimeric mice generated by adoptive bone marrow transfer between TLR2 or TLR4 and wild-type mice. We found that, in the lung, both bone marrow-derived and nonmyeloid cells contribute to TLR-dependent inflammatory responses after injury in a cell type-specific manner. We also show a novel TLR2-dependent injury mechanism that is associated with enhanced airway epithelial cell apoptosis and increased pulmonary FasL and Fas expression in the lungs from injured mice. Thus, in addition to cardiopulmonary physiological dysfunction, cell type-specific TLR and their differential response to injury may provide novel specific targets for management of patients with pulmonary contusion.

  1. Leptin Suppresses Mouse Taste Cell Responses to Sweet Compounds.

    Science.gov (United States)

    Yoshida, Ryusuke; Noguchi, Kenshi; Shigemura, Noriatsu; Jyotaki, Masafumi; Takahashi, Ichiro; Margolskee, Robert F; Ninomiya, Yuzo

    2015-11-01

    Leptin is known to selectively suppress neural and behavioral responses to sweet-tasting compounds. However, the molecular basis for the effect of leptin on sweet taste is not known. Here, we report that leptin suppresses sweet taste via leptin receptors (Ob-Rb) and KATP channels expressed selectively in sweet-sensitive taste cells. Ob-Rb was more often expressed in taste cells that expressed T1R3 (a sweet receptor component) than in those that expressed glutamate-aspartate transporter (a marker for Type I taste cells) or GAD67 (a marker for Type III taste cells). Systemically administered leptin suppressed taste cell responses to sweet but not to bitter or sour compounds. This effect was blocked by a leptin antagonist and was absent in leptin receptor-deficient db/db mice and mice with diet-induced obesity. Blocking the KATP channel subunit sulfonylurea receptor 1, which was frequently coexpressed with Ob-Rb in T1R3-expressing taste cells, eliminated the effect of leptin on sweet taste. In contrast, activating the KATP channel with diazoxide mimicked the sweet-suppressing effect of leptin. These results indicate that leptin acts via Ob-Rb and KATP channels that are present in T1R3-expressing taste cells to selectively suppress their responses to sweet compounds. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  2. Monitoring the cytoskeletal EGF response in live gastric carcinoma cells.

    Directory of Open Access Journals (Sweden)

    Marco Felkl

    Full Text Available Altered cell motility is considered to be a key factor in determining tumor invasion and metastasis. Epidermal growth factor (EGF signaling has been implicated in this process by affecting cytoskeletal organization and dynamics in multiple ways. To sort the temporal and spatial regulation of EGF-dependent cytoskeletal re-organization in relation to a cell's motile behavior time-lapse microscopy was performed on EGF-responsive gastric carcinoma-derived MKN1 cells co-expressing different fluorescently labeled cytoskeletal filaments and focal adhesion components in various combinations. The experiments showed that EGF almost instantaneously induces a considerable increase in membrane ruffling and lamellipodial activity that can be inhibited by Cetuximab EGF receptor antibodies and is not elicited in non-responsive gastric carcinoma Hs746T cells. The transient cell extensions are rich in actin but lack microtubules and keratin intermediate filaments. We show that this EGF-induced increase in membrane motility can be measured by a simple image processing routine. Microtubule plus-ends subsequently invade growing cell extensions, which start to accumulate focal complexes at the lamellipodium-lamellum junction. Such paxillin-positive complexes mature into focal adhesions by tyrosine phosphorylation and recruitment of zyxin. These adhesions then serve as nucleation sites for keratin filaments which are used to enlarge the neighboring peripheral keratin network. Focal adhesions are either disassembled or give rise to stable zyxin-rich fibrillar adhesions which disassemble in the presence of EGF to support formation of new focal adhesion sites in the cell periphery. Taken together the results serve as a basis for modeling the early cytoskeletal EGF response as a tightly coordinated and step-wise process which is relevant for the prediction of the effectiveness of anti-EGF receptor-based tumor therapy.

  3. Boosting antibody responses by targeting antigens to dendritic cells.

    Science.gov (United States)

    Caminschi, Irina; Shortman, Ken

    2012-02-01

    Delivering antigens directly to dendritic cells (DCs) in situ, by injecting antigens coupled to antibodies specific for DC surface molecules, is a promising strategy for enhancing vaccine efficacy. Enhanced cytotoxic T cell responses are obtained if an adjuvant is co-administered to activate the DC. Such DC targeting is also effective at enhancing humoral immunity, via the generation of T follicular helper cells. Depending on the DC surface molecule targeted, antibody production can be enhanced even in the absence of adjuvants. In the case of Clec9A as the DC surface target, enhanced antibody production is a consequence of the DC-restricted expression of the target molecule. Few other cells absorb the antigen-antibody construct, therefore, it persists in the bloodstream, allowing sustained antigen presentation, even by non-activated DCs. Copyright © 2011 Elsevier Ltd. All rights reserved.

  4. Monocyte-Derived Signals Activate Human Natural Killer Cells in Response to Leishmania Parasites

    Directory of Open Access Journals (Sweden)

    Helena Messlinger

    2018-01-01

    reduced the expression of CD56 mRNA and protein on NK cells. We conclude that Leishmania activate NK cells via trans-presentation of IL-18 by monocytes and by a monocyte-derived soluble factor. IL-12 is needed to elicit the IFN-γ-response of NK cells, which is likely to be an important component of the innate control of the parasite.

  5. New Modeling Approaches to Investigate Cell Signaling in Radiation Response

    Science.gov (United States)

    Plante, Ianik; Cucinotta, Francis A.; Ponomarev, Artem L.

    2011-01-01

    Ionizing radiation damages individual cells and tissues leading to harmful biological effects. Among many radiation-induced lesions, DNA double-strand breaks (DSB) are considered the key precursors of most early and late effects [1] leading to direct mutation or aberrant signal transduction processes. In response to damage, a flow of information is communicated to cells not directly hit by the radiation through signal transduction pathways [2]. Non-targeted effects (NTE), which includes bystander effects and genomic instability in the progeny of irradiated cells and tissues, may be particularly important for space radiation risk assessment [1], because astronauts are exposed to a low fluence of heavy ions and only a small fraction of cells are traversed by an ion. NTE may also have important consequences clinical radiotherapy [3]. In the recent years, new simulation tools and modeling approaches have become available to study the tissue response to radiation. The simulation of signal transduction pathways require many elements such as detailed track structure calculations, a tissue or cell culture model, knowledge of biochemical pathways and Brownian Dynamics (BD) propagators of the signaling molecules in their micro-environment. Recently, the Monte-Carlo simulation code of radiation track structure RITRACKS was used for micro and nano-dosimetry calculations [4]. RITRACKS will be used to calculate the fraction of cells traversed by an ion and delta-rays and the energy deposited in cells in a tissue model. RITRACKS also simulates the formation of chemical species by the radiolysis of water [5], notably the .OH radical. This molecule is implicated in DNA damage and in the activation of the transforming growth factor beta (TGF), a signaling molecule involved in NTE. BD algorithms for a particle near a membrane comprising receptors were also developed and will be used to simulate trajectories of signaling molecules in the micro-environment and characterize autocrine

  6. Stimulation of dendritic cells enhances immune response after photodynamic therapy

    Science.gov (United States)

    Mroz, Pawel; Castano, Ana P.; Hamblin, Michael R.

    2009-02-01

    Photodynamic therapy (PDT) involves the administration of photosensitizers followed by illumination of the primary tumor with red light producing reactive oxygen species that cause vascular shutdown and tumor cell necrosis and apoptosis. Anti-tumor immunity is stimulated after PDT due to the acute inflammatory response, priming of the immune system to recognize tumor-associated antigens (TAA). The induction of specific CD8+ Tlymphocyte cells that recognize major histocompatibility complex class I (MHC-I) restricted epitopes of TAAs is a highly desirable goal in cancer therapy. The PDT killed tumor cells may be phagocytosed by dendritic cells (DC) that then migrate to draining lymph nodes and prime naÃve T-cells that recognize TAA epitopes. This process is however, often sub-optimal, in part due to tumor-induced DC dysfunction. Instead of DC that can become mature and activated and have a potent antigen-presenting and immune stimulating phenotype, immature dendritic cells (iDC) are often found in tumors and are part of an immunosuppressive milieu including regulatory T-cells and immunosuppressive cytokines such as TGF-beta and IL10. We here report on the use of a potent DC activating agent, an oligonucleotide (ODN) that contains a non-methylated CpG motif and acts as an agonist of toll like receptor (TLR) 9. TLR activation is a danger signal to notify the immune system of the presence of invading pathogens. CpG-ODN (but not scrambled non-CpG ODN) increased bone-marrow DC activation after exposure to PDT-killed tumor cells, and significantly increased tumor response to PDT and mouse survival after peri-tumoral administration. CpG may be a valuable immunoadjuvant to PDT especially for tumors that produce DC dysfunction.

  7. Examining demand response, renewable energy and efficiencies to meet growing electricity needs

    International Nuclear Information System (INIS)

    Elliot, N.; Eldridge, M.; Shipley, A.M.; Laitner, J.S.; Nadel, S.; Silverstein, A.; Hedman, B.; Sloan, M.

    2007-01-01

    While Texas has already taken steps to improve its renewable energy portfolio (RPS), and its energy efficiency improvement program (EEIP), the level of savings that utilities can achieve through the EEIP can be greatly increased. This report estimated the size of energy efficiency and renewable energy resources in Texas, and suggested a range of policy options that might be adopted to further extend EEIP. Current forecasts suggest that peak demand in Texas will increase by 2.3 per cent annually from 2007-2012, a level of growth which is threatening the state's ability to maintain grid reliability at reasonable cost. Almost 70 per cent of installed generating capacity is fuelled by natural gas in Texas. Recent polling has suggested that over 70 per cent of Texans are willing support increased spending on energy efficiency. Demand response measures that may be implemented in the state include incentive-based programs that pay users to reduce their electricity consumption during specific times and pricing programs, where customers are given a price signal and are expected to moderate their electricity usage. By 2023, the widespread availability of time-varying retail electric rates and complementary communications and control methods will permanently change the nature of electricity demand in the state. At present, the integrated utilities in Texas offer a variety of direct load control and time-of-use, curtailable, and interruptible rates. However, with the advent of retail competition now available as a result of the structural unbundling of investor-owned utilities, there is less demand response available in Texas. It was concluded that energy efficiency, demand response, and renewable energy resources can meet the increasing demand for electricity in Texas over the next 15 years. 4 figs

  8. The need for the consideration of an Order of Pastoral Care: a proposal with responses.

    Science.gov (United States)

    Gebhart, James E

    2004-01-01

    The author notes that historically the pastoral care community was seen as a product of the pastoral care organizations. Those pastoral care organizations were actually dynamic products of the emerging pastoral community. Unfortunately, this community was not nurtured beyond the gathering of certified supervisors, counselors, and chaplains. The author contends that the establishment of the College of Pastoral Supervision and Psychotherapy (CPSP) was an attempt to correct this oversight. Thus, he suggests, it is compelling to consider the Pastoral Care Chapter as a microcosom of a possible Order of Pastoral Care. Responses to this suggestion by pastoral care colleagues accompanies the article.

  9. A True Delphi Approach: Developing a Tailored Curriculum in Response to Local Agriscience Need

    Energy Technology Data Exchange (ETDEWEB)

    Rubenstein, Eric; Thoron, Andrew; Burleson, Sarah

    2012-02-07

    The Delphi approach is a structured communication technique, developed as a systematic, interactive forecasting method which relies on a panel of experts. In this specific case experts from Industry, Education and Extension fields addressed needs for educational programs in a traditional agriculturally-based community, environmentally conscious practices in order to restore environmental integrity and multi-disciplinary approach to solve sustainability problems facing the agricultural industry. The experts were divided into two main groups, (A) Secondary and (B) Post-secondary, and answered questionnaires in three rounds: • 1st Round – Participants generated a list of knowledge, skills, and competencies followed • 2nd Round – Panelists rated each item • 3rd Round – Panelists were given the opportunity to combine and add additional items As a result, top six items from both groups were not found similar, secondary panelists centralized around employment skills and post-secondary panelists focused on content areas. Implications include a need for content-based curriculum for post-secondary graduates, utilization of true-Delphi technique for future curriculum development research and further examination of students that complete secondary and post-secondary programs in biofuels/sustainable agriculture.

  10. Radiation response of cultured human cells is unaffected by Johrei.

    Science.gov (United States)

    Hall, Zach; Luu, Tri; Moore, Dan; Yount, Garret

    2007-06-01

    Johrei has been credited with healing thousands from radiation wounds after the Hiroshima and Nagasaki bombs in 1945. This alternative medical therapy is becoming increasingly popular in the United States, as are other Energy Medicine modalities that purport to influence a universal healing energy. Human brain cells were cultured and exposed to increasing doses of ionizing radiation. Experienced Johrei practitioners directed healing intentionality toward the cells for 30 min from a distance of 20 cm and the fate of the cells was observed by computerized time-lapse microscopy. Cell death and cell divisions were tallied every 30 min before, during and after Johrei treatment for a total of 22.5 h. An equal number of control experiments were conducted in which cells were irradiated but did not receive Johrei treatment. Samples were assigned to treatment conditions randomly and data analysis was conducted in a blinded fashion. Radiation exposure decreased the rate of cell division (cell cycle arrest) in a dose-dependent manner. Division rates were estimated for each 30 min and averaged over 8 independent experiments (4 control and 4 with Johrei treatment) for each of 4 doses of X-rays (0, 2, 4 and 8 Gy). Because few cell deaths were observed, pooled data from the entire observation period were used to estimate death rates. Analysis of variance did not reveal any significant differences on division rate or death rate between treatment groups. Only radiation dose was statistically significant. We found no indication that the radiation response of cultured cells is affected by Johrei treatment.

  11. Radiation Response of Cultured Human Cells Is Unaffected by Johrei

    Directory of Open Access Journals (Sweden)

    Zach Hall

    2007-01-01

    Full Text Available Johrei has been credited with healing thousands from radiation wounds after the Hiroshima and Nagasaki bombs in 1945. This alternative medical therapy is becoming increasingly popular in the United States, as are other Energy Medicine modalities that purport to influence a universal healing energy. Human brain cells were cultured and exposed to increasing doses of ionizing radiation. Experienced Johrei practitioners directed healing intentionality toward the cells for 30 min from a distance of 20 cm and the fate of the cells was observed by computerized time-lapse microscopy. Cell death and cell divisions were tallied every 30 min before, during and after Johrei treatment for a total of 22.5 h. An equal number of control experiments were conducted in which cells were irradiated but did not receive Johrei treatment. Samples were assigned to treatment conditions randomly and data analysis was conducted in a blinded fashion. Radiation exposure decreased the rate of cell division (cell cycle arrest in a dose-dependent manner. Division rates were estimated for each 30 min and averaged over 8 independent experiments (4 control and 4 with Johrei treatment for each of 4 doses of X-rays (0, 2, 4 and 8 Gy. Because few cell deaths were observed, pooled data from the entire observation period were used to estimate death rates. Analysis of variance did not reveal any significant differences on division rate or death rate between treatment groups. Only radiation dose was statistically significant. We found no indication that the radiation response of cultured cells is affected by Johrei treatment.

  12. Interplay between CD8α+ dendritic cells and monocytes in response to Listeria monocytogenes infection attenuates T cell responses.

    Directory of Open Access Journals (Sweden)

    Dilnawaz Kapadia

    2011-04-01

    Full Text Available During the course of a microbial infection, different antigen presenting cells (APCs are exposed and contribute to the ensuing immune response. CD8α(+ dendritic cells (DCs are an important coordinator of early immune responses to the intracellular bacteria Listeria monocytogenes (Lm and are crucial for CD8(+ T cell immunity. In this study, we examine the contribution of different primary APCs to inducing immune responses against Lm. We find that CD8α(+ DCs are the most susceptible to infection while plasmacytoid DCs are not infected. Moreover, CD8α(+ DCs are the only DC subset capable of priming an immune response to Lm in vitro and are also the only APC studied that do so when transferred into β2 microglobulin deficient mice which lack endogenous cross-presentation. Upon infection, CD11b(+ DCs primarily secrete low levels of TNFα while CD8α(+ DCs secrete IL-12 p70. Infected monocytes secrete high levels of TNFα and IL-12p70, cytokines associated with activated inflammatory macrophages. Furthermore, co-culture of infected CD8α(+ DCs and CD11b+ DCs with monocytes enhances production of IL-12 p70 and TNFα. However, the presence of monocytes in DC/T cell co-cultures attenuates T cell priming against Lm-derived antigens in vitro and in vivo. This suppressive activity of spleen-derived monocytes is mediated in part by both TNFα and inducible nitric oxide synthase (iNOS. Thus these monocytes enhance IL-12 production to Lm infection, but concurrently abrogate DC-mediated T cell priming.

  13. DNA Damage Response in Hematopoietic Stem Cell Ageing.

    Science.gov (United States)

    Li, Tangliang; Zhou, Zhong-Wei; Ju, Zhenyu; Wang, Zhao-Qi

    2016-06-01

    Maintenance of tissue-specific stem cells is vital for organ homeostasis and organismal longevity. Hematopoietic stem cells (HSCs) are the most primitive cell type in the hematopoietic system. They divide asymmetrically and give rise to daughter cells with HSC identity (self-renewal) and progenitor progenies (differentiation), which further proliferate and differentiate into full hematopoietic lineages. Mammalian ageing process is accompanied with abnormalities in the HSC self-renewal and differentiation. Transcriptional changes and epigenetic modulations have been implicated as the key regulators in HSC ageing process. The DNA damage response (DDR) in the cells involves an orchestrated signaling pathway, consisting of cell cycle regulation, cell death and senescence, transcriptional regulation, as well as chromatin remodeling. Recent studies employing DNA repair-deficient mouse models indicate that DDR could intrinsically and extrinsically regulate HSC maintenance and play important roles in tissue homeostasis of the hematopoietic system. In this review, we summarize the current understanding of how the DDR determines the HSC fates and finally contributes to organismal ageing. Copyright © 2016 The Authors. Production and hosting by Elsevier Ltd.. All rights reserved.

  14. Cell response to hydroxyapatite surface topography modulated by sintering temperature.

    Science.gov (United States)

    Mealy, Jacob; O'Kelly, Kevin

    2015-11-01

    Increased mesenchymal stem cell (MSC) activity on hydroxyapatite (HA) bone tissue engineering scaffolds will improve their viability in diffusion-based in vivo environments and is therefore highly desirable. This work focused on modulating the sintered HA surface topography with a view to increasing cell activity; this was achieved by varying the sintering temperature of the HA substrates. Cells were cultured on the substrates for periods of up to 19 days and displayed a huge variation in viability. MSC metabolic activity was measured using a resazurin sodium salt assay and revealed that surfaces sintered from 1250 to 1350°C significantly outperformed their lower temperature counterparts from day one (p ≤ 0.05). Surfaces sintered at 1300°C induced 57% more cell activity than the control at day 16. No significant activity was observed on surfaces sintered below 1200°C. It is suggested that this is due to the granular morphology produced at these temperatures providing insufficient contact area for cell attachment. In addition, we propose the average surface wavelength as a more quantitative surface descriptor than those readily found in the literature. The wavelengths of the substrates presented here were highly correlated with cell activity (R(2)  = 0.9019); with a wavelength of 2.675 µm on the 1300°C surface inducing the highest cell response. © 2015 Wiley Periodicals, Inc.

  15. Metabolic Responses in Endothelial Cells Following Exposure to Ketone Bodies

    Directory of Open Access Journals (Sweden)

    Erika Meroni

    2018-02-01

    Full Text Available The ketogenic diet (KD is a high-fat, low-carbohydrate diet based on the induction of the synthesis of ketone bodies (KB. Despite its widespread use, the systemic impact of KD is not completely understood. The purpose of this study was to evaluate the effects of physiological levels of KB on HMEC-1 endothelial cells. To this aim, DNA oxidative damage and the activation of Nrf2, a known transcriptional factor involved in cell responses to oxidative stress, were assessed. The exposure of cells to KB exerted a moderate genotoxic effect, measured by a significant increase in DNA oxidative damage. However, cells pre-treated with KB for 48 h and subjected to a secondary oxidative insult (H2O2, significantly decreased DNA damage compared to control oxidized cells. This protection occurred by the activation of Nrf2 pathway. In KB-treated cells, we found increased levels of Nrf2 in nuclear extracts and higher gene expression of HO-1, a target gene of Nrf2, compared to control cells. These results suggest that KB, by inducing moderate oxidative stress, activate the transcription factor Nrf2, which induces the transcription of target genes involved in the cellular antioxidant defense system.

  16. Metabolic Responses in Endothelial Cells Following Exposure to Ketone Bodies.

    Science.gov (United States)

    Meroni, Erika; Papini, Nadia; Criscuoli, Franca; Casiraghi, Maria C; Massaccesi, Luca; Basilico, Nicoletta; Erba, Daniela

    2018-02-22

    The ketogenic diet (KD) is a high-fat, low-carbohydrate diet based on the induction of the synthesis of ketone bodies (KB). Despite its widespread use, the systemic impact of KD is not completely understood. The purpose of this study was to evaluate the effects of physiological levels of KB on HMEC-1 endothelial cells. To this aim, DNA oxidative damage and the activation of Nrf2, a known transcriptional factor involved in cell responses to oxidative stress, were assessed. The exposure of cells to KB exerted a moderate genotoxic effect, measured by a significant increase in DNA oxidative damage. However, cells pre-treated with KB for 48 h and subjected to a secondary oxidative insult (H₂O₂), significantly decreased DNA damage compared to control oxidized cells. This protection occurred by the activation of Nrf2 pathway. In KB-treated cells, we found increased levels of Nrf2 in nuclear extracts and higher gene expression of HO-1, a target gene of Nrf2, compared to control cells. These results suggest that KB, by inducing moderate oxidative stress, activate the transcription factor Nrf2, which induces the transcription of target genes involved in the cellular antioxidant defense system.

  17. A Delayed Virus Infection Model with Cell-to-Cell Transmission and CTL Immune Response

    Science.gov (United States)

    Yang, Yu; Zhang, Tonghua; Xu, Yancong; Zhou, Jinling

    In this paper, a delayed virus infection model with cell-to-cell transmission and CTL immune response is investigated. In the model, time delay is incorporated into the CTL response. By constructing Lyapunov functionals, global dynamical properties of the two boundary equilibria are established. Our results show that time delay in the CTL response process may lead to sustained oscillation. To further investigate the nature of the oscillation, we apply the method of multiple time scales to calculate the normal form on the center manifold of the model. At the end of the paper, numerical simulations are carried out, which support our theoretical results.

  18. Supply chain responsibilities and the need for an integrative ethic Management in Emerging Economies

    Directory of Open Access Journals (Sweden)

    Lothar Auchter

    2015-03-01

    Full Text Available The economic importance of the Indian Textile and Clothing (T&C industry is unquestioned. It is one of the second largest employment generating industry, after agriculture, with direct employment of over 35 million people. Tamil Nadu accounts for over 65% of the total number spinning units in India and has been reported exploiting young women workers in the spinning and textile units what is called the “Sumangali Scheme”. “Sumangali” in Tamil means ‘happily married woman’. Globalization confronts decision-makers in connection with global conditions in identifying labour standards that can serve as guidelines for corporations producing or outsourcing outside of their home country. The Article shows that in a globalized business world the concept of a conventional corporate ethic system to put all energy into the development of codes of conduct, and ethical audits and sustainability reporting falls short. This applies to industries like the Tamil Nadu textile industry, as there is no clarity with regard to the causal factors and the key players in the supply chain of such a complex social system. The Integrative Social Contract Theory (ISCT allows understanding the problem of Supply-Chain Responsibilities as a contractual relationship that denotes concrete moral responsibilities.

  19. Protective immunization with B16 melanoma induces antibody response and not cytotoxic T cell response

    International Nuclear Information System (INIS)

    Sarzotti, M.; Sriyuktasuth, P.; Klimpel, G.R.; Cerny, J.

    1986-01-01

    C57BL/6 mice immunized with three intraperitoneal injections of syngeneic, irradiated B16 melanoma cells, became resistant to B16 tumor challenge. Immunized mice had high levels of serum antibody against a membrane antigen of B16 cells. The B16 antigen recognized by the anti-B16 sera formed a major band of 90 KD in gel electrophoresis. The anti-B16 antibody was partially protective when mixed with B16 cells and injected into normal recipient mice. Surprisingly, B16 resistance mice were incapable of generating cytotoxic T cells (CTL) specific for the B16 tumor. Both spleen and lymph node cell populations from immunized mice did not generate B16-specific CTL. Allogeneic mice (DBA/2 or C3H) were also unable to generate B16-specific CTL: however, alloreactive CTL produced in these strains of mice by immunization with C57BL/6 lymphocytes, did kill B16 target cells. Interestingly, spleen cells from syngeneic mice immunized with B16 tumor produced 6-fold more interleukin-2 (IL-2) than normal spleen cells, in vitro. These data suggest that immunization with B16 tumor activates a helper subset of T cells (for antibody and IL-2 production) but not the effector CTL response

  20. Analysis of cell-mediated immune responses in support of dengue vaccine development efforts.

    Science.gov (United States)

    Rothman, Alan L; Currier, Jeffrey R; Friberg, Heather L; Mathew, Anuja

    2015-12-10

    Dengue vaccine development has made significant strides, but a better understanding of how vaccine-induced immune responses correlate with vaccine efficacy can greatly accelerate development, testing, and deployment as well as ameliorate potential risks and safety concerns. Advances in basic immunology knowledge and techniques have already improved our understanding of cell-mediated immunity of natural dengue virus infection and vaccination. We conclude that the evidence base is adequate to argue for inclusion of assessments of cell-mediated immunity as part of clinical trials of dengue vaccines, although further research to identify useful correlates of protective immunity is needed. Copyright © 2015 Elsevier Ltd. All rights reserved.

  1. Nitric Oxide And Hypoxia Response In Pluripotent Stem Cells

    Directory of Open Access Journals (Sweden)

    Estefanía Caballano Infantes

    2015-08-01

    Full Text Available The expansion of pluripotent cells (ESCs and iPSCs under conditions that maintain their pluripotency is necessary to implement a cell therapy program. Previously, we have described that low nitric oxide (NO donor diethylenetriamine/nitric oxide adduct (DETA-NO added to the culture medium, promote the expansion of these cell types. The molecular mechanisms are not yet known. We present evidences that ESC and iPSCs in normoxia in presence of low NO triggers a similar response to hypoxia, thus maintaining the pluripotency. We have studied the stability of HIF-1α (Hypoxia Inducible Factor in presence of low NO. Because of the close relationship between hypoxia, metabolism, mitochondrial function and pluripotency we have analyzed by q RT-PCR the expression of genes involved in the glucose metabolism such as: HK2, LDHA and PDK1; besides other HIF-1α target gene. We further analyzed the expression of genes involved in mitochondrial biogenesis such as PGC1α, TFAM and NRF1 and we have observed that low NO maintains the same pattern of expression that in hypoxia. The study of the mitochondrial membrane potential using Mito-Tracker dye showed that NO decrease the mitochondrial function. We will analyze other metabolic parameters, to determinate if low NO regulates mitochondrial function and mimics Hypoxia Response. The knowledge of the role of NO in the Hypoxia Response and the mechanism that helps to maintain self-renewal in pluripotent cells in normoxia, can help to the design of culture media where NO could be optimal for stem cell expansion in the performance of future cell therapies.

  2. Dissecting the Transcriptional Response to Elicitors in Vitis vinifera Cells

    Science.gov (United States)

    Belchí-Navarro, Sarai; Bru, Roque; Martínez-Zapater, José M.; Lijavetzky, Diego; Pedreño, María A.

    2014-01-01

    The high effectiveness of cyclic oligosaccharides like cyclodextrins in the production of trans-resveratrol in Vitis vinifera cell cultures is enhanced in the presence of methyl jasmonate. In order to dissect the basis of the interactions among the elicitation responses triggered by these two compounds, a transcriptional analysis of grapevine cell cultures treated with cyclodextrins and methyl jasmonate separately or in combination was carried out. The results showed that the activation of genes encoding enzymes from phenylpropanoid and stilbene biosynthesis induced by cyclodextrins alone was partially enhanced in the presence of methyl jasmonate, which correlated with their effects on trans-resveratrol production. In addition, protein translation and cell cycle regulation were more highly repressed in cells treated with cyclodextrins than in those treated with methyl jasmonate, and this response was enhanced in the combined treatment. Ethylene signalling was activated by all treatments, while jasmonate signalling and salicylic acid conjugation were activated only in the presence of methyl jasmonate and cyclodextrins, respectively. Moreover, the combined treatment resulted in a crosstalk between the signalling cascades activated by cyclodextrins and methyl jasmonate, which, in turn, provoked the activation of additional regulatory pathways involving the up-regulation of MYB15, NAC and WRKY transcription factors, protein kinases and calcium signal transducers. All these results suggest that both elicitors cause an activation of the secondary metabolism in detriment of basic cell processes like the primary metabolism or cell division. Crosstalk between cyclodextrins and methyl jasmonate-induced signalling provokes an intensification of these responses resulting in a greater trans-resveratrol production. PMID:25314001

  3. Effect of melanin on radiation response of CHO cells

    Energy Technology Data Exchange (ETDEWEB)

    Hopwood, L.E. (Medical Coll. of Wisconsin, Milwaukee (USA). Dept. of Radiation Oncology); Swartz, H.M. (Illinois Univ., Urbana (USA). Coll. of Medicine); Pajak, S. (Uniwersytet Jagiellonski, Krakow (Poland))

    1985-05-01

    The effect of the presence of melanin on the response of mammalian cells to ionizing radiation was investigated in a model system utilizing the ability of Chinese hamster ovary cells to incorporate melanin by endocytosis. Cells were incubated in monolayer cultures from 2 to 20 hours with melanin prepared from 'beef eye' or synthesized by air oxidation of 3,4-dihydroxyphenylalanine. For asynchronous cultures, the survival curve parameters for cells incubated with both types of melanin were indistinguishable from those of the same cells without added melanin. The radiation response to fractionated doses of 6 Gy separated by various periods did not indicate any effect of melanin on the extent or kinetics of repair of sublethal damage. Likewise, the repair of potentially lethal damage in plateau phase cultures was unaffected by the presence of melanin. Thus the explanation for the clinical radiation resistance of melanomas in the absence of a direct radiation effect might more likely be found in consideration of other factors such as the role of melanin in oxygen consumption or in differentiation.

  4. Responses of cells in the midbrain near-response area in monkeys with strabismus.

    Science.gov (United States)

    Das, Vallabh E

    2012-06-22

    To investigate whether neuronal activity within the supraoculomotor area (SOA-monosynaptically connected to medial rectus motoneurons and encode vergence angle) of strabismic monkeys was correlated with the angle of horizontal misalignment and therefore helps to define the state of strabismus. Single-cell neural activity was recorded from SOA neurons in two monkeys with exotropia as they performed eye movement tasks during monocular viewing. Horizontal strabismus angle varied depending on eye of fixation (dissociated horizontal deviation) and the activity of SOA cells (n = 35) varied in correlation with the angle of strabismus. Both near-response (cells that showed larger firing rates for smaller angles of exotropia) and far-response (cells that showed lower firing rates for smaller angles of exotropia) cells were identified. SOA cells showed no modulation of activity with changes in conjugate eye position as tested during smooth-pursuit, thereby verifying that the responses were related to binocular misalignment. SOA cell activity was also not correlated with change in horizontal misalignment due to A-patterns of strabismus. Comparison of SOA population activity in strabismic animals and normal monkeys (described in the literature) show that both neural thresholds and neural sensitivities are altered in the strabismic animals compared with the normal animals. SOA cell activity is important in determining the state of horizontal strabismus, possibly by altering vergence tone in extraocular muscle. The lack of correlated SOA activity with changes in misalignment due to A/V patterns suggest that circuits mediating horizontal strabismus angle and those that mediate A/V patterns are different.

  5. The need for endodontic treatment and systemic characteristics of hematopoietic stem cell transplantation patients.

    Science.gov (United States)

    Braga-Diniz, Julia Mourão; Santa-Rosa, Caroline Christine; Martins, Renata de Castro; Silva, Maria Elisa Souza E; Vieira, Leda Quercia; Ribeiro Sobrinho, Antônio Paulino

    2017-07-03

    The aim of this study is to investigate the relationship between the epidemiological and clinical profiles of patients before and after hematopoietic stem cell transplantation (HSCT) and the need for endodontic treatment. The subjects included 188 individuals enrolled in the dental care program for transplanted patients of the School of Dentistry, Federal University of Minas Gerais (Faculdade de Odontologia da Universidade Federal de Minas Gerais, FO-UFMG) from March 2011 through March 2016. The patients were subjected to an HSCT conditioning dental regimen based on a thorough clinical and radiographic evaluation. Intraoral periapical and bite-wing X-rays were obtained, and after evaluation, specific dental treatment was planned and performed. The following demographic and clinical data were collected from the patients' medical records: age, gender, transplantation stage, primary disease, transplant type, medication used, complete blood count at the time of visit, and need for endodontic treatment. The Kolmogorov-Smirnov and the chi-square tests were used. Leukemia (31.3%) and multiple myeloma (17.9%) were the most prevalent primary diseases. Most patients were subjected to allogeneic-related transplantation (83.6%). Most patients exhibited platelet counts and hemoglobin concentrations below the reference values in the pre-transplantation stage, while the neutrophil and platelet counts and the hemoglobin levels were within the reference ranges in the post-transplantation stage. The proportions of individuals requiring endodontic treatment were similar between the pre- and post-transplantation groups: 24.3% and 24.7%, respectively. The systemic conditions of the patients referred for dental treatment were compromised.

  6. Donor exosomes rather than passenger leukocytes initiate alloreactive T cell responses after transplantation

    Science.gov (United States)

    Marino, Jose; Babiker-Mohamed, Mohamed H.; Crosby-Bertorini, Patrick; Paster, Joshua T.; LeGuern, Christian; Germana, Sharon; Abdi, Reza; Uehara, Mayuko; Kim, James I.; Markmann, James F.; Tocco, Georges; Benichou, Gilles

    2016-01-01

    Transplantation of allogeneic organs and tissues represents a lifesaving procedure for a variety of patients affected with end-stage diseases. Although current immunosuppressive therapy prevents early acute rejection, it is associated with nephrotoxicity and increased risks for infection and neoplasia. This stresses the need for selective immune-based therapies relying on manipulation of lymphocyte recognition of donor antigens. The passenger leukocyte theory states that allograft rejection is initiated by recipient T cells recognizing donor major histocompatibility complex (MHC) molecules displayed on graft leukocytes migrating to the host’s lymphoid organs. We revisited this concept in mice transplanted with allogeneic skin, heart, or islet grafts using imaging flow cytometry. We observed no donor cells in the lymph nodes and spleen of skin-grafted mice, but we found high numbers of recipient cells displaying allogeneic MHC molecules (cross-dressed) acquired from donor microvesicles (exosomes). After heart or islet transplantation, we observed few donor leukocytes (100 per million) but large numbers of recipient cells cross-dressed with donor MHC (>90,000 per million). Last, we showed that purified allogeneic exosomes induced proinflammatory alloimmune responses by T cells in vitro and in vivo. Collectively, these results suggest that recipient antigen-presenting cells cross-dressed with donor MHC rather than passenger leukocytes trigger T cell responses after allotransplantation. PMID:27942611

  7. An unexpected antibody response to an engineered influenza virus modifies CD8+ T cell responses.

    Science.gov (United States)

    Thomas, Paul G; Brown, Scott A; Yue, Wen; So, Jenny; Webby, Richard J; Doherty, Peter C

    2006-02-21

    The ovalbumin(323-339) peptide that binds H2I-A(b) was engineered into the globular heads of hemagglutinin (H) molecules from serologically non-cross-reactive H1N1 and H3N2 influenza A viruses, the aim being to analyze recall CD4+ T cell responses in a virus-induced respiratory disease. Prime/challenge experiments with these H1ova and H3ova viruses in H2(b) mice gave the predicted, ovalbumin-specific CD4+ T cell response but showed an unexpectedly enhanced, early expansion of viral epitope-specific CD8+ T cells in spleen and a greatly diminished inflammatory process in the virus-infected respiratory tract. At the same time, the primary antibody response to the H3N2 challenge virus was significantly reduced, an effect that has been associated with preexisting neutralizing antibody in other experimental systems. Analysis of serum from the H1ova-primed mice showed low-level binding to H3ova but not to the wild-type H3N2 virus. Experiments with CD4+ T cell-depleted and Ig-/- mice indicated that this cross-reactive Ig is indeed responsible for the modified pathogenesis after respiratory challenge. Furthermore, the effect does not seem to be virus-dose related, although it does require infection. These findings suggest intriguing possibilities for vaccination and, at the same time, emphasize that engineered modifications in viruses may have unintended immunological consequences.

  8. Is a Response to Intervention (RTI) Approach to Preschool Language and Early Literacy Instruction Needed?

    Science.gov (United States)

    Greenwood, Charles R; Carta, Judith J; Atwater, Jane; Goldstein, Howard; Kaminski, Ruth; McConnell, Scott

    2013-05-01

    Preschool experience plays a role in children's development. However, for programs with language and early literacy goals, the question remains whether or not preschool instructional experiences are sufficiently effective to achieve these goals for all children. In a multisite study, we conducted a process-product description of preschool instruction and children's growth and outcomes in typical programs (i.e., Pre-Kindergarten, Title 1, Head Start, Tuition-Based) using a Response to Intervention (RTI) perspective. Results indicated that (a) students in their preschool year prior to kindergarten made small gains, but students starting the year in lower Tier 2 and 3 performance levels did not close initial skills gaps, (b) variations were noted by program types with varying socio-demographics and instructional processes, and (c) the quality of instruction (Tier 1) received by all was low with room for improvement. Implications for future research on the application of the RTI approach and potential benefits are discussed.

  9. Extracellular Alkalinization as a Defense Response in Potato Cells.

    Science.gov (United States)

    Moroz, Natalia; Fritch, Karen R; Marcec, Matthew J; Tripathi, Diwaker; Smertenko, Andrei; Tanaka, Kiwamu

    2017-01-01

    A quantitative and robust bioassay to assess plant defense response is important for studies of disease resistance and also for the early identification of disease during pre- or non-symptomatic phases. An increase in extracellular pH is known to be an early defense response in plants. In this study, we demonstrate extracellular alkalinization as a defense response in potatoes. Using potato suspension cell cultures, we observed an alkalinization response against various pathogen- and plant-derived elicitors in a dose- and time-dependent manner. We also assessed the defense response against a variety of potato pathogens, such as protists ( Phytophthora infestans and Spongospora subterranea ) and fungi ( Verticillium dahliae and Colletotrichum coccodes ). Our results show that extracellular pH increases within 30 min in proportion to the number of pathogen spores added. Consistently with the alkalinization effect, the higher transcription level of several defense-related genes and production of reactive oxygen species was observed. Our results demonstrate that the alkalinization response is an effective marker to study early stages of defense response in potatoes.

  10. A Myc-dependent division timer complements a cell-death timer to regulate T cell and B cell responses.

    Science.gov (United States)

    Heinzel, Susanne; Binh Giang, Tran; Kan, Andrey; Marchingo, Julia M; Lye, Bryan K; Corcoran, Lynn M; Hodgkin, Philip D

    2017-01-01

    T lymphocytes and B lymphocytes integrate activating signals to control the size of their proliferative response. Here we report that such control was achieved by timed changes in the production rate of cell-cycle-regulating proto-oncoprotein Myc, with division cessation occurring when Myc levels fell below a critical threshold. The changing pattern of the level of Myc was not affected by cell division, which identified the regulating mechanism as a cell-intrinsic, heritable temporal controller. Overexpression of Myc in stimulated T cells and B cells did not sustain cell proliferation indefinitely, as a separate 'time-to-die' mechanism, also heritable, was programmed after lymphocyte activation and led to eventual cell loss. Together the two competing cell-intrinsic timed fates created the canonical T cell and B cell immune-response pattern of rapid growth followed by loss of most cells. Furthermore, small changes in these timed processes by regulatory signals, or by oncogenic transformation, acted in synergy to greatly enhance cell numbers over time.

  11. Single-cell Western blotting after whole-cell imaging to assess cancer chemotherapeutic response.

    Science.gov (United States)

    Kang, Chi-Chih; Lin, Jung-Ming G; Xu, Zhuchen; Kumar, Sanjay; Herr, Amy E

    2014-10-21

    Intratumor heterogeneity remains a major obstacle to effective cancer therapy and personalized medicine. Current understanding points to differential therapeutic response among subpopulations of tumor cells as a key challenge to successful treatment. To advance our understanding of how this heterogeneity is reflected in cell-to-cell variations in chemosensitivity and expression of drug-resistance proteins, we optimize and apply a new targeted proteomics modality, single-cell western blotting (scWestern), to a human glioblastoma cell line. To acquire both phenotypic and proteomic data on the same, single glioblastoma cells, we integrate high-content imaging prior to the scWestern assays. The scWestern technique supports thousands of concurrent single-cell western blots, with each assay comprised of chemical lysis of single cells seated in microwells, protein electrophoresis from those microwells into a supporting polyacrylamide (PA) gel layer, and in-gel antibody probing. We systematically optimize chemical lysis and subsequent polyacrylamide gel electrophoresis (PAGE) of the single-cell lysate. The scWestern slides are stored for months then reprobed, thus allowing archiving and later analysis as relevant to sparingly limited, longitudinal cell specimens. Imaging and scWestern analysis of single glioblastoma cells dosed with the chemotherapeutic daunomycin showed both apoptotic (cleaved caspase 8- and annexin V-positive) and living cells. Intriguingly, living glioblastoma subpopulations show up-regulation of a multidrug resistant protein, P-glycoprotein (P-gp), suggesting an active drug efflux pump as a potential mechanism of drug resistance. Accordingly, linking of phenotype with targeted protein analysis with single-cell resolution may advance our understanding of drug response in inherently heterogeneous cell populations, such as those anticipated in tumors.

  12. Respiratory epithelial cell responses to cigarette smoke: the unfolded protein response.

    Science.gov (United States)

    Kelsen, Steven G

    2012-12-01

    Cigarette smoking exposes the respiratory epithelium to highly toxic, reactive oxygen nitrogen species which damage lung proteins in the endoplasmic reticulum (ER), the cell organelle in which all secreted and membrane proteins are processed. Accumulation of damaged or misfolded proteins in the ER, a condition termed ER stress, activates a complex cellular process termed the unfolded protein responses (UPR). The UPR acts to restore cellular protein homeostasis by regulating all aspects of protein metabolism including: protein translation and syntheses; protein folding; and protein degradation. However, activation of the UPR may also induce signaling pathways which induce inflammation and cell apoptosis. This review discusses the role of UPR in the respiratory epithelial cell response to cigarette smoke and the pathogenesis of lung diseases like COPD. Copyright © 2012 Elsevier Ltd. All rights reserved.

  13. Enhancement of radiation response in human hepatocarcinoma cells by Metformin

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Eun Ho; Kim, Won Woo; Kim, Joon; Jung, Won Gyun [Division of heavy ion clinical research, Korea University, Seoul (Korea, Republic of); Jeong, Jae Hoon; Jeong, Youn Kyoung; Kim, Mi Sook [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

    2012-11-15

    Metformin (1, 1-dimethylbiguanide hydrochloride), the most widely used drug to treat type 2 diabetic patients under benefit good tolerability profile and low cost, has sparked keen interest as potential anticancer agent. Preclinical studies showed that the primary mechanism of action of metformin is through its ability to activate AMP-activated protein kinase (AMPK). Metformin inhibits complex 1 in the mitochondrial electron transport chain, leading to an increase in the AMP-to-ATP ratio, then, phospholylated AMPK increase energy generation or suppress energy consumption and then, inhibits cell growth. However, important caveat in direct action theory of metformin is that millimorlar range, effective dose for inhibition tumor cell growth in vitro, cannot be achieved in patients. This is probably because metformin enter cells through the organic cation transporters OCT1 and OCT2, which is lowly expressed in human cells except liver and adipose cells. dependent pathway rather than through direct effects of the tumor cells. We analyzed combination effect of metformin and radiation focusing to HCC cell lines, which theoretically express high organic cation transporters, producing high centration of metformin in tumor cells. The purpose of this study is to investigate whether metformin had anti-tumor effects when combined with radiation as radiosensitizer in HCC. The results showed that metformin increased radiosensitizing efficacy in HCC cells , as well as in Huh7 xenograft mouse models. Interestingly, metformin effectively sensitizes IR-induced apoptosis in HCC through upregulation of cleaved PARP and caspase3 and increase synergically on DNA damage response with combined treatment.HCC, suggesting potential usefulness of combined therapy of metformin together with radiation for HCC cancer therapy.

  14. T cell response to N-formylated peptides in humans.

    Science.gov (United States)

    Ristori, G; Montesperelli, C; Fiorillo, M T; Battistini, L; Chersi, A; Sorrentino, R; Borsellino, G; Perna, A; Tramonti, D; Cannoni, S; Perrone, M P; Giubilei, F; Riccio, P; Salvetti, M; Buttinelli, C

    2001-09-01

    We present the first evidence of a T lymphocyte response to N-formylated peptides in humans. N-formylated peptide sequences from self (mitochondrial) and foreign (microbial) antigens were used to isolate antigen-specific T cell clones from healthy individuals, including a set of monozygotic twins. The observed response differed from that previously described in mouse (CD4(+) phenotype and MHC class II restriction in humans vs. CD8(+) phenotype and class I restriction in mice). These lymphocytes produce substantial amounts of IFN-gamma. They were isolated in only one of the monozygotic twins, which suggests that their expansion in the healthy immune repertoire is independent of the genetic background. Our result will help in assessing the relevance of N-formylated peptide-specific T cells in protection against infections within the human immune system.

  15. Curcumin prevents human dendritic cell response to immune stimulants

    International Nuclear Information System (INIS)

    Shirley, Shawna A.; Montpetit, Alison J.; Lockey, R.F.; Mohapatra, Shyam S.

    2008-01-01

    Curcumin, a compound found in the Indian spice turmeric, has anti-inflammatory and immunomodulatory properties, though the mechanism remains unclear. Dendritic cells (DCs) are important to generating an immune response and the effect of curcumin on human DCs has not been explored. The role curcumin in the DC response to bacterial and viral infection was investigated in vitro using LPS and Poly I:C as models of infection. CD14 + monocytes, isolated from human peripheral blood, were cultured in GM-CSF- and IL-4-supplemented medium to generate immature DCs. Cultures were incubated with curcumin, stimulated with LPS or Poly I:C and functional assays were performed. Curcumin prevents DCs from responding to immunostimulants and inducing CD4 + T cell proliferation by blocking maturation marker, cytokine and chemokine expression and reducing both migration and endocytosis. These data suggest a therapeutic role for curcumin as an immune suppressant

  16. Antigen-Specific B Cells Reactivate an Effective Cytotoxic T Cell Response against Phagocytosed Salmonella through Cross-Presentation

    NARCIS (Netherlands)

    de Wit, Jelle; Souwer, Yuri; Jorritsma, Tineke; Klaasse Bos, Hanny; ten Brinke, Anja; Neefjes, Jacques; van Ham, S. Marieke

    2010-01-01

    Background: The eradication of facultative intracellular bacterial pathogens, like Salmonella typhi, requires the concerted action of both the humoral immune response and the cytotoxic CD8(+) T cell response. Dendritic cells (DCs) are considered to orchestrate the cytotoxic CD8(+) T cell response

  17. Do we need social reports? New challenge for corporate social responsibility

    Directory of Open Access Journals (Sweden)

    Jarosławska-Sobór Sylwia

    2017-12-01

    Full Text Available Directive 2014/95/EU of the European Parliament and the Council entered into force on 1 January 2017, regards disclosure of non-financial and diversity information by certain large undertakings and groups. Its aim is to enhance the consistency and comparability of non-financial information disclosed throughout the Union. Large public-interest entities will be obligated to prepare a non-financial statement containing information relating to at least environmental matters, social and employee-related matters, respect for human rights, anti-corruption and bribery matters. What it means in practice ? Whether we need a social reports ? In this paper different aspects of new directives, it’s theoretical basement and functional range has been discussed. Opportunities and vulnerabilities, which directives sets on the path forward on CSR will be provided. On the case of designated Integrated Annual Report will be pointed elements, which can provides stakeholders with market information and infulence on an image of the company.

  18. The Cavendish Centre for integrated cancer care: assessment of patients' needs and responses.

    Science.gov (United States)

    Peace, G; Manasse, A

    2002-03-01

    The use of complementary therapies in combination with conventional medicine is increasing. In cancer care, as at the Cavendish Centre for Cancer Care in Sheffield, the range of therapies offered can include aromatherapy, massage, reflexology, shiatsu, acupuncture, homeopathy, counselling, visualization, hypnotherapy, relaxation, healing and art therapy. Before offering any therapy careful assessment of patients' needs is important as patients seeking complementary therapies may present with unrealistic hopes and expectations of benefit. There are wide variations in provision of services offering complementary cancer care throughout the United Kingdom but few offer a comprehensive assessment which is used as a baseline for both planning treatment and evaluating its outcome and which is conducted by a trained and objective practitioner who has no investment in any specific therapy. We describe the model of care developed at the Cavendish Centre with particular emphasis on the assessment process. Our model of assessment provides an opportunity for patients to tell their story, make sense of the illness experience, construct meaning from it and set realistic expectations for the chosen intervention. It also offers patients involvement and choice in decisions about their care. In addition we present evaluative data from a case series of 157 patients, 138 of whom (88%) reported improvement in their main concern on MYMOP (Measure Your Medical Outcome Profile).

  19. EU emissions trading. The need for cap adjustment in response to external shocks and unexpected developments?

    Energy Technology Data Exchange (ETDEWEB)

    Diekmann, Jochen [DIW, Berlin (Germany)

    2012-11-15

    In this paper the advantages and disadvantages of the various adaptation options will be discussed from an economic perspective. Firstly, the criteria for identifying a need for potentially legitimate adaptation should be investigated. Furthermore, the issue of appropriate timely intervention points prior to or within the trading period will be discussed. In what periods and scenarios are adjustments to the cap worthwhile from an economic perspective? To what extent could minimum prices or price ranges make sense? What role could a strategic reserve play? By addressing these issues, it will be fundamentally discussed as to how the emissions trading scheme could be further developed and strengthened by greater flexibility. After a brief characterisation of emissions trading in theory and practice in Chapter 2, Chapter 3 will identify potential external shocks and unexpected developments which may impair the functioning of an emissions trading scheme. The current problems of cap setting for the third trading period of the EU ETS will be described in Chapter 4. Against this background, cap adjustments will be discussed in Chapter 5, minimum and maximum prices in Chapter 6 and strategic reserves in emissions trading in Chapter 7. The conclusions are summarised in Chapter 8.

  20. T-cell responses to oncogenic Merkel cell polyomavirus proteins distinguish patients with Merkel cell carcinoma from healthy donors

    DEFF Research Database (Denmark)

    Lyngaa, Rikke; Pedersen, Natasja Wulff; Schrama, David

    2014-01-01

    Purpose: Merkel cell carcinoma (MCC) is a highly aggressive skin cancer with strong evidence of viral carcinogenesis. The association of MCC with the Merkel cell polyomavirus (MCPyV) may explain the explicit immunogenicity of MCC. Indeed, MCPyV-encoded proteins are likely targets for cytotoxic...... immune responses to MCC as they are both foreign to the host and necessary to maintain the oncogenic phenotype. However, to date only a single MCPyV-derived CD8 T-cell epitope has been described, thus impeding specific monitoring of T-cell responses to MCC. Method: To overcome this limitation, we scanned...... the MCPyV oncoprotein large T and small T antigens and the virus capsid protein VP1 for potential T-cell epitopes, and tested for MHC class I affinity. We confirmed the relevance of these epitopes using a high-throughput platform for T-cell enrichment and combinatorial encoding of MHC class I multimers...

  1. Global gene expression response to telomerase in bovine adrenocortical cells

    International Nuclear Information System (INIS)

    Perrault, Steven D.; Hornsby, Peter J.; Betts, Dean H.

    2005-01-01

    The infinite proliferative capability of most immortalized cells is dependent upon the presence of the enzyme telomerase and its ability to maintain telomere length and structure. However, telomerase may be involved in a greater system than telomere length regulation, as recent evidence has shown it capable of increasing wound healing in vivo, and improving cellular proliferation rate and survival from apoptosis in vitro. Here, we describe the global gene expression response to ectopic telomerase expression in an in vitro bovine adrenocortical cell model. Telomerase-immortalized cells showed an increased ability for proliferation and survival in minimal essential medium above cells transgenic for GFP. cDNA microarray analyses revealed an altered cell state indicative of increased adrenocortical cell proliferation regulated by the IGF2 pathway and alterations in members of the TGF-B family. As well, we identified alterations in genes associated with development and wound healing that support a model that high telomerase expression induces a highly adaptable, progenitor-like state

  2. Human influenza viruses and CD8(+) T cell responses.

    Science.gov (United States)

    Grant, Emma J; Quiñones-Parra, Sergio M; Clemens, E Bridie; Kedzierska, Katherine

    2016-02-01

    Influenza A viruses (IAVs) cause significant morbidity and mortality worldwide, despite new strain-specific vaccines being available annually. As IAV-specific CD8(+) T cells promote viral control in the absence of neutralizing antibodies, and can mediate cross-reactive immunity toward distinct IAVs to drive rapid recovery from both mild and severe influenza disease, there is great interest in developing a universal T cell vaccine. However, despite detailed studies in mouse models of influenza virus infection, there is still a paucity of data on human epitope-specific CD8(+) T cell responses to IAVs. This review focuses on our current understanding of human CD8(+) T cell immunity against distinct IAVs and discusses the possibility of achieving a CD8(+) T cell mediated-vaccine that protects against multiple, distinct IAV strains across diverse human populations. We also review the importance of CD8(+) T cell immunity in individuals highly susceptible to severe influenza infection, including those hospitalised with influenza, the elderly and Indigenous populations. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. Carbon monoxide from neighbouring restaurants: the need for an integrated multi-agency response.

    Science.gov (United States)

    Keshishian, C; Sandle, H; Meltzer, M; Young, Y; Ward, R; Balasegaram, S

    2012-12-01

    Carbon monoxide (CO) is a colourless, odourless toxic gas produced during incomplete combustion of carbon-based fuels. Most CO incidents reported to the UK Health Protection Agency (HPA) are due to faulty gas appliances, and legislation exists to ensure gas appliances are properly installed. We present three CO poisoning incidents of unusual origin reported to the HPA. In each, residents living above restaurants were poisoned after workers left charcoal smouldering overnight in specialist or traditional ovens whilst ventilation systems were turned off. This led to production of CO, which travelled through floorboards and built up to dangerous concentrations in the flats. Working with local authorities, these incidents were investigated and resolved, and work was conducted to prevent further occurrences. The novel nature of these CO incidents led to delays in recognition and subsequent remedial action. Although previously undescribed, it is likely that due to the number of residences built above restaurants and the rising popularity of traditional cooking methods, similar incidents may be occurring and could increase in frequency. Multi-agency response and reporting mechanisms could be strengthened. Awareness raising in professional groups and the public on the importance of correct ventilation of such appliances is vital.

  4. Histamine receptor 2 modifies dendritic cell responses to microbial ligands.

    Science.gov (United States)

    Frei, Remo; Ferstl, Ruth; Konieczna, Patrycja; Ziegler, Mario; Simon, Tunde; Rugeles, Tulia Mateus; Mailand, Susanne; Watanabe, Takeshi; Lauener, Roger; Akdis, Cezmi A; O'Mahony, Liam

    2013-07-01

    The induction of tolerance and protective immunity to microbes is significantly influenced by host- and microbiota-derived metabolites, such as histamine. We sought to identify the molecular mechanisms for histamine-mediated modulation of pattern recognition receptor signaling. Human monocyte-derived dendritic cells (MDDCs), myeloid dendritic cells, and plasmacytoid dendritic cells were examined. Cytokine secretion, gene expression, and transcription factor activation were measured after stimulation with microbial ligands and histamine. Histamine receptor 2 (H₂R)-deficient mice, histamine receptors, and their signaling pathways were investigated. Histamine suppressed MDDC chemokine and proinflammatory cytokine secretion, nuclear factor κB and activator protein 1 activation, mitogen-activated protein kinase phosphorylation, and T(H)1 polarization of naive lymphocytes, whereas IL-10 secretion was enhanced in response to LPS and Pam3Cys. Histamine also suppressed LPS-induced myeloid dendritic cell TNF-α secretion and suppressed CpG-induced plasmacytoid dendritic cell IFN-α gene expression. H₂R signaling through cyclic AMP and exchange protein directly activated by cyclic AMP was required for the histamine effect on LPS-induced MDDC responses. Lactobacillus rhamnosus, which secretes histamine, significantly suppressed Peyer patch IL-2, IL-4, IL-5, IL-12, TNF-α, and GM-CSF secretion in wild-type but not H₂R-deficient animals. Both host- and microbiota-derived histamine significantly alter the innate immune response to microbes through H₂R. Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

  5. Biotin deficiency enhances the inflammatory response of human dendritic cells.

    Science.gov (United States)

    Agrawal, Sudhanshu; Agrawal, Anshu; Said, Hamid M

    2016-09-01

    The water-soluble biotin (vitamin B7) is indispensable for normal human health. The vitamin acts as a cofactor for five carboxylases that are critical for fatty acid, glucose, and amino acid metabolism. Biotin deficiency is associated with various diseases, and mice deficient in this vitamin display enhanced inflammation. Previous studies have shown that biotin affects the functions of adaptive immune T and NK cells, but its effect(s) on innate immune cells is not known. Because of that and because vitamins such as vitamins A and D have a profound effect on dendritic cell (DC) function, we investigated the effect of biotin levels on the functions of human monocyte-derived DCs. Culture of DCs in a biotin-deficient medium (BDM) and subsequent activation with LPS resulted in enhanced secretion of the proinflammatory cytokines TNF-α, IL-12p40, IL-23, and IL-1β compared with LPS-activated DCs cultured in biotin-sufficient (control) and biotin-oversupplemented media. Furthermore, LPS-activated DCs cultured in BDM displayed a significantly higher induction of IFN-γ and IL-17 indicating Th1/Th17 bias in T cells compared with cells maintained in biotin control or biotin-oversupplemented media. Investigations into the mechanisms suggested that impaired activation of AMP kinase in DCs cultured in BDM may be responsible for the observed increase in inflammatory responses. In summary, these results demonstrate for the first time that biotin deficiency enhances the inflammatory responses of DCs. This may therefore be one of the mechanism(s) that mediates the observed inflammation that occurs in biotin deficiency.

  6. Monosaccharide-responsive phenylboronate-polyol cell scaffolds for cell sheet and tissue engineering applications.

    Directory of Open Access Journals (Sweden)

    Rachamalla Maheedhar Reddy

    Full Text Available Analyte-responsive smart polymeric materials are of great interest and have been actively investigated in the field of regenerative medicine. Phenylboronate containing copolymers form gels with polyols under alkaline conditions. Monosaccharides, by virtue of their higher affinity towards boronate, can displace polyols and solubilize such gels. In the present study, we investigate the possibility of utilizing phenylboronate-polyol interactions at physiological pH in order to develop monosaccharide-responsive degradable scaffold materials for systems dealing with cells and tissues. Amine assisted phenylboronate-polyol interactions were employed to develop novel hydrogel and cryogel scaffolds at neutral pH. The scaffolds displayed monosaccharide inducible gel-sol phase transformability. In vitro cell culture studies demonstrated the ability of scaffolds to support cell adhesion, viability and proliferation. Fructose induced gel degradation is used to recover cells cultured on the hydrogels. The cryogels displayed open macroporous structure and superior mechanical properties. These novel phase transformable phenylboronate-polyol based scaffolds displayed a great potential for various cell sheet and tissue engineering applications. Their monosaccharide responsiveness at physiological pH is very useful and can be utilized in the fields of cell immobilization, spheroid culture, saccharide recognition and analyte-responsive drug delivery.

  7. Future Research Needed to Study the Response of an Explosive Assembly to Mechanical Insults

    Energy Technology Data Exchange (ETDEWEB)

    Reaugh, J. E. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

    2017-08-28

    HE ignition caused by shear localization is the principal concern for safety analyses of postulated mechanical insults to explosive assemblies. Although prompt detonation from shock is certainly a concern, insults that lead to prompt detonation are associated with high velocity, and correspondingly rare. For high-density HMX assemblies, an impact speed (by a steel object) of 400 m/s is needed to develop a detonation in a run distance less than 30 mm. To achieve a steady plane shock, which results in the shortest run distance to detonation for a given peak pressure, the impactor diameter must exceed 60 mm, and thickness approach 20 mm. Thinner plates and/or smaller diameter ones require even higher impact velocity. Ignitions from shear localization, however, have been observed from impacts less than 50 m/s in Steven tests, less than 30 m/s from spigot impact tests, and less than 10 m/s from various drop tests. This lower velocity range is much frequent in postulated mechanical insults. Preliminary computer simulations and analyses of a variety of such tests have suggested that although each is accompanied by shear localization, there are differing detailed mechanisms at work that cause the ignitions. We identify those mechanisms that may be at work in a variety of such tests, and suggest how models of shear ignition, such as HERMES, may be revised and calibrated to conform to experiment. We suggest combining additional experiments with computer simulations and model development to begin confirm or uncover mechanisms that may be at work in a specific postulated event.

  8. Gambling and the need for new responses in Public Health with an addiction "sine substantia".

    Science.gov (United States)

    Crusco, M; Massoni, F; Luzi, E; Ricci, P; Pelosi, M; Corbosiero, P; Rapp-Ricciardi, M; Ricci, S

    2016-01-01

    The Gambling Disorder (GD) was recently defined as a behavioral addiction by the "The Diagnostic and Statistical Manual of Mental Disorders IV"( DSM-V) since the clinical, neurobiological and psychopathological similarities led it to be defined it as an addiction "sine substantia". The aim of this study is to formulate an "identikit" of the gambler, to evaluate a possible association between GD / emotional specific factors and the correlation between GD / substance abuse, GD / suicide. In the study, 41 subjects were included (31 males and 10 females) and all were diagnosed with GD. A questionnaire was distributed containing 24 questions deriving from South Oaks Gambling Screen and the DSM-IVTR. The study showed that 51% of the respondents makes use of alcohol and / or drugs; that 73% of the patients started playing in order to relieve feelings of dysphoria and suffering consequences on work as well as family life (51%). A great deal of the respondents were indebted (39%) to the extent of needing to ask for loans from usurer (17%). Furthermore, 41% of the respondents in the sample showed that GD could be transformed into an alarming risk of suicide. The correlation between GD and drug abuse may depend on the brain function and the neural circuits that support impulsive behavior and the gratification mechanisms. Emotional experiences (stress, low level of education, divorce, poor social support) could constitute a possible risk factor that increases the GD. The committed offenses related to gambling could be explained by "loss of control". The results of the present study contributes to the body of knowledge regarding the size of phenomenon from a statistical and epidemiological point of view, suggesting the necessity for targeted information on the risks connected to GD in order to capture early warning signs which enables the intervention with suitable strategies.

  9. Binding of formyl peptides to Walker 256 carcinosarcoma cells and the chemotactic response of these cells

    Energy Technology Data Exchange (ETDEWEB)

    Rayner, D.C.; Orr, F.W.; Shiu, R.P.

    1985-05-01

    N-Formylmethionylleucylphenylalanine (fMLP) induces chemotaxis in leukocytes, the response being mediated by peptide binding to a receptor on the plasma membrane. In tumor cells, this peptide has been reported to induce cellular swelling and chemotaxis in vitro and to enhance the localization of circulating tumor cells in vivo. In the Boyden chamber, the authors evaluated the migratory responses of Walker carcinosarcoma 256 cells to varying concentrations of fMLP. Sigmoidal dose-response curves were obtained with the dose of chemotactic factor that elicits a half-maximal chemotactic response of 5.0 +/- 2.5 X 10(-8) M. Checkerboard analysis indicated that these responses were dependent upon a concentration gradient of fMLP with increases in migration of circa 2 to 2.5 times that of random movement. To examine the binding of fMLP, the tumor cells were incubated with 5 X 10(-9) M fML-(/sup 3/H)P in Hanks balanced salt solution. Specific binding (0.5 to 1% of total radioligand, to whole cells inhibited by 5 X 10(-6) M fMLP) approached equilibrium after 4 to 6 h at 4 degrees C and after 6 to 10 h at 22 degrees C. Autoradiographic studies demonstrated heterogeneous binding of the peptide by tumor cells and also showed its intracellular localization. In homogenates of Walker cells prepared in 0.1 M Tris HCl, pH 7.4, with 10 mM MgCl2 and bovine serum albumin (1 mg/ml), specific binding of approximately 0.5% of total fML-(/sup 3/H)P reached equilibrium after 60 min at 4 degrees C. In whole cells and homogenates, binding was reversible by addition of unlabeled fMLP.

  10. Cell geometry dictates TNFα-induced genome response.

    Science.gov (United States)

    Mitra, Aninda; Venkatachalapathy, Saradha; Ratna, Prasuna; Wang, Yejun; Jokhun, Doorgesh Sharma; Shivashankar, G V

    2017-05-16

    Cells in physiology integrate local soluble and mechanical signals to regulate genomic programs. Whereas the individual roles of these signals are well studied, the cellular responses to the combined chemical and physical signals are less explored. Here, we investigated the cross-talk between cellular geometry and TNFα signaling. We stabilized NIH 3T3 fibroblasts into rectangular anisotropic or circular isotropic geometries and stimulated them with TNFα and analyzed nuclear translocation of transcription regulators -NFκB (p65) and MKL and downstream gene-expression patterns. We found that TNFα induces geometry-dependent actin depolymerization, which enhances IκB degradation, p65 nuclear translocation, nuclear exit of MKL, and sequestration of p65 at the RNA-polymerase-II foci. Further, global transcription profile of cells under matrix-TNFα interplay reveals a geometry-dependent gene-expression pattern. At a functional level, we find cell geometry affects TNFα-induced cell proliferation. Our results provide compelling evidence that fibroblasts, depending on their geometries, elicit distinct cellular responses for the same cytokine.

  11. PKC activation induces inflammatory response and cell death in human bronchial epithelial cells.

    Directory of Open Access Journals (Sweden)

    Hyunhee Kim

    Full Text Available A variety of airborne pathogens can induce inflammatory responses in airway epithelial cells, which is a crucial component of host defence. However, excessive inflammatory responses and chronic inflammation also contribute to different diseases of the respiratory system. We hypothesized that the activation of protein kinase C (PKC is one of the essential mechanisms of inflammatory response in airway epithelial cells. In the present study, we stimulated human bronchial lung epithelial (BEAS-2B cells with the phorbol ester Phorbol 12, 13-dibutyrate (PDBu, and examined gene expression profile using microarrays. Microarray analysis suggests that PKC activation induced dramatic changes in gene expression related to multiple cellular functions. The top two interaction networks generated from these changes were centered on NFκB and TNF-α, which are two commonly known pathways for cell death and inflammation. Subsequent tests confirmed the decrease in cell viability and an increase in the production of various cytokines. Interestingly, each of the increased cytokines was differentially regulated at mRNA and/or protein levels by different sub-classes of PKC isozymes. We conclude that pathological cell death and cytokine production in airway epithelial cells in various situations may be mediated through PKC related signaling pathways. These findings suggest that PKCs can be new targets for treatment of lung diseases.

  12. Designing, delivering and evaluating a distance learning nursing course responsive to students needs.

    Science.gov (United States)

    Sowan, Azizeh K; Jenkins, Louise S

    2013-06-01

    related to lack of time management skills and negative attitudes toward group assignments. The mean final course grade of the distance section (80±8.2) was significantly higher than the hybrid section (72.2±9.5), (t=3.5, pstudents with limited resources. Institutions have to make strategic decisions on how to optimize the use of technology to fit their individualized learning environments. Instructors need to become familiar with the characteristics of students cohort served by the course and design the course accordingly. In addition, students should be guided on how to manage their time in distance learning environments and work effectively in group assignments. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  13. Natural Killer Cell Response to Chemotherapy-Stressed Cancer Cells: Role in Tumor Immunosurveillance

    Directory of Open Access Journals (Sweden)

    Alessandra Zingoni

    2017-09-01

    Full Text Available Natural killer (NK cells are innate cytotoxic lymphoid cells that actively prevent neoplastic development, growth, and metastatic dissemination in a process called cancer immunosurveillance. An equilibrium between immune control and tumor growth is maintained as long as cancer cells evade immunosurveillance. Therapies designed to kill cancer cells and to simultaneously sustain host antitumor immunity are an appealing strategy to control tumor growth. Several chemotherapeutic agents, depending on which drugs and doses are used, give rise to DNA damage and cancer cell death by means of apoptosis, immunogenic cell death, or other forms of non-apoptotic death (i.e., mitotic catastrophe, senescence, and autophagy. However, it is becoming increasingly clear that they can trigger additional stress responses. Indeed, relevant immunostimulating effects of different therapeutic programs include also the activation of pathways able to promote their recognition by immune effector cells. Among stress-inducible immunostimulating proteins, changes in the expression levels of NK cell-activating and inhibitory ligands, as well as of death receptors on tumor cells, play a critical role in their detection and elimination by innate immune effectors, including NK cells. Here, we will review recent advances in chemotherapy-mediated cellular stress pathways able to stimulate NK cell effector functions. In particular, we will address how these cytotoxic lymphocytes sense and respond to different types of drug-induced stresses contributing to anticancer activity.

  14. Polyplex exposure inhibits cell cycle, increases inflammatory response, and can cause protein expression without cell division.

    Science.gov (United States)

    Matz, Rebecca L; Erickson, Blake; Vaidyanathan, Sriram; Kukowska-Latallo, Jolanta F; Baker, James R; Orr, Bradford G; Banaszak Holl, Mark M

    2013-04-01

    We sought to evaluate the relationship between cell division and protein expression when using commercial poly(ethylenimine) (PEI)-based polyplexes. The membrane dye PKH26 was used to assess cell division, and cyan fluorescent protein (CFP) was used to monitor protein expression. When analyzed at the whole population level, a greater number of cells divided than expressed protein, regardless of the level of protein expression observed, giving apparent consistency with the hypothesis that protein expression requires cells to pass through mitosis in order for the transgene to overcome the nuclear membrane. However, when the polyplex-exposed population was evaluated for the amount of division in the protein-expressing subpopulation, it was observed that substantial amounts of expression had occurred in the absence of division. Indeed, in HeLa S3 cells, this represented the majority of expressing cells. Of interest, the doubling time for both cell lines was slowed by ~2-fold upon exposure to polyplexes. This change was not altered by the origin of the plasmid DNA (pDNA) transgene promoter (cytomegalovirus (CMV) or elongation factor-1 alpha (EF1α)). Gene expression arrays in polyplex-exposed HeLa S3 cells showed upregulation of cell cycle arrest genes and downregulation of genes related to mitosis. Chemokine, interleukin, and toll-like receptor genes were also upregulated, suggesting activation of proinflammatory pathways. In summary, we find evidence that a cell division-independent expression pathway exists, and that polyplex exposure slows cell division and increases inflammatory response.

  15. Tracking the elusive cytotoxic T cell response in pigs

    DEFF Research Database (Denmark)

    Jungersen, Gregers; Nielsen, Morten; Overgaard, Nana Haahr

    Quantitative and qualitative assessment of antigen-specific cytotoxic T cell (CTL) responses in pigs is not a straightforward process. Through the years we have developed a series of reagents, tools and protocols to characterize peptide-specific CTL responses in pigs. The most common recombinant...... SLA heavy chains were produced and peptide binding motifs were determined by assays measuring the affinity and stability of the peptide-SLA complex (pSLA) interaction. These results have been used to train neural networks to predict the binding of any pSLA (http...... developed a protocol for intraperitoneal delivery of peptides formulated in poly(I:C)/MMG-decorated liposomes (CAF09) to investigate the influence of peptide dose on the generation of CTL vs. antibody responses. Finally, the induced CTL killing was assessed by an in vivo cytotoxicity assay, where purified...

  16. Cell mediated immune response in human antirabies revaccination

    Directory of Open Access Journals (Sweden)

    Débora Regina Veiga

    1987-04-01

    Full Text Available The occurrence of secondary cell mediated immune response (CMI in human antirabies immunization was studied. The Puenzalida & Palácios vaccine was used because it is routinely used in Brazil. CMI was evaluated by lymphoblastic transformation indices obtained in whole blood culture in the presence of rabies and control (nervous tissue antigens. Eleven volunteers submitted to revaccination constituted the group under study, while three other volunteers submitted primo vaccination were utilized as control group. A clear secondary CMI to rabies antigen was detected in all the revaccinated volunteers who showed earlier and more intense response than the control group. Response to the control antigen, however, present in all the components of the first group was not detectable in two out of the three primovaccinated and very low in the third one.

  17. Gene expression in epithelial cells in response to pneumovirus infection

    Directory of Open Access Journals (Sweden)

    Rosenberg Helene F

    2001-05-01

    Full Text Available Abstract Respiratory syncytial virus (RSV and pneumonia virus of mice (PVM are viruses of the family Paramyxoviridae, subfamily pneumovirus, which cause clinically important respiratory infections in humans and rodents, respectively. The respiratory epithelial target cells respond to viral infection with specific alterations in gene expression, including production of chemoattractant cytokines, adhesion molecules, elements that are related to the apoptosis response, and others that remain incompletely understood. Here we review our current understanding of these mucosal responses and discuss several genomic approaches, including differential display reverse transcription-polymerase chain reaction (PCR and gene array strategies, that will permit us to unravel the nature of these responses in a more complete and systematic manner.

  18. Improving health promotion through central rating of interventions: the need for Responsive Guidance.

    Science.gov (United States)

    Kok, Maarten Olivier; Bal, Roland; Roelefs, Caspar David; Schuit, Albertine Jantine

    2017-11-23

    beneficial, the evidence based-inspired ERS approach is too limited to guide both intervention development and the improvement of health promotion in practice. To better contribute to improving health promotion, a more reflexive and responsive guidance approach is required, namely one which stimulates the improvement of different intervention aspects, provides targeted recommendations to practitioners and provides feedback to those who develop and rate interventions.

  19. Influence of Dendritic Cells on B-Cell Responses during HIV Infection

    Directory of Open Access Journals (Sweden)

    Johanne Poudrier

    2012-01-01

    Full Text Available Dendritic cells (DCs modulate B-cell differentiation, activation, and survival mainly through production of growth factors such as B lymphocyte stimulator (BLyS/BAFF. DC populations have been reported to be affected in number, phenotype and function during HIV infection and such alterations may contribute to the dysregulation of the B-cell compartment. Herein, we reflect on the potential impact of DC on the pathogenesis of HIV-related B cell disorders, and how DC status may modulate the outcome of mucosal B cell responses against HIV, which are pivotal to the control of disease. A concept that could be extrapolated to the overall outcome of HIV disease, whereby control versus progression may reside in the host’s capacity to maintain DC homeostasis at mucosal sites, where DC populations present an inherent capacity of modulating the balance between tolerance and protection, and are amongst the earliest cell types to be exposed to the virus.

  20. Airway epithelial cell response to human metapneumovirus infection

    International Nuclear Information System (INIS)

    Bao, X.; Liu, T.; Spetch, L.; Kolli, D.; Garofalo, R.P.; Casola, A.

    2007-01-01

    Human metapneumovirus (hMPV) is a major cause of lower respiratory tract infections (LRTIs) in infants, elderly and immunocompromised patients. In this study, we show that hMPV can infect in a similar manner epithelial cells representative of different tracts of the airways. hMPV-induced expression of chemokines IL-8 and RANTES in primary small alveolar epithelial cells (SAE) and in a human alveolar type II-like epithelial cell line (A549) was similar, suggesting that A549 cells can be used as a model to study lower airway epithelial cell responses to hMPV infection. A549 secreted a variety of CXC and CC chemokines, cytokines and type I interferons, following hMPV infection. hMPV was also a strong inducer of transcription factors belonging to nuclear factor (NF)-κB, interferon regulatory factors (IRFs) and signal transducers and activators of transcription (STATs) families, which are known to orchestrate the expression of inflammatory and immunomodulatory mediators

  1. Hemopoietic cell precursor responses to erythropoietin in plasma clot cultures

    Energy Technology Data Exchange (ETDEWEB)

    Kennedy, W.L.

    1979-01-01

    The time dependence of the response of mouse bone marrow cells to erythropoietin (Ep) in vitro was studied. Experiments include studies on the Ep response of marrow cells from normal, plethoric, or bled mice. Results with normal marrow reveal: (1) Not all erythroid precursors (CFU-E) are alike in their response to Ep. A significant number of the precursors develop to a mature erythroid colony after very short Ep exposures, but they account for only approx. 13% of the total colonies generated when Ep is active for 48 hrs. If Ep is active more than 6 hrs, a second population of erythroid colonies emerges at a nearly constant rate until the end of the culture. Full erythroid colony production requires prolonged exposure to erythropoietin. (2) The longer erythropoietin is actively present, the larger the number of erythroid colonies that reach 17 cells or more. Two distinct populations of immediate erythroid precursors are also present in marrow from plethoric mice. In these mice, total colony numbers are equal to or below those obtained from normal mice. However, the population of fast-responding CFU-E is consistently decreased to 10 to 20% of that found in normal marrow. The remaining colonies are formed from plethoric marrow at a rate equal to normal marrow. With increasing Ep exposures, the number of large colonies produced increases. From the marrow of bled mice, total erythroid colony production is equal to or above that of normal marrow. Two populations of colony-forming cells are again evident, with the fast-responding CFU-E being below normal levels. The lack of colonies from this group was compensated in bled mice by rapid colony production in the second population. A real increase in numbers of precursors present in this pool increased the rate of colony production in culture to twice that of normal marrow. The number of large colonies obtained from bled mice was again increased as the Ep exposure was lengthened. (ERB)

  2. Temporal properties of network-mediated responses to repetitive stimuli are dependent upon retinal ganglion cell type

    Science.gov (United States)

    Im, Maesoon; Fried, Shelley I.

    2016-04-01

    Objective. To provide artificially-elicited vision that is temporally dynamic, retinal prosthetic devices will need to repeatedly stimulate retinal neurons. However, given the diversity of physiological types of retinal ganglion cells (RGCs) as well as the heterogeneity of their responses to electric stimulation, temporal properties of RGC responses have not been adequately investigated. Here, we explored the cell type dependence of network-mediated RGC responses to repetitive electric stimulation at various stimulation rates. Approach. We examined responses of ON and OFF types of RGCs in the rabbit retinal explant to five consecutive stimuli with varying inter-stimulus intervals (10-1000 ms). Each stimulus was a 4 ms long monophasic sinusoidal cathodal current, which was applied epiretinally via a conical electrode. Spiking activity of targeted RGCs was recorded using a cell-attached patch electrode. Main results. ON and OFF cells had distinct responses to repetitive stimuli. Consistent with earlier studies, OFF cells always generated reduced responses to subsequent stimuli compared to responses to the first stimulus. In contrast, a new stimulus to ON cells suppressed all pending/ongoing responses from previous stimuli and initiated its own response that was remarkably similar to the response from a single stimulus in isolation. This previously unreported ‘reset’ behavior was observed exclusively and consistently in ON cells. These contrasts between ON and OFF cells created a range of stimulation rates (4-7 Hz) that maximized the ratio of the responses arising in ON versus OFF cells. Significance. Previous clinical testing reported that subjects perceive bright phosphenes (ON responses) and also prefer stimulation rates of 5-7 Hz. Our results suggest that responses of ON cells are weak at high rates of stimulation (> ˜7 Hz) due to the reset while responses of OFF cells are strong at low rates (cells more closely match physiological patterns (Im and Fried 2015

  3. Do we still need human embryonic stem cells for stem cell-based therapies? Epistemic and ethical aspects.

    Science.gov (United States)

    Hug, Kristina; Hermerén, Göran

    2011-11-01

    While scientific community disagrees about similarities and differences between human embryonic stem (hES) cells and human induced pluripotent stem (hiPS) cells, some politicians embrace translational hiPS cell research as a replacement for translational hES cell research. We examine the ethical relevance of the main differences between hES and hiPS cell-based therapies and discuss whether, given the current state of knowledge, certain differences are essential. We discuss whether well-founded preferences can be made in hypothetical scenarios with varying levels of patient safety, treatment efficacy, treatment accessibility and ethical controversy.

  4. Mesenchymal stem cells: environmentally responsive therapeutics for regenerative medicine.

    Science.gov (United States)

    Murphy, Matthew B; Moncivais, Kathryn; Caplan, Arnold I

    2013-11-15

    Mesenchymal stem cells (MSCs) are partially defined by their ability to differentiate into tissues including bone, cartilage and adipose in vitro, but it is their trophic, paracrine and immunomodulatory functions that may have the greatest therapeutic impact in vivo. Unlike pharmaceutical treatments that deliver a single agent at a specific dose, MSCs are site regulated and secrete bioactive factors and signals at variable concentrations in response to local microenvironmental cues. Significant progress has been made in understanding the biochemical and metabolic mechanisms and feedback associated with MSC response. The anti-inflammatory and immunomodulatory capacity of MSC may be paramount in the restoration of localized or systemic conditions for normal healing and tissue regeneration. Allogeneic MSC treatments, categorized as a drug by regulatory agencies, have been widely pursued, but new studies demonstrate the efficacy of autologous MSC therapies, even for individuals affected by a disease state. Safety and regulatory concerns surrounding allogeneic cell preparations make autologous and minimally manipulated cell therapies an attractive option for many regenerative, anti-inflammatory and autoimmune applications.

  5. Variation in drug sensitivity of malignant mesothelioma cell lines with substantial effects of selenite and bortezomib, highlights need for individualized therapy.

    Directory of Open Access Journals (Sweden)

    Adam Szulkin

    Full Text Available Malignant mesothelioma cells have an epithelioid or sarcomatoid morphology, both of which may be present in the same tumor. The sarcomatoid phenotype is associated with worse prognosis and heterogeneity of mesothelioma cells may contribute to therapy resistance, which is often seen in mesothelioma. This study aimed to investigate differences in sensitivity between mesothelioma cell lines to anti-cancer drugs. We studied two novel drugs, selenite and bortezomib and compared their effect to four conventional drugs. We also investigated the immunoreactivity of potential predictive markers for drug sensitivity; Pgp, MRP-1, ERCC1, RRM1, TS, xCT and proteasome 20S subunit.We treated six mesothelioma cell lines with selenite, bortezomib, carboplatin, pemetrexed, doxorubicin or gemcitabine as single agents and in combinations. Viability was measured after 24 and 48 hours. Immunocytochemistry was used to detect predictive markers.As a single agent, selenite was effective on four out of six cell lines, and in combination with bortezomib yielded the greatest response in the studied mesothelioma cell lines. Cells with an epithelioid phenotype were generally more sensitive to the different drugs than the sarcomatoid cells. Extensive S-phase arrest was seen in pemetrexed-sensitive cell lines. MRP-1 predicted sensitivity of cell lines to treatment with carboplatin and xCT predicted pemetrexed effect.The observed heterogeneity in sensitivity of mesothelioma cell lines with different morphology highlights the need for more individualized therapy, requiring development of methods to predict drug sensitivity of individual tumors. Selenite and bortezomib showed a superior effect compared to conventional drugs, motivating clinical testing of these agents as future treatment regime components for patients with malignant mesothelioma.

  6. The mast cell integrates the splanchnic and systemic inflammatory response in portal hypertension

    Directory of Open Access Journals (Sweden)

    Arias Jorge-Luis

    2007-09-01

    Full Text Available Abstract Portal hypertension is a clinical syndrome that is difficult to study in an isolated manner since it is always associated with a greater or lesser degree of liver functional impairment. The aim of this review is to integrate the complications related to chronic liver disease by using both, the array of mast cell functions and mediators, since they possibly are involved in the pathophysiological mechanisms of these complications. The portal vein ligated rat is the experimental model most widely used to study this syndrome and it has been considered that a systemic inflammatory response is produced. This response is mediated among other inflammatory cells by mast cells and it evolves in three linked pathological functional systems. The nervous functional system presents ischemia-reperfusion and edema (oxidative stress and would be responsible for hyperdynamic circulation; the immune functional system causes tissue infiltration by inflammatory cells, particularly mast cells and bacteria (enzymatic stress and the endocrine functional system presents endothelial proliferation (antioxidative and antienzymatic stress and angiogenesis. Mast cells could develop a key role in the expression of these three phenotypes because their mediators have the ability to produce all the aforementioned alterations, both at the splanchnic level (portal hypertensive enteropathy, mesenteric adenitis, liver steatosis and the systemic level (portal hypertensive encephalopathy. This hypothetical splanchnic and systemic inflammatory response would be aggravated during the progression of the chronic liver disease, since the antioxidant ability of the body decreases. Thus, a critical state is produced, in which the appearance of noxious factors would favor the development of a dedifferentiation process protagonized by the nervous functional system. This system rapidly induces an ischemia-reperfusion phenotype with hydration and salinization of the body (hepatorenal

  7. The circadian response of intrinsically photosensitive retinal ganglion cells.

    Directory of Open Access Journals (Sweden)

    Andrew J Zele

    Full Text Available Intrinsically photosensitive retinal ganglion cells (ipRGC signal environmental light level to the central circadian clock and contribute to the pupil light reflex. It is unknown if ipRGC activity is subject to extrinsic (central or intrinsic (retinal network-mediated circadian modulation during light entrainment and phase shifting. Eleven younger persons (18-30 years with no ophthalmological, medical or sleep disorders participated. The activity of the inner (ipRGC and outer retina (cone photoreceptors was assessed hourly using the pupil light reflex during a 24 h period of constant environmental illumination (10 lux. Exogenous circadian cues of activity, sleep, posture, caffeine, ambient temperature, caloric intake and ambient illumination were controlled. Dim-light melatonin onset (DLMO was determined from salivary melatonin assay at hourly intervals, and participant melatonin onset values were set to 14 h to adjust clock time to circadian time. Here we demonstrate in humans that the ipRGC controlled post-illumination pupil response has a circadian rhythm independent of external light cues. This circadian variation precedes melatonin onset and the minimum ipRGC driven pupil response occurs post melatonin onset. Outer retinal photoreceptor contributions to the inner retinal ipRGC driven post-illumination pupil response also show circadian variation whereas direct outer retinal cone inputs to the pupil light reflex do not, indicating that intrinsically photosensitive (melanopsin retinal ganglion cells mediate this circadian variation.

  8. From microgravity to osmotic conditions: mechanical integration of plant cells in response to stress

    Science.gov (United States)

    Wojtaszek, Przemyslaw; Kasprowicz, Anna; Michalak, Michal; Janczara, Renata; Volkmann, Dieter; Baluska, Frantisek

    Chemical reactions and interactions between molecules are commonly thought of as being at the basis of Life. Research of recent years, however, is more and more evidently indicating that physical forces are profoundly affecting the functioning of life at all levels of its organiza-tion. To detect and to respond to such forces, plant cells need to be integrated mechanically. Cell walls are the outermost functional zone of plant cells. They surround the individual cells, and also form a part of the apoplast. In cell suspensions, cell walls are embedded in the cul-ture medium which can be considered as a superapoplast. Through physical and chemical interactions they provide a basis for the structural and functional cell wall-plasma membrane-cytoskeleton (WMC) continuum spanning the whole cell. Here, the working of WMC contin-uum, and the participation of signalling molecules, like NO, would be presented in the context of plant responses to stress. In addition, the effects of the changing composition of WMC continuum will be considered, with particular attention paid to the modifications of the WMC components. Plant cells are normally adapted to changing osmotic conditions, resulting from variable wa-ter availability. The appearance of the osmotic stress activates adaptory mechanisms. If the strength of osmotic stress grows relatively slowly over longer period of time, the cells are able to adapt to conditions that are lethal to non-adapted cells. During stepwise adaptation of tobacco BY-2 suspension cells to the presence of various osmotically active agents, cells diverged into independent, osmoticum type-specific lines. In response to ionic agents (NaCl, KCl), the adhe-sive properties were increased and randomly dividing cells formed clumps, while cells adapted to nonionic osmotica (mannitol, sorbitol, PEG) revealed ordered pattern of precisely positioned cell divisions, resulting in the formation of long cell files. Changes in the growth patterns were accompanied by

  9. Influence of cell cycle on responses of MCF-7 cells to benzo[a]pyrene

    Directory of Open Access Journals (Sweden)

    Giddings Ian

    2011-06-01

    Full Text Available Abstract Background Benzo[a]pyrene (BaP is a widespread environmental genotoxic carcinogen that damages DNA by forming adducts. This damage along with activation of the aryl hydrocarbon receptor (AHR induces complex transcriptional responses in cells. To investigate whether human cells are more susceptible to BaP in a particular phase of the cell cycle, synchronised breast carcinoma MCF-7 cells were exposed to BaP. Cell cycle progression was analysed by flow cytometry, DNA adduct formation was assessed by 32P-postlabeling analysis, microarrays of 44K human genome-wide oligos and RT-PCR were used to detect gene expression (mRNA changes and Western blotting was performed to determine the expression of some proteins, including cytochrome P450 (CYP 1A1 and CYP1B1, which are involved in BaP metabolism. Results Following BaP exposure, cells evaded G1 arrest and accumulated in S-phase. Higher levels of DNA damage occurred in S- and G2/M- compared with G0/G1-enriched cultures. Genes that were found to have altered expression included those involved in xenobiotic metabolism, apoptosis, cell cycle regulation and DNA repair. Gene ontology and pathway analysis showed the involvement of various signalling pathways in response to BaP exposure, such as the Catenin/Wnt pathway in G1, the ERK pathway in G1 and S, the Nrf2 pathway in S and G2/M and the Akt pathway in G2/M. An important finding was that higher levels of DNA damage in S- and G2/M-enriched cultures correlated with higher levels of CYP1A1 and CYP1B1 mRNA and proteins. Moreover, exposure of synchronised MCF-7 cells to BaP-7,8-diol-9,10-epoxide (BPDE, the ultimate carcinogenic metabolite of BaP, did not result in significant changes in DNA adduct levels at different phases of the cell cycle. Conclusions This study characterised the complex gene response to BaP in MCF-7 cells and revealed a strong correlation between the varying efficiency of BaP metabolism and DNA damage in different phases of the cell

  10. Stromal Cells and Integrins: Conforming to the Needs of the Tumor Microenvironment

    Directory of Open Access Journals (Sweden)

    Aimee Alphonso

    2009-12-01

    Full Text Available The microenvironment of a tumor is constituted of a heterogenous population of stromal cells, extracellular matrix components, and secreted factors, all of which make the tumor microenvironment distinct from that of normal tissue. Unlike healthy cells, tumor cells require these unique surroundings to metastasize, spread, and form a secondary tumor at a distant site. In this review, we discuss that stromal cells such as fibroblasts and immune cells including macrophages, their secreted factors, such as vascular endothelial growth factor, transforming growth factor β, and various chemokines, and the integrins that connect the various cell types play a particularly vital role in the survival of a growing tumor mass. Macrophages and fibroblasts are uniquely plastic cells because they are not only able to switch from tumor suppressing to tumor supporting phenotypes but also able to adopt various tumor-supporting functions based on their location within the microenvironment. Integrins serve as the backbone for all of these prometastatic operations because their function as cell-cell and cell-matrix signal transducers are important for the heterogenous components of the microenvironment to communicate.

  11. Professional Roles and Responsibilities in Meeting the Needs of Children with Speech, Language and Communication Needs: Joint Working between Educational Psychologists and Speech and Language Therapists

    Science.gov (United States)

    McConnellogue, Sheila

    2011-01-01

    There is a large population of children with speech, language and communication needs who have additional special educational needs (SEN). Whilst professional collaboration between education and health professionals is recommended to ensure an integrated delivery of statutory services for this population of children, formal frameworks should be…

  12. Classroom Behaviour Management Strategies in Response to Problematic Behaviours of Primary School Children with Special Educational Needs: Views of Special Educational Needs Coordinators

    Science.gov (United States)

    Nye, Elizabeth; Gardner, Frances; Hansford, Lorraine; Edwards, Vanessa; Hayes, Rachel; Ford, Tamsin

    2016-01-01

    Children identified with special educational needs (SEN) and behavioural difficulties present extra challenges to educators and require additional supports in school. This paper presents views from special educational needs coordinators (SENCos) on various strategies used by educators to support children identified with SEN and problematic…

  13. The Importance of the Nurse Cells and Regulatory Cells in the Control of T Lymphocyte Responses

    Directory of Open Access Journals (Sweden)

    María Guadalupe Reyes García

    2013-01-01

    Full Text Available T lymphocytes from the immune system are bone marrow-derived cells whose development and activities are carefully supervised by two sets of accessory cells. In the thymus, the immature young T lymphocytes are engulfed by epithelial “nurse cells” and retained in vacuoles, where most of them (95% are negatively selected and removed when they have an incomplete development or express high affinity autoreactive receptors. The mature T lymphocytes that survive to this selection process leave the thymus and are controlled in the periphery by another subpopulation of accessory cells called “regulatory cells,” which reduce any excessive immune response and the risk of collateral injuries to healthy tissues. By different times and procedures, nurse cells and regulatory cells control both the development and the functions of T lymphocyte subpopulations. Disorders in the T lymphocytes development and migration have been observed in some parasitic diseases, which disrupt the thymic microenvironment of nurse cells. In other cases, parasites stimulate rather than depress the functions of regulatory T cells decreasing T-mediated host damages. This paper is a short review regarding some features of these accessory cells and their main interactions with T immature and mature lymphocytes. The modulatory role that neurotransmitters and hormones play in these interactions is also revised.

  14. Cell phone use and acoustic neuroma: the need for standardized questionnaires and access to industry data.

    Science.gov (United States)

    Han, Yueh-Ying; Kano, Hideyuki; Davis, Devra L; Niranjan, Ajay; Lunsford, L Dade

    2009-09-01

    The capacity of radiofrequency from cell phones to be absorbed into the brain has prompted concerns that regular cell phone use may increase the risk of acoustic neuroma (AN) and other brain tumors. This article critically evaluates current literature on cell phone use and AN risks and proposes additional studies to clarify any possible linkage. Through a PubMed search, we identified and reviewed 10 case-control studies and 1 cohort study of AN risks associated with cell phone use and a meta-analysis of long-term mobile phone use and its association with AN and other brain tumors. Most studies did not find association between the development of AN and cell phone use, but some studies that followed cases for 10 years or more did show an association. Among 10 case-control studies, odds ratios for AN associated with regular cell phone use ranged from 0.5 (95% confidence interval [CI], 0.2-1.0) to 4.2 (95% CI, 1.8-10). Cell phone use was not associated with increased risk for AN in the Danish cohort study, which excluded business users from their study. The meta-analysis, which included 3 case-control studies, found that subjects who used cell phones for at least 10 years had a 2.4-fold greater risk of developing ipsilateral AN. In general, retrospective studies are limited in the ability to assess cell phone exposure because of recall bias and misclassification. The evaluation of AN risk factors is challenging due to its long latency. Some studies of longer term cell phone use have found an increased risk of ipsilateral AN. Adopting a prospective approach to acquire data on cell phone use, obtaining retrospective billing records that provide independent evaluations of exposures, and incorporating information on other key potential risk factors from questionnaires could markedly advance the capacity of studies to evaluate the impact of cell phones on AN.

  15. Leukemia-associated activating mutation of Flt3 expands dendritic cells and alters T cell responses.

    Science.gov (United States)

    Lau, Colleen M; Nish, Simone A; Yogev, Nir; Waisman, Ari; Reiner, Steven L; Reizis, Boris

    2016-03-07

    A common genetic alteration in acute myeloid leukemia is the internal tandem duplication (ITD) in FLT3, the receptor for cytokine FLT3 ligand (FLT3L). Constitutively active FLT3-ITD promotes the expansion of transformed progenitors, but also has pleiotropic effects on hematopoiesis. We analyzed the effect of FLT3-ITD on dendritic cells (DCs), which express FLT3 and can be expanded by FLT3L administration. Pre-leukemic mice with the Flt3(ITD) knock-in allele manifested an expansion of classical DCs (cDCs) and plasmacytoid DCs. The expansion originated in DC progenitors, was cell intrinsic, and was further enhanced in Flt3(ITD/ITD) mice. The mutation caused the down-regulation of Flt3 on the surface of DCs and reduced their responsiveness to Flt3L. Both canonical Batf3-dependent CD8(+) cDCs and noncanonical CD8(+) cDCs were expanded and showed specific alterations in their expression profiles. Flt3(ITD) mice showed enhanced capacity to support T cell proliferation, including a cell-extrinsic expansion of regulatory T (T reg) cells. Accordingly, these mice restricted alloreactive T cell responses during graft-versus-host reaction, but failed to control autoimmunity without T reg cells. Thus, the FLT3-ITD mutation directly affects DC development, indirectly modulating T cell homeostasis and supporting T reg cell expansion. We hypothesize that this effect of FLT3-ITD might subvert immunosurveillance and promote leukemogenesis in a cell-extrinsic manner. © 2016 Lau et al.

  16. Need of surveillance response systems to combat Ebola outbreaks and other emerging infectious diseases in African countries

    Science.gov (United States)

    2014-01-01

    There is growing concern in Sub-Saharan Africa about the spread of the Ebola virus disease (EVD), formerly known as Ebola haemorrhagic fever, and the public health burden that it ensues. Since 1976, there have been 885,343 suspected and laboratory confirmed cases of EVD and the disease has claimed 2,512 cases and 932 fatality in West Africa. There are certain requirements that must be met when responding to EVD outbreaks and this process could incur certain challenges. For the purposes of this paper, five have been identified: (i) the deficiency in the development and implementation of surveillance response systems against Ebola and others infectious disease outbreaks in Africa; (ii) the lack of education and knowledge resulting in an EVD outbreak triggering panic, anxiety, psychosocial trauma, isolation and dignity impounding, stigmatisation, community ostracism and resistance to associated socio-ecological and public health consequences; (iii) limited financial resources, human technical capacity and weak community and national health system operational plans for prevention and control responses, practices and management; (iv) inadequate leadership and coordination; and (v) the lack of development of new strategies, tools and approaches, such as improved diagnostics and novel therapies including vaccines which can assist in preventing, controlling and containing Ebola outbreaks as well as the spread of the disease. Hence, there is an urgent need to develop and implement an active early warning alert and surveillance response system for outbreak response and control of emerging infectious diseases. Understanding the unending risks of transmission dynamics and resurgence is essential in implementing rapid effective response interventions tailored to specific local settings and contexts. Therefore, the following actions are recommended: (i) national and regional inter-sectorial and trans-disciplinary surveillance response systems that include early warnings, as well

  17. Knowledge, Experiences and Training Needs of Health Professionals about Disaster Preparedness and Response in Southwest Ethiopia: a cross sectional study.

    Science.gov (United States)

    Berhanu, Negalign; Abrha, Hailay; Ejigu, Yohannes; Woldemichael, Kifle

    2016-09-01

    Over the past decade, the magnitude and intensity of disasters have been vividly rising globally due to the forces of nature or man. This study aimed at assessing the perceived knowledge, experiences and training needs of health professionals regarding disasters, their prevention and management in Jimma Zone, Southwest Ethiopia. An institution based cross-sectional survey was conducted on 377 health professionals taken from 9 randomly selected districts out of 18. All health professionals working at health offices, hospitals and health centers were included. Data were collected using a structured questionnaire which was developed by the investigators after reviewing the relevant literature in the field. Data were coded and entered into SPSS 20 software for cleaning and analysis. Descriptive and logistic regression analyses were done. The majority (85.1%) of the participants were able to define the concept of disaster from various perspectives; 9.7% did not know about it at all and 5.2% could describe the concept partially or misconceived it. The majority (84.3%) agreed that disaster has direct public health consequences on humans. The main public health consequence of disaster the participants mentioned was environmental pollution (65.8%). Malaria, measles and diarrhoeal diseases accounted for 35.5%, 33.1% and 10.5% of the epidemics, respectively. Only 20.6% of the respondents were trained on disaster related topics in the last two years. The majority felt that they had poor knowledge on early warning indicators of drought (48.0%) and flood (48.0%). Simialry, 50.8%, 47.7%, 51.1% and 42.6% of the participants had poor knowledge on preparedness to drought, preparedness to flood, response to drought, response to flood. On composite scale, they generally perceived to have adequate (29.4%), moderate (32.4%) and poor (38.2%) knowledge about early warning information bout, preparedness for and response to common disasters. A vast majority (92.8%) reported that they need

  18. Endoplasmic Reticulum Stress, Unfolded Protein Response, and Cancer Cell Fate

    Directory of Open Access Journals (Sweden)

    Marco Corazzari

    2017-04-01

    Full Text Available Perturbation of endoplasmic reticulum (ER homeostasis results in a stress condition termed “ER stress” determining the activation of a finely regulated program defined as unfolded protein response (UPR and whose primary aim is to restore this organelle’s physiological activity. Several physiological and pathological stimuli deregulate normal ER activity causing UPR activation, such as hypoxia, glucose shortage, genome instability, and cytotoxic compounds administration. Some of these stimuli are frequently observed during uncontrolled proliferation of transformed cells, resulting in tumor core formation and stage progression. Therefore, it is not surprising that ER stress is usually induced during solid tumor development and stage progression, becoming an hallmark of such malignancies. Several UPR components are in fact deregulated in different tumor types, and accumulating data indicate their active involvement in tumor development/progression. However, although the UPR program is primarily a pro-survival process, sustained and/or prolonged stress may result in cell death induction. Therefore, understanding the mechanism(s regulating the cell survival/death decision under ER stress condition may be crucial in order to specifically target tumor cells and possibly circumvent or overcome tumor resistance to therapies. In this review, we discuss the role played by the UPR program in tumor initiation, progression and resistance to therapy, highlighting the recent advances that have improved our understanding of the molecular mechanisms that regulate the survival/death switch.

  19. Response of a direct methanol fuel cell to fuel change

    Energy Technology Data Exchange (ETDEWEB)

    Leo, T.J. [Dpto de Sistemas Oceanicos y Navales- ETSI Navales, Univ. Politecnica de Madrid, Avda Arco de la Victoria s/n, 28040 Madrid (Spain); Raso, M.A.; de la Blanca, E. Sanchez [Dpto de Quimica Fisica I- Fac. CC. Quimicas, Univ. Complutense de Madrid, Avda Complutense s/n, 28040 Madrid (Spain); Navarro, E.; Villanueva, M. [Dpto de Motopropulsion y Termofluidodinamica, ETSI Aeronauticos, Univ. Politecnica de Madrid, Pza Cardenal Cisneros 3, 28040 Madrid (Spain); Moreno, B. [Instituto de Ceramica y Vidrio, Consejo Superior de Investigaciones Cientificas, C/Kelsen 5, Campus de la UAM, 28049 Cantoblanco, Madrid (Spain)

    2010-10-15

    Methanol and ethanol have recently received much attention as liquid fuels particularly as alternative 'energy-vectors' for the future. In this sense, to find a direct alcohol fuel cell that able to interchange the fuel without losing performances in an appreciable way would represent an evident advantage in the field of portable applications. In this work, the response of a in-house direct methanol fuel cell (DMFC) to the change of fuel from methanol to ethanol and its behaviour at different ambient temperature values have been investigated. A corrosion study on materials suitable to fabricate the bipolar plates has been carried out and either 316- or 2205-duplex stainless steels have proved to be adequate for using in direct alcohol fuel cells. Polarization curves have been measured at different ambient temperature values, controlled by an experimental setup devised for this purpose. Data have been fitted to a model taking into account the temperature effect. For both fuels, methanol and ethanol, a linear dependence of adjustable parameters with temperature is obtained. Fuel cell performance comparison in terms of open circuit voltage, kinetic and resistance is established. (author)

  20. Micronutrient supplementation and T-cell mediated immune responses in patients with tuberculosis in Tanzania

    Science.gov (United States)

    Limited studies exist regarding whether incorporating micronutrient supplements during tuberculosis (TB) treatment may improve cell-mediated immune response. We examine the effect of micronutrient supplementation on lymphocyte proliferation response to mycobacteria or T cell mitogens in a randomize...

  1. Alteration of Lymphocyte Phenotype and Function in Sickle Cell Anemia: Implications for Vaccine Responses

    Science.gov (United States)

    Balandya, Emmanuel; Reynolds, Teri; Obaro, Stephen; Makani, Julie

    2016-01-01

    Individuals with sickle cell anemia (SCA) have increased susceptibility to infections, secondary to impairment of immune function. Besides the described dysfunction in innate immunity, including impaired opsonization and phagocytosis of bacteria, evidence of dysfunction of T and B lymphocytes in SCA has also been reported. This includes reduction in the proportion of circulating CD4+ and CD8+ T cells, reduction of CD4+ helper : CD8+ suppressor T cell ratio, aberrant activation and dysfunction of regulatory T cells (Treg), skewing of CD4+ T cells towards Th2 response and loss of IgM-secreting CD27+IgMhighIgDlow memory B cells. These changes occur on the background of immune activation characterized by predominance of memory CD4+ T cell phenotypes, increased Th17 signaling and elevated levels of C-reactive protein and pro-inflammatory cytokines IL-6 and TNF-α, which may affect the immunogenicity and protective efficacy of vaccines available to prevent infections in SCA. Thus, in order to optimize the use of vaccines in SCA, a thorough understanding of T and B lymphocyte functions and vaccine reactivity among individuals with SCA is needed. Studies should be encouraged of different SCA populations, including sub-Saharan Africa where the burden of SCA is highest. This article summarizes our current understanding of lymphocyte biology in SCA, and highlights areas that warrant future research. PMID:27237467

  2. MMP19 is essential for T cell development and T cell-mediated cutaneous immune responses

    Czech Academy of Sciences Publication Activity Database

    Beck, Inken; Ruckert, R.; Brandt, K.; Mueller, M.S.; Sadowski, T.; Brauer, R.; Schirmacher, P.; Mentlein, R.; Sedláček, Radislav

    2008-01-01

    Roč. 3, č. 6 (2008), e2343-e2343 E-ISSN 1932-6203 Institutional research plan: CEZ:AV0Z50520514; CEZ:AV0Z50520701 Keywords : matrix metalloproteinase * T cell * immune response Subject RIV: EB - Genetics ; Molecular Biology

  3. Response of cultured human airway epithelial cells to X-rays and energetic α-particles

    International Nuclear Information System (INIS)

    Yang, T.C.; Holley, W.R.; Curtis, S.B.; Gruenert, D.C.; California Univ., San Francisco, CA

    1990-01-01

    Radon and its progeny, which emit α-particles during decay, may play an important role in inducing human lung cancer. To gain a better understanding of the biological effects of α-particles in human lung we studied the response of cultured human airway epithelial cells to X-rays and monoenergetic helium ions. Experimental results indicated that the radiation response of primary cultures was similar to that for airway epithelial cells that were transformed with a plasmid containing an origin-defective SV40 virus. The RBE for cell inactivation determined by the ratio of D 0 for X-rays to that for 8 MeV helium ions was 1.8-2.2. The cross-section for helium ions, calculated from the D 0 value, was about 24 μm 2 for cells of the primary culture. This cross-section is significantly smaller than the average geometric nuclear area (∼ 180 μm 2 ), suggesting that an average of 7.5 α-particles (8 MeV helium ions) per cell nucleus are needed to induce a lethal lesion. (author)

  4. Response of hematopoietic stem cells to ionizing radiation

    International Nuclear Information System (INIS)

    Simonnet, A.

    2008-12-01

    experiment that a single TPO administration rescued the IR-impaired reconstitution capacity of HSCs early after exposure. In addition, the use of marrow cells from transgenic ubiquitous luciferase-expressing donors combined with bioluminescence imaging technology provided a valuable strategy that allowed visualizing HSC homing of TPO-treated compared to untreated irradiated donors, and enabled the identification of a preferential cellular expansion sites which were inaccessible to investigation in most studies. Finally, we observed that TPO injection right after irradiation considerably attenuates IR-induced long-term injury to the stem/progenitor compartment. Altogether, these data provide novel insights in the cellular response of HSC to IR and the beneficial effects of TPO administration to these cells. (author)

  5. Non-small-cell lung cancer cells combat epidermal growth factor receptor tyrosine kinase inhibition through immediate adhesion-related responses

    Directory of Open Access Journals (Sweden)

    Wang HY

    2016-05-01

    Full Text Available Hsian-Yu Wang,1,2 Min-Kung Hsu,3,4 Kai-Hsuan Wang,1 Ching-Ping Tseng,2,4 Feng-Chi Chen,3,4 John T-A Hsu1,4 1Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes (NHRI, Zhunan, Miaoli County, 2Institute of Molecular Medicine and Bioengineering, National Chiao Tung University (NCTU, Hsinchu, 3Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes (NHRI, Zhunan, Miaoli County, 4Department of Biological Science and Technology, National Chiao Tung University (NCTU, Hsinchu, Taiwan, Republic of China Background: Epidermal growth factor receptor (EGFR tyrosine kinase inhibitors (TKIs, such as gefitinib, erlotinib, and afatinib, have greatly improved treatment efficacy in non-small cell lung cancer (NSCLC patients with drug-sensitive EGFR mutations. However, in some TKI responders, the benefits of such targeted therapies are limited by the rapid development of resistance, and strategies to overcome this resistance are urgently needed. Studies of drug resistance in cancer cells typically involve long term in vitro induction to obtain stably acquired drug-resistant cells followed by elucidation of resistance mechanisms, but the immediate responses of cancer cells upon drug treatment have been ignored. The aim of this study was to investigate the immediate responses of NSCLC cells upon treatment with EGFR TKIs.Results: Both NSCLC cells, ie, PC9 and H1975, showed immediate enhanced adhesion-related responses as an apoptosis-countering mechanism upon first-time TKI treatment. By gene expression and pathway analysis, adhesion-related pathways were enriched in gefitinib-treated PC9 cells. Pathway inhibition by small-hairpin RNAs or small-molecule drugs revealed that within hours of EGFR TKI treatment, NSCLC cells used adhesion-related responses to combat the drugs. Importantly, we show here that the Src family inhibitor, dasatinib, dramatically inhibits

  6. Human Bronchial Epithelial Cell Response to Heavy Particle Exposure

    Science.gov (United States)

    Story, Michael; Ding, Liang-Hao; Minna, John; Park, Seong-mi; Peyton, Michael; Larsen, Jill

    2012-07-01

    A battery of non-oncogenically immortalized human bronchial epithelial cells (HBECs) are being used to examine the molecular changes that lead to lung carcinogenesis after exposure to heavy particles found in the free space environment. The goal is to ultimately identify biomarkers of radioresponse that can be used for prediction of carcinogenic risk for fatal lung cancer. Our initial studies have focused on the cell line HBEC3 KT and the isogenic variant HBEC3 KTR53, which overexpresses the RASv12 mutant and where p53 has been knocked down by shRNA, and is considered to be a more oncogenically progressed variant. We have previously described the response of HBEC3 KT at the cellular and molecular level, however, the focus here is on the rate of cellular transformation after HZE radiation exposure and the molecular changes in transformed cells. When comparing the two cell lines we find that there is a maximum rate of cellular transformation at 0.25 Gy when cells are exposed to 1 GeV Fe particles, and, for the HBEC3 KTR53 there are multiple pathways upregulated that promote anchorage independent growth including the mTOR pathway, the TGF-1 pathway, RhoA signaling and the ERK/MAPK pathway as early as 2 weeks after radiation. This does not occur in the HBEC3 KT cell line. Transformed HBEC3 KT cells do not show any morphologic or phenotypic changes when grown as cell cultures. HBEC3 KTR53 cells on the other hand show substantial changes in morphology from a cobblestone epithelial appearance to a mesenchymal appearance with a lack of contact inhibition. This epithelial to mesenchymal change in morphology is accompanied by the expression of vimentin and a reduction in the expression of E-cadherin, which are hallmarks of epithelial to mesenchymal transition. Interestingly, for HBEC3 KT transformed cells there are no mutations in the p53 gene, 2 of 15 clones were found to be heterozygous for the RASV12 mutation, and 3 of 15 clones expressed high levels of BigH3, a TGFB-responsive

  7. Hydrogenated amorphous silicon coatings may modulate gingival cell response

    Science.gov (United States)

    Mussano, F.; Genova, T.; Laurenti, M.; Munaron, L.; Pirri, C. F.; Rivolo, P.; Carossa, S.; Mandracci, P.

    2018-04-01

    Silicon-based materials present a high potential for dental implant applications, since silicon has been proven necessary for the correct bone formation in animals and humans. Notably, the addition of silicon is effective to enhance the bioactivity of hydroxyapatite and other biomaterials. The present work aims to expand the knowledge of the role exerted by hydrogen in the biological interaction of silicon-based materials, comparing two hydrogenated amorphous silicon coatings, with different hydrogen content, as means to enhance soft tissue cell adhesion. To accomplish this task, the films were produced by plasma enhanced chemical vapor deposition (PECVD) on titanium substrates and their surface composition and hydrogen content were analyzed by means of X-ray photoelectron spectroscopy (XPS) and Fourier-transform infrared spectrophotometry (FTIR) respectively. The surface energy and roughness were measured through optical contact angle analysis (OCA) and high-resolution mechanical profilometry respectively. Coated surfaces showed a slightly lower roughness, compared to bare titanium samples, regardless of the hydrogen content. The early cell responses of human keratinocytes and fibroblasts were tested on the above mentioned surface modifications, in terms of cell adhesion, viability and morphometrical assessment. Films with lower hydrogen content were endowed with a surface energy comparable to the titanium surfaces. Films with higher hydrogen incorporation displayed a lower surface oxidation and a considerably lower surface energy, compared to the less hydrogenated samples. As regards mean cell area and focal adhesion density, both a-Si coatings influenced fibroblasts, but had no significant effects on keratinocytes. On the contrary, hydrogen-rich films increased manifolds the adhesion and viability of keratinocytes, but not of fibroblasts, suggesting a selective biological effect on these cells.

  8. Induction of non-responsiveness in human allergen-specific type 2 T helper cells.

    Science.gov (United States)

    Yssel, H; Fasler, S; Lamb, J; de Vries, J E

    1994-12-01

    Activation of allergen-reactive human T helper (Th)2 cells in the absence of professional antigen-presenting cells, induces non-responsiveness or anergy in these cells in vitro. This induction of anergy is accompanied by phenotypic modulation and altered cytokine production. Furthermore, peptide-treated Th2 cells fail to provide B-cell help for IgE synthesis. Recent studies indicate that impaired signal transduction via the T-cell receptor may account for the lack of responsiveness to antigenic stimulation. Here, we review present knowledge on the cell biology of non-responsive or anergic Th2 cells.

  9. Inflammatory cell response to calcium phosphate biomaterial particles: an overview.

    Science.gov (United States)

    Velard, Frédéric; Braux, Julien; Amedee, Joëlle; Laquerriere, Patrice

    2013-02-01

    Bone is a metabolically active and highly organized tissue consisting of a mineral phase of hydroxyapatite (HA) and amorphous calcium phosphate (CaP) crystals deposited in an organic matrix. One objective of bone tissue engineering is to mimic the chemical and structural properties of this complex tissue. CaP ceramics, such as sintered HA and beta-tricalcium phosphate, are widely used as bone substitutes or prosthesis coatings because of their osteoconductive properties. These ceramic interactions with tissues induce a cell response that can be different according to the composition of the material. In this review, we discuss inflammatory cell responses to CaP materials to provide a comprehensive overview of mechanisms governing the integration or loosening of implants, which remains a major concern in tissue engineering. A focus on the effects of the functionalization of CaP biomaterials highlights potential ways to increase tissue integration and limit rejection processes. Copyright © 2012 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

  10. Use of comparative genomics approaches to characterize interspecies differences in response to environmental chemicals: Challenges, opportunities, and research needs

    International Nuclear Information System (INIS)

    Burgess-Herbert, Sarah L.; Euling, Susan Y.

    2013-01-01

    A critical challenge for environmental chemical risk assessment is the characterization and reduction of uncertainties introduced when extrapolating inferences from one species to another. The purpose of this article is to explore the challenges, opportunities, and research needs surrounding the issue of how genomics data and computational and systems level approaches can be applied to inform differences in response to environmental chemical exposure across species. We propose that the data, tools, and evolutionary framework of comparative genomics be adapted to inform interspecies differences in chemical mechanisms of action. We compare and contrast existing approaches, from disciplines as varied as evolutionary biology, systems biology, mathematics, and computer science, that can be used, modified, and combined in new ways to discover and characterize interspecies differences in chemical mechanism of action which, in turn, can be explored for application to risk assessment. We consider how genetic, protein, pathway, and network information can be interrogated from an evolutionary biology perspective to effectively characterize variations in biological processes of toxicological relevance among organisms. We conclude that comparative genomics approaches show promise for characterizing interspecies differences in mechanisms of action, and further, for improving our understanding of the uncertainties inherent in extrapolating inferences across species in both ecological and human health risk assessment. To achieve long-term relevance and consistent use in environmental chemical risk assessment, improved bioinformatics tools, computational methods robust to data gaps, and quantitative approaches for conducting extrapolations across species are critically needed. Specific areas ripe for research to address these needs are recommended

  11. Persistence of T-cell immune response induced by two acellular pertussis vaccines in children five years after primary vaccination.

    Science.gov (United States)

    Palazzo, Raffaella; Carollo, Maria; Bianco, Manuela; Fedele, Giorgio; Schiavoni, Ilaria; Pandolfi, Elisabetta; Villani, Alberto; Tozzi, Alberto E; Mascart, Françoise; Ausiello, Clara M

    2016-01-01

    The resurgence of pertussis suggests the need for greater efforts to understand the long-lasting protective responses induced by vaccination. In this paper we dissect the persistence of T memory responses induced by primary vaccination with two different acellular pertussis (aP) vaccines, hexavalent Hexavac® vaccine (Hexavac) (Sanofi Pasteur MSD) and Infanrix hexa® (Infanrix) (Glaxo-SmithKline Biologicals). We evaluated magnitude and duration of T-cell responses to pertussis toxin (PT) by measuring T-cell proliferation, cytokines (IL-2 and IFNγ) production and memory subsets in two groups of children 5 years after primary vaccination. Some of the enrolled children received only primary vaccination, while others had the pre-school boost dose. Positive T-cell responses to PT were detected in 36% of children. Percentage of responsive children, T-cell proliferation and CD4IL-2+ cells were significantly higher in the children primed with Hexavac than in those who received Infanrix vaccine. No major effects of the boost on PT-specific proliferation were observed. Overall, our data documented a persistence of T-cell memory against PT in a minor fraction of children 5 years after primary vaccination. The different responses induced by Hexavac and Infanrix vaccine could rely on differences in PT inactivation process or excipients/adjuvants formulations.

  12. Cell wide responses to low oxygen exposure in Desulfovibriovulgaris Hildenborough

    Energy Technology Data Exchange (ETDEWEB)

    Mukhopadhyay, A.; Redding, A.; Joachimiak, M.; Arkin, A.; Borglin, S.; Dehal, P.; Chakraborty, R.; Geller, J.; Hazen, T.; He, Q.; Joyner, D.; Martin, V.; Wall, J.; Yang, Z.; Zhou, J.; Keasling, J.

    2007-03-11

    The responses of the anaerobic, sulfate-reducing Desulfovibrio vulgaris Hildenborough to low oxygen exposure (0.1% O{sub 2}) were monitored via transcriptomics and proteomics. Exposure to 0.1% O{sub 2} caused a decrease in growth rate without affecting viability. A concerted up regulation in the predicted peroxide stress response regulon (PerR) genes was observed in response to the 0.1% O{sub 2} exposure. Several of these candidates also showed increases in protein abundance. Among the remaining small number of transcript changes was the up regulation of the predicted transmembrane tetraheme cytochrome c3 complex. Other known oxidative stress response candidates remained unchanged during this low O{sub 2} exposure. To fully understand the results of the 0.1% O{sub 2} exposure, transcriptomics and proteomics data were collected for exposure to air using a similar experimental protocol. In contrast to the 0.1% O{sub 2} exposure, air exposure was detrimental to both the growth rate and viability and caused dramatic changes at both the transcriptome and proteome levels. Interestingly, the transcripts of the predicted PerR regulon genes were down regulated during air exposure. Our results highlight the differences in the cell wide response to low and high O{sub 2} levels of in D. vulgaris and suggest that while exposure to air is highly detrimental to D. vulgaris, this bacterium can successfully cope with periodic exposure to low O{sub 2} levels in its environment.

  13. Selection and Exergy Analysis of Fuel Cell System to Meet all Energy Needs of Residential Buildings

    OpenAIRE

    G.R. Ashari; N.Hedayat; S. Shalbaf; E.Hajidavalloo

    2011-01-01

    In this paper a polymer electrolyte membrane (PEM) fuel cell power system including burner, steam reformer, heat exchanger and water heater has been considered to meet the electrical, heating, cooling and domestic hot water loads of residential building which in Tehran. The system uses natural gas as fuel and works in CHP mode. Design and operating conditions of a PEM fuel cell system is considered in this study. The energy requirements of residential building and the num...

  14. Small-Cell Lung Cancer: Clinical Management and Unmet Needs New Perspectives for an Old Problem.

    Science.gov (United States)

    Lo Russo, Giuseppe; Macerelli, Marianna; Platania, Marco; Zilembo, Nicoletta; Vitali, Milena; Signorelli, Diego; Proto, Claudia; Ganzinelli, Monica; Gallucci, Rosaria; Agustoni, Francesco; Fasola, Gianpiero; de Braud, Filippo; Garassino, Marina Chiara

    2017-01-01

    Small cell lung cancer is a highly aggressive, difficult to treat neoplasm. Among all lung tumors, small cell lung cancers account for about 20%. Patients typically include heavy smokers in 70s age group, presenting with symptoms such as intrathoracic tumors growth, distant spread or paraneoplastic syndromes at the time of diagnosis. A useful and functional classification divides small cell lung cancers into limited disease and extensive disease. Concurrent chemo-radiotherapy is the standard treatment for limited disease, with improved survival when combined with prophylactic cranial irradiation. Platinum compounds (cisplatin/carboplatin) plus etoposide remain the cornerstone for extensive disease. Nevertheless, despite high chemo- and radio-sensitivity of this cancer, nearly all patients relapse within the first two years and the prognosis is extremely poor. A deeper understanding about small cell lung cancer carcinogenesis led to develop and test a considerable number of new and targeted agents but the results are currently weak or insufficient. To date, small cell lung cancer is still a challenge for researchers. In this review, key aspects of small cell lung cancer management and controversial points of standard and new treatments will be discussed. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  15. DNA damage response signaling in lung adenocarcinoma A549 cells following gamma and carbon beam irradiation.

    Science.gov (United States)

    Ghosh, Somnath; Narang, Himanshi; Sarma, Asitikantha; Krishna, Malini

    2011-11-01

    Carbon beams (5.16MeV/u, LET=290keV/μm) are high linear energy transfer (LET) radiation characterized by higher relative biological effectiveness than low LET radiation. The aim of the current study was to determine the signaling differences between γ-rays and carbon ion-irradiation. A549 cells were irradiated with 1Gy carbon or γ-rays. Carbon beam was found to be three times more cytotoxic than γ-rays despite the fact that the numbers of γ-H2AX foci were same. Percentage of cells showing ATM/ATR foci were more with γ-rays however number of foci per cell were more in case of carbon irradiation. Large BRCA1 foci were found in all carbon irradiated cells unlike γ-rays irradiated cells and prosurvival ERK pathway was activated after γ-rays irradiation but not carbon. The noteworthy finding of this study is the early phase apoptosis induction by carbon ions. In the present study in A549 lung adenocarcinoma, authors conclude that despite activation of same repair molecules such as ATM and BRCA1, differences in low and high LET damage responses might be due to their distinct macromolecular complexes rather than their individual activation and the activation of cytoplasmic pathways such as ERK, whether it applies to all the cell lines need to be further explored. Copyright © 2011 Elsevier B.V. All rights reserved.

  16. Cytotoxic T cell responses to Streptococcus are associated with improved prognosis of oral squamous cell carcinoma.

    Science.gov (United States)

    Wang, Jie; Sun, Feng; Lin, Xiaoyu; Li, Zaiye; Mao, Xiaohe; Jiang, Canhua

    2018-01-01

    Several species of Streptococcus, such as S. salivarius, S. mitis, and S. anginosus, are found to extensively colonize the oral cavity and the upper respiratory tract, and have been shown to increase in patients with oral squamous cell carcinoma (OSCC). Accumulating evidence have revealed that commensal bacteria are involved in antitumor immunity via T cell-mediated mechanisms, but the role of Streptococcus enrichment in OSCC is yet unclear. In this study, we stimulated peripheral blood mononuclear cells from non-cancer controls (NCs) and OSCC patients with S. salivarius, S. mitis, and S. anginosus. We observed that compared to NC subjects, OSCC patients at earlier stages had higher frequencies of granzyme B-expressing CD8 T cells for all Streptococcus species tested, while OSCC patients at more advanced stages had higher frequencies of granzyme B-expressing CD8 T cells for S. anginosus but not other Streptococcus species. In OSCC patients, the Streptococcus-reactive CD8 T cells presented significantly lower levels of PD-1 and TIM-3 expression than Streptococcus-nonreactive CD8 T cells. The clinical outcomes of OSCC patients in our cohort were tracked for 24 months after the resection of the primary tumor. In patients that did not present tumor recurrence, the frequencies of S. salivarius-reactive and S. mitis-reactive CD8 T cells were significantly higher than that in patients that developed recurrent tumor. Furthermore, in patients with tumor recurrence, the duration between primary tumor resection and tumor recurrence was positively associated with the frequencies of S. salivarius-reactive and S. anginosus-reactive CD8 T cells. Together, we demonstrated that Streptococcus-reactive CD8 T cell responses might contribute to antitumor immunity in OSCC patients. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Enabling Responsible Energy Decisions: What People Know, Want to Know, and Need to Know about Climate Change

    Science.gov (United States)

    PytlikZillig, L. M.; Tomkins, A. J.; Harrington, J. A.

    2012-12-01

    As part of a broader regional effort focused on climate change education and rural communities, this paper focuses on a specific effort to understand effective approaches to two presumably complementary goals: The goal of increasing knowledge about climate change and climate science in a community, and the goal of having communities use climate change and climate science information when making decisions. In this paper, we explore the argument that people do not need or want to know about climate change, in order to make responsible and sustainable energy decisions. Furthermore, we hypothesize that involvement in making responsible and sustainable energy decisions will increase openness and readiness to process climate science information, and thus increase learning about climate change in subsequent exposures to such information. Support for these hypotheses would suggest that rather than encouraging education to enable action (including engagement in attempts to make responsible decisions), efforts should focus on encouraging actions first and education second. To investigate our hypotheses, we will analyze and report results from efforts to engage residents from a medium-sized Midwestern city to give input on future programs involving sustainable energy use. The engagement process (which will not be complete until after the AGU deadline) involves an online survey and an optional face-to-face discussion with city officials and experts in energy-related areas. The online survey includes brief information about current local energy programs, questions assessing knowledge of climate change, and an open-ended question asking what additional information residents need in order to make good decisions and recommendations concerning the energy programs. To examine support for our hypotheses, we will report (1) relationships between subjective and objective knowledge of climate science and willingness to attend the face-to-face discussion about the city's energy decisions

  18. Functional Specialization of Skin Dendritic Cell Subsets in Regulating T Cell Responses

    Science.gov (United States)

    Clausen, Björn E.; Stoitzner, Patrizia

    2015-01-01

    Dendritic cells (DC) are a heterogeneous family of professional antigen-presenting cells classically recognized as most potent inducers of adaptive immune responses. In this respect, Langerhans cells have long been considered to be prototypic immunogenic DC in the skin. More recently this view has considerably changed. The generation of in vivo cell ablation and lineage tracing models revealed the complexity of the skin DC network and, in particular, established the existence of a number of phenotypically distinct Langerin+ and negative DC populations in the dermis. Moreover, by now we appreciate that DC also exert important regulatory functions and are required for the maintenance of tolerance toward harmless foreign and self-antigens. This review summarizes our current understanding of the skin-resident DC system in the mouse and discusses emerging concepts on the functional specialization of the different skin DC subsets in regulating T cell responses. Special consideration is given to antigen cross-presentation as well as immune reactions toward contact sensitizers, cutaneous pathogens, and tumors. These studies form the basis for the manipulation of the human counterparts of the murine DC subsets to promote immunity or tolerance for the treatment of human disease. PMID:26557117

  19. Cells that mediate NK like cytotoxicity are present in the human delayed type hypersensitivity response.

    Science.gov (United States)

    Tartof, D; Yung, C W; Curran, J J; Livingston, C; Thalji, Z

    1984-11-01

    By inducing delayed type hypersensitivity (DTH) responses under previously formed skin blisters we determined that cells which mediate natural killer (NK) like cytotoxicity are present in the DTH response in man. Similar levels of killing were not present in cells obtained from skin blisters not associated with positive DTH responses. The DTH response associated killer cell was found to be a mononuclear cell that had presumably undergone stimulation since it not only killed NK sensitive K-562 cells, but also NK resistant Daudi target cells.

  20. Dendritic cells fused with different pancreatic carcinoma cells induce different T-cell responses

    Directory of Open Access Journals (Sweden)

    Andoh Y

    2013-01-01

    Full Text Available Yoshiaki Andoh,1,2 Naohiko Makino,2 Mitsunori Yamakawa11Department of Pathological Diagnostics, 2Department of Gastroenterology, Yamagata University School of Medicine, Yamagata, JapanBackground: It is unclear whether there are any differences in the induction of cytotoxic T lymphocytes (CTL and CD4+CD25high regulatory T-cells (Tregs among dendritic cells (DCs fused with different pancreatic carcinomas. The aim of this study was to compare the ability to induce cytotoxicity by human DCs fused with different human pancreatic carcinoma cell lines and to elucidate the causes of variable cytotoxicity among cell lines.Methods: Monocyte-derived DCs, which were generated from peripheral blood mononuclear cells (PBMCs, were fused with carcinoma cells such as Panc-1, KP-1NL, QGP-1, and KP-3L. The induction of CTL and Tregs, and cytokine profile of PBMCs stimulated by fused DCs were evaluated.Results: The cytotoxicity against tumor targets induced by PBMCs cocultured with DCs fused with QGP-1 (DC/QGP-1 was very low, even though PBMCs cocultured with DCs fused with other cell lines induced significant cytotoxicity against the respective tumor target. The factors causing this low cytotoxicity were subsequently investigated. DC/QGP-1 induced a significant expansion of Tregs in cocultured PBMCs compared with DC/KP-3L. The level of interleukin-10 secreted in the supernatants of PBMCs cocultured with DC/QGP-1 was increased significantly compared with that in DC/KP-3L. Downregulation of major histocompatibility complex class I expression and increased secretion of vascular endothelial growth factor were observed with QGP-1, as well as in the other cell lines.Conclusion: The present study demonstrated that the cytotoxicity induced by DCs fused with pancreatic cancer cell lines was different between each cell line, and that the reduced cytotoxicity of DC/QGP-1 might be related to the increased secretion of interleukin-10 and the extensive induction of Tregs

  1. Increased, Durable B-Cell and ADCC Responses Associated with T-Helper Cell Responses to HIV-1 Envelope in Macaques Vaccinated with gp140 Occluded at the CD4 Receptor Binding Site.

    Science.gov (United States)

    Bogers, Willy M J M; Barnett, Susan W; Oostermeijer, Herman; Nieuwenhuis, Ivonne G; Beenhakker, Niels; Mortier, Daniella; Mooij, Petra; Koopman, Gerrit; Remarque, Edmund; Martin, Gregoire; Lai, Rachel Pei-Jen; Dey, Antu K; Sun, Yide; Burke, Brian; Ferrari, Guido; Montefiori, David; Martin, Loic; Davis, David; Srivastava, Indresh; Heeney, Jonathan L

    2017-10-01

    Strategies are needed to improve the immunogenicity of HIV-1 envelope (Env) antigens (Ag) for more long-lived, efficacious HIV-1 vaccine-induced B-cell responses. HIV-1 Env gp140 (native or uncleaved molecules) or gp120 monomeric proteins elicit relatively poor B-cell responses which are short-lived. We hypothesized that Env engagement of the CD4 receptor on T-helper cells results in anergic effects on T-cell recruitment and consequently a lack of strong, robust, and durable B-memory responses. To test this hypothesis, we occluded the CD4 binding site (CD4bs) of gp140 by stable cross-linking with a 3-kDa CD4 miniprotein mimetic, serving to block ligation of gp140 on CD4 + T cells while preserving CD4-inducible (CDi) neutralizing epitopes targeted by antibody-dependent cellular cytotoxicity (ADCC) effector responses. Importantly, immunization of rhesus macaques consistently gave superior B-cell ( P durable, lasting more than 60 weeks postimmunization. IMPORTANCE Attempts to develop HIV vaccines capable of inducing potent and durable B-cell responses have been unsuccessful until now. Antigen-specific B-cell development and affinity maturation occurs in germinal centers in lymphoid follicles through a critical interaction between B cells and T follicular helper cells. The HIV envelope binds the CD4 receptor on T cells as soluble shed antigen or as antigen-antibody complexes, causing impairment in the activation of these specialized CD4-positive T cells. We proposed that CD4-binding impairment is partly responsible for the relatively poor B-cell responses to HIV envelope-based vaccines. To test this hypothesis, we blocked the CD4 binding site of the envelope antigen and compared it to currently used unblocked envelope protein. We found superior and durable B-cell responses in macaques vaccinated with an occluded CD4 binding site on the HIV envelope antigen, demonstrating a potentially important new direction in future design of new HIV vaccines. Copyright © 2017

  2. CD4 T cells mediate both positive and negative regulation of the immune response to HIV infection: complex role of T follicular helper cells and Regulatory T cells in pathogenesis

    Directory of Open Access Journals (Sweden)

    Chansavath ePhetsouphanh

    2015-01-01

    Full Text Available HIV-1 infection results in chronic activation of cells in lymphoid tissue, including T cells, B cells and myeloid lineage cells. The resulting characteristic hyperplasia is an amalgam of proliferating host immune cells in the adaptive response, increased concentrations of innate response mediators due to viral and bacterial products, and homeostatic responses to inflammation. While it is generally thought that CD4 T cells are greatly depleted, in fact, two types of CD4 T cells appear to be increased, namely regulatory T cells (Tregs and T follicular helper cells (Tfh. These cells have opposing roles, but may both be important in the pathogenic process. Whether Tregs are failing in their role to limit lymphocyte activation is unclear, but there is no doubt now that Tfh are associated with B cell hyperplasia and increased germinal centre activity. Antiretroviral therapy (ART may reduce the lymphocyte activation, but not completely, and therefore there is a need for interventions that selectively enhance normal CD4 function without exacerbating Tfh, B cell or Treg dysfunction.

  3. Specific structural features of syndecans and heparan sulfate chains are needed for cell signaling

    Directory of Open Access Journals (Sweden)

    C.C. Lopes

    2006-02-01

    Full Text Available The syndecans, heparan sulfate proteoglycans, are abundant molecules associated with the cell surface and extracellular matrix and consist of a protein core to which heparan sulfate chains are covalently attached. Each of the syndecan core proteins has a short cytoplasmic domain that binds cytosolic regulatory factors. The syndecans also contain highly conserved transmembrane domains and extracellular domains for which important activities are becoming known. These protein domains locate the syndecan on cell surface sites during development and tumor formation where they interact with other receptors to regulate signaling and cytoskeletal organization. The functions of cell surface heparan sulfate proteoglycan have been centered on the role of heparan sulfate chains, located on the outer side of the cell surface, in the binding of a wide array of ligands, including extracellular matrix proteins and soluble growth factors. More recently, the core proteins of the syndecan family transmembrane proteoglycans have also been shown to be involved in cell signaling through interaction with integrins and tyrosine kinase receptors.

  4. Humoral and B-cell memory responses in children five years after pertussis acellular vaccine priming.

    Science.gov (United States)

    Carollo, Maria; Pandolfi, Elisabetta; Tozzi, Alberto Eugenio; Buisman, Anne-Marie; Mascart, Françoise; Ausiello, Clara Maria

    2014-04-11

    The resurgence of pertussis suggests the need for greater efforts in understanding the long-lasting protective responses induced by vaccination. In this paper we dissect the persistence of humoral and B-cell memory responses induced by primary vaccination with two different acellular pertussis (aP) vaccines, hexavalent Hexavac(®) vaccine (Hexavac) (Sanofi Pasteur MSD) and Infanrix hexa(®) (Infanrix) (GlaxoSmithKline Biologicals). We evaluated the specific immune responses in the two groups of children, 5 years after primary vaccination by measuring the persistence of IgG and antibody secreting cells (ASC) specific for vaccine antigens. Part of the enrolled children received only primary vaccination, while others had the pre-school boost dose. A similar level of antigen-specific IgG and ASC was found in Infanrix and Hexavac vaccinated children. The mean IgG levels were significantly higher in children that received the pre-school boost as compared with children that did not receive the boost dose. A longer persistence after the pre-school boost of IgG-Pertussis Toxin (PT) and IgG-pertactin levels was observed in Infanrix primed children, but it was not statistically significant. More than 80% of children presented a positive ASC B memory response. Around 50% of children still presented protective IgG-PT levels which are reduced to 36% in no-boosted children. The pre-school booster dose restores the percentage of protected children above 50%. In conclusion our data underline the importance of giving a booster dose 5 years after primary vaccination and suggest the need for a new vaccine able to induce a long lasting protective response. Copyright © 2014 Elsevier Ltd. All rights reserved.

  5. Need to Belong, Not Rejection Sensitivity, Moderates Cortisol Response, Self-Reported Stress, and Negative Affect Following Social Exclusion.

    Science.gov (United States)

    Beekman, Janine B; Stock, Michelle L; Marcus, Tara

    2016-01-01

    The present study examined if the traits need to belong (NTB) and rejection sensitivity (RS) differentially moderate the impact of experimentally manipulated social exclusion on stress and affect. Participants (N = 132) completed a survey measuring NTB and RS, and then were randomly assigned to be included or excluded during a game of Cyberball. A second survey then assessed perceived stress and negative affect, and a cortisol sample was taken. Controlling for gender and baseline cortisol levels, excluded participants high (vs. low) in NTB had significantly higher postexclusion cortisol levels, and reported greater perceived stress and negative affect. The moderating effect for RS was not found, however, and NTB and RS were not correlated. Findings suggest that the NTB moderates psychological and physiological responses to exclusion.

  6. Phenotypic differences of CD4(+) T cells in response to red blood cell immunization in transfused sickle cell disease patients.

    Science.gov (United States)

    Vingert, Benoît; Tamagne, Marie; Habibi, Anoosha; Pakdaman, Sadaf; Ripa, Julie; Elayeb, Rahma; Galacteros, Frédéric; Bierling, Philippe; Ansart-Pirenne, Hélène; Bartolucci, Pablo; Noizat-Pirenne, France

    2015-06-01

    Alloimmunization against red blood cells (RBCs) is the main immunological risk associated with transfusion in patients with sickle cell disease (SCD). However, about 50-70% of SCD patients never get immunized despite frequent transfusion. In murine models, CD4(+) T cells play a key role in RBC alloimmunization. We therefore explored and compared the CD4(+) T-cell phenotypes and functions between a group of SCD patients (n = 11) who never became immunized despite a high transfusion regimen and a group of SCD patients (n = 10) who had become immunized (at least against Kidd antigen b) after a low transfusion regimen. We studied markers of CD4(+) T-cell function, including TLR, that directly control lymphocyte function, and their spontaneous cytokine production. We also tested responders for the cytokine profile in response to Kidd antigen b peptides. Low TLR2/TLR3 expression and, unexpectedly, strong expression of CD40 on CD4(+) T cells were associated with the nonresponder status, whereas spontaneous expression of IL-10 by CD4(+) T cells and weak Tbet expression were associated with the responder status. A Th17 profile was predominant in responders when stimulated by Jb(k) . These findings implicate CD4(+) T cells in alloimmunization in humans and suggest that they may be exploited to differentiate responders from nonresponders. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. Mycoplasma Suppression of THP-1 Cell TLR Responses Is Corrected with Antibiotics

    OpenAIRE

    Zakharova, Ekaterina; Grandhi, Jaykumar; Wewers, Mark D.; Gavrilin, Mikhail A.

    2010-01-01

    Mycoplasma contamination of cultured cell lines is a serious problem in research, altering cellular response to different stimuli thus compromising experimental results. We found that chronic mycoplasma contamination of THP-1 cells suppresses responses of THP-1 cells to TLR stimuli. For example, E. coli LPS induced IL-1 beta was suppressed by 6 fold and IL-8 by 10 fold in mycoplasma positive THP-1 cells. Responses to live F. novicida challenge were suppressed by 50-fold and 40-fold respective...

  8. [Conjunctival squamous cell carcinoma: paradoxical response to interferon eyedrops].

    Science.gov (United States)

    Mata, E; Conesa, E; Castro, M; Martínez, L; de Pablo, C; González, M L

    2014-07-01

    A 67 year-old male seen for a longstanding corneal-conjunctival tumor. topical interferon α2b (IFN-α2b) 10 U/ml. A significant increase in lesion size was observed after 8 weeks. A surgical excision with cryotherapy was then performed. Pathological examination confirmed the diagnosis of squamous cell carcinoma. At this time the patient was found to have a positive HIV serology. Conjunctival intraepithelial neoplasia (CIN) is a pre-cancerous lesion of the ocular surface. Medical treatment of CIN is essentially with IFN-α2b due to its antiviral/antitumor properties. In patients with HIV, treatment response could be paradoxical. We recommend serology for HIV before treatment with topical IFN-α2b. Copyright © 2012 Sociedad Española de Oftalmología. Published by Elsevier Espana. All rights reserved.

  9. B7.1 expression on tumor cells circumvents the need of professional antigen presentation for in vitro propagation of cytotoxic T cell lines.

    Science.gov (United States)

    Iezzi, G; Protti, M P; Rugarli, C; Bellone, M

    1996-01-01

    In vitro propagation of tumor-specific CTLs, to be used for identification of tumor antigens (Ag) and/or adoptive immunotherapy, is hampered by the need of large amounts of professional antigen-presenting cells (APC) used for periodical cycles of restimulation. We evaluated whether RMA T lymphoma cells, stably transfected with the cDNA encoding for the B7.1 costimulatory molecule, provided the activation signals to CD8+ T lymphocytes in the absence of professional APC and CD4+ helper cells. We demonstrate here that long-term CD8+ cell lines can be efficiently propagated in vitro by repeated cycles of stimulation with tumor cells stably expressing B7.1. Professional APC and CD4+ helper cells are not required as far as interleukin 2 is exogenously provided. Furthermore, CD8+ blasts needed both signal 1 (Ag in the contest of the MHC molecule) and signal 2 (interaction of costimulatory molecules) for restimulation. T cell blasts in the presence of signal 1 or 2 only still retained their effector potential but did not undergo clonal expansion. These results are very promising for further applications of specific immunotherapies in humans.

  10. The Antibody-Secreting Cell Response to Infection: Kinetics and Clinical Applications

    Directory of Open Access Journals (Sweden)

    Michael J. Carter

    2017-06-01

    Full Text Available Despite the availability of advances in molecular diagnostic testing for infectious disease, there is still a need for tools that advance clinical care and public health. Current methods focus on pathogen detection with unprecedented precision, but often lack specificity. In contrast, the host immune response is highly specific for the infecting pathogen. Serological studies are rarely helpful in clinical settings, as they require acute and convalescent antibody testing. However, the B cell response is much more rapid and short-lived, making it an optimal target for determining disease aetiology in patients with infections. The performance of tests that aim to detect circulating antigen-specific antibody-secreting cells (ASCs has previously been unclear. Test performance is reliant on detecting the presence of ASCs in the peripheral blood. As such, the kinetics of the ASC response to infection, the antigen specificity of the ASC response, and the methods of ASC detection are all critical. In this review, we summarize previous studies that have used techniques to enumerate ASCs during infection. We describe the emergence, peak, and waning of these cells in peripheral blood during infection with a number of bacterial and viral pathogens, as well as malaria infection. We find that the timing of antigen-specific ASC appearance and disappearance is highly conserved across pathogens, with a peak response between day 7 and day 8 of illness and largely absent following day 14 since onset of symptoms. Data show a sensitivity of ~90% and specificity >80% for pathogen detection using ASC-based methods. Overall, the summarised work indicates that ASC-based methods may be very sensitive and highly specific for determining the etiology of infection and have some advantages over current methods. Important areas of research remain, including more accurate definition of the timing of the ASC response to infection, the biological mechanisms underlying variability

  11. Stress responses in flavivirus-infected cells: activation of unfolded protein response and autophagy

    Directory of Open Access Journals (Sweden)

    Ana-Belén eBlázquez

    2014-06-01

    Full Text Available The Flavivirus is a genus of RNA viruses that includes multiple long known human, animal and zoonotic pathogens such as Dengue virus, yellow fever virus, West Nile virus or Japanese encephalitis virus, as well as other less known viruses that represent potential threats for human and animal health such as Usutu or Zika viruses. Flavivirus replication is based on endoplasmic reticulum-derived structures. Membrane remodeling and accumulation of viral factors induce endoplasmic reticulum stress that results in activation of a cellular signaling response termed unfolded protein response (UPR, which can be modulated by the viruses for their own benefit. Concomitant with the activation of the UPR, an upregulation of the autophagic pathway in cells infected with different flaviviruses has also been described. This review addresses the current knowledge of the relationship between endoplasmic reticulum stress, UPR and autophagy in flavivirus-infected cells and the growing evidences for an involvement of these cellular pathways in the replication and pathogenesis of these viruses.

  12. The role of constitutive and inducible processes in the response of human squamous cell carcinoma cell lines to ionizing radiation

    Energy Technology Data Exchange (ETDEWEB)

    Schwartz, J.L.

    1993-01-01

    The inherent radiation sensitivity of the cells within a tumor is thought to contribute to the success or failure of radiation therapy. In vitro studies have shown that radiation sensitivity differences in squamous cell carcinoma cell lines reflect alterations in DNA repair. These alterations result from constitutive changes in chromosome organization, not radiation-inducible processes. While inducible responses may play some role in the radiation response of tumor cells, there is no evidence for their involvement in inherent tumor cell radiosensitivity differences or in the success or failure of radiotherapy for squamous cell carcinomas.

  13. The role of constitutive and inducible processes in the response of human squamous cell carcinoma cell lines to ionizing radiation

    Energy Technology Data Exchange (ETDEWEB)

    Schwartz, J.L.

    1993-06-01

    The inherent radiation sensitivity of the cells within a tumor is thought to contribute to the success or failure of radiation therapy. In vitro studies have shown that radiation sensitivity differences in squamous cell carcinoma cell lines reflect alterations in DNA repair. These alterations result from constitutive changes in chromosome organization, not radiation-inducible processes. While inducible responses may play some role in the radiation response of tumor cells, there is no evidence for their involvement in inherent tumor cell radiosensitivity differences or in the success or failure of radiotherapy for squamous cell carcinomas.

  14. To investigate the necessity of STRA6 upregulation in T cells during T cell immune responses.

    Directory of Open Access Journals (Sweden)

    Rafik Terra

    Full Text Available Our earlier study revealed that STRA6 (stimulated by retinoic acid gene 6 was up-regulated within 3 h of TCR stimulation. STRA6 is the high-affinity receptor for plasma retinol-binding protein (RBP and mediates cellular vitamin A uptake. We generated STRA6 knockout (KO mice to assess whether such up-regulation was critical for T-cell activation, differentiation and function. STRA6 KO mice under vitamin A sufficient conditions were fertile without apparent anomalies upon visual inspection. The size, cellularity and lymphocyte subpopulations of STRA6 KO thymus and spleen were comparable to those of their wild type (WT controls. KO and WT T cells were similar in terms of TCR-stimulated proliferation in vitro and homeostatic expansion in vivo. Naive KO CD4 cells differentiated in vitro into Th1, Th2, Th17 as well as regulatory T cells in an analogous manner as their WT counterparts. In vivo experiments revealed that anti-viral immune responses to lymphocytic choriomeningitis virus in KO mice were comparable to those of WT controls. We also demonstrated that STRA6 KO and WT mice had similar glucose tolerance. Total vitamin A levels are dramatically lower in the eyes of KO mice as compared to those of WT mice, but the levels in other organs were not significantly affected after STRA6 deletion under vitamin A sufficient conditions, indicating that the eye is the mouse organ most sensitive to the loss of STRA6. Our results demonstrate that 1 in vitamin A sufficiency, the deletion of STRA6 in T cells does no affect the T-cell immune responses so-far tested, including those depend on STAT5 signaling; 2 STRA6-independent vitamin A uptake compensated the lack of STRA6 in lymphoid organs under vitamin A sufficient conditions in mice; 3 STRA6 is critical for vitamin A uptake in the eyes even in vitamin A sufficiency.

  15. Evaluating prediction strategies for identification of T cell responsive mutation-derived neoepitopes in cancer

    DEFF Research Database (Denmark)

    Andersen, Sofie Ramskov; Bjerregaard, Anne-Mette; Fugmann, T.

    2016-01-01

    patients. We investigated the T cell recognition of these personalized peptide libraries using a new technology based on DNA-barcode labeled MHC multimers to detect multiple, potentially > 1000, different neoepitope specific T cell populations in a single sample. Through this unbiased comparison, we......Increasing evidences point to an important role of mutation-derived antigens in immune recognition of cancer. Current strategies for prediction of immunogenic neoepitopes results in large personalized peptide libraries, but only a minority (.... Neoepitopes are of potential valuable as predictors of response to therapy and targets for personalized immunotherapeutic approached. Consequently, there is an unmet need to understand the rules identifying immunogenic neoepitopes. Both tumor mutation mapping via exome sequencing and mass...

  16. Regulation of bacterial virulence gene expression by cell envelope stress responses.

    Science.gov (United States)

    Flores-Kim, Josué; Darwin, Andrew J

    2014-01-01

    The bacterial cytoplasm lies within a multilayered envelope that must be protected from internal and external hazards. This protection is provided by cell envelope stress responses (ESRs), which detect threats and reprogram gene expression to ensure survival. Pathogens frequently need these ESRs to survive inside the host, where their envelopes face dangerous environmental changes and attack from antimicrobial molecules. In addition, some virulence genes have become integrated into ESR regulons. This might be because these genes can protect the cell envelope from damage by host molecules, or it might help ESRs to reduce stress by moderating the assembly of virulence factors within the envelope. Alternatively, it could simply be a mechanism to coordinate the induction of virulence gene expression with entry into the host. Here, we briefly describe some of the bacterial ESRs, followed by examples where they control virulence gene expression in both Gram-negative and Gram-positive pathogens.

  17. Acrolein in cigarette smoke inhibits T-cell responses.

    Science.gov (United States)

    Lambert, Cherie; McCue, Jesica; Portas, Mary; Ouyang, Yanli; Li, JiMei; Rosano, Thomas G; Lazis, Alexander; Freed, Brian M

    2005-10-01

    Cigarette smoking inhibits T-cell responses in the lungs, but the immunosuppressive compounds have not been fully identified. Cigarette smoke extracts inhibit IL-2, IFN-gamma, and TNF-alpha production in stimulated lymphocytes obtained from peripheral blood, even when the extracts were diluted 100-fold to 1000-fold. The objective of these studies was to identify the immunosuppressive compounds found in cigarette smoke. Gas chromatography/mass spectroscopy and HPLC were used to identify and quantitate volatile compounds found in cigarette smoke extracts. Bioactivity was measured by viability and production of cytokine mRNA and protein levels in treated human lymphocytes. The vapor phase of the cigarette smoke extract inhibited cytokine production, indicating that the immunosuppressive compounds were volatile. Among the volatile compounds identified in cigarette smoke extracts, only the alpha,beta-unsaturated aldehydes, acrolein (inhibitory concentration of 50% [IC50] = 3 micromol/L) and crotonaldehyde (IC50 = 6 micromol/L), exhibited significant inhibition of cytokine production. Although the levels of aldehydes varied 10-fold between high-tar (Camel) and ultralow-tar (Carlton) extracts, even ultralow-tar cigarettes produced sufficient levels of acrolein (34 micromol/L) to suppress cytokine production by >95%. We determined that the cigarette smoke extract inhibited transcription of cytokine genes. The inhibitory effects of acrolein could be blocked with the thiol compound N-acetylcysteine. The vapor phase from cigarette smoke extracts potently suppresses cytokine production. The compound responsible for this inhibition appears to be acrolein.

  18. Analysis of H2 storage needs for early market non-motive fuel cell applications.

    Energy Technology Data Exchange (ETDEWEB)

    Johnson, Terry Alan; Moreno, Marcina; Arienti, Marco; Pratt, Joseph William; Shaw, Leo; Klebanoff, Leonard E.

    2012-03-01

    Hydrogen fuel cells can potentially reduce greenhouse gas emissions and the United States dependence on foreign oil, but issues with hydrogen storage are impeding their widespread use. To help overcome these challenges, this study analyzes opportunities for their near-term deployment in five categories of non-motive equipment: portable power, construction equipment, airport ground support equipment, telecom backup power, and man-portable power and personal electronics. To this end, researchers engaged end users, equipment manufacturers, and technical experts via workshops, interviews, and electronic means, and then compiled these data into meaningful and realistic requirements for hydrogen storage in specific target applications. In addition to developing these requirements, end-user benefits (e.g., low noise and emissions, high efficiency, potentially lower maintenance costs) and concerns (e.g., capital cost, hydrogen availability) of hydrogen fuel cells in these applications were identified. Market data show potential deployments vary with application from hundreds to hundreds of thousands of units.

  19. Review of Ocular Manifestations of Nevoid Basal Cell Carcinoma Syndrome: What an Ophthalmologist Needs to Know

    Science.gov (United States)

    Chen, Judy J.; Sartori, Juliana; Aakalu, Vinay K.; Setabutr, Pete

    2015-01-01

    Nevoid basal cell carcinoma syndrome (NBCCS) is a rare, autosomal dominant disorder characterized by multiple basal cell carcinomas (BCCs), odontogenic keratocysts, palmar and/or plantar pits, and ectopic calcifications of the falx cerebri. Myriad ophthalmologic findings are associated with NBCCS, including periocular BCCs, hypertelorism, strabismus, myelinated nerve fibers, and disorders of the retina and retinal pigment epithelium. We performed a literature search in PubMed for articles on the ophthalmologic manifestations of Gorlin syndrome, published between 1984 and 2014. Of 33 papers, 31 were included. Although Gorlin syndrome is due to mutations in a single gene, it displays variable phenotypic expressivity. Therefore, familiarity with this disorder across clinical specialties is necessary to avoid misdiagnosis. The ophthalmologist should be included in the multidisciplinary team for the management of Gorlin syndrome in order to prevent visual loss and improve the quality of life of these patients. PMID:26692711

  20. Chronic lymphocytic leukemia cells acquire regulatory B-cell properties in response to TLR9 and CD40 activation.

    Science.gov (United States)

    Ringelstein-Harlev, Shimrit; Avivi, Irit; Fanadka, Mona; Horowitz, Netanel A; Katz, Tami

    2018-02-15

    Circulating chronic lymphocytic leukemia (CLL) cells share phenotypic features with certain subsets of regulatory B-cells (Bregs). The latter cells have been reported to negatively regulate immune cell responses, mostly by provision of IL-10. The purpose of the current study was to identify and delineate Breg properties of CLL cells. B-cells and T-cells were obtained from the peripheral blood of untreated CLL patients diagnosed according to the 2008 Guidelines of the International Workshop on Chronic Lymphocytic Leukemia. Co-culture assays were used to examine the ability of CLL cells to suppress autologous T-cell immune responses. IL-10 potency of CLL cells was assessed following stimulation with activators of the toll-like receptor 9 (TLR9) or CD40 and was correlated with the inhibitory activity of the cells. TLR9-activated CLL cells were found to increase the frequency of CD4 + CD25 hi FOXp3 + regulatory T-cells (Tregs) and to inhibit autologous CD4 + T-cell proliferation. This signaling cascade proved to control IL-10 generation in CLL cells, which in turn promoted the inhibition of T-cell proliferation by CLL cells. However, CD40 activation of CLL cells, while exhibiting a similar ability to augment Treg frequency, did not either affect IL-10 generation or T-cell proliferation. In conclusion, CLL cells demonstrate a unique clonal quality of adopting Breg properties which promote modulation of T-cell characteristics. TLR9 appears to be a potent activator of regulatory abilities in CLL cells, possibly contributing to preferential immune escape of TLR9-responsive cells.

  1. Response of the ABCG2 promoter in T47D cells and BeWo cells to sex hormone treatment.

    Science.gov (United States)

    Yasuda, Satoru; Kobayashi, Masaki; Itagaki, Shirou; Hirano, Takeshi; Iseki, Ken

    2009-09-01

    The aim of this study was to elucidate the effects of sex hormones on activity of the ABCG2 promoter in different cell lines. T47D cells and BeWo cells were used as models for ABCG2-expressing cell lines, and luciferase assays using ABCG2 promoter-luciferase constructs were performed. It was shown that progesterone increased the response of the ABCG2 promoter in T47D cells but not in BeWo cells. On the other hand, estradiol had no effect on response of the ABCG2 promoter in either cell line. However, response of the ABCG2 promoter was enhanced by overexpression of ERalpha in both T47D cells and BeWo cells. T47D cells had higher sensitivity to ERalpha than did BeWo cells. Furthermore, it was shown that the inductive effect of progesterone on the ABCG2 promoter was inhibited by addition of RU486 or mithramycin A. Therefore, it was thought that the ABCG2 promoter responded to stimulation of the progesterone receptor (PR)-Sp1 pathway in T47D cells. Furthermore, progesterone suppressed the response of the ABCG2 promoter by changing the expression levels of PR-A and PR-B in BeWo cells. These findings suggested that there are differences between cell lines in the regulation mechanism of ABCG2 expression by sex hormone treatment.

  2. Innate, T-, and B-Cell Responses in Acute Human Zika Patients.

    Science.gov (United States)

    Lai, Lilin; Rouphael, Nadine; Xu, Yongxian; Natrajan, Muktha S; Beck, Allison; Hart, Mari; Feldhammer, Matthew; Feldpausch, Amanda; Hill, Charles; Wu, Henry; Fairley, Jessica K; Lankford-Turner, Pamela; Kasher, Nicole; Rago, Patrick; Hu, Yi-Juan; Edupuganti, Srilatha; Patel, Shital M; Murray, Kristy O; Mulligan, Mark J

    2018-01-06

    There is an urgent need for studies of viral persistence and immunity during human Zika infections to inform planning and conduct of vaccine clinical trials. In 5 returned US travelers with acute symptomatic Zika infection, clinical features, viral RNA levels, and immune responses were characterized. Two pregnant, flavivirus-experienced patients had viral RNA persist in plasma for >44 and >26 days. Three days after symptom onset, transient increases in proinflammatory monocytes began followed at 5 days by transient decreases in myeloid dendritic cells. Anti-Zika virus immunoglobulin M was detected at day 7 after symptom onset, persisted beyond 103 days, and remained equivocal through day 172. Zika virus-specific plasmablasts and neutralizing antibodies developed quickly; dengue virus-specific plasmablasts and neutralizing antibodies at high titers developed only in flavivirus-experienced patients. Zika virus- and dengue virus-specific memory B cells developed in both flavivirus-naive and -experienced patients. CD4+ T cells were moderately activated and produced antiviral cytokines after stimulation with Zika virus C, prM, E, and NS5 peptides in 4/4 patients. In contrast, CD8+ T cells were massively activated, but virus-specific cells that produced cytokines were present in only 2/4 patients assessed. Acute infections with Zika virus modulated antigen-presenting cell populations early. Flavivirus-experienced patients quickly recalled cross-reactive MBCs to secrete antibodies. Dengue virus-naive patients made little dengue-specific antibody but developed MBCs that cross-reacted against dengue virus. Zika virus-specific functional CD4+ T cells were readily detected, but few CD8+ T cells specific for the tested peptides were found. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.

  3. Cytomegalovirus viremia, viruria and disease after autologous peripheral blood stem cell transplantation: no need for surveillance.

    Science.gov (United States)

    Bilgrami, S; Aslanzadeh, J; Feingold, J M; Bona, R D; Clive, J; Dorsky, D; Edwards, R L; Tutschka, P J

    1999-07-01

    A retrospective evaluation of 200 consecutive recipients of autologous peripheral blood stem cell transplantation (PBSCT) was conducted to ascertain the incidence, risk factors, clinical features, complications, and outcome of cytomegalovirus (CMV) infection. A total of 26 patients (13%) developed CMV viremia (n = 5), DNAemia (n = 3), viruria (n = 18) and/or disease (n = 3) at a median of 45 days following stem cell infusion. None of the patients underwent surveillance testing for CMV. A diagnosis was established by culture and polymerase chain reaction of blood, urine or other tissue samples submitted when patients exhibited clinical features suggestive of CMV infection. Cytomegalovirus seropositivity prior to transplantation was the only statistically significant risk factor predicting subsequent identification of CMV (P < 0.001). The symptoms were severe enough in 23 patients to warrant treatment with intravenous ganciclovir. Three patients developed CMV disease; two developed fatal CMV pneumonia and one developed CMV gastritis which responded to antiviral treatment. Clinical signs and symptoms as well as viremia and viruria resolved with (20 patients) and without (three patients) treatment in the remaining individuals. All instances of CMV viremia, DNAemia, viruria and disease occurred within 3 months of stem cell infusion. These results demonstrate that CMV is a common pathogen after autologous PBSCT and may result in fatality in rare instances. Surveillance programs appear to be neither useful nor cost-effective. Diagnostic evaluation should be performed only in patients exhibiting suspicious clinical features and antiviral chemotherapy should be administered for persistent and severe signs and symptoms.

  4. The need to connect: on the cell biology of synapses, behaviors, and networks in science.

    Science.gov (United States)

    Colón-Ramos, Daniel A

    2016-11-01

    My laboratory is interested in the cell biology of the synapse. Synapses, which are points of cellular communication between neurons, were first described by Santiago Ramón y Cajal as "protoplasmic kisses that appear to constitute the final ecstasy of an epic love story." Who would not want to work on that?! My lab examines the biological mechanisms neurons use to find and connect to each other. How are synapses formed during development, maintained during growth, and modified during learning? In this essay, I reflect about my scientific journey to the synapse, the cell biological one, but also a metaphorical synapse-my role as a point of contact between the production of knowledge and its dissemination. In particular, I discuss how the architecture of scientific networks propels knowledge production but can also exclude certain groups in science. © 2016 Colón-Ramos This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

  5. Immune responses of dendritic cells after acquiring antigen from apoptotic hepatocholangioma cells caused by γ-ray

    International Nuclear Information System (INIS)

    Wu Gang; Gu Hongguang; Han Benli; Pei Xuetao

    2002-01-01

    Objective: To investigate the induction of cytotoxic T lymphocytes (CTLs) in antitumor responsiveness and therapeutic effects after dendritic cells (DCs) acquired antigen from apoptotic hepatocholangioma cells. Methods: DCs from blood mononuclear cells that maintain the characteristics of immaturity-anti-gen-capturing and-processing capacity were established in vitro by using granulocyte/macrophage colony-stimulating factor (GM-CSF) and interleukin-4. Then, apoptosis in hepatocholangioma cells was induced with γ-radiation. The experimental groups included (1) co-culture of DCs, and apoptotic cancer cells and T cells; (2) co-culture of DCs necrotic cancer cells and T cells; (3) co-culture of DCs-cultured cancer cell and T cells. These cells were co-cultured for 7 days. DCs and T cell were enriched separately. Finally, antitumor response test was carried out. Results: These cells had typical dendritic morphology, expressed high levels of CD1a, B7 and acquired antigen from apoptotic cells caused by γ-rays and induced an increased T cell-stimulatory capacity in MLR. Conclusions: DCs obtained from blood mononuclear cells using GM-CSF and IL-4 and DCs can efficiently present antigen driven from apoptotic cells caused by γ-rays and induce T cells increasing obviously. It can probably become an effective approach of DC transduction with antigen

  6. Identifying Regulators of the Immune Response to Dying Cells | Center for Cancer Research

    Science.gov (United States)

    Cytotoxic T cells are responsible for carrying out antigen-mediated immune responses against virally-infected and malignant cells. In both cases, cytotoxic T cells are stimulated by interacting with antigen presenting cells, such as dendritic cells (DCs). Infected cells produce virus-specific antigens and pathogen associated molecular patterns, which are recognized by DCs and lead to robust T cell activation. Dead or dying uninfected cells, on the other hand, release damage associated molecular patterns, but their release does not always appear to be sufficient to induce cytotoxic T cell activity. Tim Greten, M.D., of CCR’s Medical Oncology Branch, and a group of international collaborators set out to understand how immune responses against dying cancer cells are regulated. These processes are likely to be important for improving the efficacy of cancer treatment vaccines, which induce an immune reaction against a patient’s cancer cells.

  7. Differential pulmonic NK and NKT cell responses in Schistosoma japonicum-infected mice.

    Science.gov (United States)

    Cha, Hefei; Qin, Wenjuan; Yang, Quan; Xie, Hongyan; Qu, Jiale; Wang, Mei; Chen, Daixiong; Wang, Fang; Dong, Nuo; Chen, Longhua; Huang, Jun

    2017-02-01

    Natural killer cells (NK cells) and natural killer T cells (NKT cells) play a role in anti-infection, anti-tumor, transplantation immunity, and autoimmune regulation. However, the role of NK and NKT cells during Schistosoma japonicum (S. japonicum) infection has not been widely reported, especially regarding lung infections. The aim of this study was to research the NK and NKT cell response to S. japonicum infection in the lungs of mice. Using immunofluorescent histological analysis, NK and NKT cells were found near pulmonary granulomas. Moreover, flow cytometry revealed that the percentage and number of pulmonic NK cells in S. japonicum-infected mice were significantly increased (P cell number of NKT cells were decreased compared to those of normal mice (P NKT cells was increased after infection (P NKT cells (P cells (P NKT cells significantly increased (P NKT cells (P NKT cell activation during S. japonicum infection.

  8. Infection Programs Sustained Lymphoid Stromal Cell Responses and Shapes Lymph Node Remodeling upon Secondary Challenge

    Directory of Open Access Journals (Sweden)

    Julia L. Gregory

    2017-01-01

    Full Text Available Lymph nodes (LNs are constructed of intricate networks of endothelial and mesenchymal stromal cells. How these lymphoid stromal cells (LSCs regulate lymphoid tissue remodeling and contribute to immune responses remains poorly understood. We performed a comprehensive functional and transcriptional analysis of LSC responses to skin viral infection and found that LSC subsets responded robustly, with different kinetics for distinct pathogens. Recruitment of cells to inflamed LNs induced LSC expansion, while B cells sustained stromal responses in an antigen-independent manner. Infection induced rapid transcriptional responses in LSCs. This transcriptional program was transient, returning to homeostasis within 1 month of infection, yet expanded fibroblastic reticular cell networks persisted for more than 3 months after infection, and this altered LN composition reduced the magnitude of LSC responses to subsequent heterologous infection. Our results reveal the complexity of LSC responses during infection and suggest that amplified networks of LN stromal cells support successive immune responses.

  9. Deficient repair regulatory response to injury in keratoconic stromal cells.

    Science.gov (United States)

    Cheung, Isabella My; McGhee, Charles Nj; Sherwin, Trevor

    2014-05-01

    Keratoconus manifests as a conical protrusion of the cornea and is characterised by stromal thinning. This causes debilitating visual impairment, which may necessitate corneal transplantation. Hypothetically, many of the pathological features in keratoconus may be manifestations of defects in wound healing; however, as the pathobiology remains unclear, therapeutic targets related to disease mechanisms are currently lacking. This study investigated the protein expression of cytokines which may control stromal wound healing and the effect of an induced secondary injury (SI) on stromal cells from ex vivo human keratoconus and control corneas. Total protein was extracted from stromal cells from human keratoconic and non-keratoconic central corneas (n = 12) with (+SI) and without (-SI) an ex vivo corneal incision wound. The levels of interleukin 1 alpha (IL-1α), fibroblast growth factor 2 (FGF-2), nerve growth factor beta (β-NGF), insulin-like growth factor 1 (IGF-1), tumour necrosis factor alpha (TNF-α), epidermal growth factor (EGF), transforming growth factor beta 1 (TGF-β1), platelet-derived growth factor (PDGF) and hepatocyte growth factor (HGF) were quantified using chemiluminescence-based immunoarrays. In stromal cells from -SI keratoconic corneas (compared with -SI normal corneas), the levels of IL-1α, IGF-1, TNF-α and TGF-β1 were increased and the levels of HGF and β-NGF were reduced. These alterations were also observed in +SI non-keratoconic corneas (compared with -SI non-keratoconic corneas). In stromal cells from +SI keratoconic corneas (compared with -SI keratoconic corneas), the quantities of IL-1α, FGF-2, TNF-a, EGF, TGF-a1 and PDGF were decreased. The repair-modulating milieu in keratoconic corneas appears comparable to that in wounded normal corneas. Moreover, wounded keratoconic corneas may be less capable of orchestrating a normal reparative response. These novel findings may improve our understanding of the pathobiology and may facilitate

  10. Visual response properties of cells in the ventral and dorsal parts of the macaque inferotemporal cortex.

    Science.gov (United States)

    Tamura, H; Tanaka, K

    2001-05-01

    We recorded from cells in the anterio-ventral (TEav) and anterio- dorsal (TEad) parts of area TE of the inferotemporal cortex and examined their responses to a set of 100 visual stimuli in awake, fixating monkeys. In both TEav and TEad we found that, depending on the stimulus, the time course of responses varied considerably within individual cells and that there were three main factors in the variation. One factor is variance in the balance between the initial transient part of responses around 130 ms after stimulus onset and the later part after 240 ms from stimulus onset. The later parts of responses were more stimulus selective. The second factor is variance in the latency of response onset and peak and the third is variance in the speed of decay from the peak within the initial part of the responses. Stronger responses had shorter onset and peak latencies and longer decay times. The results suggest that stimulus images can be discriminated very rapidly in TEav and TEad by detecting differences in response onset. TEav cells differed from TEad cells in that they were more difficult to activate than TEad cells: the proportion of responsive TEav cells was smaller, the maximal responses of individual cells were smaller than in TEad and the number of stimuli that evoked significant responses in individual responsive cells was also smaller than in TEad. Moreover, TEav cells, overall, responded more strongly to more colorful object images than less colorful ones, while TEad cells did not show such a tendency. However, the minimum onset latency of individual cells and the sharpness of stimulus selectivity did not differ significantly between TEav and TEad. Responses of TEav cells are as selective as those of TEad cells, although there remains a possibility that the domain of selectivity differs between the two areas. These results support an earlier anatomical finding that TEav and TEad are located at the same hierarchical level of separate serial pathways rather than

  11. [T cell-mediated immune responses and the recognition of tuberculosis antigens].

    Science.gov (United States)

    Tsujimura, Kunio; Koide, Yukio

    2010-06-01

    T cell-mediated immune responses profoundly contribute to the protection against the re-activation of latently infected Mycobacterium tuberculosis. Th1 cells produce IFN-gamma to activate infected macrophages and promote the formation of granulomas around infected macrophages. CD8+, gamma delta and CD1-restricted T cells also produce IFN-gamma and participate the protective responses against bacterial growth. Th17 cells produce IL-17 to promote the mobilization of immunocompetent cells and contribute to the granuloma formation. On the contrary, Th2 cells and Tregs interfere these protective immune responses.

  12. Distinct Responses of Stem Cells to Telomere Uncapping-A Potential Strategy to Improve the Safety of Cell Therapy.

    Science.gov (United States)

    Liu, Chang Ching; Ma, Dong Liang; Yan, Ting-Dong; Fan, XiuBo; Poon, Zhiyong; Poon, Lai-Fong; Goh, Su-Ann; Rozen, Steve G; Hwang, William Ying Khee; Tergaonkar, Vinay; Tan, Patrick; Ghosh, Sujoy; Virshup, David M; Goh, Eyleen L K; Li, Shang

    2016-10-01

    In most human somatic cells, the lack of telomerase activity results in progressive telomere shortening during each cell division. Eventually, DNA damage responses triggered by critically short telomeres induce an irreversible cell cycle arrest termed replicative senescence. However, the cellular responses of human pluripotent stem cells to telomere uncapping remain unknown. We generated telomerase knockout human embryonic stem (ES) cells through gene targeting. Telomerase inactivation in ES cells results in progressive telomere shortening. Telomere DNA damage in ES cells and neural progenitor cells induces rapid apoptosis when telomeres are uncapped, in contrast to fibroblast cells that enter a state of replicative senescence. Significantly, telomerase inactivation limits the proliferation capacity of human ES cells without affecting their pluripotency. By targeting telomerase activity, we can functionally separate the two unique properties of human pluripotent stem cells, namely unlimited self-renewal and pluripotency. We show that the potential of ES cells to form teratomas in vivo is dictated by their telomere length. By controlling telomere length of ES cells through telomerase inactivation, we can inhibit teratoma formation and potentially improve the safety of cell therapies involving terminally differentiated cells as well as specific progenitor cells that do not require sustained cellular proliferation in vivo, and thus sustained telomerase activity. Stem Cells 2016;34:2471-2484. © 2016 AlphaMed Press.

  13. Naturally Occurring Extracellular Matrix Scaffolds for Dermal Regeneration: Do They Really Need Cells?

    Directory of Open Access Journals (Sweden)

    A. M. Eweida

    2015-01-01

    Full Text Available The pronounced effect of extracellular matrix (ECM scaffolds in supporting tissue regeneration is related mainly to their maintained 3D structure and their bioactive components. These decellularized matrix scaffolds could be revitalized before grafting via adding stem cells, fibroblasts, or keratinocytes to promote wound healing. We reviewed the online published literature in the last five years for the studies that performed ECM revitalization and discussed the results of these studies and the related literature. Eighteen articles met the search criteria. Twelve studies included adding cells to acellular dermal matrix (ADM, 3 studies were on small intestinal mucosa (SIS, one study was on urinary bladder matrix (UBM, one study was on amniotic membrane, and one study included both SIS and ADM loaded constructs. We believe that, in chronic and difficult-to-heal wounds, revitalizing the ECM scaffolds would be beneficial to overcome the defective host tissue interaction. This belief still has to be verified by high quality randomised clinical trials, which are still lacking in literature.

  14. Hydroxyurea in Pediatric Patients With Sickle Cell Disease: What Nurses Need to Know.

    Science.gov (United States)

    Rees, Allison L

    2016-09-01

    Sickle cell disease (SCD) is an inherited disorder in which sickled red blood cells occlude the small vessels of the body, reducing oxygen delivery to tissues and ultimately negatively affecting many of the body's major organs. Hydroxyurea has proven beneficial in the treatment of SCD and prevention of disease-related complications. The 2014 guidelines put forth by the National Heart, Lung, and Blood Institute recommend hydroxyurea treatment in infants 9 months and older, children, and adolescents with SCD-SS or SCD-Sβ(0) thalassemia regardless of clinical severity. This is a change from the 2002 guidelines in which hydroxyurea was recommended for adolescents and children with SCD-SS or SCD-Sβ(0) thalassemia with frequent episodes of pain, a history of acute chest syndrome, severe and symptomatic anemia or other severe vaso-occlusive events. Nurses play a critical role in working with patients and families to provide education, guidance, and support to improve compliance to mitigate the long-term effects of SCD. © 2015 by Association of Pediatric Hematology/Oncology Nurses.

  15. Analysis of the T Cell Response to Zika Virus and Identification of a Novel CD8+ T Cell Epitope in Immunocompetent Mice.

    Science.gov (United States)

    Pardy, Ryan D; Rajah, Maaran M; Condotta, Stephanie A; Taylor, Nathan G; Sagan, Selena M; Richer, Martin J

    2017-02-01

    Zika virus (ZIKV) is an emerging arbovirus of the Flaviviridae family. Although ZIKV infection is typically mild and self-limiting in healthy adults, infection has been associated with neurological symptoms such as Guillain-Barré syndrome, and a causal link has been established between fetal microcephaly and ZIKV infection during pregnancy. These risks, and the magnitude of the ongoing ZIKV pandemic, have created an urgent need for the development of animal models to study the immune response to ZIKV infection. Previous animal models have primarily focused on pathogenesis in immunocompromised mice. In this study, we provide a model of ZIKV infection in wild-type immunocompetent C57BL/6 mice, and have provided an analysis of the immune response to infection. We evaluated the activation of several innate immune cell types, and studied the kinetics, phenotype, and functionality of T cell responses to ZIKV infection. Our results demonstrate that ZIKV infection is mild in wild-type immunocompetent C57BL/6 mice, resulting in minimal morbidity. Our data establish that at the peak of the adaptive response, antigen-experienced CD4+ T cells polarize to a Th1 phenotype, and antigen-experienced CD8+ T cells exhibit an activated effector phenotype, producing both effector cytokines and cytolytic molecules. Furthermore, we have identified a novel ZIKV CD8+ T cell epitope in the envelope protein that is recognized by the majority of responding cells. Our model provides an important reference point that will help dissect the impact of polymorphisms in the circulating ZIKV strains on the immune response and ZIKV pathogenesis. In addition, the identification of a ZIKV epitope will allow for the design of tetramers to study epitope-specific T cell responses, and will have important implications for the design and development of ZIKV vaccine strategies.

  16. Analysis of the T Cell Response to Zika Virus and Identification of a Novel CD8+ T Cell Epitope in Immunocompetent Mice.

    Directory of Open Access Journals (Sweden)

    Ryan D Pardy

    2017-02-01

    Full Text Available Zika virus (ZIKV is an emerging arbovirus of the Flaviviridae family. Although ZIKV infection is typically mild and self-limiting in healthy adults, infection has been associated with neurological symptoms such as Guillain-Barré syndrome, and a causal link has been established between fetal microcephaly and ZIKV infection during pregnancy. These risks, and the magnitude of the ongoing ZIKV pandemic, have created an urgent need for the development of animal models to study the immune response to ZIKV infection. Previous animal models have primarily focused on pathogenesis in immunocompromised mice. In this study, we provide a model of ZIKV infection in wild-type immunocompetent C57BL/6 mice, and have provided an analysis of the immune response to infection. We evaluated the activation of several innate immune cell types, and studied the kinetics, phenotype, and functionality of T cell responses to ZIKV infection. Our results demonstrate that ZIKV infection is mild in wild-type immunocompetent C57BL/6 mice, resulting in minimal morbidity. Our data establish that at the peak of the adaptive response, antigen-experienced CD4+ T cells polarize to a Th1 phenotype, and antigen-experienced CD8+ T cells exhibit an activated effector phenotype, producing both effector cytokines and cytolytic molecules. Furthermore, we have identified a novel ZIKV CD8+ T cell epitope in the envelope protein that is recognized by the majority of responding cells. Our model provides an important reference point that will help dissect the impact of polymorphisms in the circulating ZIKV strains on the immune response and ZIKV pathogenesis. In addition, the identification of a ZIKV epitope will allow for the design of tetramers to study epitope-specific T cell responses, and will have important implications for the design and development of ZIKV vaccine strategies.

  17. Treatment of allergic asthma: Modulation of Th2 cells and their responses

    Directory of Open Access Journals (Sweden)

    Erb Klaus J

    2011-08-01

    Full Text Available Abstract Atopic asthma is a chronic inflammatory pulmonary disease characterised by recurrent episodes of wheezy, laboured breathing with an underlying Th2 cell-mediated inflammatory response in the airways. It is currently treated and, more or less, controlled depending on severity, with bronchodilators e.g. long-acting beta agonists and long-acting muscarinic antagonists or anti-inflammatory drugs such as corticosteroids (inhaled or oral, leukotriene modifiers, theophyline and anti-IgE therapy. Unfortunately, none of these treatments are curative and some asthmatic patients do not respond to intense anti-inflammatory therapies. Additionally, the use of long-term oral steroids has many undesired side effects. For this reason, novel and more effective drugs are needed. In this review, we focus on the CD4+ Th2 cells and their products as targets for the development of new drugs to add to the current armamentarium as adjuncts or as potential stand-alone treatments for allergic asthma. We argue that in early disease, the reduction or elimination of allergen-specific Th2 cells will reduce the consequences of repeated allergic inflammatory responses such as lung remodelling without causing generalised immunosuppression.

  18. Antigen-specific B cells reactivate an effective cytotoxic T cell response against phagocytosed Salmonella through cross-presentation.

    Science.gov (United States)

    de Wit, Jelle; Souwer, Yuri; Jorritsma, Tineke; Klaasse Bos, Hanny; ten Brinke, Anja; Neefjes, Jacques; van Ham, S Marieke

    2010-09-27

    The eradication of facultative intracellular bacterial pathogens, like Salmonella typhi, requires the concerted action of both the humoral immune response and the cytotoxic CD8(+) T cell response. Dendritic cells (DCs) are considered to orchestrate the cytotoxic CD8(+) T cell response via cross-presentation of bacterial antigens onto MHC class I molecules. Cross-presentation of Salmonella by DCs however, is accompanied by the induction of apoptosis in the DCs. Besides antibody production, B cells are required to clear Salmonella infection for other unknown reasons. Here we show that Salmonella-specific B cells that phagocytose Salmonella upon BCR-ligation reactivate human memory CD8(+) T cells via cross-presentation yielding a Salmonella-specific cytotoxic T cell response. The reactivation of CD8(+) T cells is dependent on CD4(+) T cell help. Unlike the DCs, B cell-mediated cross-presentation of Salmonella does not coincide with apoptosis. B cells form a new player in the activation of the cytotoxic effector arm of the immune response and the generation of effective adaptive immunity in Salmonella infection.

  19. CD28 expression is required after T cell priming for helper T cell responses and protective immunity to infection.

    Science.gov (United States)

    Linterman, Michelle A; Denton, Alice E; Divekar, Devina P; Zvetkova, Ilona; Kane, Leanne; Ferreira, Cristina; Veldhoen, Marc; Clare, Simon; Dougan, Gordon; Espéli, Marion; Smith, Kenneth G C

    2014-10-27

    The co-stimulatory molecule CD28 is essential for activation of helper T cells. Despite this critical role, it is not known whether CD28 has functions in maintaining T cell responses following activation. To determine the role for CD28 after T cell priming, we generated a strain of mice where CD28 is removed from CD4(+) T cells after priming. We show that continued CD28 expression is important for effector CD4(+) T cells following infection; maintained CD28 is required for the expansion of T helper type 1 cells, and for the differentiation and maintenance of T follicular helper cells during viral infection. Persistent CD28 is also required for clearance of the bacterium Citrobacter rodentium from the gastrointestinal tract. Together, this study demonstrates that CD28 persistence is required for helper T cell polarization in response to infection, describing a novel function for CD28 that is distinct from its role in T cell priming.

  20. Ionizing radiation affects generation of MART-1-specific cytotoxic T cell responses by dendritic cells

    International Nuclear Information System (INIS)

    Liao, Y.P.; Wang, C.-C.; McBride, W.H.

    2003-01-01

    Full text: The human MART-1/Melan-A (MART-1) melanoma tumor antigen is known to be recognized by cytotoxic T lymphocytes (CTLs) and several groups are using this target for clinical immunotherapy. Most approaches use dendritic cells (DCs) that are potent antigen presentation cells for initiating CTL responses. In order for CTL recognition to occur, DCs must display 9-residue antigenic peptides on MHC class I molecules. These peptides are generated by proteasome degradation and then transported through the endoplasmic reticulum to the cell surface where they stabilize MHC class I expression. Our previous data showed that irradiation inhibits proteasome function and, therefore, we hypothesized that irradiation may inhibit antigen processing and CTL activation, as has been shown for proteasome inhibitors. To study the importance of irradiation effects on DCs, we studied the generation MART-1-specific CTL responses. Preliminary data showed that irradiation of murine bone marrow derived DCs did not affect expression of MHC class I, II, CD80, or CD86, as assessed by flow cytometric analyses 24-hour after irradiation. The effect of irradiation on MART-1 antigen processing by DCs was evaluated using DC transduced with adenovirus MART-1 (AdVMART1). C57BL/6 mice were immunized with AdVMART1 transduced DCs, with and without prior irradiation. IFN-γ production was measured by ELISPOT assays after 10-14 days of immunization. Prior radiation treatment resulted in a significant decrease in MART-1-specific T cell responses. The ability of irradiated and non-irradiated AdVMART1/DC vaccines to protect mice against growth of murine B16 tumors, which endogenously express murine MART-1, was also examined. AdVMART1/DC vaccination protected C57BL/6 mice against challenge with viable B16 melanoma cells while DCs irradiated (10 Gy) prior to AdVMART1 transduction abrogated protection. These results suggest that proteasome inhibition in DCs by irradiation may be a possible pathway in

  1. Oncolytic measles virus enhances antitumour responses of adoptive CD8+NKG2D+ cells in hepatocellular carcinoma treatment.

    Science.gov (United States)

    Chen, Aiping; Zhang, Yonghui; Meng, Gang; Jiang, Dengxu; Zhang, Hailin; Zheng, Meihong; Xia, Mao; Jiang, Aiqin; Wu, Junhua; Beltinger, Christian; Wei, Jiwu

    2017-07-12

    There is an urgent need for novel effective treatment for hepatocellular carcinoma (HCC). Oncolytic viruses (OVs) not only directly lyse malignant cells, but also induce potent antitumour immune responses. The potency and precise mechanisms of antitumour immune activation by attenuated measles virus remain unclear. In this study, we investigated the potency of the measles virus vaccine strain Edmonston (MV-Edm) in improving adoptive CD8 + NKG2D + cells for HCC treatment. We show that MV-Edm-infected HCC enhanced the antitumour activity of CD8 + NKG2D + cells, mediated by at least three distinct mechanisms. First, MV-Edm infection compelled HCC cells to express the specific NKG2D ligands MICA/B, which may contribute to the activation of CD8 + NKG2D + cells. Second, MV-Edm-infected HCC cells stimulated CD8 + NKG2D + cells to express high level of FasL resulting in enhanced induction of apoptosis. Third, intratumoural administration of MV-Edm enhanced infiltration of intravenously injected CD8 + NKG2D + cells. Moreover, we found that MV-Edm and adoptive CD8 + NKG2D + cells, either administered alone or combined, upregulated the immune suppressive enzyme indoleamine 2,3-dioxygenase 1 (IDO1) in HCC. Elimination of IDO1 by fludarabine enhanced antitumour responses. Taken together, our data provide a novel and clinically relevant strategy for treatment of HCC.

  2. Endogenous NAMPT dampens chemokine expression and apoptotic responses in stressed tubular cells.

    Science.gov (United States)

    Benito-Martin, Alberto; Ucero, Alvaro C; Izquierdo, María Concepción; Santamaria, Beatriz; Picatoste, Belén; Carrasco, Susana; Lorenzo, Oscar; Ruiz-Ortega, Marta; Egido, Jesus; Ortiz, Alberto

    2014-02-01

    Diabetic nephropathy (DN) is the most common cause of end-stage renal disease and identification of new therapeutic targets is needed. Nicotinamide phosphoribosyltransferase (NAMPT) is both an extracellular and intracellular protein. Circulating NAMPT is increased in diabetics and in chronic kidney disease patients. The role of NAMPT in renal cell biology is poorly understood. NAMPT mRNA and protein were increased in the kidneys of rats with streptozotocin-induced diabetes. Immunohistochemistry localized NAMPT to glomerular and tubular cells in diabetic rats. The inflammatory cytokine TNFα increased NAMPT mRNA, protein and NAD production in cultured kidney human tubular cells. Exogenous NAMPT increased the mRNA expression of chemokines MCP-1 and RANTES. The NAMPT enzymatic activity inhibitor FK866 prevented these effects. By contrast, FK866 boosted TNFα-induced expression of MCP-1 and RANTES mRNA and endogenous NAMPT targeting by siRNA also had a proinflammatory effect. Furthermore, FK866 promoted tubular cell apoptosis in an inflammatory milieu containing the cytokines TNFα/IFNγ. In an inflammatory environment FK866 promoted tubular cell expression of the lethal cytokine TRAIL. These data are consistent with a role of endogenous NAMPT activity as an adaptive, protective response to an inflammatory milieu that differs from the proinflammatory activity of exogenous NAMPT. Thus, disruption of endogenous NAMPT function in stressed cells promotes tubular cell death and chemokine expression. This information may be relevant for the design of novel therapeutic strategies in DN. Copyright © 2013. Published by Elsevier B.V.

  3. Red blood cell components: Meeting the quantitative and qualitative transfusion needs.

    Science.gov (United States)

    Francis, Richard O; Spitalnik, Steven L

    2016-01-01

    Red blood cell (RBC) transfusion is a very common therapeutic intervention. However, because of multiple recent studies improving our understanding of appropriate transfusion scenarios, the total number of RBC units transfused per year is actually decreasing in the developed world and there are no longer major shortages of RBC products for general use. Nonetheless, there are an increasing number of "special" uses, which can put strains on the blood supply for particular types of products; these may produce shortages of specific types of RBCs or require collections targeting certain types of donors. This review will focus on several broad topics, including providing some examples of "special" settings that require, or could require, special types of RBC products. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  4. Application of laser tweezers Raman spectroscopy techniques to the monitoring of single cell response to stimuli

    Science.gov (United States)

    Chan, James W.; Liu, Rui; Matthews, Dennis L.

    2012-06-01

    Laser tweezers Raman spectroscopy (LTRS) combines optical trapping with micro-Raman spectroscopy to enable label-free biochemical analysis of individual cells and small biological particles in suspension. The integration of the two technologies greatly simplifies the sample preparation and handling of suspension cells for spectroscopic analysis in physiologically meaningful conditions. In our group, LTRS has been used to study the effects of external perturbations, both chemical and mechanical, on the biochemistry of the cell. Single cell dynamics can be studied by performing longitudinal studies to continuously monitor the response of the cell as it interacts with its environment. The ability to carry out these measurements in-vitro makes LTRS an attractive tool for many biomedical applications. Here, we discuss the use of LTRS to study the response of cancer cells to chemotherapeutics and bacteria cells to antibiotics and show that the life cycle and apoptosis of the cells can be detected. These results show the promise of LTRS for drug discovery/screening, antibiotic susceptibility testing, and chemotherapy response monitoring applications. In separate experiments, we study the response of red blood cells to the mechanical forces imposed on the cell by the optical tweezers. A laser power dependent deoxygenation of the red blood cell in the single beam trap is reported. Normal, sickle cell, and fetal red blood cells have a different behavior that enables the discrimination of the cell types based on this mechanochemical response. These results show the potential utility of LTRS for diagnosing and studying red blood cell diseases.

  5. Primary mediastinal large B-cell lymphoma (PMLCL): the need for prospective controlled clinical trials.

    Science.gov (United States)

    Bieri, S; Roggero, E; Zucca, E; Bertoni, F; Pianca, S; Sanna, P; Pedrinis, E; Bernier, J; Cavalli, F

    1999-09-01

    Primary mediastinal large-B cell lymphomas (PMLCL) are considered to be a distinct clinicopathologic entity among the diffuse large B-cell lymphomas. This study evaluated the prognostic factors and therapeutic outcome of PMLCL in a single-institution series. Twenty seven patients were reviewed. Nineteen of the 27 had Stage I-II and 8 had Stage III-IV disease. B-symptoms were found in 11 (41%) patients and bulky disease in 10 (37%). All patients were initially given combination chemotherapy (CT): doxorubicin-containing regimens to 23 patients (11 patients had CHOP, 12 more intensive third-generation regimens) and 4 elderly (>70 years) patients received CVP. Eleven responders were consolidated with irradiation (RT) as part of their initial treatment, with a median total dose of 39 Gy. Nineteen patients (70%) achieved clinical remission (15 CR and 4 PR) with their initial therapy. Forty-four percent of patients remained progression-free and 59% are alive at 3 years. The actuarial 10-year TTP and OS were 44% and 50%, respectively. Age >60 years, performance status >1 and IPI intermediate-high to high risk were significantly associated with poorer OS and TTP by univariate analysis (log-rank test). A better outcome was associated with the use of more aggressive chemotherapy regimens or with the inclusion of RT in the first-line treatment. In conclusion our analyses suggest that the application of radiotherapy in combination regimens and the use of more aggressive chemotherapy in the treatment of this particular lymphoma entity should be evaluated in prospective randomized trials.

  6. Primary mediastinal large B-cell lymphoma: the need for prospective controlled clinical trials.

    Science.gov (United States)

    Bieri, S; Roggero, E; Zucca, E; Bertoni, F; Pianca, S; Sanna, P; Pedrinis, E; Bernier, J; Cavalli, F

    1999-11-01

    Primary mediastinal large-B cell lymphomas (PMLCL) are considered to be a distinct clinicopathologic entity among the diffuse large B-cell lymphomas. This study evaluated the prognostic factors and therapeutic outcome of PMLCL in a single-institution series. Twenty seven patients were reviewed. Nineteen of the 27 had Stage I-II and 8 had Stage III-IV disease. B-symptoms were found in 11 (41%) and bulky disease in 10 (37%) patients. All were initially given combination chemotherapy (CT): doxorubicin-containing regimens to 23 patients (11 patients had CHOP, 12 received more intensive third-generation regimens) and 4 elderly (>70 years) patients received CVP. Eleven responders were consolidated with irradiation (RT) as part of their initial treatment, with a median total dose of 39 Gy. Nineteen patients (70%) achieved clinical remission (15 CR and 4 PR) with their initial therapy. Forty-four percent of patients remained progression-free and 59% are alive at 3 years. The actuarial 10-year time to progression (TTP) and overall survival (OS) were 44% and 50%, respectively. Age >60 years, performance status >1 and IPI intermediate-high to high risk were significantly associated with poorer OS and TTP by univariate analysis (log-rank test). A better outcome was associated with the use of more aggressive chemotherapy regimens or with the inclusion of RT in the first-line treatment. Our analyses suggest that the application of radiotherapy in combination regimens and the use of more aggressive chemotherapy in the treatment of this particular type of lymphoma should now be evaluated in prospective randomized trials.

  7. Transcriptional profile of Taxus chinensis cells in response to methyl jasmonate

    Directory of Open Access Journals (Sweden)

    Li Shu-tao

    2012-07-01

    Full Text Available Abstract Background Methyl jasmonate (MeJA has been successfully used as an effective elicitor to enhance production of taxol and other taxanes in cultured Taxus cells. However the mechanism of MeJA-mediated taxane biosynthesis remains unclear. Genomic information for species in the genus Taxus is currently unavailable. Therefore, information about the transcriptome of Taxus cells and specifically, description of changes in gene expression in response to MeJA, is needed for the better exploration of the biological mechanisms of MeJA-mediated taxane biosynthesis. Results In this research, the transcriptome profiles of T. chinensis cells at 16 hours (T16 after MeJA treatment and of mock-treated cells (T0 were analyzed by “RNA-seq” to investigate the transcriptional alterations of Taxus cell in response to MeJA elicitation. More than 58 million reads (200 bp in length of cDNA from both samples were generated, and 46,581 unigenes were found. There were 13,469 genes found to be expressed differentially between the two timepoints, including all of the known jasmonate (JA biosynthesis/JA signaling pathway genes and taxol-related genes. The qRT-PCR results showed that the expression profiles of 12 randomly selected DEGs and 10 taxol biosynthesis genes were found to be consistent with the RNA-Seq data. MeJA appeared to stimulate a large number of genes involved in several relevant functional categories, such as plant hormone biosynthesis and phenylpropanoid biosynthesis. Additionally, many genes encoding transcription factors were shown to respond to MeJA elicitation. Conclusions The results of a transcriptome analysis suggest that exogenous application of MeJA could induce JA biosynthesis/JA signaling pathway/defence responses, activate a series of transcription factors, as well as increase expression of genes in the terpenoid biosynthesis pathway responsible for taxol synthesis. This comprehensive description of gene expression information could

  8. T-cell-independent immune responses do not require CXC ligand 13-mediated B1 cell migration.

    Science.gov (United States)

    Colombo, Matthew J; Sun, Guizhi; Alugupalli, Kishore R

    2010-09-01

    The dynamic movement of B cells increases the probability of encountering specific antigen and facilitates cell-cell interactions required for mounting a rapid antibody response. B1a and B1b cells are enriched in the coelomic cavity, contribute to T-cell-independent (TI) antibody responses, and increase in number upon antigen exposure. B1 cell movement is largely governed by Cxc ligand 13 (Cxcl13), and mice deficient in this chemokine have a severe reduction in peritoneal B1 cells. In this study, we examined the role of Cxcl13-dependent B cell migration using Borrelia hermsii infection or intraperitoneal immunization with pneumococcal polysaccharide or 4-hydroxy-3-nitrophenyl-acetyl (NP)-Ficoll, all of which induce robust antibody responses from B1b cells. Surprisingly, we found that antibody responses to B. hermsii or to FhbA, an antigenic target of B1b cells, and the resolution of bacteremia were indistinguishable between wild-type and Cxcl13-/- mice. Importantly, we did not observe an expansion of peritoneal B1b cell numbers in Cxcl13-/- mice. Nonetheless, mice that had resolved infection were resistant to reinfection, indicating that the peritoneal B1b cell reservoir is not required for controlling B. hermsii. Furthermore, despite a reduced peritoneal B1b compartment, immunization with pneumococcal polysaccharide vaccine yielded comparable antigen-specific antibody responses in wild-type and Cxcl13-/- mice and conferred protection against Streptococcus pneumoniae. Likewise, immunization with NP-Ficoll elicited similar antibody responses in wild-type and Cxcl13-/- mice. These data demonstrate that homing of B1 cells into the coelomic cavity is not a requirement for generating protective TI antibody responses, even when antigen is initially localized to this anatomical compartment.

  9. Antioxidant responses to an acute ultra-endurance exercise: impact on DNA stability and indications for an increased need for nutritive antioxidants in the early recovery phase.

    Science.gov (United States)

    Neubauer, Oliver; Reichhold, Stefanie; Nics, Lukas; Hoelzl, Christine; Valentini, Judit; Stadlmayr, Barbara; Knasmüller, Siegfried; Wagner, Karl-Heinz

    2010-10-01

    Antioxidant requirements have neither been defined for endurance nor been defined for ultra-endurance athletes. To verify whether an acute bout of ultra-endurance exercise modifies the need for nutritive antioxidants, we aimed (1) to investigate the changes of endogenous and exogenous antioxidants in response to an Ironman triathlon; (2) to particularise the relevance of antioxidant responses to the indices of oxidatively damaged blood lipids, blood cell compounds and lymphocyte DNA and (3) to examine whether potential time-points of increased susceptibility to oxidative damage are associated with alterations in the antioxidant status. Blood that was collected from forty-two well-trained male athletes 2 d pre-race, immediately post-race, and 1, 5 and 19 d later was sampled. The key findings of the present study are as follows: (1) Immediately post-race, vitamin C, α-tocopherol, and levels of the Trolox equivalent antioxidant capacity, the ferric reducing ability of plasma and the oxygen radical absorbance capacity (ORAC) assays increased significantly. Exercise-induced changes in the plasma antioxidant capacity were associated with changes in uric acid, bilirubin and vitamin C. (2) Significant inverse correlations between ORAC levels and indices of oxidatively damaged DNA immediately and 1 d post-race suggest a protective role of the acute antioxidant responses in DNA stability. (3) Significant decreases in carotenoids and γ-tocopherol 1 d post-race indicate that the antioxidant intake during the first 24 h of recovery following an acute ultra-endurance exercise requires specific attention. Furthermore, the present study illustrates the importance of a diversified and well-balanced diet to maintain a physiological antioxidant status in ultra-endurance athletes in reference to recommendations.

  10. Social Pedagogy and Social Education in Colombia: A shared Institutional, Academic and Professional responsability needed for social transformation

    Directory of Open Access Journals (Sweden)

    Francisco José Del Pozo Serrano

    2018-01-01

    Full Text Available In this article we pretend to reinforces and solidifies the idea of professionalizing the Social Education as a career and important alternative to respond to the challenges, dynamics and current needs of the Colombian context. To develop the above idea, first is performed a theoretical and/or conceptual delimiting of the Social Education as an object of study Social Pedagogy. Then, we present the potential and limitations by which this crosses on the path toward its institutionalization. Afterwards, we present the different areas of intervention and main intersectoral and legislative organisms; and finally, we shared the proposal that we consider is more pertinent as academic program of Social Education with emphasis and the set of degrees of socio-educational fields approved by the Ministerio de Educación Nacional in the 2016. Definitively, it turns out indispensable deepen efforts and co-responsibility in order that the proposals of this kind does not just remain on paper, but can be settled in reality, and are continued stimulating initiatives that promote the Social Education as a transformative element from the socio-educational action.

  11. Putting Corporate Social Responsibility to Work in Mining Communities: Exploring Community Needs for Central Appalachian Wastewater Treatment

    Directory of Open Access Journals (Sweden)

    Nicholas Cook

    2015-04-01

    Full Text Available Due to the finite nature of non-renewable mineral and energy resources such as coal, resource extraction is inherently unsustainable; however, mining and related activities can contribute to sustainable development. Indeed, the principles of corporate social responsibility (CSR require that mine operators design and conduct their activities in ways that provide for net positive impacts on surrounding communities and environments. In Central Appalachia, there appears to be a particularly ripe opportunity for the coal industry to put CSR to work: participation in sustainable solutions to the long-standing problem of inadequately treated wastewater discharges—which not only represent a potential human health hazard, but also contribute to the relatively high incidence of bacterial impairments in surface waters in the region. In this paper, we outline the underlying factors of this problem and the advantages of industry-aided solutions in a region where limited economic and technical resources are not always aligned with social and environmental needs. We also suggest a framework for problem-solving, which necessarily involves all interested stakeholders, and identify the primary challenges that must be overcome in pursuit of sustainable solutions.

  12. Evaluation of cell responses toward adhesives with different photoinitiating systems.

    Science.gov (United States)

    Van Landuyt, Kirsten L; Krifka, Stephanie; Hiller, Karl-Anton; Bolay, Carola; Waha, Claudia; Van Meerbeek, Bart; Schmalz, Gottfried; Schweikl, Helmut

    2015-08-01

    The photoinitiator diphenyl-(2,4,6-trimethylbenzoyl)phosphine oxide (TPO) is more reactive than a camphorquinone/amine (CQ) system, and TPO-based adhesives obtained a higher degree of conversion (DC) with fewer leached monomers. The hypothesis tested here is that a TPO-based adhesive is less toxic than a CQ-based adhesive. A CQ-based adhesive (SBU-CQ) (Scotchbond Universal, 3M ESPE) and its experimental counterpart with TPO (SBU-TPO) were tested for cytotoxicity in human pulp-derived cells (tHPC). Oxidative stress was analyzed by the generation of reactive oxygen species (ROS) and by the expression of antioxidant enzymes. A dentin barrier test (DBT) was used to evaluate cell viability in simulated clinical circumstances. Unpolymerized SBU-TPO was significantly more toxic than SBU-CQ after a 24h exposure, and TPO alone (EC50=0.06mM) was more cytotoxic than CQ (EC50=0.88mM), EDMAB (EC50=0.68mM) or CQ/EDMAB (EC50=0.50mM). Cultures preincubated with BSO (l-buthionine sulfoximine), an inhibitor of glutathione synthesis, indicated a minor role of glutathione in cytotoxic responses toward the adhesives. Although the generation of ROS was not detected, a differential expression of enzymatic antioxidants revealed that cells exposed to unpolymerized SBU-TPO or SBU-CQ are subject to oxidative stress. Polymerized SBU-TPO was more cytotoxic than SBU-CQ under specific experimental conditions only, but no cytotoxicity was detected in a DBT with a 200μm dentin barrier. Not only DC and monomer-release determine the biocompatibility of adhesives, but also the cytotoxicity of the (photo-)initiator should be taken into account. Addition of TPO rendered a universal adhesive more toxic compared to CQ; however, this effect could be annulled by a thin dentin barrier. Copyright © 2015 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.

  13. The Reticular Cell Network : A Robust Backbone for Immune Responses

    NARCIS (Netherlands)

    Textor, Johannes; Mandl, Judith N; de Boer, Rob J

    2016-01-01

    Lymph nodes are meeting points for circulating immune cells. A network of reticular cells that ensheathe a mesh of collagen fibers crisscrosses the tissue in each lymph node. This reticular cell network distributes key molecules and provides a structure for immune cells to move around on. During

  14. CD56bright NK cells exhibit potent antitumor responses following IL-15 priming.

    Science.gov (United States)

    Wagner, Julia A; Rosario, Maximillian; Romee, Rizwan; Berrien-Elliott, Melissa M; Schneider, Stephanie E; Leong, Jeffrey W; Sullivan, Ryan P; Jewell, Brea A; Becker-Hapak, Michelle; Schappe, Timothy; Abdel-Latif, Sara; Ireland, Aaron R; Jaishankar, Devika; King, Justin A; Vij, Ravi; Clement, Dennis; Goodridge, Jodie; Malmberg, Karl-Johan; Wong, Hing C; Fehniger, Todd A

    2017-11-01

    NK cells, lymphocytes of the innate immune system, are important for defense against infectious pathogens and cancer. Classically, the CD56dim NK cell subset is thought to mediate antitumor responses, whereas the CD56bright subset is involved in immunomodulation. Here, we challenge this paradigm by demonstrating that brief priming with IL-15 markedly enhanced the antitumor response of CD56bright NK cells. Priming improved multiple CD56bright cell functions: degranulation, cytotoxicity, and cytokine production. Primed CD56bright cells from leukemia patients demonstrated enhanced responses to autologous blasts in vitro, and primed CD56bright cells controlled leukemia cells in vivo in a murine xenograft model. Primed CD56bright cells from multiple myeloma (MM) patients displayed superior responses to autologous myeloma targets, and furthermore, CD56bright NK cells from MM patients primed with the IL-15 receptor agonist ALT-803 in vivo displayed enhanced ex vivo functional responses to MM targets. Effector mechanisms contributing to IL-15-based priming included improved cytotoxic protein expression, target cell conjugation, and LFA-1-, CD2-, and NKG2D-dependent activation of NK cells. Finally, IL-15 robustly stimulated the PI3K/Akt/mTOR and MEK/ERK pathways in CD56bright compared with CD56dim NK cells, and blockade of these pathways attenuated antitumor responses. These findings identify CD56bright NK cells as potent antitumor effectors that warrant further investigation as a cancer immunotherapy.

  15. Mycoplasma suppression of THP-1 Cell TLR responses is corrected with antibiotics.

    Science.gov (United States)

    Zakharova, Ekaterina; Grandhi, Jaykumar; Wewers, Mark D; Gavrilin, Mikhail A

    2010-03-25

    Mycoplasma contamination of cultured cell lines is a serious problem in research, altering cellular response to different stimuli thus compromising experimental results. We found that chronic mycoplasma contamination of THP-1 cells suppresses responses of THP-1 cells to TLR stimuli. For example, E. coli LPS induced IL-1 beta was suppressed by 6 fold and IL-8 by 10 fold in mycoplasma positive THP-1 cells. Responses to live F. novicida challenge were suppressed by 50-fold and 40-fold respectively for IL-1beta and IL-8. Basal TLR4 expression level in THP-1 cells was decreased by mycoplasma by 2.4-fold (p = 0.0003). Importantly, cell responses to pathogen associated molecular patterns are completely restored by mycoplasma clearance with Plasmocin. Thus, routine screening of cell lines for mycoplasma is important for the maintenance of reliable experimental data and contaminated cell lines can be restored to their baseline function with antibiotic clearance of mycoplasma.

  16. Mycoplasma suppression of THP-1 Cell TLR responses is corrected with antibiotics.

    Directory of Open Access Journals (Sweden)

    Ekaterina Zakharova

    2010-03-01

    Full Text Available Mycoplasma contamination of cultured cell lines is a serious problem in research, altering cellular response to different stimuli thus compromising experimental results. We found that chronic mycoplasma contamination of THP-1 cells suppresses responses of THP-1 cells to TLR stimuli. For example, E. coli LPS induced IL-1 beta was suppressed by 6 fold and IL-8 by 10 fold in mycoplasma positive THP-1 cells. Responses to live F. novicida challenge were suppressed by 50-fold and 40-fold respectively for IL-1beta and IL-8. Basal TLR4 expression level in THP-1 cells was decreased by mycoplasma by 2.4-fold (p = 0.0003. Importantly, cell responses to pathogen associated molecular patterns are completely restored by mycoplasma clearance with Plasmocin. Thus, routine screening of cell lines for mycoplasma is important for the maintenance of reliable experimental data and contaminated cell lines can be restored to their baseline function with antibiotic clearance of mycoplasma.

  17. Enhancement of membrane stability on magnetic responsive hydrogel microcapsules for potential on-demand cell separation.

    Science.gov (United States)

    Wen, Huiyun; Gao, Ting; Fu, Zizhen; Liu, Xing; Xu, Jiatong; He, Yishu; Xu, Ningxia; Jiao, Ping; Fan, An; Huang, Saipeng; Xue, Weiming

    2017-02-10

    It is of high interest to obtain hydrogel membranes with optimum mechanical stability, which is a prerequisite to the successful fabrication of hydrogel microcapsules for cell separation. In this work, we developed magnetic responsive alginate/chitosan (MAC) hydrogel microcapsules by co-encapsulation of microbial cells and superparamagnetic iron oxide nanoparticles (SPIONs) reacting under a high voltage electrostatic field. We investigated the influence of the molecular weight of chitosan, microcapsules size, and membrane crosslinking time on the swelling behavior of microcapsules as an indicator of stability of the membranes. The results demonstrated that the suitable membrane stability conditions were obtained by a crosslinking of the microspheres with a chitosan presenting a molecular weight of 70kDa for 15-30min resulting in a membrane thickness of approximately 30mm. Considering the need of maintaining the cells inside the microcapsules, fermentation at 37°C and at neutral pH was favorable. Moreover, the MAC microcapsules sizing between 300 and 380μm were suitable for immobilizing Bacillus licheniformis in a 286h multiple fed-bath operation with no leakage of the SPIONs and cells. Overall, the results of this study provided strategies for the rational design of magnetic microcapsules exhibiting suitable mechanical stable membranes. Copyright © 2016 Elsevier Ltd. All rights reserved.

  18. Unopposed production of granulocyte-macrophage colony-stimulating factor by tumors inhibits CD8+ T cell responses by dysregulating antigen-presenting cell maturation.

    Science.gov (United States)

    Bronte, V; Chappell, D B; Apolloni, E; Cabrelle, A; Wang, M; Hwu, P; Restifo, N P

    1999-05-15

    Tumor cells gene-modified to produce GM-CSF potently stimulate antitumor immune responses, in part, by causing the growth and differentiation of dendritic cells (DC). However, GM-CSF-modified tumor cells must be gamma-irradiated or they will grow progressively, killing the host. We observed that 23 of 75 (31%) human tumor lines and two commonly used mouse tumor lines spontaneously produced GM-CSF. In mice, chronic GM-CSF production by tumors suppressed Ag-specific CD8+ T cell responses. Interestingly, an inhibitory population of adherent CD11b(Mac-1)/Gr-1 double-positive cells caused the observed impairment of CD8+ T cell function upon direct cell-to-cell contact. The inhibitory cells were positive for some markers associated with Ag presenting cells, like F4/80, but were negative for markers associated with fully mature DC like DEC205, B7. 2, and MHC class II. We have previously reported that a similar or identical population of inhibitory "immature" APC was elicited after immunization with powerful recombinant immunogens. We show here that these inhibitory cells can be elicited by the administration of recombinant GM-CSF alone, and, furthermore, that they can be differentiated ex vivo into "mature" APC by the addition of IL-4 and GM-CSF. Thus, tumors may be able to escape from immune detection by producing "unopposed" GM-CSF, thereby disrupting the balance of cytokines needed for the maturation of fully functional DC. Further, CD11b/Gr-1 double-positive cells may function as "inhibitory" APC under the influence of GM-CSF alone.

  19. Unopposed Production of Granulocyte-Macrophage Colony-Stimulating Factor by Tumors Inhibits CD8+ T Cell Responses by Dysregulating Antigen-Presenting Cell Maturation1

    Science.gov (United States)

    Bronte, Vincenzo; Chappell, Dale B.; Apolloni, Elisa; Cabrelle, Anna; Wang, Michael; Hwu, Patrick; Restifo, Nicholas P.

    2008-01-01

    Tumor cells gene-modified to produce GM-CSF potently stimulate antitumor immune responses, in part, by causing the growth and differentiation of dendritic cells (DC). However, GM-CSF-modified tumor cells must be γ-irradiated or they will grow progressively, killing the host. We observed that 23 of 75 (31%) human tumor lines and two commonly used mouse tumor lines spontaneously produced GM-CSF. In mice, chronic GM-CSF production by tumors suppressed Ag-specific CD8+ T cell responses. Interestingly, an inhibitory population of adherent CD11b(Mac-1)/Gr-1 double-positive cells caused the observed impairment of CD8+ T cell function upon direct cell-to-cell contact. The inhibitory cells were positive for some markers associated with Ag presenting cells, like F4/80, but were negative for markers associated with fully mature DC like DEC205, B7.2, and MHC class II. We have previously reported that a similar or identical population of inhibitory “immature” APC was elicited after immunization with powerful recombinant immunogens. We show here that these inhibitory cells can be elicited by the administration of recombinant GM-CSF alone, and, furthermore, that they can be differentiated ex vivo into “mature” APC by the addition of IL-4 and GM-CSF. Thus, tumors may be able to escape from immune detection by producing “unopposed” GM-CSF, thereby disrupting the balance of cytokines needed for the maturation of fully functional DC. Further, CD11b/Gr-1 double-positive cells may function as “inhibitory” APC under the influence of GM-CSF alone. PMID:10229805

  20. Radiofrequency ablation in primary non-small cell lung cancer: What a radiologist needs to know

    Science.gov (United States)

    Bhatia, Shivank; Pereira, Keith; Mohan, Prasoon; Narayanan, Govindarajan; Wangpaichitr, Medhi; Savaraj, Niramol

    2016-01-01

    Lung cancer continues to be one of the leading causes of death worldwide. In advanced cases of lung cancer, a multimodality approach is often applied, however with poor local control rates. In early non-small cell lung cancer (NSCLC), surgery is the standard of care. Only 15-30% of patients are eligible for surgical resection. Improvements in imaging and treatment delivery systems have provided new tools to better target these tumors. Stereotactic body radiation therapy (SBRT) has evolved as the next best option. The role of radiofrequency ablation (RFA) is also growing. Currently, it is a third-line option in stage 1 NSCLC, when SBRT cannot be performed. More recent studies have demonstrated usefulness in recurrent tumors and some authors have also suggested combination of RFA with other modalities in larger tumors. Following the National Lung Screening Trial (NLST), screening by low-dose computed tomography (CT) has demonstrated high rates of early-stage lung cancer detection in high-risk populations. Hence, even considering the current role of RFA as a third-line option, in view of increasing numbers of occurrences detected, the number of potential RFA candidates may see a steep uptrend. In view of all this, it is imperative that interventional radiologists be familiar with the techniques of lung ablation. The aim of this article is to discuss the procedural technique of RFA in the lung and review the current evidence regarding RFA for NSCLC. PMID:27081229

  1. Antibody and B cell responses to Plasmodium sporozoites

    Directory of Open Access Journals (Sweden)

    Johanna N Dups

    2014-11-01

    Full Text Available Antibodies are capable of blocking infection of the liver by Plasmodium sporozoites. Accordingly the induction of anti-sporozoite antibodies is a major aim of various vaccine approaches to malaria. In recent years our knowledge of the specificity and quantities of antibodies required for protection has been greatly expanded by clinical trials of various whole sporozoite and subunit vaccines. Moreover, the development of humanized mouse models and transgenic parasites have also aided our ability to assess the specificity of antibodies and their ability to block infection. Nonetheless, considerable gaps remain in our knowledge - in particular in understanding what antigens are recognized by infection blocking antibodies and in knowing how we can induce robust, long-lived antibody responses. Maintaining high levels of circulating antibodies is likely to be of primary importance, as antibodies must block infection in the short time it takes for sporozoites to reach the liver from the skin. It is clear that a better understanding of the development of protective B cell-mediated immunity will aid the development and refinement of malaria vaccines.

  2. ZFAT plays critical roles in peripheral T cell homeostasis and its T cell receptor-mediated response

    International Nuclear Information System (INIS)

    Doi, Keiko; Fujimoto, Takahiro; Okamura, Tadashi; Ogawa, Masahiro; Tanaka, Yoko; Mototani, Yasumasa; Goto, Motohito; Ota, Takeharu; Matsuzaki, Hiroshi; Kuroki, Masahide; Tsunoda, Toshiyuki; Sasazuki, Takehiko; Shirasawa, Senji

    2012-01-01

    Highlights: ► We generated Cd4-Cre-mediated T cell-specific Zfat-deficient mice. ► Zfat-deficiency leads to reduction in the number of the peripheral T cells. ► Impaired T cell receptor-mediated response in Zfat-deficient peripheral T cells. ► Decreased expression of IL-7Rα, IL-2Rα and IL-2 in Zfat-deficient peripheral T cells. ► Zfat plays critical roles in peripheral T cell homeostasis. -- Abstract: ZFAT, originally identified as a candidate susceptibility gene for autoimmune thyroid disease, has been reported to be involved in apoptosis, development and primitive hematopoiesis. Zfat is highly expressed in T- and B-cells in the lymphoid tissues, however, its physiological function in the immune system remains totally unknown. Here, we generated the T cell-specific Zfat-deficient mice and demonstrated that Zfat-deficiency leads to a remarkable reduction in the number of the peripheral T cells. Intriguingly, a reduced expression of IL-7Rα and the impaired responsiveness to IL-7 for the survival were observed in the Zfat-deficient T cells. Furthermore, a severe defect in proliferation and increased apoptosis in the Zfat-deficient T cells following T cell receptor (TCR) stimulation was observed with a reduced IL-2Rα expression as well as a reduced IL-2 production. Thus, our findings reveal that Zfat is a critical regulator in peripheral T cell homeostasis and its TCR-mediated response.

  3. Follicular Helper T (Tfh) Cells Mediate IgE Antibody Response to Airborne Allergens

    Science.gov (United States)

    Kobayashi, Takao; Iijima, Koji; Dent, Alexander L.; Kita, Hirohito

    2016-01-01

    Background Type 2 helper T (Th2) cells have long been believed to play a pivotal role in allergic immune responses, including IgE antibody production and type 2 cytokine-mediated inflammation and pathology. A new T cell subset, T follicular helper cells (Tfh) cells, is specialized in supporting B cell maturation and antibody production. Objective To investigate the roles of Tfh cells in allergic immune responses. Methods Naïve mice were exposed to cytokines or natural allergens through the airways. Development of allergic immune responses was analyzed by collecting draining lymph nodes (LNs) and sera and by challenging the animals. Cytokine reporter mice and gene-deficient mice were used to dissect the immunologic mechanisms. Results We observed the development of IL-4-producing Tfh cells and Th2 cells in draining LNs following airway exposure to IL-1 family cytokines or natural allergens. Tfh cells and Th2 cells demonstrated unique phenotypes, tissue localization, and cytokine responses. Tfh cells supported the sustained production of IgE antibody in vivo in the absence of other T cell subsets or even when Th2 cell functions were severely compromised. Conversely, conditional deficiency of the master regulator Bcl6 in CD4+ T cells resulted in a marked reduction in Tfh cells and IgE antibody levels, but type 2 cytokine responses and eosinophilic inflammation in the airways remained unaffected. Conclusion Tfh cells play critical roles in the regulation of IgE antibody production. Allergic immune responses to airborne allergens likely involve two distinct subsets of IL-4-producing CD4+ T cells, namely Tfh cells and Th2 cells. PMID:27325434

  4. The influence of Listeria monocytogenes cells on the primary immunologic response in irradiated mice

    International Nuclear Information System (INIS)

    Borowski, J.; Jokoniuk, P.

    1977-01-01

    The influence of killed Listeria monocytogenes cells on the primary immunologic response in mice irradiated with 300 or 500 R was studied. The immunologic response of the mice to sheep red blood cells used as antigen was assessed at the cellular level (by counting PFC) and humoral level. Injection of killed Listeria monocytogenes cells before irradiation of the mice diminished the immunosuppressive effect of roentgen radiation. Injection of the cells after irradiation accelerated regeneration of immunologic reactivity in the irradiated mice. (author)

  5. SAP expression in invariant NKT cells is required for cognate help to support B-cell responses.

    Science.gov (United States)

    Detre, Cynthia; Keszei, Marton; Garrido-Mesa, Natividad; Kis-Toth, Katalin; Castro, Wilson; Agyemang, Amma F; Veerapen, Natacha; Besra, Gurdyal S; Carroll, Michael C; Tsokos, George C; Wang, Ninghai; Leadbetter, Elizabeth A; Terhorst, Cox

    2012-07-05

    One of the manifestations of X-linked lymphoproliferative disease (XLP) is progressive agammaglobulinemia, caused by the absence of a functional signaling lymphocyte activation molecule (SLAM)-associated protein (SAP) in T, invariant natural killer T (NKT) cells and NK cells. Here we report that α-galactosylceramide (αGalCer) activated NKT cells positively regulate antibody responses to haptenated protein antigens at multiple checkpoints, including germinal center formation and affinity maturation. Whereas NKT cell-dependent B cell responses were absent in SAP(-/-).B6 mice that completely lack NKT cells, the small number of SAP-deficient NKT cells in SAP(-/-).BALB/c mice adjuvated antibody production, but not the germinal center reaction. To test the hypothesis that SAP-deficient NKT cells can facilitate humoral immunity, SAP was deleted after development in SAP(fl/fl).tgCreERT2.B6 mice. We find that NKT cell intrinsic expression of SAP is dispensable for noncognate helper functions, but is critical for providing cognate help to antigen-specific B cells. These results demonstrate that SLAM-family receptor-regulated cell-cell interactions are not limited to T-B cell conjugates. We conclude that in the absence of SAP, several routes of NKT cell-mediated antibody production are still accessible. The latter suggests that residual NKT cells in XLP patients might contribute to variations in dysgammaglobulinemia.

  6. [Prediction of the molecular response to pertubations from single cell measurements].

    Science.gov (United States)

    Remacle, Françoise; Levine, Raphael D

    2014-12-01

    The response of protein signalization networks to perturbations is analysed from single cell measurements. This experimental approach allows characterizing the fluctuations in protein expression levels from cell to cell. The analysis is based on an information theoretic approach grounded in thermodynamics leading to a quantitative version of Le Chatelier principle which allows to predict the molecular response. Two systems are investigated: human macrophages subjected to lipopolysaccharide challenge, analogous to the immune response against Gram-negative bacteria and the response of the proteins involved in the mTOR signalizing network of GBM cancer cells to changes in partial oxygen pressure. © 2014 médecine/sciences – Inserm.

  7. Lowering T Cell Activation Thresholds and Deregulating Homeostasis to Facilitate Immunotherapeutic Responses to Treat Prostate Cancer

    National Research Council Canada - National Science Library

    Kwon, Eugene D

    2006-01-01

    ... to develop immune-based therapies for prostate cancer Hence, relatively straightforward manipulations that induce specific T cell responses against prostate tumors or epithelial tissues, especially...

  8. T Cell Factor 1-Expressing Memory-like CD8(+) T Cells Sustain the Immune Response to Chronic Viral Infections.

    Science.gov (United States)

    Utzschneider, Daniel T; Charmoy, Mélanie; Chennupati, Vijaykumar; Pousse, Laurène; Ferreira, Daniela Pais; Calderon-Copete, Sandra; Danilo, Maxime; Alfei, Francesca; Hofmann, Maike; Wieland, Dominik; Pradervand, Sylvain; Thimme, Robert; Zehn, Dietmar; Held, Werner

    2016-08-16

    Chronic infections promote the terminal differentiation (or "exhaustion") of T cells and are thought to preclude the formation of memory T cells. In contrast, we discovered a small subpopulation of virus-specific CD8(+) T cells that sustained the T cell response during chronic infections. These cells were defined by, and depended on, the expression of the transcription factor Tcf1. Transcriptome analysis revealed that this population shared key characteristics of central memory cells but lacked an effector signature. Unlike conventional memory cells, Tcf1-expressing T cells displayed hallmarks of an "exhausted" phenotype, including the expression of inhibitory receptors such as PD-1 and Lag-3. This population was crucial for the T cell expansion that occurred in response to inhibitory receptor blockade during chronic infection. These findings identify a memory-like T cell population that sustains T cell responses and is a prime target for therapeutic interventions to improve the immune response in chronic infections. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. STAT3-blocked whole-cell hepatoma vaccine induces cellular and humoral immune response against HCC.

    Science.gov (United States)

    Han, Qiuju; Wang, Yaqun; Pang, Min; Zhang, Jian

    2017-11-07

    Whole-cell tumor vaccines have shown much promise; however, only limited success has been achieved for the goal of eliciting robust tumor-specific T-cell responses. Hepatocellular carcinoma (HCC) cells, H22 and Hepa1-6, were modified by blocking the STAT3 signaling pathway with a STAT3 decoy oligodeoxynucleotide, and the immunogenicity and possibility of using these cell lysates as a vaccine were evaluated. STAT3-blocked whole HCC cell lysates inhibited tumor growth and tumorigenesis, and prolonged the survival of tumor-bearing mice. In addition, STAT3-blocked whole HCC cell lysates stimulated the activation of T cells and natural killer (NK) cells, and enhanced the infiltration of cytotoxic CD8 + T cells in the tumor tissues. In addition, the maturation of dendritic cells (DCs) was enhanced, which promoted the generation of immunological memory against HCC. Furthermore, secondary immune responses could be primed as soon as these immunized mice were challenged with HCC cells, accompanied by T cell and NK cell activation and infiltration. Additionally, immunization with this vaccine decreased the generation of Tregs and the production of TGF-β and IL-10. Importantly, STAT3-blocked whole HCC cell lysates prevented HCC-mediated exhaustion of T cells and NK cells, showing low expression of checkpoint molecules such as PD-1 and TIGIT on T cells and NK cells in the immunized mice. The newly generated STAT3-blocked whole-cell HCC vaccine has potential for cancer cell vaccination.

  10. Osteoblast cell response to surface-modified carbon nanotubes

    International Nuclear Information System (INIS)

    Zhang Faming; Weidmann, Arne; Nebe, J. Barbara; Burkel, Eberhard

    2012-01-01

    In order to investigate the interaction of cells with modified multi-walled carbon nanotubes (MWCNTs) for their potential biomedical applications, the MWCNTs were chemically modified with carboxylic acid groups (–COOH), polyvinyl alcohol (PVA) polymer and biomimetic apatite on their surfaces. Additionally, human osteoblast MG-63 cells were cultured in the presence of the surface-modified MWCNTs. The metabolic activities of osteoblastic cells, cell proliferation properties, as well as cell morphology were studied. The surface modification of MWCNTs with biomimetic apatite exhibited a significant increase in the cell viability of osteoblasts, up to 67.23%. In the proliferation phases, there were many more cells in the biomimetic apatite-modified MWCNT samples than in the MWCNTs–COOH. There were no obvious changes in cell morphology in osteoblastic MG-63 cells cultured in the presence of these chemically-modified MWCNTs. The surface modification of MWCNTs with apatite achieves an effective enhancement of their biocompatibility.

  11. Involvement of CD8+ T cell-mediated immune responses in LcrV DNA vaccine induced protection against lethal Yersinia pestis challenge.

    Science.gov (United States)

    Wang, Shixia; Goguen, Jon D; Li, Fusheng; Lu, Shan

    2011-09-09

    Yersinia pestis (Y. pestis) is the causative pathogen of plague, a highly fatal disease for which an effective vaccine, especially against mucosal transmission, is still not available. Like many bacterial infections, antigen-specific antibody responses have been traditionally considered critical, if not solely responsible, for vaccine-induced protection against Y. pestis. Studies in recent years have suggested the importance of T cell immune responses against Y. pestis infection but information is still limited about the details of Y. pestis antigen-specific T cell immune responses. In current report, studies are conducted to identify the presence of CD8+ T cell epitopes in LcrV protein, the leading antigen of plague vaccine development. Furthermore, depletion of CD8+ T cells in LcrV DNA vaccinated Balb/C mice led to reduced protection against lethal intranasal challenge of Y. pestis. These findings establish that an LcrV DNA vaccine is able to elicit CD8+ T cell immune responses against specific epitopes of this key plague antigen and that a CD8+ T cell immune response is involved in LcrV DNA vaccine-elicited protection. Future studies in plague vaccine development will need to examine if the presence of detectable T cell immune responses, in particular CD8+ T-cell immune responses, will enhance the protection against Y. pestis in higher animal species or humans. Copyright © 2010 Elsevier Ltd. All rights reserved.

  12. Analyses of Potential Predictive Markers and Response to Targeted Therapy in Patients with Advanced Clear-cell Renal Cell Carcinoma

    Directory of Open Access Journals (Sweden)

    Yan Song

    2015-01-01

    Full Text Available Background: Vascular endothelial growth factor-targeted agents are standard treatments in advanced clear-cell renal cell carcinoma (ccRCC, but biomarkers of activity are lacking. The aim of this study was to investigate the association of Von Hippel-Lindau (VHL gene status, vascular endothelial growth factor receptor (VEGFR or stem cell factor receptor (KIT expression, and their relationships with characteristics and clinical outcome of advanced ccRCC. Methods: A total of 59 patients who received targeted treatment with sunitinib or pazopanib were evaluated for determination at Cancer Hospital and Institute, Chinese Academy of Medical Sciences between January 2010 and November 2012. Paraffin-embedded tumor samples were collected and status of the VHL gene and expression of VEGFR and KIT were determined by VHL sequence analysis and immunohistochemistry. Clinical-pathological features were collected and efficacy such as response rate and Median progression-free survival (PFS and overall survival (OS were calculated and then compared based on expression status. The Chi-square test, the Kaplan-Meier method, and the Lon-rank test were used for statistical analyses. Results: Of 59 patients, objective responses were observed in 28 patients (47.5%. The median PFS was 13.8 months and median OS was 39.9 months. There was an improved PFS in patients with the following clinical features: Male gender, number of metastatic sites 2 or less, VEGFR-2 positive or KIT positive. Eleven patients (18.6% had evidence of VHL mutation, with an objective response rate of 45.5%, which showed no difference with patients with no VHL mutation (47.9%. VHL mutation status did not correlate with either overall response rate (P = 0.938 or PFS (P = 0.277. The PFS was 17.6 months and 22.2 months in VEGFR-2 positive patients and KIT positive patients, respectively, which was significantly longer than that of VEGFR-2 or KIT negative patients (P = 0.026 and P = 0.043. Conclusion

  13. Comparison of microglia and infiltrating CD11c+ cells as antigen presenting cells for T cell proliferation and cytokine response

    DEFF Research Database (Denmark)

    Wlodarczyk, Agnieszka; Løbner, Morten; Cédile, Oriane

    2014-01-01

    (DC) and macrophages infiltrate the CNS during experimental autoimmune encephalomyelitis (EAE). Microglia are not considered to be as effective APC as DC or macrophages. METHODS: In this work we compared the antigen presenting capacity of CD11c+ and CD11c- microglia subsets with infiltrating CD11c......+ APC, which include DC. The microglial subpopulations (CD11c- CD45dim CD11b+ and CD11c+ CD45dim CD11b+) as well as infiltrating CD11c+ CD45high cells were sorted from CNS of C57BL/6 mice with EAE. Sorted cells were characterised by flow cytometry for surface phenotype and by quantitative real-time PCR...... for cytokine expression. They were co-cultured with primed T cells to measure induction of T cell proliferation and cytokine response. RESULTS: The number of CD11c+ microglia cells increased dramatically in EAE. They expressed equivalent levels of major histocompatibility complex and co-stimulatory ligands CD...

  14. Approach to a case of multiple irregular red cell antibodies in a liver transplant recipient: Need for developing competence.

    Science.gov (United States)

    Dara, Ravi C; Tiwari, Aseem K; Pandey, Prashant; Arora, Dinesh

    2015-01-01

    Liver transplant procedure acts as a challenge for transfusion services in terms of specialized blood components, serologic problems, and immunologic effects of transfusion. Red cell alloimmunization in patients awaiting a liver transplant complicate the process by undue delay or unavailability of compatible red blood cell units. Compatible blood units can be provided by well-equipped immunohematology laboratory, which has expertise in resolving these serological problems. This report illustrates resolution of a case with multiple alloantibodies using standard techniques, particularly rare antisera. Our case re-emphasizes the need for universal antibody screening in all patients as part of pretransfusion testing, which helps to identify atypical antibodies and plan for appropriate transfusion support well in time. We recommend that the centers, especially the ones that perform complex procedures like solid organ transplants and hematological transplants should have the necessary immunohematological reagents including rare antisera to resolve complex cases of multiple antibodies as illustrated in this case.

  15. Approach to a case of multiple irregular red cell antibodies in a liver transplant recipient: Need for developing competence

    Directory of Open Access Journals (Sweden)

    Ravi C Dara

    2015-01-01

    Full Text Available Liver transplant procedure acts as a challenge for transfusion services in terms of specialized blood components, serologic problems, and immunologic effects of transfusion. Red cell alloimmunization in patients awaiting a liver transplant complicate the process by undue delay or unavailability of compatible red blood cell units. Compatible blood units can be provided by well-equipped immunohematology laboratory, which has expertise in resolving these serological problems. This report illustrates resolution of a case with multiple alloantibodies using standard techniques, particularly rare antisera. Our case re-emphasizes the need for universal antibody screening in all patients as part of pretransfusion testing, which helps to identify atypical antibodies and plan for appropriate transfusion support well in time. We recommend that the centers, especially the ones that perform complex procedures like solid organ transplants and hematological transplants should have the necessary immunohematological reagents including rare antisera to resolve complex cases of multiple antibodies as illustrated in this case.

  16. Kinetics of memory B cell and plasma cell responses in the mice immunized with plague vaccines.

    Science.gov (United States)

    Zhang, X; Wang, Q; Bi, Y; Kou, Z; Zhou, J; Cui, Y; Yan, Y; Zhou, L; Tan, Y; Yang, H; Du, Z; Han, Y; Song, Y; Zhang, P; Zhou, D; Yang, R; Wang, X

    2014-03-01

    In our previous studies, we found that plague vaccines can induce long-term antibody response, but no significant antibody boost was observed when the immunized mice were challenged with virulent Yersinia pestis. However, a booster vaccination of subunit vaccine on week 3 after primary immunization elicited a significantly higher antibody titre than a single dose, whereas no significant antibody titre difference was observed between a single dose and two doses of EV76 vaccination. To address these issues, in this study, we first investigated the kinetics of memory B cells and plasma cells in the mice immunized with EV76 or F1 protein by flow cytometry and then determined antibody titre in five groups of mice immunized with various vaccination strategy. The results showed that memory B cells dropped to a low level at day 56 after primary immunization. In contrast, plasma cells were maintained for more than 98 days. The group with primary immunization of EV76 and booster of F1 antigen developed a higher antibody titre than the group with immunization of F1 antigen and booster of EV76. This result supports a hypothesis that an excess of antigens can neutralize pre-existing antibodies, and then the redundant antigen induces antibody boost. Taken together, a boost of antibody titre after revaccination may be dependent on the existence of memory B cells and an excess of antigen vaccination. In addition, this study showed an ideal immunization strategy that involves first immunization with a live attenuated vaccine, such as EV76, and then with a subunit vaccine. © 2014 John Wiley & Sons Ltd.

  17. Whole-cell biosensor for label-free detection of GPCR-mediated drug responses in personal cell lines.

    Science.gov (United States)

    Hillger, Julia M; Schoop, Jeffison; Boomsma, Dorret I; Slagboom, P Eline; IJzerman, Adriaan P; Heitman, Laura H

    2015-12-15

    Deciphering how genetic variation in drug targets such as G protein-coupled receptors (GPCRs) affects drug response is essential for precision medicine. GPCR signaling is traditionally investigated in artificial cell lines which do not provide sufficient physiological context. Patient-derived cell lines such as lymphoblastoid cell lines (LCLs) could represent the ideal cellular model system. Here we describe a novel label-free, whole-cell biosensor method for characterizing GPCR-mediated drug responses in LCLs. Generally, such biosensor technology is deemed only compatible with adherent cell lines. We optimized and applied the methodology to study cellular adhesion properties as well as GPCR drug responses in LCLs, which are suspension cells. Coating the detector surface with the extracellular matrix protein fibronectin resulted in cell adherence and allowed detection of cellular responses. A prototypical GPCR present on these cells, i.e. the cannabinoid receptor 2 (CB2), was selected for pharmacological characterization. Receptor activation with the agonist JWH133, blockade by antagonist AM630 as well as downstream signaling inhibition by PTX could be monitored sensitively and receptor-specifically. Potencies and effects were comparable between LCLs of two genetically unrelated individuals, providing the proof-of-principle that this biosensor technology can be applied to LCLs, despite their suspension cell nature, in order to serve as an in vitro model system for the evaluation of individual genetic influences on GPCR-mediated drug responses. Copyright © 2015 Elsevier B.V. All rights reserved.

  18. Unconventional Pro-inflammatory CD4+ T Cell Response in B Cell-Deficient Mice Infected with Trypanosoma cruzi

    Directory of Open Access Journals (Sweden)

    Melisa Gorosito Serrán

    2017-11-01

    Full Text Available Chagas disease, caused by the parasite Trypanosoma cruzi, is endemic in Latin America but has become a global public health concern by migration of infected people. It has been reported that parasite persistence as well as the intensity of the inflammatory immune response are determinants of the clinical manifestations of the disease. Even though inflammation is indispensable for host defense, when deregulated, it can contribute to tissue injury and organ dysfunction. Here, we report the importance of B cells in conditioning T cell response in T. cruzi infection. Mice deficient in mature B cells (muMT mice infected with T. cruzi exhibited an increase in plasma TNF concentration, TNF-producing CD4+ T cells, and mortality. The increase in TNF-producing CD4+ T cells was accompanied by a reduction in IFNγ+CD4+ T cells and a decrease of the frequency of regulatory Foxp3+, IL-10+, and IL17+CD4+ T cells populations. The CD4+ T cell population activated by T. cruzi infection, in absence of mature B cells, had a high frequency of Ly6C+ cells and showed a lower expression of inhibitory molecules such as CTLA-4, PD-1, and LAG3. CD4+ T cells from infected muMT mice presented a high frequency of CD62LhiCD44− cells, which is commonly associated with a naïve phenotype. Through transfer experiments we demonstrated that CD4+ T cells from infected muMT mice were able to condition the CD4+ T cells response from infected wild-type mice. Interestingly, using Blimp-flox/flox-CD23icre mice we observed that in absence of plasmablast/plasma cell T. cruzi-infected mice exhibited a higher number of TNF-producing CD4+ T cells. Our results showed that the absence of B cells during T. cruzi infection affected the T cell response at different levels and generated a favorable scenario for unconventional activation of CD4+ T cell leading to an uncontrolled effector response and inflammation. The product of B cell differentiation, the plasmablast/plasma cells, could be able

  19. The controversial impact of B cells subsets on immune response to pneumococcal vaccine in HIV-1 patients

    Directory of Open Access Journals (Sweden)

    Olga Tsachouridou

    2015-09-01

    Conclusions: Low concentrations of total B cells and exhausted memory B cells was the strongest independent predictor of poor pneumococcal vaccine responsiveness, emphasizing that B cell subset disturbances are associated with a poor vaccine response among HIV-infected patients.

  20. Artifactual voltage response recorded from hair cells with patch-clamp amplifiers.

    Science.gov (United States)

    Masetto, S; Weng, T; Valli, P; Correia, M J

    1999-06-23

    Patch-clamp amplifiers (PCAs) are commonly used to characterize voltage- and current-clamp responses in the same cell. However, the cell membrane voltage response can be severely distorted by PCAs working in the current-clamp mode. Here we compare the voltage response of pigeon semicircular canal hair cells in situ, recorded with two different PCAs, and with a classic microelectrode bridge amplifier (BA). We found that the voltage response of hair cells recorded with PCAs differed significantly from that recorded with the BA. The true hair cell membrane voltage response to positive current steps was characterized by a strongly damped oscillation, whose frequency and duration depended on hair cell location in the sensory crista ampullaris.

  1. Design and Response of a Structural Multifunctional Fuel Cell

    National Research Council Canada - National Science Library

    South, Joseph; Baechle, Daniel; Hilton, Corydon; DeSchepper, Daniel; Wetzel, Eric

    2008-01-01

    .... In this study, structural fuel cells are proposed and evaluated. A structural multifunctional fuel cell system is designed so that material elements participating in power and energy processes are also carrying significant structural loads...

  2. Long-Lasting Complete Responses in Patients with Metastatic Melanoma after Adoptive Cell Therapy with Tumor-Infiltrating Lymphocytes and an Attenuated IL2 Regimen

    DEFF Research Database (Denmark)

    Andersen, Rikke; Donia, Marco; Ellebæk, Eva

    2016-01-01

    with progressive treatment-refractory metastatic melanoma, good clinical performance, age ... partial responses (ORR 42%). Median overall survival was 21.8 months. Tumor regression was associated with a higher absolute number of infused tumor-reactive T cells. Moreover, induction and persistence of antimelanoma T-cell responses in the peripheral blood was strongly correlated to clinical response...... to treatment. CONCLUSIONS: TIL-ACT with a reduced IL2 decrescendo regimen results in long-lasting complete responses in patients with treatment-refractory melanoma. Larger randomized trials are needed to elucidate whether clinical efficacy is comparable with TIL-ACT followed by HD bolus IL2. Clin Cancer Res...

  3. Tumor cell dormancy as an adaptive cell stress response mechanism [version 1; referees: 4 approved

    Directory of Open Access Journals (Sweden)

    Laura Vera-Ramirez

    2017-12-01

    Full Text Available Metastases are responsible for most cancer-related deaths. The kinetics of tumor relapse is highly heterogeneous, ranging from recurrences shortly after diagnosis to years or even decades after the initial treatment. This subclinical period is known as tumor dormancy, in which residual disease remains in an undetectable state before finally appearing as an overtly proliferative metastasis. Despite recent advances in our understanding of the molecular mechanisms leading to tumor dormancy, it is still a poorly understood phase of cancer progression, which limits opportunities for the design of successful therapeutic interventions. The influence of the tumor microenvironment at the metastatic site and anti-metastatic immune responses have been shown to play a crucial role in the onset and maintenance of metastatic dormancy. However, there is still a significant gap in our understanding of how dormant cells remain viable in a quiescent state for long periods of time. Here, we review the latest experimental evidence shedding light on the biological processes that enable dormant tumor cells to endure the multiple stresses encountered at the metastatic site.

  4. Synergy among rat T cells in the proliferative response to alloantigen

    International Nuclear Information System (INIS)

    Wright, P.W.; Loop, S.M.; Bernstein, I.D.

    1979-01-01

    A synergistic interaction in the proliferative response to alloantigen is described for mixtures of rat thymus and lymph node cells. The optimal conditions for synergy are quantitatively defined. Regression analysis of the slope of the dose-response curve has been utilized to estimate the degree of interaction in thymus--lymph node cell mixtures. The slope of the response of cell mixtures was noted to be significantly greater than the slope for the response of lympth node cells alone. Irradiation was shown to have a differential effect on the response of thymus and lymph node cells in mixtures. Irradiated thymus cells retained the capacity for synergy in mixtures, whereas irradiated lymph node cells did not. Additional studies have demonstrated that both de novo protein synthesis and specific antigen recognition by both responding cell populations in mixtures was required for maximal synergy. These studies demonstrate that synergy cannot be explained as an artifact of altered cell density in vitro. They establish that thymus cells and lymph node cells represent distinct subsets which manifest qualitatively different functions in the proliferative response to alloantigen. Thymus cells can respond directly to alloantigen by proliferation but also have the capacity to amplify the proliferative response of lymph node cells, a capacity which is resistant to X irradiation but requires recognition of alloantigen and de novo protein synthesis. Lymph node cells may similarly respond by proliferation to alloantigen but lack the amplifier activity of thymus cells. Synergy for rat lymphoidcells, like mouse lymphoid cells, has been shown to involve an interaction of thymus-derived lymphocytes

  5. Definitive radiotherapy in basaloid squamous cell carcinoma of the head and neck; need for more aggressive modalities?

    Energy Technology Data Exchange (ETDEWEB)

    Thariat, J.; Ahamad, A.; El-Naggar, A.K.; Williams, M.; Allen, P.K.; Weber, R.S.; Ang, K.K.; Garden, A.S. [MD Anderson Cancer Center, Houston (United States)

    2006-11-15

    Basaloid squamous cell carcinoma (B.S.C.C.) and poorly differentiated squamous cell carcinoma (P.D.S.C.C.) were similarly curable with the above multimodal treatment consisting of radiotherapy, chemotherapy and neck dissection when indicated. The apparent worse prognosis of B.S.C.C. in the literature may be due to the lack of comparison by grade and stage. B.S.C.C., phenotypically, can be viewed as an undifferentiated variant of S.C.C.. However, there is no clear dissimilarity between B.S.C.C. and other subgroups of conventional S.C.C. as for the therapeutic response to radiotherapy. A case control study is ongoing. (author)

  6. Cross-talk between cd1d-restricted nkt cells and γδ cells in t regulatory cell response

    Directory of Open Access Journals (Sweden)

    Huber Sally A

    2011-01-01

    Full Text Available Abstract CD1d is a non-classical major histocompatibility class 1-like molecule which primarily presents either microbial or endogenous glycolipid antigens to T cells involved in innate immunity. Natural killer T (NKT cells and a subpopulation of γδ T cells expressing the Vγ4 T cell receptor (TCR recognize CD1d. NKT and Vγ4 T cells function in the innate immune response via rapid activation subsequent to infection and secrete large quantities of cytokines that both help control infection and modulate the developing adaptive immune response. T regulatory cells represent one cell population impacted by both NKT and Vγ4 T cells. This review discusses the evidence that NKT cells promote T regulatory cell activation both through direct interaction of NKT cell and dendritic cells and through NKT cell secretion of large amounts of TGFβ, IL-10 and IL-2. Recent studies have shown that CD1d-restricted Vγ4 T cells, in contrast to NKT cells, selectively kill T regulatory cells through a caspase-dependent mechanism. Vγ4 T cell elimination of the T regulatory cell population allows activation of autoimmune CD8+ effector cells leading to severe cardiac injury in a coxsackievirus B3 (CVB3 myocarditis model in mice. CD1d-restricted immunity can therefore lead to either immunosuppression or autoimmunity depending upon the type of innate effector dominating during the infection.

  7. Self-assembled nanofiber coatings for controlling cell responses

    NARCIS (Netherlands)

    Barros, Raquel C.; Gelens, Edith; Bulten, Erna; Tuin, Annemarie; de Jong, Menno R; Kuijer, Roel; van Kooten, Theo G

    Nanofibers are thought to enhance cell adhesion, growth, and function. We demonstrate that the choice of building blocks in self-assembling nanofiber systems can be used to control cell behavior. The use of 2 D-coated, self-assembled nanofibers in controlling lens epithelial cells, fibroblasts, and

  8. A response calculus for immobilized T cell receptor ligands

    DEFF Research Database (Denmark)

    Andersen, P S; Menné, C; Mariuzza, R A

    2001-01-01

    To address the molecular mechanism of T cell receptor (TCR) signaling, we have formulated a model for T cell activation, termed the 2D-affinity model, in which the density of TCR on the T cell surface, the density of ligand on the presenting surface, and their corresponding two-dimensional affini...

  9. Control of Humoral Response in Renal Transplantation by Belatacept Depends on a Direct Effect on B Cells and Impaired T Follicular Helper-B Cell Crosstalk.

    Science.gov (United States)

    Leibler, Claire; Thiolat, Allan; Hénique, Carole; Samson, Chloé; Pilon, Caroline; Tamagne, Marie; Pirenne, France; Vingert, Benoit; Cohen, José L; Grimbert, Philippe

    2018-03-01

    Generation of de novo donor-specific antibodies ( dn DSAs) after renal transplant is recognized as the leading cause of late transplant failure. Hence, the optimal immunosuppressive strategies to limit dn DSA development need to be defined. Recent clinical trials using the novel costimulatory blockade agent CTLA4-Ig (Belatacept) have shown that kidney transplant recipients (KTRs) treated with Belatacept have better graft survival and function and a lower proportion of dn DSAs than control-treated KTRs. Mechanisms involved in the control of humoral responses by Belatacept remain to be investigated. Here, we analyzed the effect of Belatacept on different steps of the B cell-mediated response in humans. In vitro , Belatacept reduced plasmablast differentiation, Ig production, and the expression of the major transcription factor involved in plasma cell function, Blimp-1, in a T cell-independent manner. Moreover, Belatacept induced activation of the STAT3 transcription factor in stimulated B cells and reduced the expression of CD86. Additionally, Belatacept blocked CD28-mediated activation of T follicular helper cells (Tfhs) in an autologous Tfh-memory B cells model. We then validated these observations in KTRs treated with Belatacept, who had a reduced proportion of blood effector B cells and activated Tfh (PD1 + ICOS + ) compared with control-treated KTRs. Our in vitro and in vivo results suggest that Belatacept modulates B cell function directly and at the level of B cell-Tfh interaction. These mechanisms likely account for the optimal control of humoral responses observed in KTRs treated with Belatacept. Copyright © 2018 by the American Society of Nephrology.

  10. Glucose responsive insulin production from human embryonic germ (EG) cell derivatives

    International Nuclear Information System (INIS)

    Clark, Gregory O.; Yochem, Robert L.; Axelman, Joyce; Sheets, Timothy P.; Kaczorowski, David J.; Shamblott, Michael J.

    2007-01-01

    Type 1 diabetes mellitus subjects millions to a daily burden of disease management, life threatening hypoglycemia and long-term complications such as retinopathy, nephropathy, heart disease, and stroke. Cell transplantation therapies providing a glucose-regulated supply of insulin have been implemented clinically, but are limited by safety, efficacy and supply considerations. Stem cells promise a plentiful and flexible source of cells for transplantation therapies. Here, we show that cells derived from human embryonic germ (EG) cells express markers of definitive endoderm, pancreatic and β-cell development, glucose sensing, and production of mature insulin. These cells integrate functions necessary for glucose responsive regulation of preproinsulin mRNA and expression of insulin C-peptide in vitro. Following transplantation into mice, cells become insulin and C-peptide immunoreactive and produce plasma C-peptide in response to glucose. These findings suggest that EG cell derivatives may eventually serve as a source of insulin producing cells for the treatment of diabetes

  11. Bone marrow function. I. Peripheral T cells are responsible for the increased auto-antiidiotype response of older mice

    International Nuclear Information System (INIS)

    Kim, Y.T.; Goidl, E.A.; Samarut, C.; Weksler, M.E.; Thorbecke, G.J.; Siskind, G.W.

    1985-01-01

    After immunization with trinitrophenyl (TNP)-Ficoll, mice produced both anti-TNP antibodies and auto-anti-idiotype (auto-anti-Id) antibodies specific for the anti-TNP antibody. Older animals produced more auto-anti-Id than did young animals. When mice were exposed to a normally lethal dose of irradiation while their bone marrow (BM) was partially shielded, they survived and slowly (6 wk) regained immune function, as indicated by the number of nucleated cells in their spleen and the in vitro primary plaque-forming cell (PFC) response of their spleen cells to TNP-treated aminoethylated polyacrylamide beads. Recovery is presumably the result of repopulation of the peripheral lymphoid system by cells originating in the BM. By enzyme-linked immunosorbent assay (ELISA), and by hapten-augmentable PFC assay, the authors show that, after recovery from irradiation with their BM shielded, old animals produce low auto-anti-Id responses, like those of young animals. The transfer of splenic T cells into mice irradiated with their BM shielded provided evidence that the magnitude of the auto-anti-Id response is controlled by the peripheral T cells. Thus, mice that received splenic T cells from aged donors produced high levels of auto-anti-Id while those that received splenic T cells from young donors produce low levels of auto-anti-Id

  12. Lactobacilli Modulate Natural Killer Cell Responses In Vitro

    DEFF Research Database (Denmark)

    Fink, Lisbeth Nielsen; Christensen, Hanne Risager; Frøkiær, Hanne

    of certain lactic acid bacteria has been shown to increase in vivo NK cytotoxicity. Here, we investigated how human gut flora-derived lactobacilli affect NK cells in vitro, by measuring proliferation and IFN-gamma production of human NK cells upon bacterial stimulation. CD3-CD56+ NK cells were isolated from...... monocytes present, probably because cytokines, secreted by monocytes having engulfed bacteria, stimulated the NK cells. In contrast, a Lactobacillus paracasei strain caused the NK cells to proliferate only in the presence of monocytes. These results demonstrate that various strains of lactobacilli have...

  13. EFFECT OF TRIIODOTHYRONINE ON CELLS AND ON THEIR RESPONSE TO INFECTION BY POLIOVIRUSES1

    Science.gov (United States)

    Murphy, William H.; Bullis, Cora

    1962-01-01

    Murphy, W. H. (The University of Michigan, Ann Arbor) and Cora Bullis. Effect of triiodothyronine on cells and on their response to infection by polioviruses. J. Bacteriol. 83:641–648. 1962.—An analysis was made of the effect of triiodothyronine (T3) at physiological (1 μg/ml) and maximal subliminal toxic levels (35 μg/ml) on HeLa-S3, HeLa-Gey, Chang-liver, and Maben cells, and on their response to infection by cytopathic and submoderate (noncytopathic) mutants of type 2 poliovirus. Assays of cell response to T3 alone, or in combination with the mutants of poliovirus, were made by conventional monolayer cell culture techniques, by study of the effect of T3 on plating efficiency of cells, and by study of its influence on colonies of cell variants. Cellular response to liminal doses of T3 was characterized by agglutination of cells and thickening of the cell membrane. Compact colonies of Chang-liver and Maben cells were the most sensitive to maximal subliminal amounts of T3. T3 in combination with cytopathic or submoderate (noncytopathic) mutants of poliovirus slightly increased the rate of destruction of cells susceptible to virus, but did not influence yield of virus from cell cultures. T3 at physiological or subliminal concentrations did not induce cytopathic response of cell cultures latently infected by submoderate poliovirus. Images PMID:14477441

  14. Baseline levels of influenza-specific CD4 memory T-cells affect T-cell responses to influenza vaccines.

    Science.gov (United States)

    He, Xiao-Song; Holmes, Tyson H; Sasaki, Sanae; Jaimes, Maria C; Kemble, George W; Dekker, Cornelia L; Arvin, Ann M; Greenberg, Harry B

    2008-07-02

    Factors affecting immune responses to influenza vaccines have not been studied systematically. We hypothesized that T-cell and antibody responses to the vaccines are functions of pre-existing host immunity against influenza antigens. During the 2004 and 2005 influenza seasons, we have collected data on cellular and humoral immune reactivity to influenza virus in blood samples collected before and after immunization with inactivated or live attenuated influenza vaccines in healthy children and adults. We first used cross-validated lasso regression on the 2004 dataset to identify a group of candidate baseline correlates with T-cell and antibody responses to vaccines, defined as fold-increase in influenza-specific T-cells and serum HAI titer after vaccination. The following baseline parameters were examined: percentages of influenza-reactive IFN-gamma(+) cells in T and NK cell subsets, percentages of influenza-specific memory B-cells, HAI titer, age, and type of vaccine. The candidate baseline correlates were then tested with the independent 2005 dataset. Baseline percentage of influenza-specific IFN-gamma(+) CD4 T-cells was identified as a significant correlate of CD4 and CD8 T-cell responses, with lower baseline levels associated with larger T-cell responses. Baseline HAI titer and vaccine type were identified as significant correlates for HAI response, with lower baseline levels and the inactivated vaccine associated with larger HAI responses. Previously we reported that baseline levels of CD56(dim) NK reactivity against influenza virus inversely correlated with the immediate T-cell response to vaccination, and that NK reactivity induced by influenza virus depended on IL-2 produced by influenza-specific memory T-cells. Taken together these results suggest a novel mechanism for the homeostasis of virus-specific T-cells, which involves interaction between memory helper T-cells, CD56(dim) NK and DC. These results demonstrate that assessment of baseline biomarkers may

  15. Baseline levels of influenza-specific CD4 memory T-cells affect T-cell responses to influenza vaccines.

    Directory of Open Access Journals (Sweden)

    Xiao-Song He

    Full Text Available BACKGROUND: Factors affecting immune responses to influenza vaccines have not been studied systematically. We hypothesized that T-cell and antibody responses to the vaccines are functions of pre-existing host immunity against influenza antigens. METHODOLOGY/PRINCIPAL FINDINGS: During the 2004 and 2005 influenza seasons, we have collected data on cellular and humoral immune reactivity to influenza virus in blood samples collected before and after immunization with inactivated or live attenuated influenza vaccines in healthy children and adults. We first used cross-validated lasso regression on the 2004 dataset to identify a group of candidate baseline correlates with T-cell and antibody responses to vaccines, defined as fold-increase in influenza-specific T-cells and serum HAI titer after vaccination. The following baseline parameters were examined: percentages of influenza-reactive IFN-gamma(+ cells in T and NK cell subsets, percentages of influenza-specific memory B-cells, HAI titer, age, and type of vaccine. The candidate baseline correlates were then tested with the independent 2005 dataset. Baseline percentage of influenza-specific IFN-gamma(+ CD4 T-cells was identified as a significant correlate of CD4 and CD8 T-cell responses, with lower baseline levels associated with larger T-cell responses. Baseline HAI titer and vaccine type were identified as significant correlates for HAI response, with lower baseline levels and the inactivated vaccine associated with larger HAI responses. Previously we reported that baseline levels of CD56(dim NK reactivity against influenza virus inversely correlated with the immediate T-cell response to vaccination, and that NK reactivity induced by influenza virus depended on IL-2 produced by influenza-specific memory T-cells. Taken together these results suggest a novel mechanism for the homeostasis of virus-specific T-cells, which involves interaction between memory helper T-cells, CD56(dim NK and DC

  16. Cellular aspects of tolerance. V. The in vivo cooperative role of acceessory and thymus derived cells in responsiveness and unresponsiveness of SJL mice

    International Nuclear Information System (INIS)

    Fujiwara, M.; Cinader, B.

    1974-01-01

    Adult (8-week-old) SJL mice reach a relatively low degree of tolerance when injected with aggregate free rabbit γ-globulin (RGG). To analyze this phenomenon, we first examined indirect plaque-forming responses (PFC) in terms of participation of accessory and thymus-derived cells. Double transfer experiments were used; accessory cells were removed from donor cells by filtration over glasswool and their capacity reduced in recipients by 3 day preirradiation or by horse erythrocyte-mediated blockage. Using this type of experimental arrangement we found that the antibody response to RGG required the cooperation of accessory and thymus-derived cells. The induction of tolerance was affected by the presence of accessory cells. Preirradiated secondary recipients were reconstituted with spleen cells from accessory cell-deprived donors which had received thymus and bone marrow cells. In some experiments, the thymus and bone marrow cells were passed over glasswool. The primary recipients were left untreated or were given tolerogen. A more profound state of tolerance (reduction in plaque forming response) was the consequence of the incapacitation or removal of accessory cells. The magnitude of the reduction in PFC was directly related to the completeness of accessory cell removal and incapacitation. Responsiveness could be restored by administration of irradiated spleen cells as a source of accessory cells. The need for thymus-derived (T) cells in the antibody response was demonstrated by double transfer experiments in which the primary recipient was restored with thymus cells alone, bone marrow cells alone, or with a mixture of cell types

  17. Lysophosphatidic acid receptor-5 negatively regulates cellular responses in mouse fibroblast 3T3 cells

    Energy Technology Data Exchange (ETDEWEB)

    Dong, Yan; Hirane, Miku; Araki, Mutsumi [Division of Cancer Biology and Bioinformatics, Department of Life Science, Faculty of Science and Engineering, Kinki University, 3-4-1, Kowakae, Higashiosaka, Osaka 577-8502 (Japan); Fukushima, Nobuyuki [Division of Molecular Neurobiology, Department of Life Science, Faculty of Science and Engineering, Kinki University, 3-4-1, Kowakae, Higashiosaka, Osaka 577-8502 (Japan); Tsujiuchi, Toshifumi, E-mail: ttujiuch@life.kindai.ac.jp [Division of Cancer Biology and Bioinformatics, Department of Life Science, Faculty of Science and Engineering, Kinki University, 3-4-1, Kowakae, Higashiosaka, Osaka 577-8502 (Japan)

    2014-04-04

    Highlights: • LPA{sub 5} inhibits the cell growth and motile activities of 3T3 cells. • LPA{sub 5} suppresses the cell motile activities stimulated by hydrogen peroxide in 3T3 cells. • Enhancement of LPA{sub 5} on the cell motile activities inhibited by LPA{sub 1} in 3T3 cells. • The expression and activation of Mmp-9 were inhibited by LPA{sub 5} in 3T3 cells. • LPA signaling via LPA{sub 5} acts as a negative regulator of cellular responses in 3T3 cells. - Abstract: Lysophosphatidic acid (LPA) signaling via G protein-coupled LPA receptors (LPA{sub 1}–LPA{sub 6}) mediates a variety of biological functions, including cell migration. Recently, we have reported that LPA{sub 1} inhibited the cell motile activities of mouse fibroblast 3T3 cells. In the present study, to evaluate a role of LPA{sub 5} in cellular responses, Lpar5 knockdown (3T3-L5) cells were generated from 3T3 cells. In cell proliferation assays, LPA markedly stimulated the cell proliferation activities of 3T3-L5 cells, compared with control cells. In cell motility assays with Cell Culture Inserts, the cell motile activities of 3T3-L5 cells were significantly higher than those of control cells. The activity levels of matrix metalloproteinases (MMPs) were measured by gelatin zymography. 3T3-L5 cells stimulated the activation of Mmp-2, correlating with the expression levels of Mmp-2 gene. Moreover, to assess the co-effects of LPA{sub 1} and LPA{sub 5} on cell motile activities, Lpar5 knockdown (3T3a1-L5) cells were also established from Lpar1 over-expressing (3T3a1) cells. 3T3a1-L5 cells increased the cell motile activities of 3T3a1 cells, while the cell motile activities of 3T3a1 cells were significantly lower than those of control cells. These results suggest that LPA{sub 5} may act as a negative regulator of cellular responses in mouse fibroblast 3T3 cells, similar to the case for LPA{sub 1}.

  18. Lysophosphatidic acid receptor-5 negatively regulates cellular responses in mouse fibroblast 3T3 cells

    International Nuclear Information System (INIS)

    Dong, Yan; Hirane, Miku; Araki, Mutsumi; Fukushima, Nobuyuki; Tsujiuchi, Toshifumi

    2014-01-01

    Highlights: • LPA 5 inhibits the cell growth and motile activities of 3T3 cells. • LPA 5 suppresses the cell motile activities stimulated by hydrogen peroxide in 3T3 cells. • Enhancement of LPA 5 on the cell motile activities inhibited by LPA 1 in 3T3 cells. • The expression and activation of Mmp-9 were inhibited by LPA 5 in 3T3 cells. • LPA signaling via LPA 5 acts as a negative regulator of cellular responses in 3T3 cells. - Abstract: Lysophosphatidic acid (LPA) signaling via G protein-coupled LPA receptors (LPA 1 –LPA 6 ) mediates a variety of biological functions, including cell migration. Recently, we have reported that LPA 1 inhibited the cell motile activities of mouse fibroblast 3T3 cells. In the present study, to evaluate a role of LPA 5 in cellular responses, Lpar5 knockdown (3T3-L5) cells were generated from 3T3 cells. In cell proliferation assays, LPA markedly stimulated the cell proliferation activities of 3T3-L5 cells, compared with control cells. In cell motility assays with Cell Culture Inserts, the cell motile activities of 3T3-L5 cells were significantly higher than those of control cells. The activity levels of matrix metalloproteinases (MMPs) were measured by gelatin zymography. 3T3-L5 cells stimulated the activation of Mmp-2, correlating with the expression levels of Mmp-2 gene. Moreover, to assess the co-effects of LPA 1 and LPA 5 on cell motile activities, Lpar5 knockdown (3T3a1-L5) cells were also established from Lpar1 over-expressing (3T3a1) cells. 3T3a1-L5 cells increased the cell motile activities of 3T3a1 cells, while the cell motile activities of 3T3a1 cells were significantly lower than those of control cells. These results suggest that LPA 5 may act as a negative regulator of cellular responses in mouse fibroblast 3T3 cells, similar to the case for LPA 1

  19. B7h-expressing dendritic cells and plasma B cells mediate distinct outcomes of ICOS costimulation in T cell-dependent antibody responses

    Directory of Open Access Journals (Sweden)

    Larimore Kevin

    2012-06-01

    Full Text Available Abstract Background The ICOS-B7h costimulatory receptor-ligand pair is required for germinal center formation, the production of isotype-switched antibodies, and antibody affinity maturation in response to T cell-dependent antigens. However, the potentially distinct roles of regulated B7h expression on B cells and dendritic cells in T cell-dependent antibody responses have not been defined. Results We generated transgenic mice with lineage-restricted B7h expression to assess the cell-type specific roles of B7h expression on B cells and dendritic cells in regulating T cell-dependent antibody responses. Our results show that endogenous B7h expression is reduced on B cells after activation in vitro and is also reduced in vivo on antibody-secreting plasma B cells in comparison to both naïve and germinal center B cells from which they are derived. Increasing the level of B7h expression on activated and plasma B cells in B-B7hTg mice led to an increase in the number of antibody-secreting plasma cells generated after immunization and a corresponding increase in the concentration of antigen-specific high affinity serum IgG antibodies of all isotypes, without affecting the number of responding germinal center B cells. In contrast, ICOS costimulation mediated by dendritic cells in DC-B7hTg mice contributed to germinal center formation and selectively increased IgG2a production without affecting the overall magnitude of antibody responses. Conclusions Using transgenic mice with lineage-restricted B7h expression, we have revealed distinct roles of ICOS costimulation mediated by dendritic cells and B cells in the regulation of T cell-dependent antibody responses.

  20. Reduction of IL-17A Might Suppress the Th1 Response and Promote the Th2 Response by Boosting the Function of Treg Cells during Silica-Induced Inflammatory Response In Vitro

    Directory of Open Access Journals (Sweden)

    Wen Tang

    2014-01-01

    Full Text Available Silica inhalation can induce chronic lung inflammation and fibrosis. Upon silica stimulation, activated macrophages trigger the T-lymphocyte which can differentiate into many different types of Th cells, including the recently discovered Th17 cells. IL-17A, the typical Th17 cytokine, is reported in some inflammatory diseases. However, the role of IL-17A in silica-induced inflammatory response is still not clear. The regulatory mechanism of silica-induced Th17 response also needs to be investigated. So we established a mice primary cell coculture system (macrophage and lymphocyte to investigate the role of IL-17A in silica-induced inflammatory response in vitro, by using anti-IL-17A mAb and IL-1Ra. Both anti-IL-17A mAb and IL-1Ra decreased the level of IL-17A and increased the function of Treg cells. The Th1 response was suppressed and the Th2 response was promoted by the addition of anti-IL-17A mAb or IL-1Ra. IL-1Ra treatment decreased the level of IL-6, whereas the levels of IL-23 and ROR-γt were increased. Our study demonstrated that IL-17A reduction altered the pattern of silica-induced Th responses by boosting the function of Treg cells in vitro. Blocking the function of IL-1 signal pathway could suppress the level of IL-17A, which played the major role in modulating silica-induced Th responses in vitro.

  1. T-cell responses targeting HIV Nef uniquely correlate with infected cell frequencies after long-term antiretroviral therapy.

    Directory of Open Access Journals (Sweden)

    Allison S Thomas

    2017-09-01

    Full Text Available HIV-specific CD8+ T-cell responses limit viral replication in untreated infection. After the initiation of antiretroviral therapy (ART, these responses decay and the infected cell population that remains is commonly considered to be invisible to T-cells. We hypothesized that HIV antigen recognition may persist in ART-treated individuals due to low-level or episodic protein expression. We posited that if persistent recognition were occurring it would be preferentially directed against the early HIV gene products Nef, Tat, and Rev as compared to late gene products, such as Gag, Pol, and Env, which have higher barriers to expression. Using a primary cell model of latency, we observed that a Nef-specific CD8+ T-cell clone exhibited low-level recognition of infected cells prior to reactivation and robust recognition shortly thereafter. A Gag-specific CD8+ T-cell clone failed to recognized infected cells under these conditions, corresponding with a lack of detectable Gag expression. We measured HIV-specific T-cell responses in 96 individuals who had been suppressed on ART for a median of 7 years, and observed a significant, direct correlation between cell-associated HIV DNA levels and magnitudes of IFN-γ-producing Nef/Tat/Rev-specific T-cell responses. This correlation was confirmed in an independent cohort (n = 18. Correlations were not detected between measures of HIV persistence and T-cell responses to other HIV antigens. The correlation with Nef/Tat/Rev-specific T-cells was attributable to Nef-specific responses, the breadth of which also correlated with HIV DNA levels. These results suggest that ongoing Nef expression in ART-treated individuals drives preferential maintenance and/or expansion of T-cells reactive to this protein, implying sensing of infected cells by the immune system. The direct correlation, however, suggests that recognition does not result in efficient elimination of infected cells. These results raise the possibility that

  2. Follicular helper T cells mediate IgE antibody response to airborne allergens.

    Science.gov (United States)

    Kobayashi, Takao; Iijima, Koji; Dent, Alexander L; Kita, Hirohito

    2017-01-01

    T H 2 cells have long been believed to play a pivotal role in allergic immune responses, including IgE antibody production and type 2 cytokine-mediated inflammation and pathology. A new T-cell subset, follicular helper T (T FH ) cells, is specialized in supporting B-cell maturation and antibody production. We sought to investigate the roles of T FH cells in allergic immune responses. Naive mice were exposed to cytokines or natural allergens through the airways. Development of allergic immune responses was analyzed by collecting draining lymph nodes and sera and by challenging the animals. Cytokine reporter mice and gene-deficient mice were used to dissect the immunologic mechanisms. We observed the development of IL-4-producing T FH cells and T H 2 cells in draining lymph nodes after airway exposure to IL-1 family cytokines or natural allergens. T FH and T H 2 cells demonstrated unique phenotypes, tissue localization, and cytokine responses. T FH cells supported the sustained production of IgE antibody in vivo in the absence of other T-cell subsets or even when T H 2 cell functions were severely compromised. Conversely, conditional deficiency of the master regulator Bcl6 in CD4 + T cells resulted in a marked reduction in T FH cell numbers and IgE antibody levels, but type 2 cytokine responses and eosinophilic inflammation in the airways remained unaffected. T FH cells play critical roles in the regulation of IgE antibody production. Allergic immune responses to airborne allergens likely involve 2 distinct subsets of IL-4-producing CD4 + T cells, namely T FH and Th2 cells. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  3. CD8+T Cell Immune Response in Immunocompetent Mice during Zika Virus Infection.

    Science.gov (United States)

    Huang, Huarong; Li, Shihua; Zhang, Yongli; Han, Xiaojuan; Jia, Baoqian; Liu, Hongtao; Liu, Dandan; Tan, Shuguang; Wang, Qihui; Bi, Yuhai; Liu, William J; Hou, Baidong; Gao, George Fu; Zhang, Fuping

    2017-11-15

    Zika virus (ZIKV) infection causees neurologic complications, including Guillain-Barré syndrome in adults and central nervous system (CNS) abnormalities in fetuses. We investigated the immune response, especially the CD8 + T cell response in C57BL/6 (B6) wild-type (WT) mice, during ZIKV infection. We found that a robust CD8 + T cell response was elicited, major histocompatibility complex class I-restricted CD8 + T cell epitopes were identified, a tetramer that recognizes ZIKV-specific CD8 + T cells was developed, and virus-specific memory CD8 + T cells were generated in these mice. The CD8 + T cells from these infected mice were functional, as evidenced by the fact that the adoptive transfer of ZIKV-specific CD8 + T cells could prevent ZIKV infection in the CNS and was cross protective against dengue virus infection. Our findings provide comprehensive insight into immune responses against ZIKV and further demonstrate that WT mice could be a natural and easy-access model for evaluating immune responses to ZIKV infection. IMPORTANCE ZIKV infection has severe clinical consequences, including Guillain-Barré syndrome in adults, microcephaly, and congenital malformations in fetuses and newborn infants. Therefore, study of the immune response, especially the adaptive immune response to ZIKV infection, is important for understanding diseases caused by ZIKV infection. Here, we characterized the CD8 + T cell immune response to ZIKV in a comprehensive manner and identified ZIKV epitopes. Using the identified immunodominant epitopes, we developed a tetramer that recognizes ZIKV-specific CD8 + T cells in vivo , which simplified the detection and evaluation of ZIKV-specific immune responses. In addition, the finding that tetramer-positive memory CD8 + T cell responses were generated and that CD8 + T cells can traffic to a ZIKV-infected brain greatly enhances our understanding of ZIKV infection and provides important insights for ZIKV vaccine design. Copyright © 2017 American

  4. The response of high and low polyamine producing cell lines to aluminum and calcium stress

    Science.gov (United States)

    Sridev Mohapatra; Smita Cherry; Rakesh Minocha; Rajtilak Majumdar; Palaniswamy Thangavel; Stephanie Long; Subhash C. Minocha

    2010-01-01

    The diamine putrescine (Put) has been shown to accumulate in tree leaves in response to high Al and low Ca in the soil, leading to the suggestion that this response may provide a physiological advantage to leaf cells under conditions of Al stress. The increase in Put is reversed by Ca supplementation in the soil. Using two cell lines of poplar (Populus nigra...

  5. The dance of the perivascular and endothelial cells: mechanisms of brain response to immune signaling.

    Science.gov (United States)

    Saper, Clifford B

    2010-01-14

    The mechanisms underlying the brain response to systemic inflammation remain unclear. In this issue of Neuron, Serrats and colleagues demonstrate that two cell types that produce prostaglandins that act on the brain, perivascular and endothelial cells, have an unexpectedly complex interaction in regulating the timing and types of brain responses that occur.

  6. In situ tumor destruction: towards in vivo modulation of immune responses by dendritic cells.

    NARCIS (Netherlands)

    Brok, M.H.M.G.M. den

    2006-01-01

    Dendritic cells (DC's) are professional antigen presenting cells that play a critical role in initiation of immune responses. In recent years, it has become evident that tumor antigens presented by ex vivo generated DC can evoke tumor-specific responses in cancer patients. Although promising results

  7. A Smac mimetic augments the response of urothelial cancer cells to gemcitabine and cisplatin.

    Science.gov (United States)

    Lee, Eugene K; Jinesh G, Goodwin; Laing, Naomi M; Choi, Woonyoung; McConkey, David J; Kamat, Ashish M

    2013-09-01

    Cisplatin-based chemotherapy is considered the gold standard for patients with advanced bladder cancer. However, despite initial response, many patients will relapse; therefore, novel salvage treatment strategies are desperately needed. Herein, we studied a mechanism based treatment combination using a Smac mimetic with standard chemotherapy. Using a panel of 10 urothelial cancer cell lines, we exposed them to a combination of gemcitabine, cisplatin, and a Smac mimetic. Sensitivity was determined using a DNA fragmentation assay. We determined that three cell lines (UMUC-3, UMUC-13, and RT4v6) were considered sensitive to the combination of gemcitabine and cisplatin and an additional three cell lines were sensitized to gemcitabine and cisplatin with the addition of the Smac mimetic (UMUC-6, UMUC-12, and UMUC-18). We next explored the constitutive expression of selected members of the IAP family (XIAP, cIAP-1, cIAP-2, and Survivin), the BCL family (BCL-2, BCLXL, and BAX) and Smac using gene expression profiling and western blotting. We determined that RNA and protein expression of SMAC, selected members of the IAP family and members of the BCL family did not correlate to drug sensitivity. Lastly, using an in vivo mouse model, we determined that treatment with the Smac mimetic in combination with gemcitabine and cisplatin resulted in increased apoptosis, decreased microvessel density and decreased cellular proliferation. This novel treatment strategy may be effective in patients with advanced urothelial carcinoma and warrants further investigation.

  8. Immune Responses to Dengue and Zika Viruses—Guidance for T Cell Vaccine Development

    Directory of Open Access Journals (Sweden)

    Claude Roth

    2018-02-01

    Full Text Available Despite numerous efforts to identify the molecular and cellular effectors of the adaptive immunity that induce a long-lasting immunity against dengue or Zika virus infection, the specific mechanisms underlying such protective immunity remain largely unknown. One of the major challenges lies in the high level of dengue virus (DENV seroprevalence in areas where Zika virus (ZIKV is circulating. In the context of such a pre-existing DENV immunity that can exacerbate ZIKV infection and disease, and given the lack of appropriate treatment for ZIKV infection, there is an urgent need to develop an efficient vaccine against DENV and ZIKV. Notably, whereas several ZIKV vaccine candidates are currently in clinical trials, all these vaccine candidates have been designed to induce neutralizing antibodies as the primary mechanism of immune protection. Given the difficulty to elicit simultaneously high levels of neutralizing antibodies against the different DENV serotypes, and the potential impact of pre-existing subneutralizing antibodies induced upon DENV infection or vaccination on ZIKV infection and disease, additional or alternative strategies to enhance vaccine efficacy, through T cell immunity, are now being considered. In this review, we summarize recent discoveries about cross-reactive B and T cell responses against DENV and ZIKV and propose guidelines for the development of safe and efficient T cell vaccines targeting both viruses.

  9. Responses of Cultured Tobacco Cells to Cryptogein, a Proteinaceous Elicitor from Phytophthora cryptogea1

    Science.gov (United States)

    Blein, Jean-Pierre; Milat, Marie-Louise; Ricci, Pierre

    1991-01-01

    In culture, the phytopathogenic fungus Phytophthora cryptogea secretes a protein which elicits hypersensitive-like necroses and protects tobacco plants against invasion by the pathogen Phytophthora parasitica var. nicotianae. This protein, named cryptogein, has been purified and its amino acid sequence determined. In this work, we studied the effect of cryptogein on tobacco cell suspension cultures. Cryptogein was lethal at about 0.10 micromolar. When added at sublethal doses, it elicited the production of ethylene and phytoalexins. It also induced a rapid increase in pH and conductivity of the extracellular medium without affecting the integrity of the plasma membrane. Cryptogein reduced the fusicoccin-induced acidification of the extracellular medium. The concentration which inhibited the fusicoccin response by 50% was 0.8 nanomolar, while 1 micromolar erythrosine B, an ATPase inhibitor, was needed to produce the same inhibition. However, cryptogein did not inhibit the activity of a purified plasma membrane ATPase. Results of binding studies with whole cells suggested the presence of elicitor-binding sites with a high affinity for cryptogein. The involvement of the plasma membrane during the initial interaction between elicitor and cells is discussed. PMID:16668010

  10. Impaired antibody response causes persistence of prototypic T cell-contained virus.

    Directory of Open Access Journals (Sweden)

    Andreas Bergthaler

    2009-04-01

    Full Text Available CD8 T cells are recognized key players in control of persistent virus infections, but increasing evidence suggests that assistance from other immune mediators is also needed. Here, we investigated whether specific antibody responses contribute to control of lymphocytic choriomeningitis virus (LCMV, a prototypic mouse model of systemic persistent infection. Mice expressing transgenic B cell receptors of LCMV-unrelated specificity, and mice unable to produce soluble immunoglobulin M (IgM exhibited protracted viremia or failed to resolve LCMV. Virus control depended on immunoglobulin class switch, but neither on complement cascades nor on Fc receptor gamma chain or Fc gamma receptor IIB. Cessation of viremia concurred with the emergence of viral envelope-specific antibodies, rather than with neutralizing serum activity, and even early nonneutralizing IgM impeded viral persistence. This important role for virus-specific antibodies may be similarly underappreciated in other primarily T cell-controlled infections such as HIV and hepatitis C virus, and we suggest this contribution of antibodies be given consideration in future strategies for vaccination and immunotherapy.

  11. Unmet Medical Needs in Non-Small-Cell Lung Cancer Treatment: How to Design Pre-Emptive Combination Therapies

    Directory of Open Access Journals (Sweden)

    Niki Karachaliou

    2014-11-01

    Full Text Available The rapidly expanding catalogue of human oncogenic mutations, coupled with difficulties in identifying the cellular targets of active compounds in phenotypic screens, has refocused drug discovery efforts on inhibitors of specific cellular proteins. This new ‘target-based’ approach has enjoyed some spectacular successes in several types of tumours, including non-small-cell lung cancer (NSCLC. Epidermal growth factor receptor (EGFR mutations occur in 17% of NSCLC patients, with notable response to single agent therapy. Unfortunately, all patients eventually develop acquired resistance to EGFR tyrosine kinase inhibitors (TKIs, while complete remission rate to EGFR TKIs monotherapy is low. Priming BIM, a proapoptotic signalling BH3-only protein, induces sensitivity to erlotinib [Tarceva®] in EGFR-mutant cell lines. Synthetic lethal approaches and pre-emptive therapies based on the initial expression of BIM may significantly improve treatment outcomes. EGFR mutations result in transient pro-death imbalance of survival and apoptotic signalling in response to EGFR inhibition. Src homology 2 domain-containing phosphatase 2 is essential to the balance between extracellular signal-regulated kinase, phosphoinositide- 3-kinase/protein kinase B and signal transducer and activator of transcription 3 activity. Furthermore, stromal hepatocyte growth factor confers EGFR TKI resistance and induces inter-receptor crosstalk with Ephrin Type-A receptor 2, CDCP1, AXL, and JAK1. A better understanding of the complex cancer molecular biology of EGFR mutant lung cancer is crucial for development of effective treatment and design of successful future clinical studies.

  12. Fast Response, Load-Matching Hybrid Fuel Cell: Final Technical Progress Report

    Energy Technology Data Exchange (ETDEWEB)

    Key, T. S.; Sitzlar, H. E.; Geist, T. D.

    2003-06-01

    Hybrid DER technologies interconnected with the grid can provide improved performance capabilities compared to a single power source, and, add value, when matched to appropriate applications. For example, in a typical residence, the interconnected hybrid system could provide power during a utility outage, and also could compensate for voltage sags in the utility service. Such a hybrid system would then function as a premium power provider and eliminate the potential need for an uninterruptible power supply. In this research project, a proton exchange membrane (PEM) fuel cell is combined with an asymmetrical ultracapacitor to provide robust power response to changes in system loading. This project also considers the potential of hybrid DER technologies to improve overall power system compatibility and performance. This report includes base year accomplishments of a proposed 3-year-option project.

  13. CD8(+)NKT-like cells regulate the immune response by killing antigen-bearing DCs.

    Science.gov (United States)

    Wang, Chao; Liu, Xi; Li, Zhengyuan; Chai, Yijie; Jiang, Yunfeng; Wang, Qian; Ji, Yewei; Zhu, Zhongli; Wan, Ying; Yuan, Zhenglong; Chang, Zhijie; Zhang, Minghui

    2015-09-15

    CD1d-dependent NKT cells have been extensively studied; however, the function of CD8(+)NKT-like cells, which are CD1d-independent T cells with NK markers, remains unknown. Here, we report that CD1d-independent CD8(+)NKT-like cells, which express both T cell markers (TCRβ and CD3) and NK cell receptors (NK1.1, CD49b and NKG2D), are activated and significantly expanded in mice immunized with GFP-expressing dendritic cells. Distinct from CD1d-dependent NKT cells, CD8(+)NKT-like cells possess a diverse repertoire of TCRs and secrete high levels of IFN-gamma but not IL-4. CD8(+)NKT-like cell development is normal in CD1d(-/-) mice, which suggests that CD8(+)NKT-like cells undergo a unique development pathway that differs from iNKT cells. Further functional analyses show that CD8(+)NKT-like cells suppress T-cell responses through elimination of dendritic cells in an antigen-specific manner. Adoptive transfer of antigen-specific CD8(+)NKT-like cells into RIP-OVA mice prevented subsequent development of diabetes in the animals induced by activated OT-I CD8 T cells. Our study suggests that CD8(+)NKT-like cells can function as antigen-specific suppressive cells to regulate the immune response through killing antigen-bearing DCs. Antigen-specific down regulation may provide an active and precise method for constraining an excessive immune response and avoiding bypass suppression of necessary immune responses to other antigens.

  14. CD8+NKT-like cells regulate the immune response by killing antigen-bearing DCs

    Science.gov (United States)

    Wang, Chao; Liu, Xi; Li, Zhengyuan; Chai, Yijie; Jiang, Yunfeng; Wang, Qian; Ji, Yewei; Zhu, Zhongli; Wan, Ying; Yuan, Zhenglong; Chang, Zhijie; Zhang, Minghui

    2015-01-01

    CD1d-dependent NKT cells have been extensively studied; however, the function of CD8+NKT-like cells, which are CD1d-independent T cells with NK markers, remains unknown. Here, we report that CD1d-independent CD8+NKT-like cells, which express both T cell markers (TCRβ and CD3) and NK cell receptors (NK1.1, CD49b and NKG2D), are activated and significantly expanded in mice immunized with GFP-expressing dendritic cells. Distinct from CD1d-dependent NKT cells, CD8+NKT-like cells possess a diverse repertoire of TCRs and secrete high levels of IFN-gamma but not IL-4. CD8+NKT-like cell development is normal in CD1d−/− mice, which suggests that CD8+NKT-like cells undergo a unique development pathway that differs from iNKT cells. Further functional analyses show that CD8+NKT-like cells suppress T-cell responses through elimination of dendritic cells in an antigen-specific manner. Adoptive transfer of antigen-specific CD8+NKT-like cells into RIP-OVA mice prevented subsequent development of diabetes in the animals induced by activated OT-I CD8 T cells. Our study suggests that CD8+NKT-like cells can function as antigen-specific suppressive cells to regulate the immune response through killing antigen-bearing DCs. Antigen-specific down regulation may provide an active and precise method for constraining an excessive immune response and avoiding bypass suppression of necessary immune responses to other antigens. PMID:26369936

  15. Flow cytometric quantification of radiation responses of murine peritoneal cells

    International Nuclear Information System (INIS)

    Tokita, N.; Raju, M.R.

    1982-01-01

    Methods have been developed to distinguish subpopulations of murine peritoneal cells, and these were applied to the measurement of early changes in peritoneal cells after irradiation. The ratio of the two major subpopulations in the peritoneal fluid, lymphocytes and macrophages, was measured rapidly by means of cell volume distribution analysis as well as by hypotonic propidium iodide (PI) staining. After irradiation, dose and time dependent changes were noted in the cell volume distributions: a rapid loss of peritoneal lymphocytes, and an increase in the mean cell volume of macrophages. The hypotonic PI staining characteristics of the peritoneal cells showed two or three distinctive G 1 peaks. The ratio of the areas of these peaks was also found to be dependent of the radiation dose and the time after irradiation. These results demonstrate that these two parameters may be used to monitor changes induced by irradiation (biological dosimetry), and to sort different peritoneal subpopulations

  16. Complete response of metastatic renal cancer with dendritic cell vaccine

    Directory of Open Access Journals (Sweden)

    Dall'Oglio Marcos

    2003-01-01

    Full Text Available INTRODUCTION: We report a case of metastatic renal cell carcinoma that presented involution following therapy with dendritic cells. CASE REPORT: Male, 51-year old patient underwent left radical nephrectomy in September 1999 due to renal cell carcinoma, evolved with recurrence of the neoplasia in January 2002, confirmed by resection of the lesion. A vaccine therapy based on dendritic cells was then performed during 5 months (4 applications. After this period, there was occurrence of new lesions, whose resection revealed areas of necrosis and inflammatory infiltrate. DISCUSSION: The outcome of renal cell carcinoma is influenced by prognostic factors that confer more aggressive tumor characteristics. However, in cases of recurrence, the systemic therapy with dendritic cells-based vaccine can be associated with a better outcome with regression of disease.

  17. Outer hair cell piezoelectricity: frequency response enhancement and resonance behavior.

    Science.gov (United States)

    Weitzel, Erik K; Tasker, Ron; Brownell, William E

    2003-09-01

    Stretching or compressing an outer hair cell alters its membrane potential and, conversely, changing the electrical potential alters its length. This bi-directional energy conversion takes place in the cell's lateral wall and resembles the direct and converse piezoelectric effects both qualitatively and quantitatively. A piezoelectric model of the lateral wall has been developed that is based on the electrical and material parameters of the lateral wall. An equivalent circuit for the outer hair cell that includes piezoelectricity shows a greater admittance at high frequencies than one containing only membrane resistance and capacitance. The model also predicts resonance at ultrasonic frequencies that is inversely proportional to cell length. These features suggest all mammals use outer hair cell piezoelectricity to support the high-frequency receptor potentials that drive electromotility. It is also possible that members of some mammalian orders use outer hair cell piezoelectric resonance in detecting species-specific vocalizations.

  18. Effect of radiation doses rate on SOS response induction in irradiated Escherichia coli Cells

    International Nuclear Information System (INIS)

    Cuetara Lugo, Elizabeth B.; Fuentes Lorenzo, Jorge L.; Almeida Varela, Eliseo; Prieto Miranda, Enrique F.; Sanchez Lamar, Angel; Llagostera Casal, Montserrat

    2005-01-01

    The present work is aimed to study the effect of radiation dose rate on the induction of SOS response in Escherichia coli cells. We measured the induction of sul A reporter gene in PQ-37 (SOS Chromotest) cells. Lead devises were built with different diameter and these were used for diminishing the dose rate of PX- -30M irradiator. Our results show that radiation doses rate significantly modifies the induction of SOS response. Induction factor increases proportionally to doses rate in Escherichia coli cells defective to nucleotide excision repair (uvrA), but not in wild type cells. We conclude that the dose rate affects the level of induction of SOS response

  19. Sustained CD8+ T-cell responses induced after acute parvovirus B19 infection in humans

    DEFF Research Database (Denmark)

    Norbeck, Oscar; Isa, Adiba; Pöhlmann, Christoph

    2005-01-01

    Murine models have suggested that CD8+ T-cell responses peak early in acute viral infections and are not sustained, but no evidence for humans has been available. To address this, we longitudinally analyzed the CD8+ T-cell response to human parvovirus B19 in acutely infected individuals. We...... observed striking CD8+ T-cell responses, which were sustained or even increased over many months after the resolution of acute disease, indicating that CD8+ T cells may play a prominent role in the control of parvovirus B19 and other acute viral infections of humans, including potentially those generated...

  20. International stem cell tourism and the need for effective regulation. Part II: Developing sound oversight measures and effective patient support.

    Science.gov (United States)

    Cohen, Cynthia B; Cohen, Peter J

    2010-09-01

    Part I of this article, published in the March 2010 issue of the Kennedy Institute of Ethics Journal, traces and addresses the provision of unproven stem cell treatments in Russia and India, examines the concept of innovative treatment, and concludes that stronger regulations are needed to protect the health and informed choices of patients. The current paper, Part II, proposes that the regulatory frameworks for the development of safe and efficacious treatments in effect in the United States and the United Kingdom provide examples of strong oversight measures from which countries seeking to obtain international credibility for their biotechnological competence could draw when developing regulations for stem cell treatments. Major sources of information available to persons who consider receiving such unproven treatments are explored in order to understand and address their concerns. The paper concludes with proposed measures to inform those considering the pursuit of unproven stem cell treatments abroad more accurately about their efficacy and safety and provide them with improved medical and social support in their home countries.

  1. Pheochromocytoma (PC12 Cell Response on Mechanobactericidal Titanium Surfaces

    Directory of Open Access Journals (Sweden)

    Jason V. Wandiyanto

    2018-04-01

    Full Text Available Titanium is a biocompatible material that is frequently used for making implantable medical devices. Nanoengineering of the surface is the common method for increasing material biocompatibility, and while the nanostructured materials are well-known to represent attractive substrata for eukaryotic cells, very little information has been documented about the interaction between mammalian cells and bactericidal nanostructured surfaces. In this study, we investigated the effect of bactericidal titanium nanostructures on PC12 cell attachment and differentiation—a cell line which has become a widely used in vitro model to study neuronal differentiation. The effects of the nanostructures on the cells were then compared to effects observed when the cells were placed in contact with non-structured titanium. It was found that bactericidal nanostructured surfaces enhanced the attachment of neuron-like cells. In addition, the PC12 cells were able to differentiate on nanostructured surfaces, while the cells on non-structured surfaces were not able to do so. These promising results demonstrate the potential application of bactericidal nanostructured surfaces in biomedical applications such as cochlear and neuronal implants.

  2. Direct-to-consumer stem cell marketing and regulatory responses.

    Science.gov (United States)

    Sipp, Douglas

    2013-09-01

    There is a large, poorly regulated international market of putative stem cell products, including transplants of processed autologous stem cells from various tissues, cell processing devices, cosmetics, and nutritional supplements. Despite the absence of rigorous scientific research in the form of randomized clinical trials to support the routine use of such products, the market appears to be growing and diversifying. Very few stem cell biologics have passed regulatory scrutiny, and authorities in many countries, including the United States, have begun to step up their enforcement activities to protect patients and the integrity of health care markets.

  3. Loss of BCG Viability Adversely Affects the Direct Response of Urothelial Carcinoma Cells to BCG Exposure

    Science.gov (United States)

    Shah, Gopitkumar; Zhang, Guangjian; Chen, Fanghong; Cao, YanLi; Kalyanaraman, Balaraman; See, William

    2018-01-01

    INTRODUCTION The attenuated mycobacterium Bacille Calmette Guerin (BCG) is widely utilized as intravesical “immunotherapy” for the treatment of non-muscle invasive urothelial carcinoma. Previous studies have demonstrated that in both the laboratory and clinical setting, BCG viability is a variable that correlates with anti-tumor efficacy. This study evaluated how loss of BCG viability impacted a number of molecular and phenotypic intermediate endpoints that characterize, and/or contribute to, the direct effect of BCG on Urothelial carcinoma (UC) cells. MATERIALS AND METHODS Two human UC cell lines were used to study the effect of loss of BCG viability on the tumor cell response to BCG. The cellular response to BCG rendered non-viable by heat killing (hk) was compared to the response to viable BCG. The response endpoints evaluated included the induction of oxidative stress, activation of intracellular signaling pathways, gene transactivation, and phenotypic changes. RESULTS Loss of viability resulted in a quantitative decrease in the tumor cell response, relative to viable BCG, for all of the measured endpoints. The decrease in response varied by cell line, ranging from 15% to 100% of the response to viable BCG. While quantitatively different, non-viable BCG continued to induce responses that were qualitatively similar to BCG relative to untreated controls. CONCLUSIONS BCG viability is an important variable influencing the direct tumor cell response to BCG. Although the magnitude of it effects are attenuated, hkBCG remains active for the induction of BCG responsive biologic endpoints. PMID:24035882

  4. Chitin recognition via chitotriosidase promotes pathologic type-2 helper T cell responses to cryptococcal infection.

    Directory of Open Access Journals (Sweden)

    Darin L Wiesner

    2015-03-01

    Full Text Available Pulmonary mycoses are often associated with type-2 helper T (Th2 cell responses. However, mechanisms of Th2 cell accumulation are multifactorial and incompletely known. To investigate Th2 cell responses to pulmonary fungal infection, we developed a peptide-MHCII tetramer to track antigen-specific CD4+ T cells produced in response to infection with the fungal pathogen Cryptococcus neoformans. We noted massive accruement of pathologic cryptococcal antigen-specific Th2 cells in the lungs following infection that was coordinated by lung-resident CD11b+ IRF4-dependent conventional dendritic cells. Other researchers have demonstrated that this dendritic cell subset is also capable of priming protective Th17 cell responses to another pulmonary fungal infection, Aspergillus fumigatus. Thus, higher order detection of specific features of fungal infection by these dendritic cells must direct Th2 cell lineage commitment. Since chitin-containing parasites commonly elicit Th2 responses, we hypothesized that recognition of fungal chitin is an important determinant of Th2 cell-mediated mycosis. Using C. neoformans mutants or purified chitin, we found that chitin abundance impacted Th2 cell accumulation and disease. Importantly, we determined Th2 cell induction depended on cleavage of chitin via the mammalian chitinase, chitotriosidase, an enzyme that was also prevalent in humans experiencing overt cryptococcosis. The data presented herein offers a new perspective on fungal disease susceptibility, whereby chitin recognition via chitotriosidase leads to the initiation of harmful Th2 cell differentiation by CD11b+ conventional dendritic cells in response to pulmonary fungal infection.

  5. Chitin Recognition via Chitotriosidase Promotes Pathologic Type-2 Helper T Cell Responses to Cryptococcal Infection

    Science.gov (United States)

    Wiesner, Darin L.; Specht, Charles A.; Lee, Chrono K.; Smith, Kyle D.; Mukaremera, Liliane; Lee, S. Thera; Lee, Chun G.; Elias, Jack A.; Nielsen, Judith N.; Boulware, David R.; Bohjanen, Paul R.; Jenkins, Marc K.; Levitz, Stuart M.; Nielsen, Kirsten

    2015-01-01

    Pulmonary mycoses are often associated with type-2 helper T (Th2) cell responses. However, mechanisms of Th2 cell accumulation are multifactorial and incompletely known. To investigate Th2 cell responses to pulmonary fungal infection, we developed a peptide-MHCII tetramer to track antigen-specific CD4+ T cells produced in response to infection with the fungal pathogen Cryptococcus neoformans. We noted massive accruement of pathologic cryptococcal antigen-specific Th2 cells in the lungs following infection that was coordinated by lung-resident CD11b+ IRF4-dependent conventional dendritic cells. Other researchers have demonstrated that this dendritic cell subset is also capable of priming protective Th17 cell responses to another pulmonary fungal infection, Aspergillus fumigatus. Thus, higher order detection of specific features of fungal infection by these dendritic cells must direct Th2 cell lineage commitment. Since chitin-containing parasites commonly elicit Th2 responses, we hypothesized that recognition of fungal chitin is an important determinant of Th2 cell-mediated mycosis. Using C. neoformans mutants or purified chitin, we found that chitin abundance impacted Th2 cell accumulation and disease. Importantly, we determined Th2 cell induction depended on cleavage of chitin via the mammalian chitinase, chitotriosidase, an enzyme that was also prevalent in humans experiencing overt cryptococcosis. The data presented herein offers a new perspective on fungal disease susceptibility, whereby chitin recognition via chitotriosidase leads to the initiation of harmful Th2 cell differentiation by CD11b+ conventional dendritic cells in response to pulmonary fungal infection. PMID:25764512

  6. Natural Killer Dendritic Cells Enhance Immune Responses Elicited by α-Galactosylceramide-Stimulated Natural Killer T Cells

    Directory of Open Access Journals (Sweden)

    Sung Won Lee

    2013-01-01

    Full Text Available Natural killer dendritic cells (NKDCs possess potent anti-tumor activity, but the cellular effect of NKDC interactions with other innate immune cells is unclear. In this study, we demonstrate that the interaction of NKDCs and natural killer T (NKT cells is required for the anti-tumor immune responses that are elicited by α-galactosylceramide (α-GC in mice. The rapid and strong expression of interferon-γ by NKDCs after α-GC stimulation was dependent on NKT cells. Various NK and DC molecular markers and cytotoxic molecules were up-regulated following α-GC administration. This up-regulation could improve NKDC presentation of tumor antigens and increase cytotoxicity against tumor cells. NKDCs were required for the stimulation of DCs, NK cells, and NKT cells. The strong anti-tumor immune responses elicited by α-GC may be due to the down-regulation of regulatory T cells. Furthermore, the depletion of NKDCs dampened the tumor clearance mediated by α-GC-stimulated NKT cells in vivo. Taken together, these results indicate that complex interactions of innate immune cells might be required to achieve optimal anti-tumor immune responses during the early stages of tumorigenesis.

  7. Fibronectin is Essential for Reparative Cardiac Progenitor Cell Response Following Myocardial Infarction

    Science.gov (United States)

    Konstandin, Mathias H.; Toko, Haruhiro; Gastelum, Grady M.; Quijada, Pearl; De La Torre, Andrea; Quintana, Mercedes; Collins, Brett; Din, Shabana; Avitabile, Daniele; Völkers, Mirko; Gude, Natalie; Fässler, Reinhard; Sussman, Mark A.

    2013-01-01

    Rationale Adoptive transfer of cardiac progenitor cells (CPCs) has entered clinical application despite limited mechanistic understanding of the endogenous response following myocardial infarction (MI). Extracellular matrix (ECM) undergoes dramatic changes after MI and therefore might be linked to CPC-mediated repair. Objective Demonstrate the significance of Fibronectin (Fn), a component of the ECM, for induction of the endogenous CPC response to MI. Methods and Results This report shows that presence of CPCs correlates with expression of Fn during cardiac development and after MI. In vivo, genetic conditional ablation of Fn blunts CPC response measured 7 days after MI through reduced proliferation and diminished survival. Attenuated vasculogenesis and cardiogenesis during recovery was evident at the end of a 12 week follow-up period. Impaired CPC-dependent reparative remodeling ultimately leads to continuous decline of cardiac function in Fn knockout animals. In vitro, Fn protects and induces proliferation of CPCs via β1-Integrin-FAK-Stat3-Pim1 but Akt-independent mechanism. Conclusion Fn is essential for endogenous CPC expansion and repair needed for stabilization of cardiac function after MI. PMID:23652800

  8. Progenitor cells of erythroblasts: an in vitro investigation of erythropoietin-responsive cells of guinea pig bone marrow

    International Nuclear Information System (INIS)

    Rosse, C.; Beaufait, D.W.

    1978-01-01

    The experiments were designed to therst whether erythroblast progenitor cell function could be demonstrated in a morphological cell type designated as transitional cells. Two cell fractions were obtained from the bone marrow of normal and polycythemic guinea pigs. One fraction (F1) was enriched in transitional cells and contained few other cell types which could be considered as candidates for erythropoietin responsive cells (ERC). The other fraction (F2) contained undifferentiated blast cells as well as transitional cells. The effect of human urinary erythropoiesis stimulating factors (ESF) on heme synthesis was compared in these two fractions by measuring 59 Fe incorporation into heme. ESF was more effective in stimulating heme synthesis in guinea pig bone marrow cells than homologous sera obtained from anemic or hypoxic animals. The majority of ERC sedimented in F2, but the stimulation index was comparable in the two fractions. It was confirmed by radioautography that the ESF response in F1 was due to the generation of proerythroblasts and basophilic erythroblasts that incorporated 55 Fe. The generation of these cells in F1 was dependent on the addition of ESF to the cultures, whereas 55 Fe-labeled erythroblasts were recovered from cultures of F2 not supplemented with ESF. ESF induced a proportion of transitional cells to incorporate 55 Fe in both F1 and F2. Transitional cells were the only cell type in which heme synthesis was dependent on ESF. Radioautography with 55 Fe identified a proportion of these cells as ERC in both F1 and F2 fractions of bone marrow obtained from normal and polycythemic guinea pigs. The present studies show that some transitional cells function as progenitors of erythroblasts because they respond to ESF by initiation of heme synthesis and by transformation into the earliest recognizable erythroid cells

  9. Efficient Generation of Glucose-Responsive Beta Cells from Isolated GP2+ Human Pancreatic Progenitors

    DEFF Research Database (Denmark)

    Ameri, Jacqueline; Borup, Rehannah; Prawiro, Christy

    2017-01-01

    Stem cell-based therapy for type 1 diabetes would benefit from implementation of a cell purification step at the pancreatic endoderm stage. This would increase the safety of the final cell product, allow the establishment of an intermediate-stage stem cell bank, and provide a means for upscaling β...... cell manufacturing. Comparative gene expression analysis revealed glycoprotein 2 (GP2) as a specific cell surface marker for isolating pancreatic endoderm cells (PECs) from differentiated hESCs and human fetal pancreas. Isolated GP2+ PECs efficiently differentiated into glucose responsive insulin...

  10. Feasibility of a rapid response mechanism to meet policymakers' urgent needs for research evidence about health systems in a low income country: a case study.

    Science.gov (United States)

    Mijumbi, Rhona M; Oxman, Andrew D; Panisset, Ulysses; Sewankambo, Nelson K

    2014-09-10

    Despite the recognition of the importance of evidence-informed health policy and practice, there are still barriers to translating research findings into policy and practice. The present study aimed to establish the feasibility of a rapid response mechanism, a knowledge translation strategy designed to meet policymakers' urgent needs for evidence about health systems in a low income country, Uganda. Rapid response mechanisms aim to address the barriers of timeliness and relevance of evidence at the time it is needed. A rapid response mechanism (service) designed a priori was offered to policymakers in the health sector in Uganda. In the form of a case study, data were collected about the profile of users of the service, the kinds of requests for evidence, changes in answers, and courses of action influenced by the mechanism and their satisfaction with responses and the mechanism in general. We found that in the first 28 months, the service received 65 requests for evidence from 30 policymakers and stakeholders, the majority of whom were from the Ministry of Health. The most common requests for evidence were about governance and organization of health systems. It was noted that regular contact between the policymakers and the researchers at the response service was an important factor in response to, and uptake of the service. The service seemed to increase confidence for policymakers involved in the policymaking process. Rapid response mechanisms designed to meet policymakers' urgent needs for research evidence about health systems are feasible and acceptable to policymakers in low income countries.

  11. Impaired TLR9 responses in B cells from patients with systemic lupus erythematosus.

    Science.gov (United States)

    Gies, Vincent; Schickel, Jean-Nicolas; Jung, Sophie; Joublin, Aurélie; Glauzy, Salomé; Knapp, Anne-Marie; Soley, Anne; Poindron, Vincent; Guffroy, Aurélien; Choi, Jin-Young; Gottenberg, Jacques-Eric; Anolik, Jennifer H; Martin, Thierry; Soulas-Sprauel, Pauline; Meffre, Eric; Korganow, Anne-Sophie

    2018-03-08

    B cells play a central role in systemic lupus erythematosus (SLE) pathophysiology but dysregulated pathways leading to a break in B cell tolerance remain unclear. Since Toll-like receptor 9 (TLR9) favors the elimination of autoreactive B cells in the periphery, we assessed TLR9 function in SLE by analyzing the responses of B cells and plasmacytoid dendritic cells (pDCs) isolated from healthy donors and patients after stimulation with CpG, a TLR9 agonist. We found that SLE B cells from patients without hydroxychloroquine treatment displayed defective in vitro TLR9 responses, as illustrated by the impaired upregulation of B cell activation molecules and the diminished production of various cytokines including antiinflammatory IL-10. In agreement with CD19 controlling TLR9 responses in B cells, decreased expression of the CD19/CD21 complex on SLE B cells was detected as early as the transitional B cell stage. In contrast, TLR7 function was preserved in SLE B cells, whereas pDCs from SLE patients properly responded to TLR9 stimulation, thereby revealing that impaired TLR9 function in SLE was restricted to B cells. We conclude that abnormal CD19 expression and TLR9 tolerogenic function in SLE B cells may contribute to the break of B cell tolerance in these patients.

  12. Endocannabinoids and inflammatory response in periodontal ligament cells.

    Science.gov (United States)

    Özdemir, Burcu; Shi, Bin; Bantleon, Hans Peter; Moritz, Andreas; Rausch-Fan, Xiaohui; Andrukhov, Oleh

    2014-01-01

    Endocannabinoids are associated with multiple regulatory functions in several tissues. The main endocannabinoids, anandamide (AEA) and 2-arachidonylglycerol (2-AG), have been detected in the gingival crevicular fluid of periodontitis patients, but the association between periodontal disease or human periodontal ligament cells (hPdLCs) and endocannabinoids still remain unclear. The aim of the present study was to examine the effects of AEA and 2-AG on the proliferation/viability and cytokine/chemokine production of hPdLCs in the presence/absence of Porphyromonas gingivalis lipopolysaccharide (P. gingivalis LPS). The proliferation/viability of hPdLCs was measured using 3,4,5-dimethylthiazol-2-yl-2,5-diphenyl tetrazolium bromide (MTT)-assay. Interleukin-6 (IL-6), interleukin-8 (IL-8), and monocyte chemotactic protein-1 (MCP-1) levels were examined at gene expression and protein level by real-time PCR and ELISA, respectively. AEA and 2-AG did not reveal any significant effects on proliferation/viability of hPdLCs in the absence of P. gingivalis LPS. However, hPdLCs viability was significantly increased by 10-20 µM AEA in the presence of P. gingivalis LPS (1 µg/ml). In the absence of P. gingivalis LPS, AEA and 2-AG did not exhibit any significant effect on the expression of IL-8 and MCP-1 expression in hPdLCs, whereas IL-6 expression was slightly enhanced by 10 µM 2-AG and not affected by AEA. In P.gingivalis LPS stimulated hPdLCs, 10 µM AEA down-regulated gene-expression and protein production of IL-6, IL-8, and MCP-1. In contrast, 10 µM 2-AG had an opposite effect and induced a significant up-regulation of gene and protein expression of IL-6 and IL-8 (P<0.05) as well as gene-expression of MCP-1 in P. gingivalis LPS stimulated hPdLCs. Our data suggest that AEA appears to have an anti-inflammatory and immune suppressive effect on hPdLCs' host response to P.gingivalis LPS, whereas 2-AG appears to promote detrimental inflammatory processes. In conclusion, AEA and 2

  13. Endocannabinoids and inflammatory response in periodontal ligament cells.

    Directory of Open Access Journals (Sweden)

    Burcu Özdemir

    Full Text Available Endocannabinoids are associated with multiple regulatory functions in several tissues. The main endocannabinoids, anandamide (AEA and 2-arachidonylglycerol (2-AG, have been detected in the gingival crevicular fluid of periodontitis patients, but the association between periodontal disease or human periodontal ligament cells (hPdLCs and endocannabinoids still remain unclear. The aim of the present study was to examine the effects of AEA and 2-AG on the proliferation/viability and cytokine/chemokine production of hPdLCs in the presence/absence of Porphyromonas gingivalis lipopolysaccharide (P. gingivalis LPS. The proliferation/viability of hPdLCs was measured using 3,4,5-dimethylthiazol-2-yl-2,5-diphenyl tetrazolium bromide (MTT-assay. Interleukin-6 (IL-6, interleukin-8 (IL-8, and monocyte chemotactic protein-1 (MCP-1 levels were examined at gene expression and protein level by real-time PCR and ELISA, respectively. AEA and 2-AG did not reveal any significant effects on proliferation/viability of hPdLCs in the absence of P. gingivalis LPS. However, hPdLCs viability was significantly increased by 10-20 µM AEA in the presence of P. gingivalis LPS (1 µg/ml. In the absence of P. gingivalis LPS, AEA and 2-AG did not exhibit any significant effect on the expression of IL-8 and MCP-1 expression in hPdLCs, whereas IL-6 expression was slightly enhanced by 10 µM 2-AG and not affected by AEA. In P.gingivalis LPS stimulated hPdLCs, 10 µM AEA down-regulated gene-expression and protein production of IL-6, IL-8, and MCP-1. In contrast, 10 µM 2-AG had an opposite effect and induced a significant up-regulation of gene and protein expression of IL-6 and IL-8 (P<0.05 as well as gene-expression of MCP-1 in P. gingivalis LPS stimulated hPdLCs. Our data suggest that AEA appears to have an anti-inflammatory and immune suppressive effect on hPdLCs' host response to P.gingivalis LPS, whereas 2-AG appears to promote detrimental inflammatory processes. In conclusion

  14. Gene Expression Programs in Response to Hypoxia: Cell Type Specificity and Prognostic Significance in Human Cancers.

    Directory of Open Access Journals (Sweden)

    2006-01-01

    Full Text Available BACKGROUND: Inadequate oxygen (hypoxia triggers a multifaceted cellular response that has important roles in normal physiology and in many human diseases. A transcription factor, hypoxia-inducible factor (HIF, plays a central role in the hypoxia response; its activity is regulated by the oxygen-dependent degradation of the HIF-1alpha protein. Despite the ubiquity and importance of hypoxia responses, little is known about the variation in the global transcriptional response to hypoxia among different cell types or how this variation might relate to tissue- and cell-specific diseases. METHODS AND FINDINGS: We analyzed the temporal changes in global transcript levels in response to hypoxia in primary renal proximal tubule epithelial cells, breast epithelial cells, smooth muscle cells, and endothelial cells with DNA microarrays. The extent of the transcriptional response to hypoxia was greatest in the renal tubule cells. This heightened response was associated with a uniquely high level of HIF-1alpha RNA in renal cells, and it could be diminished by reducing HIF-1alpha expression via RNA interference. A gene-expression signature of the hypoxia response, derived from our studies of cultured mammary and renal tubular epithelial cells, showed coordinated variation in several human cancers, and was a strong predictor of clinical outcomes in breast and ovarian cancers. In an analysis of a large, published gene-expression dataset from breast cancers, we found that the prognostic information in the hypoxia signature was virtually independent of that provided by the previously reported wound signature and more predictive of outcomes than any of the clinical parameters in current use. CONCLUSIONS: The transcriptional response to hypoxia varies among human cells. Some of this variation is traceable to variation in expression of the HIF1A gene. A gene-expression signature of the cellular response to hypoxia is associated with a significantly poorer prognosis

  15. Endogenous Tim-1 (Kim-1) promotes T-cell responses and cell-mediated injury in experimental crescentic glomerulonephritis.

    Science.gov (United States)

    Nozaki, Yuji; Nikolic-Paterson, David J; Snelgrove, Sarah L; Akiba, Hisaya; Yagita, Hideo; Holdsworth, Stephen R; Kitching, A Richard

    2012-05-01

    The T-cell immunoglobulin mucin 1 (Tim-1) modulates CD4(+) T-cell responses and is also expressed by damaged proximal tubules in the kidney where it is known as kidney injury molecule-1 (Kim-1). We sought to define the role of endogenous Tim-1 in experimental T-cell-mediated glomerulonephritis induced by sheep anti-mouse glomerular basement membrane globulin acting as a planted foreign antigen. Tim-1 is expressed by infiltrating activated CD4(+) cells in this model, and we studied the effects of an inhibitory anti-Tim-1 antibody (RMT1-10) on immune responses and glomerular disease. Crescentic glomerulonephritis, proliferative injury, and leukocyte accumulation were attenuated following treatment with anti-Tim-1 antibodies, but interstitial foxp3(+) cell accumulation and interleukin-10 mRNA were increased. T-cell proliferation and apoptosis decreased in the immune system along with a selective reduction in Th1 and Th17 cellular responses both in the immune system and within the kidney. The urinary excretion and renal expression of Kim-1 was reduced by anti-Tim-1 antibodies reflecting diminished interstitial injury. The effects of anti-Tim-1 antibodies were not apparent in the early phase of renal injury, when the immune response to sheep globulin was developing. Thus, endogenous Tim-1 promotes Th1 and Th17 nephritogenic immune responses and its neutralization reduces renal injury while limiting inflammation in cell-mediated glomerulonephritis.

  16. Shaping Successful and Unsuccessful CD8 T Cell Responses Following Infection

    OpenAIRE

    Cox, Maureen A.; Zajac, Allan J.

    2010-01-01

    CD8 T cells play a vital role in the immunological protection against intracellular pathogens. Ideally, robust effector responses are induced, which eradicate the pathogen, and durable memory CD8 T cells are also established, which help confer protection against subsequent reinfection. The quality and magnitude of these responses is dictated by multiple factors, including their initial interactions with professional antigen-presenting cells, as well as the cytokine milieu and availability of ...

  17. Direct longitudinal comparison over 12 month of T-cell responses to prophylactic HPV vaccines

    OpenAIRE

    Pacher, Sina Kristin

    2011-01-01

    Background: L1-specific T helper cell responses induced by prophylactic HPV vaccines Gardasil and Cervarix were compared. The quadrivalent vaccine Gardasil contains virus-like particles (VLP) of HPV types 6, 11, 16, and 18 adjuvanted with aluminium salts. Cervarix contains VLP of types 16 and 18 together with the TLR 4 stimulating adjuvant AS04. T helper cells are important for B cell differentiation, sustained memory, activation of recall reactions, and thus anamnestic responses. Only few re...

  18. Pancreatic beta cells from db/db mice show cell-specific [Ca2+]i and NADH responses to glucose but not to alpha-ketoisocaproic acid

    DEFF Research Database (Denmark)

    Gustavsson, Natalia; Larsson-Nyrén, Gerd; Lindström, Per

    2005-01-01

    induced cell-specific NADH responses in all 3 models, but KIC did so only in lean mouse [beta] cells. CONCLUSIONS: A cell-specific response may be induced at several steps of beta-cell stimulus-secretion coupling. Mitochondrial metabolism generates a cell-specific response in normal beta cells......OBJECTIVE: We recently showed that timing and magnitude of the glucose-induced cytoplasmic calcium [Ca2+]i response are reproducible and specific for the individual beta cell. We now wanted to identify which step(s) of stimulus-secretion coupling determine the cell specificity of the [Ca2+]i...

  19. Sympathetic glial cells and macrophages develop different responses to Trypanosoma cruzi infection or lipopolysaccharide stimulation.

    Science.gov (United States)

    de Almeida-Leite, Camila Megale; Silva, Isabel Cristina Costa; Galvão, Lúcia Maria da Cunha; Arantes, Rosa Maria Esteves

    2014-07-01

    Nitric oxide (NO) participates in neuronal lesions in the digestive form of Chagas disease and the proximity of parasitised glial cells and neurons in damaged myenteric ganglia is a frequent finding. Glial cells have crucial roles in many neuropathological situations and are potential sources of NO. Here, we investigate peripheral glial cell response to Trypanosoma cruzi infection to clarify the role of these cells in the neuronal lesion pathogenesis of Chagas disease. We used primary glial cell cultures from superior cervical ganglion to investigate cell activation and NO production after T. cruzi infection or lipopolysaccharide (LPS) exposure in comparison to peritoneal macrophages. T. cruzi infection was greater in glial cells, despite similar levels of NO production in both cell types. Glial cells responded similarly to T. cruzi and LPS, but were less responsive to LPS than macrophages were. Our observations contribute to the understanding of Chagas disease pathogenesis, as based on the high susceptibility of autonomic glial cells to T. cruzi infection with subsequent NO production. Moreover, our findings will facilitate future research into the immune responses and activation mechanisms of peripheral glial cells, which are important for understanding the paradoxical responses of this cell type in neuronal lesions and neuroprotection.

  20. CD4 T-helper cell cytokine phenotypes and antibody response following tetanus toxoid booster immunization

    Science.gov (United States)

    Routine methods for enumerating antigen-specific T-helper cells may not identify low-frequency phenotypes such as Th2 cells. We compared methods of evaluating such responses to identify tetanus toxoid- (TT) specific Th1, Th2, Th17 and IL10+ cells. Eight healthy subjects were given a TT booster vacci...

  1. Live cell microscopy of DNA damage response in Saccharomyces cerevisiae

    DEFF Research Database (Denmark)

    Pinela da Silva, Sonia Cristina; Gallina, Irene; Eckert-Boulet, Nadine Valerie

    2012-01-01

    live cell imaging allows for multiple cellular markers to be monitored over several hours. This chapter reviews useful fluorescent markers and genotoxic agents for studying the DNA damage response in living cells and provides protocols for live cell imaging, time-lapse microscopy, and for induction...

  2. Human Dental Pulp Cells Responses to Apatite Precipitation from Dicalcium Silicates

    Directory of Open Access Journals (Sweden)

    Wei-Yun Lai

    2015-07-01

    Full Text Available Unraveling the mechanisms behind the processes of cell attachment and the enhanced proliferation that occurs as a response to the presence of calcium silicate-based materials needs to be better understood so as to expand the applications of silicate-based materials. Ions in the environment may influence apatite precipitation and affect silicate ion release from silicate-based materials. Thus, the involvement of apatite precipitate in the regulation of cell behavior of human dental pulp cells (hDPCs is also investigated in the present study, along with an investigation of the specific role of cell morphology and osteocalcin protein expression cultured on calcium silicate (CS with different Dulbecco’s modified Eagle’s medium (DMEM. The microstructure and component of CS cement immersion in DMEM and P-free DMEM are analyzed. In addition, when hDPCs are cultured on CS with two DMEMs, we evaluate fibronectin (FN and collagen type I (COL secretion during the cell attachment stage. The facilitation of cell adhesion on CS has been confirmed and observed both by scanning with an electron microscope and using immunofluorescence imaging. The results indicate that CS is completely covered by an apatite layer with tiny spherical shapes on the surface in the DMEM, but not in the P-free DMEM. Compared to the P-free DMEM, the lower Ca ion in the DMEM may be attributed to the formation of the apatite on the surfaces of specimens as a result of consumption of the Ca ion from the DMEM. Similarly, the lower Si ion in the CS-soaked DMEM is attributed to the shielding effect of the apatite layer. The P-free DMEM group releases more Si ion increased COL and FN secretion, which promotes cell attachment more effectively than DMEM. This study provides new and important clues regarding the major effects of Si-induced cell behavior as well as the precipitated apatite-inhibited hDPC behavior on these materials.

  3. Signaling network of dendritic cells in response to pathogens: a community-input supported knowledgebase

    Directory of Open Access Journals (Sweden)

    Nudelman Irina

    2010-10-01

    Full Text Available Abstract Background Dendritic cells are antigen-presenting cells that play an essential role in linking the innate and adaptive immune systems. Much research has focused on the signaling pathways triggered upon infection of dendritic cells by various pathogens. The high level of activity in the field makes it desirable to have a pathway-based resource to access the information in the literature. Current pathway diagrams lack either comprehensiveness, or an open-access editorial interface. Hence, there is a need for a dependable, expertly curated knowledgebase that integrates this information into a map of signaling networks. Description We have built a detailed diagram of the dendritic cell signaling network, with the goal of providing researchers with a valuable resource and a facile method for community input. Network construction has relied on comprehensive review of the literature and regular updates. The diagram includes detailed depictions of pathways activated downstream of different pathogen recognition receptors such as Toll-like receptors, retinoic acid-inducible gene-I-like receptors, C-type lectin receptors and nucleotide-binding oligomerization domain-like receptors. Initially assembled using CellDesigner software, it provides an annotated graphical representation of interactions stored in Systems Biology Mark-up Language. The network, which comprises 249 nodes and 213 edges, has been web-published through the Biological Pathway Publisher software suite. Nodes are annotated with PubMed references and gene-related information, and linked to a public wiki, providing a discussion forum for updates and corrections. To gain more insight into regulatory patterns of dendritic cell signaling, we analyzed the network using graph-theory methods: bifan, feedforward and multi-input convergence motifs were enriched. This emphasis on activating control mechanisms is consonant with a network that subserves persistent and coordinated responses to

  4. State of the art: Multi-fuel reformers for automotive fuel cell applications. Problem identification and research needs

    Energy Technology Data Exchange (ETDEWEB)

    Westerholm, R. [Stockholm Univ. (Sweden). Dept. of Analytical Chemistry; Pettersson, L.J. [Royal Inst. of Tech., Stockholm (Sweden). Dept. of Chemical Engineering and Technology

    1999-12-01

    On an assignment from the Transport and Communications Research Board (KFB) a literature study and a study trip to the USA and Great Britain have been performed. The literature study and the study trip was made during late spring and autumn 1999.The purpose of the project was to collect available information about the chemical composition of the product gas from a multi-fuel reformer for a fuel cell vehicle. It was furthermore to identify problems and research needs. The report recommends directions for future major research efforts. The results of the literature study and the study trip led to the following general conclusions: With the technology available today it does not seem feasible to develop a highly efficient and reliable multi-fuel reformer for automotive applications, i. e. for applications where all types of fuels ranging from natural gas to heavy diesel fuels can be used. The potential for developing a durable and reliable system is considerably higher if dedicated fuel reformers are used.The authors propose that petroleum-derived fuels should be designed for potential use in mobile fuel cell applications. In the present literature survey and the site visit discussions we found that there are relatively low emissions from fuel cell engines compared to internal combustion engines. However, the major research work on reformers/fuel cells have been performed during steady-state operation. Emissions during start-up, shutdown and transient operation are basically unknown and must be investigated in more detail. The conclusions and findings in this report are based on open/available information, such as discussions at site visits, reports, scientific publications and symposium proceedings.

  5. CD4 + CELL RESPONSE TO ANTI-RETROVIRAL THERAPY (ARTs ...

    African Journals Online (AJOL)

    enhances immunity by sustained HIV- viral suppression, increase in CD4+ cell count and immune restoration. ... Seventy three (70.9%) of patients still had immune depletion with low CD4+ cell counts at one year of receiving HAART. ..... homeostasis and function in advanced HIV disease. Science 1997; 277: 112- 116. 7.

  6. The comparison of radiation responses in MCF-7 and HeLa cells

    Energy Technology Data Exchange (ETDEWEB)

    Kang, Mi Young; Jang, Eun Yeong; Ryu, Tae Ho; Chung, Dong-Min; Kim, Jin Hong; Kim, Jin Kyu [Advanced Radiation Technology Institute, Jeongeup (Korea, Republic of)

    2014-11-15

    Activation of this pathway temporarily arrests cells at the G1 or G2 checkpoints of cell cycle, or terminates DNA replication and cell division. The present study was carried out to identify the fate of cells to cope with DNA damage stress. Cellular responses following IR treatment were different depending on the characteristics (origin, organism and genes expressed etc.) of cell line used and extent of genomic injury. p53 expression level was increased in a dose-dependent manner in both cells. IR induced a drastic increase in expression of p21 in MCF-7 compared to that in HeLa cells. Cell cycle analysis using flow cytometry showed a significant accumulation in G2/M phase after treatment of MCF-7 with IR. This study identified that IR-induced cell fates were determined through p53-dependent activation of p21, which resulted in senescence of MCF-7 cells and autophagy of HeLa cells.

  7. Whole-cell biosensor for label-free detection of GPCR-mediated drug responses in personal cell lines

    NARCIS (Netherlands)

    Hillger, J.M.; Schoop, J.; Boomsma, D.I.; Slagboom, P.E.; IJzerman, A.P.; Heitman, L.H.

    2015-01-01

    Deciphering how genetic variation in drug targets such as G protein-coupled receptors (GPCRs) affects drug response is essential for precision medicine. GPCR signaling is traditionally investigated in artificial cell lines which do not provide sufficient physiological context. Patient-derived cell

  8. Targeting CD4(+) T-Helper Cells Improves the Induction of Antitumor Responses in Dendritic Cell-Based Vaccination

    NARCIS (Netherlands)

    Aarntzen, Erik H. J. G.; de Vries, I. Jolanda M.; Lesterhuis, W. Joost; Schuurhuis, Danita; Jacobs, Joannes F. M.; Bol, Kalijn; Schreibelt, Gerty; Mus, Roel; de Wilt, Johannes H. W.; Haanen, John B. A. G.; Schadendorf, Dirk; Croockewit, Alexandra; Blokx, Willeke A. M.; van Rossum, Michelle M.; Kwok, William W.; Adema, Gosse J.; Punt, Cornelis J. A.; Figdor, Carl G.

    2013-01-01

    To evaluate the relevance of directing antigen-specific CD4(+) T helper cells as part of effective anticancer immunotherapy, we investigated the immunologic and clinical responses to vaccination with dendritic cells (DC) pulsed with either MHC class I (MHC-I)-restricted epitopes alone or both MHC

  9. Direct contact between dendritic cells and bronchial epithelial cells inhibits T cell recall responses towards mite and pollen allergen extracts in vitro

    DEFF Research Database (Denmark)

    Papazian, Dick; Wagtmann, Valery R; Hansen, Soren

    2015-01-01

    Background: Airway epithelial cells (AECs) form a polarized barrier along the respiratory tract. They are the first point of contact with airborne antigens and are able to instruct resident immune cells to mount appropriate immune responses by either soluble or contact-dependent mechanisms....... Objective: We hypothesize that a healthy, polarized epithelial cell layer inhibits inflammatory responses toward allergens to uphold homeostasis. Methods: Using an in vitro co-culture model of the airway epithelium, where a polarized cell layer of bronchial epithelial cells can interact with dendritic cells...... cell recall responses towards Bet v 1, Phl p 5 and Der p 1 in vitro, suggesting that AECs-DC contact in vivo constitute a key element in mucosal homeostasis. This article is protected by copyright. All rights reserved....

  10. Dysregulated cytokine production by dendritic cells modulates B cell responses in the NZM2410 mouse model of lupus.

    Directory of Open Access Journals (Sweden)

    Allison Sang

    Full Text Available The breakdown in tolerance of autoreactive B cells in the lupus-prone NZM2410-derived B6.Sle1.Sle2.Sle3 (TC mice results in the secretion of autoantibodies. TC dendritic cells (DCs enhance B cell proliferation and antibody secretion in a cytokine-dependent manner. However, the specific cytokine milieu by which TC DCs activate B cells was not known. In this study, we compared TC and C57BL/6 (B6 control for the distribution of DC subsets and for their production of cytokines affecting B cell responses. We show that TC DCs enhanced B cell proliferation through the production of IL-6 and IFN-γ, while antibody secretion was only dependent on IL-6. Pre-disease TC mice showed an expanded PDCA1(+ cells prior to disease onset that was localized to the marginal zone and further expanded with age. The presence of PDCA1(+ cells in the marginal zone correlated with a Type I Interferon (IFN signature in marginal zone B cells, and this response was higher in TC than B6 mice. In vivo administration of anti-chromatin immune complexes upregulated IL-6 and IFN-γ production by splenic DCs from TC but not B6 mice. The production of BAFF and APRIL was decreased upon TC DC stimulation both in vitro and in vivo, indicating that these B cell survival factors do not play a role in B cell modulation by TC DCs. Finally, TC B cells were defective at downregulating IL-6 expression in response to anti-inflammatory apoptotic cell exposure. Overall, these results show that the TC autoimmune genetic background induces the production of B cell-modulating inflammatory cytokines by DCs, which are regulated by the microenvironment as well as the interplay between DC.

  11. Dysregulated Cytokine Production by Dendritic Cells Modulates B Cell Responses in the NZM2410 Mouse Model of Lupus

    Science.gov (United States)

    Sang, Allison; Zheng, Ying-Yi; Yin, Yiming; Dozmorov, Igor; Li, Hao; Hsu, Hui-Chen; Mountz, John D.; Morel, Laurence

    2014-01-01

    The breakdown in tolerance of autoreactive B cells in the lupus-prone NZM2410-derived B6.Sle1.Sle2.Sle3 (TC) mice results in the secretion of autoantibodies. TC dendritic cells (DCs) enhance B cell proliferation and antibody secretion in a cytokine-dependent manner. However, the specific cytokine milieu by which TC DCs activate B cells was not known. In this study, we compared TC and C57BL/6 (B6) control for the distribution of DC subsets and for their production of cytokines affecting B cell responses. We show that TC DCs enhanced B cell proliferation through the production of IL-6 and IFN-γ, while antibody secretion was only dependent on IL-6. Pre-disease TC mice showed an expanded PDCA1+ cells prior to disease onset that was localized to the marginal zone and further expanded with age. The presence of PDCA1+ cells in the marginal zone correlated with a Type I Interferon (IFN) signature in marginal zone B cells, and this response was higher in TC than B6 mice. In vivo administration of anti-chromatin immune complexes upregulated IL-6 and IFN-γ production by splenic DCs from TC but not B6 mice. The production of BAFF and APRIL was decreased upon TC DC stimulation both in vitro and in vivo, indicating that these B cell survival factors do not play a role in B cell modulation by TC DCs. Finally, TC B cells were defective at downregulating IL-6 expression in response to anti-inflammatory apoptotic cell exposure. Overall, these results show that the TC autoimmune genetic background induces the production of B cell-modulating inflammatory cytokines by DCs, which are regulated by the microenvironment as well as the interplay between DC. PMID:25093822

  12. Molecular signatures in response to Isoliquiritigenin in lymphoblastoid cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Jae-Eun; Hong, Eun-Jung; Nam, Hye-Young [National Biobank of Korea, Center for Genome Science, Korea National Institute of Health, Korea Centers for Disease Control and Prevention (Korea, Republic of); Hwang, Meeyul [Research Center for Biomedical Resource of Oriental Medicine, Daegu Haany University (Korea, Republic of); Kim, Ji-Hyun [National Biobank of Korea, Center for Genome Science, Korea National Institute of Health, Korea Centers for Disease Control and Prevention (Korea, Republic of); Han, Bok-Ghee, E-mail: bokghee@nih.go.kr [National Biobank of Korea, Center for Genome Science, Korea National Institute of Health, Korea Centers for Disease Control and Prevention (Korea, Republic of); Jeon, Jae-Pil, E-mail: jpjeon@cdc.go.kr [National Biobank of Korea, Center for Genome Science, Korea National Institute of Health, Korea Centers for Disease Control and Prevention (Korea, Republic of)

    2012-10-19

    Highlights: Black-Right-Pointing-Pointer We identified the inhibitory effect of ISL on cell proliferation of LCLs. Black-Right-Pointing-Pointer We found ISL-induced genes and miRNAs through microarray approach. Black-Right-Pointing-Pointer ISL-treated LCLs represented gene expression changes in cell cycle and p53 pathway. Black-Right-Pointing-Pointer We revealed 12 putative mRNA-miRNA functional pairs associated with ISL effect. -- Abstract: Isoliquiritigenin (ISL) has been known to induce cell cycle arrest and apoptosis of various cancer cells. However, genetic factors regulating ISL effects remain unclear. The aim of this study was to identify the molecular signatures involved in ISL-induced cell death of EBV-transformed lymphoblastoid cell lines (LCLs) using microarray analyses. For gene expression and microRNA (miRNA) microarray experiments, each of 12 LCL strains was independently treated with ISL or DMSO as a vehicle control for a day prior to total RNA extraction. ISL treatment inhibited cell proliferation of LCLs in a dose-dependent manner. Microarray analysis showed that ISL-treated LCLs represented gene expression changes in cell cycle and p53 signaling pathway, having a potential as regulators in LCL survival and sensitivity to ISL-induced cytotoxicity. In addition, 36 miRNAs including five miRNAs with unknown functions were differentially expressed in ISL-treated LCLs. The integrative analysis of miRNA and gene expression profiles revealed 12 putative mRNA-miRNA functional pairs. Among them, miR-1207-5p and miR-575 were negatively correlated with p53 pathway- and cell cycle-associated genes, respectively. In conclusion, our study suggests that miRNAs play an important role in ISL-induced cytotoxicity in LCLs by targeting signaling pathways including p53 pathway and cell cycle.

  13. Antibody-independent control of gamma-herpesvirus latency via B cell induction of anti-viral T cell responses.

    Directory of Open Access Journals (Sweden)

    Kelly B McClellan

    2006-06-01

    Full Text Available B cells can use antibody-dependent mechanisms to control latent viral infections. It is unknown whether this represents the sole function of B cells during chronic viral infection. We report here that hen egg lysozyme (HEL-specific B cells can contribute to the control of murine gamma-herpesvirus 68 (gammaHV68 latency without producing anti-viral antibody. HEL-specific B cells normalized defects in T cell numbers and proliferation observed in B cell-/- mice during the early phase of gammaHV68 latency. HEL-specific B cells also reversed defects in CD8 and CD4 T cell cytokine production observed in B cell-/- mice, generating CD8 and CD4 T cells necessary for control of latency. Furthermore, HEL-specific B cells were able to present virally encoded antigen to CD8 T cells. Therefore, B cells have antibody independent functions, including antigen presentation, that are important for control of gamma-herpesvirus latency. Exploitation of this property of B cells may allow enhanced vaccine responses to chronic virus infection.

  14. An Analysis of Natural T Cell Responses to Predicted Tumor Neoepitopes

    Directory of Open Access Journals (Sweden)

    Anne-Mette Bjerregaard

    2017-11-01

    Full Text Available Personalization of cancer immunotherapies such as therapeutic vaccines and adoptive T-cell therapy may benefit from efficient identification and targeting of patient-specific neoepitopes. However, current neoepitope prediction methods based on sequencing and predictions of epitope processing and presentation result in a low rate of validation, suggesting that the determinants of peptide immunogenicity are not well understood. We gathered published data on human neopeptides originating from single amino acid substitutions for which T cell reactivity had been experimentally tested, including both immunogenic and non-immunogenic neopeptides. Out of 1,948 neopeptide-HLA (human leukocyte antigen combinations from 13 publications, 53 were reported to elicit a T cell response. From these data, we found an enrichment for responses among peptides of length 9. Even though the peptides had been pre-selected based on presumed likelihood of being immunogenic, we found using NetMHCpan-4.0 that immunogenic neopeptides were predicted to bind significantly more strongly to HLA compared to non-immunogenic peptides. Investigation of the HLA binding strength of the immunogenic peptides revealed that the vast majority (96% shared very strong predicted binding to HLA and that the binding strength was comparable to that observed for pathogen-derived epitopes. Finally, we found that neopeptide dissimilarity to self is a predictor of immunogenicity in situations where neo- and normal peptides share comparable predicted binding strength. In conclusion, these results suggest new strategies for prioritization of mutated peptides, but new data will be needed to confirm their value.

  15. Empirical evaluation of cell critical volume dose vs. cell response function for pink mutations in tradescantia

    International Nuclear Information System (INIS)

    Varma, M.N.; Bond, V.P.

    1982-01-01

    Microdosimetric spectra for 0.43, 1.8, and 14.7 MeV neutrons, and for 215 kVp x rays and 1250 keV gammas were used in conjunction with relative biological effectiveness (RBE) values for pink mutations in Tradescantia to obtain an effectiveness function (i.e., a cell critical volume dose vs. cell response function). This effectiveness function (or hit size weighting function) provides the probability of inducing a biological effect of interest (in the present study, pink mutations in Tradescantia) as a function of lineal energy density y. In a preliminary analysis the critical value of y above which pink mutations are seen was 4.5 keV/μm, and the value of y at which the probability reaches unity was 115 keV/μm. Idealized but approximate event size distributions for mono-LET particles ranging from 10 to 5000 keV/μm were generated, and these distributions were weighted by the effectiveness function to determine the pink mutation frequencies. Results are compared with measured pink mutation frequencies for 11 keV/μm ( 12 C) and 31 keV/μm ( 20 Ne) ions

  16. In Vitro Use of Autologous Dendritic Cells Improves Detection of T Cell Responses to Hepatitis B Virus (HBV) Antigens

    NARCIS (Netherlands)

    Carotenuto, Patrizia; Artsen, Andre; Niesters, Hubert G.; Osterhaus, Albert D.; Pontesilli, Oscar

    T lymphocyte responses to hepatitis B virus (HBV) core antigen (HBcAg) are vigorous and easily detectable in vitro during recovery from acute hepatitis B but significantly weaker in patients with chronic HBV infection. In contrast, T cell responses to hepatitis B surface antigen (HBsAg) are almost

  17. Noise enhances the rapid nitric oxide production by bone cells in response to fluid shear stress.

    Science.gov (United States)

    Bacabac, Rommel G; Van Loon, Jack J W A; Smit, Theo H; Klein-Nulend, Jenneke

    2009-01-01

    Stochastic resonance is exhibited by many biological systems, where the response to a small stimulus is enhanced with the aid of noise. This intriguing possibility provides a novel paradigm for understanding previously reported osteogenic benefits of low amplitude dynamic loading. However, it is unknown whether bone cell mechanosensitivity is enhanced by noise as an alternative mechanism for an amplified response to small stresses. We studied whether noise of varying intensities enhanced the mechanosensitivity of MC3T3-E1 cells. Nitric oxide (NO) production was measured as the parameter for bone cell activation. Dynamic fluid shear stress stimulated bone cells provided an initial-stress kick was implemented. Without the initial stress-kick bone cells did not release a significant amount of NO demonstrating an essential non-linearity to bone cell responses to stress and the possibility of stochastic resonance in bone cell mechanosensitivity. The rapid NO response of MC3T3-E1 cells to a small periodic fluid shear stress was increased with the addition of noise compared to the response to stress with only noise. This confirms the possibility of stochastic resonance enhancement of NO production by bone cells. Since NO regulate bone formation as well as resorption, our results suggest that noise enhances the activity of bone cells in driving the mechanical adaptation of bone.

  18. CNS cell-type localization and LPS response of TLR signaling pathways [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Gizelle M. McCarthy

    2017-07-01

    Full Text Available Background: Innate immune signaling in the brain has emerged as a contributor to many central nervous system (CNS pathologies, including mood disorders, neurodegenerative disorders, neurodevelopmental disorders, and addiction. Toll-like receptors (TLRs, a key component of the innate immune response, are particularly implicated in neuroimmune dysfunction. However, most of our understanding about TLR signaling comes from the peripheral immune response, and it is becoming clear that the CNS immune response is unique. One controversial aspect of neuroimmune signaling is which CNS cell types are involved. While microglia are the CNS cell-type derived from a myeloid lineage, studies suggest that other glial cell types and even neurons express TLRs, although this idea is controversial. Furthermore, recent work suggests a discrepancy between RNA and protein expression within the CNS. Methods: To elucidate the CNS cell-type localization of TLRs and their downstream signaling molecules, we isolated microglia and astrocytes from the brain of adult mice treated with saline or the TLR4 ligand lipopolysaccharide (LPS. Glial mRNA and protein expression was compared to a cellular-admixture to determine cell-type enrichment. Results: Enrichment analysis revealed that most of the TLR pathway genes are localized in microglia and changed in microglia following immune challenge. However, expression of Tlr3 was enriched in astrocytes, where it increased in response to LPS. Furthermore, attempts to determine protein cell-type localization revealed that many antibodies are non-specific and that antibody differences are contributing to conflicting localization results. Conclusions: Together these results highlight the cell types that should be looked at when studying TLR signaling gene expression and suggest that non-antibody approaches need to be used to accurately evaluate protein expression.

  19. Interleukin-1β Produced in Response to Islet Autoantigen Presentation Differentiates T-Helper 17 Cells at the Expense of Regulatory T-Cells

    Science.gov (United States)

    Bertin-Maghit, Sebastien; Pang, Dimeng; O'Sullivan, Brendan; Best, Shannon; Duggan, Emily; Paul, Sanjoy; Thomas, Helen; Kay, Thomas W.H.; Harrison, Leonard C.; Steptoe, Raymond; Thomas, Ranjeny

    2011-01-01

    OBJECTIVE The effectiveness of tolerizing immunotherapeutic strategies, such as anti-CD40L or dendritic cells (DCs), is greater when administered to young nonobese diabetic (NOD) mice than at peak insulitis. RelBlo DCs, generated in the presence of an nuclear factor-κB inhibitor, induce T-regulatory (Treg) cells and suppress inflammation in a model of rheumatoid arthritis. Interleukin (IL)-1β is overexpressed in humans and mice at risk of type 1 diabetes, dysregulates Treg cells, and accelerates diabetes in NOD mice. We investigated the relationship between IL-1β production and the response to RelBlo DCs in the prediabetic period. RESEARCH DESIGN AND METHODS We injected RelBlo DCs subcutaneously into 4- or 14-week-old NOD mice and tracked the incidence of diabetes and effect on Treg cell function. We measured the expression of proinflammatory cytokines by stimulated splenocytes and unstimulated islets from mice of different ages and strains and proliferative and cytokine responses of T effectors to Treg in vitro. RESULTS Tolerizing RelBlo DCs significantly inhibited diabetes progression when administered to 4-week-old but not 14-week-old mice. IL-1β production by NOD splenocytes and mRNA expression by islets increased from 6 to 16 weeks of age when major histocompatibility complex (MHC)-restricted islet antigen presentation to autoreactive T-cells occurred. IL-1 reduced the capacity of Treg cells to suppress effector cells and promoted their conversion to Th17 cells. RelBlo DCs exacerbated the IL-1–dependent decline in Treg function and promoted Th17 conversion. CONCLUSIONS IL-1β, generated by islet-autoreactive cells in MHC-susceptible mice, accelerates diabetes by differentiating Th17 at the expense of Treg. Tolerizing DC therapies can regulate islet autoantigen priming and prevent diabetes, but progression past the IL-1β/IL-17 checkpoint signals the need for other strategies. PMID:20980463

  20. Restriction of IL-22-producing T cell responses and differential regulation of regulatory T cell compartments by zinc finger transcription factor Ikaros.

    Science.gov (United States)

    Heller, Jennifer J; Schjerven, Hilde; Li, Shiyang; Lee, Aileen; Qiu, Ju; Chen, Zong-Ming E; Smale, Stephen T; Zhou, Liang

    2014-10-15

    Proper immune responses are needed to control pathogen infection at mucosal surfaces. IL-22-producing CD4(+) T cells play an important role in controlling bacterial infection in the gut; however, transcriptional regulation of these cells remains elusive. In this study, we show that mice with targeted deletion of the fourth DNA-binding zinc finger of the transcription factor Ikaros had increased IL-22-producing, but not IL-17-producing, CD4(+) T cells in the gut. Adoptive transfer of CD4(+) T cells from these Ikaros-mutant mice conferred enhanced mucosal immunity against Citrobacter rodentium infection. Despite an intact in vivo thymic-derived regulatory T cell (Treg) compartment in these Ikaros-mutant mice, TGF-β, a cytokine well known for induction of Tregs, failed to induce Foxp3 expression in Ikaros-mutant CD4(+) T cells in vitro and, instead, promoted IL-22. Aberrant upregulation of IL-21 in CD4(+) T cells expressing mutant Ikaros was responsible, at least in part, for the enhanced IL-22 expression in a Stat3-dependent manner. Genetic analysis using compound mutations further demonstrated that the aryl hydrocarbon receptor, but not RORγt, was required for aberrant IL-22 expression by Ikaros-mutant CD4(+) T cells, whereas forced expression of Foxp3 was sufficient to inhibit this aberrant cytokine production. Together, our data identified new functions for Ikaros in maintaining mucosal immune homeostasis by restricting IL-22 production by CD4(+) T cells. Copyright © 2014 by The American Association of Immunologists, Inc.