2,430 research outputs found
T Cell responses to whole SARS Coronavirus in humans
No full textEffective vaccines should confer long-term protection against future outbreaks of severe acute respiratory syndrome (SARS) caused by a novel zoonotic coronavirus (SARS-CoV) with unknown animal reservoirs. We conducted a cohort study examining multiple parameters of immune responses to SARS-CoV infection, aiming to identify the immune correlates of protection. We used a matrix of overlapping peptides spanning whole SARS-CoV proteome to determine T cell responses from 128 SARS convalescent samples by ex vivo IFN-γ ELISPOT assays. Approximately 50% of convalescent SARS patients were positive for T cell responses, and 90% possessed strongly neutralizing Abs. Fifty-five novel T cell epitopes were identified, with spike protein dominating total T cell responses. CD8+ T cell responses were more frequent and of a greater magnitude than CD4+ T cell responses (p < 0.001).
Polychromatic cytometry analysis indicated that the virus-specific T cells from the severe group tended to be a central memory phenotype (CD27+/CD45RO+) with a significantly higher frequency of polyfunctional CD4+ T cells producing IFN-γ, TNF-α, and IL-2, and CD8+ T cells producing IFN-γ, TNF-α, and CD107a (degranulation), as compared with the mild-moderate group. Strong T cell responses correlated significantly (p < 0.05) with higher neutralizing Ab. The serum cytokine profile during acute infection indicated a significant elevation of innate immune responses. Increased Th2 cytokines were observed in patients with fatal infection. Our study provides a roadmap for the immunogenicity of SARS-CoV and types of immune responses that may be responsible for the virus clearance, and should serve as a benchmark for SARS-CoV vaccine design and evaluation
An ecological design philosophy: Randolph T. Hester's design for ecological democracy
No full textThis paper provides an extended review of Randolph T. Hester's Design for ecological democracy (2006). Initially, a brief introduction to the book, its author and the works position in the literature is given, before a broad summary of the book's central argument is provided. The paper then considers the three key themes Hester explores: enabling form, resilient form and impelling form. Through this discussion, linkages are made to wider concepts of ecology in planning practice as well as political and planning theory. The paper concludes that Design for ecological democracy provides not only an engaging philosophy for the future, but also a series of case study‐supported interlinked practical methods for change for the way the built environment is shaped
Author's personal copy Ventral hippocampal molecular pathways and impaired neurogenesis associated with 5-HT 1A and 5-HT 1B receptors disruption in mice
No full texth i g h l i g h t s Deletion of both 5-HT 1A and 5-HT 1B receptors induce higher emotionality in mice. Behavior was associated with 723 differentially expressed genes in the hippocampus Ingenuity analyses revealed gene changes associated with neurogenesis function Cell survival but not proliferation was decreased in the hippocampus of mutant-mice. a r t i c l e i n f o t r a c t The serotonergic system has been widely implicated in stress related psychiatric disorders such as depression and anxiety. Generation of receptor knockout mice has offered a new approach to study processes underlying anxiety. For instance, knockout mice for both 5-HT 1A and 5-HT 1B receptors (5-HT 1A/1B −/− ) display an anxious phenotype, associated with robust physiological and neurochemical changes related to brain serotonin function. As ventral hippocampus is a key region in the mediation and genesis of anxiety, we explored the transcriptome changes induced by the genetic inactivation of these two receptors in 5-HT 1A/1B −/− mice. Dissociation of ventral vs. dorsal hippocampus was confirmed by the over-expression of selective markers in both regions. 723 genes were observed up/down regulated in 5-HT 1A/1B −/− mice. Using Ingenuity, biological networks and signal transduction pathway analysis corresponding to the identified gene revealed putative dysregulation of nervous system development and function, especially genes associated with long-term potentiation and adult neurogenesis (including Bdnf, Camk2a, Camk4, and Klf9). Furthermore, immunohistochemistry experiments studying adult hippocampal neurogenesis in adult 5-HT 1A/1B −/− mice showed a decreased survival, but not proliferation of newborn cells in our model
DNA fusion gene vaccination mobilizes effective anti-leukemic cytotoxic T lymphocytes from a tolerized repertoire
No full textThe majority of known human tumor-associated antigens derive from non-mutated self proteins. T cell tolerance, essential to prevent autoimmunity, must therefore be cautiously circumvented to generate cytotoxic T cell responses against these targets. Our strategy uses DNA fusion vaccines to activate high levels of peptide-specific CTL. Key foreign sequences from tetanus toxin activate tolerance-breaking CD4+ T cell help. Candidate MHC class Ibinding tumor peptide sequences are fused to the C terminus for optimal processing and presentation. To model performance against a leukemia-associated antigen in a tolerized setting, we constructed a fusion vaccine encoding an immunodominant CTL epitopederived from Friend murine leukemia virus gag protein (FMuLVgag) and vaccinated tolerant FMuLVgag-transgenic (gag-Tg) mice. Vaccination with the construct induced epitopespecificIFN-c-producing CD8+ T cells in normal and gag-Tg mice. The frequency and avidity of activated cells were reduced in gag-Tg mice, and no autoimmune injury resulted. However, these CD8+ T cells did exhibit gag-specific cytotoxicity in vitro and in vivo. Also, epitope-specific CTL killed FBL-3 leukemia cells expressing endogenous FMuLVgag antigen and protected against leukemia challenge in vivo. These results demonstrate a simple strategy to engage anti-microbial T cell help to activate epitope-specific polyclonal CD8+ T cell responses from a residual tolerized repertoire
ORIGINAL ARTICLES Influence of paeonol on expression of COX-2 and p27 in HT-29 cells
No full textAuthor contributions: Ye JM performed the majority of experiments and wrote the manuscript, Zhang JB cultured the HT-29 cell line; Deng T designed the study, participated in writing and editing the manuscript
"Put your own house in order first": local perceptions of EU influence on Romani integration policies in the Czech Republic
No full textThis article examines the influence of the European Union (EU) on the development and implementation of Romani integration policy in the Czech Republic from the perspective of those responsible for policy delivery. Based on analysis of key policy documents and research conducted in the Czech Republic, this article first examines how Romani integration became a more important issue during membership negotiations and then discusses how the criticism of the European Commission's Regular Reports was received by those responsible for implementing pro-Romani policies. Finally, the paper assesses how the status of full EU membership has impacted on integration policy. The article concludes that while funding for Romani integration projects has benefitted some groups, the overall impression of the EU is of a remote institution, quick to criticise and unwilling to practise what it preaches
Characterization of the 5-HT(7) receptor as a new therapeutic target for the treatment of pain
No full text[eng] The work showed in this Thesis has been part of the “5-HT7 and neuropathic pain” project in the pharmaceutical company Esteve. Thus, the aim of this Thesis was in line with the goal of the 5-HT7 project at Esteve, focused on drug discovery of 5-HT7 receptor ligands for the treatment of neuropathic pain.
Taking the advantage of a genetic approach (5-HT7 receptor knockout mice) and pharmacological tools (5-HT7 receptor ligands) we investigated at the preclinical level the role of 5-HT7 receptors in nociception and the therapeutic interest of 5-HT7 receptor ligands on pain treatment. The 5-HT7 receptor ligands used were SB-258719 and SB-269970 as 5- HT7 receptor antagonists, and AS-19, MSD-5a, E-55888 and E-57431 as 5-HT7 receptor agonists. E-55888 and E-57431 developed by Esteve were described for the first time and their binding profile and functionality (cAMP formation) were examined. In vivo behavioural studies were performed in mice and rats subjected to nociceptive, inflammatory, neurogenic or neuropathic pain conditions.
Our results showed that 5-HT7 receptors per se were not involved in the nociceptive response to a normally noxius stimulus, although when co-activated together with opioid receptors potentiated the opioidergic analgesic response in nociceptive pain conditions. Indeed, 5-HT7 receptor knockout and wild-type mice showed similar sensitivity to a noxious heat stimulus, and systemic administration of the 5-HT7 receptor agonist E-55888 or the 5-HT7 receptor antagonist SB-258719 showed no effects on acute nociceptive pain using the tail flick test in mice. However, the 5-HT7 receptor agonist E-55888 enhanced the morphine-induced analgesia in this test and this potentiation was significantly reversed by the 5-HT7 receptor antagonist SB-258719.
On the other hand, we studied the role of 5-HT7 receptors in pain conditions involving central sensitization. We showed that the 5-HT7 receptor agonists AS-19, E-55888 and E-57431 inhibited capsaicin-induced mechanical hypersensitivity, nerve injury-induced mechanical and thermal hypersensitivity and reduced the phase II formalin-induced nociception. In contrast, a promotion of mechanical hypersensitivity after administration of the 5-HT7 receptor antagonists SB-258719 and SB-269970 was observed. This reduction of hypersensitivity by agonists and promotion of hypersensitivity by antagonists was reversed by antagonists and agonists, respectively. It is important to note that effectiveness of the treatment with 5-HT7 receptor agonists was not masked by non-specific motor effects, as no motor incoordination was found in the rota-rod test at the doses used and no tolerance to the effect was evidenced following repeated systemic administrations.
The antinociceptive effects exerted by systemic 5-HT7 receptor agonists seemed to be mediated by 5-HT7 receptors localized in the spinal cord. We found that intrathecal administration of the 5-HT7 receptor agonist E-57431 inhibited mechanical hypersensitivity secondary to capsaicin injection and nerve injury-induced mechanical hypersensitivity. In contrast, a pronociceptive effect was observed after local intraplantar injection of the selective 5-HT7 receptor agonist E-57431 in the capsaicin model. Thus, the antinociceptive role mediated by central 5-HT7 receptors seems to predominate over their pronociceptive role at the periphery, resulting in an overall analgesic effect when 5-HT7 receptor agonists are administered by a systemic route. In line with these spinal antinociceptive effects, we found an increased immunoreactivity of 5-HT7 receptors in the ipsilateral dorsal horn of the spinal cord in sciatic nerve-injured mice. This increased 5-HT7 receptor expression in the dorsal horn induced by nerve injury could represent a physiological, compensatory, protective spinal mechanism relevant to the control of nociception in neuropathic pain conditions.
We observed that 5-HT7 receptors co-localized with GABAergic neurons in the ipsilateral dorsal horn of the spinal cord. Therefore, we suggested that an indirect action through activation of 5-HT7 receptors localized on inhibitory interneurons may be responsible of the antinociceptive effects observed after administration of 5-HT7 receptor agonists.
Finally, using 5-HT7 receptor knockout mice, we demonstrated that the 5-HT7 receptor agonists AS-19, E-55888 and E-57431 exerted in vivo target specific effects on pain control. We observed that systemic administration of these 5-HT7 receptor agonists reduced phase II formalin-induced nociception in wild-type but not in 5-HT7 receptor knockout mice. Taken together, these data add a piece of knowledge to the role played by 5-HT7 receptors in the control of pain and point to a new potential use of 5-HT7 receptor agonists as promising drugs for the treatment of neuropathic pain.[cat] El treball mostrat en aquesta Tesi ha format part del projecte “5-HT7 i dolor neuropàtic” de l’empresa farmacèutica Esteve. Per tant, els objectius d’aquesta Tesi estan en línea amb l’objectiu del projecte 5-HT7 d’Esteve focalitzat en el descobriment de compostos amb afinitat pel receptor 5-HT7 pel tractament del dolor neuropàtic.
A partir de l’aproximació genètica amb l’ús de ratolins genoanul•lats pel receptor 5-HT7 i d’eines farmacològiques com compostos amb afinitat pel receptor 5-HT7, vàrem investigar a nivell preclínic el paper dels receptors 5-HT7 en el dolor i l’interès terapèutic dels lligands del receptor 5-HT7 en dolor. Entre els compostos utilitzats hi trobem el SB-258719 i el SB- 269970 com antagonistes pel receptor 5-HT7, i el AS-19, MSD-5a, E-55888 i el E-57431 com agonistes pel receptor 5-HT7. E-55888 i E-57431 van ser descrits per primera vegada i es va estudiar el seu perfil d’afinitat, selectivitat i funcionalitat. Es van realitzar estudis de comportament in vivo en ratolí i rata sotmesos a unes condicions de dolor nociceptiu, inflamatori, neurogènic i neuropàtic.
Els nostres resultats van mostrar que els receptors 5-HT7 per si mateixos no estaven implicats en la resposta a un estímul nociu, mentre que sí interaccionen amb el sistema opiodèrgic en condicions de dolor nociceptiu. Ratolins genoanul•lats pel receptor 5-HT7 van mostrar la mateixa sensibilitat enfront un estímul tèrmic nociu. L’administració sistèmica de l’agonista del receptor 5-HT7 E-55888 o l’antagonista del receptor 5-HT7 SB-258719 no van mostrar efecte en el dolor agut nociceptiu. En canvi, vàrem observar que els efectes antinociceptius de la morfina per via oral obtinguts en resposta a l’estímul tèrmic nociu del tail-flick, eren potenciats amb l’administració sistèmica conjunta de l’agonista del receptor 5-HT7 E-55888. Aquesta potenciació va ser revertida al mateix temps amb la coadministració de l’antagonista del receptor 5-HT7 SB-258719.
També vàrem estudiar el paper dels receptors 5-HT7 en condicions de dolor i sensibilització central. L’administració sistèmica d’agonistes selectius pel receptor 5-HT7 inhibia la hipersensibilitat mecànica induïda per capsaicina, la hipersensibilitat mecànica i tèrmica induïda per la lesió del nervi ciàtic, i el dolor induït per la fase II del model de la formalina. Això suggeria la implicació dels receptors 5-HT7 en condicions de sensibilització central. En canvi, es va observar una promoció de la hipersensibilitat mecànica amb els antagonistes del receptor 5-HT7. Tant els efectes dels agonistes i antagonistes del receptor 5-HT7 es van revertir amb la coadministració d’antagonistes i agonistes del receptor 5-HT7, respectivament. És important senyalar que les dosis amb eficàcia analgèsica dels agonistes del receptor 5-HT7 eren inferior a les dosis que produïen efectes adversos amb el test del rota-rod. A més, no es va observar tolerància de l’efecte analgèsic amb l’administració de dosis repetides de l’agonista del receptor 5-HT7 E-57431.
L’efecte analgèsic obtingut amb l’administració sistèmica dels agonistes pel receptor 5-HT7 semblava ser degut a l’activació de receptors 5-HT7 localitzats a nivell espinal. Vàrem trobar que l’administració intratecal de l’agonista del receptor 5-HT7 E-57431 inhibia la hipersensibilitat mecànica secundària a la injecció de capsaicina i la induïda per la lesió del nervi ciàtic. En canvi, es va observar un increment de la hipersensibilitat mecànica induïda per capsaicina amb la injecció local intraplantar de l’agonista del receptor 5-HT7 E-57431. En resum, l’efecte antinociceptiu obtingut a través de l’activació dels receptors 5-HT7 a nivell espinal sembla predominar respecte l’efecte pronociceptiu de la perifèria quan s’administra sistèmicament un agonista pel receptor 5-HT7. En línea amb l’efecte antinociceptiu observat a nivell espinal, vàrem trobar un increment de la immunoreactivitat dels receptors 5-HT7 de l’asta dorsal de la medul•la espinal en ratolins amb lesió del nervi ciàtic. Aquest increment en l’expressió del receptor 5-HT7 en l’asta dorsal induït per la lesió del nervi podria representar un mecanisme espinal fisiològic, compensatori i protector rellevant pel control de dolor en condicions de dolor neuropàtic.
Vàrem observar una col•localització dels receptors 5-HT7 en cèl•lules GABAèrgiques. En aquest sentit, l’activació dels receptors 5-HT7 col•localitzats en interneurones inhibitòries de l’asta dorsal de la medul•la espinal podria ser el mecanisme d’acció implicat en els efectes antinociceptius observats amb els agonistes del receptor 5-HT7.
Finalment, utilitzant ratolins genoanul•lats pel receptor 5-HT7, vàrem demostrar que els agonistes pel receptor 5-HT7 AS-19, E-55888 i E-57431 exercien efectes diana específics em el control de dolor. L’administració subcutània d’aquests agonistes pel receptor 5-HT7 reduïren la nocicepció induïda per formalina de la fase II en ratolins salvatges però no en ratolins genoanul•lats, suggerint una especificitat dels efectes obtinguts in vivo a través del receptor 5-HT7.
Aquest treball aporta un millor coneixement del paper del receptor 5-HT7 en el control del dolor i suggereix un nou potencial ús terapèutic dels agonistes pel receptor 5-HT7 com a fàrmacs prometedors pel tractament del dolor neuropàtic
Gestão de benefícios na etapa do projeto de empreendimentos para a saúde: Managing benefits in the design of healthcare facilities in the UK
No full textProposal: The healthcare system in the United kingdomis passing through transformation and change for improvement and innovation. Within this context, healthcare facilities are being developed in a complex multi-stakeholder environment, which usually have diverse and conflicting interests and no experience in design. This contributes for difficulties in managing their requirements, leading to low quality of design. Aiming to contribute for the management of these projects, a benefits management model is being developed and introduced in the sector by the University of Salford. This model intends to support the consideration of different stakeholders’ expectations in project development. In this sense, the aim of this paper was to bring discussions about how such approach could be adopted to support the design process within those projects. This research was developed through the participation on the model implementation, in addition to a literature review on benefits management and design approaches that are used in the UK and that could support benefits management in the design process. Main findings are related to a need for anticipating the participation of designers on project development and straightening the relationship between designers and decision makers. As a result, recommendations could be done to support benefits management throughout the design process. Keywords: Design process, project management, benefits realisatio
HT 20
No full textMiniature 1 x ¾. The signee on the certificates seems to be K Andes. Each volume has about 30 to 36 pages after an individual T of C. There are about twelve fables in each volume. No illustrations.Heirloom Tradition
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