The impact of DM on MHC class II–restricted antigen presentation can be altered by manipulation of MHC–peptide kinetic stability

DM edits the peptide repertoire presented by major histocompatibility complex class II molecules by professional antigen-presenting cells (APCs), favoring presentation of some peptides over others. Despite considerable research by many laboratories, there is still significant uncertainty regarding the biochemical attributes of class II–peptide complexes that govern their susceptibility to DM editing. Here, using APCs that either do or do not express DM and a set of unrelated antigens, we found that the intrinsic kinetic stability of class II–peptide complexes is tightly correlated with the effects of DM editing within APCs. Furthermore, through the use of kinetic stability variants of three independent peptides, we demonstrate that increasing or decreasing the kinetic stability of class II–peptide complexes causes a corresponding alteration in DM editing. Finally, we show that the spontaneous kinetic stability of class II complexes correlates directly with the efficiency of presentation by DM+ APCs and the immunodominance of that class II–peptide complex during an immune response. Collectively, these results suggest that the pattern of DM editing in APCs can be intentionally changed by modifying class II–peptide interactions, leading to the desired hierarchy of presentation on APCs, thereby promoting recruitment of CD4 T cells specific for the preferred peptides during an immune response

Imprinting and Editing of the Human CD4 T Cell Response to Influenza Virus

Immunity to influenza is unique among pathogens, in that immune memory is established both via intermittent lung localized infections with highly variable influenza virus strains and by intramuscular vaccinations with inactivated protein-based vaccines. Studies in the past decades have suggested that the B cell responses to influenza infection and vaccination are highly biased by an individual's early history of influenza infection. This reactivity likely reflects both the competitive advantage that memory B cells have in an immune response and the relatively limited diversity of epitopes in influenza hemagglutinin that are recognized by B cells. In contrast, CD4 T cells recognize a wide array of epitopes, with specificities that are heavily influenced by the diversity of influenza antigens available, and a multiplicity of functions that are determined by both priming events and subsequent confrontations with antigens. Here, we consider the events that prime and remodel the influenza-specific CD4 T cell response in humans that have highly diverse immune histories and how the CD4 repertoire may be edited in terms of functional potential and viral epitope specificity. We discuss the consequences that imprinting and remodeling may have on the potential of different human hosts to rapidly respond with protective cellular immunity to infection. Finally, these issues are discussed in the context of future avenues of investigation and vaccine strategies

integration of an organic rankine cycle and a photovoltaic unit for micro scale chp applications in the residential sector

Abstract The purpose of this work is to analyse the performance of a novel system for combined heat and power (CHP) generation in small-scale applications. The system is based on an Organic Rankine Cycle (ORC) fed with biomass and a photovoltaic (PV) unit. The ORC and PV sub-systems operate in parallel to produce the required electrical energy. A preliminary investigation is performed to define the proper size of the photovoltaic unit. Afterwards, the analysis is focused on the hybrid system and a comparison between the two configurations is carried out. This work demonstrates the potential for integrating biomass and solar energy resources: during daylight, solar radiation is significant and the ORC system can be switched off or operated at partial load. Furthermore, the adoption of biomass makes it possible to overcome the intermittency of solar resource, increase the self-consumed electrical energy, and produce thermal energy, thereby saving natural gas for heating purposes

¿Quién y cómo se construye el ‘nosotros’? La construcción narrativa del ‘nosotros catalán’ a partir de los acontecimientos del 1714

This paper is based on an empirical research conducted in Catalonia. The aim of the study was to analyse the possible links between students’ ethnicity and identities and the ways in which they narrate the history of the communities they live in. By means of questionnaires (340) and interviews (14), a group of 13-16 years old students were required to narrate the historical events of the 11th of September of 1714 which are commemorated in the Catalan national day. Data was analysed through narrative analyses and the results were compared using statistical tests. The results suggest that, in their historical narratives, students construct a homogeneous ‘Catalan we’ that can be exclude students from minority linguistic, ethnic or national communities. We conclude the paper by discussing the implications of these results in history and social studies education in the Catalan community and elsewhere

Interventions to Promote Cancer Awareness and Early Presentation: Systematic Review

Low cancer awareness contributes to delay in presentation for cancer symptoms and may lead to delay in cancer diagnosis. The aim of this study was to review the evidence for the effectiveness of interventions to raise cancer awareness and promote early presentation in cancer to inform policy and future research. We searched bibliographic databases and reference lists for randomised controlled trials of interventions delivered to individuals, and controlled or uncontrolled studies of interventions delivered to communities. We found some evidence that interventions delivered to individuals modestly increase cancer awareness in the short term and insufficient evidence that they promote early presentation. We found limited evidence that public education campaigns reduce stage at presentation of breast cancer, malignant melanoma and retinoblastoma

Oral activated charcoal prevents experimental cerebral malaria in mice and in a randomized controlled clinical trial in man did not interfere with the pharmacokinetics of parenteral artesunate.

BACKGROUND: Safe, cheap and effective adjunct therapies preventing the development of, or reducing the mortality from, severe malaria could have considerable and rapid public health impact. Oral activated charcoal (oAC) is a safe and well tolerated treatment for acute poisoning, more recently shown to have significant immunomodulatory effects in man. In preparation for possible efficacy trials in human malaria, we sought to determine whether oAC would i) reduce mortality due to experimental cerebral malaria (ECM) in mice, ii) modulate immune and inflammatory responses associated with ECM, and iii) affect the pharmacokinetics of parenteral artesunate in human volunteers. METHODS/PRINCIPAL FINDINGS: We found that oAC provided significant protection against P. berghei ANKA-induced ECM, increasing overall survival time compared to untreated mice (p<0.0001; hazard ratio 16.4; 95% CI 6.73 to 40.1). Protection from ECM by oAC was associated with reduced numbers of splenic TNF(+) CD4(+) T cells and multifunctional IFNgamma(+)TNF(+) CD4(+) and CD8(+) T cells. Furthermore, we identified a whole blood gene expression signature (68 genes) associated with protection from ECM. To evaluate whether oAC might affect current best available anti-malarial treatment, we conducted a randomized controlled open label trial in 52 human volunteers (ISRCTN NR. 64793756), administering artesunate (AS) in the presence or absence of oAC. We demonstrated that co-administration of oAC was safe and well-tolerated. In the 26 subjects further analyzed, we found no interference with the pharmacokinetics of parenteral AS or its pharmacologically active metabolite dihydroartemisinin. CONCLUSIONS/SIGNIFICANCE: oAC protects against ECM in mice, and does not interfere with the pharmacokinetics of parenteral artesunate. If future studies succeed in establishing the efficacy of oAC in human malaria, then the characteristics of being inexpensive, well-tolerated at high doses and requiring no sophisticated storage would make oAC a relevant candidate for adjunct therapy to reduce mortality from severe malaria, or for immediate treatment of suspected severe malaria in a rural setting. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN64793756

Brazilian Adolescents Infected by HIV: Epidemiologic Characteristics and Adherence to Treatment

Over the last 3 decades since the first AIDS cases appeared, we have witnessed great progress in therapeutic methodologies that have transformed the evolution of the disease from debilitating and fatal, into chronic and controllable. HIV-infected children are arriving at adolescence and bringing specific challenges, not only to themselves, but also to their families and caregivers. This retrospective study sets forth epidemiological and treatment characteristics of 46 HIV-infected adolescents followed in a specialized university service relating said characteristics to therapy adherence assessed through a combination of three indirect methods. Therapy adherence did not reveal any association with either epidemiologic characteristics regarding age, sex, school level, household composition, age at diagnosis, mode of infection, knowledge of diagnosis, treatment time, or initial antiretroviral scheme. Patients with good therapy adherence presented lower viral load and used a smaller number of antiretroviral schemes