Functional avidity of tumor antigen-specific CTL recognition directly correlates with the stability of MHC/peptide multimer binding to TCR.

Avidity of Ag recognition by tumor-specific T cells is one of the main parameters that determines the potency of a tumor rejection Ag. In this study we show that the relative efficiency of staining of tumor Ag-specific T lymphocytes with the corresponding fluorescent MHC class I/peptide multimeric complexes can considerably vary with staining conditions and does not necessarily correlate with avidity of Ag recognition. Instead, we found a clear correlation between avidity of Ag recognition and the stability of MHC class I/peptide multimeric complexes interaction with TCR as measured in dissociation kinetic experiments. These findings are relevant for both identification and isolation of tumor-reactive CTL.

Phase I safety and immunogenicity trial of Plasmodium vivax CS derived long synthetic peptides adjuvanted with montanide ISA 720 or montanide ISA 51.

We assessed the safety, tolerability, and immunogenicity of a mixture of three synthetic peptides derived from the Plasmodium vivax circumsporozoite protein formulated in Montanide ISA 720 or Montanide ISA 51. Forty healthy malaria-naive volunteers were allocated to five experimental groups (A-E): four groups (A-D) were immunized intramuscularly with 50 and 100 μg/dose injections of a mixture of N, R, and C peptides formulated in the two different adjuvants at 0, 2, and 4 months and one group was administered placebo. Vaccines were immunogenic, safe, well tolerated, and no serious adverse events related to the vaccine occurred. Seroconversion occurred in > 90% of the vaccines and antibodies recognized the sporozoite protein on immunofluorescent antibody test. Vaccines in Montanide ISA 51 showed a higher sporozoite protein recognition and interferon production. Results encourage further testing of the vaccine protective efficacy.

HLA-C cell surface expression and control of HIV/AIDS correlate with a variant upstream of HLA-C.

A variant 35 kb upstream of the HLA-C gene (-35C/T) was previously shown to associate with HLA-C mRNA expression level and steady-state plasma HIV RNA levels. We genotyped this variant in 1,698 patients of European ancestry with HIV. Individuals with known seroconversion dates were used for disease progression analysis and those with longitudinal viral load data were used for viral load analysis. We further tested cell surface expression of HLA-C in normal donors using an HLA-C-specific antibody. We show that the -35C allele is a proxy for high HLA-C cell surface expression, and that individuals with high-expressing HLA-C alleles progress more slowly to AIDS and control viremia significantly better than individuals with low HLA-C expressing alleles. These data strongly implicate high HLA-C expression levels in more effective control of HIV-1, potentially through better antigen presentation to cytotoxic T lymphocytes or recognition and killing of infected cells by natural killer cells.

Acknowledgment and health in police officers

The way colleagues and supervisors acknowledge specific contribution and efforts of individuals is crucial for occupational mental health and well being. It contributes to improve the self image of employees and it gives a sense to the activities performed. We carried out a study about occupational health in police officers with a special emphasis on acknowledgment and reward. A questionnaire was sent to 1000 police officers working for a cantonal administration in Switzerland. In total, 695 participants answered the questionnaire. We used the French version of the Langner's questionnaire on psychiatric symptoms to identify cases characterized by potential mental health problems. Multiple choice items (6 modalities ranging from "not at all" to "tremendously") to measure acknowledgment were used. Answers were later dichotomized (low annoyance- high annoyance). Questions we used are: "Do you feel annoyed due to a lack of support and attention from your supervisors?" "Do you feel annoyed because the authorities (politics, judges, etc.) have a low consideration of your occupation?" "Do you feel annoyed due to a low appreciation by the public?" and "Do you feel annoyed due to a lack of acknowledgment by the hierarchy?". The score for psychiatric symptoms was high for 86 police officers for whom health might be at risk. Acknowledgment aspects associated with a high score for psychiatric symptoms are : high annoyance due to a lack of support and attention from supervisors (odds ratio [OR] 3.2, 95% confidence interval [CI] 2.0 to 5.1), high annoyance because authorities seems to have a low consideration for police officers (OR 2.7, 95% CI 1.7 to 4.3), high annoyance due to a low appreciation by the public (OR 1.8, 95% CI 1.2 to 2.9), and high annoyance due to a lack of acknowledgment by the hierarchy (OR 3.0, 95% CI 1.9 to 4.8). Preserving mental health in occupations characterized by high emotional demand is challenging. The results from our study suggest that appropriate acknowledgment might contribute to the prevention of mental health problems. Further research should address a potential causal relation of acknowledgment on mental health.

Immune responses to airborne fungi and non-invasive airway diseases.

Inhalation of fungal particles is a ubiquitous way of exposure to microorganisms during human life; however, this exposure may promote or exacerbate respiratory diseases only in particular exposure conditions and human genetic background. Depending on the fungal species and form, fungal particles can induce symptoms in the lung by acting as irritants, aeroallergens or pathogens causing infection. Some thermophilic species can even act in all these three ways (e.g. Aspergillus, Penicillium), mesophilic species being only involved in allergic and/or non-allergic airway diseases (e.g. Cladosporium, Alternaria, Fusarium). The goal of the present review is to present the current knowledge on the interaction between airborne fungal particles and the host immune system, to illustrate the differences of immune sensing of different fungal species and to emphasise the importance of conducting research on non-conventional mesophilic fungal species. Indeed, the diversity of fungal species we inhale and the complexity of their composition have a direct impact on fungal particle recognition and immune system decision to tolerate or respond to those particles, eventually leading to collateral damages promoting airway pathologies.

Benchmarking for routines and organizational knowledge

We use best practice benchmarking rationales to propose a dynamic research design that accounts for the endogenous components of across-firms heterogeneous routines to study changes in performance and their link to organizational knowledge investments. We thus contribute to the operationalization of management theoretical frameworks based on resources and routines. The research design employs frontier measures that provide industry-level benchmarking in organizational settings, and proposes some new indicators for firm-level strategic benchmarking. A profit-oriented analysis of the U.S. technology industry during 2000-2011 illustrates the usefulness of our design. Findings reveal that industry revival following economic distress comes along with wider gaps between best and worst performers. Second stage analyses show that increasing intangibles stocks is positively associated with fixed target benchmarking, while enhancing R&D spending is linked to local frontier progress. The discussion develops managerial interpretations of the benchmarking measures that are suitable for control mechanisms and reward systems.

Startegy selection during exploratory behavior: sex differences, uncertainty and risk managment

This study deals with the psychological processes underlying the selection of appropriate strategy during exploratory behavior. A new device was used to assess sexual dimorphisms in spatial abilities that do not depend on spatial rotation, map reading or directional vector extraction capacities. Moreover, it makes it possible to investigate exploratory behavior as a specific response to novelty that trades off risk and reward. Risk management under uncertainty was assessed through both spontaneous searching strategies and signal detection capacities. The results of exploratory behavior, detection capacities, and decision-making strategies seem to indicate that women's exploratory behavior is based on risk-reducing behavior while men behavior does not appear to be influenced by this variable. This difference was interpreted as a difference in information processing modifying beliefs concerning the likelihood of uncertain events, and therefore influencing risk evaluation.

Vaccination with a recombinant protein encoding the tumor-specific antigen NY-ESO-1 elicits an A2/157-165-specific CTL repertoire structurally distinct and of reduced tumor reactivity than that elicited by spontaneous immune responses to NY-ESO-1-expressing Tumors.

In a recent vaccination trial assessing the immunogenicity of an NY-ESO-1 (ESO) recombinant protein administered with Montanide and CpG, we have obtained evidence that this vaccine induces specific cytolytic T lymphocytes (CTL) in half of the patients. Most vaccine-induced CTLs were directed against epitopes located in the central part of the protein, between amino acids 81 and 110. This immunodominant region, however, is distinct from another ESO CTL region, 157-165, that is a frequent target of spontaneous CTL responses in A2+ patients bearing ESO tumors. In this study, we have investigated the CTL responses to ESO 157-165 in A2+ patients vaccinated with the recombinant protein. Our data indicate that after vaccination with the protein, CTL responses to ESO 157-165 are induced in some, but not all, A2+ patients. ESO 157-165-specific CTLs induced by vaccination with the ESO protein were functionally heterogeneous in terms of tumor recognition and often displayed decreased tumor reactivity as compared with ESO 157-165-specific CTLs isolated from patients with spontaneous immune responses to ESO. Remarkably, protein-induced CTLs used T-cell receptors similar to those previously isolated from patients vaccinated with synthetic ESO peptides (Vbeta4.1) and distinct from those used by highly tumor-reactive CTLs isolated from patients with spontaneous immune responses (Vbeta1.1, Vbeta8.1, and Vbeta13.1). Together, these results demonstrate that vaccination with the ESO protein elicits a repertoire of ESO 157-165-specific CTLs bearing T-cell receptors that are structurally distinct from those of CTLs found in spontaneous immune responses to the antigen and that are heterogeneous in terms of tumor reactivity, being often poorly tumor reactive.

Projecting the self to past and future in mental time

Introduction: Human experience takes place in the line of mental-time (MT) created through imagination of oneself in different time-points in past or future (self-projection in time). Here we manipulated self-projection in MT not only with respect to one's life-events but also with respect to one's faces from different past and future time-points. Methods: We here compared MTT with respect to one's facial images from different time points in past and future (study 1: MT-faces) as well as with respect to different past and future life events (study 2: MT-events). Participants were asked to make judgments about past and future face images and past and future events from three different time-points: the present (Now), eight years earlier (Past) or eight years later (Future). In addition, as a control task participants were asked to make recognition judgments with respect to faces and memory-related judgments with respect to events without changing their habitual self-location in time. Behavioral measures and functional magnetic resonance imaging (fMRI) activity after subtraction of recognition and memory related activities show both absolute MT and relative MT effects for faces and events, signifying a fundamental brain mechanism of MT, disentangled from episodic memory functions. Results: Behavioural and event-related fMRI activity showed three independent effects characterized by (1) similarity between past recollection and future imagination, (2) facilitation of judgments related to the future as compared to the past, and (3) facilitation of judgments related to time-points distant from the present. These effects were found with respect to faces and events suggesting that the brain mechanisms of MT are independent of whether actual life episodes have to be re-/pre-experienced and recruited a common cerebral network including the medial-temporal, precuneus, inferior-frontal, temporo-parietal, and insular cortices. Conclusions: These behavioural and neural data suggest that self-projection in time is a crucial aspect of MT, relying on neural structures encoding memory, mental imagery, and self. Furthermore our results emphasize the idea that mental temporal processing is more strongly directed to future prediction than to past recollection.

Eight years experience from a skeletal dysplasia referral center in a tertiary hospital in Southern India: A model for the diagnosis and treatment of rare diseases in a developing country.

We report on a series of 514 consecutive diagnoses of skeletal dysplasia made over an 8-year period at a tertiary hospital in Kerala, India. The most common diagnostic groups were dysostosis multiplex group (n = 73) followed by FGFR3 (n = 49) and osteogenesis imperfecta and decreased bone density group (n = 41). Molecular confirmation was obtained in 109 cases. Clinical and radiographic evaluation was obtained in close diagnostic collaboration with expert groups abroad through Internet communication for difficult cases. This has allowed for targeted biochemical and molecular studies leading to the correct identification of rare or novel conditions, which has not only helped affected families by allowing for improved genetic counseling and prenatal diagnosis but also resulted in several scientific contributions. We conclude that (1) the spectrum of genetic bone disease in Kerala, India, is similar to that of other parts of the world, but recessive entities may be more frequent because of widespread consanguinity; (2) prenatal detection of skeletal dysplasias remains relatively rare because of limited access to expert prenatal ultrasound facilities; (3) because of the low accessibility to molecular tests, precise clinical-radiographic phenotyping remains the mainstay of diagnosis and counseling and of gatekeeping to efficient laboratory testing; (4) good phenotyping allows, a significant contribution to the recognition and characterization of novel entities. We suggest that the tight collaboration between a local reference center with dedicated personnel and expert diagnostic networks may be a proficient model to bring current diagnostics to developing countries. © 2014 Wiley Periodicals, Inc.

The major histocompatibility complex and perfumers' descriptions of human body odors

The MHC (major histocompatibility complex) is a group of genes that play a crucial role in immune recognition and in tolerance of tissue grafting. The MHC has also been found to influence body odors, body odor preferences, and mate choice in mice and humans. Here we test whether verbal descriptions of human body odors can be linked to the MHC. We asked 45 male students to live as odor neutral as possible for two consecutive days and to wear a T-shirt during the nights. The odors of these T-shirts were then described by five evaluators: two professional perfumers and three laymen. One of the perfumers was able to describe the T-shirt odors in such a way that some of the allelic specificity of the MHC was significantly revealed (after Bonferroni correction for multiple testing). This shows that, although difficult, some people are able to describe MHCcorrelated body odor components.

Purpura of the face and neck: an atypical clinical presentation revealing a hepatosplenic T cell lymphoma

BACKGROUND: Hepatosplenic T cell lymphoma (HSTL) is a rare but very aggressive peripheral T cell lymphoma whose initial silent clinical presentation unfortunately delays the diagnosis and worsens the prognosis of patient survival. Efforts should be aimed at early recognition and treatment. METHODS: We describe a case of a 62-year-old woman who presented at our clinic with a non-palpable purpuric eruption of the face. Investigations revealed thrombocytopenia with hepatosplenomegaly, which showed rapid progression together with accentuation of the purpura. Two months later, a bone marrow biopsy revealed the diagnosis of a HSTL. RESULTS: The patient received six cycles of CHOP chemotherapy (vincristine, cyclophosphamide, doxorubicin, methylprednisolone) followed by a well-tolerated autologous bone marrow graft. Normalization of the platelet count resulted in regression of the purpuric rash. CONCLUSION: To our knowledge, this is the first report of a facial thrombocytopenic purpura as the inaugural symptom of HSTL. It emphasizes the privileged position of the dermatologist for early recognition of potentially lethal HSTL.

Defining and searching for structural motifs using DeepView/Swiss-PdbViewer.

BACKGROUND: Today, recognition and classification of sequence motifs and protein folds is a mature field, thanks to the availability of numerous comprehensive and easy to use software packages and web-based services. Recognition of structural motifs, by comparison, is less well developed and much less frequently used, possibly due to a lack of easily accessible and easy to use software. RESULTS: In this paper, we describe an extension of DeepView/Swiss-PdbViewer through which structural motifs may be defined and searched for in large protein structure databases, and we show that common structural motifs involved in stabilizing protein folds are present in evolutionarily and structurally unrelated proteins, also in deeply buried locations which are not obviously related to protein function. CONCLUSIONS: The possibility to define custom motifs and search for their occurrence in other proteins permits the identification of recurrent arrangements of residues that could have structural implications. The possibility to do so without having to maintain a complex software/hardware installation on site brings this technology to experts and non-experts alike.

Rewarding civil service performance through team bonuses : findings, analysis and recommendations

Performance-related pay within public organizations is continuing to spread. Although it can help to strengthen an entrepreneurial spirit in civil servants, its implementation is marred by technical, financial, managerial and cultural problems. This article identifies an added problem, namely the contradiction that exists between a managerial discourse that emphasizes the team and collective performance, on the one hand, and the use of appraisal and reward tools that are above all individual, on the other. Based on an empirical survey carried out within Swiss public organizations, the analysis shows that the team is currently rarely taken into account and singles out the principal routes towards an integrated system for the management and rewarding of civil servants.

Juvenile Crime Prevention Community Grand Fund Outcomes Report and FY2002 Juvenile Justice Youth Development Program Summary, January 2002

This document contains two related, but separate reports. The Juvenile Crime Prevention Community Grant Fund Outcomes Report is a summary of outcomes from services and activities funded through the Juvenile Crime Prevention Community Grant Fund in FY2001. The Juvenile Justice Youth Development Program Summary describes Iowa communities’ current prevention and sanction programs supported with funding from the Division of Criminal and Juvenile Justice Planning (CJJP) during FY2002. The material in Juvenile Crime Prevention Community Grant Fund Outcomes Report is presented in response to a legislative mandate to report specific prevention outcomes for the community Grant Fund. It includes a brief description of a Youth Development Results Framework established by the Iowa Collaboration for Youth Development. Outcomes are reported using this results framework, which was developed by a number of state agencies as a common tool for various state programs involving youth development related planning and funding processes. Included in this report is a description of outcomes from the prevention activities funded, all or in part, by the Community Grant Fund, as reported by local communities. The program summaries presented in the Juvenile Justice Youth Development Program Summary provide an overview of local efforts to implement their 2002 Juvenile Justice Youth Development plans and include prevention and sanction programs funded through the combined resources of the State Community Grant Fund and the Federal Title V Prevention, Juvenile Justice & Delinquency Prevention Act Formula Grant and Juvenile Accountability Incentive Block Grant programs. These combined funds are referred to in this document as the Juvenile Justice Youth Development (JJYD) funds. To administer the JJYD funds, including funds from the Community Grant Fund, CJJP partners with local officials to facilitate a community planning process that determines the communities’ priorities for the use of the funds. The local planning is coordinated by the Iowa’s Decategorization Boards (Decats). These local officials and/or their staff have been leaders in providing oversight or staff support to a variety of local planning initiatives (e.g. child welfare, Comprehensive Strategy Pilot Projects, Empowerment, other) and bring child welfare and community planning experience to the table for the creation of comprehensive community longterm planning efforts. The allocation of these combined funds and the technical assistance received by the Decats from CJJP is believed to have helped enhance both child welfare and juvenile justice efforts locally and has provided for the recognition and establishment of connections for joint child welfare/juvenile justice planning. The allocation and local planning approach has allowed funding from CJJP to be “blended” or “braided” with other local, state, and federal dollars that flow to communities as a result of their local planning responsibilities. The program descriptions provided in this document reflect services and activities supported with JJYD funds. In many cases, however, additional funding sources have been used to fully fund the programs. Most of the information in this document’s two reports was submitted to CJJP by the communities through an on- line planning and reporting process established jointly by the DHS and CJJP.