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Epstein-Barr virus (EBV) is an oncovirus associated with several human malignancies including posttransplant lymphoproliferative disease in immunosuppressed patients. We show here that anti-EBV T-cell receptor–like monoclonal antibodies (TCR-like mAbs) E1, L1, and L2 bound to their respective HLA-A*0201-restricted EBV peptides EBNA1562-570, LMP1125-133, and LMP2A426-434 with high affinities and specificities. These mAbs recognized endogenously presented targets on EBV B lymphoblastoid cell lines (BLCLs), but not peripheral blood mononuclear cells, from which they were derived. Furthermore, these mAbs displayed similar binding activities on several BLCLs, despite inherent heterogeneity between different donor samples. A single weekly administration of the naked mAbs reduced splenomegaly, liver tumor spots, and tumor burden in BLCL-engrafted immunodeficient NOD-SCID/Il2rg−/− mice. In particular, mice that were treated with the E1 mAb displayed a delayed weight loss and significantly prolonged survival. In vitro, these TCR-like mAbs induced early apoptosis of BLCLs, thereby enhancing their Fc-dependent phagocytic uptake by macrophages. These data provide evidence for TCR-like mAbs as potential therapeutic modalities to target EBV-associated diseases.

Signal transduction induced by chimeric antigen receptors (CARs) is generally believed to rely on the activity of the SRC family kinase (SFK) LCK, as is the case with T cell receptor (TCR) signaling. Here, we show that CAR signaling occurs in the absence of LCK. This LCK-independent signaling requires the related SFK FYN and a CD28 intracellular domain within the CAR. LCK-deficient CAR-T cells are strongly signaled through CAR and have better in vivoefficacy with reduced exhaustion phenotype and enhanced induction of memory and proliferation. These distinctions can be attributed to the fact that FYN signaling tends to promote proliferation and survival, whereas LCK signaling promotes strong signaling that tends to lead to exhaustion. This non-canonical signaling of CAR-T cells provides insight into the initiation of both TCR and CAR signaling and has important clinical implications for improvement of CAR function.

In the main, project management subscribes to an objective view of the organisation, relatively free of political and psychosocial tensions. But, this may be misleading in the context of projects where the stakes are numerous and complex. The article views the project from three perspectives: the conventional rational perspective, with the prism of the mandate; the atypical political perspective, with the prism of the principals; and the atypical psychosocial perspective, with the prism of the agents. It emerges that the rational perspective may be sufficient to assess and manage a project when efficiency prevails in both the parent and the client organisations. However, the project manager would be better served to use an integrative approach that also includes the political perspective when the organisations involved have differing expectations regarding the project, as well as the psychosocial perspective when project team members have a great deal of autonomy.

Tuberculosis is a major cause of mortality and morbidity due to infectious disease. However, current clinical diagnostic methodologies such as PCR, sputum culture, or smear microscopy are not ideal. Antibody-based assays are a suitable alternative but require specific antibodies against a suitable biomarker. Mycolic acid, which has been found in patient sputum samples and comprises a large portion of the mycobacterial cell wall, is an ideal target. However, generating anti-lipid antibodies using traditional hybridoma methodologies is challenging and has limited the exploitation of this lipid as a diagnostic marker. We describe here the isolation and characterization of four anti-mycolic acid antibodies from a nonimmune antibody phage display library that can detect mycolic acids down to a limit of 4.5ng. All antibodies were specific for the methoxy subclass of mycolic acid with weak binding for α mycolic acid and did not show any binding to closely related lipids or other Mycobacterium tuberculosis(Mtb) derived lipids. We also determined the clinical utility of these antibodies based on their limit of detection for mycobacteria colony forming units (CFU). In combination with an optimized alkaline hydrolysis method for rapid lipid extraction, these antibodies can detect 105CFU of Mycobacterium bovisBCG, a close relative of Mtband therefore represent a novel approach for the development of diagnostic assays for lipid biomarkers.

For half a century, the significant development of intensive farming has led to a massive use of products such as pesticides. The excessive use of these substances has contaminated surface water and groundwater. Some drinking water extraction points have also had to be abandoned. Around 30 years ago, in the southwest of France, a group of farmers decided to improve their farming methods, as well as developing new best environmental practices, such as grass strips along streams and riparian forests. By combining ELECTRE TRI-C, a sorting multi-criteria model, with a GIS, we were able to assign each farming parcel to one of the five levels of risk associated with surface water pesticide contamination. We also assessed the effectiveness of best environmental practices, and found that their use led to a reduction in the risk of pesticide transfer. This methodology re-enforces decision support tools for both water resource managers and agricultural and environmental stakeholders.

Introduction: Almost 2 billion people travel aboard commercial airlines every year, with about 20% developing symptoms of the common cold within 1 wk after air travel. We hypothesize that hypobaric hypoxic conditions associated with air travel may contribute to immune impairment. Methods: We studied the effects of hypobaric hypoxic conditions during a simulated flight at 8000 ft (2438 m) cruising altitude on immune and stress markers in 52 healthy volunteers (mean age 31) before and on days 1, 4, and 7 after the flight. We did a cohort study using a generalized estimating equation to examine the differences in the repeated measures. Results: Our findings show that the hypobaric hypoxic conditions of a 10-h overnight simulation flight are not associated with severe immune impairment or abnormal IgA or cortisol levels, but with transient impairment in some parameters: we observed a transient decrease in lymphocyte proliferative responses combined with an upregulation in CD69 and CD14 cells and a decrease in HLA-DR in the immediate days following the simulated flight that normalized by day 7 in most instances. Discussion: These transient immune changes may contribute to an in-creased susceptibility to respiratory infections commonly seen after long-haul flights. [ABSTRACT FROM AUTHOR]

In this study we describe the derivation and immunological characterization of a primary epithelial cell type from the human umbilical cord membrane. These cord lining epithelial cells (CLECs) expressed and/or secreted isoforms of the nonclassical human leukocyte antigen class I (HLA-1b) glycoproteins, HLA-G and E. Conditioned media from CLECs inhibited mitogen-stimulated T-lymphocyte responses, and in a mixed leukocyte reaction (MLR) assay, cocultured CLECs inhibited allogeneic responses with a concomitant reduction in proinflammatory cytokines. Using a transwell coculture system, it was demonstrated that these immunoregulatory effects were mediated by soluble factors secreted by CLECs, in a dose-dependent manner. Functional studies using HLA-G blocking antibody showed that the effects of CLEC-secreted products could be inhibited, thus demonstrating a significant and important role for soluble HLA-G. In vivo, we show that transplanted CLECs could be maintained for extended periods in immunocompetent mice where xenorejection rapidly destroyed primary keratinocytes, a control human epithelial cell type. Additionally, CLECs delayed the rejection of keratinocytes and extended their survival when cotransplanted, indicating an ability to protect adjacent human cell types that would otherwise be rejected if transplanted alone. We also show that CLECs transduced with a modified human proinsulin gene were transplanted intraperitoneally into streptozotocin (STZ)-induced diabetic mice, resulting in significantly lower levels of serum glucose compared to control mice. This study has characterized the immunological properties of CLECs and tested a potential therapeutic application in the treatment of a type 1 diabetes mouse model.

In environmental risk analysis, many explanatory factors, often with highly complex interaction relationships, need to be taken into account. This is the case, for example, in the relation between agricultural practices and the quality of superficial aquatic ecosystems. Suspended solids are responsible for clogging salmonid spawning areas and hence for reductions in their populations. We studied the risks of erosion across two small watersheds in Normandy (France) on the scale of the agricultural plot – the level on which good practices can be applied. Plots were defined according to quantitative as well as qualitative criteria: connectivity to the stream, slope, plant cover, presence of embankments and erosion of the banks in the case of plots beside the river. By combining the ELECTRE III multicriteria analysis method to a geographical information system (GIS), it was possible to discriminate zones that present a risk with respect to particle emission and then to present the results in map form to provide decision-making aid for local actors.

AbstractRecently, new applications based on detection of delayed neutrons (DNs) or delayed photons produced during photofission have shown the need for new basic nuclear data. Indeed, available data for DNs are scarce, incomplete, and sometimes contradictory. An experimental campaign has been dedicated to DN measurements for some important actinides with a bremsstrahlung end-point energy spectrum up to 20 MeV. The experiments were carried out at the electron accelerator facility ELSA installed at the Commissariat à l’Energie Atomique (CEA) center of Bruyères-le-Châtel, France. Delayed neutrons were measured by 12 3He counters embedded in an annular polyethylene cylinder. Delayed neutron absolute yields were determined. Different irradiation-decay time combinations allowed the extraction of the averaged six-group parameters of DNs. Similarly to the nuclear reactor physics, these groups are formed by lumping DN precursors according to their half-lives. The DN time dependence is then expressed by the sum of group contributions.In this paper, DN absolute yields and six-group parameters for 235U at 15 and 18 MeV and 237Np at 15 MeV are presented. The 235U and 237Np absolute DN yields are found slightly lower than those published in the literature. For 235U, the six-group parameters show no dependence on incident electron energy from 10 to 18 MeV. In addition, the group parameters are very close to those of 237Np. This work helped to resolve the discrepancies of the photofission DN parameters for 235U while the six-group parameters for 237Np are reported for the first time.

Receptors for the fragment crystallizable region of immunoglobulin-G (FcγRs) play an important role in linking the humoral and cellular arms of the immune response. In this study, we present a comprehensive functional comparison of 2 human Fc-receptors, FcγRI and FcγRIIa. Activation of FcγRI results in a novel signaling cascade that links phospholipase D1 to sphingosine kinase-1 in U937 cells and primary human monocytes. This induces the expression of proinflammatory mediators and is associated with trafficking of immune complexes into human leukocyte antigen-DM positive antigen-processing compartments coupled with improved MHC class II–mediated antigen presentation to T lymphocytes. In contrast, activation of FcγRIIa elicits signaling through phospholipase Cγ1, resulting in increases in intracellular calcium, activation of nicotinamide adenine dinucleotide phosphate-oxidative burst, and differential membrane trafficking combined with impaired antigen presentation and proinflammatory cytokine expression. These data provide a mechanistic insight into the disparate activities associated with Fc receptors in immunity, namely, reinforcement of immune responses through stimulation of proinflammatory signaling and antigen presentation, versus the maintenance of immunologic homeostasis through the noninflammatory clearance of immune complexes.

Conditions for the elaboration of nanostructured varistors by spark plasma sintering (SPS) are investigated, using 8‐nm zinc oxide nanoparticles synthesized following an organometallic approach. A binary system constituted of zinc oxide and bismuth oxide nanoparticles is used for this purpose. It is synthesized at room temperature in an organic solution through the hydrolysis of dicyclohexylzinc and bismuth acetate precursors. Sintering of this material is performed by SPS at various temperatures and dwell times. The determination of the microstructure and the chemical composition of the as‐prepared ceramics are based on scanning electron microscopy and X‐ray diffraction analysis. The nonlinear electrical characteristics are evidenced by current–voltage measurements. The breakdown voltage of these nanostructured varistors strongly depends on grain sizes. The results show that nanostructured varistors are obtained by SPS at sintering temperatures ranging from 550 to 600 °C.

Microbial HSPs (heat-shock proteins) are implicated in the induction of the innate and adaptive arms of the immune response. We set out to determine whether peptides complexed with HSP70 generate efficient CTL (cytolytic T-lymphocyte) responses. Human dendritic cells pulsed with peptide-loaded microbial HSP70 complexes generate potent antigen-specific CTL responses. Using fluorescence anisotropy, we have calculated the peptide-binding affinity of mycobacterial HSP70 (KD=14 μM) and show that 120 pM HSP70-bound peptide is sufficient to generate a peptide-specific CTL response that is four orders of magnitude more efficient than the peptide alone. Through the generation of mycobacterial HSP70 truncations, we find that the minimal 136 amino acid, mycobacterial HSP70 peptide-binding domain is sufficient to generate CTL responses. The design of an HSP70 mutant, in which the peptide-binding site of HSP70 is filled with a bulky hydrophobic residue, leads to a large decrease in the peptide-binding affinity. This mutant HSP70 retains stimulatory capacity but is unable to generate CTL and has separated antigen delivery from immunostimulation of dendritic cells.

External gross observations of the eye and its adnexae, ocular reflexes, anterior ocular segment biomicroscopic examinations, fundic examinations performed with an indirect ophthalmoscope, and/or electroretinographic investigations (ERG) were carried out on 112 7-12-month-old Yucatan micropigs, on 18 6-8-week-old, and 81 2-10-month old Gottingen minipigs to evaluate the incidence of observed ocular abnormalities and to compare the ERG waves. A statistical comparison was performed for these findings.The most important ocular defects were classified as remnants of embryological vascular tissue. The other findings were considered either as embryonic remnants or of nondeterminate etiology. The most noteworthy findings were, in decreasing order of incidence, for Yucatan micropigs, 6-8 week-old and 2-10-monfh-old Gottingen minipigs, respectively, hyaloid artery remnants (82.1%, 83.3%, and 46.3%), pupillary

Three maximum temperature detectors, based on CMOS/DMOS smart power technology, are presented. The first two circuits rely on the bandgap reference principle, while the third uses a self-biased bipolar transistor to measure the leakage current thermal variation of the reversed collector-base junction.

In plants, N‐linked glycans are processed in the Golgi apparatus to complex‐type N‐glycans of limited size containing a β(1,2)‐xylose and/or an α(1,3)‐fucose residue. Larger mono‐ and bi‐antennary N‐linked complex glycans have not often been described. This study has re‐examined the structure of such plant N‐linked glycans, and, through both immunological and structural data, it is shown that the antennae are composed of Lewis a (Lea) antigens, comprising the carbohydrate sequence Galβ1‐3[Fucα1‐4]GlcNAc. Furthermore, a fucosyltransferase activity involved in the biosynthesis of this antigen was detected in sycamore cells. This is the first characterization in plants of a Lewis antigen that is usually found on cell‐surface glycoconjugates in mammals and involved in recognition and adhesion processes. Lea‐containing N‐linked glycans are widely distributed in plants and highly expressed at the cell surface, which may suggest a putative function in cell/cell communication.

EPEL, ELISSA A., ANNE E. MOYER, CHLOE D. MARTIN, SUSAN MACARY, NANCY CUMMINGS, JUDITH RODIN, AND MARIELLE REBUFFE‐SCRIVE. Stress‐induced Cortisol, mood, and fat distribution in men. Obes Res. 1999;7:9–15. Objective: A previous study in our laboratory (Moyer et al., Obes Res. 1994;2:255‐62 found that, in response to uncontrollable laboratory stress, women with a high waist‐to‐hip ratio (WHR) had higher Cortisol reactivity, poorer coping skills, and lower anger responses than women with low WHR. We aimed to compare high WHR men's stress responses to these women. Research Methods and Procedures: The current study examined Cortisol reactivity and psychological data of 27 healthy high WHR men exposed to the same laboratory challenges as the women from our previous study. Men's data are discussed in relation to that of the high and low WHR women. Results: Men responded to the stress with increases in both Cortisol and blood pressure. In comparison with the high and low WHR women, men had significantly higher total cortisof on the stress day. However, when comparing a sub‐sample of men and women matched in WHR's, differences in Cortisol secretion were greatly diminished and no longer significant. In addition, men had higher desire for control than both high and low WHR women, and lower mood reactivity than low WHR women. Despite the lower mood reactivity of high WHR groups, the high mood reactors among the high WHR women, and to a lesser extent, men, tended to have higher Cortisol reactivity. Discussion: These results suggest that the psychological differences and greater exposure to Cortisol observed amon; the high WHR men and women may have played a role ii contributing to their greater abdominal fat depots. Discussion: These results suggest that the psychological differences and greater exposure to cortisol observed among the high WHR men and women may have played a role contributing to their greater abdominal fat depots.

Provides information on the X-plot, a technique used to predict oil recovery in waterfloods. Application of the technique in an oil reservoir in Egypt; Advantages of using the technique; X-plot calculation.

Looks at the use of the decision tree approach in Gulf of Suez Petroleum Company's well workover program. Information about the company's October field; Details on the workover evaluation.

Le défi majeur du monde agricole aujourd’hui est de réduire de façon drastique l’usage des pesticides tout en maintenant un niveau de rendement, de qualité et de rentabilité satisfaisant. Dans le cadre d’un projet de recherche, nous avons étudié l’usage des produits phytosanitaires dans le Bordelais. Nous avons ensuite évalué les performances des systèmes viticoles existants afin de construire des scénarios de changement de pratiques pour réduire le recours aux pesticides, et préserver l’environnement et la santé humaine. Trente-huit viticulteurs pratiquant différents modes de conduite ont été interrogés. Les systèmes ont été évalués en utilisant deux méthodes d’analyse multicritère d’aide à la décision appartenant à la famille des méthodes ELECTRE : ELECTRE Tri-C et ELECTRE III. Sept critères d’évaluation ont été retenus, dont trois pour les performances socioéconomiques (rentabilité économique, charge de travail, complexité du système viticole) et quatre pour les performances environnementales (pression phytosanitaire, écotoxicité des pesticides, pratiques agroécologiques, niveau de la dérive des produits). Trois scénarios de changement de pratiques ont été construits en intégrant les bonnes pratiques identifiées sur le terrain : un scénario conventionnel raisonné optimisé (scénario Raisonné-Max) ; deux scénarios en démarche agroécologique : Agroécologie(avec usage optimisé de produits de synthèse) et Agroécologie-Bio(sans produits de synthèse). ELECTRE Tri-C a permis d’affecter chaque système viticole ainsi que les trois scénarios dans l’une des quatre catégories prédéfinies de performance. Puis ELECTRE III les a classés dans chaque catégorie. On note une supériorité de la performance socio-éco-environnementale des scénarios agroécologiques et des systèmes biologiques. Cela tient principalement à un niveau de valorisation de la production plus élevé dans ces systèmes et à un niveau de pression phytosanitaire plus faible lié aux pratiques plus favorables au renforcement de la biodiversité. Ces résultats axés sur des démarches concrètes et réalistes constituent des modèles adaptables à des exploitations viticoles conventionnelles.

En s’appuyant sur une revue de la littérature, l’article propose un état de l’art centré sur l’agroécologie, concept polysémique, afin d’en éclairer la portée pour la viticulture et son application, dans le cadre d’un projet de recherche destiné à comprendre et construire la transition agroécologique dans les vignobles. L’agroécologie est tour à tour considérée comme une discipline scientifique proposant une analyse systémique en intégrant des sciences humaines et sociales, un ensemble de pratiques intégrant les principes de l’écologie en agronomie (travailler avec la nature), ou un mouvement social. L’échelle d’analyse a progressivement été élargie depuis le niveau de la parcelle agricole vers celui des territoires, jusqu’à des approches globales du système alimentaire. La vigne est une monoculture pérenne pour laquelle les enjeux de la transition agroécologique sont particulièrement importants eu égard notamment à la forte pression des pesticides appliqués en vue de la protection phytosanitaire. Ce débat, devenu sociétal, implique une évolution des systèmes de production viticole afin de satisfaire les enjeux environnementaux et de santé publique. Pour construire et évaluer des scénarios de transition agroécologique auprès des professionnels de la filière, nous avons réalisé une revue de la littérature qui a pu mettre en évidence différentes pratiques agroécologiques dans les vignobles : préservation de la biodiversité, baisse de l’usage des pesticides par une régulation des bioagresseurs et des adventices, conservation de la qualité des sols, adaptation au changement climatique. Elle permet également de discuter des enjeux d’élargissement de l’acception du concept d’agroécologie dans le contexte actuel. Ces éléments sont essentiels à l’identification de critères d’évaluation pour la construction de scénarios d’évolution des modes conventionnels de production viticole dans le cadre de la transition écologique.

Objective.Fidelity metrics can provide insight into the extent to which experiential programs are implemented as they were designed to be. The UNC Eshelman School of Pharmacy at the University of North Carolina at Chapel Hill implemented a new curriculum that included a series of three, two-month introductory pharmacy practice experiences (IPPEs). The objective of this study was to design a logic model for the first IPPE within the series, identify key variables to program implementation, define fidelity indices and benchmarks, and compute a single fidelity score for each IPPE site.

Objective.To explore and evaluate open-ended feedback on entrustable professional activities (EPAs) provided by preceptors to Doctor of Pharmacy (PharmD) students completing their first practice experience.

Cytotoxic lymphocytes normally kill virus-infected cells by apoptosis induction. Cytotoxic granule-dependent apoptosis induction engages the intrinsic apoptosis pathway, whereas death receptor (DR)-dependent apoptosis triggers the extrinsic apoptosis pathway. Hantaviruses, single-stranded RNA viruses of the order Bunyavirales, induce strong cytotoxic lymphocyte responses in infected humans. Cytotoxic lymphocytes, however, are largely incapable of eradicating hantavirus-infected cells. Here, we show that the prototypic hantavirus, Hantaan virus (HTNV), induces TRAIL production but strongly inhibits TRAIL-mediated extrinsic apoptosis induction in infected cells by downregulating DR5 cell surface expression. Mechanistic analyses revealed that HTNV triggers both 26S proteasome-dependent degradation of DR5 through direct ubiquitination of DR5 and hampers DR5 transport to the cell surface. These results corroborate earlier findings, demonstrating that hantavirus also inhibits cytotoxic cell granule-dependent apoptosis induction. Together, these findings show that HTNV counteracts intrinsic and extrinsic apoptosis induction pathways, providing a defense mechanism utilized by hantaviruses to inhibit cytotoxic cell-mediated eradication of infected cells.

To examine entrustable professional activities (EPAs) as an assessment tool for student pharmacists completing early practice experiences.

Circulating virus-specific T lymphocytes may contribute to immune surveillance against dengue in the skin.

Dendritic cells (DCs) are highly potent initiators of adaptive immune responses and, as such, represent promising tools for immunotherapeutic applications. Despite their potential, the current efficacy of DC-based immunotherapies is poor. CD137 ligand (CD137L) signaling has been used to derive a novel type of DCs from human peripheral blood monocytes, termed CD137L-DCs. Here, we report that CD137L-DCs induce more potent cytotoxic T-cell responses than classical DCs (cDCs). Furthermore, in exploring several DC maturation factors for their ability to enhance the potency of CD137L-DCs, we found the combination of interferon γ (IFNγ) and the mixed Toll-like receptor (TLR)7/8 agonist R848, to display the highest efficacy in potentiating the T-cell co-stimulatory activity of CD137L-DCs. Of particular importance, CD137L-DCs were found to be more efficient than cDCs in activating autologous T cells targeting the cytomegalovirus (CMV)-derived protein pp65. Specifically, CD137L-DC-stimulated T cells were found to secrete higher levels of IFNγ and killed 2–3 times more HLA-matched, pp65-pulsed target cells than T cells activated by cDCs. Finally, in addition to stimulating CD8+T cells, CD137L-DCs efficiently activated CD4+T cells. Taken together, these findings demonstrate the superior potency of CD137L-stimulated DCs in activating CMV-specific, autologous T cells, and encourage the further development of CD137L-DCs for antitumor immunotherapy.

Objectives.To identify and characterize postgraduate year 2 (PGY2) pharmacy residency programs with a secondary emphasis on academia.

The mechanism of action of a serotype-specific natural human antibody against dengue virus has been identified.