337 research outputs found

    Status Offenders Should Be Removed From the Juvenile Court

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    Inadequate financial resources and overcrowded juvenile placement facilities have frequently been cited as grounds for the abrogation of the juvenile court\u27s practice of retaining jurisdiction over status offenders. In this article, Judge Quinn suggests the existence of even more compelling reasons which support diversion of status offenders to programs better suited to their particular needs. The author contends that the juvenile court\u27s jurisdiction should be confined to matters of fact-finding and adjudication, rather than intruding into areas within the domain of the parents, and into areas in which the court lacks the necessary expertise. It is argued that diversion of status offenders would also eliminate the traumatic experience of courtroom appearances and the frequently unnecessary period of incarceration. Abrogation of jurisdiction would enable the court to devote its energies and resources to its primary concerns of abuse and juvenile crime

    Overview of the Main Propulsion System for the NASA Ares I Upper Stage

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    A functional overview of the Main Propulsion System (MPS) of the NASA Ares I Upper Stage is provided. In addition to a simple overview of the key MPS functions and design philosophies, major lessons learned are discussed. The intent is to provide a technical overview with enough detail to allow engineers outside of the MPS Integrated Product Team (IPT) to develop a rough understanding of MPS operations, components, design philosophy, and lessons learned

    “Everywhere where people live, they are all subordinated to me”: the influence of the imperial steppe ideology on the Mongol Empire’s cultural exchange and diplomacy

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    This thesis will argue that the Mongolian Empire’s policies of cultural exchange and diplomacy towards the Latin world were driven by an imperial steppe ideology whose core characteristic was to achieve universal dominion. The thesis will make this argument by explicitly linking these two broad agendas of diplomatic engagement and cultural exchange to each other and placing them within the context of the Mongol ideology of universal rule. The thesis will make this argument by first examining the imperial steppe ideology of the nomadic empires which preceded the Mongol Empire in order to demonstrate that they also considered universal rule to be a key factor in their respective ideological basis. The early history of the Mongol Empire will then be examined to show the ideological continuities with the previous empires. Subsequently, the individuals and groups which comprised the empire’s administration will have their religious and cultural backgrounds examined in order to indicate why they retained the universal nature of the imperial steppe ideology. Following this, examples of cultural exchange and trade within the Mongol Empire and with its neighbouring states will be situated within the context of the universalism of the imperial steppe ideology. Finally, diplomatic engagement between the Mongol Empire and the Latin world will also be placed within the ideological framework of the empire’s goal of achieving universal rule. It is hoped that the thesis will provoke further questions and research into the field of Mongolian history concerning the ideological foundations of the empire and its effect on their policies

    Learning Behaviour for Service Personalisation and Adaptation

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    Context-aware applications within pervasive environments are increasingly being developed as services and deployed in the cloud. As such these services are increasingly required to be adaptive to individual users to meet their specific needs or to reflect the changes of their behavior. To address this emerging challenge this paper introduces a service-oriented personalisation framework for service personalisation with special emphasis being placed on behavior learning for user model and service function adaptation. The paper describes the system architecture and the underlying methods and technologies including modelling and reasoning, behavior analysis and a personalisation mechanism. The approach has been implemented in a service-oriented prototype system, and evaluated in a typical scenario of providing personalised travel assistance for the elderly using the help-on-demand services deployed on smartphone

    Induction of lytic cycle sensitizes Epstein-Barr virus infected B cells to NK cell killing that is counteracted by virus-mediated NK cell evasion mechanisms in late lytic cycle

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    Epstein-Barr Virus (EBV) persists for the lifetime of the infected host despite eliciting strong immune responses. This persistence requires a fine balance between the host immune system and EBV immune evasion. Accumulating evidence suggests an important role for natural killer (NK) cells in this balance. NK cells can kill EBV-infected cells undergoing lytic replication in vitro, and studies in both humans and mice with reconstituted human immune systems have shown that NK cells can limit EBV replication and prevent infectious mononucleosis. We now show that NK cells, via NKG2D and DNAM-1 interactions, recognize and kill EBV-infected cells undergoing lytic replication and that expression of a single EBV lytic gene, BZLF1, is sufficient to trigger sensitization to NK cell killing. We also present evidence suggesting the possibility of the existence of an as-yet-unidentified DNAM-1 ligand which may be particularly important for killing lytically infected normal B cells. Furthermore, while cells entering the lytic cycle become sensitized to NK cell killing, we observed that cells in the late lytic cycle are highly resistant. We identified expression of the vBcl-2 protein, BHRF1, as one effective mechanism by which EBV mediates this protection. Thus, contrary to the view expressed in some reports, EBV has evolved the ability to evade NK cell responses. IMPORTANCE This report extends our understanding of the interaction between EBV and host innate responses. It provides the first evidence that the susceptibility to NK cell lysis of EBV-infected B cells undergoing lytic replication is dependent upon the phase of the lytic cycle. Induction of the lytic cycle is associated with acquired sensitization to NK cell killing, while progress through the late lytic cycle is associated with acquired resistance to killing. We provide mechanistic explanations for this novel observation, indicating important roles for the BZLF1 immediate early transactivator, the BHRF1 vBcl-2 homologue, and a novel ligand for the DNAM-1 NK cell receptor

    Real-world outcomes of sipuleucel-T treatment in PROCEED, a prospective registry of men with metastatic castration-resistant prostate cancer.

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    BackgroundThe large registry, PROVENGE Registry for the Observation, Collection, and Evaluation of Experience Data (PROCEED)(NCT01306890), evaluated sipuleucel-T immunotherapy for asymptomatic/minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC).MethodsPROCEED enrolled patients with mCRPC receiving 3 biweekly sipuleucel-T infusions. Assessments included overall survival (OS), serious adverse events (SAEs), cerebrovascular events (CVEs), and anticancer interventions (ACIs). Follow-up was for ≥3 years or until death or study withdrawal.ResultsIn 2011-2017, 1976 patients were followed for 46.6 months (median). The median age was 72 years, and the baseline median prostate-specific antigen level was 15.0 ng/mL; 86.7% were white, and 11.6% were African American. Among the patients, 1902 had 1 or more sipuleucel-T infusions. The median OS was 30.7 months (95% confidence interval [CI], 28.6-32.2 months). Known prognostic factors were independently associated with OS in a multivariable analysis. Among the 1255 patients who died, 964 (76.8%) died of prostate cancer (PC) progression. The median time from the first infusion to PC death was 42.7 months (95% CI, 39.4-46.2 months). The incidence of sipuleucel-T-related SAEs was 3.9%. The incidence of CVEs was 2.8%, and the rate per 100 person-years was 1.2 (95% CI, 0.9-1.6). The CVE incidence among 11,972 patients with mCRPC from the Surveillance, Epidemiology, and End Results-Medicare database was 2.8%; the rate per 100 person-years was 1.5 (95% CI, 1.4-1.7). One or more ACIs (abiraterone, enzalutamide, docetaxel, cabazitaxel, or radium 223) were received by 77.1% of the patients after sipuleucel-T; 32.5% and 17.4% of the patients experienced 1- and 2-year treatment-free intervals, respectively.ConclusionsPROCEED provides contemporary survival data for sipuleucel-T-treated men in a real-world setting of new life-prolonging agents, which will be useful in discussing treatment options with patients and in powering future trials with sipuleucel-T. The safety and tolerability of sipuleucel-T in PROCEED were consistent with previous findings

    Brief report: Search for DNA markers in two autistic males with the fragile X syndrome

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    Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44601/1/10803_2005_Article_BF02211885.pd

    The missing link in EBV immune evasion:the BDLF3 gene induces ubiquitination and downregulation of MHC class I and MHC class II

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    The ability of Epstein-Barr virus (EBV) to spread and persist in human populations relies on a balance between host immune responses and EBV immune evasion. CD8(+) cells specific for EBV late lytic cycle antigens show poor recognition of target cells compared to immediate early and early antigen-specific CD8(+) cells. This phenomenon is due in part to the early EBV protein BILF1, whose immunosuppressive activity increases with lytic cycle progression. However, published data suggest the existence of a hitherto unidentified immune evasion protein further enhancing protection against late EBV antigen-specific CD8(+) cells. We have now identified the late lytic BDLF3 gene as the missing link accounting for efficient evasion during the late lytic cycle. Interestingly, BDLF3 also contributes to evasion of CD4(+) cell responses to EBV. We report that BDLF3 downregulates expression of surface major histocompatibility complex (MHC) class I and class II molecules in the absence of any effect upon other surface molecules screened, including CD54 (ICAM-1) and CD71 (transferrin receptor). BDLF3 both enhanced internalization of surface MHC molecules and reduced the rate of their appearance at the cell surface. The reduced expression of surface MHC molecules correlated with functional protection against CD8(+) and CD4(+) T cell recognition. The molecular mechanism was identified as BDLF3-induced ubiquitination of MHC molecules and their subsequent downregulation in a proteasome-dependent manner. IMPORTANCE Immune evasion is a necessary feature of viruses that establish lifelong persistent infections in the face of strong immune responses. EBV is an important human pathogen whose immune evasion mechanisms are only partly understood. Of the EBV immune evasion mechanisms identified to date, none could explain why CD8(+) T cell responses to late lytic cycle genes are so infrequent and, when present, recognize lytically infected target cells so poorly relative to CD8(+) T cells specific for early lytic cycle antigens. The present work identifies an additional immune evasion protein, BDLF3, that is expressed late in the lytic cycle and impairs CD8(+) T cell recognition by targeting cell surface MHC class I molecules for ubiquitination and proteasome-dependent downregulation. Interestingly, BDLF3 also targets MHC class II molecules to impair CD4(+) T cell recognition. BDLF3 is therefore a rare example of a viral protein that impairs both the MHC class I and class II antigen-presenting pathways
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