Priority Queues for Computer Simulations

The present invention is embodied in new priority queue data structures for event list management of computer simulations, and includes a new priority queue data structure and an improved event horizon applied to priority queue data structures. ne new priority queue data structure is a Qheap and is made out of linked lists for robust, fast, reliable, and stable event list management and uses a temporary unsorted list to store all items until one of the items is needed. Then the list is sorted, next, the highest priority item is removed, and then the rest of the list is inserted in the Qheap. Also, an event horizon is applied to binary tree and splay tree priority queue data structures to form the improved event horizon for event management

Synchronous Parallel Emulation and Discrete Event Simulation System with Self-Contained Simulation Objects and Active Event Objects

The present invention is embodied in a method of performing object-oriented simulation and a system having inter-connected processor nodes operating in parallel to simulate mutual interactions of a set of discrete simulation objects distributed among the nodes as a sequence of discrete events changing state variables of respective simulation objects so as to generate new event-defining messages addressed to respective ones of the nodes. The object-oriented simulation is performed at each one of the nodes by assigning passive self-contained simulation objects to each one of the nodes, responding to messages received at one node by generating corresponding active event objects having user-defined inherent capabilities and individual time stamps and corresponding to respective events affecting one of the passive self-contained simulation objects of the one node, restricting the respective passive self-contained simulation objects to only providing and receiving information from die respective active event objects, requesting information and changing variables within a passive self-contained simulation object by the active event object, and producing corresponding messages specifying events resulting therefrom by the active event objects

Synchronous parallel system for emulation and discrete event simulation

A synchronous parallel system for emulation and discrete event simulation having parallel nodes responds to received messages at each node by generating event objects having individual time stamps, stores only the changes to state variables of the simulation object attributable to the event object, and produces corresponding messages. The system refrains from transmitting the messages and changing the state variables while it determines whether the changes are superseded, and then stores the unchanged state variables in the event object for later restoral to the simulation object if called for. This determination preferably includes sensing the time stamp of each new event object and determining which new event object has the earliest time stamp as the local event horizon, determining the earliest local event horizon of the nodes as the global event horizon, and ignoring the events whose time stamps are less than the global event horizon. Host processing between the system and external terminals enables such a terminal to query, monitor, command or participate with a simulation object during the simulation process

Parallel Proximity Detection for Computer Simulation

The present invention discloses a system for performing proximity detection in computer simulations on parallel processing architectures utilizing a distribution list which includes movers and sensor coverages which check in and out of grids. Each mover maintains a list of sensors that detect the mover's motion as the mover and sensor coverages check in and out of the grids. Fuzzy grids are includes by fuzzy resolution parameters to allow movers and sensor coverages to check in and out of grids without computing exact grid crossings. The movers check in and out of grids while moving sensors periodically inform the grids of their coverage. In addition, a lookahead function is also included for providing a generalized capability without making any limiting assumptions about the particular application to which it is applied. The lookahead function is initiated so that risk-free synchronization strategies never roll back grid events. The lookahead function adds fixed delays as events are scheduled for objects on other nodes

A Double-Blind Randomized Phase I Clinical Trial Targeting ALVAC-HIV Vaccine to Human Dendritic Cells

BACKGROUND: We conducted a novel pilot study comparing different delivery routes of ALVAC-HIV (vCP205), a canarypox vaccine containing HIV gene inserts: env, gag and pol. We explored the concept that direct ex vivo targeting of human dendritic cells (DC) would enhance the immune response compared to either conventional intramuscular or intradermal injections of the vaccine alone. METHODOLOGY/PRINCIPAL FINDINGS: Healthy HIV-1 uninfected volunteers were administered ALVAC-HIV or placebo by intramuscular injection (i.m.), intradermal injection (i.d.) or subcutaneous injection (s.q.) of autologous ex vivo transfected DC at months 0, 1, 3 and 6. All vaccine delivery routes were well tolerated. Binding antibodies were observed to both the ALVAC vector and HIV-1 gp160 proteins. Modest cellular responses were observed in 2/7 individuals in the DC arm and 1/8 in the i.m. arm as determined by IFN-γ ELISPOT. Proliferative responses were most frequent in the DC arm where 4/7 individuals had measurable responses to multiple HIV-1 antigens. Loading DC after maturation resulted in lower gene expression, but overall better responses to both HIV-1 and control antigens, and were associated with better IL-2, TNF-α and IFN-γ production. CONCLUSIONS/SIGNIFICANCE: ALVAC-HIV delivered i.m., i.d. or s.q. with autologous ex vivo transfected DC proved to be safe. The DC arm was most immunogenic. Proliferative immune responses were readily detected with only modest cytotoxic CD8 T cell responses. Loading mature DC with the live viral vaccine induced stronger immune responses than loading immature DC, despite increased transgene expression with the latter approach. Volunteers who received the autologous vaccine loaded mature DC developed a broader and durable immune response compared to those vaccinated by conventional routes. TRIAL REGISTRATION: ClinicalTrials.gov NCT00013572

Ghostwriting at Elite Academic Medical Centers in the United States

Jeffrey Lacasse and Jonathan Leo assess ghostwriting policies at 50 academic medical centers in the United States and find that only 10 explicitly prohibit ghostwriting

Knowledge of ghostwriting and financial conflicts-of-interest reduces the perceived credibility of biomedical research

<p>Abstract</p> <p>Background</p> <p>While the impact of conflicts-of-interest (COI) is of increasing concern in academic medicine, there is little research on the reaction of practicing clinicians to the disclosure of such conflicts. We developed two research vignettes presenting a fictional antidepressant medication study, one in which the principal investigator had no COI and another in which there were multiple COI disclosed. We confirmed the face validity of the COI vignette through consultation with experts. Hospital-based clinicians were randomly assigned to read one of these two vignettes and then administered a credibility scale.</p> <p>Findings</p> <p>Perceived credibility ratings were much lower in the COI group, with a difference of 11.00 points (31.42%) on the credibility scale total as calculated through the Mann-Whitney U test (95% CI = 6.99 - 15.00, <it>p </it>< .001). Clinicians in the COI group were also less likely to recommend the antidepressant medication discussed in the vignette (Odds Ratio = 0.163, 95% CI = .03 = 0.875).</p> <p>Conclusions</p> <p>In this study, increased disclosure of COI resulted in lower credibility ratings.</p

Matrix Metalloproteinase Proteolysis of the Myelin Basic Protein Isoforms Is a Source of Immunogenic Peptides in Autoimmune Multiple Sclerosis

Matrix metalloproteinases (MMPs) play a significant role in the fragmentation of myelin basic protein (MBP) and demyelination leading to autoimmune multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). The classic MBP isoforms are predominantly expressed in the oligodendrocytes of the CNS. The splice variants of the single MBP gene (Golli-MBP BG21 and J37) are widely expressed in the neurons and also in the immune cells. The relative contribution of the individual MMPs to the MBP cleavage is not known.To elucidate which MMP plays the primary role in cleaving MBP, we determined the efficiency of MMP-2, MMP-8, MMP-9, MMP-10, MMP-12, MT1-MMP, MT2-MMP, MT3-MMP, MT4-MMP, MT5-MMP and MT6-MMP in the cleavage of the MBP, BG21 and J37 isoforms in the in vitro cleavage reactions followed by mass-spectroscopy analysis of the cleavage fragments. As a result, we identified the MMP cleavage sites and the sequence of the resulting fragments. We determined that MBP, BG21 and J37 are highly sensitive to redundant MMP proteolysis. MT6-MMP (initially called leukolysin), however, was superior over all of the other MMPs in cleaving the MBP isoforms. Using the mixed lymphocyte culture assay, we demonstrated that MT6-MMP proteolysis of the MBP isoforms readily generated, with a near quantitative yield, the immunogenic N-terminal 1-15 MBP peptide. This peptide selectively stimulated the proliferation of the PGPR7.5 T cell clone isolated from mice with EAE and specific for the 1-15 MBP fragment presented in the MHC H-2(U) context.In sum, our biochemical observations led us to hypothesize that MT6-MMP, which is activated by furin and associated with the lipid rafts, plays an important role in MS pathology and that MT6-MMP is a novel and promising drug target in MS especially when compared with other individual MMPs

A novel myelin P0–specific T cell receptor transgenic mouse develops a fulminant autoimmune peripheral neuropathy

Autoimmune-prone nonobese diabetic mice deficient for B7-2 spontaneously develop an autoimmune peripheral neuropathy mediated by inflammatory CD4+ T cells that is reminiscent of Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy. To determine the etiology of this disease, CD4+ T cell hybridomas were generated from inflamed tissue–derived CD4+ T cells. A majority of T cell hybridomas were specific for myelin protein 0 (P0), which was the principal target of autoantibody responses targeting nerve proteins. To determine whether P0-specific T cell responses were sufficient to mediate disease, we generated a novel myelin P0–specific T cell receptor transgenic (POT) mouse. POT T cells were not tolerized or deleted during thymic development and proliferated in response to P0 in vitro. Importantly, when bred onto a recombination activating gene knockout background, POT mice developed a fulminant form of peripheral neuropathy that affected all mice by weaning age and led to their premature death by 3–5 wk of age. This abrupt disease was associated with the production of interferon γ by P0-specific T cells and a lack of CD4+ Foxp3+ regulatory T cells. Collectively, our data suggest that myelin P0 is a major autoantigen in autoimmune peripheral neuropathy